CN101045724A - Coupling method for preparing quinolone intermediate - Google Patents
Coupling method for preparing quinolone intermediate Download PDFInfo
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Abstract
This invention disclosed a new preparation method of 7 -cyclo amido - 1 - cyclopropyl - 1, 4 - dihydro- 8 - methoxyl group - 4 - oxo - 3 - quinoline carboxylic acid.
Description
Invention field
The present invention relates to the preparation of certain quinolone intermediate.The present invention relates to a kind of be used to prepare 7-ring amino-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid's the novel method for the treatment of different things alike.
Background of invention
Antimicrobial quinolone compounds (3S, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid and (3S, 5R)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid is disclosed in United States Patent (USP) 6,329,391, the document is incorporated herein by reference.The synthetic of various quinolone compounds had report in the literature, and for example United States Patent (USP) 6,329, and 391; United States Patent (USP) 6,803,469; People's such as B.Ledoussal " Non 6-Fluoro Substituted Quinolone Antibacterials:Structureand Activity ", J.Med Chem., the 35th volume, the 198th page to 200 pages (1992); People's such as V.Cecchetti " Studies on 6-Aminoquinolines:Synthesis andAntibacterial Evaluation of 6-Amino-8-methylquinolones ", J.Med.Chem., the 39th volume, the 436th page to 445 pages (1996); People's such as V.Cecchetti " Potent 6-Desfluoro-8-methylquinolones as New Lead Compounds inAntibacterial Chemotherapy ", J.Med.Chem., the 39th volume, the 4952nd page to 4957 pages (1996).Yet this area need be used to prepare improving one's methods of these Antimicrobe compounds.
Summary of the invention
The present invention relates to a kind of preparation (3S that is used for, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid and (3S, 5R)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid's novel method.
In one embodiment, the present invention relates to a kind of method that is used to prepare the quinolone of replacement, this quinolone has formula (I):
Formula (I);
R wherein
1Be C
1-C
4Alkyl; R
2Be C
1-C
4Alkyl or C
3-C
6Cycloalkyl; R
4And R
5Be independently selected from amino, C respectively
1-C
4The amino of alkylamino, protection and C
1-C
4Alkyl; And n is 1 or 2;
This method comprises: in the presence of suitable alkali, the compound of formula (II) compound with formula (III) reacted in about 20 ℃ to about 80 ℃, with posthydrolysis:
Formula (II) formula (III);
R wherein
3Be selected from C unsubstituted or that replace
1-C
4Acyloxy; And R
1, R
2, R
4, R
5With n as defined above.
In another embodiment of aforesaid method, for the compound of the formula I of gained, R
1Be methyl.
In another embodiment of aforesaid method, for the compound of the formula I of gained, R
2Be cyclopropyl.
In another embodiment of aforesaid method, for the compound of the formula I of gained, R
4Be methyl.
In another embodiment of aforesaid method, for the compound of formula II, R
3Be acetoxyl group.
In another embodiment of aforesaid method, for the compound of formula I and formula III, R
5Be amino.
In another embodiment of aforesaid method, for the compound of formula I and formula III, R
5Be amino-tertbutyloxycarbonyl.In another embodiment of aforesaid method, wherein for the compound of formula I and formula III, R
5Be amino-tertbutyloxycarbonyl, Compound I also experiences one and goes the protection process.
In another embodiment of aforesaid method, for the compound of the formula I of gained, this compound is:
In another embodiment of aforesaid method, the compound of formula (III) is:
In another embodiment of aforesaid method, the compound of formula (II) is:
In another embodiment of aforesaid method, described alkali is selected from triethylamine, diisopropylethylamine, triisopropylamine and 1,8-diazabicylo [5.4.0]-7-undecylene.In another embodiment of aforesaid method, described alkali is triethylamine.
Detailed Description Of The Invention
Be used for amino or C
1-C
4The blocking group of alkylamino comprises, but be not limited to, carbamate groups, for example trichloro-ethoxycarbonyl, tribromo ethoxycarbonyl, carbobenzoxy-(Cbz), right-the nitro carbobenzoxy-(Cbz), neighbour-bromo-benzyloxycarbonyl, uncle-penta oxygen carbonyl, uncle-butoxy carbonyl, right-methoxyl group benzyloxy carbonyl, 3, the 4-dimethoxy-benzyloxycarbonyl; Acyl group, for example C
1-C
4The halo ethanoyl is as (single-, two-or three-) acetyl bromide, (single-, two-or three-) chloracetyl and (single-, two-or three-) acetyl fluoride base; Aralkyl, for example benzyl, diphenyl methyl and trityl.In one embodiment, described amido protecting group is uncle-butoxy carbonyl.
This paper has described the preparation method as the quinolone of the replacement of the described various structures of general formula I, wherein R
1Be C
1-C
4Alkyl, R
2Be C
1-C
4Alkyl or C
3-C
6Cycloalkyl, and R
4And R
5Be independently selected from amino, C respectively
1-C
4The amino of alkylamino, protection and C
1-C
4Alkyl.Will be as general formula I I (R wherein
1, R
2Such as definition, R
3Be selected from C unsubstituted or that replace
1-C
4Acyloxy, fluorine, chlorine and bromine) described in the boron ester inner complex of the 7-fluoroquinolone acid reactor of packing into.Use then as general formula III (R wherein
4And R
5As the definition, and n is 1 or 2) described in suitable this solid of cyclic amine side chain solution dilution; And will be dissolved in the generation that tertiary amine base in the suitable organic solvent is used for linked reaction.This linked reaction is maintained at about between 20 ℃ and about 80 ℃ until finishing.Finishing of available HPLC, TLC or IR spectroscopic analysis detection reaction, it is known to those skilled in the art.Can remove reaction solvent by distillation fraction and reduce volume, then reactant be diluted to begin the hydrolysis of boron ester inner complex with caustic-alkali aqueous solution.Add that thermal distillation can be carried out about 2 to 6 hours or up to there not being distillate to observe again under vacuum.Available HPLC, TLC or this reaction process of IR optical spectrum monitor.After finishing, reach under about 7 or 7 up to the pH value by adding this reaction of acid neutralization.Then organic, the immiscible solvent of water (for example methylene dichloride) are added in the reaction mixture, and stir, be separated subsequently.Remove this organic phase, and repeat such extraction process if desired.The reactor of then organic extract being packed into if necessary, is concentrated into about 50% volume, and handles to realize removing of blocking group, as tertbutyloxycarbonyl (Boc) with aqueous acid (example hydrochloric acid).This protective reaction process of available HPLC, TLC or IR optical spectrum monitor.When reaction is finished, two-phase mixture is separated.Organic phase is removed and available additional organic solvents extracts from reactor.Dilute with water acidifying water and remove residual organic solvent.Between about 7 and about 8, simultaneously temperature is maintained at about 30 ℃ to about 70 ℃ with the pH value of aqueous caustic conditioned reaction solution.About 40 ℃ to about 60 ℃ of following agitation as appropriate precipitated solid at least about one hour, then the cooling.Solid can and wash with water by the suction filtration separation.Can be in vacuum drying oven about 40 ℃ to about 60 ℃ of these solid phase prods of drying, the gained yield is generally between about scope of 70% to 90%.
Formula (I) formula (II) formula (III)
The reactant of formula III as defined above.In one embodiment, III is a piperidines.In another embodiment, III be (3S, 5S)-3-amino-5-methyl piperidine.In another embodiment, III be (3S, 5S)-(5-methyl-piperidines-3-yl)-t-butyl carbamate.
In one embodiment, R
4Be methyl.
In one embodiment, R
5Be amino-uncle-butoxy carbonyl.In another embodiment, R
5Be amino.
In one embodiment, R
1Be methyl.
In one embodiment, R
2Be cyclopropyl.
In another embodiment of aforesaid method, for the compound of the formula I of gained, this compound is:
In another embodiment of aforesaid method, the compound of formula II is:
The solvent that can be used for this reaction is unrestricted as long as it does not have the opposite effect to this reaction, and includes, but not limited to nitrile such as acetonitrile; Acid amides such as N, dinethylformamide, N,N-dimethylacetamide; Pyrrolidone is as N-Methyl pyrrolidone; Sulfoxide such as dimethyl sulfoxide (DMSO); Ether, for example methyl tertiary butyl ether (MTBE), glycol dimethyl ether (DME), ether, tetrahydrofuran (THF), Di Iso Propyl Ether, dioxane, methyl-phenoxide, diethylene glycol diethyl ether; Aromatic hydrocarbons such as benzene,toluene,xylene; Halohydrocarbon such as methylene dichloride, chloroform; And ester such as ethyl acetate, butylacetate.Can mix and use these solvents.In one embodiment, solvent is an acetonitrile.
The alkali that can be used for this reaction comprises, but be not limited to, alkylamine such as DIPEA (diisopropylethylamine), the N-alkyl morpholine, the N-alkyl pyrrolidine, the N-Alkylpiperidine, uncle-diaza-bicyclo amine such as DBU (1,8-diazabicylo [5.4.0]-7-undecylene), DABCO (1,4-diazabicylo [2.2.2] octane) and DBN (1,5-diazabicylo [4.3.0]-5-nonene), that replace and arylamine such as pyridine non-replacement, DMAP (N, N-dimethylamino phenylpiperidines), pyrimidine, N-alkyl pyrroles, the N-alkyl imidazole, the N-alkyl carbazole, N-alkyl indoles and triazine, guanidine alkali such as tetraalkyl guanidine, and N, N-dialkyl group piperazine.In one embodiment, described alkali is selected from triethylamine, diisopropylethylamine, triisopropylamine and 1,8-diazabicylo [5.4.0]-7-undecylene.In another embodiment, described alkali is triethylamine.
The amount of used alkali can be compound of formula III or its salt molar weight about 1 to about 4 times.
The used amount of general formula I I compound or its salt can be compound of formula III or its salt molar weight about 0.8 to about 1.5 times.
This paper has also described the preparation method as the described 7-fluoroquinolone of following general formula (II) boric acid ester.Boron oxide organic carboxyl acid R
3CO
2H and carboxylic acid anhydride (R
3CO)
2O handles, wherein R
3Be selected from C unsubstituted or that replace
1-C
4Alkyl.Mixture heating up to about 90 ℃ to about 130 ℃ about 1 to about 4 hours, is cooled to about 20 ℃ to about 90 ℃, and adds as the described functionalized 7-fluoroquinolone of general formula I V.For the 7-fluoroquinolone of general formula I V, R
1Be C
1-C
4Alkyl, and R
2Be C
1-C
4Alkyl or C
3-C
8Cycloalkyl.Should react and be heated to about 90 ℃ to about 130 ℃ about 3 to about 9 hours once more, cooling then.In reaction, add aromatic solvent then, for example toluene.Add another kind of solvent then in reaction mixture, for example t-butyl methyl ether precipitates to obtain product.After being chilled to about 0 ℃ to about 25 ℃, by filtering to isolate product and washing with ether.Can be at this solid phase prod of vacuum drying oven inner drying, the gained yield is generally between 70% to 90% scope.
Formula (II) formula (IV)
Embodiment:
Embodiment 1:(3S, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid and malate thereof synthetic.
A. (3S, 5S)-(5-methyl-piperidines-3-yl)-t-butyl carbamate (8) synthetic:
(2S)-and 1-(1, the 1-dimethyl ethyl)-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters, (2).With compound (1) (5.50kg, 42.60mol), methyl alcohol (27L) packs in one 50 liters the reactor, and be chilled to 10 ℃-15 ℃.Add thionyl chloride (10.11kg, 2.0 equivalents) by addition funnel in 65 minutes time, exterior cooling is lower than 30 ℃ with holding temperature simultaneously.Stir gained solution about 1.0 hours at 25 ℃ ± 5 ℃, boil off methyl alcohol under the decompression after this.(3 * 2.5L) azeotropic are to remove residual methyl alcohol with gained thickness oily matter and ethyl acetate.Residue is dissolved in the ethyl acetate (27.4L), puts in the reactor of 50L, and by in 30 minutes time, adding triethylamine (3.6kg) neutralization from addition funnel.Neutral temperature maintains by exterior cooling and is lower than 30 ℃.The triethylamine hydrochloride of the suspension by removing by filter gained, and with clarifying mother liquor together with pack into the reactor of 50L of DMAP (0.53kg).Feed hopper by hot water heating in 30 minutes time adds two carbonic acid, two-tert-butyl ester (8.43kg), simultaneously exterior cooling with holding temperature at about 20 ℃ to 30 ℃.Use the TLC analyzing and testing after 1 hour, react completely.With ice-cold 1N HCl (2 * 7.5L), (1 * 7.5L) washing organic phase and is used dried over mgso to saturated sodium bicarbonate solution.Filter this mixture by nutsch filter, and remove ethyl acetate under the decompression, it is smashed to pieces and filter to obtain intermediate (2) white solid (5.45kg, 52.4%) with MTBE (10.0L) to produce crystallization slurry.Analyze: C
11H
17NO
5Calculated value: C, 54.3; H, 7.04; N, 5.76.Detected value: C, 54.5; H, 6.96; N, 5.80.HRMS (ESI
+) for the C that expects
11H
18NO
5, [M+H] 244.1185.Detected value 244.1174;
1H NMR (CDCl
3, 500MHz): δ=4.54 (dd, J=3.1,9.5Hz, 1H), 3.7 (s, 3H), 2.58-2.50 (m, 1H), 2.41 (ddd, 1H, J=17.6,9.5,3.7), 2.30-2.23 (m, 1H), 1.98-1.93 (m, 1H), 1.40 (s, 9H);
13C NMR (CDCl
3, 125.70MHz) δ 173.3,171.9, and 149.2,83.5,58.8,52.5,31.1,27.9,21.5; 70.2 ℃ of Mp.
(2S, 4E)-1-(1, the 1-dimethyl ethyl)-4-[(dimethylamino) methylene radical]-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters (3).With intermediate (2) (7.25kg, 28.8mol), (7.7kg 44.2mole) packs in one 50 liters of reactors for DME (6.31kg) and Bredereck reagent.Stirred solution and be heated to 75 ℃ ± 5 ℃ at least three hours.Carry out with HPLC monitoring reaction.In one hour time, reactant is chilled to 0 ℃ ± 5 ℃, forms precipitation during this period.With this mixture maintain 0 ℃ ± 5 ℃ one hour, and filter by nutsch filter, and with product in vacuum drying oven 30 ℃ ± 5 ℃ dryings at least 30 hours to obtain intermediate (3) white crystalline solid (6.93kg, 77.9%).Analyze: C
14H
22N
2O
5Calculated value: C, 56.4; H, 7.43; N, 9.39.Detected value C, 56.4; H, 7.32; N, 9.48; HRMS (ESI
+) for the C that expects
14H
22N
2O
5, [M+H] 299.1607.Detected value 299.1613;
1H NMR (CDCl
3, 499.8MHz) δ=7.11 (s, 1H), 4.54 (dd, 1H, J=10.8,3.6), 3.74 (s, 3H), 3.28-3.19 (m, 1H), 3.00 (s, 6H), 2.97-2.85 (m, 1H), 1.48 (s, 9H);
13C NMR (CDCl
3, 125.7MHz) δ=172.6,169.5,150.5,146.5,90.8,82.2,56.0,52.3,42.0,28.1,26.3.Mp?127.9℃。
(2S, 4S)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters (4).With one 10 gallons of Pfaudler reactors of nitrogen inerting, and the ESCAT 1425% palladium carbon dust of packing into (50% soaks into, the weight that 0.58kg soaks into), intermediate (3) (1.89kg, 6.33mol) and Virahol (22.4kg).Stirred reaction mixture is 18 hours under 45 ℃ of 310kPa (45psi) hydrogen.Then reaction mixture is chilled to room temperature and by the diatomite in the nutsch filter (Celite) (0.51kg) layer filter to remove catalyzer.Decompression mother liquid evaporation is down left standstill crystallization and is gone out 4 (1.69kg, 100%) to obtain thickness oily matter, and it is 93: 7 non-enantiomer mixtures.By preparation HPLC purified product blend sample to provide the material that is used for analytical data.Analyze: C
12H
19NO
5Calculated value: C, 56.0; H, 7.44; N, 5.44.Detected value C, 55.8; H, 7.31; N, 5.44; MS (ESI
+) for the C that expects
12H
19NO
5, [M+H] 258.1342.Detected value 258.1321;
1H NMR (CDCl
3, 499.8MHz) δ=4.44 (m, 1H), 3.72 (s, 3H), 2.60-2.48 (m, 2H), 1.59-1.54 (m, 1H), 1.43 (s, 9H), 1.20 (d, J=6.8Hz, 3H);
13C NMR (CDCl
3, 125.7MHz) δ=175.7,172.1,149.5,83.6,57.4,52.5,37.5,29.8,27.9,16.2.Mp89.9℃。
(1S, 3S)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate (5).With intermediate (4) (3.02kg, 11.7mol), dehydrated alcohol (8.22kg) and MTBE (14.81kg) pack in one 50 liters of reactors.Stir this solution and be chilled to 0 ℃ ± 5 ℃, and (1.36kg is 35.9mol) so that temperature of reaction maintains 0 ℃ ± 5 ℃ to add sodium borohydride with aliquot.Observe a small amount of bubbling.Make reaction mixture be warming up to 10 ℃ ± 5 ℃, and in one hour time, add calcium chloride dihydrate (2.65kg) so that temperature of reaction maintains 10 ℃ ± 5 ℃ in the reinforced mode of low speed.In one hour, make reaction be warming up to 20 ℃ ± 5 ℃, and 20 ℃ ± 5 ℃ restir 12 hours.Reaction is cooled to-5 ℃ ± 5 ℃, adds ice-cold 2N HCl (26.9kg) to keep temperature of reaction at 0 ℃ ± 5 ℃ with given pace.Stop to stir so that be separated.Remove lower floor's water (pH=1).The reactor of in five minutes, saturated sodium bicarbonate aqueous solution (15.6kg) being packed into.Stop to stir so that be separated.Remove lower floor's water (pH=8).With pack into reactor and stirring at least 10 minutes of sal epsom (2.5kg).By the nutsch filter filtering mixt, and under reduced pressure concentrate to obtain intermediate (5) (1.80kg, 66%).Analyze: C
11H
23NO
4Calculated value: C, 56.6H, 9.94; N, 6.00.Detected value C, 56.0; H, 9.68; N, 5.96; HRMS (ESI
+) for the C that expects
11H
24NO
4, [M+H] 234.1705.Detected value 234.1703;
1H NMR (CDCl
3, 500MHz) δ=6.34 (d, J=8.9Hz, 1H, N
H), 4.51 (t, J=5.8,5.3Hz, 1H, NHCHCH
2O
H), 4.34 (t, J=5.3,5.3Hz, 1H, CH3CHCH
2O
H), 3.46-3.45, (m, 1H, NHC
H), 3.28 (dd, J=10.6,5.3Hz, NHCHC
HHOH), 3.21 (dd, J=10.2,5.8Hz, 1H, CH
3CHC
HHOH), 3.16 (dd, J=10.2,6.2Hz, 1H, NHCHCH
HOH), 3.12 (dd, J=10.6,7.1Hz, 1H, CH
3CHCH
HOH), 1.53-1.50 (m, 1H, CH
3C
HCHHOH), 1.35 (s, 9H, O (C
H 3)
3, 1.30 (ddd, J=13.9,10.2,3.7Hz, 1H, NHCHCH
HCH), 1.14 (ddd, J=13.6,10.2,3.4Hz, 1H, NHCHC
HHCH), 0.80 (d, J=6.6Hz, 3H, CH
3);
13C NMR (CDCl
3, 125.7MHz) δ 156.1,77.9, and 50.8,65.1,67.6,65.1,35.6,32.8,29.0,17.1.Mp?92.1℃。
(2S, 4S)-methylsulfonic acid 2-t-butoxycarbonyl amino-5-mesyloxy-4-methyl-pentyl ester (6).With intermediate (5) isopropyl acetate (i-PrOAc) (5.1kg) (11.8kg) solution add one 50 liters of reactors, subsequently with other 7.9kg i-PrOAc flushing.Reaction is cooled to 15 ℃ ± 5 ℃ and add triethylamine (TEA) (7.8kg) when keeping design temperature.To react and further be cooled to 0 ℃ ± 5 ℃ and when keeping design temperature, add methylsulfonyl chloride (MsCl) (6.6kg) to reaction solution.To react stirred for several hour and finish with HPLC or TLC monitoring reaction.Finish this reaction by adding saturated bicarbonate aqueous solution, and with the 10% cold triethylamine aqueous solution, the cold HCl aqueous solution, cold the saturated bicarbonate aqueous solution and final saturation common salt aqueous solution wash separating obtained organic phase in succession.With the organic phase drying, filter, and be lower than 55 ℃ ± 5 ℃ vacuum concentration until the solid/liquid slurry that obtains comprising intermediate (6).This slurry is directly used in subsequent reaction and need not further characterizes.
(3S, 5S)-(1-benzyl-5-methyl-piperidines-3-yl)-t-butyl carbamate (7).With the pure benzylamine of the 9.1kg one 50 liters of reactors of packing into.With reactor rise to 55 ℃ and with temperature maintenance in 60 ℃ ± 5 ℃ to reactor add intermediate (6) (8.2kg) 1,2-glycol dimethyl ether (DME) is solution (14.1kg).This solution is added finish after, stir this stoichiometric numbers hour and finish at 60 ℃ ± 5 ℃ with TLC or HPLC monitoring.Reaction is chilled to envrionment temperature and removes volatile matter (DME) by rotary evaporation under the vacuum.With 15% (volume/volume) ethyl acetate/hexane solution dilution of residue with 11.7kg, and 20% (weight) wet chemical with 18.7kg is handled when stirring.Obtain three-phase mixture after leaving standstill.Remove the water of bottom, and intermediate phase is placed the next door.Collect upper organic phase and preserve and merge with extract with other extraction.With the isolated intermediate phase twice of 15% (volume/volume) ethyl acetate/hexane solution extraction of 11.7kg amount, with each extract and former organic being harmonious also.The organic extract that merges is transferred in the Rotary Evaporators, and under vacuum, removes and desolvate until remaining oily residue.Then by intermediate (7) oil of large-scale preparation chromatogram purification residue to obtain purifying.
(3S, 5S)-(5-methyl-piperidines-3-yl)-carboxylamine tertiary butyl ester (8).The solid palladium carbon (E101,10 weight %) that under nitrogen gas stream, 0.6kg 50% is soaked into one 40 force containers that boost of packing into.The reactor of under nitrogen, dehydrated alcohol (13.7kg) solution of 3.2kg intermediate (7) being packed into then.Use the nitrogen purge reactor, be pressed into hydrogen with 310kPa (45psi) then.When hydrogen pressure is 310kPa (45psi) reaction is heated to 45 ℃ keeping then.React until finishing with TLC or LC monitoring.Reaction is chilled to envrionment temperature, emptying, and pass to nitrogen.By diatomite layer filtering reaction thing, and with this solid of 2.8kg absolute ethanol washing.By rotating evaporation concentration filtrate under the vacuum: TLC R until obtaining waxy solid to obtain intermediate (8)
f(silica gel F
254, 70: 30 volume/volume ethyl acetate-hexanes, KMnO
4Colour developing)=0.12;
1H NMR (300MHz, CDCl
3) δ 5.31 (br s, 1H), 3.80-3.68 (m, 1H), 2.92 (d, J=11.4Hz, 1H), 2.77 (AB quart, J
AB=12.0Hz, Δ v=50.2Hz, 2H), 2.19 (t, J=10.7Hz, 1H), 1.82-1.68 (m, 2H), 1.54 (br s, 1H), 1.43 (s, 9H), 1.25-1.15 (m, 1H), 0.83 (d, J=6.6Hz, 3H);
13C NMR (75MHz, CDCl
3) δ 155.3,78.9,54.3,50.8,45.3,37.9,28.4,27.1,19.2; MS (ESI+) m/z 215 (M+H), 429 (2M+H).
B.1-cyclopropyl-7-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (19) synthetic:
Intermediate (12): to pack into dry toluene (12L) solution of intermediate (11) (1.2kg, 7.7mol, 1.0 equivalents) of reactor, add subsequently ethylene glycol (1.8L, 15.7mol, 4.2 equivalents) and solid right-toluene semi-annular jade pendant acid (120g, 10 weight %).Stirred reaction mixture is at least 30 minutes at ambient temperature, is heated to backflow then, and it is complete until analyzing (15%EtOAc/ hexane volume/volume) detection reaction with TLC to collect water/methylbenzene azeotropic thing in Dean Stark receiver pope.After finishing, reaction is chilled to envrionment temperature and inclines to the aqueous solution (6L) of sodium bicarbonate.Organic toluene shifted out mutually and with saturated sodium bicarbonate solution (6L), distilled water (2 * 6L) and saturated aqueous common salt (6L) washing.Organic phase is shifted out and uses MgSO
4Drying is filtered, and decompression is evaporated down to obtain intermediate (12) oil (1.3kg, 86%).This material is used for the subsequent reaction step, need not be further purified.
Intermediate (13): with anhydrous tetrahydro furan (12L) solution of intermediate (12) (1.2kg, 6.0mol, the 1.0 equivalents) reactor of packing into, and-40 ℃ of addings just-(2.5M is dissolved in hexane to butyllithium, 2.6L, 6.6mol, 1.1 equivalent), in reinforced process, keep this temperature all the time simultaneously.Add trimethyl borate (0.9L, 7.8mol, 1.3 equivalents)-40 ℃ of stirring reactions at least one hour and to this mixture, the while holding temperature is at-40 ℃ or be lower than-40 ℃.Detect and finish until analyze (30%EtOAc/ hexane volume/volume) with TLC-40 ℃ of stirred reaction mixtures at least one hour.Temperature reaction is to-30 ℃ and slowly add acetate (3L) a little.After reinforced the finishing, add entry (0.5L) to reaction, and make mixture be warming up to envrionment temperature rapidly, stir simultaneously and spend the night.From reaction, remove organic solvent by distillation under reducing pressure at 45 ℃.The water (6L) and 30% hydrogen peroxide (0.7L, 1.0 equivalents) that slowly add 3 to 4 volumes at ambient temperature to reaction residue provide cooling with the control heat release simultaneously.Finish until detecting envrionment temperature stirring reaction at least one hour with TLC (15%EtOAc/ hexane volume/volume).Reaction mixture is chilled to 0 ℃ to 5 ℃, and with the superoxide of 10% aqueous solution of sodium bisulfite (2L) decomposing excessive that adds.Detect the superoxide result of mixture, and add (1.2L) acidification reaction of 6N HCl (aqueous solution) to guarantee to bear.Stirring reaction is until finishing with TLC or NMR analyzing and testing hydrolysis reaction.Collect the gained solid to obtain intermediate (13) yellow solid (1.0kg, 79%) by suction filtration.
Intermediate (14): will be dissolved in dry toluene (2.7kg, 3.1L) intermediate in (13) (0.53kg, 3.0mol, the 1.0 equivalents) reactor of packing into.In this solution, add methyl-sulfate (0.49kg, 3.9mol, 1.30 equivalents), add solid carbonic acid potassium (0.58kg, 4.2mol, 1.4 equivalents) subsequently.Reaction mixture is heated to backflow and keeps at least 1 hour until finishing with the HPLC detection.During this period, observe and acutely emit gas.Then reaction is cooled to envrionment temperature and with distilled water (3.2L) and 30%NaOH (solution) (0.13kg, 0.33 equivalent) together with its dilution.Isolate water, and extract remaining toluene phase more than twice, remove water at every turn with the combination of distilled water (3.2L) and 30%NaOH (solution) (0.13kg, 0.33 equivalent).By concentrating upper organic phase in about 40 ℃ of vacuum distillings (＜10kPa (100mbar)) until obtaining spissated toluene solution.Gained solution is cooled to envrionment temperature, veritifies quality and yield by HPLC, and forward to the synthetic next step need not be further purified (theoretical yield of intermediate (14) supposition, 0.56kg).
Intermediate (15a, b): with 1.8kg (2.1L) dry toluene and sodium hydride (0.26kg, 6.6mol, 2.20 equivalents) (as the dispersion of 60 weight % in the mineral oil) reactor of packing into together.When this reaction mixture during, add diethyl carbonate (0.85kg, 7.2mol, 2.4 equivalents) to this mixture at 1 hour internal heating to 90 ℃.The toluene solution that derives from the intermediate (14) (～1.0 equivalent) of preceding step is added reaction, and holding temperature is at 90 ℃ ± 5 ℃ simultaneously.Between this charge period, can be observed gas and emit.After reinforced finishing, stirring reaction at least 30 minutes or until finishing with the HPLC analyzing and testing.After finishing, mixture is cooled to envrionment temperature and under agitation uses the aqueous sulfuric acid (3.8kg, 3.9mol, 1.3 equivalents) of 10 weight % to dilute.Make and be separated and remove lower floor's water.By under about 40 ℃ of vacuum (＜10kPa (100mbar)) concentrate remaining organic phase until obtaining spissated toluene solution.Gained solution is cooled to envrionment temperature, and forward to the synthetic next step need not be further purified (intermediate (and 15a, b) Jia Ding theoretical yield, 0.85kg).
Intermediate (16a, b; 17a, b): intermediate (15a, b) toluene solution of (0.85kg ,～3.0mol ,～1.0 equivalents) reactor of packing into that will derive from preceding step.Add dimethyl formamide-dimethyl-acetal (0.54kg, 4.5mol, 1.5 equivalents) to reactor then, and gained solution is heated to reflux temperature (～95 ℃ to 105 ℃).When temperature maintenance during, low boiling point solvent (coming self-reacting methyl alcohol) is distilled at 〉=90 ℃.Continued heating at least 1 hour or until finishing with the HPLC analyzing and testing.After finishing, will comprise intermediate (16a, b) reactant of mixture is cooled to envrionment temperature, and with toluene (1.8kg, 2.1L) and cyclopropylamine (0.21kg, 3.6mol, 1.2 equivalents) add together the reaction in.Finish until detecting envrionment temperature stirring reaction at least 30 minutes with HPLC.After finishing, under agitation use aqueous sulfuric acid (2.9kg, 3.0mol, the 1.0 equivalents) diluting reaction of 10 weight %, make then to be separated.Remove water, and (＜10kPa (100mbar)) concentrates organic phase by distillation under about 40 ℃ of decompressions.When reaching desired concn, solution is cooled to envrionment temperature, and will comprise intermediate (17a, b) toluene solution of mixture forward to synthetic next step need not be further purified (intermediate (and 17a, b) Jia Ding theoretical yield ,～1.1kg).
Intermediate (18): at ambient temperature with intermediate (17a, b) (～4.7kg ,～3.0mol) the mixture solution reactor of packing into.Add N to reactor, O-two (trimethyl silyl) ethanamide (0.61kg, 3.0mol, 1.0 equivalents), and reaction was heated to reflux temperature (～105 to 115 ℃) at least 30 minutes or until finishing with the HPLC analyzing and testing.Were it not for and finish, to the N of reaction adding additional quantity, O-two (trimethyl silyl) ethanamide (0.18kg, 0.9mol, 0.3 equivalent) is finished to reach.After finishing, with reaction be cooled to be lower than 40 ℃ and under about 40 ℃ of decompressions (＜10kPa (100mbar)) remove organic solvent by distillation and form until precipitation.Reaction is chilled to envrionment temperature, and isolates precipitated solid by suction filtration, and with distilled water wash twice (1 * 1.8L, 1 * 0.9L).With solid drying to obtain intermediate (18) white solid (0.76kg, 82%).This material need not to be further purified and promptly is used for next reactions steps.
Intermediate (19): at ambient temperature to the reactor solid intermediate (18) (0.76kg ,～2.5mol ,～1.0 equivalents) of packing into, add subsequently ethanol (5.3kg, 6.8L) and the aqueous hydrochloric acid of 32 weight % (1.1kg, 10mol).Reaction mixture is risen to reflux temperature (76 ℃ to 80 ℃), and this mixture at first becomes homogeneous phase during this period, becomes heterogeneous subsequently.Finish with this mixture heating up backflow at least 5 hours or until analyze (15%EtOAc/ hexane volume/volume) detection with TLC.After finishing, reaction is chilled to 0 ℃ ± 5 ℃, and uses ethanol (1.7kg) washing subsequently by the filtering separation precipitated solid and with distilled water (1.7kg).With isolated solid drying to obtain intermediate (19) white solid (0.65kg ,～95%).
1H?NMR(CDCl
3，300MHz)δ(ppm)：14.58(s，1H)，8.9(s，1H)，8.25(m，1H)，7.35(m，1H)，4.35(m，1H)，4.08(s，3H)，1.3(m，2H)，1.1(m，2H)。
19F?NMR(CDCl
3+CFCl
3，292MHz)δ(ppm)：-119。HPLC: press area 99.5%.
C.1-cyclopropyl-7-fluoro-8-methoxyl group-4-oxo-1, synthetic (20) of 4-dihydroquinoline-3-carboxylic acid boron ester inner complex:
With boron oxide (2.0kg, the 29mol) reactor of packing into, use subsequently Glacial acetic acid (8.1L, 142mol) and diacetyl oxide (16.2L, 171mol) dilution.With the gained mixture heating up to reflux temperature at least 2 hours.Reactant is cooled to 40 ℃, and (14.2kg 51mol) adds to reaction mixture with solid 7-fluoroquinolone acid intermediate (19).Mixture was heated to reflux temperature at least 6 hours once more.Carry out with HPLC and NMR monitoring reaction.Mixture is cooled to about 90 ℃, and toluene (45L) is added in the reaction.To react and further be cooled to 50 ℃, and t-butyl methyl ether (19L) will be added in the reaction mixture to impel the product precipitation.Mixture is cooled to 20 ℃ then, and by filtering to isolate solid phase prod (19).In 40 ℃ of vacuum ovens (7kPa (50 holder)), wash isolated solid with t-butyl methyl ether (26L) before the drying then.The product yield that intermediate in this reaction (20) is obtained is 86.4%.Raman(cm
-1)：3084.7，3022.3，2930.8，1709.2，1620.8，1548.5，1468.0，1397.7，1368.3，1338.5，1201.5，955.3，653.9，580.7，552.8，384.0，305.8。NMR(CDCl
3，300MHz)δ(ppm)：9.22(s，1H)，8.38-8.33(m，1H)，7.54(t，J＝9.8Hz，1H)，4.38-4.35(m，1H)，4.13(s，3H)，2.04(s，6H)，1.42-1.38(m，2H)，1.34-1.29(m，2H)。TLC (Whatman MKC18F silica gel, 60 , 200 μ m), moving phase: 1: 1 (volume/volume) CH
3CN: 0.5N NaCl (aq), UV (254/366nm) shows; R
f=0.4-0.5.
D.1-cyclopropyl-7-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (20) and (3S, 5S)-coupling of (5-methyl-piperidines-3-yl)-carboxylamine tertiary butyl ester (8), (3S, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid's malate (25) synthetic:
With solid intermediate (20) (4.4kg, the 10.9mol) reactor of packing into, at room temperature use subsequently triethylamine (TEA) (2.1L, 14.8mol) and piperidines side chain intermediate (8) (2.1kg, acetonitrile 9.8mol) (33.5L, 15.7L/kg) solution dilution.With the gained mixture heating up to about 50 ℃ until the reaction just complete.With HPLC or anti-phase TLC monitoring reaction process.When finishing, reaction is cooled to about 35 ℃, and makes an appointment with half so that reaction volume is reduced to by evaporation acetonitrile under the vacuum between 0 to 53kPa (400 holder).The reactor of then 3.0N NaOH (aq) solution of 28.2kg being packed into, and this temperature rises to about 40 ℃.Continued distillation under the vacuum 1 to 4 hour or until there not being distillate to be observed again.Then reaction is chilled to room temperature and monitors this hydrolysis reaction with HPLC or anti-phase TLC.After finishing, reaction mixture is neutralized to pH is between 6 and 8 by adding～4 to 5kg Glacial acetic acid.To add reactor as the methylene dichloride of the 12.7kg (9.6L) of extraction agent then, stir this mixture, and make to be separated, and organic methylene dichloride is removed mutually.Use the extra re-extract process twice of methylene dichloride of 12.7kg (9.6L), collect lower floor's organic phase at every turn.Aqueous phase discarded and organic extract is incorporated in the independent reactor.Reactant is heated to 40 ℃, and reaction volume is reduced to approximately half by distillation.The reactor of then 20.2kg 6.0N HCl (aq) solution being packed into adjusts the temperature to 35 ℃, and stirs at least 12 hours so that the Boc protective reaction takes place.Monitor this reaction with HPLC or anti-phase TLC.When finishing, stop to stir and making being separated.Remove lower floor's organic phase and place the next door.To add reactor as the methylene dichloride of the 12.7kg (9.6L) of extraction agent then, stir this mixture, and make to be separated, and organic methylene dichloride is removed mutually.Organic extract is merged and discard.Rise to about 50 ℃ with the remaining water of 18.3kg distilled water diluting and with temperature.Under the vacuum (13-53kPa (100-400 holder)) distill with from the reaction remove residual methylene dichloride.3.0N NaOH (aq) solution with about 9.42kg is adjusted to reaction pH value between 7.8 to 8.1 then, keeps temperature of reaction to be lower than 65 ℃ simultaneously.Reaction is chilled to 50 ℃, and before this mixture is chilled to room temperature ageing precipitated solid at least one hour.Isolate solid and with twice of the distilled water wash of 5.2kg amount by suction filtration.With vacuumizing with this solid drying at least 12 hours, in 55 ℃ convection oven dry 12 hours in addition then.The output that reached of intermediate (23) is 3.2kg (79%) in this embodiment.With 3.2kg solid intermediate (23) reactor of packing into, and with this solid suspension in 95% ethanol as the 25.6kg of solvent.The solid D that adds 1.1kg then to reactor, L MALIC ACID (24), and with mixture heating up to reflux temperature (～80 ℃).With distilled water (～5.7L) add to reaction until realizing dissolving fully, and add the gac of 0.2kg.With reaction mixture by a strainer realize purifying, it is chilled to 45 ℃ and preserve at least 2 hours time so that crystallization occurs.Reaction mixture further is chilled to 5 ℃, and isolates the solid of suspension with suction filtration.Use this solid of 95% washing with alcohol of 6.6kg then, and with vacuum lower pumping drying at least 4 hours.Then at 45 ℃ of at least 12 hours intermediates (24) (70%) of further dry this solid in convection oven to obtain 3.1kg.NMR(D
2O，300MHz)δ(ppm)：8.54(s，1H)，7.37(d，J＝9.0Hz，1H)，7.05(d，J＝9.0Hz，1H)，4.23-4.18(m，1H)，4.10-3.89(m，1H)，3.66(br?s，1H)，3.58(s，3H)，3.45(d，J＝9.0Hz，1H)，3.34(d，J＝9.3Hz，1H)，3.16(d，J＝12.9Hz，1H)，2.65(dd，J＝16.1，4.1Hz，1H)，2.64-2.53(m，1H)，2.46(dd，J＝16.1，8.0Hz，1H)，2.06(br?s，1H)，1.87(d，J＝14.4Hz，1H)，1.58-1.45(m，1H)，1.15-0.95(m，2H)，0.91(d，J＝6.3Hz，3H)，0.85-0.78(m，2H)。TLC (Whatman MKC18F silica gel, 60 , 200 μ m), moving phase: 1: 1 (volume/volume) CH
3CN: 0.5N NaCl (aqueous solution), UV (254/366nm) shows.HPLC: moving phase H
2O and 0.1% formic acid/acetonitrile and 0.1% formic acid are used 88%H
2O/ formic acid is to 20%H
2O/ formic acid gradient elution, Zorbax SB-C8 4.6mm * 150mm chromatographic column, Part No. 883975.906,1.5ml/ minute flow velocity, 20 minute working time, 292nm, monitor model G1314A, S/N JP72003849, quaternary pump model G1311A, S/N US72102299, automatic sampler model G1313A, S/N DE14918139, de-gassing vessel model G1322A, S/N JP73007229; The general retention time of intermediate (19): 13.0 minutes; The general retention time of intermediate (20): 11.6 minutes; The general retention time of intermediate (21): 16.3 minutes; The general retention time of intermediate (22): 18.2 minutes; The general retention time of intermediate (23): 8.6 minutes; The general retention time of compound (25): 8.6 minutes.
Except as otherwise noted, all comprise that the amount of quantity, per-cent, mark and ratio is understood that to be modified by speech " pact ", and amount is not intended to represent significant figure.
" one (a, an) " and " described (the) " are meant " one or more " unless otherwise indicated, herein.
The relevant portion of all documents of quoting in detailed Description Of The Invention all is incorporated herein branch for your guidance; It is to its approval as prior art of the present invention that the quoting of any document not can be regarded as.When any implication of term in any implication of term in this written document record or definition and the document that is incorporated herein by reference or define when conflicting, will be as the criterion with the implication or the definition of giving term in this written document record.
Although illustrated and described the present invention with specific embodiments, it will be apparent to those skilled in the art that many other variations and modifications may be made in the case of without departing from the spirit and scope of protection of the present invention.Therefore, in additional claims, comprise all such changes and modifications in the scope of the invention consciously.
Claims (13)
1. method that is used to prepare suc as formula the quinolone of the replacement of I:
Formula I
R wherein
1Be C
1-C
4Alkyl;
R
2Be C
1-C
4Alkyl or C
3-C
6Cycloalkyl;
R
4And R
5Be selected from amino, C independently of one another
1-C
4The amino of alkylamino, protection and C
1-C
4Alkyl; With
N is 1 or 2;
Described method comprises: in the presence of suitable alkali, the compound of the formula II compound with formula III reacted in about 20 ℃ to about 80 ℃, with posthydrolysis:
R wherein
3Be selected from C unsubstituted or that replace
1-C
4Acyloxy; And R
1, R
2, R
4, R
5With n as defined above.
2. the method for claim 1, wherein for the compound of the formula I of gained, R
1Be methyl.
3. the method for claim 1, wherein for the compound of the formula I of gained, R
2Be cyclopropyl.
4. the method for claim 1, wherein for the compound of the formula I of gained, R
4Be methyl.
5. the method for claim 1, wherein for the compound of formula II, R
3Be acetoxyl group.
6. the method for claim 1, wherein for the compound of formula I and III, R
5Be amino.
7. the method for claim 1, wherein for the compound of formula I and III, R
5Be amino-tertbutyloxycarbonyl.
8. method as claimed in claim 7, wherein the compound of the formula I of gained goes the protection process.
9. the method for claim 1, wherein for the compound of the formula I of gained, described compound is:
10. the method for claim 1, wherein the compound of formula III is:
11. the method for claim 1, the compound of its Chinese style II is:
12. the method for claim 1, wherein said alkali are selected from triethylamine, diisopropylethylamine, triisopropylamine and 1,8-diazabicylo [5.4.0]-7-undecylene.
13. method as claimed in claim 12, wherein said alkali are triethylamine.
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| CN103145615A (en) * | 2013-03-20 | 2013-06-12 | 浙江医药股份有限公司新昌制药厂 | Posttreatment method of nemonoxacin chelate |
| CN103819401A (en) * | 2012-11-19 | 2014-05-28 | 浙江中欣化工股份有限公司 | Synthesis method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinolyl-3-carboxylic acid |
| CN109452288A (en) * | 2018-12-19 | 2019-03-12 | 王兴翠 | The composition and its method of administration for preventing and treating great Jiang bacterial wilt |
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| JPH0778065B2 (en) * | 1990-07-06 | 1995-08-23 | 杏林製薬株式会社 | (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O ▲ above 3 ▼, O ▲ above 4) bis (acyloxy-O) Boron compound, salt thereof, and method for producing the same |
| NO304832B1 (en) * | 1992-05-27 | 1999-02-22 | Ube Industries | Aminokinolone derivatives and anti-HIV agents |
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2006
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819401A (en) * | 2012-11-19 | 2014-05-28 | 浙江中欣化工股份有限公司 | Synthesis method of 1-cyclopropyl-4-oxo-7-fluoro-8-methoxy-1,4-dihydroquinolyl-3-carboxylic acid |
| CN103819401B (en) * | 2012-11-19 | 2016-04-13 | 浙江中欣氟材股份有限公司 | The synthetic method of the fluoro-8-methoxyl group-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid of 1-cyclopropyl-4-oxo-7- |
| CN103145615A (en) * | 2013-03-20 | 2013-06-12 | 浙江医药股份有限公司新昌制药厂 | Posttreatment method of nemonoxacin chelate |
| CN103145615B (en) * | 2013-03-20 | 2015-07-29 | 浙江医药股份有限公司 | A kind of post-treating method of Nai Nuosha star inner complex |
| CN109452288A (en) * | 2018-12-19 | 2019-03-12 | 王兴翠 | The composition and its method of administration for preventing and treating great Jiang bacterial wilt |
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