CN101045695B - Hydro-reduction method for preparing quinolone intermediate - Google Patents
Hydro-reduction method for preparing quinolone intermediate Download PDFInfo
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Abstract
This invention relates to a new style hydrogenation method of preparing diol without loop intermediate from cyclic intermediate, used in antibacterial Quinolone synthesizing.
Description
Invention field
The present invention relates to the preparation of certain quinolone intermediate.The present invention relates to a kind of novel direct hydrogenation method for preparing acyclic two alcohol intermediates from cyclic intermediate.
Background of invention
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-FluoroSubstituted Quinolone Antibacterials:Structure and 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 and Antibacterial Evaluationof 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 in AntibacterialChemotherapy ", J.Med.Chem., the 39th volume, the 4952nd page 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 novel hydro-reduction method and be used for the synthetic intermediate of antimicrobial quinolone with preparation.
In one embodiment, the present invention relates to prepare quinolone intermediate with following formula:
Formula (I);
Wherein n is 1 or 2; X is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl; And Z is selected from CO
2X and COX, wherein X is as defined above;
Said method comprising the steps of: at-20 ℃ to about 10 ℃ approximately, the C of volume ratio about 100/0 to about 20/80
1-C
4Alkanol and C
2-C
6Make the compound and about 2 to the about 4 normal sodium borohydride reactions of formula (II) in the mixture of ether, add about 1.5 to about 3.0 normal calcium salts at about 5 ℃ to about 15 ℃ subsequently,
Formula (II)
Wherein Y is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl; And X, Z and n define suc as formula (I).
In another embodiment of aforesaid method, X is C
1-C
4Alkyl.
In another embodiment of aforesaid method, X is a methyl.
In another embodiment of aforesaid method, X is the tertiary butyl.
In another embodiment of aforesaid method, Z is a tertbutyloxycarbonyl.
In another embodiment of aforesaid method, described calcium salt is a calcium chloride.
In another embodiment of aforesaid method, the compound of formula (II) be (2S, 4S)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters.
In another embodiment of aforesaid method, the compound of formula (II) be (2S, 4R)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters.
In another embodiment of aforesaid method, the compound of formula (I) be (1S, 3S)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
In another embodiment of aforesaid method, the compound of formula (I) be (1S, 3R)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
In another embodiment of aforesaid method, described alkanol solvent is an ethanol.
In another embodiment of aforesaid method, described ether solvents is a methyl tertiary butyl ether.
In another embodiment of aforesaid method, ethanol: the solvent volume ratio of methyl tertiary butyl ether is 33: 67.
Detailed Description Of The Invention
The protecting group that is used for nitrogen includes, but not limited to acyl group such as ethanoyl, phenylacetyl and formyl radical; Carbamate groups such as tertbutyloxycarbonyl or uncle's penta oxygen carbonylamino manthanoate.
The protecting group that is used for carboxyl includes, but not limited to C
1-C
4Alkyl such as methyl, ethyl, just-propyl group, sec.-propyl and just-butyl; Aryl such as phenyl, naphthyl; Aralkyl such as benzyl, diphenyl methyl.
The compound of general formula (I) can carry out hydro-reduction by the compound that makes general formula (II) and react and prepare.
Formula (I);
Formula (II)
For the compound of formula I and II, n is 1 or 2; X is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl; Z is selected from CO
2X and COX, wherein X is as defined above; And Y is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl.
In one embodiment, the compound of formula (I) be (1S, 3S)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
In another embodiment, the compound of formula (I) be (1S, 3R)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
In one embodiment, the compound of formula (II) be (2S, 4S)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters:
In another embodiment, the compound of formula (II) be (2S, 4R)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters:
The solvent that can be used for this reaction is not to be particularly limited, as long as it does not react on this reaction, and comprises, for example, alcohol, for example methyl alcohol, ethanol, propyl alcohol, Virahol, butanols; Ether, for example methyl tertiary butyl ether (MTBE), ethylene glycol dimethyl ether, ether, tetrahydrofuran (THF), Di Iso Propyl Ether, dioxane; Aromatic hydrocarbons such as benzene,toluene,xylene; Halohydrocarbon such as methylene dichloride, chloroform, ethylene dichloride.These solvents can mix use by various ratios.
In one embodiment, the ratio of the mixture of alkanol and ether can be about 100: 0 to about 20: 80 (volume/volume).
In one embodiment, the ratio of alkanol and ether is 33: 67 (volume/volume).
The reductive agent that can be used for this reaction is a sodium borohydride, itself and the combination of suitable calcium salt.The calcium salt that can be used for this reaction includes, but not limited to calcium chloride and Calcium Bromide.
In one embodiment, spendable calcium salt is a calcium chloride.
Can make an appointment with-20 ℃, add about 1.5 to about 3.0 normal calcium salts at about 5 ℃ to about 15 ℃ subsequently to about 10 ℃ of mixing cpd II, solvent and about 2 to 4 normal sodium borohydrides.
Can carry out this reaction by each gram reactant of about 10mL to 100mL.
Can monitor finishing of this reaction by known technology, include, but not limited to HPLC, TLC and IR.
Embodiment:
Embodiment 1:(3S, 5S)-7-[3-amino-5-methyl-piperidyl]-1-cyclopropyl-1,4-dihydro-8-first
Synthesizing of oxygen base-4-oxo-3-quinoline carboxylic acid and malate thereof
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 ester, (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; HRM8 (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 ester (4).With one 10 gallons of Pfaudler reactors of nitrogen inerting, and the ESCAT 142 5% palladium carbon dusts 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 (45 pounds/square inch) 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.Mp?89.9℃。
(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.Reaction mixture is warming up to 10 ℃ ± 5 ℃, and in one hour time, adds 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
2OH), 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-amyl group 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)-t-butyl carbamate (8).The solid palladium carbon (E101,10 weight %) that under nitrogen gas stream, 0.6kg50% 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/z215 (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.Reacting by heating 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 homogeneous phase 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%).
1HNMR(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)。
19FNMR(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,
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 the 0kPa to 53kPa (400 holder).The reactor of then 3.0N NaOH (aq) solution of 28.2kg being packed into, and 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, it is between 6 and 8 that the Glacial acetic acid by adding～4kg to 5kg is neutralized to pH with reaction mixture.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,
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 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 (12)
1. method that is used to prepare the quinolone intermediate, described intermediate has following formula
Formula I;
Wherein,
N is 1 or 2;
X is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl; With
Z is selected from CO
2X and COX, wherein X is as defined above;
Said method comprising the steps of: at-20 ℃ to 10 ℃, the C of volume ratio 100/0 to 20/80
1-C
4Alkanol and C
2-C
6Make the compound and 2 to the 4 normal sodium borohydride reactions of formula II in the mixture of ether, add the calcium salt that 1.5 to 3.0 equivalents are selected from calcium chloride and Calcium Bromide at 5 ℃ to 15 ℃ subsequently,
Formula II
Wherein Y is selected from C
1-C
4Alkyl, C
6-C
10Aryl or alkylaryl and C
3-C
6Cycloalkyl; Define with X, n and Z such as formula I.
2. the method for claim 1, wherein X is C
1-C
4Alkyl.
3. method as claimed in claim 2, wherein X is a methyl.
4. the method for claim 1, wherein Z is a tertbutyloxycarbonyl.
5. method as claimed in claim 2, wherein Y is a methyl.
6. the method for claim 1, wherein said calcium salt is a calcium chloride.
7. the method for claim 1, wherein the compound of formula II be (2S, 4S)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters.
8. the method for claim 1, wherein the compound of formula II be (2S, 4R)-1-(1, the 1-dimethyl ethyl)-4-methyl-5-oxo-1,2-tetramethyleneimine dicarboxylic acid-2-methyl esters.
9. the method for claim 1, wherein the compound of formula I be (1S, 3S)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
10. the method for claim 1, wherein the compound of formula I be (1S, 3R)-(4-hydroxyl-1-methylol-3-methyl-butyl)-t-butyl carbamate:
11. the method for claim 1, wherein said alkanol are ethanol, described ether is methyl tertiary butyl ether.
12. method as claimed in claim 11, wherein ethanol is 33: 67 to the solvent volume ratio of methyl tertiary butyl ether.
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