CN114105999A - Synthesis method of danofloxacin mesylate - Google Patents
Synthesis method of danofloxacin mesylate Download PDFInfo
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- CN114105999A CN114105999A CN202111435609.8A CN202111435609A CN114105999A CN 114105999 A CN114105999 A CN 114105999A CN 202111435609 A CN202111435609 A CN 202111435609A CN 114105999 A CN114105999 A CN 114105999A
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- danofloxacin
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- MYDXUJMODAZBGN-UHFFFAOYSA-N 6-bromo-5-methyl-2-methylsulfanyl-1h-[1,2,4]triazolo[1,5-a]pyrimidin-7-one Chemical compound CC1=C(Br)C(=O)N2NC(SC)=NC2=N1 MYDXUJMODAZBGN-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960004745 danofloxacin mesylate Drugs 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 48
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000001914 filtration Methods 0.000 claims abstract description 29
- 239000002253 acid Substances 0.000 claims abstract description 22
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000011230 binding agent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 claims abstract description 13
- 229960004385 danofloxacin Drugs 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- ISYQWKOXKGJREA-RSLHMRQOSA-N (1s,4s)-2,5-diazabicyclo[2.2.1]heptane;dihydrobromide Chemical compound Br.Br.C1N[C@@H]2CN[C@H]1C2 ISYQWKOXKGJREA-RSLHMRQOSA-N 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000005303 weighing Methods 0.000 description 15
- 239000000463 material Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 6
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 238000004321 preservation Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 2
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a method for synthesizing danofloxacin mesylate, belonging to the technical field of medical preparations taking pyridonic acid compounds as organic active ingredients. Adding cyclopropanecarboxylic acid into a mixed feed liquid of N-methyl bridged piperazine and an acid binding agent, and completely carrying out piperazine condensation reaction at 80-120 ℃ to obtain danofloxacin; adding water and methanesulfonic acid into danofloxacin, stirring and filtering to form danofloxacin aqueous solution; and refluxing the danofloxacin aqueous solution at 80-120 ℃, preserving heat and salifying, and crystallizing and drying to obtain a finished product of danofloxacin mesylate. The method avoids the use of a large amount of organic solvents in piperazine condensation reaction, overcomes the defects of heavy workshop odor and serious pollution, and prepares the finished product with good quality and high purity.
Description
Technical Field
The application relates to a method for synthesizing danofloxacin mesylate, belonging to the technical field of medical preparations taking pyridonic acid compounds as organic active ingredients.
Background
Danofloxacin mesylate is a third-generation quinolone antibacterial drug, is firstly introduced by the American Co, is marketed in China such as Mexico in 1990, is approved as a second-class new veterinary drug in China in 2001, has strong antibacterial effects on gram-positive bacteria (G +), certain anaerobic bacteria and mycoplasma, and is mainly used for treating respiratory tract infection of livestock and poultry (G +) bacteria, certain anaerobic bacteria, mycoplasma and spirochete infection.
The existing danofloxacin mesylate synthesis route is shown as a formula (1):
the method is characterized in that dihydrobromide, cyclopropane carboxylic acid, methanesulfonic acid and the like are used as raw materials, dioxane, methanol and the like are used as solvents, acid-binding agents such as triethylamine or tri-n-propylamine and the like are added, and the reaction is carried out at a certain temperature for more than 24 hours to ensure that the piperazine condensation reaction is complete.
Disclosure of Invention
In view of the above, the present application provides a method for synthesizing high-purity and high-yield danofloxacin, which does not use organic solvent and only requires 2 times of filtration and purification.
Specifically, the method is realized through the following scheme:
a method for synthesizing danofloxacin mesylate comprises the following steps:
(1) preparation of N-methyl bridged piperazine: stirring and mixing (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide and sodium hydroxide at normal temperature, adding an acid-binding agent, and filtering to obtain a mixed feed liquid of N-methyl bridged piperazine and the rest acid-binding agent;
(2) piperazine condensation reaction of cyclopropane carboxylic acid: adding cyclopropanecarboxylic acid into the mixed material liquid, condensing and reacting for 12-36h at 80-120 ℃, monitoring the reaction completion by TLC (thin layer chromatography), adding water and methanesulfonic acid, stirring and filtering to obtain a danofloxacin aqueous solution;
(3) and (3) performing a danofloxacin salifying reaction: adding an organic solvent into the danofloxacin aqueous solution, refluxing at 80-120 ℃, and preserving heat to form salt;
(4) danofloxacin mesylate crystal: after heat preservation and salt formation, gradient cooling is carried out to 0-5 ℃, and filtering, rinsing and drying are carried out to obtain the danofloxacin mesylate finished product.
The main reaction of the application is piperazine condensation reaction, in the reaction, an acid binding agent is excessively added, the acid binding agent not only serves as an acid binding agent and a solvent in the preparation of N-methyl bridged piperazine, bromate is diluted by the liquid acid binding agent, the use of a large amount of solvent in the original process is eliminated, sodium bromide can be removed without the need of solvent by matching with filtering, the problem of large odor in workshop production is solved, meanwhile, the residual acid binding agent which does not participate in the reaction also participates in the piperazine condensation reaction, cyclopropanecarboxylic acid is added into the mixed solution of the N-methyl bridged piperazine and the prepared solution for the piperazine condensation reaction, the unit consumption of products is reduced, one-time filtering after the piperazine condensation reaction and one-time filtering after crystallization are carried out, the two-step filtering endows the advantages of simple operation to the purification process, the purification effect is good, the prepared danofloxacin mesylate finished product has good quality and high yield.
Further, as preferable:
the molar ratio of the (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide to the sodium hydroxide to the liquid acid-binding agent is 1 (1-1.5) to (1-2), wherein the liquid acid-binding agent mainly comprises tri-n-propylamine, triethylamine, DBU (diazabicyclo), DBN (1, 5-diazabicyclo [4.3.0] non-5-ene) and the like. In the scheme, a slightly excessive acid-binding agent participates in the reaction, the self characteristics of the acid-binding agent are exerted, the effect of diluting bromate is realized in the preparation of N-methyl bridged piperazine, and sodium bromide generated in the preparation process is removed by matching with filtration, so that the use of a large amount of solvent can be avoided compared with the conventional dilution removal by adding an organic solvent dioxane.
In step (2), (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide salt, cyclopropanecarboxylic acid: the molar ratio of the methanesulfonic acid to the methanesulfonic acid is 1 (1-1.5) to 1-1.5, the weight of the added water is 1-2 times of the feeding amount of the cyclopropane carboxylic acid, the piperazine condensation reaction temperature is 100-120 ℃, and the reaction time is 12-24 hours.
In the step (3), the organic solvent is one of methanol, ethanol, glycol and acetone; the adding amount of the organic solvent is 0.2-0.5 time of the water amount; the temperature for heat preservation of the salt formation is 100-120 ℃, and the time for heat preservation reaction is 0.5-2 h.
In the step (4), the danofloxacin mesylate is subjected to gradient cooling crystallization in a way that the temperature is kept for 0.5-1h every time the danofloxacin mesylate is reduced by 5-10 ℃ until the temperature is reduced to 0-5 ℃, and then filtering is carried out.
Compared with the prior art, the synthesis method does not need to add an additional organic solvent in piperazine condensation reaction, improves reactant concentration and reaction conversion rate, reduces the generation of impurities in the reaction process, solves the problem of large production smell by eliminating the solvent, further drives the subsequent purification effect of danofloxacin mesylate, improves product quality and yield, and has great significance for industrial production.
Detailed Description
The invention is illustrated below by way of examples, which are to be understood as being illustrative and not limiting. The scope and core content of the invention are to be determined by the claims.
In the preparation process, the proportion of each main material is generally controlled as follows: for every 65g of dihydrobromide, 50g of diazabicyclo, 75g of cyclopropanecarboxylic acid and 30g of methanesulfonic acid were added. The comparison of the preparation effect of the formula (1) in the present case and the background art is shown in table 1.
Table 1: comparison table of preparation effects of different processes
As can be seen from comparison of Table 1, the scheme is superior to the scheme of formula (1) in both the input amount of raw and auxiliary materials and the cycle of the process, and the purification process and the yield of the finished product are also obviously improved.
Table 2: effect of different piperazine reaction parameters on the reaction
The temperature and the time in the piperazine condensation reaction are a pair of parameters which influence each other, and the scheme respectively compares three stages of low temperature (80 ℃), medium temperature (100 ℃) and high temperature (120 ℃), and the results show that the reaction speed is slow and the reaction period is long under the low temperature condition, while the reaction speed is fast and the reaction period is short under the high temperature condition, but the temperature can be increased only by pressurizing under the high temperature condition, and the high temperature needs to be matched with a high pressure kettle, but compared with the improvement of the molar yield, the synthesis efficiency of the high temperature reaction is relatively ideal under the low temperature condition, the medium temperature condition and the high temperature condition.
Table 3: effect of different Material ratios on piperazine condensation reaction (100 ℃ C.)
| Serial number | Acid-binding agent | Amount of cyclopropanecarboxylic acid | Molar yield |
| 1 | DBU | 1 times of | 94.5％ |
| 2 | Tri-n-propylamine | 1 times of | 90.5％ |
| 3 | DBN | 1 times of | 94.0％ |
| 4 | DBU | 1.2 times of | 95.4％ |
| 5 | DBU | 2.0 times of | 95.9％ |
The influence on the materials is mainly reflected in the use of an acid-binding agent and cyclopropane carboxylic acid, and as can be seen from the table 3, the acid-binding agent is preferably DBU, and at the moment, the piperazine condensation reaction is more complete and the molar yield is higher; the addition of the cyclopropane carboxylic acid increases, the piperazine condensation reaction is more complete, the molar yield is higher, but the material consumption is increased, and the method is not economical.
Table 4: effect of different salt-forming parameters on the reaction
| Serial number | Reaction temperature | Reaction time | Molar yield |
| 1 | 80℃ | 4h | 100.0％ |
| 2 | 100℃ | 2h | 100.0％ |
| 3 | 120℃ | 0.5h | 100.0％ |
Table 4 the results show that: the higher the salt-forming reaction temperature is, the shorter the reaction time is; when the temperature is too high, an autoclave is needed for reaction, and the others have no influence.
Table 5: effect of different crystallization parameters on the reaction
| Serial number | Temperature gradient | Time of temperature reduction | Purity of the product |
| 1 | 5℃ | 0.5h | 99.0％ |
| 2 | 5℃ | 1h | 99.5％ |
| 3 | 10℃ | 0.5h | 98.5％ |
| 4 | 10℃ | 1h | 99.0％ |
Table 5 the results show that: the slower the cooling rate (cooling gradient), the better the crystallization effect and the higher the product purity; the product purity is low due to the rapid temperature reduction.
Several specific examples are given below to illustrate the technical solution.
Example 1
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of diazabicyclo, stirring for 1h, filtering, taking filtrate, adding 75g of cyclopropanecarboxylic acid, reacting at 80 ℃ for 30h, monitoring the reaction completion by a TLC (thin layer chromatography) spot plate, adding 250g of water, adjusting the pH to 5.0 by using methanesulfonic acid, heating to 80 ℃, filtering, reacting at 80 ℃ for 4h, cooling, keeping the temperature for 30min every 5 ℃, cooling to 5 ℃, performing suction filtration, drying a filter cake at 60 ℃ in vacuum for 12h, weighing to obtain 100.5g of danofloxacin mesylate, obtaining the liquid phase purity of 99.5%, and calculating the molar yield by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material to obtain 93.6%.
Example 2
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of diazabicyclo, stirring for 1h, filtering, taking filtrate, adding 75g of cyclopropanecarboxylic acid, reacting for 20h at 100 ℃, monitoring the reaction completion by a TLC (thin layer chromatography) spot plate, adding 250g of water, adjusting the pH to 5.0 by using methanesulfonic acid, heating to 100 ℃, filtering, reacting for 2h at 100 ℃, cooling, keeping the temperature for 30min every time when the temperature is reduced by 10 ℃, cooling to 0 ℃, performing suction filtration, drying a filter cake for 12h at 60 ℃ in vacuum, weighing to obtain 101.5g of danofloxacin mesylate, wherein the liquid phase purity is 98.5%, and the molar yield is 94.5% calculated by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material.
Example 3
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of diazabicyclo, stirring for 1h, filtering, taking filtrate, adding 75g of cyclopropanecarboxylic acid, keeping the pressure of 0.2MPa in a sealed manner, heating to 120 ℃ for reaction for 18h, monitoring the reaction completion by a TLC (thin layer chromatography) point plate, adding 250g of water, adjusting the pH to 5.0 by methanesulfonic acid, keeping the pressure of 0.2MPa in a sealed manner, heating to 120 ℃, filtering, reacting the filtrate at 120 ℃ for 30min, cooling, keeping the temperature for 30min every 10 ℃, cooling to 0 ℃, carrying out suction filtration, drying a filter cake at 60 ℃ in vacuum for 12h, weighing 103.5g of methanesulfonic acid danofloxacin, weighing the liquid phase purity to be 99.0%, and calculating the molar yield to be 96.4% by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material.
Example 4
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of tri-n-propylamine, stirring for 1h, filtering, taking filtrate, adding 75g of cyclopropanecarboxylic acid, keeping the pressure of 0.2Mpa in a sealed manner, reacting for 20h at 120 ℃, monitoring the reaction completion by a TLC (thin layer chromatography) point plate, adding 250g of water, adjusting the pH to 4.5 by methanesulfonic acid, heating to 100 ℃, filtering, reacting the filtrate for 2h at 100 ℃, after the reaction is finished, cooling, keeping the temperature for 1h when the temperature is reduced to 5 ℃, cooling to 0 ℃, filtering, vacuum-drying a filter cake for 12h at 60 ℃, weighing 98.5g of danofloxacin mesylate, obtaining the liquid phase purity of 99.1%, and calculating by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material to obtain the molar yield of 91.7%.
Example 5
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of DBN (1, 5-diazabicyclo [4.3.0] non-5-ene), stirring for 1h, filtering, taking filtrate, adding 75g of cyclopropanecarboxylic acid, reacting for 16h at 100 ℃, monitoring the reaction completion by a TLC (thin layer chromatography) point plate, adding 250g of water, adjusting the pH to 4.5 by using methanesulfonic acid, heating to 100 ℃, filtering, reacting the filtrate for 2h at 100 ℃, finishing the reaction, cooling, keeping the temperature for 1h at 5 ℃ every time, cooling to 0 ℃, carrying out suction filtration, drying a filter cake for 12h at 60 ℃ in vacuum, weighing to obtain 101.0g of danofloxacin mesylate, having a liquid phase purity of 99.3%, and calculating by using (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material to obtain a molar yield of 94.0%.
Example 6
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of diazabicyclo, stirring for 1h, filtering, taking filtrate, adding 90g of cyclopropanecarboxylic acid, reacting at 100 ℃ for 16h, monitoring the reaction completion by a TLC (thin layer chromatography) spot plate, adding 250g of water, adjusting the pH to 4.5 by using methanesulfonic acid, heating to 80 ℃, filtering, reacting the filtrate at 80 ℃ for 4h, cooling, keeping the temperature for 30min every time when the temperature is reduced by 5 ℃, cooling to 5 ℃, performing suction filtration, drying a filter cake at 60 ℃ in vacuum for 12h, weighing to obtain 102.5g of danofloxacin mesylate, wherein the liquid phase purity is 99.6%, and the molar yield is 95.4% calculated by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material.
Example 7
Weighing 65g of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, adding 20g of sodium hydroxide and 50g of diazabicyclo, stirring for 1h, filtering, taking filtrate, adding 150g of cyclopropanecarboxylic acid, reacting at 100 ℃ for 16h, monitoring the reaction completion by a TLC (thin layer chromatography) spot plate, adding 250g of water, adjusting the pH to 5.0 by using methanesulfonic acid, heating to 80 ℃, filtering, reacting the filtrate at 80 ℃ for 4h, cooling, keeping the temperature for 30min every time when the temperature is reduced by 5 ℃, cooling to 5 ℃, performing suction filtration, drying a filter cake at 60 ℃ in vacuum for 12h, weighing to obtain 103.0g of danofloxacin mesylate, wherein the liquid phase purity is 99.2%, and the molar yield is 95.9% calculated by taking (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide as a main material.
Claims (10)
1. A synthetic method of danofloxacin mesylate is characterized by comprising the following steps:
(1) stirring and mixing (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide and NaOH at normal temperature, adding excessive acid-binding agent, filtering to obtain mixed feed liquid of N-methyl bridged piperazine and the rest acid-binding agent,
(2) adding cyclopropanecarboxylic acid into the mixed liquid, completely carrying out piperazine condensation reaction at 80-120 ℃ to obtain danofloxacin, adding water and methanesulfonic acid, stirring and filtering to form danofloxacin aqueous solution;
(3) and refluxing the danofloxacin aqueous solution at 80-120 ℃, preserving heat and salifying, and crystallizing and drying to obtain a finished product of danofloxacin mesylate.
2. The method for synthesizing danofloxacin mesylate according to claim 1, wherein in the step (1), the molar ratio of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, NaOH and the acid-binding agent is 1: 1-1.5: 1-2.
3. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (1), the acid-binding agent is one or a mixture of two or more of tri-n-propylamine, triethylamine, DBU and DBN.
4. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (2), the piperazine condensation reaction temperature is 100-120 ℃, and the reaction time is 12-24 h.
5. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (2), the molar ratio of (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane dihydrobromide, cyclopropane carboxylic acid and methanesulfonic acid is 1: 1-1.5.
6. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (2), the adding weight of the water is 1-2 times of the charging weight of the cyclopropane carboxylic acid.
7. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (3), an organic solvent is added into the danofloxacin aqueous solution, and the adding mass of the organic solvent is 0.2-0.5 times of the adding mass of water.
8. The process according to claim 7, wherein the synthesis of danofloxacin mesylate comprises the following steps: the organic solvent is any one of methanol, ethanol, glycol and acetone as a solvent.
9. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (3), the crystallization is carried out in a gradient cooling mode, the temperature of the salified product is kept for 0.5-1h at the temperature of 5-10 ℃ every time until the temperature is reduced to 0-5 ℃, and a finished product is obtained by filtering and drying.
10. The process for synthesizing danofloxacin mesylate according to claim 1, wherein: in the step (3), the salt forming temperature is 100-.
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