CN103936717B - A kind of delafloxacin intermediate and preparation method thereof - Google Patents
A kind of delafloxacin intermediate and preparation method thereof Download PDFInfo
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- 0 Cc(c(F)c(cc1C(C(C(O*)=O)=CNc(c(F)c2)nc(N)c2F)=O)F)c1F Chemical compound Cc(c(F)c(cc1C(C(C(O*)=O)=CNc(c(F)c2)nc(N)c2F)=O)F)c1F 0.000 description 1
- GCIUCMRUMOAHKR-UHFFFAOYSA-N Nc(c(F)c1)nc(N)c1F Chemical compound Nc(c(F)c1)nc(N)c1F GCIUCMRUMOAHKR-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- 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
Abstract
A kind of new intermediate that the present invention relates to delafloxacin and preparation method thereof.The present invention provides the compound with novel fluoroquinolone mother nucleus structure to be shown below.This compounds can prepare through single step reaction with existing starting compound, and operation is easy, and yield is higher.This compounds is when the synthesis of novel fluoroquinolone antibacterial agent delafloxacin and salt thereof, and purity and yield Integrated comparative have great progress than prior art.
Description
Technical field
The present invention relates to the preparation method technical field of delafloxacin, be specifically related to a kind of intermediate and the system thereof of delafloxacin
Preparation Method.
Background technology
After late 1970s finds norfloxacin, flouroquinolone drugs is developed rapidly, existing large-tonnage product listing.
Owing to having fluorine atom at 6 bit strips of parent nucleus quinolinones ring, therefore claim fluoroquinolone.Delafloxacin (structural formula is shown below) is
Fluorine quinolone compounds (numbering: WQ-3034), the chemistry of a kind of brand new developed by Yong Yong pharmaceutical Co. Ltd of Japan
Entitled 1-(6-amino-3,5-bis-fluoro-2-pyridine radicals) the fluoro-7-of the chloro-6-of-8-(3-hydroxyl-1-azepine-1-Tetramethylene. base)-4-oxo-Isosorbide-5-Nitrae-dihydro
-3-quinoline carboxylic acid, U.S. Abbott company obtains its exploitation license (numbering: ABT-492) existing is carried out by Rib-X company subsequently
III clinical trial phase.
Delafoxacin is a new generation's wide spectrum fluoroquinolone antibiotic.This product is compared with other quinoline ketone antibacterial, to gram sun
Property bacterium more effective, the particularly methicillin-resistant staphylococcus aureus (MRSA) to other methods for quinolones antibacterial agents drug resistances.
The first public declaration of FDA, is appointed as having treatment acute bacterial skin and skin structure infection by delafloxacin
And the qualification medication of the acquired pneumonia day after tomorrow (CABP) (ABSSSI).
The synthesis of Delafloxacin has multiple route, wherein the reaction scheme A(WO9711068 of Yong Yong drugmaker of Japan) as
Shown in lower:
In above-mentioned route, high from the intramolecular condensation single step reaction temperature of compound 5 to compound 6, produce more impurity and cause
Yield is low, and acid hydrolysis and the amino deprotection steps of compound 6 ester bond need high temperature reflux.
The reaction scheme B(WO2006015194 of U.S.'s Abbott Laboratories) as follows:
This route makes to need in reaction scheme to introduce a step chloro, and the protection step of increase hydroxyl, road with compound 9 for raw material
In line, NCS chloro may cause multiple sites chloro thus introduces impurity, reduces yield and purity.
The present inventor in view of the foregoing, considers the factor such as product yield and purity, with reference to existing literature method, creative
Discovery and prepare a kind of new delafloxacin intermediate.
Summary of the invention
It is an object of the invention to provide a kind of delafloxacin new intermediate and preparation method thereof.This new intermediate preparation method
Simply, improve yield and the purity of delafloxacin.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
Formula 1 such as following formula:
R is alkyl, aryl or aralkyl. preferably, R is the alkyl of the alkyl of C1-C6, more preferably C1-C4.
Above-mentioned formula 1, its chemical name is 1-(6-amino-3,5-difluoro pyridine-2-base) the chloro-6-of-8-fluoro-7-(3-hydroxyl azacyclo-
Butane-1-base)-4 oxo-1,4 dihydroquinoline-3-carboxylates.
The preparation method of above-mentioned general formula compound 1, the method is to be deposited at alkali with 3-hydroxy azetidine hydrochlorate by formula 14 compound
Target compound 1 is prepared at lower generation nucleophilic substitution:
Wherein, R is alkyl, aryl or aralkyl. preferably, R is the alkyl of the alkyl of C1-C6, more preferably C1-C4.
The preparation method of above-mentioned general formula compound 1, available alkali includes various inorganic base and organic base, preferably organic base. the most inorganic
Alkali is selected from classes such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrofining and sodium hydrides
Like alkali;Organic base is selected from triethylamine, various lutidines, diisopropylethylamine, 1,8-diazabicylo [5.4.0] 11 carbon-7-
The similar alkali such as alkene, 1,4-diazabicylo [2.2.2] octane, 1,5-diazabicylo [4.3.0] 11 carbon-7-alkene. preferably 1,8-diaza
Bicyclo-[5.4.0] 11 carbon-7-alkene.
The preparation method of above-mentioned general formula compound 1, reaction temperature is generally 0-100 DEG C, preferably 20-60 DEG C;Response time is general
It is 10 minutes to 48 hours, preferably 30 minutes-3 hours.
The preparation method of above-mentioned general formula compound 1, the 1-5 that consumption is starting compound 14 of 3-hydroxy azetidine hydrochlorate
Mole again, the mole of preferably 1-2 times, the mole of most preferably 1.2 times. the consumption of alkali is usually starting compound 14
The mole of 1-5 times, the mole of preferably 1-3 times, the mole of most preferably 2.5 times.
Compound 14 of the present invention also can be prepared by following method, and reaction scheme is as follows:
Described step 1:
Based on WO971108, compound shown in formula 3 leads to method according to this area and is condensed to obtain ethoxy propylene in carboxylic acid anhydrides with orthoformic acid esters
Acid esters compound 4.Reaction temperature is generally 0-160 DEG C, preferably 50-150 DEG C, and the response time is generally 10 minutes to 48
Hour, preferably 1-10 hour.The usage amount of described orthoformate relative to compound shown in formula 3 be equimolar or more than,
Preferably 1-10 times, more preferably 1.6 molar equivalents use.The usage amount of described carboxylic acid anhydrides relative to compound shown in formula 3 is
Equimolar or more than, preferably 1-10 times, more preferably 3 molar equivalents use.
Described step 2:
Based on gained ethoxy acrylic ester compound 4 in WO971108, step one in organic solvent with 2,6-diaminourea 3,
The condensation of 5-difluoro pyridine prepares compound shown in formula 5.Reaction temperature is generally 0-100 DEG C, preferably 0-50 DEG C, the response time
Generally 10 minutes to 48 hours, preferably 30 minutes to 3 hours.Relative to compound shown in formula 4,2,6-diaminourea
3,5-difluoro pyridines generally can use to about 5 molar equivalents by about 1 molar equivalent, and preferably 1 molar equivalent is worked as to 3 moles
Amount uses, and more preferably 1.1 molar equivalents use.Available solvent includes ether solvent, such as ether, THF, methyl tertbutyl
Ether, THP etc.；Halogenated hydrocarbons, such as, dichloromethane, chloroform, carbon tetrachloride, dichloroethanes etc.；Aromatic solvent, such as first
Benzene, benzene, dimethylbenzene, trimethylbenzene, chlorobenzene etc.；And esters solvent, such as ethyl acetate etc.；With other solvents, such as second
Nitrile, N-Methyl pyrrolidone, N, N-dimethyl pyrrolidone, dimethyl sulfoxide etc. or its suitable mixture.Preferred solvent is
Other solvents, more preferably NMP and acetonitrile mixed solvent.
Step 3: shown in the formula 5 prepared by various methods, compound is in organic solvent, sends out in the presence of lewis acid, alkali etc.
Raw self-condensation, prepares compound shown in formula 14；
Wherein, R is alkyl, aryl or aralkyl；Preferably, R stands alone as the alkyl of C1-C6, more preferably C1-C4
Alkyl.Described step 3 includes, in organic solvent, self-condensation occurs in the presence of lewis acid, alkali etc., prepares formula
Compound shown in 14.Available organic solvent includes acetonitrile, NMP, DMF, DMAC, DMSO, DMI etc. or its suitable mixture,
Available lewis acid includes lithium chloride, aluminum chloride, iron chloride, boron trifluoride, Columbium pentachloride., preferably lithium chloride.Available bases bag
Include various inorganic base such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrofining, hydrogen
Change similar alkali and various organic base such as triethylamine, various lutidines, diisopropylethylamine, the 1,8-diazabicylos [5.4.0] such as sodium
11 carbon-7-alkene, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane, 1, the similar alkali such as 5-diazabicylo [4.3.0] 11 carbon-7-alkene, preferably
For organic base, more preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.Reaction temperature is generally 0-100 DEG C, is preferably
0-50 DEG C, the response time is generally 10 minutes to 48 hours, preferably 1-5 hour.Relative to compound shown in formula 5, lewis
Acid generally can use to about 5 molar equivalents by about 1 molar equivalent, and preferably 1 molar equivalent uses, more to 3 molar equivalents
Preferably 2 molar equivalents use, and alkali generally can use to about 5 molar equivalents by about 1 molar equivalent, preferably 1 molar equivalent
Using to 3 molar equivalents, more preferably 1.1 molar equivalents use.
Beneficial effects of the present invention: the present invention provides a kind of compound with novel fluoroquinolone mother nucleus structure and synthetic method thereof.
This compounds can prepare through single step reaction with existing starting compound, and operation is easy, and yield is higher.Such chemical combination
Thing is when the synthesis of novel fluoroquinolone antibacterial agent delafloxacin and salt thereof, and purity and yield Integrated comparative are than existing skill
Art has great progress.
Detailed description of the invention
Further illustrate the present invention by embodiment below, but described embodiment is not meant to limit the scope of the invention.
Embodiment 1
Wherein R be ethyl formula 5 shown in the preparation of compound:
In there-necked flask, add compound 3(20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and second
Anhydride (20.21mL, 0.21mol) is heated with stirring to back flow reaction (~ 139 DEG C) 3h, is down to room temperature, and reactant liquor is with NMP-
Acetonitrile (50mL-50mL) dilutes, and adds 1mL distilled water, prepares compound 4 and direct plunges into next step reaction without isolation.
Addition 2,6-diaminourea-3,5-difluoro pyridine (11.38g, 0.078mol), NMP-acetonitrile in there-necked flask
(50mL-50mL), stirring and dissolving, under room temperature, it is added dropwise to step reactant liquor, drips to finish to be stirred at room temperature and react 1h.Reaction drop
Add in 160mL distilled water, separate out bright yellow solid, filter, successively with acetonitrile-water (48mL-24mL), water (50mL)
Making beating washing, 60 DEG C of vacuum drying obtain 28.4g yellow powder, HPLC98.4%.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
Wherein R be ethyl formula 5 shown in the preparation of compound:
In there-necked flask, add compound 3(20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and second
Anhydride (20.21mL, 0.21mol) is heated with stirring to 100 DEG C of back flow reaction 10h, is down to room temperature, and reactant liquor is with NMP(100mL)
Dilution, adds 1mL distilled water, prepares compound 4 and direct plunges into next step reaction without isolation.
Addition 2 in there-necked flask, 6-diaminourea-3,5-difluoro pyridine (11.38g, 0.078mol), acetonitrile (100mL),
Stirring and dissolving, under room temperature, is added dropwise to step reactant liquor, drips to finish to be stirred at room temperature and reacts 1h.Reactant liquor is added dropwise to 160mL distilled water
In, separate out bright yellow solid, filter, be dried to obtain 28.1g yellow powder, HPLC98.1%.Fusing point:
148-150 DEG C of 1HNMR (400MHz, CDCl3) δ 1.13 (t, 3H), 4.25 (q, 2H), 4.66 (b rs, 2H), 7.33 (t, 1H),
7.58 (m, 1H), 8.96 (d, 1H), 11.33 (brs, 1H).
Embodiment 3
Wherein R be ethyl formula 5 shown in the preparation of compound:
In there-necked flask, add compound 3(20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and second
Anhydride (20.21mL, 0.21mol) is heated with stirring to back flow reaction (~ 139 DEG C) 3h, is down to room temperature, and reactant liquor is with NMP (100mL)
Dilution, adds 1mL distilled water, prepares compound 4 and direct plunges into next step reaction without isolation.
Addition 2,6-diaminourea-3,5-difluoro pyridine (11.38g, 0.078mol), NMP(100mL in there-necked flask),
Stirring and dissolving, under room temperature, is added dropwise to step reactant liquor, drips to finish to be stirred at room temperature and reacts 1.5h.Reactant liquor is added dropwise to 160mL distillation
In water, separate out bright yellow solid, be dried to obtain 25.2g yellow powder, HPLC98.0%.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 4
Wherein R be ethyl formula 5 shown in the preparation of compound:
In there-necked flask, add compound 3(20g, 0.071mol), triethyl orthoformate (18.97mL, 0.11mol) and second
Anhydride (20.21mL, 0.21mol) is heated with stirring to back flow reaction (~ 139 DEG C) 3h, is down to room temperature, and reactant liquor is with acetonitrile (100mL)
Dilution, adds 1mL distilled water, prepares compound 4 and direct plunges into next step reaction without isolation.
Addition 2 in there-necked flask, 6-diaminourea-3,5-difluoro pyridine (12.41g, 0.085mol), acetonitrile (100mL),
Stirring and dissolving, under room temperature, is added dropwise to step reactant liquor, drips and finishes 40 DEG C of stirring reaction 2h.Reactant liquor is added dropwise to 160mL distillation
In water, separate out bright yellow solid, filter, be dried to obtain 24.3g yellow powder, HPLC97.5%.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 5
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL)
Stirring and dissolving, is added dropwise to DBU(10.57mL, 0.071mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 2h, prepare chemical combination
Thing 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips Bi Shengzhi 50 DEG C stirring reaction 1h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 150mL), separates out yellow powder.Filter, be dried to obtain 28.1g yellow powder, HPLC99.0%.M/z(MH+)
468.08,1H NMR (400MHz, DMSO) δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H), 4.22(q,
2H), 4.44(m, 1H), 4.61(m, 2H) and, 5.66(d, 1H), 6.68(s, 2H) and, 7.72(d, 1H), 7.92
(dd, 1H).
Embodiment 6
Wherein R be phenyl formula 1-2 shown in the preparation of compound:
In there-necked flask add compound 5-1(31g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL)
Stirring and dissolving, is added dropwise to DBU(10.57mL, 0.071mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 3h, prepare chemical combination
Thing 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips Bi Shengzhi 50 DEG C stirring reaction 1.5h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water
Solution (10%, 150mL), separates out buff powder.Filter, be dried to obtain 29.2g buff powder, HPLC98.3%.
M/z(MH+) 516.25,1H NMR (400MHz, DMSO) δ 3.25(s, 1H), 4.16 (m, 2H), 4.47(m,
1H), 4.60(m, 2H), 5.69(d, 1H) and, 6.71(s, 2H), 6.81-7.22(m, 5H) and, 7.70(d, 1H),
7.96(dd, 1H).
Embodiment 7
Wherein R be benzyl formula 1-3 shown in the preparation of compound:
In there-necked flask add compound 5-3(31.8g, 0.064mol), lithium chloride (5.45g, 0.13mol), add
DMF (140mL) stirring and dissolving, is added dropwise to DBU(10.57mL, 0.071mol under ice bath), drip to finish to be warmed to room temperature and stir reaction
2.5h, prepares compound 14-3 and direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips Bi Shengzhi 50 DEG C stirring reaction 3h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 150mL), separates out yellow powder.Filter, be dried to obtain 27.3g yellow powder, HPLC98.2%.M/z(MH+)
530.13,1HNMR (400MHz, DMSO) δ 3.33(s, 1H), 4.18(q, 2H), 4.41(m, 1H), 4.56(s,
2H), 4.63(m, 2H), 5.72(d, 1H) and, 6.68(s, 2H), 7.21-7.33(m, 5H) and, 7.83(d, 1H),
7.94(dd, 1H).
Embodiment 8
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL)
Stirring and dissolving, is added dropwise to DBU(12.49mL, 0.084mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 1h, prepare chemical combination
Thing 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(27.57mL, 0.185mol), drips Bi Shengzhi 50 DEG C stirring reaction 1h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 150mL), separates out yellow powder.Filter, be dried to obtain 28.1g yellow powder, HPLC98.8%.M/z(MH+)
468.08,1H NMR (400MHz, DMSO) δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H), 4.22(q,
2H), 4.44(m, 1H), 4.61(m, 2H) and, 5.66(d, 1H), 6.68(s, 2H) and, 7.72(d, 1H), 7.92
(dd, 1H).
Embodiment 9
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL)
Stirring and dissolving, is added dropwise to DBU(10.57mL, 0.071mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 2h, prepare chemical combination
Thing 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips to finish to be warmed to room temperature and stirs reaction 3h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 150mL), separates out yellow powder.Filtering, washing, vacuum drying obtains 23.3g yellow powder, HPLC98.9%.
M/z(MH+) 468.08,1H NMR (400MHz, DMSO) δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H),
4.22(q, 2H), 4.44(m, 1H), 4.61(m, 2H) and, 5.66(d, 1H), 6.68(s, 2H) and, 7.72(d, 1H),
7.92(dd, 1H).
Embodiment 10
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMSO (100mL)
Stirring and dissolving, is added dropwise to DBU(12.49mL, 0.084mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 1.5h, preparedization
Compound 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips Bi Shengzhi 50 DEG C stirring reaction 2h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 120mL), separates out yellow powder.Filtering, washing, vacuum drying obtains 25.2g yellow powder, HPLC99.1%.
M/z(MH+) 468.08,1H NMR (400MHz, DMSO) δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H),
4.22(q, 2H), 4.44(m, 1H), 4.61(m, 2H) and, 5.66(d, 1H), 6.68(s, 2H) and, 7.72(d, 1H),
7.92(dd, 1H).
Embodiment 11
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add NMP (150mL)
Stirring and dissolving, is added dropwise to DBU(10.57mL, 0.071mol under ice bath), drip to finish to be warmed to room temperature and stir reaction 1.5h, preparedization
Compound 14 direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (10.1g, 0.092mol), under ice bath, be added dropwise to DBU
(22.98mL, 0.153mol), drips Bi Shengzhi 30 DEG C stirring reaction 1h.Under ice bath, in reactant liquor, it is added dropwise to citric acid water-soluble
Liquid (10%, 150mL), separates out yellow powder.Filtering, washing, vacuum drying obtains 27.6g yellow powder, HPLC98.3%.
M/z(MH+) 468.08,1H NMR (400MHz, DMSO) δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H),
4.22(q, 2H), 4.44(m, 1H), 4.61(m, 2H) and, 5.66(d, 1H), 6.68(s, 2H) and, 7.72(d, 1H),
7.92(dd, 1H).
Embodiment 12
Wherein R be ethyl formula 1 shown in the preparation of compound:
In there-necked flask add compound 5(28g, 0.064mol), lithium chloride (5.45g, 0.13mol), add DMF (140mL)
Stirring and dissolving, is added dropwise to a year DIPEA (DIEA) (11.73mL, 0.071mol) under ice bath, drip Bi Shengzhi room
Temperature stirring reaction 2h, prepares compound 14 and direct plunges into next step reaction without isolation.
Upwards step reactant liquor adds 3-hydroxy azetidine hydrochlorate (8.1g, 0.074mol), under ice bath, be added dropwise to N, N-
Diisopropylethylamine (DIEA) (25.29mL, 0.153mol), drips Bi Shengzhi 60 DEG C stirring reaction 1h.Under ice bath, to reaction
Liquid is added dropwise to aqueous citric acid solution (10%, 150mL), separates out yellow powder.Filter, successively with water, ethanol making beating washing,
Vacuum drying obtains 23.0g yellow powder, HPLC98.5%.M/z(MH+) 468.08,1H NMR (400MHz, DMSO)
δ 1.28 (t, 3H), 3.32(s, 1H), 4.06 (m, 2H), 4.22(q, 2H), 4.44(m, 1H) and, 4.61(m, 2H),
5.66(d, 1H), 6.68(s, 2H), 7.72(d, 1H) and, 7.92(dd, 1H).
Embodiment 13
Compound 1(5g, 0.011mol is added in there-necked flask), ethanol 50mL, stirring, in faint yellow suspended, adds 4%
Sodium hydrate aqueous solution (containing NaOH0.85g) 20mL, is warming up to 50 DEG C of reaction 1h, is down to room temperature, filters, washing, very
Sky is dried and to obtain white powder 4.2g, purity 99.2%(HPLC).
The preparation of embodiment 14:delafloxacin
In there-necked flask add embodiment 11 products therefrom (3.5g, 0.76mmol), DMF(35mL) be creamy white suspended
Liquid, adds glacial acetic acid (3.0mL), is stirred at room temperature after clarifying completely to solution and is added dropwise to distilled water 70mL, filters, washing,
It is evaporated, obtains 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) and, 7.81
(d, 1H), 7.95(dd, 1H), 8.69(d, 1H) and, 14.34(brs, 1H).
Claims (13)
- The preparation method of the most following general formula compound 1, it is characterised in that: the method is by following formula 14 compound and 3-hydroxyl azacyclo- Butane hydrochlorate occurs nucleophilic substitution to prepare in the presence of a base:Described compound 14 is obtained by following reaction scheme:Compound shown in step 1 formula 3 and orthoformic acid esters are condensed to obtain ethoxy acrylic ester compound 4, step 1 in carboxylic acid anhydrides Middle gained ethoxy acrylic ester compound 4 is in organic solvent with 2, and 6-diaminourea 3, the condensation of 5-difluoro pyridine prepares formula 5 institute Showing compound, shown in formula 5, compound is in organic solvent, in the presence of lewis acid, alkali, self-condensation occurs, prepares formula Compound shown in 14；R is alkyl, aryl or aralkyl.
- 2. the preparation method of general formula compound 1 as claimed in claim 1, it is characterised in that: R is the alkyl of C1-C6.
- 3. the preparation method of general formula compound 1 as claimed in claim 2, it is characterised in that: R is the alkyl of C1-C4.
- 4. the preparation method of general formula compound 1 as claimed in claim 1, it is characterised in that: described alkali is selected from potassium carbonate, carbonic acid The inorganic base of sodium, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrofining and sodium hydride.
- 5. the preparation method of general formula compound 1 as claimed in claim 1, it is characterised in that: described alkali is organic base.
- 6. the preparation method of general formula compound 1 as claimed in claim 5, it is characterised in that: described organic base selected from triethylamine, two Picoline, 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.
- 7. the preparation method of general formula compound 1 as claimed in claim 6, it is characterised in that: described organic base is 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
- 8. the preparation method of general formula compound 1 as claimed in claim 1, it is characterised in that: the use of 3-hydroxy azetidine hydrochlorate The mole that amount is 1-5 times of starting compound 14.
- 9. the preparation method of general formula compound 1 as claimed in claim 8, it is characterised in that: the use of 3-hydroxy azetidine hydrochlorate The mole that amount is 1-2 times of starting compound 14.
- 10. the preparation method of general formula compound 1 as claimed in claim 9, it is characterised in that: 3-hydroxy azetidine hydrochlorate Consumption is the mole of 1.2 times of starting compound 14.
- The preparation method of 11. general formula compounds 1 as claimed in claim 1, it is characterised in that: the consumption of alkali is starting compound 14 The mole of 1-5 times.
- The preparation method of 12. general formula compounds 1 as claimed in claim 11, it is characterised in that: the consumption of alkali is starting compound 14 The mole of 1-3 times.
- The preparation method of 13. general formula compounds 1 as claimed in claim 12, it is characterised in that: the consumption of alkali is starting compound 14 The mole of 2.5 times.
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| CN105968099B (en) * | 2016-05-12 | 2018-09-25 | 扬子江药业集团有限公司 | A kind of process for purification of De Lasha stars |
| CN108084161A (en) * | 2017-12-28 | 2018-05-29 | 北京沃邦医药科技有限公司 | The preparation method of De Lasha stars and its intermediate |
| CN108033948A (en) * | 2017-12-28 | 2018-05-15 | 北京沃邦医药科技有限公司 | A kind of preparation of De Lasha stars and its intermediate |
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