CN103755684B - A kind of preparation method of baquiloprim - Google Patents
A kind of preparation method of baquiloprim Download PDFInfo
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- CN103755684B CN103755684B CN201410046400.6A CN201410046400A CN103755684B CN 103755684 B CN103755684 B CN 103755684B CN 201410046400 A CN201410046400 A CN 201410046400A CN 103755684 B CN103755684 B CN 103755684B
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention provides a kind of preparation method of baquiloprim, this preparation method's mild condition, easy to operate, yield is high, and cost is low.Specifically comprise the following steps: take meta-aminotoluene as starting raw material, intermediate 8-amino-7-toluquinoline is obtained through Skraup reaction, nitrated, nitroreduction, take uridylic as starting raw material, be obtained by reacting intermediate 5-dimethylamine 6-Methyl Uracil hydrochloride through Mannich, then methylate through condensation, Eschweiler-Clarke with intermediate 8-amino-7-toluquinoline, chloro, ammonia solution eight step Reactive Synthesis baquiloprim.Preparation method of the present invention, raw material is easy to get, simple to operate, is conducive to suitability for industrialized production.
Description
Technical field
Invention belongs to Trimethoprim field for animals, relates to a kind of preparation method of baquiloprim.
Background technology
Sulfa drugs is the maximum medicine of global veterinary drug industry usage quantity, and be the generation improving anti-microbial activity and reduce resistance, must use with Trimethoprim compatibility, thus Trimethoprim is widely used, and also has huge demand.
Trimethyl phosphate is conventional Trimethoprim, its shortcoming is that the transformation period is short, metabolism release rate is fast, when the sulfa drugs longer with transformation period such as sulphamethazine, sulfadimethoxine, sulfamonomethoxines share, the synergy of short period of time can only be played, have impact on clinical drug effect.
Wellcome Foundation company transform 5 of Trimethyl phosphate substituted-phenyls as substd quinolines base, obtain 5-[8-(dimethylamino-7-methyl-5-quinolyl] methyl-2,4-di-amino-pyrimidine, i.e. baquiloprim (Baquiloprim), there is the broad spectrum antibiotic activity similar to Trimethyl phosphate, eliminating the transformation period then extends greatly, can overcome the synergetic property shortcoming of Trimethyl phosphate.Baquiloprim and sulphamethazine have been made compound preparation Zaquilan with the ratio of 1:5 by Pitman-Moore company, in 1991 in Britain's listing, are mainly used in the inflammation treatment of the heavy livestock such as pig, ox.Subsequently in the listing of multiple countries such as Belgium, Ireland, New Zealand, Denmark, the U.S., the compound preparation of baquiloprim and other sulfa drugs also goes on the market successively, is widely applied.Current baquiloprim there is no producer at home and declares, and has wide market outlook.
Summary of the invention
The invention provides a kind of preparation method of baquiloprim, object is to provide a kind of simple, cheap synthetic method.
For solving the problems of the technologies described above, the present invention is achieved by the following technical solutions:
A preparation method for baquiloprim, the method comprises the following steps:
A, employing Skraup reaction, by meta-aminotoluene and glycerine condensation, obtained 7-toluquinoline (intermediate I);
B, 7-toluquinoline (intermediate I) and concentrated nitric acid, the vitriol oil are nitrated, obtained 8-nitro-7-toluquinoline (intermediate II);
C, 8-nitro-7-toluquinoline (intermediate II) hydrogenating reduction nitro under raney ni catalysis, obtained 8-amino-7-toluquinoline (intermediate III);
D, employing Mannich reaction take uridylic as raw material, with dimethylamine, formaldehyde condensation, and obtained 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV);
E, 8-amino-7-toluquinoline (intermediate III) and 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV) heat condensation in ethylene glycol, obtained 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V);
F, employing Eschweiler-Clarke reaction, 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V) and formaldehyde methylate, obtained 5-(8-dimethylamino-7-toluquinoline-5-base) uridylic (intermediate VI);
G, 5-(8-dimethylamino-7-toluquinoline-5-base) uridylic (intermediate VI) and phosphorus oxychloride generation chloro, the obtained chloro-5-of 2,4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII);
H, 2,4-bis-chloro-5-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII) and benzylamine replace, then through acid hydrolysis, obtained baquiloprim.
The preparation method of baquiloprim described above, concrete operation step is as follows:
(1) in glycerine, add meta-aminotoluene, elemental iodine, the vitriol oil, 140 DEG C of back flow reaction, after reaction terminates, be separated and obtain 7-toluquinoline (intermediate I); The mol ratio of described glycerine, meta-aminotoluene, elemental iodine and the vitriol oil is 4.0:1.0:0.05:4.0;
(2) step (1) gained 7-toluquinoline (intermediate I) is dissolved in the vitriol oil, at 0 ~ 5 DEG C, drips 65% concentrated nitric acid carry out nitrated, after reaction terminates, be separated and obtain 8-nitro-7-toluquinoline (intermediate II); Described 7-toluquinoline (intermediate I) is 1.0:1.2 with the mol ratio of concentrated nitric acid;
(3) be dissolved in solvent by step (2) gained 8-nitro-7-toluquinoline (intermediate II), use raney ni catalysis hydrogenation at 40 DEG C, reduction nitro, after reaction terminates, is separated and obtains 8-amino-7-toluquinoline (intermediate III); Described reaction solvent is methyl alcohol, ethanol or ethyl acetate; Described 8-nitro-7-toluquinoline (intermediate II) is 1.0:0.2 with the mass ratio of Raney's nickel;
(4) at 0 DEG C, dimethylamine agueous solution is joined in formalin, then add uridylic, react at 50 DEG C, after reaction terminates, be separated and obtain 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV); Described reaction solvent is water; The mol ratio of described dimethylamine, formaldehyde and uridylic is 1.8:1.0:1.0;
(5) step (3) gained 8-amino-7-toluquinoline (intermediate III) is dissolved in solvent with step (4) gained 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV), 135 DEG C of reactions, after reaction terminates, be separated and obtain 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V); Described reaction solvent is ethylene glycol; Described 8-amino-7-toluquinoline (intermediate III) is 1.0:1.0 with the mol ratio of 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV);
(6) step (5) gained 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V) is dissolved in formic acid, add formalin back flow reaction, after reaction terminates, be separated and obtain 5-(8-dimethylamino-7-toluquinoline-5-base) uridylic (intermediate VI); Described reaction solvent is formic acid; Described 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V) is 1.0:3.0 with the mol ratio of formaldehyde;
(7) step (6) gained 5-(8-dimethylamino-7-toluquinoline-5-base) uridylic (intermediate VI) is dissolved in phosphorus oxychloride, back flow reaction at 110 DEG C, after reaction terminates, be separated and obtain the chloro-5-of 2,4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII); Described reaction solvent is phosphorus oxychloride;
(8) by step (7) gained 2, the chloro-5-of 4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII) is dissolved in benzylamine, 100 DEG C of reactions, after reaction terminates, evaporate to dryness, adds the vitriol oil, room temperature reaction, after reaction terminates, be separated and obtain baquiloprim (compound 8); Described reaction solvent is benzylamine and the vitriol oil.
In existing methodical 8th step ammonolysis reaction, for intermediate VII and ammonia ethanolic soln reaction under high pressure 9h at 150 DEG C obtain baquiloprim, yield 37%, the method condition is harsh, and temperature is high, and pressure is large, and require high to conversion unit, long reaction time, yield is low.And the 8th step reaction conditions of the present invention is gentle, require low to plant and instrument, yield is high.
Mild condition of the present invention, easy to operate, yield is high, and cost is low, and raw material is easy to get, and is conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the reaction scheme figure of baquiloprim of the present invention.
Embodiment
In the present invention, the synthetic method step of baquiloprim is as follows:
Take meta-aminotoluene as starting raw material, 8-amino-7-toluquinoline (intermediate III) is obtained through Skraup reaction, nitrated, nitroreduction, take uridylic as starting raw material, be obtained by reacting 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV) through Mannich, then methylate through condensation, Eschweiler-Clarke with 8-amino-7-toluquinoline (intermediate III), chloro, ammonia solution eight step Reactive Synthesis baquiloprim.Its concrete reaction scheme as shown in Figure 1.
Below in conjunction with specific embodiment, the present invention is further detailed explanation.
Embodiment 1
(1) in 1L there-necked flask, glycerine (230mL is added, 3.1mol), meta-aminotoluene (80.3mL, 0.75mol), elemental iodine (9.5g, 37.5mmol), mechanical stirring, the slow dropping vitriol oil (165mL, 3.1mol), 140 DEG C of backflow 2h are warming up to after dripping off, add frozen water 200mL after cooling to dilute, 30% sodium hydroxide solution is dripped under ice bath, be neutralized to pH>9, add ethyl acetate 500mL extraction, wash with water 300mL × 3, add anhydrous sodium sulfate drying, suction filtration, evaporate to dryness ethyl acetate, obtain brown yellow oil liquid 1(97g, yield 90.3%), i.e. obtained 7-toluquinoline (intermediate I).
(2) in 1L there-necked flask, add the vitriol oil (230mL, 4.3mol), under ice bath and mechanical stirring, add intermediate I (97g, 0.68mol), slowly 65% concentrated nitric acid (54mL, 0.82mol) is dripped after dissolving, at room temperature 1h is stirred after dripping off, under mechanical stirring by reaction solution impouring frozen water 2L, suction filtration, washing filter cake, dry, obtain yellow powdery solid 2(70g, yield 55%), fusing point 183-185 DEG C, i.e. obtained 8-nitro-7-toluquinoline (intermediate II).
(3) in 1L there-necked flask, ethanol 300mL is added, intermediate II (52g, 276mmol), Raney's nickel 10.4g(weight in wet base), logical hydrogen at 40 DEG C, TLC detects to reacting completely, suction filtration, filtrate reduced in volume to three/mono-, adds hot water 500mL, is chilled to crystallizing at room temperature, suction filtration, drying, obtains yellow needle-like crystals 3(40g, yield 95.2%), fusing point 42-45 DEG C, i.e. obtained 8-amino-7-toluquinoline (intermediate III).
(4) in 1L there-necked flask, 37% formaldehyde solution (81mL is added, 1.0mol), water 225mL, 40% dimethylamine agueous solution (225mL is added under ice bath and mechanical stirring, 1.8mol), stir 20min, add uridylic (108g, 1.0mol), at room temperature stir 48h, evaporate to dryness, adds ethanol 300mL, is adjusted to pH<2 with concentrated hydrochloric acid, recrystallization, suction filtration, dry, obtain white powder crystal 4(187g, yield 94.4%), i.e. obtained 5-dimethylamine 6-Methyl Uracil hydrochloride (intermediate compound IV).
(5) in 1L there-necked flask, intermediate III (54g is added, 0.34mol), intermediate compound IV (70g, 0.34mol), ethylene glycol 360mL, at 135 DEG C, stir 7h, be chilled to room temperature, suction filtration, ethanol 100mL washs, dry, obtain brown powder solid 5(80g, yield 83.3%), fusing point 301-304 DEG C, i.e. obtained 5-(8-amino-7-toluquinoline-5-base) uridylic (intermediate V).
(6) in 2L there-necked flask, add intermediate V(105g, 0.37mol), 37% formaldehyde solution (85mL, 1.13mol), 88% formic acid 1250mL, 120 DEG C of backflow 24h, evaporate to dryness, the 100mL that adds water dissolves, pH=8 is neutralized to 30% sodium hydroxide solution, suction filtration, filter cake use water 200mL × 3 are washed, dry, obtain brown powder solid 6(105g, yield 91%), fusing point 265-270 DEG C, i.e. obtained 5-(8-dimethylamino-7-toluquinoline-5-base) uridylic (intermediate VI).
(7) in 1L there-necked flask, add phosphorus oxychloride 200mL, intermediate VI (20g, 64.5mmol), 9h is reacted at 100 DEG C, steam near dry, in impouring water, stirring and dissolving, suction filtration removing insolubles, pH>9 is neutralized to, suction filtration, filter cake 50% aqueous ethanolic solution recrystallization with 30% sodium hydroxide solution, obtain yellow particle shape crystal 7(14.1g, yield 63%), i.e. the obtained chloro-5-of 2,4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII).
(8) in 1L there-necked flask, add the chloro-5-of 2,4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine (intermediate VII) (20g, 58mmol) be dissolved in benzylamine 300mL, 100 DEG C are stirred 30min, evaporated under reduced pressure.Add vitriol oil 50mL, stirring at room temperature 5h, in impouring frozen water, pH>9 is neutralized to, suction filtration, filter cake 50% aqueous ethanolic solution recrystallization with 30% sodium hydroxide solution, obtain yellow particle shape crystal baquiloprim (compound 8) (12.8g, 72%), fusing point 235-237 DEG C.Anal. calcd for C
17H
20N
6: C, 66.21; H, 6.54; N, 27.25. Found: C, 66.26; H, 6.50; N, 27.24。HRMS (ESI): calcd for C
17H
21N
6: 309.3888 found 309.3879.。
The above is only preferred embodiment of the present invention, and be not restriction the present invention being made to other form, any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the Equivalent embodiments of equivalent variations.But everyly do not depart from technical solution of the present invention content, any simple modification, equivalent variations and the remodeling done above embodiment according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Claims (1)
1. a preparation method for baquiloprim, is characterized in that, the method comprises the following steps:
A, employing Skraup reaction, by meta-aminotoluene and glycerine condensation, obtained intermediate I;
B, intermediate I and concentrated nitric acid, the vitriol oil are nitrated, obtained intermediate II;
C, intermediate II be hydrogenating reduction nitro under raney ni catalysis, obtained intermediate III;
D, employing Mannich reaction take uridylic as raw material, with dimethylamine, formaldehyde condensation, and obtained intermediate compound IV;
E, intermediate III and intermediate compound IV heat condensation in ethylene glycol, obtained intermediate V;
F, employing Eschweiler-Clarke reaction intermediate V and formaldehyde methylate, obtained intermediate VI;
G, intermediate VI and phosphorus oxychloride generation chloro, obtained intermediate VII;
H, intermediate VII replace with benzylamine, then through acid hydrolysis, obtained baquiloprim;
Wherein, in above-mentioned steps, intermediate I is 7-toluquinoline, intermediate II is 8-nitro-7-toluquinoline, intermediate III is 8-amino-7-toluquinoline, intermediate IV is 5-dimethylamine 6-Methyl Uracil hydrochloride, intermediate V is 5-(8-amino-7-toluquinoline-5-base) 6-Methyl Uracil, intermediate VI is 5-(8-dimethylamino-7-toluquinoline-5-base) 6-Methyl Uracil, intermediate VII is the chloro-5-of 2,4-bis-((8-dimethylamino-7-toluquinoline-5-base) methyl) pyrimidine;
Concrete operation step is as follows:
(1) in glycerine, add meta-aminotoluene, elemental iodine, the vitriol oil, 140 DEG C of back flow reaction, after reaction terminates, be separated and obtain intermediate I; The mol ratio of described glycerine, meta-aminotoluene, elemental iodine and the vitriol oil is 4.0:1.0:0.05:4.0;
(2) step (1) gained intermediate I is dissolved in the vitriol oil, at 0 ~ 5 DEG C, drips 65% concentrated nitric acid carry out nitrated, after reaction terminates, be separated and obtain intermediate II; The mol ratio of described intermediate I and concentrated nitric acid is 1.0:1.2;
(3) be dissolved in solvent by step (2) gained intermediate II, use raney ni catalysis hydrogenation at 40 DEG C, reduction nitro, after reaction terminates, is separated and obtains intermediate III; Described reaction solvent is methyl alcohol, ethanol or ethyl acetate; The mass ratio of described intermediate II and Raney's nickel is 1.0:0.2;
(4) at 0 DEG C, dimethylamine agueous solution is joined in formalin, then add uridylic, react at 50 DEG C, after reaction terminates, be separated and obtain intermediate compound IV; Described reaction solvent is water; The mol ratio of described dimethylamine, formaldehyde and uridylic is 1.8:1.0:1.0;
(5) step (3) gained intermediate III and step (4) gained intermediate compound IV are dissolved in solvent, 135 DEG C of reactions, after reaction terminates, are separated and obtain intermediate V; Described reaction solvent is ethylene glycol; Described intermediate III is 1.0:1.0 with the mol ratio of intermediate compound IV;
(6) step (5) gained intermediate V is dissolved in formic acid, adds formalin back flow reaction, after reaction terminates, be separated and obtain intermediate VI; Described reaction solvent is formic acid; The mol ratio of described intermediate V and formaldehyde is 1.0:3.0;
(7) step (6) gained intermediate VI is dissolved in phosphorus oxychloride, back flow reaction at 110 DEG C, after reaction terminates, is separated and obtains intermediate VII; Described reaction solvent is phosphorus oxychloride;
(8) step (7) gained intermediate VII is dissolved in benzylamine, 100 DEG C of reactions, after reaction terminates, evaporate to dryness, adds the vitriol oil, room temperature reaction, after reaction terminates, is separated and obtains baquiloprim; Described reaction solvent is benzylamine and the vitriol oil.
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| CN105055313B (en) * | 2015-09-21 | 2018-01-30 | 河南亚卫动物药业有限公司 | Compound sulfonamide class nano-emulsion preparation that a kind of livestock and poultry use and preparation method thereof |
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| EP0051879A2 (en) * | 1980-11-11 | 1982-05-19 | The Wellcome Foundation Limited | Substituted pyrimidines, their synthesis and compositions containing them, their use in medicine and intermediates for making them |
| CN102649786A (en) * | 2011-02-28 | 2012-08-29 | 郑州福源动物药业有限公司 | Preparation method for 2, 4-diamino-5-(8-dimethylamino-7-methyl-5-quinolyl Methyl)-2, 4-(1H and 3H) pyrimidine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0051879A2 (en) * | 1980-11-11 | 1982-05-19 | The Wellcome Foundation Limited | Substituted pyrimidines, their synthesis and compositions containing them, their use in medicine and intermediates for making them |
| CN102649786A (en) * | 2011-02-28 | 2012-08-29 | 郑州福源动物药业有限公司 | Preparation method for 2, 4-diamino-5-(8-dimethylamino-7-methyl-5-quinolyl Methyl)-2, 4-(1H and 3H) pyrimidine |
Non-Patent Citations (1)
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| Chemical synthesis of oligonucleotides containing (M+4) guanine;Ruoling Guo, et al.;《Nucleosides, Nucleotides and Nucleic Acids》;20051231;第24卷(第5-7期);第1081-1083页 * |
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