CN107629000A - The preparation method of 5 chloracetyl of QAB-149 intermediate 8 benzyloxy 2 (1H) quinolinone - Google Patents
The preparation method of 5 chloracetyl of QAB-149 intermediate 8 benzyloxy 2 (1H) quinolinone Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of benzyloxy 2 (1H) quinolinone of 5 chloracetyl of QAB-149 intermediate 8; with o-aminoanisole, cinnamoyl chloride, alchlor; trifluoromethanesulfonic acid; chloracetyl chloride, bromobenzyl is raw material, by amidation process; ring closure reaction; Friedel-Crafts reaction, hydroxylating four-step reaction, the preparation method is that it is a kind of in high yield, low cost, the three wastes are few, easy to operate, safe, suitable industrialized preparation method.
Description
Technical field
The present invention relates to a kind of preparation method of QAB-149 intermediate, and in particular to a kind of QAB-149 intermediate 5- chlorine
The preparation method of (the 1H)-quinolinone of acetyl group -8- benzyloxies -2.
Background technology
QAB-149（Indacaterol）, trade name maleic acid QAB-149 inhalation powder spray, is a kind of chemicals, is changed
Scientific name claims（R）-5-[2-（5,6- diethyl indane -2- base amino）- 1- ethoxys] -8- hydroxyls -1H- quinoline-2-one, molecule
Formula is C24H28N2O3, and molecular weight 392.49100, QAB-149 is antiasthmatic（Bronchodilator）, it is clinically main suitable
For Adult chronic's obstructive disease of lung（COPD）There are 5 minutes to work, continue 24 hours for the maintaining treatment of patient, QAB-149
The characteristics of.This product is produced by Novartis of Switzerland, in the individual countries and regions listing in the whole world more than 70 since 2009；2012
June in year is ratified to list in China through national Bureau of Drugs Supervision, trade name Ang Run（Onbrez®）, it is domestic first granted for treating
COPD LABA class unitary agents, head to head clinical data show, with salmeterol（LABA class early stage medicines）Compare, indenes
Da Teluo can significantly improve in, the Major Clinical evaluation index of patients of severe COPD, while its security and tolerance are good；With
C19H22BrNO4S2（LAMA class medicines）Compare, QAB-149 therapeutic equivalence in terms of Pulmonary Function improvement, had difficulty in breathing alleviating
Tiotropium Bromide is significantly better than with terms of quality of making the life better.
The preparation of maleic acid QAB-149 needs (the 1H)-quinolinone of key intermediate 5- chloracetyl -8- benzyloxies -2, mesh
The method of preceding report is as follows：
Patent No. US2003/0153597A1, US2004/0242622A1 and US2003/0229058A1 is with 8- hydroxyls in the prior art
Base Quinoline N-Oxide is raw material, and aceticanhydride reaction, is then reset in alchlor, phenolic hydroxyl group benzyl protection obtains 5- acetyl
Base -8- benzyloxies -2（1H)-quinolinone；
US2012/0046467A1 is that oxidant prepares 8-hydroxyquinoline nitrogen oxides with mCPBA using 8-hydroxyquinoline as raw material,
React, then reset in alchlor, phenolic hydroxyl group benzyl protection obtains 5- acetyl group -8- benzyloxies -2 with aceticanhydride（1H)-quinoline
Quinoline ketone；
WO2004/087668 and WO2005/123684 is using 8-hydroxyquinoline ketone as raw material, and aceticanhydride reacts and in alchlor
Reset, phenolic hydroxyl group protection, then carry out chlorination by the use of trimethyl benzyl dichloro ammonium iodate as chlorinating agent, obtain 5- chloracetyls
(the 1H)-quinolinone of base -8- benzyloxies -2；
How much but there is reaction complexity, yield in the method for (the 1H)-quinolinone of 5- chloracetyls -8- benzyloxies -2 made above
Low, the three wastes are more, the defects of security difference, research and develop a kind of 5- acetyl group -8- benzyloxies -2 that can overcome disadvantages described above（1H)-quinoline
Ketone preparation method, turn into those skilled in the art's technical problem urgently to be resolved hurrily.
The content of the invention
The technical problems to be solved by the invention are the shortcomings that overcoming prior art, there is provided a kind of QAB-149 intermediate
The preparation method of (the 1H)-quinolinone of 5- chloracetyl -8- benzyloxies -2, with o-aminoanisole, cinnamoyl chloride, alchlor,
Trifluoromethanesulfonic acid, chloracetyl chloride, bromobenzyl are raw material, by amidation process, ring closure reaction, Friedel-Crafts reaction, hydroxylating four
Step reaction, the preparation method is that it is a kind of in high yield, low cost, the three wastes are few, easy to operate, safe, suitable industrialized system
Preparation Method.
In order to solve the above technical problems, a kind of QAB-149 intermediate 5- chloracetyl -8- benzyloxies of present invention offer -
The preparation method of 2 (1H)-quinolinones, specifically includes following steps：
（1）Cinnamoyl chloride is added in reaction bulb, adds stirring solvent 5min, adds DMAP, be then added dropwise again solvent and
O-aminoanisole is stirred at 0-30 DEG C, and reaction is controlled in progress, after reaction terminates, is washed with 5% HCl, liquid separation, organic phase
Washed three times with 5% NaOH solution, then liquid separation, dry organic phase, thickening filtration obtains intermediate 1；
（2）Step is added in reaction bulb（1）In obtained intermediate 1, solvent is added into reaction bulb, adds AlCl3, stir
30min is mixed, is warming up to 110-150 DEG C, reaction is controlled in progress, after completion of the reaction, successively through being concentrated under reduced pressure, cools, filters, in obtaining
Mesosome 2；
Intermediate 1 is counted by volume：Solvent=1：5-10；
（3）Step is added in there-necked flask（2）In obtained intermediate 2, catalysts and solvents are added into there-necked flask, are heated to
50-60 DEG C, chloracetyl chloride is slowly added into there-necked flask, it is 40-100 DEG C to control temperature, and chloracetyl chloride is uniformly added portionwise, and stirs
Middle control reaction is mixed, after reaction terminates, water dilution is added, filtering, obtains intermediate 3；
（4）Alkali is added in solvent, adds step（3）Obtained intermediate 3, then be added dropwise halogenation benzyl, middle control analysis, instead
Should after, concentrate acetonitrile, reaction solution is added to the water, it is filtered, drying, you can obtain 5- chloracetyl -8- benzyloxies -
2 (1H)-quinolinones.
The technical scheme that further limits of the present invention is：
Further, in the preparation method of foregoing (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2,
Specifically include following steps：
（1）Cinnamoyl chloride is added in reaction bulb, adds CH2Cl25min is stirred, DMAP is added, CH is then added dropwise again2Cl2
Stirred with o-aminoanisole at 0-30 DEG C, reaction is controlled in progress, after reaction terminates, is washed with 5% HCl, liquid separation is organic
Mutually washed three times with 5% NaOH solution, then liquid separation, dry organic phase, thickening filtration obtains intermediate 1；
（2）Step is added in reaction bulb（1）In obtained intermediate 1, chlorobenzene is added into reaction bulb, adds AlCl3, stir
30min is mixed, is warming up to 120 DEG C, reaction is controlled in progress, after completion of the reaction, successively through being concentrated under reduced pressure, cools, filtering, obtains intermediate
2；
Intermediate 1 is counted by volume：Solvent=1：5-10；
（3）Step is added in there-necked flask（2）In obtained intermediate 2, TfOH is added into there-necked flask, is heated to 50-60 DEG C,
Chloracetyl chloride is slowly added into there-necked flask, it is 40-100 DEG C to control temperature, and chloracetyl chloride is uniformly added portionwise, and is controlled in stirring anti-
Should, after reaction terminates, water dilution is added, filtering, obtains intermediate 3；
（4）Potassium carbonate is added in acetonitrile, adds step（3）Obtained intermediate 3, cylite, middle control point is then added dropwise
Analysis, after completion of the reaction, acetonitrile is concentrated, reaction solution is added to the water, filtered, drying, you can obtain 5- chloracetyl -8- benzyls
Epoxide -2 (1H)-quinolinone.
In the preparation method of foregoing (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, step
（1）Middle solvent is one kind in dichloroethanes, chloroform or carbon tetrachloride.
In the preparation method of foregoing (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, step
（2）Middle solvent is bromobenzene or dichloro-benzenes.
In the preparation method of foregoing (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, step
（3）Middle catalyst is AlCl3、ZnCl2、H3PO4、H2SO4Or FeCl3In one kind；Step（3）Middle solvent is dichloromethane, three
One kind in chloromethanes, dichloroethanes, chlorobenzene, dichloro-benzenes or bromobenzene.
In the preparation method of foregoing (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, step
（4）Alkali is N, one kind in N- diisopropylethylamine, sodium carbonate, sodium acid carbonate, triethylamine, pyridine, N-methylmorpholine or NMP；
Step（4）Middle solvent is one kind in methanol, ethanol, DMF, DMSO, dioxane or THF；Halogenation benzyl is benzyl chloride.
The beneficial effects of the invention are as follows：
（1）The route of the present invention is novel, and the similar synthetic route does not have been reported that.
（2）Reactions steps are few, former route reaction step 5 step, and the route reaction step is reacted for 4 steps.
（3）Raw material is easy to get, and is easy to industrialize, and former route chlorination reagent uses trimethyl benzyl dichloro ammonium iodate, the reagent
It is expensive, and be not easy to obtain, variation route cost of material is cheap, ample supply of commodities on the market, reduces cost, and the process of guarantee is entered in order
OK.
（4）High income, former route total recovery 35%, variation route total recovery 60%, yield improves 25%.
（5）The three wastes are few, and variation route total recovery is higher, and relatively former route quantity of three wastes is greatly decreased.
（6）Safety, former route use mCPBA or CH3COOOH is aoxidized, and reaction is not easy to operate, very big potential safety hazard be present,
Variation route reaction is gentle, safe operation, and post processing is simple.
The preparation method of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, with O-methoxy
Aniline, cinnamoyl chloride, alchlor, trifluoromethanesulfonic acid, chloracetyl chloride, bromobenzyl are raw material, anti-by amidation process, cyclization
Should, Friedel-Crafts reaction, hydroxylating four-step reaction, be it is a kind of in high yield, low cost, few, easy to operate, safe, the suitable work of the three wastes
The preparation method of industry.
Brief description of the drawings
Fig. 1 is the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- of embodiment of the present invention benzyloxies -2
Method reacting flow chart.
Embodiment
DMAP Chinese names DMAP in the present embodiment, TfOH Chinese name trifluoromethayl sulfonic acid.
Embodiment 1
A kind of preparation side for (1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 that the present embodiment provides
Method, as shown in figure 1, specifically including following steps：
（1）Cinnamoyl chloride is added in reaction bulb, adds stirring solvent 5min, adds DMAP, be then added dropwise again solvent and
O-aminoanisole is stirred at 0-30 DEG C, and reaction is controlled in progress, after reaction terminates, is washed with 5% HCl, liquid separation, organic phase
Washed three times with 5% NaOH solution, then liquid separation, dry organic phase, thickening filtration obtains intermediate 1；
（2）Step is added in reaction bulb（1）In obtained intermediate 1, solvent is added into reaction bulb, adds AlCl3, stir
30min is mixed, is warming up to 110-150 DEG C, reaction is controlled in progress, after completion of the reaction, successively through being concentrated under reduced pressure, cools, filters, in obtaining
Mesosome 2；
Intermediate 1 is counted by volume：Solvent=1：5-10；
（3）Step is added in there-necked flask（2）In obtained intermediate 2, catalysts and solvents are added into there-necked flask, are heated to
50-60 DEG C, chloracetyl chloride is slowly added into there-necked flask, it is 40-100 DEG C to control temperature, and chloracetyl chloride is uniformly added portionwise, and stirs
Middle control reaction is mixed, after reaction terminates, water dilution is added, filtering, obtains intermediate 3；
（4）Alkali is added in solvent, adds step（3）Obtained intermediate 3, then be added dropwise halogenation benzyl, middle control analysis, instead
Should after, concentrate acetonitrile, reaction solution is added to the water, it is filtered, drying, you can obtain 5- chloracetyl -8- benzyloxies -
2 (1H)-quinolinones.
In the present embodiment, step（1）Middle solvent is CH2Cl2, dichloroethanes, one in chloroform or carbon tetrachloride
Kind；Step（2）Middle solvent is one kind in chlorobenzene, bromobenzene or dichloro-benzenes；Step（3）Middle catalyst is TfOH, AlCl3、ZnCl2、
H3PO4、H2SO4Or FeCl3In one kind；Step（3）Middle solvent be TfOH, dichloromethane, chloroform, dichloroethanes, chlorobenzene,
One kind in dichloro-benzenes or bromobenzene, TfOH both make catalyst, also make solvent；Step（4）Alkali is potassium carbonate, N, N- diisopropyl second
One kind in amine, sodium carbonate, sodium acid carbonate, triethylamine, pyridine, N-methylmorpholine or NMP；Step（4）Middle solvent is acetonitrile, first
One kind in alcohol, ethanol, DMF, DMSO, dioxane or THF；Halogenation benzyl is cylite or benzyl chloride.
Embodiment 2
A kind of preparation side for (1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 that the present embodiment provides
Method, as shown in figure 1, specifically including following steps：
（1）10g cinnamoyl chlorides are added in 250ml reaction bulbs, add 100mlCH2Cl25min is stirred, is added
DMAP0.73g, 20ml CH are then added dropwise2Cl2Reaction is controlled in being stirred with 8.8g o-aminoanisoles RT, after reaction terminates, is used
30ml*3 5% HCl washings, liquid separation, organic phase are washed three times with 30m,l*3 5% NaOH solution again, liquid separation, and drying is organic
Phase, thickening filtration finally obtain 14.6g intermediates 1, yield 91.8%；
（2）10g intermediates 1 are added in 250ml reaction bulbs, chlorobenzene 100ml is added, adds AlCl320.2g stirring
30min, 120 DEG C are warming up to, middle control reaction, after completion of the reaction, is concentrated under reduced pressure, cools, filtering, obtain 5.2g intermediates 2, yield
81%；
（3）5 grams of intermediates 2 are added in 50ml there-necked flasks, add 10ml TfOH, are heated to 50-60 DEG C, start slowly to add
Enter chloracetyl chloride, reaction is controlled in stirring, after reaction terminates, cooling, add the dilution of 100ml water, filtering, obtain 7.36 grams of intermediates 3.
Yield 89%；
（4）4.5 grams of potassium carbonate are added in 20ml acetonitriles, add 5 grams of intermediates 3,3 grams of cylites, middle control analysis is added dropwise.Instead
After answering, acetonitrile is concentrated, reaction solution is added to the water, filtered, drying, obtain 6.3 grams of 5- chloracetyl -8- benzyloxies -2
(1H)-quinolinone, yield 91%.
Embodiment 3
A kind of preparation side for (1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 that the present embodiment provides
Method, specifically include following steps：
（1）10g cinnamoyl chlorides are added in 250ml reaction bulbs, add 100mlCH2Cl25min is stirred, is added
DMAP0.73g, 20ml CH are then added dropwise2Cl2Reaction is controlled in being stirred with 9g o-aminoanisoles RT, after reaction terminates, is used
30ml*3 5% HCl washings, liquid separation, organic phase are washed three times with 30m,l*3 5% NaOH solution again, liquid separation, and drying is organic
Phase, thickening filtration finally obtain 15g intermediates 1, yield 94.3%；
（2）10g intermediates 1 are added in 250ml reaction bulbs, chlorobenzene 100ml is added, adds AlCl3 20.2g stirring
30min, 110 DEG C are warming up to, middle control reaction, after completion of the reaction, is concentrated under reduced pressure, cools, filtering, obtain 5.5g intermediates 2, yield
85%；
（3）5 grams of intermediates 2 are added in 50ml there-necked flasks, 10ml TfOH is added, is heated to 40 DEG C, start to be slowly added to chlorine
Chloroacetic chloride, reaction is controlled in stirring, after reaction terminates, cooling, add the dilution of 100ml water, filtering, obtain 7.52 grams of yields of intermediate 3.
91%；
（4）4.5 grams of potassium carbonate are added in 20ml acetonitriles, add 5 grams of intermediates 3,3 grams of cylites, middle control analysis is added dropwise.Instead
After answering, acetonitrile is concentrated, reaction solution is added to the water, filtered, drying, obtain 6.3 grams of 5- chloracetyl -8- benzyloxies -2
(1H)-quinolinone, yield 91%.
In addition to the implementation, the present invention can also have other embodiment.It is all to use equivalent substitution or equivalent transformation shape
Into technical scheme, all fall within the protection domains of application claims.
Claims (6)
1. a kind of preparation method of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2, its feature exist
In specifically including following steps：
（1）Cinnamoyl chloride is added in reaction bulb, adds stirring solvent 5min, adds DMAP, be then added dropwise again solvent and
O-aminoanisole is stirred at 0-30 DEG C, and reaction is controlled in progress, after reaction terminates, is washed with 5% HCl, liquid separation, organic phase
Washed three times with 5% NaOH solution, then liquid separation, dry organic phase, thickening filtration obtains intermediate 1；
（2）Step is added in reaction bulb（1）In obtained intermediate 1, solvent is added into reaction bulb, adds AlCl3, stir
30min is mixed, is warming up to 110-150 DEG C, reaction is controlled in progress, after completion of the reaction, successively through being concentrated under reduced pressure, cools, filters, in obtaining
Mesosome 2；
Intermediate 1 is counted by volume：Solvent=1：5-10；
（3）Step is added in there-necked flask（2）In obtained intermediate 2, catalysts and solvents are added into there-necked flask, are heated to
50-60 DEG C, chloracetyl chloride is slowly added into there-necked flask, it is 40-100 DEG C to control temperature, and chloracetyl chloride is uniformly added portionwise, and stirs
Middle control reaction is mixed, after reaction terminates, water dilution is added, filtering, obtains intermediate 3；
（4）Alkali is added in solvent, adds step（3）Obtained intermediate 3, then be added dropwise halogenation benzyl, middle control analysis, instead
Should after, concentrate acetonitrile, reaction solution is added to the water, it is filtered, drying, you can obtain 5- chloracetyl -8- benzyloxies -
2 (1H)-quinolinones.
2. the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 according to claim 1
Method, it is characterised in that：Specifically include following steps：
（1）Cinnamoyl chloride is added in reaction bulb, adds CH2Cl25min is stirred, DMAP is added, CH is then added dropwise again2Cl2
Stirred with o-aminoanisole at 0-30 DEG C, reaction is controlled in progress, after reaction terminates, is washed with 5% HCl, liquid separation is organic
Mutually washed three times with 5% NaOH solution, then liquid separation, dry organic phase, thickening filtration obtains intermediate 1；
（2）Step is added in reaction bulb（1）In obtained intermediate 1, chlorobenzene is added into reaction bulb, adds AlCl3, stir
30min is mixed, is warming up to 120 DEG C, reaction is controlled in progress, after completion of the reaction, successively through being concentrated under reduced pressure, cools, filtering, obtains intermediate
2；
Intermediate 1 is counted by volume：Solvent=1：5-10；
（3）Step is added in there-necked flask（2）In obtained intermediate 2, TfOH is added into there-necked flask, is heated to 50-60 DEG C,
Chloracetyl chloride is slowly added into there-necked flask, it is 40-100 DEG C to control temperature, and chloracetyl chloride is uniformly added portionwise, and is controlled in stirring anti-
Should, after reaction terminates, water dilution is added, filtering, obtains intermediate 3；
（4）Potassium carbonate is added in acetonitrile, adds step（3）Obtained intermediate 3, cylite, middle control point is then added dropwise
Analysis, after completion of the reaction, acetonitrile is concentrated, reaction solution is added to the water, filtered, drying, you can obtain 5- chloracetyl -8- benzyls
Epoxide -2 (1H)-quinolinone.
3. the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 according to claim 1
Method, it is characterised in that：Step（1）Described in solvent be dichloroethanes, chloroform or carbon tetrachloride in one kind.
4. the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 according to claim 1
Method, it is characterised in that：Step（2）Described in solvent be bromobenzene or dichloro-benzenes.
5. the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 according to claim 1
Method, it is characterised in that：Step（3）The middle catalyst is AlCl3、ZnCl2、H3PO4、H2SO4Or FeCl3In one kind；Step
Suddenly（3）Described in solvent be dichloromethane, chloroform, dichloroethanes, chlorobenzene, dichloro-benzenes or bromobenzene in one kind.
6. the preparation of (the 1H)-quinolinone of QAB-149 intermediate 5- chloracetyl -8- benzyloxies -2 according to claim 1
Method, it is characterised in that：Step（4）Described alkali is N, N- diisopropylethylamine, sodium carbonate, sodium acid carbonate, triethylamine, pyrrole
One kind in pyridine, N-methylmorpholine or NMP；Step（4）Described in solvent be methanol, ethanol, DMF, DMSO, dioxane or
One kind in THF；The halogenation benzyl is benzyl chloride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988111A (en) * | 2019-05-06 | 2019-07-09 | 淮北师范大学 | A kind of impurity and its synthetic method of maleic acid datro |
| CN113121430A (en) * | 2021-05-08 | 2021-07-16 | 岳阳新华达制药有限公司 | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone |
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| WO1995025104A1 (en) * | 1994-03-15 | 1995-09-21 | Smithkline Beecham P.L.C. | Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity |
| WO2008120003A1 (en) * | 2007-04-03 | 2008-10-09 | Astrazeneca Ab | Substituted piperidines for use in the treatment of bacterial infections |
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| WO1995025104A1 (en) * | 1994-03-15 | 1995-09-21 | Smithkline Beecham P.L.C. | Novel heterocyclic ethanolamine derivatives with beta-adrenoreceptor agonistic activity |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988111A (en) * | 2019-05-06 | 2019-07-09 | 淮北师范大学 | A kind of impurity and its synthetic method of maleic acid datro |
| CN113121430A (en) * | 2021-05-08 | 2021-07-16 | 岳阳新华达制药有限公司 | Preparation method of 5- (alpha-halogenated butyryl) -8-hydroxyquinoline-2-ketone |
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