CN101781299B - One-pot synthesis method for key intermediate of carbostyril medicaments - Google Patents
One-pot synthesis method for key intermediate of carbostyril medicaments Download PDFInfo
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- CN101781299B CN101781299B CN2010103002513A CN201010300251A CN101781299B CN 101781299 B CN101781299 B CN 101781299B CN 2010103002513 A CN2010103002513 A CN 2010103002513A CN 201010300251 A CN201010300251 A CN 201010300251A CN 101781299 B CN101781299 B CN 101781299B
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Abstract
The invention discloses a one-pot synthesis method for the key intermediate of carbostyril medicaments as disclosed in formula (I-1) or formula (I-2). The synthesis method comprises the following steps: in an organic solvent, reacting the polysubstituted acyl chlorides disclosed in formula (II) and acrylate compounds disclosed in formula (III) in the presence of an acid binding agent; after completely reacting, directly adding the products into amine-group compounds and alkaline matters disclosed in formula (V) or formula (IV) to carry out reaction without separation; and after the reaction finishes, separating and purifying to obtain the key intermediate (I-1) or (I-2) of the carbostyril medicaments. The synthesis method integrates three steps of reactions into the one-pot method, and no separation or purification is needed in the reaction process, thereby simplifying the steps for synthesizing carbostyril compounds. The invention reduces the rate of charge in the reaction process, saves the raw materials, has a high reaction yield, saves the operating cost and reduces the production cost.
Description
Technical field
The present invention relates to the one-pot synthesis method of QNS key intermediate.
Background technology
Comprecin is one of clinical most popular anti-infective; Owing to QNS have has a broad antifungal spectrum, anti-microbial activity strong, do not have the first-selection that advantage such as cross resistance becomes clinical drug combination with other microbiotic, become first type of antibiotic medication.
The synthetic method according to bibliographical information of QNS all will be passed through three-step reaction basically and just can be obtained its key intermediate, and then goes to be hydrolyzed and substitution reaction obtains QNS, and synthesis step is long, and running cost is higher.The present invention promptly is under this background, and the compound method of QNS key intermediate is studied, and incorporates three-step reaction into one pot and reacts, and the centre does not need any separation and purification, obtains the QNS key intermediate.
Summary of the invention
The technical problem that the present invention will solve is to incorporate the three-step reaction in the original QNS key intermediate preparation into one pot to carry out; Pilot process does not carry out any separation and purification operation, and a kind of one-pot synthesis method of QNS key intermediate is provided.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is following:
A kind of structure is suc as formula the one-pot synthesis method of the QNS key intermediate shown in (I-1) or the formula (I-2); Said compound method is: in organic solvent; Acrylic ester compound shown in polysubstituted acyl chlorides shown in the formula (II) and the formula (III) reacts in the presence of acid binding agent; The back that reacts completely directly adds aminated compounds and the alkaline matter shown in formula V or the formula (IV) and reacts without separating, and reacts to finish after separation and purification obtains described QNS key intermediate (I-1) or (I-2);
In formula (I-1), formula (I-2), formula (II), formula (III), formula (IV) or the formula V:
R
1, R
2Independently be selected from one of following separately: hydrogen, C
1～C
6Alkyl, C
5～C
6Naphthenic base, C
1～C
6Alkyl oxy, C
1～C
6Alcohol radical, C
1～C
6Ether, C
1～C
6Alkyl sulfenyl, C
1～C
6Thiol group, C
1～C
6Thioether group, C
1～C
6Alkylamino radical, C
1～C
6Carboxylic acid group, heterocyclic aryl, heterocyclic aryl alkylidene group, benzyl, substituted benzyl, C
6～C
7Aryl, substituted aryl;
R
3, R
4Independently be selected from C separately
1～C
6Alkyl, C
5～C
6Naphthenic base, heterocyclic aryl alkylidene group, benzyl, substituted benzyl, C
5～C
7Aryl or substituted aryl;
R
5Be hydrogen, halogen or nitro;
R
6Be halogen;
R
7Be selected from halogen, C
1～C
3Alkyl or contain the group that the substituted polycyclic amines compounds of N forms, as
R is C
1～C
6Alkyl, C
1～C
6Haloalkyl, cyclopropyl, aryl, halogenated aryl etc.;
A is N atom or C-R
8Group, wherein R
8Be halogen or C
1～C
3Alkyl.
Progressive, R
1, R
2Be preferably hydrogen separately, perhaps R
1Be hydrogen, R
2Be selected from one of following: C
1～C
6Alkyl, C
5～C
6Naphthenic base, C
1～C
6Alkyl oxy, C
1～C
6Alcohol radical, C
1～C
6Ether, C
1～C
6Alkyl sulfenyl, C
1～C
6Thiol group, C
1～C
6Thioether group, C
1～C
6Alkylamino radical, C
1～C
6Carboxylic acid group, heterocyclic aryl, heterocyclic aryl alkylidene group, benzyl, substituted benzyl, C
6～C
7Aryl, substituted aryl.
Heterocyclic aryl alkylidene group of the present invention refers to replaced by alkylidene group on the ring of heterocyclic aryl, like benzopyrrole 2 methylene radical or imidazoles-2-methylene radical etc.; The phenyl ring of described substituted benzyl can be by hydroxyl, nitro, C
1～C
3Groups such as alkyl replace, like the 4-hydroxybenzyl; Described aryl is preferably phenyl; The aromatic ring of described substituted aryl can be by hydroxyl, nitro, C
1～C
3Groups such as alkyl replace; Alcohol radical of the present invention, ether, thiol group, thioether group, carboxylic acid group lose the group that a Wasserstoffatoms obtains by the alkyl in the alcohol of correspondence, ether, mercaptan, thioether, the carboxylic acid.
Among the present invention, described halogen is preferably F.
Organic solvent of the present invention can be selected from one of following or any several kinds mixed solvent: 1. benzene, 2. chlorobenzene, 3. dichlorobenzene, 4. toluene, 5. YLENE, 6. DMSO 99.8MIN., 7. N, dinethylformamide, 8. dioxane.
The preferred said compound of the present invention (II), compound (III) they are 1: 0.9～1.5: 0.9～1.5 with the molar ratio of compound (IV) or compound (V), more preferably 1: 0.9～1.2: 0.9～1.2.
Acid binding agent of the present invention can be mineral alkali or organic bases, specifically can be selected from one of following: 1. yellow soda ash, 2. salt of wormwood, 3. sodium hydroxide, 4. Pottasium Hydroxide, 5. pyridine, 6. 4-dimethylamino pyridine, 7. triethylamine, 8. triethylene diamine; Preferred acid binding agent is triethylamine, pyridine or salt of wormwood.It is 0.8～3.0: 1 that the present invention recommends the molar ratio of said acid binding agent and compound (II), preferred 1.0～2.5: 1.
Volume of organic solvent consumption according to the invention is recommended as 1～4ml/mmol in the mole number of compound (II).
It is one of following that alkaline matter of the present invention can be selected from: yellow soda ash, salt of wormwood, triethylamine, sodium hydroxide, Pottasium Hydroxide, pyridine; Preferred alkaline matter is salt of wormwood or yellow soda ash; The molar ratio of described alkaline matter and compound (II) is 0.8～2.5: 1.
Preferred said polysubstituted acyl chlorides of the present invention and acrylic ester compound were room temperature reaction 2～20 hours.
The present invention reacts TLC following response terminal point after preferably adding aminated compounds and alkaline matter in reflux temperature.
Separation and purification of the present invention can be carried out according to following steps: the gained reaction solution was with the hcl acidifying of massfraction 2～20% after reaction finished; The mixed solution separatory; The gained water is used ethyl acetate extraction, and extraction gained organic phase is used anhydrous magnesium sulfate drying, filters; The filtrating precipitation obtains bullion, and bullion gets described QNS key intermediate through recrystallization.Recrystallization solvent alcohols mass concentration is 5～20% alcohol solution, and described alcohol can be methyl alcohol, ethanol, Virahol etc.
Compared with prior art; One kettle way of the present invention prepares the key intermediate formula (I-1) of QNS and the beneficial effect of formula (I-2) is mainly reflected in: 1) three-step reaction and become one kettle way; The centre does not need any separation and purification operation, has simplified the synthesis step of carbostyril compound; 2) reduce the feed ratio in the reaction process, practiced thrift raw material; 3) obtained reaction yield preferably; 4) practice thrift process cost, reduced production cost.
(4) specific embodiment
With specific embodiment technical scheme of the present invention is further specified below, but protection scope of the present invention is not limited thereto:
The present invention relates to by (II), (III) and (IV) or (V) prepared key intermediate (I-1) and (I-2) as shown in table 1:
Table 1
Embodiment 1:
In the 25mL flask, add II-1 (5.0mmol), III-1 (5.0mmol), triethylamine (10mmol), the about 8mL of solvent benzol, stirring and dissolving; At room temperature the about 5h of reaction adds yellow soda ash 8mmol and IV-16mmol to reacting completely, and under reflux state, is stirred to (the TLC: sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 1, total recovery about 55% through 5% aqueous ethanolic solution recrystallization.
Compound 1 characterizes: IR (KBr) v:3058,2989,2886,1730,1624,1521,1482,1439,1229,1008cm
-1.
1H NMR (CDCl
3, 400MHz): d 1.31 (t, J=7.2Hz, 3H, CH
3), 1.38 (t, J=7.6Hz, 3H, CH
3), 4.27-4.39 (m, 4H), 5.03 (d, J=6.0Hz, 2H, CH
2), 8.12 (t, J=9.2Hz, 1H, ArH), 8.33 (s, 1H, CH=C) .MS (70eV): m/z (%)=357 (M
+).
Embodiment 2
Reaction formula is similar with embodiment 1, in the 25mL flask, adds II-1 (10.0mmol), III-1 (10.0mmol), triethylamine (22mmol), the about 20mL of solvent chlorobenzene, stirring and dissolving; At room temperature the about 6h of reaction adds yellow soda ash 20mmol and IV-2 (13mmol) to reacting completely, and under reflux state, is stirred to (the TLC: sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 2, total recovery about 50% through 5% aqueous ethanolic solution recrystallization.
Compound 2 characterizes: IR (KBr) v:2989,2867,1737,1629,1488,1341,1249,1088cm
-1.
1H NMR (CDCl
3, 400MHz): d0.92 (d, J=6.8Hz, 3H, CH
3), 1.16 (d, J=6.8Hz, 3H, CH
3), 1.28 (t, J=7.2Hz, 3H, CH
3), 1.39 (t, J=7.2Hz, 3H, CH
3), 2.55-2.59 (m, 1H, CH), 4.21-4.30 (m, 2H, CH
2), 4.35-4.41 (m, 2H, CH
2), 5.13-5.14 (m, 1H, CH), 8.13-8.19 (m, 1H, ArH) 8.73 (s, 1H, CH=C) .MS (70eV): m/z (%)=399 (M
+).
Embodiment 3
Reaction formula is similar with embodiment 1, in the 25mL flask, adds II-1 (5.0mmol), III-1 (5.0mmol), triethylamine (10mmol), the about 8mL of solvent benzol, stirring and dissolving; At room temperature the about 5h of reaction adds yellow soda ash 8mmol and IV-4 (6mmol) to reacting completely, and under reflux state, is stirred to (the TLC: sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 4, total recovery about 52% through 15% aqueous ethanolic solution recrystallization.
Compound 4 characterizes: IR (KBr) v:2988,2856,1731,1625,1490,1342,1245,1098cm
-1.
1H NMR (CDCl
3, 400MHz): d 0.71 (t, J=7.2Hz, 3H, CH
3), 0.82-0.86 (m, 1H, CH), 0.97 (d, J=6.4Hz, 3H, CH
3), 1.03-1.05 (m, 2H, CH
2), 1.12 (t, J=7.2Hz, 3H, CH
3), 1.21 (t, J=7.2Hz, 3H, CH
3), 4.06-4.09 (m, 2H, CH
2), 4.12-4.21 (m, 2H, CH
2), 5.11-5.13 (m, 1H, CH), 7.92 (t, J=10.0Hz, 1H, ArH), 8.60 (s, 1H, CH=C) .MS (70eV): m/z (%)=413 (M
+).
Embodiment 4
Reaction formula is similar with embodiment 1, in the 100mL flask, adds II-1 (20.0mmol), III-1 (21.0mmol), triethylamine (45mmol), the about 40mL of solvent xylene, stirring and dissolving; At room temperature the about 7h of reaction adds yellow soda ash 28mmol and IV-5 (25mmol) to reacting completely, and under reflux state, is stirred to (the TLC: sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 5, total recovery about 49% through 20% aqueous ethanolic solution recrystallization.
Compound 5 characterizes: IR (KBr) v:3213,2986,2842,1748,1690,1631,1510,1483,1342,1243,1188,1059cm
-1.
1H NMR (CDCl
3, 400MHz): d1.22 (t, J=7.2Hz, 3H, CH
3), 1.28 (t, J=7.2Hz, 3H, CH
3), 4.17-4.22 (m, 2H, CH
2), 4.31-4.39 (m, 2H, CH
2), 6.65 (s, 1H, CH), 7.37-7.39 (m, 2H, ArH), 7.52-7.54 (m, 2H, ArH), 8.11-8.16 (m, 1H, ArH), 8.20 (s, 1H, CH=C) .MS (70eV): m/z (%)=433 (M
+).
Embodiment 5
Reaction formula is similar with embodiment 1, in the 150ml flask, adds II-1 (25.0mmol), III-1 (26.0mmol), triethylamine (50mmol), the about 70mL of solvent xylene, stirring and dissolving; At room temperature react about 8 hours to reacting completely, add yellow soda ash (22mmol) and IV-6 (28mmol), under reflux state, be stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction three times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 6, total recovery about 50% through 18% aqueous ethanolic solution recrystallization.
Compound 6 characterizes: IR (KBr) v:3303,2989,2876,1739,1692,1645,1520,1463,1341,1240,1167,1089cm
-1.
1H NMR (CDCl
3, 400MHz): d 1.28-1.37 (m, 6H, CH
3), 3.33-3.34 (m, 1H, CH), 3.85-3.87 (m, 2H, CH
2), 4.31-4.34 (m, 4H, CH
2), 7.05-7.21 (m, 5H, ArH), 8.12-8.14 (m, 1H, ArH), 8.59 (s, 1H, CH=C) .MS (70eV): m/z (%)=447 (M
+).
Embodiment 6
Reaction formula is similar with embodiment 1, in the 150mL flask, adds II-1 (25.0mmol), III-1 (26.0mmol), triethylamine (50mmol), the about 70mL of solvent xylene, stirring and dissolving; At room temperature the about 8h of reaction adds yellow soda ash 22mmol and IV-7 28mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 7, total recovery about 50% through 18% aqueous ethanolic solution recrystallization.
Compound 6 characterizes: IR (KBr) v:3433,2925,2887,1732,1642,1466,1342,1243,1121,1078cm
-1.
1H NMR (CDCl
3, 400MHz): d 1.24 (t, J=7.2Hz, 3H, CH
3), 1.29 (t, J=7.2Hz, 3H, CH
3), 3.11-3.13 (m, 2H, CH
2), 3.42-3.45 (m, 1H, CH), 4.12-4.13 (m, 2H, CH
2), 4.23-4.26 (m, 2H, CH
2), 5.14 (s, 1H, OH), 6.15-6.17 (m, 2H, ArH), 7.22-7.25 (m, 2H, ArH), 8.15-8.17 (m, 1H, ArH), 8.26 (s, 1H, CH) .MS (70eV): m/z (%)=463 (M
+).
Embodiment 7
Reaction formula is similar with embodiment 1, in the 100mL flask, adds II-1 (20.0mmol), III-1 (21.0mmol), triethylamine (45mmol), the about 40mL of solvent xylene, stirring and dissolving; At room temperature the about 7h of reaction adds yellow soda ash 28mmol and IV-8 25mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 8, total recovery about 49% through 20% aqueous ethanolic solution recrystallization.
Compound 8 characterizes: IR (KBr) v:3443,2925,2867,1735,1632,1486,1345,1243,1121,1078cm
-1.
1H NMR (CDCl
3, 400MHz): d1.26 (t, J=7.2Hz, 3H, CH
3), 1.32 (t, J=7.2Hz, 3H, CH
3), 3.92-3.93 (m, 1H, CH), 4.17-4.19 (m, 2H, CH
2), 4.26-4.28 (m, 2H, CH
2), 7.19-7.22 (m, 5H, ArH), 8.15-8.17 (m, 1H, ArH), 8.89 (s, 1H, CH) .MS (70eV): m/z (%)=472 (M
+).
Embodiment 8
Reaction formula is similar with embodiment 1, in the 150mL flask, adds II-1 (25.0mmol), III-1 (26.0mmol), triethylamine (50mmol), the about 70mL of solvent xylene, stirring and dissolving; At room temperature the about 8h of reaction adds yellow soda ash 22mmol and IV-9 28mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 9, total recovery about 50% through 18% aqueous ethanolic solution recrystallization.
Compound 9 characterizes: IR (KBr) v:3502,3455,2928,2877,1742,1646,1434,1356,1232,1129,1078cm
-1.
1H NMR (CDCl
3, 400MHz): d1.25 (t, J=7.2Hz, 3H, CH
3), 1.37 (t, J=7.2Hz, 3H, CH
3), 3.42-3.43 (m, 1H, CH), 3.72-3.75 (m, 2H, CH
2), 4.19-4.21 (m, 2H, CH
2), 4.28-4.31 (m, 2H, CH
2), 8.15-8.17 (m, 1H, ArH), 8.89 (s, 1H, CH) .MS (70 eV): m/z (%)=387 (M
+).
Embodiment 9
Reaction formula is similar with embodiment 1, in the 25mL flask, adds II-1 (10.0mmol), III-1 (10.0mmol), triethylamine (22mmol), the about 20mL of solvent chlorobenzene, stirring and dissolving; At room temperature the about 6h of reaction adds yellow soda ash 20mmol and IV-10 (13mmol) to reacting completely, and under reflux state, is stirred to (the TLC: sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 5% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 10, total recovery about 48% through 5% aqueous ethanolic solution recrystallization.
Compound 10 characterizes: IR (KBr) v:3455,2968,2837,1740,1649,1447,1356,1266,1196,1078cm
-1.
1H NMR (CDCl
3, 400MHz): d1.21 (t, J=7.2Hz, 3H, CH
3), 1.32 (t, J=7.2Hz, 3H, CH
3), 2.22-2.23 (m, 2H, CH
2), 2.35 (s, 3H, CH
3), 2.54-2.57 (m, 2H, CH
2), 3.12-3.15 (m, 1H, CH), 4.12-4.15 (m, 2H, CH
2), 4.24-4.29 (m, 2H, CH
2), 8.12-8.15 (m, 1H, ArH), 9.01 (s, 1H, CH) .MS (70eV): m/z (%)=431 (M
+).
Embodiment 10
Reaction formula is similar with embodiment 1, in the 100mL flask, adds II-1 (20.0mmol), III-1 (21.0mmol), triethylamine (45mmol), the about 40mL of solvent xylene, stirring and dissolving; At room temperature the about 7h of reaction adds yellow soda ash 28mmol and IV-11 25mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 10% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 11, total recovery about 49% through 20% aqueous ethanolic solution recrystallization.
Compound 11 characterizes: IR (KBr) v:3435,2968,2839,1744,1649,1467,1359,1246,1157,1098cm
-1.
1H NMR (CDCl
3, 400MHz): d1.24 (t, J=7.2Hz, 3H, CH
3), 1.35 (t, J=7.2Hz, 3H, CH
3), 2.92-2.93 (m, 2H, CH
2), 3.54-3.57 (m, H, CH), 4.13-4.15 (m, 2H, CH
2), 4.29-4.31 (m, 2H, CH
2), 7.45 (s, 1H, ArH), 8.22-8.24 (m, 1H, ArH), 8.34 (s, 1H, ArH), 9.11 (s, 1H, CH) .MS (70eV): m/z (%)=437 (M
+).
Embodiment 11
Reaction formula is similar with embodiment 1, in the 150mL flask, adds II-12 (25.0mmol), III-1 (26.0mmol), triethylamine (50mmol), the about 70mL of solvent xylene, stirring and dissolving; At room temperature the about 8h of reaction adds yellow soda ash 25mmol and V-12 28mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 5% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 12, total recovery about 47% through 18% aqueous ethanolic solution recrystallization.
Compound 12 characterizes: IR (KBr) v:3123,2988,2859,1734,1648,1462,1324,1252,1151,1108cm
-1.
1H NMR (CDCl
3, 400MHz): d1.12 (t, J=7.2Hz, 3H, CH
3), 1.22 (t, J=7.2Hz, 3H, CH
3), 2.35 (s, 3H, CH
3), 4.12-4.17 (m, 2H, CH
2), 4.43-4.46 (m, 2H, CH
2), 6.33 (m, H, ArH), 9.12 (s, 1H, ArH) .MS (70eV): m/z (%)=260 (M
+).
Embodiment 12
Reaction formula is similar with embodiment 1, in the 25mL flask, adds II-13 (10.0mmol), III-1 (10.0mmol), triethylamine (22mmol), the about 20mL of solvent chlorobenzene, stirring and dissolving; At room temperature the about 6h of reaction adds yellow soda ash 20mmol and V-13 13mmol to reacting completely, and under reflux state, is stirred to (the TLC sherwood oil: ETHYLE ACETATE=3: 1) that reacts completely; Hcl acidifying with 5% is to pH=1-2, and separatory is with ethyl acetate extraction 3 times; Organic phase merges, and anhydrous magnesium sulfate drying spends the night, and filters; Precipitation, bullion gets midbody 13, total recovery about 46% through 5% aqueous ethanolic solution recrystallization.
Compound 13 characterizes: IR (KBr) v:3123,2988,2859,1734,1648,1462,1324,1252,1151,1108cm
-1.
1H NMR (CDCl
3, 400MHz): d1.21-1.33 (m, 7H, CH
2, CH
3), 4.22-4.33 (m, 3H, CH, CH
2), 8.15-8.17 (m, 1H, ArH), 8.89 (s, 1H, CH) .MS (70eV): m/z (%)=311 (M
+).
Claims (9)
1. a structure is suc as formula the one-pot synthesis method of the QNS key intermediate shown in (I-1) or the formula (I-2); Said compound method is: in organic solvent; Acrylic ester compound shown in polysubstituted acyl chlorides shown in the formula (II) and the formula (III) reacts in the presence of acid binding agent; The back that reacts completely directly adds aminated compounds and the alkaline matter shown in formula V or the formula (IV) and reacts without separating, and reacts to finish after separation and purification obtains described QNS key intermediate (I-1) or (I-2);
In formula (I-1), formula (I-2), formula (II), formula (III), formula (IV) or the formula V:
R
1, R
2Independently be selected from one of following separately: hydrogen, C
1～C
6Alkyl, C
5～C
6Naphthenic base, C
1～C
6Alkyl oxy, C
1～C
6Alcohol radical, C
1～C
6Ether, C
1～C
6Alkyl sulfenyl, C
1～C
6Thiol group, C
1～C
6Thioether group, C
1～C
6Alkylamino radical, C
1～C
6Carboxylic acid group, heterocyclic aryl alkylidene group, benzyl, substituted benzyl, C
6～C
7Aryl, substituted aryl; Described heterocyclic aryl alkylidene group is benzopyrrole-2-methylene radical or imidazoles-2-methylene radical; The phenyl ring of described substituted benzyl is by hydroxyl, nitro or C
1～C
3Alkyl replace; Described aryl is a phenyl; The aromatic ring of described substituted aryl is by hydroxyl, nitro or C
1～C
3Alkyl replace; Described alcohol radical, ether, thiol group, thioether group, carboxylic acid group lose the group that a Wasserstoffatoms obtains by the alkyl in the alcohol of correspondence, ether, mercaptan, thioether, the carboxylic acid;
R
3, R
4Independently be selected from C separately
1～C
6Alkyl or C
5～C
6Cyclic alkyl;
R
5Be hydrogen or halogen;
R
6Be halogen;
R
7Be selected from halogen or C
1～C
3Alkyl;
R is C
1～C
6Alkyl, C
1～C
6Haloalkyl or cyclopropyl;
A is N atom or C-R
8Group, wherein R
8Alkyl for halogen or C1～C3.
2. the one-pot synthesis method of QNS key intermediate as claimed in claim 1; It is characterized in that described organic solvent is selected from one of following or any several kinds mixed solvent: 1. benzene, 2. chlorobenzene, 3. dichlorobenzene, 4. toluene, 5. YLENE, 6. DMSO 99.8MIN., 7. N, dinethylformamide, 8. dioxane.
3. the one-pot synthesis method of QNS key intermediate as claimed in claim 1 is characterized in that said compound (II), compound (III) are 1: 0.9～1.5: 0.9～1.5 with compound (IV) or molar ratio (V).
4. the one-pot synthesis method of QNS key intermediate as claimed in claim 1, it is one of following to it is characterized in that described acid binding agent is selected from: 1. yellow soda ash, 2. salt of wormwood, 3. sodium hydroxide, 4. Pottasium Hydroxide, 5. pyridine, 6. 4-dimethylamino pyridine, 7. triethylamine, 8. triethylene diamine; The molar ratio of said acid binding agent and compound (II) is 0.8～3.0: 1.
5. the one-pot synthesis method of QNS key intermediate as claimed in claim 1, it is one of following to it is characterized in that described alkaline matter is selected from: yellow soda ash, salt of wormwood, triethylamine, sodium hydroxide, Pottasium Hydroxide, pyridine; The molar ratio of described alkaline matter and compound (II) is 0.8～2.5: 1.
6. the one-pot synthesis method of QNS key intermediate as claimed in claim 1 is characterized in that said polysubstituted acyl chlorides and acrylic ester compound were room temperature reaction 2～20 hours.
7. the one-pot synthesis method of QNS key intermediate as claimed in claim 1 reacts under reflux temperature after it is characterized in that adding aminated compounds and alkaline matter.
8. the one-pot synthesis method of QNS key intermediate as claimed in claim 1; It is characterized in that described separation and purification carries out according to following steps: reaction finishes back gained reaction solution with the hcl acidifying of massfraction 2～20%, the mixed solution separatory, and the gained water is used ethyl acetate extraction; Extraction gained organic phase is used anhydrous magnesium sulfate drying; Filter, the filtrating precipitation obtains bullion, and bullion gets described QNS key intermediate through recrystallization.
9. the one-pot synthesis method of QNS key intermediate as claimed in claim 8 is characterized in that described recrystallization is that 5～20% alcohol solution is a recrystallization solvent with pure mass concentration.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030911A (en) * | 1987-07-24 | 1989-02-08 | 拜尔公司 | The method for preparing quinolone carboxylic acid |
| CN1109877A (en) * | 1993-12-10 | 1995-10-11 | 拜尔公司 | One-pot process for the preparation of 3-quinolone carboxylic acid derivatives |
| US5703233A (en) * | 1993-10-27 | 1997-12-30 | Archimica Spa | Quinilone disulfide as intermediates |
-
2010
- 2010-01-13 CN CN2010103002513A patent/CN101781299B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1030911A (en) * | 1987-07-24 | 1989-02-08 | 拜尔公司 | The method for preparing quinolone carboxylic acid |
| US5703233A (en) * | 1993-10-27 | 1997-12-30 | Archimica Spa | Quinilone disulfide as intermediates |
| CN1109877A (en) * | 1993-12-10 | 1995-10-11 | 拜尔公司 | One-pot process for the preparation of 3-quinolone carboxylic acid derivatives |
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