CN106543170A - 8 chlorine, 1 cyclopropyl, 7 fluorine, 9 methyl, 4 oxygen, 4 hydrogen quinolizine, 3 carboxylate and its synthetic method - Google Patents
8 chlorine, 1 cyclopropyl, 7 fluorine, 9 methyl, 4 oxygen, 4 hydrogen quinolizine, 3 carboxylate and its synthetic method Download PDFInfo
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- C07D455/02—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing not further condensed quinolizine ring systems
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Abstract
The invention provides a kind of 4 hydrogen quinolizine of 8 chlorine, 1 cyclopropyl 7 fluorine, 9 methyl, 4 oxygen, 3 carboxylate and its synthetic method.The synthetic method comprises the steps：By compound 6 and tert-butyl chloro-silicane under alkali effect, reacted in the first solvent, obtained compound 12；By compound 12 and 3 ethyoxyl, 2 fluoropropene acyl chlorides under cryogenic, reacted in the second solvent under alkali effect, obtain compound 13；Compound 13 and acid are reacted into cyclization in the 3rd solvent, compound 14 is obtained；Compound 14 is reacted in hydrogen chloride/methyl alcohol or hydrogen chloride/ethanol solution, compound 15 is obtained；Compound 15 and POCl3 are reacted in the 4th solvent, end-product is obtained.The synthetic method of the present invention first carry out ring closure reaction, after carry out the hydrolysis of cyano group, the yield of intermediate steps can be effectively improved.
Description
Technical field
The present invention relates to a kind of fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- carboxylates of the chloro- 1- cyclopropyl -7- of 8- and its conjunction
Into method, belong to chemosynthesis technical field.
Background technology
In prior art, the synthesis side of the fluoro- 9- methyl -4- oxygen -4- hydrogen of the chloro- 1- cyclopropyl -7- of 8--quinolizine -3- carboxylates
Method is carried out by following synthetic route：
In this synthetic route, due to the yield of compound 9 being prepared by compound 8 and being prepared by compound 9
The low yield of compound 10 is obtained, the gross production rate of this two step only has 25% or so, cause the chloro- 1- cyclopropyl -7- of final product 8-
The yield of fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- carboxylates (compound 11) is low.
The content of the invention
In view of the defect that above-mentioned prior art is present, the purpose of the present invention is to propose to a kind of chloro- 1- cyclopropyl -7- of 8- are fluoro-
9- methyl -4- oxygen -4- hydrogen-quinolizine -3- carboxylates and its synthetic method, it is possible to increase the yield of intermediate steps, so as to improve most
The yield of the fluoro- 9- methyl -4- oxygen -4- hydrogen of the chloro- 1- cyclopropyl -7- of the 8--quinolizine -3- carboxylates of end-product.
The purpose of the present invention is achieved by the following technical programs：
A kind of synthetic method of the fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- carboxylates of the chloro- 1- cyclopropyl -7- of 8-, its conjunction
Into flow process it is as follows：
Which comprises the steps：
Step one, by compound 5- cyclopropyl -6- ethyls -2- hydroxyls cigarette cyanogen (6) and tert-butyl chloro-silicane in alkali
Under effect, reacted in the first solvent, obtained compound 2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- second
Base cigarette cyanogen (12)；
Step 2, by compound 2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- ethyl cigarette cyanogen and 3- ethoxies
Base -2- fluoropropenes acyl chlorides is reacted under cryogenic conditions and alkali effect, in the second solvent, obtains compound (Z) -2- [(uncles
Butyldimethyl silicon substrate) oxygen] -5- cyclopropyl -6- (the amyl- 4- alkene -2- bases of the fluoro- 3- oxygen of 5- ethyoxyl -4-) cigarette cyanogen (13)；
Step 3, by compound (Z) -2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- (5- ethyoxyl -4-
The amyl- 4- alkene -2- bases of fluoro- 3- oxygen) cigarette cyanogen and acid reacts cyclization in the 3rd solvent, obtains the fluoro- 8- hydroxyls of compound 1-cyclopropyl base -7-
Base -9- methyl -4- -4 hydrogen of oxygen-quinolizine -3- cyano group (14)；
Step 4, by compound 1-cyclopropyl base -7- fluoro- 8- hydroxyls -9- methyl -4- -4 hydrogen of oxygen-quinolizine -3- cyano group in chlorination
Reacted in hydrogen/methyl alcohol or hydrogen chloride/ethanol solution, obtained the fluoro- 8- hydroxyls -9- methyl -4- of compound 1-cyclopropyl base -7-
- 4 hydrogen of oxygen-quinolizine -3- carboxylates (15)；
Step 5, by compound 1-cyclopropyl base -7- fluoro- 8- hydroxyls -9- methyl -4- -4 hydrogen of oxygen-quinolizine -3- carboxylates and three
Chlorethoxyfos are reacted in the 4th solvent, obtain the fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolines of the chloro- 1- cyclopropyl -7- of compound 8-
Piperazine -3- carboxylates (11).
In above-mentioned synthetic method, first solvent can be the common solvent of suitable this area, it is preferred that step
In one, first solvent include the one kind in dichloromethane, toluene, acetonitrile, tetrahydrofuran and DMF or
Several combinations.
In above-mentioned synthetic method, it is preferred that in step one, the alkali include triethylamine, diisopropylethylamine, imidazoles and
The combination of one or more in N-methylmorpholine.
In above-mentioned synthetic method, it is preferred that in step 2, the cryogenic conditions are -100-0 DEG C.
In above-mentioned synthetic method, it is preferred that in step 2, the alkali includes hexamethl disilamine base lithium, hexamethyl two
The combination of one or more in silicon Sodamide, hexamethl disilamine base potassium and lithium diisopropylamine.
In above-mentioned synthetic method, second solvent can be the common solvent of suitable this area, it is preferred that step
In two, second solvent is one or more in tetrahydrofuran, 2- methyltetrahydrofurans, toluene and methyl tertiary butyl ether(MTBE)
Combination.
In above-mentioned synthetic method, the 3rd solvent can be the common solvent of suitable this area, it is preferred that step
In three, the 3rd solvent includes the combination of one or more in toluene, dimethylbenzene and benzene.
In above-mentioned synthetic method, the acid can be suitable acid commonly used in the art, it is preferred that in step 3, institute
Acid is stated for p-methyl benzenesulfonic acid and/or Loprazolam.
In above-mentioned synthetic method, the 4th solvent can be the common solvent of suitable this area, it is preferred that step
In five, it is DMF, DMA, N- methylpyrroles that the 4th solvent is the 4th solvent
The combination of one or more in the combination of one or more in alkanone, 1,2- dichloroethanes, dichloromethane and toluene.
In above-mentioned synthetic method, it is preferred that the compound 5- cyclopropyl -6- ethyls -2- hydroxyl cigarette cyanogen is by such as
Lower section method is prepared：
Under nitrogen protection, diphenyl phosphorus oxygen, paraformaldehyde, toluene, morpholine and mixed in hydrochloric acid are reacted, obtains chemical combination
Thing
By compoundReacted in tetrahydrofuran solvent with n-BuLi/hexane solution, so
After add the third formaldehyde of ring and reacted, obtain compound
By compoundReacted with tert-butyl group potassium alcoholate, obtained compound
By compoundReacted in the mixed solvent of toluene and triethylamine with propionyl chloride, obtained compound
By compoundReacted in the dimethyl formamide solution of sodium hydride with cyanoacetamide, obtained
Compound 5- cyclopropyl -6- ethyls -2- hydroxyls cigarette cyanogen (6).
The present invention also provides the fluoro- 9- methyl -4- oxygen -4- of the chloro- 1- cyclopropyl -7- of 8- that above-mentioned synthetic method is prepared
Hydrogen-quinolizine -3- carboxylates.
The present invention prominent effect be：
The synthetic method elder generation of the fluoro- 9- methyl -4- oxygen -4- hydrogen of the chloro- 1- cyclopropyl -7- of the 8--quinolizine -3- carboxylates of the present invention
Carry out ring closure reaction, after carry out the hydrolysis of cyano group, the yield of intermediate steps can be effectively improved, can be by the yield of intermediate steps
More than 60% is brought up to, so as to the fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- of the chloro- 1- cyclopropyl -7- of the 8- for improving final product
The yield of carboxylate.
Specific embodiment
In order to be more clearly understood to the technical characteristic of the present invention, purpose and beneficial effect, now to skill of the invention
Art scheme carry out it is described further below, but it is not intended that to the present invention can practical range restriction.Institute in following embodiments
Experimental technique is stated, if no special instructions, conventional method is；The reagent and material, if no special instructions, can be from business way
Footpath obtains.
Embodiment
The present embodiment provides a kind of fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- carboxylates of the chloro- 1- cyclopropyl -7- of 8-, its
Synthesize by the following method：
(1) synthesis of compound 2：
Diphenyl phosphorus oxygen (180g), paraformaldehyde (32g), toluene (2L), morpholine are sequentially added under nitrogen protection
(85.3g), concentrated hydrochloric acid (20mL), is heated to 110 DEG C and uses fraction water device water-dividing.Reaction 30 minutes.Reaction temperature is slowly dropped
To 0 to 5 DEG C, continue stirring 1.5 hours.Then filter, dry filter cake, obtain compound 2 (255g, yield：95.2%).Chemical combination
The mass spectrometric data of thing 2 is：MS(ESI)302(M+H).
(2) synthesis of compound 3：
Under nitrogen protection, compound 2 (255g), tetrahydrofuran (1.8L) are added in reaction bulb.At 0 to 5 DEG C, slowly
N-BuLi/hexane solution (610mL, 2.5M) is added dropwise, and is stirred 1 hour under 0 to 5 DEG C of temperature conditionss.Then to reaction
The third formaldehyde of ring (89g) is added dropwise in liquid, and is reacted 30 minutes under 0 to 5 DEG C of temperature conditionss.The ammonium chloride solution of reactant liquor saturation
Liquid (1L) is quenched, and separates organic phase, and water is mutually extracted with dichloromethane (500mL), merges organic phase and uses saturated common salt water washing.
Anhydrous sodium sulfate drying organic phase, filters, and filtrate is concentrated to dryness and obtains compound 3 (314.3g, yield：100%).Compound 3
Mass spectrometric data be：MS(ESI)372(M+H).
(3) synthesis of compound 4：
Compound 3 (314.3g) is dissolved in anhydrous tetrahydro furan (3L), nitrogen atmosphere is replaced into, by the four of compound 3
Hydrogen tetrahydrofuran solution is down to 0 to 10 DEG C, is dividedly in some parts tert-butyl group potassium alcoholate (142.4g), is stirred overnight at room temperature.Reactant liquor is cooled to 0 and arrives
10 DEG C, frozen water (1L), petroleum ether (1L) are added in reactant liquor, is stirred 10 minutes, point liquid.Water is mutually extracted with petroleum ether (0.5L)
Once, merge organic phase and use saturated common salt water washing.Anhydrous sodium sulfate drying, filters, and filtrate is concentrated to dryness and obtains final product crude product
(130g), vacuum distillation obtains compound 4 (90g, the yield for purifying：69.2%).The spectral data of compound 4 is：1HNMR
(400MHz, CDCl3)：δ0.2(m,2H),0.63(m,2H),1.30(m,1H),2.78(t,4H),3.71(t,4H),4.18
(dd,1H),5.92(d,1H)；MS(ESI)154(M+H).
(4) synthesis of compound 5：
Compound 4 (88g) is dissolved in into toluene (0.5L), triethylamine (75.4g), nitrogen displacement is added.0 to 5 DEG C are cooled to,
Propionyl chloride (63.7g) is added dropwise, is stirred overnight at room temperature.Saturated aqueous ammonium chloride (0.5L) is added in reactant liquor and is separated organic
Phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are filtered, and filtrate is concentrated to dryness, obtain compound 5 (109g,
Yield：90.8%).The spectral data of compound 5 is：1HNMR (400M Hz, CDCl3)：δ0.55(m,2H),1.02(m,2H),
1.16 (t, 3H), 1.38 (m, 1H), 2.37 (q, 2H) 3.45 (t, 4H), 3.75 (t, 4H), 7.10 (s, 1H)；MS(ESI)210(M
+H)。
(5) synthesis of compound 6：
Sodium hydride (30g) is added in DMF (0.5L) at 0 to 5 DEG C, cyanoacetamide is added dropwise
(50.1g) DMF (150mL) solution, stirs 30 minutes.Then at 0 to 5 DEG C be added dropwise compound 5
(109g) DMF solution, reaction stirring were heated to 80 DEG C after 1 hour, and insulated and stirred is overnight.Reaction knot
Reactant liquor is down to room temperature by Shu Hou, is poured into frozen water (2L), and the hydrochloric acid using 1N under 0 to 10 DEG C of temperature conditionss adjusts reaction
The pH value of liquid is stirred 3 hours at 0 to 5 DEG C to 2 to 3, is filtered, and dry cake obtains compound 6 (41g, yield：43.8%).
The spectral data of compound 6 is：1HNMR (400MHz, CDCl3)：δ0.55(m,2H),0.97(m,2H),1.35(t,3H),1.69
(m,1H),2.90(q,2H)7.61(s,1H)；MS(ESI)189(M+H).
(6) synthesis of compound 12：
6 (40g), dichloromethane (0.3L), tert-butyl chloro-silicane (48g) are sequentially added, 0 to 5 DEG C are cooled to, is dripped
Plus triethylamine (43g), it is stirred overnight at room temperature.Reactant liquor is poured into water, separate organic phase be washed with water wash, saturated common salt washing
Wash, anhydrous sodium sulfate drying, filter, filtrate is concentrated to dryness, crude product is beaten 4 hours at a temperature of 0 DEG C, mistake with methyl alcohol (100mL)
Filter, dry cake obtain compound 12 (55.2g, yield：86%).The spectral data of compound 12 is：1HNMR (400MHz,
CDCl3)：δ0.45(s,6H),058(m,2H),0.90(m,3H),1.69(m,2H),1.02(s,9H),1.28(t,3H),1.78
(m,1H),2.94(q,2H),7.41(s,1H)；MS(ESI)303(M+H).
(7) synthesis of compound 13：
Compound 12 (35g), tetrahydrofuran (0.35L) are added in reaction bulb 1, nitrogen displacement is cooled to -70 to -65
DEG C, sodium hexamethyldisilazide/toluene solution (420mL, 0.5M) is slowly added dropwise, and keeps stirring 1 at -70 to -65 DEG C little
When.3- ethyoxyls -2- fluoropropene acyl chlorides (21.2g), tetrahydrofuran (0.35L) are added in reaction bulb 2, nitrogen displacement, are dropped
Temperature is to -70 to -65 DEG C.Reactant liquor in reaction bulb 1 is added drop-wise in reaction bulb 2 and -70 to -65 DEG C are maintained the temperature at, is incubated
Stirring 1 hour.It is slowly increased to 0 DEG C.Insulated and stirred 1 hour.Reactant liquor saturated ammonium chloride solution (1L) is quenched, and separates organic
Phase, merges organic phase after water methyl tertiary butyl ether(MTBE), and washed with saturated sodium bicarbonate, saturated common salt water washing.Organic phase
Anhydrous sodium sulfate drying, filters, and filtrate is concentrated to dryness.Obtain compound 13 (48.4g, yield：100%).The matter of compound 13
Modal data is：MS(ESI)419(M+H).
(8) synthesis of compound 14：
By compound 13 (48.4g), toluene (0.5L), p-methyl benzenesulfonic acid (11g) add reaction bulb in, be warming up to 110
DEG C and stir 2 hours.After reaction terminates, reactant liquor is down to into room temperature, concentration adds ethyl acetate (150mL) to add after removing toluene
Heat backflow 1 hour, adds petroleum ether (180mL), flows back 30 minutes, is cooled to room temperature, stirs 2 hours, then filters, filter cake
Compound 14 (29.3g, yield are obtained after drying：98.3%).The spectral data of compound 14 is：1HNMR (400MHz,
CDCl3)：δ0.5(s,2H),0829(m,2H),2.17(m,1H),2.28(s,1H),2.78(s,3H),71(d,0.5H),7.48
(d,0.5H)7.64(s,1H),9.2(d,1H)；MS(ESI)259(M+H).
(9) synthesis of compound 15：
Compound 14 (29.3g), ethanol/hydrogen chloride solution (0.3L, 8N) are added in reaction bulb, at 0 DEG C, stirring 3 is little
When, water (3mL) is added, 80 DEG C are heated to, is reacted 4 hours.After reaction terminates, reactant liquor is cooled to into room temperature, frozen water is poured into
(300mL) in, stir 30 minutes, then filter, dry cake obtains compound 15 (20.3g, yield：60%).Compound 15
Spectral data be：1HNMR (400MHz, CDCl3)：δ0.5(s,2H),082(m,2H),0.90(m,3H),140(t,2H),
2.17(m,1H),2.50(s,3H),4.42(q,2H),7.21(s,1H),8.95(d,1H),9.69(s,1H),10.62(s,
1H)；MS(ESI)305(M+H).
(10) synthesis of compound 11：
DMF (100mL) is added in reaction bulb, nitrogen displacement is down to 0 to 5 DEG C, it is slow to drip
Plus POCl3 (30g), insulated and stirred 1.5 hours, the DMF (100mL) that compound 15 (15g) is added dropwise are molten
Liquid, is warming up to 25 to 30 DEG C and is stirred overnight.To pour in reactant liquor in frozen water (500mL), separate organic phase, water mutually uses dichloromethane
Alkane is extracted three times, wash with saturated sodium bicarbonate aqueous solution, saturated common salt water washing after merging organic phase, and anhydrous sodium sulfate is dry
It is dry, to filter, filtrate is concentrated to dryness.Obtain crude product 11 (13g).Crude product 11 (10g) is added to methyl tertiary butyl ether(MTBE) (50mL), plus
Heat is back to complete molten, is slowly added to petroleum ether (100mL), is cooled to 0 to 5 DEG C；Filter, filter cake is rinsed with petroleum ether, after being dried
Obtain 11 (the fluoro- 9- methyl -4- oxygen -4- hydrogen of the chloro- 1- cyclopropyl -7- of 8--quinolizine -3- carboxylic acid, ethyl esters (7.5g, yield of sterling：
50%), purity is 95%).Spectral data is as follows：1HNMR (400MHz, CDCl3)：δ0.75(m,2H),1.08(m,2H),1.44
(q,3H),2.30(m,1H),3.07(s,3H),4.44(q,2H),8.34(s,1H),9.44(d,1H)；MS(ESI)324(M+
H)。
As seen from the above-described embodiment, compound 12 prepares the yield of compound 13 and obtains chemical combination by compound 14
The yield of thing 15 is substantially significantly improved, the fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolines of the chloro- 1- cyclopropyl -7- of 8- of the present invention
The synthetic method of piperazine -3- carboxylates, can greatly improve the yield of intermediate steps, so as to the chloro- 1- rings of the 8- for improving final product
The yield of the fluoro- 9- methyl -4- oxygen -4- hydrogen of propyl group -7--quinolizine -3- carboxylates.
Claims (11)
1. the synthetic method of the fluoro- 9- methyl -4- oxygen -4- hydrogen of the chloro- 1- cyclopropyl -7- of a kind of 8--quinolizine -3- carboxylates, which includes
Following steps：
Step one, by compound 5- cyclopropyl -6- ethyl -2- hydroxyl cigarette cyanogen and tert-butyl chloro-silicane under alkali effect,
Reacted in the first solvent, obtained compound 2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- ethyl cigarette cyanogen；
Step 2, by compound 2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- ethyl cigarette cyanogen and 3- ethyoxyl -2-
Fluoropropene acyl chlorides is reacted in the presence of cryogenic conditions and alkali, in the second solvent, obtains compound (Z) -2- [(tertiary fourths
Base dimethyl silicon substrate) oxygen] -5- cyclopropyl -6- (the amyl- 4- alkene -2- bases of the fluoro- 3- oxygen of 5- ethyoxyl -4-) cigarette cyanogen；
Step 3, by compound (Z) -2- [(t-Butyldimethylsilyl) oxygen] -5- cyclopropyl -6- (the fluoro- 3- of 5- ethyoxyl -4-
The amyl- 4- alkene -2- bases of oxygen) the cigarette cyanogen and acid reaction cyclization in the 3rd solvent, obtain the fluoro- 8- hydroxyls -9- of compound 1-cyclopropyl base -7-
Methyl -4- -4 hydrogen of oxygen-quinolizine -3- cyano group；
Step 4, by compound 1-cyclopropyl base -7- fluoro- 8- hydroxyls -9- methyl -4- -4 hydrogen of oxygen-quinolizine -3- cyano group hydrogen chloride/
Reacted in methyl alcohol or hydrogen chloride/ethanol solution, obtained the fluoro- 8- hydroxyls -9- methyl -4- oxygen of compound 1-cyclopropyl base -7- -4
Hydrogen-quinolizine -3- carboxylates；
Step 5, by compound 1-cyclopropyl base -7- fluoro- 8- hydroxyls -9- methyl -4- -4 hydrogen of oxygen-quinolizine -3- carboxylates and trichlorine oxygen
Phosphorus is reacted in the 4th solvent, obtains the fluoro- 9- methyl -4- oxygen -4- hydrogen-quinolizine -3- of the chloro- 1- cyclopropyl -7- of compound 8-
Carboxylate.
2. synthetic method according to claim 1, it is characterised in that：In step one, first solvent includes dichloromethane
The combination of one or more in alkane, toluene, acetonitrile, tetrahydrofuran and N,N-dimethylformamide.
3. synthetic method according to claim 1, it is characterised in that：In step one, the alkali includes triethylamine, diisopropyl
The combination of one or more in base ethamine, imidazoles and N-methylmorpholine.
4. synthetic method according to claim 1, it is characterised in that：In step 2, the cryogenic conditions are -100-0 DEG C.
5. synthetic method according to claim 1, it is characterised in that：In step 2, the alkali includes hexamethl disilamine
The combination of one or more in base lithium, hexamethl disilamine base sodium, hexamethl disilamine base potassium and lithium diisopropylamine.
6. synthetic method according to claim 1, it is characterised in that：In step 2, second solvent be tetrahydrofuran,
The combination of one or more in 2- methyltetrahydrofurans, toluene and methyl tertiary butyl ether(MTBE).
7. synthetic method according to claim 1, it is characterised in that：In step 3, it is described acid be p-methyl benzenesulfonic acid and/or
Loprazolam.
8. synthetic method according to claim 1, it is characterised in that：In step 3, the 3rd solvent is toluene, diformazan
The combination of one or more in benzene and benzene.
9. synthetic method according to claim 1, it is characterised in that：In step 5, the 4th solvent be N, N- diformazans
One kind in base formamide, DMAC N,N' dimethyl acetamide, 1-METHYLPYRROLIDONE, 1,2- dichloroethanes, dichloromethane and toluene
Or several combinations.
10. synthetic method according to claim 1, it is characterised in that the compound 5- cyclopropyl -6- ethyl -2- hydroxyls
Base cigarette cyanogen is prepared via a method which to obtain：
Under nitrogen protection, diphenyl phosphorus oxygen, paraformaldehyde, toluene, morpholine and mixed in hydrochloric acid are reacted, obtains compound
By compoundReacted in tetrahydrofuran solvent with n-BuLi/hexane solution, then added again
Enter the third formaldehyde of ring to be reacted, obtain compound
By compoundReacted with tert-butyl group potassium alcoholate, obtained compound
By compoundReacted in the mixed solvent of toluene and triethylamine with propionyl chloride, obtained compound
By compoundReacted in the dimethyl formamide solution of sodium hydride with cyanoacetamide, obtained chemical combination
Thing 5- cyclopropyl -6- ethyl -2- hydroxyl cigarette cyanogen.
The fluoro- 9- methyl -4- of the chloro- 1- cyclopropyl -7- of 8- that synthetic method described in 11. any one of claim 1-10 is prepared
Oxygen -4- hydrogen-quinolizine -3- carboxylates.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996039407A1 (en) * | 1995-06-06 | 1996-12-12 | Abbott Laboratories | Quinolizinone type compounds |
| US5693813A (en) * | 1997-02-26 | 1997-12-02 | Abbott Laboratories | Process for preparation of 4H-4-oxo-quinolizine-3-carboxylic acid |
-
2016
- 2016-10-27 CN CN201610952553.6A patent/CN106543170B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996039407A1 (en) * | 1995-06-06 | 1996-12-12 | Abbott Laboratories | Quinolizinone type compounds |
| US5693813A (en) * | 1997-02-26 | 1997-12-02 | Abbott Laboratories | Process for preparation of 4H-4-oxo-quinolizine-3-carboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| QUN LI ET AL.: "Synthesis and Structure-Activity Relationships of 2-Pyridones: A Novel Series of Potent DNA Gyrase Inhibitors as Antibacterial Agents", 《J. MED. CHEM.》 * |
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