CN105085395B - Shellfish reaches the preparation method of quinoline - Google Patents

Shellfish reaches the preparation method of quinoline Download PDF

Info

Publication number
CN105085395B
CN105085395B CN201410190912.XA CN201410190912A CN105085395B CN 105085395 B CN105085395 B CN 105085395B CN 201410190912 A CN201410190912 A CN 201410190912A CN 105085395 B CN105085395 B CN 105085395B
Authority
CN
China
Prior art keywords
compound
quinoline
reaction
shellfish
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410190912.XA
Other languages
Chinese (zh)
Other versions
CN105085395A (en
Inventor
李建其
刘育
邴绍昌
吴夏冰
周爱南
黄雷
金仁力
王健
蒋敏
王磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Pharmaceutical Industry
China National Medicines Guorui Pharmaceutical Co Ltd
Original Assignee
Shanghai Institute of Pharmaceutical Industry
China National Medicines Guorui Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Pharmaceutical Industry, China National Medicines Guorui Pharmaceutical Co Ltd filed Critical Shanghai Institute of Pharmaceutical Industry
Priority to CN201410190912.XA priority Critical patent/CN105085395B/en
Publication of CN105085395A publication Critical patent/CN105085395A/en
Application granted granted Critical
Publication of CN105085395B publication Critical patent/CN105085395B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Abstract

The invention discloses the preparation method that a kind of shellfish reaches quinoline, comprise the following steps：By compound (9) in a solvent, reacted with reducing agent, the raceme that shellfish reaches quinoline is then collected from reaction product；The invention has the advantages that：Compound (9) is the noval chemical compound for having no document report, the present invention prepares shellfish up to quinoline raceme again with compound (8) through compound (9), products therefrom yield increases substantially and (is more than 47%), is noticeably greater than former patent yield (26%)；Gained shellfish is high up to the purity of quinoline raceme, stable and controllable for quality, is conducive to follow-up resolution reaction, with larger positive effect and actual application value.Reaction equation is as follows.

Description

Shellfish reaches the preparation method of quinoline
Technical field
Quinoline ((1R, 2S) -1- (bromo- 2- methoxyl groups of 6- are reached the present invention relates to a kind of medicine shellfish for treating multi-drug resistance tuberculosis Quinoline -3-) -4- dimethylamino -1- phenyl -2- (1- naphthyls) -2- butanol) raceme preparation method.
Background technology
Tuberculosis is a class chronic infectious disease as caused by mycobacterium tuberculosis, can involve whole body multiple organ system. The World Health Organization counts, and the whole world about 1/3 population infection mycobacterium tuberculosis and there are about 3800 people and die from daily every year Tuberculosis [Curr Opin Immunol, 2011,23 (4):464-472.].Tuberculosis seriously threatens the mankind as 21 century One of principal disease of health.
The main cause for causing tuberculosis to spread in the world is that mycobacterium tuberculosis has powerful survival ability. In fact, mycobacterium tuberculosis is as a kind of most threatening pathogen, having evolved a series of mechanism can at each Can approach on come resist host immune response (Current Topics in Medicinal Chemistry, 2013,13(22),2808-2849).Another major reason for causing tuberculosis to spread rapidly is then the appearance of drug resistance.By The lack of standardization of existing antituberculotic is used in people, in addition the increase of floating population, multi-drug resistant tuberculosis is in the world Spread rapidly.Multi-drug resistance tuberculosis has turned into what great public health problem was effectively controlled with global tuberculosis in many countries Obstacle.
In in June, 1992, the article for the relevant resistant tuberculosis that disease prevention and control center of the U.S. (CDC) is delivered, formally Propose the concept of " multi-drug resistance tuberculosis " (MDR-TB).I.e. multi-drug resistant (multidrug resistance) refers to tubercle bacillus extremely Less to a kind of line antituberculotic resistance [American Journal of Health- including isoniazid, rifampin System Pharmacy,2013,70(22),1984-1994.]。
On December 28th, 2012, FDA (FDA) is public by accelerating examination and approval procedures to have approved Johnson ＆ Johnson Sirturo (bedaquiline, shellfish reaches quinoline) under department, when can use without other alternative medicines, is used as multi-drug resistant knot of being grown up The part of core (MDR-TB) therapeutic alliance.Shellfish turns into the first anti-multi-drug resistant tubercular drugs passed through by FDA certifications up to quinoline.
Shellfish is up to treatment multi-drug resistance tuberculosis medicine of the quinoline as the first approval listings of FDA, due to its mechanism of action and now There is the difference of antituberculotic, once occurring being sent to great expectations.Shellfish is that it has aimed at tuberculosis up to the brand-new mechanism of action of quinoline A kind of enzyme-ATP synzyme [Science, 2005,307 (5707), 223-227.] of pathogen-mycobacterium tuberculosis of disease.This Outside, also document report shellfish reaches the effect of quinoline in the cell to mycobacterium tuberculosis, display shellfish up to quinoline be by suppressing The proton translocation chain of the ATP synzyme of mycobacteria kills mycobacterium tuberculosis, and this is a kind of brand-new to tackle tuberculosis branch The action pathway of bacillus.It means that cross resistance is not present with other antituberculotics up to quinoline in shellfish, this will be substantially reduced The resistance to the action of a drug of tubercle bacillus.The result of study of the document also shows that shellfish shows that good confrontation is more up to quinoline in macrophage The activity of medicine resistant tuberculosis bacterium, points out it to have effect [the Antimicrobial Agents and for shortening treatment time Chemotherapy,2006,50(6),1921-1926.)。
Shellfish reports less, the predominantly compound patent US2005148581 and work of Yuan Yan companies up to the synthetic route of quinoline Skill patent CN101180302, is mainly concerned with two important intermediates:The bromo- 3- benzyls -2 methoxy quinoline (compounds of 6- 5) with 3- (dimethylamino) -1- (1- naphthyls) -1- acetone (compound 6).The compound 6 of compound 5 obtains Bei Da through condensation reaction The raceme (compound 10) of quinoline, then shellfish is obtained up to quinoline through splitting.
Its main synthesis step is as follows：
The subject matter of the route is that the yield that compound 5 and compound 6 are reacted under conditions of LDA is very low (26%). Cause yield is low to have two reasons, one is the α positions hydrogen of carbonyl is removed at reaction conditions in compound 6, the carbon of generation bear from Son occurs intermolecular a variety of side reactions, causes reaction product very miscellaneous to carbonyl attack；The second is due to the enol of compound 6 Change (as follows), cause raw material to convert completely.In addition, thus the shellfish of gained is not high up to the purity of quinoline raceme, sternly Ghost image rings the efficiency of its fractionation.
For the defect of the synthetic route of improving document report, the generation of accessory substance in reaction is reduced, raw material conversion is improved Rate and shellfish reach the purity of quinoline raceme, it is necessary to develop a new synthetic route.
The content of the invention
It is an object of the invention to provide the preparation method that a kind of shellfish reaches quinoline, to overcome the defect that prior art is present.
The method of the present invention, comprises the following steps：
By compound (9) in a solvent, reacted with reducing agent, reaction temperature is 10~100 DEG C, the reaction time is 2~24 Hour, reaction temperature preferably is 20~60 DEG C, and the reaction time is 2~6 hours, and shellfish is then collected from reaction product reaches quinoline Raceme；
Described solvent is selected from THF, ethanol, methanol, 1,4- dioxane or isopropanol；
Described reducing agent is selected from sodium borohydride, palladium carbon, iron powder/hydrochloric acid, iron powder/acetic acid, stannous chloride, platinum oxide or zinc Powder/ammonium chloride；
Iron powder/hydrochloric acid refers to the mixture of iron powder and hydrochloric acid, wherein, the equivalent of iron powder is the 3-10eq of compound 9, excellent 3-6eq is selected, hydrochloric acid adjusts system pH to 3-5；
Zinc powder/ammonium chloride be zinc powder and ammonium chloride mixture, wherein, the equivalent of zinc powder is the 3-10eq of compound 9, It is preferred that 3-6eq, the equivalent of ammonium chloride is the 6-10eq, preferably 6-8eq of compound 9；
Reaction equation is as follows：
Described compound (9), compound or its optical isomer with formula (9) structural formula：
The preparation method of the compound (9), comprises the following steps：
(1) compound (7) and DMF dimethylacetal (DMF-DMA) are reacted, 90-120 DEG C, reaction 24-48 hours, oily compounds 8 are obtained after being evaporated；
Or, compound (7) is reacted in the solvent containing DMF-DMA, 90-120 DEG C, react 24-48 hours, be evaporated After obtain oily compounds 8；
Described solvent is selected from dimethylbenzene or toluene, and solvent load is 2-10 times of the weight of compound 7；
DMF-DMA and the equivalent of compound 7 are 1.2-2eq；
Reaction equation is as follows：
(2) compound (8) and compound (5) are reacted in tetrahydrofuran, is then collected from reaction product and obtain one To isomers (9)；
The equivalent preferably 1 of compound (5) and compound (8):1.05-1:1.2, compound 5 and LDA equivalent are 1.3- 1.5eq, 2 times -5 times of tetrahydrofuran consumption preferred compound (5)；Preferably -78 ° of temperature~and to -20 DEG C, the reaction time is 1-12 Hour；Reaction equation is as follows：
The present invention is raw materials used and reagent is commercially available；
It is of the invention compared with the method for disclosed report, advantage is：
With compound (8) for synthon, it is to avoid α position hydrogen and enolization in intermediate react, and reduce side reaction Occur, improve the conversion ratio of your raw material 5 and the total recovery of reaction, cost is greatly lowered.The purity of products therefrom 9 is high, It is adapted to large-scale industrial production.
With compound (8) for synthon, intermediate 6, easily preparation than former patent route, raw materials used to be easy to get, system Standby cost is low.
Compound 9 is the noval chemical compound for having no document report, and the present invention prepares shellfish again with compound (8) through compound (9) Up to the method for quinoline raceme, document report is also had no, with novelty；Products therefrom yield, which is increased substantially, (to be more than 47%), it is noticeably greater than former patent yield (26%)；Gained shellfish is high up to the purity of quinoline raceme, stable and controllable for quality, is conducive to Follow-up resolution reaction.
To sum up, method disclosed by the invention and application, overcome defect and deficiency that document has reported preparation method, have Novelty, larger positive effect and actual application value.
Embodiment
The present invention is further illustrated by way of following embodiments, but does not therefore limit the present invention to described reality Apply among a scope.The experimental method of unreceipted actual conditions in the embodiment, conventionally and condition, or according to business Product specification is selected.
Embodiment 1
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
1- acetonaphthones (170.0g, 1.0mol) are added in DMF-DMA (178.0g, 1.5mol) at room temperature, and heating rises Temperature is to 120 DEG C, after 24h, is cooled to room temperature, adds toluene 200ml dilutions, then by solvent at 55 DEG C evaporated under reduced pressure, residual Thing adds toluene 200ml dilutions, in evaporated under reduced pressure at 55 DEG C, obtains yellow oil 230.1g, crude yield 102%, HPLC Purity 98.5%, can be directly used for the next step.
1H-NMR(CDCl3)δ：2.93-3.14(m,6H)；5.73 (d, 1H, J=12.4Hz)；7.38-7.49(m,2H)； (7.82 d, 1H, J=12.4Hz)；7.78 (m, 1H), 8.14-3.18 (m, 2H), 8.29 (d, 2H, J=8.4Hz), 9.45 (d, 2H, J=8.8Hz) .ESI-MS (m/z)=226.2 [M+H]+
Embodiment 2
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
1- acetonaphthones (150.0g, 0.88mol) are added in DMF-DMA (57.5g, 1.5mol) at room temperature, and heating rises Temperature is to 90 DEG C, after 24h, is cooled to room temperature, adds toluene 200ml dilutions, then by solvent at 55 DEG C evaporated under reduced pressure, residue Toluene 200ml dilution is added, in evaporated under reduced pressure at 55 DEG C, yellow oil 202.5g is obtained, crude yield 102%, HPLC is pure Degree 98.8%.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 3
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
1- acetonaphthones (250.0g, 1.47mol) are added in DMF-DMA (262.5g, 2.20mol) at room temperature, heating Be warming up to 90 DEG C, after 48h, be cooled to room temperature, add toluene 200ml dilutions, then by solvent at 55 DEG C evaporated under reduced pressure, residual Thing adds toluene 200ml dilutions, in evaporated under reduced pressure at 55 DEG C, obtains yellow oil 334.2g, crude yield 101%, HPLC Purity 98.2%.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 4
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
1- acetonaphthones (340.0g, 2.0mol) are added in DMF-DMA (286.0g, 2.4mol) at room temperature, and heating rises Temperature is to 90 DEG C, after 24h, is cooled to room temperature, adds toluene 200ml dilutions, then by solvent at 55 DEG C evaporated under reduced pressure, residue Toluene 200ml dilution is added, in evaporated under reduced pressure at 55 DEG C, yellow oil 459.2g is obtained, crude yield 102%, HPLC is pure Degree 98.5%.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 5
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
1- acetonaphthones (400.0g, 2.35mol) are added in DMF-DMA (560.0g, 4.70mol) at room temperature, heating Be warming up to 90 DEG C, after 24h, be cooled to room temperature, add toluene 200ml dilutions, then by solvent at 55 DEG C evaporated under reduced pressure, residual Thing adds toluene 200ml dilutions, in evaporated under reduced pressure at 55 DEG C, obtains yellow oil 545.3g, crude yield 103%, HPLC Purity 98.4%.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 5
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
The toluene that 1- acetonaphthones (280.0g, 1.65mol) are added to DMF-DMA (294.0g, 2.47mol) at room temperature is molten In liquid (5.6L), be heated to 100 DEG C, after 24h, be cooled to room temperature, then by solvent at 55 DEG C evaporated under reduced pressure, residue Toluene 1.0L dilutions are added, in evaporated under reduced pressure at 55 DEG C, yellow oil 235.2g, crude yield 104%, HPLC purity are obtained 98.0%, it can be directly used for the next step.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 6
The preparation of 3- dimethylaminos -2- (1- naphthyls) -propyl- 2- alkene -1- ketone (compound 8)
The dimethylbenzene that 1- acetonaphthones (170.0g, 1.0mol) are added to DMF-DMA (178.0g, 15mol) at room temperature is molten In liquid (56L), be heated to 110 DEG C, after 24h, be cooled to room temperature, then by solvent at 55 DEG C evaporated under reduced pressure, residue Ortho-xylene 1.0ml dilution is added, in evaporated under reduced pressure at 65 DEG C, yellow oil 228.0g is obtained, crude yield 101%, HPLC purity 98.8%.ESI-MS (m/z)=226.2 [M+H]+
Embodiment 7
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 3- alkene - The preparation of 2- alcohol (compound 9)
Tetrahydrofuran 90ml is added in four-hole bottle, -78 DEG C are cooled to, add LDA90ml (2M cyclohexane solution, 1.3eq), then it is slowly added dropwise after compound 5 (45.0g is dissolved in 25ml THF), completion of dropping and continues to stir at -78 DEG C Mix 1h.6h is reacted after compound 8 (29.4g is dissolved in 20ml THF solution, 1.05eq), completion of dropping is added dropwise.By reaction solution - 20 DEG C are risen to, reaction is quenched with 2N glacial acetic acid THF solution 50ml.Reaction is warmed to room temperature after being quenched, and add water 150ml, has separated Machine phase, aqueous phase is extracted with ethyl acetate 2 times (100*2 times), merges organic phase, anhydrous sodium sulfate drying.After filtering, by organic phase It is evaporated, obtains dark oily content.Dark oily content is transferred in 500ml single port bottle, 200ml absolute ethyl alcohols are added, backflow is beaten Slurry, is filtered while hot.Filtrate is cooled to room temperature crystallization, and the solid being filtrated to get is recrystallized with 100ml absolute ethyl alcohols, obtains off-white color and consolidates Body 42.3g, HPLC purity 92.3%, yield 55.8%.1H-NMR(CDCl3)δ：1.25-1.28(m,6H)；4.21(s,3H), 5.73 (d, 1H, J=12.4Hz), 5.89 (s, 3H), 6.88-6.89 (m, 3H), 7.12-7.15 (m, 3H), 7.26-7.30 (m, 1H), 7.49-7.50 (m, 1H), 7.55-7.86 (m, 3H), 7.88-7.90 (m, 2H), 7.96 (s, 1H), 8.59 (d, 2H, J= 8.8Hz), 8.89 (s, 1H) .ESI-MS (m/z)=553.2 [M+H]+
Embodiment 8
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 3- alkene - The preparation of 2- alcohol (compound 9)
Tetrahydrofuran 450ml is added in four-hole bottle, -20 DEG C are cooled to, add LDA180ml (2M cyclohexane solution, 1.3eq), then it is slowly added dropwise after compound 5 (90.0g is dissolved in 55ml THF), completion of dropping and continues to stir at -20 DEG C Mix 1h.1h is reacted after compound 8 (51.5g is dissolved in 50ml THF solution, 1.2eq), completion of dropping is added dropwise.According to implementation The post-processing approach of example 7 obtains off-white powder 86.2g, HPLC purity 93.5%, yield 56.8%.
Embodiment 9
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 3- alkene - The preparation of 2- alcohol (compound 9)
Tetrahydrofuran 300ml is added in four-hole bottle, -20 DEG C are cooled to, add LDA297ml (2M cyclohexane solution, 1.3eq), continue after compound 5 (150.0g is dissolved in 140ml THF), completion of dropping is then slowly added dropwise at -20 DEG C Stir 1h.12h is reacted after compound 8 (123.5g is dissolved in 110ml THF solution, 1.2eq), completion of dropping is added dropwise.According to The post-processing approach of embodiment 7 obtains off-white powder 236.5g, HPLC purity 94.6%, yield 56.8%.
Embodiment 10
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 3- alkene - The preparation of 2- alcohol (compound 9)
Tetrahydrofuran 600ml is added in four-hole bottle, -78 DEG C are cooled to, add LDA594ml (2M cyclohexane solution, 1.3eq), then it is slowly added dropwise after compound 5 (300g is dissolved in 280ml THF), completion of dropping and continues to stir at -20 DEG C Mix 1h.6h is reacted after compound 8 (257.0g is dissolved in 250ml THF solution, 1.2eq), completion of dropping is added dropwise.According to reality The post-processing approach for applying example 7 obtains off-white powder 473.0g, HPLC purity 93.5%, yield 56.3%.
Embodiment 11
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 3- alkene - The preparation of 2- alcohol (compound 9)
Tetrahydrofuran 600ml is added in four-hole bottle, -78 DEG C are cooled to, add LDA594ml (2M cyclohexane solution, 1.5eq), then it is slowly added dropwise after compound 5 (500g is dissolved in 490ml THF), completion of dropping and continues to stir at -20 DEG C Mix 1h.6h is reacted after compound 8 (411.6g is dissolved in 400ml THF solution, 1.2eq), completion of dropping is added dropwise.According to reality The post-processing approach for applying example 7 obtains off-white powder 474.6g, HPLC purity 92.8%, yield 56.0%.
Embodiment 12
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol The preparation of (shellfish reaches the raceme of quinoline)
Compound 9 (300.0g, 0.54mol) is dissolved in 1.5L THF, iodine 69.0g is sequentially added at room temperature, Sodium borohydride 40.0g, is warming up to TLC after 65 DEG C of backflows, 2h and shows that raw material reaction is complete, be cooled to room temperature, methanol 500ml is added dropwise Reaction is quenched.Gained white solid dichloromethane 600ml suspends after solvent is evaporated, and 10% sodium hydroxide 100ml washings have Organic phase is separated after machine phase, layering, aqueous phase is extracted once again with dichloromethane 200ml, merge organic phase, anhydrous sodium sulfate is done It is dry, it is evaporated gained solid absolute ethyl alcohol recrystallization after organic phase and once, obtains white solid 240.0g, purity 95.6%, yield 85%.1H-NMR(CDCl3)δ：1.28-1.30(m,6H),1.85-1.89(m,2H),2.43-2.46(m,2H),4.26(s, 3H), 5.74 (d, 1H, J=12.4Hz), 5.93 (s, 3H), 6.89-90 (m, 3H), 7.13-7.17 (m, 3H), 7.26-7.30 (m,1H),7.49-7.50(m,1H),7.55-7.86(m,3H),7.89-7.91(m,3H),7.96(s,1H),8.59(d,2H,J =8.8Hz), 8.89 (s, 1H) .ESI-MS (m/z)=553.2 [M+H]+
Embodiment 13
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol Prepare
Compound 9 (500.0g, 0.9mol) is dissolved in 1.5L THF, 10%Pd/C30.0g is added at room temperature, it is empty Room temperature catalytic hydrogenation after gas displacement, reacts complete after 12 hours, after palladium carbon is filtered out, and is evaporated organic phase, and gained solid is with anhydrous Ethyl alcohol recrystallization once, obtains white solid 40.0g, purity 96.3%, yield 88%.
Embodiment 14
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol Prepare
Compound 9 (400.0g, 0.72mol) is dissolved in 1.2L ethanol, reduced iron powder 200.0g is added at room temperature, Concentrated hydrochloric acid 100ml, is heated to backflow, reacts complete after 2 hours, after iron powder is filtered out while hot, is evaporated organic phase, and gained solid is used Absolute ethyl alcohol is recrystallized once, obtains white solid 340.2g, purity 98.4%, yield 85%.
Embodiment 15
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol Prepare
Compound 9 (800.0g, 0.14mol) is dissolved in 2.4L ethanol, reduced iron powder 400.0g is added at room temperature, Glacial acetic acid 3.0ml, is heated to backflow, reacts complete after 2 hours, after iron powder is filtered out while hot, is evaporated organic phase, and gained solid is used Absolute ethyl alcohol is recrystallized once, obtains white solid 6.9g, purity 96.5%, yield 86%.
Embodiment 16
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol Prepare
Compound 9 (650.0g, 0.12mol) is dissolved in 2.4L ethanol, stannous chloride 447.0g is added at room temperature, Concentrated hydrochloric acid 100ml, is heated to backflow, reacts complete after 2 hours, after the solid generated in reaction is filtered out, is evaporated organic phase, institute Obtain solid to be recrystallized once with absolute ethyl alcohol, obtain white solid 559.0g, purity 97.3%, yield 86%.
Embodiment 17
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol) Preparation
Compound 9 (500.0g, 0.9mol) is dissolved in 2.5L ethanol, zinc powder 294.0g, chlorination are added at room temperature Ammonium 95.0g, is heated to backflow, reacts complete after 2 hours, after zinc powder is filtered out while hot, is evaporated organic phase, gained solid nothing Water-ethanol is recrystallized once, obtains white solid 559.0g, purity 97.3%, yield 86%.
Embodiment 18
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol) Preparation
Compound 9 (750.0g, 1.125mol) is dissolved in 2.5L methanol, platinum oxide 2.55g, room are added at room temperature Warm catalytic hydrogenation, reacts complete, after platinum oxide is filtered out, is evaporated organic phase, gained solid recrystallizing methanol one after 2 hours It is secondary, obtain white solid 838.5g, purity 98.2%, yield 85.6%.
Embodiment 19
1- (the bromo- 2 methoxy quinoline -3- bases of 6-) -4- (dimethylamino) -2- (naphthalene -1- bases) -1- phenyl butyl- 2- alcohol) Preparation
Compound 9 (300.0g, 1.125mol) is dissolved in 1.6L isopropanol, 10%Pd/ is added at room temperature C3.0g, room temperature catalytic hydrogenation reacts complete, after Pd/C is filtered out, is evaporated organic phase, gained solid isopropanol weight after 6 hours Crystallization once, obtains white solid 265.0g, purity 98.5%, yield 86.1%.
Embodiment 20
(1R, 2S) -1- (the bromo- 2 methoxy quinoline -3- of 6-) -4- dimethylamino -1- phenyl -2- (1- naphthyls) -2- butanol The preparation of (shellfish reaches quinoline)
The first step：Into salt, split.Compound 10 (91.3g, 0.15mol) is suspended in 240ml acetone at room temperature, The DMSO solution 35ml of resolving agent (R)-(-)-dinaphthol phosphate (52.8g, 0.15mol) is added dropwise.After completion of dropping, solution becomes Clarification, reaction solution is stirred at room temperature temperature rising reflux 1h after 1h, is then slowly cooled to room temperature, and is filtered after stirring 2h, gained white Solids washed with acetone 2 times.Solid obtained by suction filtration is beaten 2h with 220ml acetone reflux, after being then slowly cooled to room temperature Suction filtration, gained solid be washed once with acetone 50ml, and white clumpy solid 165.0g is obtained after drying.
Second step：It is free.The white solid that the first step is obtained is suspended in 150ml toluene, then adds 10% carbonic acid Potassium solution 40ml, then heats the mixture to backflow, is cooled to after room temperature and is layered, and separates after organic phase with water 50ml at 80 DEG C Washing 2 times, the toluene layer separated is directly concentrated under reduced pressure into dry without drying at 56 DEG C.White solid 150ml after being evaporated Alcohol reflux is beaten 1h, then slowly cools to 0 DEG C, and stirs 1h at low temperature, filters, and filter cake is washed with 50ml ethanol, so 70 DEG C are dried in vacuo to obtain white solid 35.6g, yield 39%, HPLC purity 99.6%, ee values 99.8% afterwards.1HNMR (300MHz,CDCl3):δ=8.89 (s, 1H), 8.61d, J=8.6Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.92 (d, J =7.4Hz, 1H), 7.87 (d, J=8.1Hz, 1H), 7.72 (d, J=8.8Hz, 1H), 7.68-7.56 (m, 3H, H7, H16), 7.48 (t, J=7.6Hz, 1H), 7.30 (t, J=7.7Hz, 1H), 7.17-7.10 (m, 2H), 6.93-6.83 (m, 3H), 5.89 (s,1H),4.21(s,3H),2.60–2.51(m,1H),2.18–2.02(m,2H),1.99(s,6H),1.95–1.85(m,1H) .HRMS(ESI)calcd.forC32H32BrN2O2[M+H]+55.1642；found555.1671.

Claims (7)

1. shellfish reaches the preparation method of quinoline, it is characterised in that comprise the following steps：
By compound (9) in a solvent, reacted with reducing agent, the raceme that shellfish reaches quinoline is then collected from reaction product；Instead Answer formula as follows：
2. according to the method described in claim 1, it is characterised in that reaction temperature is 10~100 DEG C, the reaction time is 2~24 Hour.
3. according to the method described in claim 1, it is characterised in that reaction temperature is 20~60 DEG C, the reaction time is 2~6 small When.
4. according to the method described in claim 1, it is characterised in that described solvent is selected from THF, ethanol, methanol, Isosorbide-5-Nitrae-dioxy Six rings or isopropanol.
5. according to the method described in claim 1, it is characterised in that described reducing agent be selected from sodium borohydride, palladium carbon, iron powder/ Hydrochloric acid, iron powder/acetic acid, stannous chloride, platinum oxide or zinc powder/ammonium chloride.
6. according to the method described in claim 1, it is characterised in that the preparation method of the compound (9), including as follows walk Suddenly：
(1) compound (7) and DMF dimethylacetal (DMF-DMA) are reacted, then from reaction product Collect compound (8)；
Or, compound (7) is reacted in the solvent containing DMF-DMA and then compound (8) is collected from reaction product, instead Answer formula as follows：
(2) compound (8) and compound (5) are reacted in tetrahydrofuran, is then collected from reaction product and obtain compound (9), it is a pair pairs of isomers；Reaction equation is as follows：
7. method according to claim 6, it is characterised in that the equivalent of compound (5) and compound (8) is 1:1.05- 1:1.2, compound 5 and LDA equivalent are 1.3-1.5eq, and tetrahydrofuran consumption is 2 times -5 times of compound (5)；Temperature for- 78 DEG C~-20 DEG C, the reaction time is 1-12 hours.
CN201410190912.XA 2014-05-07 2014-05-07 Shellfish reaches the preparation method of quinoline Active CN105085395B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410190912.XA CN105085395B (en) 2014-05-07 2014-05-07 Shellfish reaches the preparation method of quinoline

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410190912.XA CN105085395B (en) 2014-05-07 2014-05-07 Shellfish reaches the preparation method of quinoline

Publications (2)

Publication Number Publication Date
CN105085395A CN105085395A (en) 2015-11-25
CN105085395B true CN105085395B (en) 2017-09-26

Family

ID=54566822

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410190912.XA Active CN105085395B (en) 2014-05-07 2014-05-07 Shellfish reaches the preparation method of quinoline

Country Status (1)

Country Link
CN (1) CN105085395B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106432057A (en) * 2016-09-17 2017-02-22 青岛云天生物技术有限公司 Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate
CN109387594B (en) * 2017-08-08 2021-01-19 武汉武药科技有限公司 Method for separating and analyzing Bedaquinoline optical isomer
CN109422679B (en) * 2017-08-30 2021-06-25 武汉武药科技有限公司 Purification of bedaquiline and preparation method of stable crystal form
CN112574175B (en) * 2019-09-29 2023-11-14 南京长澳医药科技有限公司 Quinoline compound, preparation method and application thereof
KR102303635B1 (en) * 2020-07-01 2021-09-17 동아에스티 주식회사 PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612340A (en) * 1993-10-01 1997-03-18 Ciba-Geigy Corporation Pyrimidineamine derivatives and processes for the preparation thereof
CN1671667A (en) * 2002-07-25 2005-09-21 詹森药业有限公司 Quinoline derivatives and their use as mycobacterial inhibitors
CN101180302A (en) * 2005-05-25 2008-05-14 詹森药业有限公司 Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol
JP2011168519A (en) * 2010-02-17 2011-09-01 Univ Of Tokyo Manufacturing method of optically active ketone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612340A (en) * 1993-10-01 1997-03-18 Ciba-Geigy Corporation Pyrimidineamine derivatives and processes for the preparation thereof
CN1671667A (en) * 2002-07-25 2005-09-21 詹森药业有限公司 Quinoline derivatives and their use as mycobacterial inhibitors
CN101180302A (en) * 2005-05-25 2008-05-14 詹森药业有限公司 Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol
JP2011168519A (en) * 2010-02-17 2011-09-01 Univ Of Tokyo Manufacturing method of optically active ketone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
A highly efficient regioselective one-pot synthesis of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones using K5CoW12O40•3H2O as a heterogeneous recyclable catalyst;Srinivas Kantevari,等;《Tetrahedron》;20071006;第63卷(第52期);13024–13031 *
Catalytic Asymmetric Synthesis of R207910;Saga, Yutaka 等;《Journal of the American Chemical Society》;20100520;第132卷(第23期);7905–7907 *
Synthesis of a novel series of 6,6"-disubstituted 4,4"-bipyrimidines by radical anion coupling: New π-accepting ligands for coordination chemistry;Ioachim, Elena;《European Journal of Organic Chemistry》;20050712(第17期);3775-3780 *

Also Published As

Publication number Publication date
CN105085395A (en) 2015-11-25

Similar Documents

Publication Publication Date Title
CN105085395B (en) Shellfish reaches the preparation method of quinoline
CN114105859B (en) Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane
CN106279074B (en) A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized
CN105085396B (en) For preparing shellfish up to intermediate of quinoline and its preparation method and application
CN105418460B (en) Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof
TWI363056B (en) Anticancer compounds, intermediates and the method for preparation thereof
CN104387320B (en) A kind of preparation method of high-purity milrinone
WO2013020460A1 (en) Atazanavir preparation method
CN104478877B (en) The method preparing Lei Dipawei intermediate
CN106365986A (en) Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam
CN105566319A (en) Preparation method of (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane
CN104356092A (en) Preparation method for vortioxetine
CN104744430A (en) Benzothiepin derivative and preparation method thereof
CN101270074A (en) Method for preparing high purity mitiglinide calcium
CN103467445B (en) Preparation method of alogliptin benzoate
CN103613568A (en) Preparation method of naphthonone and analogues thereof
CN103121976A (en) Preparation method of N-monosubstituted homopiperazines
CN103159747A (en) Synthetic method of lapatinib
CN109320583A (en) A kind of dehydroabietic acid benzimidazole thioether class Hete rocyclic derivatives with anti-tumor activity and its preparation method and application
CN110372614B (en) Tetrahydroquinoxaline compound, preparation method and application thereof
CN107778257A (en) A kind of synthetic method of bridged piperazine derivatives
JP2019131563A (en) Tetrahydro-isohumulone derivatives, and methods of making and using the same
JP2019108326A (en) Alantolactone/isoalantolactone spiro aryl isoxazoline compounds and a method of using the same
CN102086147A (en) Preparation method of substituted phenol
CN107286155A (en) The method for preparing 6,7- dihydro -5H- pyrrolopyridine hydrochlorides

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP02 Change in the address of a patent holder

Address after: 232000 No.16 Chaoyang East Road, Huainan Economic and Technological Development Zone, Anhui Province

Patentee after: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd.

Patentee after: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY

Address before: 230035 north side of Chaoyang East Road, Huainan Economic and Technological Development Zone, Huainan City, Anhui Province

Patentee before: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd.

Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY

CP02 Change in the address of a patent holder