JP2007077047A - Method for producing 2-fluoro-6-o-substituted ketolide derivative and its intermediate - Google Patents
Method for producing 2-fluoro-6-o-substituted ketolide derivative and its intermediate Download PDFInfo
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- 239000003835 ketolide antibiotic agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- -1 triethylsilyl group Chemical group 0.000 claims description 27
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 13
- 229960003276 erythromycin Drugs 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 230000004060 metabolic process Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000003120 macrolide antibiotic agent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UXLKPEKVOFUGJR-UHFFFAOYSA-N 5-iodo-3-pyridazin-3-yl-1,2-oxazole Chemical compound O1C(I)=CC(C=2N=NC=CC=2)=N1 UXLKPEKVOFUGJR-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 206010057190 Respiratory tract infections Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 2
- IWHJPYXAFGKABF-UHFFFAOYSA-N 1,1-dibromoethene Chemical compound BrC(Br)=C IWHJPYXAFGKABF-UHFFFAOYSA-N 0.000 description 1
- MXDRPNGTQDRKQM-UHFFFAOYSA-N 3-methylpyridazine Chemical compound CC1=CC=CN=N1 MXDRPNGTQDRKQM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- NNGXBBVERLGDJT-XGWLXJMGSA-N CC[C@H]([C@](C)([C@H]([C@H]1C2C1)[C@@H](C)C([C@H](C)C[C@@](C)([C@@H]([C@@H](C)C([C@]1(C)F)=O)O[C@@H](C3=C)O[C@H](C)C[C@@H]3N(C)C)OCC#Cc3cc(/C(/N)=C/C=C\N)n[o]3)=O)OC2=O)OC1=O Chemical compound CC[C@H]([C@](C)([C@H]([C@H]1C2C1)[C@@H](C)C([C@H](C)C[C@@](C)([C@@H]([C@@H](C)C([C@]1(C)F)=O)O[C@@H](C3=C)O[C@H](C)C[C@@H]3N(C)C)OCC#Cc3cc(/C(/N)=C/C=C\N)n[o]3)=O)OC2=O)OC1=O NNGXBBVERLGDJT-XGWLXJMGSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- PENDGIOBPJLVBT-HMMOOPTJSA-N abt-773 Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@]1(C)OC\C=C\C=1C=C2C=CC=CC2=NC=1)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O PENDGIOBPJLVBT-HMMOOPTJSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007330 chocolate agar Substances 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 101150076810 erm gene Proteins 0.000 description 1
- YVTFLQUPRIIRFE-QUMKBVJLSA-N erythronolide A Chemical compound CC[C@H]1OC(=O)[C@H](C)[C@@H](O)[C@H](C)[C@@H](O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O YVTFLQUPRIIRFE-QUMKBVJLSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- YEMJHNYABQHWHL-UHFFFAOYSA-N tributyl(ethynyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C#C YEMJHNYABQHWHL-UHFFFAOYSA-N 0.000 description 1
- OKJXGZPXDVEZET-UHFFFAOYSA-N tributyl-(3-pyridazin-3-yl-1,2-oxazol-5-yl)stannane Chemical compound O1C([Sn](CCCC)(CCCC)CCCC)=CC(C=2N=NC=CC=2)=N1 OKJXGZPXDVEZET-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
本発明は、マクロライド系抗菌剤に分類される、エリスロマイシンA誘導体の新規製造方法及びその中間体に関する。 The present invention relates to a novel process for producing erythromycin A derivatives and intermediates thereof, which are classified as macrolide antibacterial agents.
クラリスリマイシンおよびアジスロマイシンに代表される第２世代マクロライド系抗菌剤は、1990年代前半に登場し、その優れた治療効果により、現在では呼吸器感染症の治療薬として広く臨床の場で用いられている。しかし、近年これらマクロライド系抗菌剤が使用されている呼吸器感染症領域において、エリスロマイシン耐性肺炎球菌等の増加が治療上の大きな問題となりつつあり、これら耐性菌に対して強い活性を有する新規マクロライド系抗菌剤の研究開発が活発に行われた。その結果、エリスロマイシン耐性肺炎球菌等に対して強い活性を有するマクロライド化合物として、テリスロマイシン（HMR3647，特許文献１）、セスロマイシン（ABT-773，特許文献２）等が見出され、さらに薬効増強を図った２−フルオロケトライド（特許文献３）等も報告されるに至った。 Second-generation macrolide antibacterial agents represented by clarithromycin and azithromycin appeared in the first half of the 1990s, and due to their excellent therapeutic effects, they are now widely used in the clinical setting as therapeutic agents for respiratory infections. ing. However, in the field of respiratory infections where these macrolide antibacterial agents are used in recent years, an increase in erythromycin-resistant pneumococci has become a major therapeutic problem, and new macros with strong activity against these resistant bacteria. Research and development of ride antibacterial agents were actively conducted. As a result, as a macrolide compound having strong activity against erythromycin-resistant pneumococci, etc., terisromycin (HMR3647, Patent Document 1), cesromycin (ABT-773, Patent Document 2), etc. were found, and further enhanced efficacy 2-Fluoroketolide (Patent Document 3) and the like that aim to achieve this have been reported.
この2−フルオロケトライド化合物群の中から、耐性菌活性のみならず、薬物相互作用の観点から、長年にわたってマクロライド系抗菌剤の問題とされてきたヒト型Cyp3A4代謝に対する安定性を改善したケトライド化合物として、5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１1−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートが見出された（特許文献４）。 Among these 2-fluoroketolide compound groups, ketolide compounds that have improved stability against human Cyp3A4 metabolism, which has been a problem of macrolide antibacterial agents for many years from the viewpoint of drug interaction as well as resistant bacterial activity 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3 -Oxoerythronolide A 11,12-cyclic carbamate was found (Patent Document 4).
この5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１1−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートの一般的な製造方法は、最終工程において6位側鎖上の芳香環部分を、パラジウム触媒等を用いて導入するため、最終生成物中に金属、試薬、試薬由来の分解物等が多く混在してしまうことから、最終目的物の単離精製が煩雑となり、工業スケールでの実施が困難なものとなっている。 This 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3- In the general production method of oxoerythronolide A 11,12-cyclic carbamate, an aromatic ring part on the 6-position side chain is introduced using a palladium catalyst or the like in the final step, so that a metal is contained in the final product. In addition, since many reagents and degradation products derived from the reagent are mixed, it is difficult to isolate and purify the final target product, and it is difficult to implement it on an industrial scale.
本発明の目的は、エリスロマイシン耐性肺炎球菌等に対し優れた抗菌活性を有し、かつヒト型Cyp3A4代謝に対し安定な5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１1−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートの工業スケールで実施可能な新規製造法と、製造上有用な中間体を提供することである。 The object of the present invention is to have 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino- which has excellent antibacterial activity against erythromycin-resistant pneumococci and the like and is stable against human Cyp3A4 metabolism. 6-O- [3- [3- (3-Pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate And to provide intermediates that are useful in manufacturing.
本発明者等は、種々製造法を検討した結果、
式（I）
As a result of studying various production methods, the present inventors,
Formula (I)
（式中、Rは水酸基の保護基を示し、好ましくはアセチル基、プロピオニル基、ベンゾイル基、トリメチルシリル基、トリエチルシリル基またはt-ブチルジメチルシリル基を示す）で表される化合物を鍵中間体として経由することにより、高純度の目的化合物を工業スケールで製造可能であることを見出し本発明を完成した。 (Wherein R represents a protecting group for a hydroxyl group, preferably an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group or a t-butyldimethylsilyl group) Through this process, it was found that the target compound of high purity can be produced on an industrial scale, and the present invention was completed.
すなわち本発明は
（１）式
That is, the present invention provides the formula
（式中、Rは水酸基の保護基を示し、好ましくはアセチル基、プロピオニル基、ベンゾイル基、トリメチルシリル基、トリエチルシリル基又はt-ブチルジメチルシリル基を示す）で表される化合物および式 (Wherein R represents a hydroxyl-protecting group, and preferably represents an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group)
（式中、Xは脱離基、好ましくはヨウ素原子、臭素原子、塩素原子、トルエンスルホニルオキシ基、メチルスルホニルオキシ基またはトリフロロメチルスルホニルオキシ基を示す。）で表される化合物を反応させることを特徴とする、式 (Wherein X represents a leaving group, preferably an iodine atom, bromine atom, chlorine atom, toluenesulfonyloxy group, methylsulfonyloxy group or trifluoromethylsulfonyloxy group). Characterized by the formula
（式中、Ｒは前述と同義）で示される化合物の製造方法。
（２）式
(Wherein, R is as defined above).
(2) Formula
（式中、Rは水酸基の保護基を示す）で表される化合物。
である。
(Wherein R represents a hydroxyl-protecting group).
It is.
本発明の製造方法及び化合物により、5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１1−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを工業的に可能な方法で、高い純度で製造することができた。 According to the production method and compound of the present invention, 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate could be produced with high purity by an industrially possible method.
本発明で、水酸基の保護基とはこの分野で利用できる水酸基の保護基を意味し、好ましいものとしてはアセチル基、プロピオニル基、ベンゾイル基、トリメチルシリル基、トリエチルシリル基またはt-ブチルジメチルシリル基をあげることができる。 In the present invention, the hydroxyl-protecting group means a hydroxyl-protecting group that can be used in this field, and preferred examples include an acetyl group, a propionyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group. I can give you.
本発明で、脱離基とはこの分野で利用できる一般的な脱離基を意味し、好ましいものとしてヨウ素原子、臭素原子、塩素原子、トルエンスルホニルオキシ基、メチルスルホニルオキシ基またはトリフロロメチルスルホニルオキシ基をあげることができる。 In the present invention, the leaving group means a general leaving group that can be used in this field, and preferred is an iodine atom, bromine atom, chlorine atom, toluenesulfonyloxy group, methylsulfonyloxy group, or trifluoromethylsulfonyl. An oxy group can be mentioned.
本発明では、ジャーナル・オブ・メディシナル・ケミストリー 第46巻10号1796頁（2003年）記載の、式（II） In the present invention, the formula (II) described in Journal of Medicinal Chemistry, Vol. 46, No. 10, page 1796 (2003)
（式中、Rは前記と同義である。）で表される化合物と、式（III）
（式中、Xは脱離基、好ましくはヨウ素原子、臭素原子、塩素原子、トルエンスルホニルオキシ基、メチルスルホニルオキシ基またはトリフロロメチルスルホニルオキシ基を示す。）で表される化合物をトリエチルアミン等の塩基存在下、ビス（トリフェニルホスフィン）パラジウムジクロライド等のパラジウム試薬と共に、アセトニトリル等の不活性溶媒中、室温から加熱還流の条件で作用させ式(I)で示される化合物を得る。 (Wherein X represents a leaving group, preferably an iodine atom, a bromine atom, a chlorine atom, a toluenesulfonyloxy group, a methylsulfonyloxy group or a trifluoromethylsulfonyloxy group) In the presence of a base, the compound represented by the formula (I) is obtained by reacting with a palladium reagent such as bis (triphenylphosphine) palladium dichloride in an inert solvent such as acetonitrile at room temperature to heating under reflux.
得られた式(I)で示される化合物は続いて、例えばメタノール中、室温又は加熱還流させる方法などにより２´位の脱保護を行い、式（I）におけるＲが水素原子である、5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを得ることができる。 The obtained compound represented by the formula (I) is subsequently deprotected at the 2 ′ position by, for example, a method of refluxing in methanol at room temperature or under heating, and in the formula (I), R is a hydrogen atom. O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3-oxoerythrono DoA 11,12-cyclic carbamate can be obtained.
本製造法においては、式（I）で示される化合物において不溶物の濾去、水溶液の液性の違いを利用した有機溶媒による抽出精製等を行うことが可能なため、続く２´位保護基を除去した後、結晶化により高純度の5−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１1−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを工業スケールで製造することが可能である。 In this production method, the insoluble matter in the compound represented by the formula (I) can be removed by filtration, extraction and purification with an organic solvent using the difference in liquidity of the aqueous solution, etc. After removal of azobenzene, high-purity 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5- [Il] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate can be produced on an industrial scale.
実施例
以下、実施例により本発明をさらに詳細に説明する。
参考例１
（１）カリウムt-ブトキシド8.9g(80mmol)をTHF 50mlに溶解し氷冷下３−メチルピリダジン5g(53mmol)のTHF溶液（10ml）を約5分かけて滴下した。反応混合物を室温で1.5時間攪拌した後、氷冷下亜硝酸t-ブチル 12.6ml(106mmol)のTHF溶液(10ml)を約5分かけて滴下し、その後室温で19時間攪拌した。反応混合物を減圧濃縮し水20mlを加え、その後4N-塩酸水溶液を加え中和した。この混合物を減圧濃縮し、析出した結晶を濾取して３−ピリダジンアルドキシムの高極性異性体 1.8gを得た。母液は塩析して酢酸エチルで抽出（５０ml、２回）、有機層を硫酸マグネシウムで乾燥後減圧濃縮した。残渣にヘキサンを加え、得られた粉末を濾取して、３−ピリダジンアルドキシムの低極性・高極性の異性体混合物2.8gを得た。合計4.6g(収率71%)の３−ピリダジンアルドキシムを得た。
Examples Hereinafter, the present invention will be described in more detail by way of examples.
Reference example 1
(1) Potassium t-butoxide (8.9 g, 80 mmol) was dissolved in THF (50 ml), and a solution of 3-methylpyridazine (5 g, 53 mmol) in THF (10 ml) was added dropwise over about 5 minutes. The reaction mixture was stirred at room temperature for 1.5 hours, and then a solution of t-butyl nitrite 12.6 ml (106 mmol) in THF (10 ml) was added dropwise over about 5 minutes under ice-cooling, and then stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure, 20 ml of water was added, and then 4N-hydrochloric acid aqueous solution was added for neutralization. This mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 1.8 g of a highly polar isomer of 3-pyridazine aldoxime. The mother liquor was salted out and extracted with ethyl acetate (50 ml, twice). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue, and the resulting powder was collected by filtration to obtain 2.8 g of a low-polarity and high-polar isomer mixture of 3-pyridazine aldoxime. A total of 4.6 g (yield 71%) of 3-pyridazine aldoxime was obtained.
低極性異性体
MS(ESI) m/z 145.9[M+Na]+
1H-NMR(200 MHz, DMSO-d6) δ(ppm) 7.79(dd, J=9.01, 5.05Hz, 1H)，7.84(s, 1H)，8.57(dd, J=8.79,1.76Hz, 1H), 9.23(dd, J=4.83,1.76Hz, 2H)，12.43(s, 1H)
Low polar isomer
MS (ESI) m / z 145.9 [M + Na] +
1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm) 7.79 (dd, J = 9.01, 5.05 Hz, 1H), 7.84 (s, 1H), 8.57 (dd, J = 8.79, 1.76 Hz, 1H ), 9.23 (dd, J = 4.83, 1.76Hz, 2H), 12.43 (s, 1H)
高極性異性体
MS(ESI) m/z 145.9[M+Na]+
1H-NMR(200 MHz, DMSO-d6) δ(ppm) 7.72(m, 1H)，8.02 (dd, J=8.79,1.76Hz, 1H), 8.34(s, 1H)，9.20(dd, J=4.83,1.76Hz, 1H)，12.1(s, 1H)
High polar isomer
MS (ESI) m / z 145.9 [M + Na] +
1 H-NMR (200 MHz, DMSO-d 6 ) δ (ppm) 7.72 (m, 1H), 8.02 (dd, J = 8.79,1.76Hz, 1H), 8.34 (s, 1H), 9.20 (dd, J = 4.83,1.76Hz, 1H), 12.1 (s, 1H)
（２）300mlナスフラスコに、上記３−ピリダジンアルドキシム異性体混合物3.7g(30mmol)、酢酸エチル100ml、トリブチルエチニルスズ8.5ml（d 1.09, 25mmol）、炭酸水素ナトリウム6.3g（75mmol）、水5ml、N-クロロコハク酸イミド4.0g（30mmol）を順次加え、室温で16時間攪拌した。水5mlをさらに加え4時間攪拌した後、飽和炭酸水素ナトリウム水溶液100mlを加え分液した。水層を酢酸エチルで抽出後有機層を合わせ、飽和食塩水で洗浄、硫酸マグネシウムで乾燥した。減圧濃縮の後ヘキサンを加え析出した粉末を濾別し、母液を減圧濃縮してトリ−ｎ−ブチル−｛［３−（ピリダジン−３−イル）］イソキサゾール−５−イル｝スズの粗生成物を得た。 (2) In a 300 ml eggplant flask, 3.7 g (30 mmol) of the above 3-pyridazine aldoxime isomer mixture, 100 ml of ethyl acetate, 8.5 ml of tributylethynyltin (d 1.09, 25 mmol), 6.3 g (75 mmol) of sodium bicarbonate, 5 ml of water Then, 4.0 g (30 mmol) of N-chlorosuccinimide was sequentially added, and the mixture was stirred at room temperature for 16 hours. After further adding 5 ml of water and stirring for 4 hours, 100 ml of a saturated aqueous sodium hydrogen carbonate solution was added to separate the layers. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, hexane was added and the precipitated powder was filtered off. The mother liquor was concentrated under reduced pressure to give a crude product of tri-n-butyl-{[3- (pyridazin-3-yl)] isoxazol-5-yl} tin. Got.
この粗生成物をTHF100mlに溶解し、ヨウ素3.2g(25.2mmol)を一度に加えた。反応混合物を室温で35分攪拌した後反応混合物を6%チオ硫酸ナトリウム水溶液にあけ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、硫酸マグネシウムで乾燥後減圧濃縮し、残渣にヘキサンを加え析出している結晶を濾取した。この結晶をヘキサンで洗浄、乾燥して３−(５−ヨードイソキサゾール−3−イル)ピリダジン 2.9gを得た。
MS(ESI) m/z 295.9[M+Na]+
1H NMR (200 MHz, CDCl3) δppm 7.36(s, 1H) 7.62(dd, J=8.35, 4.83Hz, 1H) 8.22(dd, J=8.35,1.76Hz, 1H) 9.26(dd, J=4.83,1.76Hz, 1H)
This crude product was dissolved in 100 ml of THF and 3.2 g (25.2 mmol) of iodine was added in one portion. The reaction mixture was stirred at room temperature for 35 minutes, then poured into 6% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with hexane and dried to obtain 2.9 g of 3- (5-iodoisoxazol-3-yl) pyridazine.
MS (ESI) m / z 295.9 [M + Na] +
1 H NMR (200 MHz, CDCl 3 ) δppm 7.36 (s, 1H) 7.62 (dd, J = 8.35, 4.83Hz, 1H) 8.22 (dd, J = 8.35,1.76Hz, 1H) 9.26 (dd, J = 4.83 , 1.76Hz, 1H)
５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートの合成 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3-oxo Synthesis of erythronolide A 11,12-cyclic carbamate
（１）ジャーナル・オブ・メディシナル・ケミストリー 第46巻10号1795頁〜1798頁（2003年）記載の方法により合成した２´−Ｏ−ベンゾイル−５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−３−オキソ−６−Ｏ−プロパルギルエリスロノリドＡ １１，１２−サイクリックカーバメート 7.59g (10.0mmol)、参考例１により合成した３−(５−ヨードイソキサゾール−3−イル)ピリダジン 2.73g (10.0mmol)、ビス（トリフェニルホスフィン）パラジウムジクロリド（II） 351mg(0.5mmol)、アセトニトリル152ml、トリエチルアミン76mlを混合し、60℃で8時間攪拌した。反応混合物を減圧濃縮して得られた残渣に、酢酸イソプロピル22.8mlおよびメチルt-ブチルエーテル152mlを加え撹拌後、析出した不溶物を濾去した。濾液に2mol/lの塩酸50mlを加え撹拌後分液した。有機層を2mol/lの塩酸20mlで再抽出した後、水層を合わせメチルt-ブチルエーテル20mlで洗浄した。水層に酢酸イソプロピル100mlを加えたのち、4 mol/l水酸化ナトリウム水溶液を加えｐH12とした。分液後、有機層を飽和食塩水23mlで洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、２´−Ｏ−ベンゾイル−５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメート7.46g（収率82.5%）を得た。
MS(ESI) m/z 904.3[M+H]+
1H NMR (300 MHz, CDCl3) δppm 0.90(t,J=7.46Hz,3H) 2.27(s,6H) 3.69(s,1H) 3.78(d,J=17.55Hz,1H) 3.88(d,J=17.55Hz,1H) 4.57(d,J=7.50Hz,1H) 5.70(s,1H) 7.42-7.50(m,2H) 7.49(s,1H) 7.55-7.63(m,1H) 7.60(dd, J=8.40,5.10Hz,1H) 8.01-8.07(m,2H) 8.28(dd,J=8.40,1.80Hz,1H) 9.24(dd,J=5.10,1.80Hz,1H)
(1) 2'-O-benzoyl-5-O-desosaminyl-3,11-dideoxy-2 synthesized by the method described in Journal of Medicinal Chemistry, Vol. 46, No. 10, pages 1795 to 1798 (2003) -Fluoro-11-amino-3-oxo-6-O-propargylerythronolide A 11,12-cyclic carbamate 7.59 g (10.0 mmol), 3- (5-iodoisoxazole- synthesized according to Reference Example 1 3-yl) pyridazine (2.73 g, 10.0 mmol), bis (triphenylphosphine) palladium dichloride (II) (351 mg, 0.5 mmol), acetonitrile (152 ml), and triethylamine (76 ml) were mixed and stirred at 60 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, and 22.8 ml of isopropyl acetate and 152 ml of methyl t-butyl ether were added to the residue and stirred, and the precipitated insoluble material was removed by filtration. 50 ml of 2 mol / l hydrochloric acid was added to the filtrate and the mixture was stirred and separated. The organic layer was re-extracted with 20 ml of 2 mol / l hydrochloric acid, and the aqueous layers were combined and washed with 20 ml of methyl t-butyl ether. After adding 100 ml of isopropyl acetate to the aqueous layer, a 4 mol / l aqueous sodium hydroxide solution was added to adjust the pH to 12. After separation, the organic layer was washed with 23 ml of saturated brine. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, 2'-O-benzoyl-5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- 7.46 g (82.5% yield) of (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate was obtained.
MS (ESI) m / z 904.3 [M + H] +
1 H NMR (300 MHz, CDCl 3 ) δppm 0.90 (t, J = 7.46Hz, 3H) 2.27 (s, 6H) 3.69 (s, 1H) 3.78 (d, J = 17.55Hz, 1H) 3.88 (d, J = 17.55Hz, 1H) 4.57 (d, J = 7.50Hz, 1H) 5.70 (s, 1H) 7.42-7.50 (m, 2H) 7.49 (s, 1H) 7.55-7.63 (m, 1H) 7.60 (dd, J = 8.40,5.10Hz, 1H) 8.01-8.07 (m, 2H) 8.28 (dd, J = 8.40,1.80Hz, 1H) 9.24 (dd, J = 5.10,1.80Hz, 1H)
（２）上記（１）で得た化合物7.46g(8.25mmol)をメタノール37.3mlに溶解させ9時間加熱還流させた後、減圧濃縮した。濃縮残渣にイソプロピルアルコール22.4mlを加え50℃に加熱した後、ヘプタン22.4mlを加えた。2時間氷冷した後、析出物を濾取し、イソプロピルアルコール7.5mlとヘプタン7.5mlの混合溶媒で洗浄した。得られた粉末をイソプロピルアルコール75mlに加熱溶解し不要物を濾過した後、常圧下で溶媒を55ml加熱留去した。一晩撹拌放冷後、2時間氷浴に浸し、析出物を濾取した。イソプロピルアルコール5mlで洗浄し、50℃で真空乾燥させることにより、５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメート4.27g（収率65%）を得た。 (2) The compound 7.46 g (8.25 mmol) obtained in (1) above was dissolved in 37.3 ml of methanol and heated to reflux for 9 hours, and then concentrated under reduced pressure. After adding 22.4 ml of isopropyl alcohol to the concentrated residue and heating to 50 ° C., 22.4 ml of heptane was added. After cooling with ice for 2 hours, the precipitate was collected by filtration and washed with a mixed solvent of 7.5 ml of isopropyl alcohol and 7.5 ml of heptane. The obtained powder was dissolved by heating in 75 ml of isopropyl alcohol, and unnecessary substances were filtered off. Then, 55 ml of the solvent was distilled off by heating under normal pressure. The mixture was allowed to cool overnight and then immersed in an ice bath for 2 hours, and the precipitate was collected by filtration. By washing with 5 ml of isopropyl alcohol and vacuum drying at 50 ° C., 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl ) Isoxazolyl-5-yl] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate 4.27 g (yield 65%) was obtained.
２´−Ｏ−ベンゾイル−５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートの合成
（１）参考例１（１）の方法で合成した３−ピリダジンアルドキシム1.23g(10mmol)、炭酸水素ナトリウム2.10g(25mmol)、酢酸エチル19.7ml、水1.23mlをアルゴンガス雰囲気下で混合し、ジャーナル・オブ・アメリカン・ケミカル・ソサイエティー 第107巻, 7号, 2023頁-2032頁（1985年）記載の方法に従い合成した1,1-ジブロモエテン 6.5mlおよびN−クロロコハク酸イミド1.34g(10mmol)を加えた。室温下で一晩撹拌した後、不溶物を濾去し、濾液の上層を分取し、水20mlで洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮し、濃縮残渣をシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン：トリエチルアミン＝６：10：0.2）により精製し、３−(５−ブロモイソキサゾール−3−イル)ピリダジン 115ｍg（収率５%）を得た。
MS(ESI) m/z 225.8 [M+H]+
1H NMR (300MHz,CDCl3) δppm 7.20 (s,1H) 7.63 (dd,J=8.70,5.10 Hz,1H) 8.22 (dd,J=8.70,1.80Hz,1H) 9.27 (dd,J=5.10,1.80Hz,1H)
2'-O-benzoyl-5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2 -Propynyl] -3-oxoerythronolide A Synthesis of 11,12-cyclic carbamate (1) 1.23 g (10 mmol) of 3-pyridazine aldoxime synthesized by the method of Reference Example 1 (1), 2.10 g of sodium bicarbonate (25 mmol), 19.7 ml of ethyl acetate and 1.23 ml of water were mixed under an argon gas atmosphere, and the method described in Journal of American Chemical Society Vol. 107, No. 7, pp. 2023-2032 (1985) was followed. 6.5 ml of 1,1-dibromoethene synthesized and 1.34 g (10 mmol) of N-chlorosuccinimide were added. After stirring overnight at room temperature, the insoluble material was removed by filtration, and the upper layer of the filtrate was separated and washed with 20 ml of water. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, the concentrated residue was purified by silica gel column chromatography (acetone: hexane: triethylamine = 6: 10: 0.2) to give 3- (5-bromoisoxazol-3-yl) pyridazine 115 mg (yield 5%) was obtained.
MS (ESI) m / z 225.8 [M + H] +
1 H NMR (300MHz, CDCl 3 ) δppm 7.20 (s, 1H) 7.63 (dd, J = 8.70,5.10 Hz, 1H) 8.22 (dd, J = 8.70,1.80Hz, 1H) 9.27 (dd, J = 5.10, 1.80Hz, 1H)
（２）ジャーナル・オブ・メディシナル・ケミストリー 第46巻10号1795頁〜1798頁（2003年）記載の方法により合成した２´−Ｏ−ベンゾイル−５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−３−オキソ−６−Ｏ−プロパルギルエリスロノリドＡ １１，１２−サイクリックカーバメート152mg (0.20mmol)、上記（１）で合成した３−(５−ブロモイソキサゾール−3−イル)ピリダジン54.2mg (0.24mmol)、テトラキス（トリフェニルホスフィン）パラジウム11.6mg(0.01mmol)、アセトニトリル1.5ml、トリエチルアミン0.8mlを混合し、60℃で5時間攪拌した。テトラキス（トリフェニルホスフィン）パラジウム34.8mg(0.03mmol)を追加し、60℃で更に12時間攪拌した。反応混合物を減圧濃縮後、定法に従い後処理を行い、実施例１の（１）で得た化合物147ｍg（収率81%）を得た。 (2) 2'-O-benzoyl-5-O-desosaminyl-3,11-dideoxy-2 synthesized by the method described in Journal of Medicinal Chemistry, Vol. 46, No. 10, pages 1795 to 1798 (2003) -Fluoro-11-amino-3-oxo-6-O-propargylerythronolide A 11,12-cyclic carbamate 152 mg (0.20 mmol), 3- (5-bromoisoxazole- synthesized in (1) above 3-yl) pyridazine (54.2 mg, 0.24 mmol), tetrakis (triphenylphosphine) palladium (11.6 mg, 0.01 mmol), acetonitrile (1.5 ml), and triethylamine (0.8 ml) were mixed and stirred at 60 ° C. for 5 hours. Tetrakis (triphenylphosphine) palladium (34.8 mg, 0.03 mmol) was added, and the mixture was further stirred at 60 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and worked up according to the usual method to obtain 147 mg (yield 81%) of the compound obtained in Example 1 (1).
参考例２：抗菌活性試験
被験化合物として５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを用い、エリスロマイシン耐性肺炎球菌、エリスロマイシン耐性連鎖球菌に対する抗菌活性を、National Committee for Clinical Laboratory Standards (NCCLS) guidelinesに準じた微量液体希釈法による最小発育阻止濃度（MIC）で評価した。
Reference Example 2: Antibacterial activity test 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl as a test compound ] -2-propynyl] -3-oxoerythronolide A 11,12-cyclic carbamate, antibacterial activity against erythromycin-resistant pneumococci and erythromycin-resistant streptococci according to the National Committee for Clinical Laboratory Standards (NCCLS) guidelines In addition, the minimum inhibitory concentration (MIC) by the micro liquid dilution method was evaluated.
羊血液寒天培地およびチョコレート寒天培地で一夜培養した肺炎球菌をMueller-Hinton broth （MHB）で0.5 McFarand相当に懸濁し、これらを10倍に希釈（約107 CFU/ml）して接種用菌液とした。これらの菌液５mlを３%馬溶血液添加の２価イオン濃度調整済みMHBおよびHaemophilus test mediumに約5×105 CFU/mlの菌量となるように感受性試験用マイクロプレートに接種した。これらを３５℃、通常環境下で20時間培養後に各化合物のMICを測定した。 Streptococcus pneumoniae cultured overnight in sheep blood agar and chocolate agar is suspended in Mueller-Hinton broth (MHB) to the equivalent of 0.5 McFarand and diluted 10-fold (approximately 10 7 CFU / ml) It was. 5 ml of these bacterial solutions were inoculated into a microplate for susceptibility testing so that the amount of bacteria was about 5 × 10 5 CFU / ml in MHB and Haemophilus test medium with 3% equine hemolysis added. These were cultured at 35 ° C. in a normal environment for 20 hours, and then the MIC of each compound was measured.
その結果、被験化合物のＭＩＣは、耐性肺炎球菌(erm(B)遺伝子)には0.008μg/ml、耐性連鎖球菌(erm遺伝子)には0.03μg/mlであった。 As a result, the MIC of the test compound was 0.008 μg / ml for resistant pneumococci (erm (B) gene) and 0.03 μg / ml for resistant streptococci (erm gene).
参考例３：Cyp阻害試験
Cyp阻害試験は被験化合物を添加した後、蛍光基質を添加する前に45分間のプレインキュベーションを行った。その他はCrespiらの方法（Crespi CL, et al., Analyt. Biochem. 1997, 248, 188-190）に準拠して行った。
Reference Example 3: Cyp inhibition test
In the Cyp inhibition test, 45 minutes pre-incubation was performed after adding the test compound and before adding the fluorescent substrate. Others were performed according to the method of Crespi et al. (Crespi CL, et al., Analyt. Biochem. 1997, 248, 188-190).
被験化合物としては、５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを用いた。 As a test compound, 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl ] -3-Oxoerythronolide A 11,12-cyclic carbamate was used.
被験化合物のCyp3A4に対する阻害の強さは、それぞれ0.96μＭであり、Cyp3A4阻害作用が弱く、安全性に優れることが確認された。 The strength of inhibition of the test compound against Cyp3A4 was 0.96 μM, respectively, confirming that the Cyp3A4 inhibitory action was weak and the safety was excellent.
参考例４：従来製法
WO99/21871号およびUS6124269号に記した方法により合成した５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−３−オキソ−６−Ｏ−プロパルギルエリスロノリドＡ １１，１２−サイクリックカーバメート0.8g (1.22mmol)、３−(５−ヨードイソキサゾール−3−イル)ピリダジン 0.4g (1.46mmol)、ビス（トリフェニルホスフィン）パラジウムクロリド（II） 0.04g (0.06mmol)、アセトニトリル10ml、トリエチルアミン5mlを混合し、系内をアルゴン置換した後、６０℃で１４時間攪拌した。
Reference example 4: Conventional manufacturing method
5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-3-oxo-6-O-propargylerythronolide A 11,12 synthesized by the method described in WO99 / 21871 and US6124269 -Cyclic carbamate 0.8 g (1.22 mmol), 3- (5-iodoisoxazol-3-yl) pyridazine 0.4 g (1.46 mmol), bis (triphenylphosphine) palladium chloride (II) 0.04 g (0.06 mmol) Then, 10 ml of acetonitrile and 5 ml of triethylamine were mixed, and the system was purged with argon, followed by stirring at 60 ° C. for 14 hours.
反応混合物を減圧濃縮して得られた残渣を、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール：２５％アンモニア水＝19：1：0.1）により精製し、ジエチルエーテル-ヘキサンにて固化、濾取、乾燥して５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメート 0.59g（収率60%）を得た。 The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol: 25% aqueous ammonia = 19: 1: 0.1), solidified with diethyl ether-hexane, filtered and dried. 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] -3- 0.59 g (60% yield) of oxoerythronolide A 11,12-cyclic carbamate was obtained.
本発明により、５−Ｏ−デソサミニル−３，１１−ジデオキシ−２−フルオロ−１１−アミノ−６−Ｏ−[３−[３−（３−ピリダジル）イソキサゾリル−５−イル]−２−プロピニル]−３−オキソエリスロノリドＡ １１，１２−サイクリックカーバメートを工業的に可能な方法で、高い純度で製造することができたので、医薬品製造に有用である。
According to the invention, 5-O-desosaminyl-3,11-dideoxy-2-fluoro-11-amino-6-O- [3- [3- (3-pyridazyl) isoxazolyl-5-yl] -2-propynyl] Since -3-oxoerythronolide A 11,12-cyclic carbamate can be produced with high purity by an industrially possible method, it is useful for pharmaceutical production.
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