CN112881542B - Stable isotope deuterium-labeled danofloxacin and synthetic method thereof - Google Patents
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 title claims abstract description 30
- 229910052805 deuterium Inorganic materials 0.000 title claims abstract description 30
- 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 title claims abstract description 28
- 229960004385 danofloxacin Drugs 0.000 title claims abstract description 27
- 238000010189 synthetic method Methods 0.000 title claims description 5
- 238000001308 synthesis method Methods 0.000 claims abstract description 10
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 claims abstract description 9
- UXAWXZDXVOYLII-YUMQZZPRSA-N tert-butyl (1s,4s)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1[C@@H]2N(C(=O)OC(C)(C)C)C[C@H]1NC2 UXAWXZDXVOYLII-YUMQZZPRSA-N 0.000 claims abstract description 9
- KNEXGVPHPGXAGF-UHFFFAOYSA-N 1-cyclopropyl-6,7-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(F)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 KNEXGVPHPGXAGF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 125000006847 BOC protecting group Chemical group 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 13
- 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 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 230000006837 decompression Effects 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004750 isotope dilution mass spectroscopy Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940087646 methanolamine Drugs 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 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 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940007526 advocin Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960004745 danofloxacin mesylate Drugs 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a stable isotope deuterium-labeled danofloxacin and a synthesis method thereof, wherein the synthesis method comprises the following steps: s1: deuterated iodomethane and (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane are reacted to introduce stable isotope deuterium-labeled methyl; s2: removing BOC protecting group; s3: and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-formic acid to prepare the stable isotope deuterium-labeled danofloxacin. The danofloxacin marked by the stable isotope deuterium and the synthesis method thereof have the advantages of cheap and easily obtained raw materials, mild reaction conditions, short route, no shedding of the stable isotope deuterium, easy separation and purification of products, high yield, high chemical purity and stable isotope abundance which reach more than 99 percent, and good economy.
Description
Technical Field
The invention relates to the field of isotope labeling, in particular to stable isotope deuterium-labeled danofloxacin and a synthesis method thereof.
Background
Danofloxacin mesylate was first introduced by the american pfeiffer company and marketed in mexico et al in 1990 under the trade name Advocin. Is approved as a second class of national new veterinary drug in China in 2001, is mainly used for treating respiratory tract infection of livestock and poultry, and has the characteristics of wide antibacterial spectrum, strong antibacterial activity, no drug resistance, small adverse reaction, high oral bioavailability, convenient use and the like.
For quantitative analysis of danofloxacin, stable Isotope Dilution Mass Spectrometry (IDMS) is mainly used at present. IDMS uses a stable isotope labeled compound with the same molecular structure as a detected substance as an internal standard substance, uses a high-resolution liquid chromatography-mass spectrometer (LC-MS) to detect, measures the ratio of ions with corresponding mass numbers through a mass spectrometer and compares the ratio with a standard ratio to achieve the purpose of accurate quantification. The isotope internal standard can effectively eliminate the recovery rate difference of the sample in the chemical and physical pretreatment steps, thereby avoiding the deviation of the loss in the sample treatment process to the detection result.
At present, the stable isotope deuterium-labeled danofloxacin product is mainly from abroad, no company is independently researched and developed and produced at home, and a synthetic method of the stable isotope deuterium-labeled danofloxacin is not reported. Therefore, there is a need to provide a method for synthesizing stable isotope labeled danofloxacin.
Disclosure of Invention
The invention aims to solve the technical problem of providing stable isotope deuterium-labeled danofloxacin and a synthesis method thereof, which can obtain stable isotope labeled danofloxacin with very high chemical purity and isotope abundance, and can be used as a stable isotope internal standard for IDMS (intermediate frequency mass spectrometry) to quantitatively analyze the danofloxacin.
The technical scheme adopted by the invention for solving the technical problems is to provide a synthetic method of stable isotope deuterium labeled danofloxacin, which comprises the following steps: s1: deuterated iodomethane and (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane are reacted to introduce stable isotope deuterium-labeled methyl; s2: removing BOC protecting group; s3: and (3) reacting the product obtained in the step (S2) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxyquinoline-3-formic acid to obtain the stable isotope deuterium-labeled danofloxacin.
Further, the step S1 process is as follows: dissolving (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane in tetrahydrofuran, preserving heat at 0~5 ℃ for 5-10 minutes, adding 60wt% sodium hydride in batches, keeping the temperature at 0~5 ℃, dropwise adding deuterated iodomethane at 1~2 drop/second, preserving heat at 0~5 ℃ for reaction for 30-60 minutes, recovering to room temperature, filtering, and performing decompression spin-drying on the solvent to obtain the product.
Further, the molar ratio of (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane, sodium hydride and deuterated iodomethane is 1:2~3:2~3.
Further, the step S2 process is as follows: dissolving the product obtained in the step S1 in 1,4-dioxane, preserving the temperature at 0~5 ℃ for 5 to 10 minutes, dropwise adding 36 to 38wt% hydrochloric acid at the speed of 1~2 drops/second, keeping the temperature at 0~5 ℃, then reacting at 25 to 30 ℃ for 30 to 60 minutes, and carrying out decompression spin drying on the solvent to obtain the product.
Further, the molar ratio of the product of the step S1 to hydrochloric acid is 1:0.01 to 0.05.
Further, the step S3 process is as follows: and (3) dissolving the product obtained in the step (S2), 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxyquinoline-3-formic acid and 1,8-diazabicyclo [5.4.0] undec-7-ene in pyridine, reacting at the temperature of 95-105 ℃ for 8-12 hours, performing reduced pressure spin drying on the solvent, and performing column chromatography separation and purification to obtain the stable isotope deuterium-labeled danofloxacin.
Further, the molar ratio of the product of step S2, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1,8-diazabicyclo [5.4.0] undec-7-ene is 1:1 to 1.5:3~4.
Further, the present invention provides a stable isotope deuterium-labeled danofloxacin prepared by the above synthesis method, which has a molecular structure:
the invention has the following beneficial effects: the invention provides stable isotope deuterium labeled danofloxacin and a synthesis method thereof, which can be used as a standard reagent for quantitatively detecting danofloxacin and have the following advantages:
(1) The synthesis process has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, short route, no shedding of stable isotope deuterium, and capability of obtaining a product marked by the stable isotope deuterium at a specific position.
(2) The product of the invention is easy to separate and purify, has high yield, has chemical purity and stable isotope abundance of more than 99 percent, and can fully meet the requirement of standard reagent for quantitatively detecting the danofloxacin.
(3) The invention has high use value and good economical efficiency.
Drawings
FIG. 1 shows stable isotope deuterium labeled danofloxacin-D obtained in example 1 of the present invention 3 Mass spectrum of (2).
FIG. 2 shows the stable isotope deuterium-labeled danofloxacin-D obtained in example 1 of the present invention 3 Nuclear magnetic resonance hydrogen spectrum of (a).
FIG. 3 shows the stable isotope deuterium-labeled danofloxacin-D obtained in example 1 of the present invention 3 The high performance liquid chromatogram of (1).
Detailed Description
The invention is further described in the following examples, which should not be construed as limiting the invention.
Example 1
The synthesis of stable isotope deuterium labeled danofloxacin was as follows:
s1.2.5g (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane is dissolved in 300mL tetrahydrofuran, the temperature is kept at 0~5 ℃ for 5 minutes, 1.45g 60wt% sodium hydride is added in batches, the temperature is kept at 0~5 ℃, 2.0mL deuterated iodomethane is dripped at 1~2 dripping/second speed, then the temperature is kept at 0~5 ℃ for reaction for 40 minutes, the temperature is restored to room temperature, and then the product is obtained by filtering and decompression spin-drying the solvent;
s2, dissolving the product obtained in the step S1 in 100mL of 1, 4-dioxane, preserving the heat of 0~5 ℃ for 10 minutes, dripping 10mL of 36 to 38wt% hydrochloric acid at the speed of 1~2 drops/second, keeping the temperature of 0~5 ℃, then reacting at the temperature of 25 to 30 ℃ for 60 minutes, and carrying out decompression and spin drying on the solvent to obtain the product;
and S3, dissolving the product obtained in the step S2, 4.5g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-formic acid and 7.0g of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 30mL of pyridine, reacting at the temperature of 95-105 ℃ for 10 hours, performing column chromatography separation and purification by using a dichloromethane/methanol/triethylamine system as an eluent after solvent is dried in a decompression and spinning mode to obtain the danofloxacin marked by the stable isotope deuterium, wherein the chemical purity and the stable isotope abundance of the obtained product are both more than 99%.
The mass spectrum of the product obtained in this example obtained by LC-MS is shown in fig. 1, and as can be seen from fig. 1, there is a molecular ion peak M/z =361.1 ([ M + H)] + ）。
The product obtained in this example was treated with DMSO-D 6 As a solvent, a nuclear magnetic resonance hydrogen spectrum shown in figure 2 is obtained by Bruke-400M nuclear magnetic resonance instrument detection, and as can be seen from figure 2, no absorption peak is found at the chemical shift of-2.32 ppm.
The combination of mass spectrum and nuclear magnetic data shows that the product structure is danofloxacin-D 3 。
Meanwhile, the product sample obtained in this example was dissolved in methanol toAcetonitrile: 20mM phosphoric acid solution =20:80 as mobile phase, passing through a liquid phase column (Athena C18-WP 4.6X 250mm,5 um) with a column temperature of 30 deg.C at a flow rate of 1.0mL/min, and obtaining danofloxacin-D by DAD detector 3 As shown in fig. 3, it can be seen from fig. 3 that the sample purity of (a) is 99% or more.
Example 2
The synthesis of stable isotope deuterium labeled danofloxacin was as follows:
s1.3.0g (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane is dissolved in 400mL tetrahydrofuran, the temperature is kept at 0~5 ℃ for 5 minutes, 1.6g of 60wt% sodium hydride is added in batches, the temperature is kept at 0~5 ℃, 2.5mL of deuterated iodomethane is dripped at 1~2 dripping/second speed, then the temperature is kept at 0~5 ℃ for reaction for 60 minutes, the temperature is restored to room temperature, and then the product is obtained by filtering and decompression spin-drying the solvent;
s2, dissolving the product obtained in the step S1 in 100mL of 1, 4-dioxane, preserving the heat of 0~5 ℃ for 10 minutes, dripping 20mL of 36-38wt% hydrochloric acid at the speed of 1~2 drops/second, keeping the temperature of 0~5 ℃, then reacting at the temperature of 25-30 ℃ for 60 minutes, and carrying out decompression spin drying on the solvent to obtain the product;
and S3, dissolving the product obtained in the step S2, 5.0g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-formic acid and 7.6g of 1, 8-diazabicyclo [5.4.0] undec-7-ene in 50mL of pyridine, reacting at the temperature of 95-105 ℃ for 12 hours, performing column chromatography separation and purification by using a dichloromethane/methanol/triethylamine system as an eluent after the solvent is dried in a decompression and spinning mode to obtain the stable isotope deuterium-labeled danofloxacin, wherein the chemical purity and the stable isotope abundance of the obtained product are both more than 99%.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (4)
1. A synthetic method of stable isotope deuterium labeled danofloxacin is characterized by comprising the following steps:
s1: deuterated iodomethane and (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane are reacted to introduce stable isotope deuterium-labeled methyl;
s2: removing BOC protecting group;
s3: reacting the product obtained in the step S2 with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-formic acid to obtain stable isotope deuterium-labeled danofloxacin;
the step S1 process is as follows: dissolving (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane in tetrahydrofuran, preserving heat at 0~5 ℃ for 5-10 minutes, adding 60wt% sodium hydride in batches, keeping the temperature at 0~5 ℃, dropwise adding deuterated iodomethane at 1~2 drop/second, preserving heat at 0~5 ℃ for reaction for 30-60 minutes, recovering to room temperature, filtering, and performing decompression spin-drying on the solvent to obtain a product;
the step S2 comprises the following processes: dissolving the product obtained in the step S1 in 1,4-dioxane, preserving heat at 0~5 ℃ for 5-10 minutes, dropwise adding 36-38wt% hydrochloric acid at 1~2 drops/second, keeping the temperature at 0~5 ℃, then reacting at 25-30 ℃ for 30-60 minutes, and carrying out decompression spin drying on the solvent to obtain the product;
the step S3 comprises the following processes: and (3) dissolving the product obtained in the step (S2), 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxyquinoline-3-formic acid and 1,8-diazabicyclo [5.4.0] undec-7-ene in pyridine, reacting at the temperature of 95-105 ℃ for 8-12 hours, performing reduced pressure spin drying on the solvent, and performing column chromatography separation and purification to obtain the stable isotope deuterium-labeled danofloxacin.
2. The synthesis method of claim 1, wherein the molar ratio of (1S, 4S) -2-BOC-2,5-diazabicyclo [2.2.1] heptane, sodium hydride and deuterated iodomethane is 1:2~3:2~3.
3. The synthesis method according to claim 1, wherein the molar ratio of the product of step S1 to hydrochloric acid is 1:0.01 to 0.05.
4. The synthesis method according to claim 1, wherein the molar ratio of the product of step S2, 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1,8-diazabicyclo [5.4.0] undec-7-ene is 1:1 to 1.5:3~4.
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| EP0282001B1 (en) * | 1987-03-13 | 1991-12-11 | Kowa Company, Ltd. | Azoxy compounds and process for production thereof |
| EP0882049B1 (en) * | 1996-02-23 | 2002-11-20 | Bayer Ag | Possibly substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo- 4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolin carboxylic acids and their derivatives |
| US6878713B2 (en) * | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
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