CN108623583B - Preparation method of iridium-catalyzed moxifloxacin side chain intermediate - Google Patents
Preparation method of iridium-catalyzed moxifloxacin side chain intermediate Download PDFInfo
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- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical group COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- RRBLNPCNHNHAFW-NEPJUHHUSA-N (4ar,7as)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C([C@H]1NCCC[C@H]1C1=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-NEPJUHHUSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 23
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 5
- 239000012018 catalyst precursor Substances 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 4
- KPSSIOMAKSHJJG-UHFFFAOYSA-N neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 claims description 4
- 239000013110 organic ligand Substances 0.000 claims description 4
- JJFNYKMZELJLBL-UHFFFAOYSA-N 6-benzyl-1,2,3,4-tetrahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C(NCCC2)=C2C(=O)N1CC1=CC=CC=C1 JJFNYKMZELJLBL-UHFFFAOYSA-N 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 2
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical group [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 claims 1
- 239000000539 dimer Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 11
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 3
- 238000012827 research and development Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 12
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 229960003702 moxifloxacin Drugs 0.000 description 9
- 230000008569 process Effects 0.000 description 8
- 238000005086 pumping Methods 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002699 waste material Substances 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 150000003949 imides Chemical class 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- GJAWHXHKYYXBSV-UHFFFAOYSA-N pyridinedicarboxylic acid Natural products OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 2
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- MKRBAPNEJMFMHU-UHFFFAOYSA-N 1-benzylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CC=CC=C1 MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RRBLNPCNHNHAFW-UHFFFAOYSA-N 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C2CCCNC2C(=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010011509 Crystalluria Diseases 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- PVUHFYTXFNLVLM-UHFFFAOYSA-N [Ir+].COC1=CCCC=CCC1 Chemical class [Ir+].COC1=CCCC=CCC1 PVUHFYTXFNLVLM-UHFFFAOYSA-N 0.000 description 1
- TVRHDFJMHSSQCP-UHFFFAOYSA-M [Ir]Cl.C1CC=CCCC=C1 Chemical class [Ir]Cl.C1CC=CCCC=C1 TVRHDFJMHSSQCP-UHFFFAOYSA-M 0.000 description 1
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000006208 aza-Diels-Alder reaction Methods 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000003009 desulfurizing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- LVPMIMZXDYBCDF-UHFFFAOYSA-N isocinchomeronic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)N=C1 LVPMIMZXDYBCDF-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an iridium-catalyzed preparation method of a moxifloxacin side chain intermediate, which comprises the following steps: under the catalysis of a chiral catalyst, 6-benzyl-pyrrolo [3,4-b ] pyridine-5, 7-diketone and hydrogen are subjected to asymmetric hydrogenation reaction in an organic solvent to obtain the (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane. The preparation method has the advantages of high efficiency, strong substrate universality and high enantioselectivity, and has wide application prospect in the fields of asymmetric synthesis and medicine research and development.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of a moxifloxacin side chain intermediate (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane.
Background
Moxifloxacin hydrochloride is a fourth generation ultra-broad spectrum quinolone drug developed by Bayer corporation in Germany 1999, and the drug shows broad spectrum antibacterial activity in vitro on gram-positive bacteria, gram-negative bacteria, anaerobic bacteria, acid-fast bacteria and atypical microorganisms such as mycoplasma, chlamydia and legionella, has strong antibacterial activity and wide antibacterial spectrum, and is not easy to generate resistant bacteriaThe medicine is effective to common drug-resistant bacteria, and has long half-life period and less adverse reaction. (Jiangzhongya, junk essence, moxifloxacin hydrochloride for treating respiratory tract infection 40 cases of clinical analysis, China modern practical medicine journal, 2007, 6: 10-11. Chengyong, moxifloxacin pharmacological characteristics and medication safety research progress and analysis, Chinese medical guideline, 2011, 9: 186--) Antibacterial activity of the bacteria, and gram-positive (G) activity+) The antibacterial action of bacteria and atypical pathogenic bacteria is 4-10 times stronger than that of ciprofloxacin. And has no obvious phototoxicity and high solubility, and reduces the risk of forming crystalluria. (Liu Jiu Yu, Guo Hui Yu. spectral high-efficiency novel quinolone antibacterial drug moxifloxacin. foreign medicine-antibiotic itemization, 2002, 23: 274- & 278. Zheng Hu. pharmaceutical chemistry. Beijing: people health publishing agency, 2007, 297- & 307. Mayue. development of fluoroquinolone antibiotic. foreign medicine pharmaceutical itemization, 2001, 28: 240- & 292)
The (S, S) -2,8-diazabicyclo [4.3.0] nonane is a key intermediate in the synthesis process of moxifloxacin, and for the preparation of the (S, S) -2,8-diazabicyclo [4.3.0] nonane, pyridine dicarboxylic acid is industrially used as a raw material, and then the target product (S, S) -2,8-diazabicyclo [4.3.0] nonane is obtained by a method of dianhydride formation, amidation ring opening, ring closing, secondary reduction and chemical resolution. In the route, a pyridine ring needs to be reduced under high pressure, and chemical resolution is carried out at the same time, so that the yield is low, the production cost of moxifloxacin is high, and the structure is as follows:
at present, three routes exist for the synthesis of moxifloxacin side chains at home and abroad. (Wangfutong, Li modest and, Pentosing. Moxifloxacin Synthesis methods. pharmaceutical developments, 2003,27(4): 217-220. U Motterle R, Arvotti G, Bergantino E, Castellin A, Fogal S, Galvagni M.Synthesis of (4as, 7as) -octahydro-1H-pyro [3,4, b ] pyridine. US:100215,2010-09-10. Uygur. Pederson, Tomas. stice, Claus. Purch, et al. methods for the preparation of pharmaceutical compositions containing l-bicyclic substituted-3-quinolonecarboxylic acid derivatives. CN:94100328,1995-01-25.) although patents have also appeared in recent years with respect to the synthesis of moxifloxacin side chains, some of the three synthetic routes have been modified.
The three synthetic routes are now set forth below:
the first synthetic route starts with a pyridine dihalide 4 (formula 2). (Wang Z, Feng S, Cheng Y.A Novel and Economical Process for preparation (S, S) -2,8-Diazabicyclo [4,3,0] nonane and Its Enantiomer. US:085480, 2008-07-17) first, in the presence of NaH, DMF was used as a solvent, and dihalogen 4 was alkylated with a sulfonamide to give product 5. Since the mixture of NaH and DMF is easily explosive and difficult to handle in industrial production, there is a patent report that alkylation with EtONa and EtOH can improve the safety of synthesis and obtain better results. And (3) carrying out non-asymmetric hydrogenation on the pyridine unit in the compound 5 under the catalysis of Pd-C to obtain a product 6. The product 6 is a racemate and the desired isomer 6a with (S, S) configuration is obtained by chiral resolution, while its enantiomer 6b is a waste product of the synthetic route. 6a, desulfurizing by hydrogen bromide and propionic acid to obtain the moxifloxacin side chain 2 with high optical purity. The greatest disadvantage of this synthetic route is that asymmetric catalytic hydrogenation is used to obtain a pair of enantiomers, which are then resolved by chiral means to give the desired isomer 6a with the (S, S) configuration, the enantiomer 6b being a waste product of the synthetic route. This not only severely reduces the overall yield of the synthesis, but also increases the steps of chiral resolution and reduces the synthesis efficiency. In addition, the raw material pyridine dihalide 4 is obtained by three-step reaction of 2, 3-dicarboxylpyridine (7, formula 3) through carboxylic acid methyl esterification, methyl ester reduction to alcohol and alcohol halogenation. Therefore, the preparation of the starting material 4 is troublesome.
Formula 2. one of the known synthetic routes for moxifloxacin side chain
The second synthetic route uses 2, 3-dicarboxylpyridine 7as raw material (formula 3))。(Ramakrishnan A,Bhawsar S,Narayana V.Improved Process for the Preparation of (S,S)-2,8-Dazabicyclo[4,3,0]Us 125425,2009-10-15.) diacid 7 is first treated with acetic anhydride to give the corresponding anhydride, which is then reacted with benzylamine to give imide 8. And carrying out non-asymmetric hydrogenation on the pyridine unit in the product 8 under the catalysis of Pd-C to obtain a compound 9. 9 is racemic body, wherein the imide structure is NaBH4-BF3Or reduction in an aluminum red solution to give racemic amine 10. 10 by chiral resolution to give the desired isomer 10a having the (S, S) configuration. 10a is hydrogenated under the catalysis of Pd-C to remove a benzyl protecting group, and then the moxifloxacin side chain 2 is obtained. Similar to the first synthetic route, this synthetic route also has the disadvantage that the desired isomer 10a is obtained by means of chiral resolution, while its enantiomer forms a waste of this synthetic route. In contrast, the raw materials and reagents used in the route are simple and easy to obtain, and the reaction conditions are mild, so that the route is a synthetic route adopted by the existing factory.
Formula 3. second of the known synthetic routes to the moxifloxacin side chain
The third synthesis route is very similar to the second synthesis route except that in the process the imide 8 is obtained by a two-step reaction of aza-Diels-Alder reaction with electron-deficient N-benzylmaleimide 12 using an electron-rich aza-diene 11. (Uwe P, Andrea K, Thomas S, et al
Deivate. DE:4208792, 1993-09-23.) imide 8 is subjected to four steps of catalytic hydrogenation, imide reduction, chiral resolution and benzyl deprotection to obtain moxifloxacin side chain.
Formula 4. third of the known synthetic route for the side chain of moxifloxacin
Throughout the developed synthetic route for the moxifloxacin side chain, we can find that the main problems with the known route are: a pair of enantiomers is obtained by a non-asymmetric method, and then the required isomer is obtained by chiral resolution, and the enantiomer becomes waste of the synthetic routes. The generation of these wastes not only greatly reduces the overall yield of the synthesis, but also requires the addition of a chiral resolution step to obtain the desired isomer, thereby greatly affecting the efficiency of the synthesis and increasing the production cost. Meanwhile, the wastes can bring certain pollution to the environment. Therefore, the known synthesis route of the moxifloxacin side chain is not in good accordance with the requirements of green chemistry. It is worth mentioning that: of the three routes, the synthetic route (formula 3) taking 2, 3-dicarboxylpyridine as the raw material is most suitable for industrial production and is the main route for synthesizing the side chain of moxifloxacin at present.
The synthesis process with green color, high yield and low cost is the aim and development trend of synthesizing chiral drugs and intermediates. Synthetically, the approach to achieve this goal: a catalytic asymmetric process is used instead of the chiral resolution process. Therefore, the development of the catalytic asymmetric process of the moxifloxacin side chain is a trend of realizing green and low-cost synthesis of the moxifloxacin side chain.
The patent prepares the needed enantiomer-chiral (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane from the oxidative dehydrogenation product (6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3,4-b ] pyridine-5, 7-dione) of the racemate 9 (6-benzyl-hexahydro-pyrrolo [3,4-b ] pyridine-5, 7-dione) generated by the catalytic hydrogenation reaction in the second step by the synthesis strategy of 'asymmetric catalytic hydrogenation'.
Disclosure of Invention
The invention provides an asymmetric synthesis method of a chiral moxifloxacin side chain intermediate, which comprises the step of carrying out asymmetric hydrogenation reaction on 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3,4-b ] pyridine-5, 7-diketone and hydrogen to prepare chiral (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane.
A preparation method of an iridium-catalyzed moxifloxacin side chain intermediate comprises the following steps: under the catalysis of a chiral catalyst, 6-benzyl-pyrrolo [3,4-b ] pyridine-5, 7-diketone and hydrogen are subjected to asymmetric hydrogenation reaction in an organic solvent to obtain the (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane;
the chiral catalyst is generated in situ by an iridium catalyst precursor and a chiral organic ligand before reaction;
the reaction formula is as follows:
preferably, the chiral organic ligand is one or more of L1-L8:
preferably, the iridium catalyst precursor is an iridium salt containing an anion and an ancillary ligand, preferably (1, 5-cyclooctadiene) iridium (I) chloride dimer [ Ir (COD) Cl]2Or methoxy (1, 5-cyclooctadiene) iridium (I) dimer [ Ir (OMe) (COD)]2。
Preferably, the organic solvent is tert-butanol, isopropanol or neopentyl alcohol.
Preferably, the chiral catalyst is generated in an alcohol solvent.
Preferably, the molar ratio of the chiral catalyst to the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3,4-b ] pyridine-5, 7-dione is 1: 2000-1: 100;
preferably, the pressure of the hydrogen gas is 5atm to 50 atm.
Preferably, the temperature of the asymmetric hydrogenation reaction is 25 ℃ to 80 ℃.
Compared with the prior art, the invention has the beneficial effects that: the preparation method has the advantages of high efficiency, strong substrate universality and high enantioselectivity, and has wide application prospect in the fields of asymmetric synthesis and medicine research and development.
Detailed Description
The following examples illustrate specific embodiments of the present invention and should not be construed as limiting the scope of the invention.
Example 1
(1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L1(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), the system is passed through a vacuum line, replaced with nitrogen for 3 times, 2mL of freshly distilled degassed toluene is added, the solution is stirred at room temperature for 1 hour, the solvent is removed under reduced pressure to give a brown solid, 2mL of tert-butanol solvent is added after 2 hours of vacuum evacuation, the solution is added with 6-benzyl-pyrrolo [3,4-b ] solvent]A vial of pyridine-5, 7-dione (0.5mmol) was charged into the autoclave, and after six hydrogen replacements, the initial hydrogen pressure was 20bar, and the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 89%, the ee value was 87%.
1H NMR(CDCl3)δppm：1.52(2H，dt，J＝11.6，5.8Hz)，1.66(1H， dt，J＝6.8，13.3Hz)，1.98(1H，dt，J＝5.9，13.3Hz)，2.68(1H，dt，J＝ 11.7，5.9Hz)，2.79(1H，dt，J＝11.7，5.9Hz)，2.87(1H，dd，J＝6.9， 7.2Hz)，3.85(1H，d，J＝7.2Hz)，4.66(2H，s)，7.26～7.37(5H，m)。
Example 2
(1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L1(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), vacuum-pumping the system, replacing with nitrogen for 3 times, adding 2mL of freshly distilled degassed t-butanol, stirring the solution at room temperature for 1 hour, removing the solvent under reduced pressure to obtain a brown solid, vacuum-pumping for 2 hours, adding 2mL of t-butanol solvent, adding the solution containing 6-benzyl-pyrrolo [3,4-b ] -b]A vial of pyridine-5, 7-dione (0.5mmol) was charged into an autoclave, which was replaced with hydrogen six times to give an initial hydrogen pressure of 20bar, the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 92% and the ee value was 95%.
Example 3
(1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L2(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), vacuum-pumping the system, replacing with nitrogen for 3 times, adding 2mL of freshly distilled degassed t-butanol, stirring the solution at room temperature for 1 hour, removing the solvent under reduced pressure to obtain a brown solid, vacuum-pumping for 2 hours, adding 2mL of t-butanol solvent, adding the solution containing 6-benzyl-pyrrolo [3,4-b ] -b]A vial of pyridine-5, 7-dione (0.5mmol) was charged into the autoclave, and after six hydrogen replacements, the initial hydrogen pressure was 20bar, and the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 76% and the ee value was 81%.
Example 4
(1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L2(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), vacuum-pumping the system, replacing with nitrogen for 3 times, adding 2mL of freshly distilled degassed t-butanol, stirring the solution at room temperature for 1 hour, removing the solvent under reduced pressure to obtain a brown solid, vacuum-pumping for 2 hours, adding 2mL of t-butanol solvent, adding the solution containing 6-benzyl-pyrrolo [3,4-b ] -b]A vial of pyridine-5, 7-dione (0.5mmol) was charged into the autoclave, which was replaced with hydrogen six times, and then the initial hydrogen pressure was set to 30bar, and the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 84% and the ee value was 75%.
Example 5
(1S,6R)-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L3(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), vacuum-pumping the system, replacing with nitrogen for 3 times, adding 2mL of freshly distilled degassed t-butanol, stirring the solution at room temperature for 1 hour, removing the solvent under reduced pressure to obtain a brown solid, vacuum-pumping for 2 hours, adding 2mL of t-butanol solvent, adding the solution containing 6-benzyl-pyrrolo [3,4-b ] -b]A vial of pyridine-5, 7-dione (0.5mmol) was charged into the autoclave, which was replaced with hydrogen six times, and then the initial hydrogen pressure was set to 30bar, and the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 82% and the ee value 67%.
Example 6
(1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0]Asymmetric hydrogenation of nonane: in a 10mL reaction tube, phosphine ligand L1(0.005mmol) and [ Ir (COD) Cl were added]2(0.005mmol), the system was passed through a vacuum line, replaced with nitrogen 3 times, 2mL of freshly distilled degassed isopropanol was added, the solution was stirred at room temperature for 1 hour, the solvent was removed under reduced pressure to give a brown solid, 2mL of isopropanol solvent was added after vacuum extraction for 2 hours, and the solution was added to a solution containing 6-benzyl-pyrrolo [3,4-b ] -c]A vial of pyridine-5, 7-dione (0.5mmol) was charged into the autoclave, and after six hydrogen replacements, the initial hydrogen pressure was 20bar, and the reaction was stirred at 90 ℃ for 24 hours. Cooling, carefully releasing gas, opening the autoclave, taking out the vial, draining the solvent, detecting the conversion rate by NMR, detecting the enantiomeric excess value by liquid chromatography, and carrying out column chromatography to obtain the product. The conversion was 89%, the ee value was 91%.
Claims (6)
1. The preparation method of the iridium-catalyzed moxifloxacin side chain intermediate is characterized by comprising the following steps: under the catalysis of a chiral catalyst, 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3,4-b ] pyridine-5, 7-diketone and hydrogen are subjected to asymmetric hydrogenation reaction in an organic solvent to obtain (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4,3,0] nonane;
the chiral catalyst is generated in situ by an iridium catalyst precursor and a chiral organic ligand before reaction;
the reaction formula is as follows:
the chiral organic ligand is L1:
L1
the iridium catalyst precursor is (1, 5-cyclooctadiene) iridium chloride (I) dimer [ Ir (COD) Cl]2。
2. The iridium-catalyzed preparation method of moxifloxacin side chain intermediate as claimed in claim 1, wherein the organic solvent is tert-butanol, isopropanol or neopentyl alcohol solvent.
3. The iridium-catalyzed preparation method of moxifloxacin side chain intermediate as claimed in claim 2, characterized in that the chiral catalyst is generated in an alcohol solvent.
4. The preparation method of the iridium-catalyzed moxifloxacin side chain intermediate as claimed in claim 1, wherein the molar ratio of the chiral catalyst to 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3,4-b ] pyridine-5, 7-dione is 1: 2000-1: 100.
5. The preparation method of the iridium-catalyzed moxifloxacin side chain intermediate as claimed in claim 1, wherein the pressure of hydrogen is 5atm to 50 atm.
6. The preparation method of the iridium-catalyzed moxifloxacin side chain intermediate as claimed in claim 1, wherein the temperature of the asymmetric hydrogenation reaction is 25-80 ℃.
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