CN1493562A - 7-substituted aminomethyl fluoroquinolone derivatives with antibacterial activity and preparation method - Google Patents
7-substituted aminomethyl fluoroquinolone derivatives with antibacterial activity and preparation method Download PDFInfo
- Publication number
- CN1493562A CN1493562A CNA021123780A CN02112378A CN1493562A CN 1493562 A CN1493562 A CN 1493562A CN A021123780 A CNA021123780 A CN A021123780A CN 02112378 A CN02112378 A CN 02112378A CN 1493562 A CN1493562 A CN 1493562A
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- Prior art keywords
- reaction
- derivative
- temperature
- methyl
- fluoroquinolone
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 6
- -1 7-substituted aminomethyl fluoroquinolone Chemical class 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 claims abstract description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 229910004373 HOAc Inorganic materials 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
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- 230000007062 hydrolysis Effects 0.000 claims description 12
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- 239000000203 mixture Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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- XNIVKSPSCYJKBL-UHFFFAOYSA-N 2h-1,2-benzoxazine-6-carboxylic acid Chemical compound O1NC=CC2=CC(C(=O)O)=CC=C21 XNIVKSPSCYJKBL-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001931 aliphatic group Chemical group 0.000 claims description 7
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- 150000004982 aromatic amines Chemical class 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- 238000010992 reflux Methods 0.000 claims description 5
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
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- 150000003839 salts Chemical class 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- NTIGNJOEVBTPJJ-UHFFFAOYSA-N 3,3-dibromopentane Chemical compound CCC(Br)(Br)CC NTIGNJOEVBTPJJ-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
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- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
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- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- 229910020667 PBr3 Inorganic materials 0.000 claims 3
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 3
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims 3
- 238000006987 Nef reaction Methods 0.000 claims 2
- 150000001448 anilines Chemical class 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- ZCJAYDKWZAWMPR-UHFFFAOYSA-N 1-chloro-2-fluorobenzene Chemical compound FC1=CC=CC=C1Cl ZCJAYDKWZAWMPR-UHFFFAOYSA-N 0.000 claims 1
- QKSCBRHANPRVRG-UHFFFAOYSA-N 1-cyclopropyl-7-[(cyclopropylamino)methyl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(F)C(CNC3CC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 QKSCBRHANPRVRG-UHFFFAOYSA-N 0.000 claims 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
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- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000007800 oxidant agent Substances 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 2
- KGVSAAYEAPSTLR-UHFFFAOYSA-N 4-(aminomethyl)-3-fluoro-1H-quinolin-2-one Chemical class NCC1=C(C(NC2=CC=CC=C12)=O)F KGVSAAYEAPSTLR-UHFFFAOYSA-N 0.000 abstract 1
- 241000192125 Firmicutes Species 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 29
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- CFLBIADORGSMCX-UHFFFAOYSA-N 2h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC=NC2=CC(C(=O)O)=CC=C21 CFLBIADORGSMCX-UHFFFAOYSA-N 0.000 description 10
- YJZWOFMQJMPNMM-UHFFFAOYSA-N 3-fluoro-4-methyl-1h-quinolin-2-one Chemical compound C1=CC=C2C(C)=C(F)C(=O)NC2=C1 YJZWOFMQJMPNMM-UHFFFAOYSA-N 0.000 description 10
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- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000588772 Morganella morganii Species 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000207961 Sesamum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 241000607766 Shigella boydii Species 0.000 description 1
- 241000607760 Shigella sonnei Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- XMQNUWMJGMQOPE-UHFFFAOYSA-N acetonitrile;piperazine Chemical compound CC#N.C1CNCCN1 XMQNUWMJGMQOPE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- FXICHSQUUNYSCS-UHFFFAOYSA-N azane;chlorobenzene Chemical compound N.ClC1=CC=CC=C1 FXICHSQUUNYSCS-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940115939 shigella sonnei Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 229920001187 thermosetting polymer Polymers 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000010267 two-fold dilution method Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A site-7 substituted aminomethyl fluoroquinolone derivative with antibacterial action to gram-positive bacteria and its preparing process are disclosed.
Description
Technical field
This belongs to the pharmaceutical chemistry synthesis technical field, relates to 7 substituted amine methyl fluoro quinolone derivatives and preparation method thereof.
Background technology
In the past few decades, Pharmaceutical Chemists have been made extensive work on the structural modification of fluoroquinolone, obtained great achievement, tens fluoroquinolone antibacterial agents such as norfloxicin are successively arranged, Ciprofloxacin, Ofloxacine USP 23, levofloxacins etc. go on the market in all parts of the world.(Zhou Weicheng etc., fluoroquinolone drug research new development Chinese Journal of New Drugs 2000,9:667).The important structure feature of these medicines is exactly that 7 bit strips have ring-shaped fat amine, and these substituting groups all are to be combined on mother's ring of fluoroquinolone by nitrogen-atoms.On the contrary, the rosoxasin of early discovery is connected to pyridyl (Carabareas PM at 7, Brundage RP, Gelotte KO, et al.1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acids.J.Heterocycl.Chem.1984,21:1857).Amino cyclopropyl is incorporated into levofloxacin female ring gained derivative T-3761 (pazufloxacin) broad spectrum antibiotic activity is arranged, to most clinical isolates activity are Ofloxacine USP 23 and norfloxicin 2～32 times, are 1～8 times of tosulfloxacin (tosufloxacin).Oral to comprising the G of the drug-fast pseudomonas aeruginosa of fluoroquinolone
+And G
-Microbial lung, urethra and system infect effectively.(Fukaoka?Y，Ikeda?Y，Yamashiro?Y，et?al.In?vitro?and?in?vivo?antibacterial?activity?of?T-3761，Antimicrob.Agent.Chemother.1993，37：384.)。
The norfloxicin Ciprofloxacin
The Ofloxacine USP 23 levofloxacin
Rosoxacln???????????????????????pazufloxacin
As can be seen from the above, owing to have its 7 bit substituent of fluoroquinolone of anti-microbial activity bigger mutability is arranged, although done many work at present in this respect, 7 groups still have the space of modification.The more important thing is, although in the fluoroquinolone medicines structure of listing, female ring all is to connect by the carbonnitrogen bond key with 7 bit substituents at present, this may not play absolute effect to the anti-microbial activity that keeps the fluoroquinolone medicine, why like this, one of reason might be because the convenience of chemosynthesis.Just because the difficulty of chemosynthesis, 7 side chains encircle with carbon-carbon bond key fluoroquinolone even with female, known example and few on the document, the structural modification of this respect may have new discovery, therefore, researching and developing 7 side chains and the fluoroquinolone that female ring connects with the carbon-carbon bond key, to seek to have the fluoro quinolone derivative of high anti-microbial activity, is that people institute is very expected.
Summary of the invention
One of technical issues that need to address of the present invention are to disclose a series of 7 substituted amine methyl fluoro quinolone derivatives with anti-microbial activity, to satisfy medicine industry field and people's needs;
Two of the technical issues that need to address of the present invention provide the preparation method of said derivative.
Technical conceive of the present invention is such:
Consider that 7 bit strips have a basic group (as amido) that the anti-microbial activity and the pharmacokinetic property of quinolone are had material impact, the substituting group that the present invention will contain N is connected in the female ring of different fluoroquinolones by a methene key, thereby has synthesized 7 substituted amine methyl fluoro quinolone derivatives of the present invention.
7 substituted amine methyl fluoro quinolone derivatives of the present invention are the compound with one of following general structure:
In the formula:
R
1And R
2Can be identical, also can be different, R
1, R
2Be H, aliphatic group or aryl radical; Or NR
1R
2Be ring texture, preferably:
NR
1R
2Can be
N=1,2;
Or NR
1R
2For
R
3And R
4Can be identical, also can be different, R
3, R
4Be H or alkyl;
Z is O, S, NH or NR
5, R
5Be aliphatic group or aryl radical etc.
Preferred R
1, R
2Be H, C
1～C
10Aliphatic group, C
3～C
6The phenyl of ring-shaped fat alkyl, replacement (or not replacing) or aryl radical such as heterocycle, most preferred R
1Or R
2Be H, C
1～C
4Chain or ring-shaped fat alkyl or single (or many) halos (or methyl substituted) phenyl or pyridyl, as methyl, ethyl, sec.-propyl, cyclopropyl, 4-chloro-phenyl-, 3-chloro-4-fluorophenyl, 2, a kind of in 4-lutidine-6-base;
Preferred R
3, R
4Be H, C
1～C
6Alkyl, most preferred is H, a kind of in methyl, ethyl, propyl group, the sec.-propyl;
Preferred R
5Be C
1～C
6Aliphatic group or the aryl radical of the phenyl of replacement (or not replacing) or heterocycle etc., most preferred is a kind of in methyl, ethyl, the 4-p-methoxy-phenyl;
Preferred compound is: 1-cyclopropyl-6,8-two fluoro-7-cyclopropyl amino methyl isophthalic acids, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid, 1-cyclopropyl-6,8-two fluoro-7-(3-chloro-4-fluoroanilino) methyl isophthalic acid, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid, (S)-3-methyl-9-fluoro-10-[N-ethyl-3-chloro-4-fluoroanilino] methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, (S)-3-methyl-9-fluoro-10-(4-fluoroanilino) methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid etc.
Derivative of the present invention also comprises the various adductss of pharmaceutically acceptable above-claimed cpd, comprises the hydrate of above-claimed cpd, the salt of forming with mineral acid, organic acid or the salt of forming with alkali.
The compound of being addressed can adopt one of following three kinds of methods to be prepared:
Method 1:
This method comprises the steps:
(1) reduction reaction of 7-nitre methyl fluoro quinolone:
With 7-nitre methyl fluoro quinolone is starting raw material, and in alcoholic solvent, under the catalysis of Raney nickel (Raney Ni), hydrogenation reduction is collected the 7-amine methyl fluoro quinolone then from reaction product;
Said solvent comprises ethanol or ethylene glycol monomethyl ether, and temperature of reaction is 20～50 ℃, and pressure is normal pressure～10atm;
(2) cyclisation of 7-amine methyl fluoro quinolone: place solvent, alkaline matter and dihalo hydrocarbon to carry out ring-closure reaction the 7-amine methyl fluoro quinolone of step (1), from reaction product, collect the cyclisation thing of 7-amine methyl fluoro quinolone then;
Said solvent is an acetonitrile, DMF, DMSO or pyridine; Said dihalo hydrocarbon is dibromo pentane or dichlorobutane etc.; Said alkaline matter is K
2CO
3, Na
2CO
3, KOH or triethylamine etc.The processing condition of reaction are: temperature is a room temperature to 150 ℃, and preferred molar ratio is:
7-amine methyl fluoro quinolone: dihalo hydrocarbon=1: 1～1: 1.3;
(3) hydrolysis: the cyclization product of step (2) is hydrolyzed in the mixture of HCl and HOAc, the mol ratio of concentrated hydrochloric acid and HOAc with 1: 3 for well.Its processing condition are as follows: temperature is a room temperature to 100 ℃, collects-7 substituted amine methyl fluoro quinolone derivatives of target product of the present invention----then from reaction product.
Its reaction expression is as follows:
Wherein: n is 1 or 2, R
6Represent cyclopropyl, R
7Represent F, or R
7And R
61 and 8 formation one six-membered cyclic structure, i.e. R with quinolone
7And R
6Be OCH
2CHCH
3, CH
3Configuration can be S type or its raceme; R
8Represent alkyl or hydrogen, preferred R
8Be ethyl.
7-nitre methyl fluoro quinolone can adopt document (Zhang Zhenfa, Zhou Weicheng, the nucleophilic substitution reaction of fluoroquinolone and Nitromethane 99Min..Chinese Journal of Pharmaceuticals 2002,33 (5): 209～211) reported method is prepared, and the present invention repeats no more.
Adopt method of the present invention, can prepare as code name easily be target compounds such as A1 and B1, shown in table 3 and table 4.
Method 2:
This method comprises the steps:
(1) Nef of 7-nitre methyl fluoro quinolone reaction: with the alcohol and water that contains 1～4 carbon atom is solvent, or be solvent with the two-phase system of water/ethyl acetate, under the condition of alkaline matter and buffer reagent existence, being adopted as potassium permanganate solution is oxygenant, collect the aldehyde that is transformed by 7-nitre methyl fluoro quinolone then from reaction product, code name is VII.The processing condition of reaction are as follows:
Temperature of reaction is-10 a ℃～room temperature, and preferred temperature is-10～0 ℃, and said alcohols material can preferably adopt methyl alcohol, ethanol or the trimethyl carbinol; Said alkaline matter can preferably adopt NaH, sodium alkoxide, NaOH or KOH and composition thereof; Said buffer reagent preferably adopts MgSO
4, H
3BO
3Or Na
2B
4O
7And composition thereof;
When being solvent with methyl alcohol, KOH is an alkali, Na
2B
4O
7During for buffer reagent, obtain corresponding aldehyde VIIa, VIIb, VIIc and VIId smoothly by 4 nitre methyl intermediate compound IV a, IVb, IVc and IVd, its physicochemical constant sees Table 1;
(2) reduction reaction: with NaBH
4Reductive agent is reduced to alcohol with the aldehyde of step (2), and the processing condition of reaction are as follows: temperature of reaction is-10 ℃～80 ℃, and preferred temperature be-5～5 ℃, and after reaction finished, collection was by the aldehyde institute reductive alcohol of step (2) from reaction product;
Aldehyde VIIa, the VIIb, VIIc and the VIId that adopt said process step (1) can be addressed are reduced to corresponding pure VIIIa, VIIIb, VIIIc and VIIId, and its physicochemical constant sees Table 2;
(3) bromination reaction: with PBr
3Be bromizating agent, the alcohol of step (2) is changed into hydrobromic ether, the processing condition of reaction are as follows: temperature of reaction is-10 ℃～80 ℃, and preferred temperature is-5～5 ℃, alcohol and PBr
3Mol ratio be: alcohol: PBr
3=1: 1, reaction is collected hydrobromic ether after finishing from reaction product;
VIIIa, the VIIIb, VIIIc and the VIIId that adopt said process step (2) can be addressed change into corresponding hydrobromic ether IXa, IXb, IXc and IXd;
(4) replace and hydrolysis reaction: hydrobromic ether IX and suitable aminated compounds are solvent with the acetonitrile, to reflux temperature, carry out substitution reaction in room temperature, obtain substituent VI, then substituent VI is hydrolyzed in water, from reaction product, collect target product of the present invention, 7 substituted amine methyl fluoro quinolone derivatives.
Said suitable aminated compounds comprises C
1～C
10Fat uncle's ammonia or parahelium, C
3～C
6Ring-shaped fat uncle ammonia or parahelium, replace phenylamino, N-alkyl substituted benzene amine or heterocycle ammonia as
With
N wherein, R
3, R
4
With the definition of Z and the n of this Instructions Page 2 and page 3, R
3, R
4Identical with the definition of Z; IX with the ratio of aminated compounds is: 1: 1～1: 10;
Said hydrolytic reagent is the mixture of HCl and HOAc, and the mol ratio of HCl and HOAc is suitable with 1: 1～5, and hydrolysis temperature is 10～110 ℃.
When being substituting agent with ring-shaped fat secondary amine, can wait the mole or amine is excessive a little and the condition of room temperature under carry out, code name is A24, A28～A34, B11～B13, B19～B26, C17～C19, C25～C29, D4～D6, the target compound of D11～D18.Be (the seeing Table 3～6) of realizing by this method;
When being substituting agent with the N-alkyl benzene amine, because its reactive behavior is low, substitution reaction compares slowly in room temperature, be preferably in and carry out substitution reaction under the acetonitrile reflux conditions, substituent VI can be obtained smoothly, the target compound that code name is A35, C30, C31 (seeing Table 3,5) can be obtained after the hydrolysis.
When having two secondary amino groups in the ring-shaped fat amine, just there be single the replacement and disubstituted selective problems.Reaction with piperazine is an example, equimolar piperazine and aforesaid IXa directly are woven into room temperature reaction in the acetonitrile, the principal product VI that obtains has the female ring of two quinolones, obtaining corresponding code name through hydrolysis is the target compound (seeing Table 3) of A36, and it is A37 target compound (seeing Table 3) that same high piperazine and IXa reaction can obtain code name through hydrolysis again.
Change feed way, the acetonitrile solution of IXa splashed in 10 times the piperazine acetonitrile solution, room temperature reaction, single substitution product, promptly obtaining code name through hydrolysis again is A25～A27, B14～B18, C20～C24, the target compound of D7～D10 (seeing Table 3～6).
According to the method for synthetic single substituted piperazine derivatives, in the acetonitrile solution of excessive primary amine such as cyclopropylamine, splash into the acetonitrile solution of IX, most applications can be with the primary amine of yield acquisition preferably list substitution product.Having only the very little methylamine of steric hindrance, may be owing to disubstituted reason, and the yield of single substitution product is lower.It is A2～A8 that further hydrolysis obtains code name, B2～B8, C1～C7, D1, the target compound of D2 (seeing Table 3～6).The reaction expression of this method is as follows:
Wherein: R
1And R
2Definition the same, R
6Represent cyclopropyl, R
7Represent F, or R
7And R
61 and 8 formation one six-membered cyclic structure, i.e. R with quinolone
7And R
6Be OCH
2CHCH
3, CH
3Configuration can be S type or its raceme; R
8Represent alkyl or hydrogen, preferred R
8Be ethyl.
The data of table 1 aldehyde VII
Cp is a cyclopropyl
The data of the pure VIII of table 2
Method 3:
This method comprises the steps:
(1) reduction amination: reduction amination is a kind of common method that aldehyde ketone is changed into amine, because synthetic intermediate VII is an aromatic aldehyde in method 2 steps (1), it and aromatic amine should more easily form rare Fu Shi alkali (schiff ' sbase), therefore intermediate VII and the aromatic amine of being addressed can be reacted in alcoholic solvent, the rare Fu Shi alkali that is obtained does not add separation, uses NaBH again
3The CN reduction.The processing condition of reaction are as follows: the temperature of reaction for preparing rare Fu Shi alkali is room temperature～80 ℃, and the temperature of reduction reaction is 0 a ℃～room temperature.After reaction finished, collecting code name from reaction product was the compound of VI; Preferred alcoholic solvent is methyl alcohol or ethanol
Said aromatic amine comprises the phenylamino or the fragrant heterocycle ammonia of replacement (or not replacing), as 4-chlorobenzene ammonia, 3-chloro-4-Fluoroaniline, 6-amido-2, and a kind of in the 4-lutidine;
(2) methylation reaction: with the code name of step (1) gained be the compound of VI in methyl alcohol with formaldehyde and NaBH
3CN carries out methylation reaction.The processing condition of reaction are as follows: temperature of reaction is 0 a ℃～room temperature, and reaction is collected methylate after finishing from reaction product;
(3) hydrolysis reaction: with the reaction that is hydrolyzed under 10～110 ℃ temperature of the mixture of the product of step (1) or (2) and HCl and HOAc, the mol ratio of HCl and HOAc is collected target product of the present invention with 1: 1～5 for suitable from reaction product.Its reaction expression is as follows:
Wherein: R
1Definition the same, Ar is for replacing the phenyl or the aromatic heterocyclic of (or not replacing), as 4-chloro-phenyl-, 3-chloro-4-fluorophenyl, 2, a kind of in 4-lutidine-6-base; R
6Represent cyclopropyl, R
7Represent F, or R
7And R
61 and 8 formation one six-membered cyclic structure, i.e. R with quinolone
7And R
6Be OCH
2CHCH
3, CH
3Configuration can be S type or its raceme; R
8Represent alkyl or hydrogen, preferred R
8Be ethyl.
As being example, the fluorochlorobenzene amine of aldehyde VIIa and equivalent is woven into adds thermosetting Schiff alkali in the ethanol, with NaBH with 3-chloro-4-fluoroaniline
3The reduction that methylates of CN and methanol mixture, the product VI that obtains
3Get the target compound that code name is A13 through hydrolysis again.In like manner, can obtain code name is A9～A21, B9, B10, C8～C16, C32, the target compound of D3 (seeing Table 3～6).
Wherein: the preparation of C32 is to get intermediate VI with aldehyde VIIc and para-fluoroaniline reduction amination
4, without separating again and formaldehyde and NaBH
3CN methylate VI
5, get C32 through hydrolysis.
All target compounds of this paper have all carried out the antibacterial activity in vitro test, with document (Liu Qing, Zhou Weicheng, Yu Aizhen etc.: 7-[4-(2,4-two amidos quinazoline-6-yl) piperazine-1-yl]-the synthetic and anti-microbial activity Chinese Journal of Pharmaceuticals 1996 of 6-fluoroquinolone compound, 27:104) Bao Dao agar two-fold dilution method has been measured them (preceding 5 kinds has been G to following 16 strain laboratory standard bacterium
+Bacterium, the back 11 strains be the G bacterium) external minimum inhibitory concentration (MIC): golden Portugal bacterium 26003 (Staphylococcus aureus), staphylococcus epidermidis 26069 (Streptococcusepidermidis), pneumococcus 31002 (Streptococcus pneuminiae), Staphylococcus albus 26101 (Staphylococcus albus), faecalis 32220 (Streptococcus enteridis), intestinal bacteria 44102 (Escherichia coli), Song Shi Shigellae 51081 (Shigella Sonnei), Shigella bogdii 51313 (Shigella boydii), Proteus mirabilis 49005 (Proteus mirabilis), proteus vulgaris 49085 (Proteus vugaris), Morgan Bacillus proteus 49086 (Proteus morganii), pneumobacillus 46101 (Klebsiella pneumoniae), Salmonella enteritidis 50041 (Salmonella enteridis), Corynebacterium diphtheriae 50097 (Salmonella typhi), citrobacter 48017 (Salmonella citrobacter), serratia marcescens 41002 (Serratia marcescens).The results are shown in Table 11 for it.
By table 11 as seen, compound of the present invention has tangible anti-microbial activity.To all G that surveyed
-Bacterium, A1, C4, the D1 activity is equal to or slightly better in lomefloxacin.A2 is better active, to Shigella bogdii, and pneumobacillus, Salmonella enteritidis and citrobacter activity are better than lomefloxacin and pazufloxacin, A5 is active suitable with lomefloxacin substantially, and to the Song Shi Shigellae, pneumobacillus and citrobacter activity are better than lomefloxacin and pazufloxacin.In all target compounds, the anti-G of D2
-The bacterium activity is stronger, to the bacterial strain of being surveyed, except that Bacillus proteus and serratia marcescens, to other 9 strain G
-The bacterium activity is better than pazufloxacin and lomefloxacin.
To the effect of G+ bacterium, A9～A18, C8～C15 and D3 activity are stronger, and C12 is better than lomefloxacin, pazufloxacin and vancomycin to the effects of all the other 4 strain G+ bacterium except that faecalis.C9 is to golden Portugal bacterium, and the activity of pneumococcus and form staph also is better than all contrast medicines.
Table 3.1-cyclopropyl-6,8-two fluoro-7-substituted amine methyls-1, the data of 4-dihydro-4-Oxoquinoline-3-carboxylic acid derivative
A: all hydrochloride water/ethyl alcohol recrystallizations, free alkali spent glycol monomethyl ether/ethyl alcohol recrystallization.
B: the results of elemental analyses of following several compound chlorine (found/calcd): A22:9.38/9.23; A26:14.97/15.17; A21:12.46/12.12; A20:7.39/7.13; A36:9.66/9.71.
C: the molecular weight (found/calcd) that records with HREIMS.
D: structural formula is seen the 7th page.
E: yield is by last two steps.
Table 4.1-ethyl-6,8-two fluoro-7-substituted amine methyls-1, the data of 4-dihydro-4-Oxoquinoline-3-carboxylic acid derivative
A: all hydrochloride water/ethyl alcohol recrystallizations, free alkali spent glycol monomethyl ether/ethyl alcohol recrystallization.
B: the results of elemental analyses of following several compound chlorine (found/calcd): B11:9.27/9.18; B19:15.62/15.80; B10:11.99/12.37; B9:7.18/7.31.
C: yield is by last two steps.
Table 5.3-(S)-methyl-9-fluoro-10-substituted amine methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de]-1, the data of 4-benzoxazine-6-carboxylic acid derivative
A: all hydrochloride water/ethyl alcohol recrystallizations, free alkali spent glycol monomethyl ether/ethyl alcohol recrystallization.
The ultimate analysis (found/calcd) of b:C24 and C16 chlorine: 14.92/14.79; 11.94/11.87.
The molecular weight that c:HREIMS records (found/calcd).
D:DMSO is a solvent, g/100ml.
E: yield is by last two steps.
Table 6.3-methyl-9-fluoro-10-substituted amine methyl-7-oxo-2,3-dihydro-7H-pyridine [1,2,3-de]-1, the data of 4-benzoxazine-6-carboxylic acid derivative
A: all compound water/ethyl alcohol recrystallizations, have only D3 spent glycol monomethyl ether/ethyl alcohol recrystallization.
B: yield is by last two steps.
Table 7. compd A 1～A37
a 1HNMR data (δ ppm)
| ??No | ??COOH b | ??H 2 | ??H 5 | ????CH 2 | ????cycloproyl | ????NR 1R 2 |
| ??A1 | ??14.50(br) | ??8.73(s) | ??7.88(d，J＝9.2Hz) | ????3.93(s) | ????4.16～4.17(m，1H)1.21～1.23(m，4H) | ????6.20(br) |
| ??A2 | ??14.40(br) | ??8.77(s) | ??7.98?d，J＝8.8Hz) | ????4.37(s) | ????4.13～4.14(m，1H)，1.21～1.26(m，4H) | ????3.09(q，J＝6.8Hz，2H)，1.21～1.26(m，3H) |
| ??A3 | ??14.30(br) | ??8.76(s) | ??8.00(d，J＝8.8Hz) | ????4.37(s) | ????4.13～4.16(m，1H)，1.24～1.29(br，2H)， ????1.19～1.22(m，2H) | ????2.98(t，J＝8.0Hz，2H)，1.29～1.77(m，2H)，0.93(t， ????J＝7.2Hz，3H) |
| ??A4 | ??14.30(br) | ??8.78(s) | ??8.00(dd，J 1＝8.8Hz， ??J 2＝1.2Hz) | ????4.36(s) | ????4.16～4.17(m，1H)，1.22～1.27(br，2H)， ????1.04～1.08(m，2H | ????3.43～3.52(m，1H)，1.37(d，J＝6.8Hz，6H) |
| ??A5 | ??14.30(br) | ??8.78(s) | ??8.00(dd，J 1＝8.8Hz， ??J 2＝1.2Hz) | ????4.44(s) | ????4.16～4.18(m，1H)，1.22～1.28(m，4H) | ????0.91～0.95(m，2H)，0.75～0.83(m，2H)，2.74～2.80(m， ????1H). |
| ??A6 | ??14.30(br) | ??8.78(s) | ??8.00(dd，J 1＝8.8Hz， ??J 2＝1.2Hz) | ????4.37(s) | ????4.16～4.17(m，1H)，1.29(br，2H)， ????1.21～1.24(m，2H) | ????3.19(t，J＝8.0Hz，2H)，1.65～1.71(m，2H)， ????1.33～1.39(m，2H)，0.91(t，J＝7.6Hz，3H) |
| ??A7 | ??14.25(br) | ??8.78(s) | ??8.00(dd，J 1＝8.8Hz， ??J 2＝1.6Hz) | ????4.32(s) | ????4.15～4.16(m，1H)，1.28～1.31(m，2H)， ????1.21～1.25(m，2H) | ????4.44(s，9H) |
| ??A8 | ??14.30(br) | ??8.78(s) | ??7.98(dd，J 1＝8.8Hz， ??J 2＝1.2Hz) | ????4.37(s) | ????4.16～4.17(m，1H)，1.19～1.30(m.4H) | ????3.15～3.18(m，1H)，2.18～2.20(m，2H)，1.79～1.82(m， ????2H)，1.61～1.64(m，1H)，1.44～1.53(m，2H)，1.19～1.30 ????(m，3H) |
| ??A9 | ??14.30(br) | ??8.69(s) | ??7.82(d，J＝8.8Hz) | ????4.50(s) | ????4.11～4.13(m，1H.)，1.15～1.20(m，4H) | ????7.12(t，J＝7.6Hz，2H)，7.78(d.J＝7.6Hz，2H)，6.68(t， ????J＝7.6Hz，1H) |
| ??A10 | ??14.45(br) | ??8.74(s) | ??7.91(dd，J 1＝9.6Hz， ??J 2＝1.2Hz) | ????4.48(s) | ????4.17～4.20(m，1H)，1.20～1.22(m，4H) | ????7.11(d，J＝12.0Hz，2H)，6.72(d，J＝12.0Hz，2H) |
| ??A11 | ??14.45(br) | ??8.74(s) | ??7.93(dd，J 1＝8.0Hz， ??J 2＝1.2Hz) | ????4.50(s) | ????4.17～4.20(m，1H)，1.21～1.22(m，4H) | ????7.07～7.70(m，1H)，6.57～6.72(m，3H) |
| ??A12 | ??14.45(s) | ??8.73(s) | ??7.91(dd，J 1＝9.2Hz， ??J 2＝1.6Hz) | ????4.48(s) | ????4.14～4.18(m，1H)， ????1.19(d，J＝6.4Hz，4H) | ????6.98(t，J＝8.8Hz，2H) ????6.78(dd，J 1＝8.8Hz，J 2＝4.4Hz，2H) |
| A13 | ??14.40(br) | ??8.73(s) | ??7.92(d，J＝8.0Hz) | ????4.47(s) | ????4.15～4.19(m，1H)， ????1.21(d，J＝6.0Hz，4H) | ????7.12(t，J＝9.0Hz，1H)，6.79～6.82(m，1H)， ????6.63～6.67(m，1H) |
| A14 | ??14.40(br) | ??8.73(s) | ??7.90(d，J＝8.8Hz) | ????4.46(d， ????J＝2.4Hz) | ????4.15～4.19(m，1H)，1.20～1.22(m，4H) | ????7.01(m，1H)，6.65(m，1H)，6.45～6.49(m，1H) |
| A15 | ??14.40(s) | ??8.72(s) | ??7.87(dd，J 1＝9.2Hz， ??J 2＝1.2Hz) | ????4.54(d， ????J＝5.6Hz) | ????4.14～4.18(m，1H)， ????1.19(d，J＝5.6Hz，4H) | ????7.07～7.14(m，1H)，7.05～7.13(m，1H)，6.62～6.68 b(m， ????1H) |
| A16 | ??14.50(br) | ??8.70(s) | ??7.85(d，J＝9.2Hz) | ????4.54(s) | ????4.09～4.10(m，1H)，1.11～1.15(br，4H) | ????7.03(d，J＝8Hz，2H)，6.85(d，J＝8Hz，2H)，2.16(s，3H) |
| A17 | ??14.45(br) | ??8.72(s) | ??7.88(d，J＝9.2Hz) | ????4.45(d， ????J＝4.8Hz) | ????4.17～4.19(m，1H)，1.21～1.23(br，4H) | ????6.83(d，J＝8Hz，1～H)，6.51(s，1H)，6.44(d，J＝8Hz， ????1H) |
| A18 | ??14.45(s) | ??8.72(s) | ??7.87(dd，J 1＝9.2Hz， ??J 2＝1.2Hz) | ????4.91(s) | ????4.17～4.18(m，1H)，1.17～1.24(m，4H) | ????6.83(s，1H)，6.67(s，1H)，2.45(s，3H)，2.32(s，3H) |
| A19 | ??14.45(br) | ??8.72(s) | ??7.87(br) | ????4.49(br?2H) | ????4.13～4.14(m，1H)，1.15～1.24(m，4H) | ????7.24(br，2H)，6.79(br，2H)，3.47(br，4H)，2.06(br， ????4H) |
| A20 | ??14.50(s) | ??8.73(s) | ??7.89(d，J＝8.8Hz) | ????4.49(s) | ????4.16～4.17(m，1H)，1.02～1.05(m，4H) | ????7.95(d，J＝9.2Hz，2H)，7.54(d，J＝9.2Hz，2H)， ????3.37～3.45(m，4H)，1.85～1.87(m，4H)，1.61(br，2H) |
| A21 | ??14.45(s) | ??8.73(s) | ??7.89(d，J＝8.8Hz) | ????4.53(s) | ????4.10～4.11(m，1H)，1.12～1.19(m，4H) | ????6.91(dd，AB，J＝8.8Hz，Δ＝24.8Hz，4H) ????3.61(br，2H)，3.46(br，2H) ????3.13(br，2H)，2.95?(br，2H)，2.80(s，3H) |
| A22 | ??14.25(br) | ??8.78(s) | ??8.00(d，J＝8.8Hz) | ????4.61(s) | ????4.16～4.17(m，1H)，1.26(br，2H)， ????1.05～1.20(m，2H) | ????3.31～3.55(m，4H)1.90～2.06(m，4H) |
| A23 | ??14.30(br) | ??8.78(s) | ??8.00(d，J＝8.8Hz) | ????4.49(s) | ????4.15～4.16(m，1H)，1.20～1.24(m，4H) | ????3.25?(br，4H，1.75(br，4H)1.53(br，2H) |
| A24 | ??14.40(br) | ??8.77(s) | ??7.99(d，J＝8.8Hz) | ????4.53(s) | ????4.16～4.17(m，1H)，1.18～1.27(m，4H) | ????3.85?(br，4H)，3.30?(br，4H) |
| A25 | ??14.40(br) | ??8.75(s) | ??7.93(dd，J 1＝8.8Hz， ??J 2＝1.2Hz) | ????4.12～4.17 ????(m) | ????1.20～1.22(m，4H)，4.12～4.17(m，1H) | ????3.22～3.24(m，4H)，3.07～3.09(m，4H) |
| A26 | ??14.45(br) | ??8.79(s) | ??7.95(d，J＝8.8Hz) | ????3.98(s) | ????4.18～4.19(m，1H)，1.20～1.23(m，4H) | ????3.28～3.31(m，2H)，2.99～3.11(m，3H)，2.54～2.59(m， ????1H)，2.34～2.39(m，1H)，1.20～1.23(m，3H) |
| A27 | ??14.30(br) | ??8.76(s) | ??7.90(d，J＝8.8Hz) | ????3.85(s) | ????4.16～4.18(m，1H)，1.15～1.20(m，4H) | ????3.19～3.22(m，2H)，2.98(d，J＝10.4Hz，2H)，2.13(t， ????J＝12.0Hz，2H)，1.15～1.20(m，6H) |
| A28 | ??14.45(br) | ??8.76(s) | ??7.94(d，J＝8.0Hz) | ????3.83(s) | ????4.16～4.17(m，1H)，1.05～1.24(m，4H) | ????3.31～3.32(m，2H)2.99～3.15(m，4H)，2.72(s，3H)， ????2.49～2.72，(m，2H) |
| A29 | ??14.30(br) | ??8.77(s) | ??7.96(dd，J 1＝9.2Hz， ??J 2＝1.2Hz) | ????4.08(s) | ????4.17～4.20(m，1H)，1.20～1.26(m，4H) | ????3.45～3.47(m，2H)，3.19～3.22(m，2H)，3.01～3.12(m， ????4H)，2.98～3.07(m，2H)，1.20～1.26(m，3H) |
| A30 | ??14.30(br) | ??8.75(s) | ??7.92(d，J＝8.8Hz) | ??3.94(s) | ????4.14～4.15(m，1H)，1.20～1.22(m，4H) | 3.70～3.73(m，2H)，3.42～3.44(m，2H，)，3.34～3.36(m， 2H)，3.14～3.16(m，2H)，2.88(br，4H) |
| A31 | ??14.45(br) | ??8.78(s) | ??8.00(d，J＝8.4Hz) | ??4.58(s) | ????4.16～4.17(m，1H)，1.21～1.25(m，4H) | 7.24(t，J＝8.0Hz，1H)，6.99(s，1H)，6.92～6.95(m，1H)， 6.83～6.85?(m，1H)，3.41～3.45(m，8H) |
| A32 | ??14.45(br) | ??8.81(s) | ??8.04(d，J＝8.8Hz) | ??4.61(s) | ????4.19(br，1H)，1.25(br，4H) | 6.92(d，J＝8.4Hz，2H)，7.01(d，J＝8.4Hz，2H)，(3.67(s， 3H)，3.47(br，4H)，3.32(br，4H) |
| A33 | ??14.45(br) | ??8.80(s) | ??8.04(d，J＝8.8Hz) | ??4.61(s) | ????4.19～4.20(br，1H)，1.21～1.23(br，4H) | 6.88～7.02(m，4H)，3.70(s，3H)，3.45(br，4H)，3.23 (br，4H) |
| A34 | ??14.53(br) | ??8.78(s) | ??8.00(d，J＝9.2Hz) | ??5.77(s) | ????4.17～4.18(m，1H)，1.24(br，2H)， ????1.19～1.22(m，2H) | 9.29(s，1H)，7.75(s，1H)，7.70(s，1H) |
| A35 | ??14.50(br) | ??8.73(s) | ??7.89(d，J＝8.8Hz) | ??4.72(s) | ????4.15～4.17(m，1H)，1.16～1.18(br，4H) | 7.16～7.18(m，2H)，6.87～6.89(m，2H)，6.66～6.69(m， 1H)，3.39(q，J＝7.2Hz，2H)，1.07(t，J＝7.2Hz，3H) |
| A36 | ??14.45(br) | ??8.79(s， ??2H) | ??7.96(dd，J＝8.8Hz， ??2H) | ??4.24(s，4H) | ????4.15～4.16(m，2H)，1.24～1.29(br，4H)， ????1.19～1.21(m，4H) | 3.23(br，8H) |
| A37 | ??14.50(br) | ??8.77(s， ??2H) | ??7.95(dd，J 1＝8.8Hz， ??J 2＝1.2Hz，2H) | ??4.41(s，4H) | ????4.13～4.15(m，2H)，1.19～1.21(m，8H) | 3.45(br，4H)，3.26～3.28(m，4H)， 2.10(br，2H) |
A: with DMSO-d
6Be solvent.
B: add D
2O disappears.
Table 8. compound B-11～B26
a 1HNMR data (δ ppm)
| ??No | ??COOH b | ??H 2 | ????H 5 | ????CH 2 | ??Et | ????NR 1R 2 |
| ??B1 | ??14.50(br) | ??8.96(s) | ????7.92(d，J＝9.2Hz) | ????3.92(s) | ??4.61～4.67(m，2H)，1.47(t，J＝6.8Hz，3H) | ????6.80(br) |
| ??B2 | ??14.40(br) | ??9.03(s) | ????8.05(d，J＝9.2Hz) | ????4.37(s) | ??4.64～4.65(m，2H)，1.50(t，J＝6.4Hz，3H) | ????2.65(s，3H) |
| ??B3 | ??14.40(br) | ??9.05(s) | ????8.05(dd，J 1＝9.2Hz， ????J 2＝1.6Hz) | ????4.35(s) | ??4.64～4.67(m，2H)，1.51(t，J＝6.8Hz，3H) | ????3.09(q，J＝7.2Hz，2H)，1.28(t，J＝7.2Hz，3H) |
| ??B4 | ??14.40(br) | ??9.06(s) | ????8.06(d，J＝8.8Hz) | ????4.39(s) | ??4.65～4.68(m，2H)，0.92(t，J＝8Hz，3H) | ????3.02(t，J＝8Hz，2H)，1.67～1.69(m，2H)，1.48(t， ????J＝7.2Hz，3H) |
| ??B5 | ??14.40(br) | ??9.03(s) | ????8.03(d，J＝8Hz) | ????4.35(s) | ??4.64～4.66(m，2H)，1.51(t，J＝7.2Hz，3H) | ????3.47～3.50(m，1H)，1.35(d，J＝7.2Hz，6H) |
| ??B6 | ??14.40(br) | ??9.05(s) | ????8.05(d，J＝9.2Hz) | ????4.37(s) | ??4.64～4.67(m，2H)，1.51(t，J＝6.8Hz，3H) | ????3.03(t，J＝7.6Hz，2H)，1.68(p，J＝7.6Hz，2H)，1.35(h， ????J＝7.6Hz，2H)，0.91(t，J＝7.2Hz，3H) |
| ??B7 | ??14.42(br) | ??9.04(s) | ????8.04(d，J＝8.8Hz) | ????4.31(s) | ??4.64～4.66(m，2H)，1.52(t，J＝6.8Hz，3H) | ????1.44(s，9H) |
| ??B8 | ??14.45(br) | ??9.06(s) | ????8.05(dd，J 1＝8.8Hz， ????J 2＝1.6Hz) | ????4.39(s) | ??4.64～4.68(m，2H)，1.48(t，J＝6.8Hz，3H) | ????3.19(br，1H).2.17～2.19(m，2H)，1.79～1.82(m，2H)， ????1.61～1.64(m，1H)，1.40～1.46(m，2H)，1.23～1.33(m， ????2H)，1.11～1.18(m，1H) |
| ??B9 | ??14.60(br) | ??9.01(s) | ????7.97(d，J＝9.2Hz) | ????4.51(s) | ??4.64～4.66(m，2H)，1.42(t，J＝7.2Hz，3H) | ????7.57(d，J＝8.4Hz，2H)，6.75(d，J＝8.4Hz，2H)， ????4.37～4.43(br，4H)，1.86(br，4H)，1.61(br，2H) |
| ??B10 | ??14.50(br) | ??9.02(s) | ????7.97(d，J＝8.4Hz) | ????4.53(s) | ??4.61～4.63(m，2H)，1.42(t，J＝7.0Hz，3H) | ????6.99(d，J＝8.4Hz，2H)，6.92(d，J＝8.4Hz，2H)，3.64(d， ????J＝9.6Hz，2H)，3.48(d，J＝9.2Hz，2H)，3.16(br，4H)， ????2.79(s，3H) |
| ??B11 | ??14.45(br) | ??8.95(s) | ????8.05(d，J＝9.2Hz) | ????4.58～4.61 ????(m) | ??4.58～4.61(m，2H)，1.46(t，J＝6.8Hz，3H) | ????3.41～3.63(br，4H)，1.97(br，4H) |
| ??B12 | ??14.50(br) | ??9.07(s) | ????8.06(d，J＝8.8Hz) | ????4.48(s) | ??4.65～4.67(m，2H)，1.50(t，J＝6.8Hz，3H) | ????3.45(br，2H)，3.06(br，2H)，1.69～1.83(m，4H)， ????1.64～1.67(m，1H)，1.33～1.36(m，1H) |
| ??B13 | ??14.45(br) | ??8.97(s) | ????8.05(d，J＝8.8Hz) | ????4.52(s) | ??4.61～4.62(m，2H)，1.47(t，J＝6.8Hz，3H) | ????3.81(br，4H)，3.31(br，4H) |
| ??B14 | ??14.50(br) | ??9.02(s) | ????7.99(dd，J 1＝9.2Hz， ????J 2＝1.2Hz) | ????3.83(s) | 4.63～4.66(m，2H)，1.44(t，J＝6.8Hz，3H) | ????3.05(br，4H)，2.70(br，4H) |
| ??B15 | ??14.40(br) | ??9.01(s) | ????8.02(d，J＝8.0Hz) | ????4.36(s) | 4.64～4.67(m，2H)，1.46(t，J＝6.8Hz，3H) | ????3.36(br，4H)，3.15～3.23(m，4H)，2.02～2.07(m，2H) |
| ??B16 | ??14.50(br) | ??9.01(s) | ????8.00(dd，J＝8.8Hz， ????J＝1.2Hz) | ????3.85(s) | 4.58～4.64?9m，2H)，1.45(t，J＝7.2Hz，3H) | ????3.19～3.24(m，2H)，2.90～2.99(m，3H)，2.44(t， ????J＝11.6Hz，1H)，1.17(d，J＝6.8Hz，3H) |
| ??B17 | ??14.45(br) | ??8.86(s) | ????7.95(dd，J 1＝9.2Hz， ????J 2＝1.6Hz) | ????4.24(s) | 4.58～4.61(m，2H)，1.44(t，J＝6.8Hz，3H) | ????4.20～4.24(m，1H)，3.09～3.12(m，1H)，2.80～2.84(m， ????1H)，2.52～2.68(m，2H)，2.20～2.23(m，1H)，1.24(d， ????J＝5.6Hz，3H)，1.11(d，J＝6.8Hz，3H) |
| ??B18 | ??14.45(br) | ??8.86(s) | ????7.95(d，J＝9.2Hz) | ????3.85(s) | 4.56～4.60(m，2H)，1.44(t，J＝7.0Hz，3H) | ????3.18～3.23(m，2H)，2.97～3.00(m，2H)，2.14(t， ????J＝11.6Hz，2H)，1.16(d，J＝7.2Hz，6H) |
| ??B19 | ??a | ??9.52 ??(br) | ????8.46(br) | ????5.11(br) | 5.11(br，2H)，1.88(br，3H，) | ????4.32(br，4H，)，4.15(br，2H，)，4.04(br，2H，)，3.24(s， ????3H，) |
| ??B20 | ??14.43(br) | ??9.02(s) | ????7.99(d，J＝9.2Hz) | ????4.13(s) | 4.64～4.66(m，2H)，1.48(t，J＝6.8Hz，3H) | ????3.48～3.51(br，2H)，3.25(br，2H)，3.04～3.13(m，6H)， ????1.24(t，J＝7.4Hz，3H) |
| ??B21 | ??14.45(br) | ??8.98(s) | ????7.99(d，J＝8.8Hz) | ????4.08(s) | 4.61～4.63(m，2H)，1.46(t，J＝6.8Hz，3H) | ????3.72～3.74(m，2H)，3.17～3.199(m，8H)，2.93(br， ????2H) |
| ??B22 | ??14.40(br) | ??9.01(s) | ????8.03(d，J＝8.8Hz) | ????4.34(s) | 4.63～4.69(m，2H)，1.47(t，J＝6.8Hz，3H) | ????7.21～7.23(m，1H)，6.97(br，1H)，6.89～6.90(m，1H)， ????6.79～6.81(m，1H)，3.34(br，4H)，3.16(br，4H) |
| ??B23 | ??14.45(br) | ??8.94(s) | ????8.04(d，J＝8.8Hz) | ????4.58～4.62 ????(m) | 4.58～4.62(m，2H)，1.48(t，J＝6.8Hz，3H)， | ????6.90(dd，J＝9.2Hz，4H)，3.41～3.47(m，4H)， ????3.30～3.33(m，4H)，3.66(s，3H) |
| ??B24 | ??14.40(br) | ??9.06(s) | ????8.07(d，J＝8.0Hz) | ????4.62(s) | 4.67～4.69(m，2H)，1.52(t，J＝6.8Hz，3H) | ????6.88～7.04(m，4H)，3.79(s，3H)，3.21～3.60(br，8H) |
| ??B25 | ??14.43(br) | ??8.94(s) | ????7.96(d，J＝8.8Hz) | ????4.08(s) | 4.57～4.58(m，2H)，1.42(t，J＝6.8Hz，3H) | ????7.53(m，2H)，7.44～7.52(m，3H)，4.47～4.50(m，1H)， ????1.64(d，J＝.8Hz，3H)，3.08(br，8H) |
| ??B26 | ??14.40(br) | ??9.04(s) | ????8.05(dd，J 1＝9.2Hz， ????J 2＝1.6Hz) | ????5.75(s) | 4.65～4.67(m，2H)，1.47(t，J＝6.6Hz，3H) | ????9.24(s，1H)，7.76(s，1H)，7.68(s，1H) |
The solvent of a:B19 is CF
3COOD, all the other use DMSO-d
6
B: add D
2O disappears.
Table 9. Compound C 1～C32
a 1HNMR data (δ ppm)
| ??No | ??COOH b | ????H 5，H 8 | ????NCH 2 | ????H 3，Me | ??OCH 2 | ???NR 1R 2 |
| ??C1 | ??14.83(br) | ????9.07(s) ????7.69(d，J＝9.2Hz) | ????4.26(dd，AB，J AB＝13.2Hz， ????Δ＝0.11ppm) | ????4.98～5.01(m) ????1.7(d，J＝7.2Hz) | ??4.4～4.68(m) | ????3.06(q，J＝7.2Hz，2H)，1.50(d，J＝6.8Hz，3H) |
| ??C2 | ??14.83(br) | ????9.08(s) ????7.68(d，J＝9.6Hz) | ????4.27(dd，AB，J AB＝13.6Hz， ????Δ＝0.12ppm) | ????5.00～5.02(m) ????1.50(d，J＝6.8Hz) | ??4.54～4.68(m) | ????2.93(t，J＝8.0Hz，2H)，1.67～1.77(m，2H)，0.92 ????(t，J＝7.2Hz，3H). |
| ??C3 | ??14.83(br) | ????9.08(s) ????7.69(d，J＝9.6Hz) | ????4.26(dd，AB，J AB＝7.2Hz， ????Δ＝0.13ppm) | ????5.00～5.02(m) ????1.51(d，J＝6.8Hz) | ??4.56～4.68(m) | ????3.41～3.44(m，1H)，1.36(d，J＝6.8Hz，6H) |
| ??C4 | ??14.90(s) | ????9.08(s) ????7.69(d，J＝9.2Hz) | ????4.35(dd，AB，J AB＝13.6Hz， ????Δ＝0.09ppm) | ????5.00～5.02(m) ????1.50(d，J＝6.8Hz) | ??4.54～4.69(m) | ????2.72～2.75(m，1H)，0.92～0.96(br，2H)， ????0.72～0.77(m，2H) |
| ??C5 | ??14.83(br) | ????9.07(s) ????7.68(d，J＝9.6Hz) | ????4.27(dd，AB，J AB＝13.6Hz， ????Δ＝0.12ppm) | ????5.00～5.03(m) ????1.47(d，J＝6.8Hz) | ??4.54～4.68(m) | ????2.97(t，J＝7.6Hz，2H)，1.61(p，J＝7.6Hz，2H)， ????1.31(h，J＝7.6Hz，2H)，0.86(t，J＝7.6Hz，3H) |
| ??C6 | ??14.95(br) | ????8.97(s) ????7.65(d，J＝9.6Hz) | ????4.23(dd，AB，J AB＝9.4Hz， ????Δ＝0.13ppm) | ????4.93～4.95(m) ????1.49(d，J＝6.8Hz) | ??4.17～4.25(m) | ????1.40(s，9H) |
| ??C7 | ??14.85(br) | ????8.93(s) ????7.66(d，J＝9.6Hz) | ????4.29(s) | ????4.90(br) ????1.47?d，J＝6.8Hz) | ??4.55～4.67(m) | ????3.09(br，1H)，2.09(br，2H)，1.76(br，2H)， ????1.59(br，1H)，1.08～1.36(m，5H) |
| ??C8 | ??14.90(br) | ????9.0(s) ????7.60(d，J＝9.6Hz) | ????4.38(d，J＝13.2Hz). | ????4.95～4.99(m) ????1.45(d，J＝6.8Hz) | ??4.44～4.70(m) | ????7.06～7.08(m，2H)，6.696.70(m，2H)， ????6.546.56(m，1H)，5.88(br，1H) |
| ??C9 | ??14.96(s) | ????9.04(s) ????7.62(d，J＝9.6Hz) | ????4.37(d，J＝6.4Hz) | ????4.97～4.99(m) ????1.47(d，J＝6.8Hz) | ??4.43～4.70(m) | ????7.08(d，J＝6.8，2H)，6.69(d，J＝6.8，2H)，6.18 ????(t，J＝6.0Hz，1H) |
| ??C10 | ??14.90(br) | ????9.02(s) ????7.61(d，J＝10.0Hz) | ????4.4?1(d，J＝6.4Hz) | ????4.97～4.99(m) ????1.49(d，J＝7.2Hz) | ??4.45～4.71(m) | ????7.05(t，J＝8.0Hz，1H)，6.71(br，1H)，6.62～6.64 ????(m，1H)，6.51～6.53(m，1H)，6.33(br，1H) |
| ??C11 | ??14.97(s) | ????9.03(s) ????7.61(d，J＝9.6Hz) | ????4.37(d，J＝6.0Hz) | ????4.96～4.98(m) ????1.46(d，J＝6.4Hz) | ??4.42～4.68(m) | ????6.89(t，J＝8.8Hz，82H)，6.65～6.69(m，2H)， ????5.86 b(m,1H) |
| C12 | ??14.95(s) | ????9.04(s) ????7.62(d，J＝10.0Hz) | ??4.39(d，J＝6.0Hz) | ????4.98～5.00(m) ????1.48(d，J＝6.8Hz) | ?4.44～4.71(m) | ??7.09(t，J＝9.0Hz，1H)，6.78～6.80(m，1H)， ??6.62～6.66(m，1H)，6.24 b(t，J＝6.0Hz，1H) |
| C13 | ??14.98(s) | ????9.03(s) ????7.61(d，J＝9.6Hz) | ??4.38(d，J＝6.0Hz) | ????4.97～4.99(m) ????1.47(d，J＝6.8Hz) | ?4.27～4.70(m) | ??6.88(d，J＝8.4Hz，2H)，6.60(d，J＝8.4Hz，2H)， ??5.69 b(m，1H)，2.11(s，3H) |
| C14 | ??14.88(s) | ????8.97(s) ????7.59(d，J＝10.0Hz) | ??4.40(s) | ????4.94～4.98(m) ????1.49(d，J＝6.8Hz) | ?4.43～4.69(m) | ??6.80～6.81(m，1H)，6.52(br，1H)，6.42～6.45 ??(m，1H)，5.44 b(s，1H)，2.09(s，3H)，2.03(s， ??3H) |
| C15 | ??14.95(br) | ????8.97(s) ????7.65(d，J＝9.6Hz) | ??4.75(s) | ????4.93～4.95(m) ????1.47(d，J＝6.4Hz) | ?4.49～4.70(m) | ??6.79(s，1H)，6.64(s，1H)，2.42(s，3H)，2.30 ??(s，3H) |
| C16 | ??14.89(br) | ????8.92(s) ????7.59(d，J＝9.2Hz) | ??4.51(s) | ????4.87～4.89(m) ????1.40(d，J＝6.8Hz) | ?4.36～4.58(m) | ??6.96(dd，AB，J＝8.8Hz，Δ＝0.15ppm，4H)， ??3.68?(br，2H)，3.44?(br，2H)，3.11(br，2H)，2.94 ??(br，2H)，2.81(s，3H) |
| C17 | ??14.89(br) | ????9.08(s) ????7.72(d，J＝9.6Hz) | ??4.52(dd，AB，J＝13.6Hz， ??Δ＝0.16ppm) | ????5.01～5.03(m) ????1.51(d，J＝7.2Hz) | ?4.57～4.69(m) | ??3.49?(br，2H)，3.17(br，2H)，1.92～2.04(m， ??4H) |
| C18 | ??14.89(br) | ????9.08(s) ????7.72(d，J＝9.6Hz) | ??4.39(dd，AB，J＝13.2Hz) | ????5.01～5.05(m) ????1.51(d，J＝7.2Hz) | ?4.50～4.64(m) | ??3.42(br，2H)，3.02?(br，2H)，1.79(br，4H)， ??1.65(br，1H)，1.37(br，1H) |
| C19 | ??14.83(br) | ????8.98(s) ????7.70(d，J＝9.6Hz) | ??4.54(d，J＝5.6Hz) | ????4.93～4.95(m) ????1.49(d，J＝6.8Hz) | ?4.48～4.64(m) | ??3.84(br，4H)，3.30(br，4H) |
| C20 | ??14.83(br) | ????9.05(s) ????7.68(d，J＝9.6Hz) | ??4.03(dd，AB，J AB＝13.6Hz， ??Δ＝0.14ppm) | ????5.00～5.02(m) ????1.50(d，J＝6.4Hz) | ?4.56～4.67(m) | ??3.43(br，8H) |
| C21 | ??14.85(br) | ????9.07(s) ????7.69(d，J＝10.0Hz) | ??4.48(dd，AB，J AB＝13.2Hz， ??Δ＝0.11ppm) | ????4.89～4.91(m) ????1.50(d，J＝6.8m) | ?4.56～4.66(m) | ??3.55～3.57(m，4H)，3.24～3.69(m，4H)，2.20 ??(br，2H) |
| C22 | ??14.85(br) | ????9.02(s) ????7.68(d，J＝9.6Hz) | ??3.87(dd，AB，J＝13.6Hz， ??Δ＝0.13ppm) | ????4.96～4.97(m) ????1.03(d，J＝6.8Hz) | ?4.55～4.67(m) | ??3.01～3.62(m，7H)，1.25(d，J＝6.8Hz，3H) |
| C23 | ??14.85(br) | ????8.94(s) ????7.66(d，J＝9.2Hz) | ??4.47～4.61(m) | ????4.89(br) ????1.15(d，J＝6.4Hz) | ?4.47～4.61(m) | ??4.02～4.05(m，1H)，3.40(br，2H)，3.23～3.26 ??(m，1H)，3.03～3.05(m，1H)，2.76～2.80(m， ??1H)，1.41～1.45(m，6H) |
| C24 | ??14.89?(br) | ????8.96(s) ????7.66(d，J＝9.2Hz) | ??4.25(dd，AB，J＝8.0Hz， ??Δ＝0.11ppm) | ????4.92～4.94(m) ????1.47(d，J＝6.8Hz) | ?4.53～4.66(m) | ??3.50～3.55(br，2H)，3.41～3.43(m，2H)， ??2.80～2.82(m，2H)，1.23(d，J＝6.4Hz，6H) |
| C25 | ??14.92(br) | ????8.92(s) ????7.64(d，J＝9.6Hz) | ??4.19(s) | ????4.88～4.89(m) ????1.47(d，J＝6.4Hz) | ?4.45～4.60(m) | ??3.45(br，4H)，3.19(br，4H)，2.79(s，3H) |
| C26 | ??14.80(br) | ????8.96(s) ????7.67(d，J＝9.6Hz) | ??4.07(s) | ????4.92～4.94(m) ????1.48(d，J＝6.8Hz) | ?4.48～4.62(m) | ??3.21～3.46(m，12H) |
| C27 | ??14.89(br) | ???8.95(s) ???7.68(d，J＝9.6Hz) | ?4.49～4.65(m) | ????4.92～4.94(m) ????1.49(d，J＝6.8Hz) | ???4.49～4.65(m) | ??7.23(t，J＝8.0Hz，1H)，6.97(s，1H)，6.90～6.93 ??(m，1H)，6.82～6.84(m，1H)，3.42(br，8H) |
| C28 | ??14.85(br) | ???9.08(s)，7.71(d， ???J＝9.6Hz) | ?4.51(dd，AB，J＝13.6Hz，Δ ?＝0.11ppm) | ????5.01～5.03(m) ????1.51(d，J＝6.8Hz) | ???4.53～4.66(m) | ??5.95(d，J＝8.8Hz，2H)，6.85(d，J＝8.8Hz，2H)， ??3.64(s，3H)，3.42(br，4H)，3.29(br，4H) |
| C29 | ??14.83(br) | ???8.91(s) ???7.63(d，J＝9.2Hz) | ?4.17(s) | ????4.86～4.87(m) ????1.44(d，J＝6.8Hz) | ???4.51～4.57(m) | ??7.44～7.48(m，5H)，3.13～3.21?(br，8H)， ??4.51～4.57(m，1H)，1.62(d，J＝6.8Hz，3H) |
| C30 | ??14.95(br) | ???9.03(s) ???7.60(d，J＝10.0Hz) | ?4.63(s) | ????4.97～4.99(m) ????1.47(d，J＝6.8Hz) | ???4.43～4.68(m) | ??7.14～7.16(m，2H)，6.85～6.87(m，2H)， ??6.62～6.63?(m，1H)，3.38(q，J＝7.2Hz，2H)， ??1.04(t，J＝7.2Hz，3H) |
| C31 | ??14.89(br) | ???9.02(s) ???7.60(d，J＝10.0Hz) | ?4.62(s) | ????4.97～4.98(m) ????1.46(d，J＝6.8Hz) | ???4.43～4.67(m) | ??7.16～7.18(m，1H)，6.94～6.96(m，1H)， ??6.78～6.82(m?1H)，3.36(q，J＝6.8Hz，2H)，1.03 ??(t，J＝6.8Hz，3H) |
| C32 | ??14.85(br) | ???8.85(s) ???7.49(d，J＝9.2Hz) | ?4.62(s) | ????4.82～4.84(m) ????1.39(d，J＝6.8Hz) | ???4.37～4.61(m) | ??6.92～7.02(m，4H)，2.86(s，3H) |
A: with DMSO-d
6Be solvent.
B: add D
2O disappears.
Table 10. Compound D 1～D18
a 1HNMR data (δ ppm)
| No | ??COOH b | ????H 5，H 8 | ??NCH 2 | ????H 3，Me | ???OCH 2 | ????NR 1R 2 |
| D1 | ?14.80(br) | ????9.06(s) ????7.69(d，J＝10Hz) | ??4.29(dd，AB，J AB＝8.0Hz， ??Δ＝0.12ppm) | ????5.00～5.03(m) ????1.51(d，J＝6.8Hz) | ???4.48～4.64(m) | ????2.61(s，3H) |
| D2 | ?14.90(br) | ????9.06(s) ????7.68(d，J＝9.6Hz) | ??4.35(dd，AB，J AB＝13.2Hz， ??Δ＝0.10ppm) | ????4.98～5.02(m) ????1.51(d，J＝6.8Hz) | ???4.544.69(m) | ????2.69～2.74(m，1H)，0.92～0.96(br，2H)， ????0.72～0.77(m，2H) |
| D3 | ?14.92(br) | ????9.02(s) ????7.62(d，J＝10Hz) | ??4.41(d，J＝5.6Hz) | ????4.98～4.99(m) ????1.50(d，J＝6.8Hz) | ???4.45～4.67(m) | ????7.08(d，J＝9.2Hz，2H)，6.70(d，J＝9.2Hz，2H)， ????6.12b(t，J＝6.0Hz，1H) |
| D4 | ?14.89(br) | ????9.08(s) ????7.72?(d，J＝9.6Hz) | ??4.50(m) | ????5.01～5.03(m) ????1.51(d，J＝7.2Hz) | ???4.50～4.68(m) | ????3.53(br，2H)，3.26～3.28(m，2H)，1.92～2.04(m， ????4H) |
| D5 | ?14.89(br，) | ????9.09(s) ????7.73(d，J＝9.2Hz) | ??4.42(br) | ????5.02(m) ????1.50(d，J＝6.8Hz) | ???4.55～4.67(m) | ????3.433.53(m，2H)，3.04(br，2H)，1.79(br，4H)， ????1.65?(br，1H)，1.40(br，1H) |
| D6 | ?14.90(br) | ????8.94(s) ????7.70(d，J＝9.6Hz) | ??4.54(d，J＝2.8Hz) | ????4.88～4.90(m) ????1.47(d，J＝6.8Hz) | ???4.47～4.61(m) | ????3.70(br，4H)，3.25(br，4H) |
| D7 | ?14.85?(br) | ????8.89(s) ????7.64(d，J＝9.6Hz) | ??4.03(dd，AB，J AB＝13.2Hz， ??Δ＝0.04ppm) | ????4.85～4.87(m) ????1.46(d，J＝6.8Hz) | ???4.49～4.66(m) | ????3.15～3.17(m，4H)，2.92～2.94(m，4H) |
| D8 | ?14.95?(br) | ????8.94(s) ????7.69(d，J＝10.0Hz) | ??4.41(s) | ????4.89～4.91(m) ????1.48(d，J＝6.8Hz) | ???4.49～4.62(m) | ????3.55～3.57(m，2H)3.48～3.50(m，2H) ????3.37～3.39(m，2H)3.23～3.26(m，2H) ????2.10～2.15(m，2H) |
| D9 | ?14.80(br) | ????9.04(s) ????7.61(d，J＝9.6Hz) | ??3.87(s) | ????4.86～4.87(m) ????1.45(d，J＝6.8Hz) | ???4.45～4.66(m) | ????3.21～3.23(m，2H)，2.95～3.00(m，3H)， ????2.60～2.62(m，1H)，2.29～231(m，1H)，1.21(d， ????J＝6.4Hz，3H) |
| D10 | ??14.89?(br) | ????8.88(s) ????7.65(d，J＝9.6Hz) | ??4.25(s) | ????4.85～4.87(m) ????1.21(d，J＝6.4Hz) | 4.45～4.59(m) | ??3.38～3.49(m，4H)，2.71～2.73(m，2H)，1.46(d， ??J＝6.8Hz，6H) |
| D11 | ??14.80?(br) | ????8.92(s) ????7.64?(d，J＝9.6Hz) | ??4.00(s) | ????4.87～4.89(m) ????1.46(d，J＝6.8Hz) | 4.49～4.66(m) | ??3.24(br，4H)，2.93(br，4H)，2.75(s，3H) |
| D12 | ??14.90(br) | ????8.94(s) ????7.65(d，J＝9.6Hz) | ??4.07(d，J＝5.2Hz) | ????4.90～4.92(m) ????1.47(d，J＝6.8Hz) | 4.50～4.67(m) | ??3.70～3.73(m，2H)，3.29～3.34(m，4H)，3.03(br ??4H)，3.16～3.18(m，2H) |
| D13 | ??14.89(br) | ????9.07(s) ????7.70(d，J＝9.6Hz) | ??4.50(dd，AB，J＝13.6Hz， ??Δ＝0.13ppm) | ????5.02～5.04(m) ????1.53(d，J＝6.8Hz) | 4.53～4.65(m) | ??7.24(t，J＝8.0Hz，1H)，7.01?(br，1H).6.92～6.94 ??(m，1H)，6.84～6.85(m，1H)，3.45(br，8H) |
| D14 | ??14.90(br) | ????8.93(s) ????7.70(d，J＝9.2Hz) | ??4.51～4.64(m) | ????4.90～4.92(m) ????1.49(d，J＝6.8Hz) | 4.51～4.64(m) | ??6.92(d，J＝8.0Hz，2H)，6.84(d，J＝8.0Hz，2H)， ??3.67(s，3H)，3.43(br，8H) |
| D15 | ??14.95(br) | ????9.12(s) ????7.75(d，J＝9.6Hz) | ??4.56～4.70(m) | ????5.02～5.04(m) ????1.51(d，J＝6.8Hz) | 4.56～4.70(m) | ??6.89～7.01(m，4H)，3.78(s，3H)，3.39(br，6H)， ??3.29(br，2H) |
| D16 | ??14.89(br) | ????8.91(s) ????7.64(d，J＝9.6Hz) | ??4.13(s) | ????4.87～4.88(m) ????1.45(d，J＝6.4Hz) | 4.50～4.65(m) | ??7.42～7.50(m，5H)，3.08～3.28(m，8H)，1.62(d， ??J＝7.2Hz，3H)，4.46(m，1H) |
| D17 | ??14.90(br) | ????9.09(s) ????7.70(d，J＝9.2Hz) | ??5.61(dd，AB，J AB＝13.2Hz， ??Δ＝0.08ppm) | ????5.01～5.02(m) ????1.47(d，J＝6.4Hz) | 4.51～4.69(m) | ??9.13(s，1H)，7.65(d，J＝14.4Hz，2H) |
| D18 | ??14.80(br) | ????8.86(s) ????7.61(d，J＝10Hz) | ??5.58(s) | ????4.57～4.84(m) ????1.41(d，J＝6.8Hz) | 4.44～4.67(m) | ??8.76(s，1H)，8.01(s，1H) |
A: with DMSO-d
6Be solvent.
B: add D
2O disappears.
Table 11 in-vitro antibacterial test-results (MIC, μ g/ml)
*: Sau: golden Portugal bacterium, 41002 (Serratia marcescens) Sep: staphylococcus epidermidis, Spn: pneumococcus, the Sah Staphylococcus albus, Ste: faecalis, Ec: intestinal bacteria, Sso: Song Shi Shigellae, Sbo: Shigella bogdii, Pmi: Proteus mirabilis, Pv: proteus vulgaris, Pmo: Morgan Bacillus proteus, Kp: pneumobacillus, Sae: Salmonella enteritidis, S keeps: Corynebacterium diphtheriae, Sci: citrobacter, Sma: serratia marcescens
| Bacterium | ??Sau | ??Sep | ??Spn | ??Sal | ??Ste | ??Ec | ??Son | ??Sbo | ?Pmi | ?Pv | ?Pmo | ??Kp | ??Sae | ??Sty | ??Sci | ?Sma |
| Lomefloxacin | ??0.78 | ??0.78 | ??0.195 | ??3.13 | ????25 | ??0.098 | ??0.098 | ??0.098 | ?0.39 | ??0.78 | ?0.195 | ??0.098 | ??0.098 | ??0.195 | ??0.098 | ?0.195 |
| ????Pazufloxacin | ?0.195 | ??0.39 | ??0.049 | ??3.13 | ?0.195 | ??0.049 | ??0.049 | ??0.049 | ?0.049 | ?0.049 | ?0.049 | ??0.049 | ??0.049 | ??0.049 | ??0.049 | ?0.049 |
| Vancomycin | ??0.39 | ??0.78 | ??0.098 | ??0.78 | ??0.78 | ?＞6.25 | ?＞6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ?＞6.25 | ?＞6.25 | ?＞6.25 | ?＞6.25 | ＞6.25 |
| ????A1 | ??12.5 | ??12.5 | ???0.78 | ????25 | ??＞25 | ??0.098 | ??0.098 | ??0.098 | ?0.195 | ??0.39 | ?0.098 | ??0.098 | ??0.098 | ??0.098 | ??0.098 | ?0.195 |
| ????A2 | ＞6.25 | ＞6.25 | ???0.78 | ＞6.25 | ＞6.25 | ??0.098 | ???0.39 | ≤0.049 | ??0.39 | ??0.78 | ?0.098 | ≤0.049 | ≤0.049 | ??0.098 | ≤0.049 | ?0.195 |
| ????A3 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ??1.56 | ???0.78 | ??0.195 | ??0.195 | ??1.56 | ??3.13 | ??0.39 | ???0.39 | ???0.39 | ???0.39 | ??0.195 | ??0.78 |
| ????A4 | ＞6.25 | ＞6.25 | ???1.56 | ＞6.25 | ＞6.25 | ???0.39 | ???0.39 | ??0.195 | ??1.56 | ??6.25 | ??0.78 | ??0.098 | ???0.39 | ???0.39 | ??0.098 | ??0.78 |
| ????A5 | ??3.13 | ??6.25 | ??0.195 | ＞6.25 | ＞6.25 | ??0.195 | ≤0.049 | ??0.098 | ??0.78 | ??1.56 | ?0.195 | ≤0.049 | ??0.195 | ??0.195 | ≤0.049 | ??0.78 |
| ????A6 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ＞6.25 | ???0.39 | ???1.56 | ???0.39 | ??3.13 | ＞6.25 | ??0.78 | ≤0.049 | ???0.39 | ???0.78 | ??0.098 | ??0.39 |
| ????A7 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ＞6.25 | ???1.56 | ???1.56 | ???0.78 | ＞6.25 | ＞6.25 | ??3.13 | ???0.39 | ???1.56 | ???1.56 | ???0.39 | ??3.13 |
| ????A8 | ＞6.25 | ??6.25 | ???1.56 | ＞6.25 | ??6.25 | ???0.78 | ???0.78 | ???0.78 | ＞6.25 | ＞6.25 | ??3.13 | ??0.195 | ???1.56 | ???1.56 | ??0.195 | ??3.13 |
| ????A9 | ??0.78 | ??1.56 | ??0.049 | ??3.13 | ＞6.25 | ???1.56 | ???0.78 | ???0.39 | ??6.25 | ??6.25 | ??3.13 | ???0.78 | ???1.56 | ???1.56 | ???0.39 | ＞6.25 |
| ????A10 | ??0.39 | ??1.56 | ＜0.049 | ??1.56 | ????25 | ???3.13 | ???1.56 | ???1.56 | ??6.25 | ??6.25 | ??6.25 | ???1.56 | ???1.56 | ???1.56 | ???1.56 | ????25 |
| ????A11 | ?0.195 | ??1.56 | ＜0.049 | ??1.56 | ????25 | ???1.56 | ???1.56 | ???0.78 | ??3.13 | ??3.13 | ??3.13 | ???1.56 | ???1.56 | ???1.56 | ???1.56 | ??12.5 |
| ????A12 | ??0.78 | ??1.56 | ??0.049 | ??3.13 | ??0.39 | ???1.56 | ???0.78 | ??0.195 | ??6.25 | ??6.25 | ??3.13 | ???0.78 | ???1.56 | ???1.56 | ???0.39 | ＞6.25 |
| ????A13 | ??0.39 | ??1.56 | ???0.39 | ??1.56 | ＞6.25 | ???1.56 | ???1.56 | ???1.56 | ??6.25 | ??6.25 | ??3.13 | ???1.56 | ???1.56 | ???3.13 | ???0.78 | ＞6.25 |
| ????A14 | ??0.78 | ??1.56 | ???0.39 | ??3.13 | ??3.13 | ???1.56 | ???0.78 | ???0.78 | ??6.25 | ??6.25 | ??3.13 | ???0.78 | ???3.13 | ???3.13 | ???0.78 | ＞6.25 |
| ????A15 | ??1.56 | ??3.13 | ???1.56 | ??3.13 | ＞6.25 | ???3.13 | ???3.13 | ???0.78 | ＞6.25 | ＞6.25 | ＞6.25 | ???1.56 | ???6.25 | ???6.25 | ???1.56 | ＞6.25 |
| ????A16 | ??0.39 | ??1.56 | ??0.049 | ??3.13 | ??0.78 | ???3.13 | ???0.78 | ???0.39 | ??6.25 | ＞6.25 | ??3.13 | ???1.56 | ???3.13 | ???3.13 | ???0.78 | ＞6.25 |
| ????A17 | ??0.39 | ??0.78 | ??0.098 | ??1.56 | ＞6.25 | ???3.13 | ???1.56 | ???1.56 | ＞6.25 | ＞6.25 | ＞6.25 | ???1.56 | ???6.25 | ???6.25 | ???1.56 | ＞6.25 |
| ????A18 | ??0.39 | ??1.56 | ??0.098 | ??3.13 | ＞6.25 | ??1.56 | ??0.78 | ??0.39 | ＞6.25 | ＞6.25 | ??6.25 | ???0.78 | ??3.13 | ??1.56 | ??0.78 | ＞6.25 |
| ????A19 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ＞6.25 | ??3.13 | ??0.78 | ??0.78 | ??6.25 | ??6.25 | ??3.13 | ???0.78 | ??3.13 | ??3.13 | ??1.56 | ??6.25 |
| ????A20 | ＞6.25 | ＞6.25 | ???1.56 | ＞6.25 | ??0.39 | ??3.13 | ??0.78 | ??0.78 | ??6.25 | ＞6.25 | ??3.13 | ???0.78 | ??3.13 | ??3.13 | ??0.78 | ??3.13 |
| ????A21 | ??0.39 | ??1.56 | ??0.195 | ??6.25 | ??0.39 | ??1.56 | ??0.78 | ??0.39 | ??6.25 | ??6.25 | ??6.25 | ???0.78 | ??1.56 | ??1.56 | ??0.39 | ＞6.25 |
| ????A22 | ??12.5 | ??12.5 | ???1.56 | ??＞25 | ??＞25 | ??1.56 | ??0.39 | ??0.39 | ??3.13 | ??6.25 | ??1.56 | ???1.56 | ??1.56 | ??1.56 | ??0.39 | ??1.56 |
| ????A23 | ??12.5 | ????25 | ???1.56 | ??＞25 | ??＞25 | ??3.13 | ??0.78 | ??0.78 | ??12.5 | ??12.5 | ??3.13 | ???1.56 | ??1.56 | ??3.13 | ??0.78 | ??3.13 |
| ????A24 | ??12.5 | ??12.5 | ??0.195 | ??＞25 | ??＞25 | ??6.25 | ??3.13 | ??3.13 | ??12.5 | ????25 | ??6.25 | ???3.13 | ??6.25 | ??6.25 | ??3.13 | ??12.5 |
| ????A25 | ??6.25 | ??6.25 | ???6.25 | ＞6.25 | ＞6.25 | ??1.56 | ??1.56 | ??0.78 | ＞6.25 | ??6.25 | ??0.78 | ??0.195 | ??1.56 | ??0.78 | ?0.195 | ??0.78 |
| ????A26 | ??6.25 | ????25 | ???3.13 | ??＞25 | ??＞25 | ??3.13 | ??3.13 | ??3.13 | ??＞25 | ????25 | ??6.25 | ???3.13 | ??3.13 | ??3.13 | ??3.13 | ??3.13 |
| ????A27 | ??12.5 | ??12.5 | ???1.56 | ??＞25 | ??＞25 | ??1.56 | ??1.56 | ??1.56 | ????25 | ????25 | ??6.25 | ???3.13 | ??3.13 | ??3.13 | ??1.56 | ????25 |
| ????A28 | ??12.5 | ??12.5 | ???1.56 | ????25 | ??＞25 | ??1.56 | ??1.56 | ??1.56 | ??6.25 | ??6.25 | ??1.56 | ???1.56 | ??1.56 | ??1.56 | ??1.56 | ??3.13 |
| ????A29 | ＞6.25 | ＞6.25 | ???1.56 | ＞6.25 | ＞6.25 | ??0.39 | ??0.39 | ??0.39 | ＞6.25 | ＞6.25 | ??1.56 | ???0.39 | ??0.78 | ??0.78 | ?0.195 | ??3.13 |
| ????A30 | ??12.5 | ????25 | ???3.13 | ??＞25 | ??＞25 | ??6.25 | ??1.56 | ??1.56 | ????25 | ????25 | ??12.5 | ???6.25 | ??6.25 | ??6.25 | ??1.56 | ????25 |
| ????A31 | ??6.25 | ＞6.25 | ???0.78 | ＞6.25 | ＞6.25 | ＞6.25 | ??6.25 | ??6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ??6.245 | ＞6.25 | ＞6.25 | ??6.25 | ＞6.25 |
| ????A32 | ??12.5 | ??12.5 | ???3.13 | ????25 | ??＞25 | ????25 | ??12.5 | ??12.5 | ?＞215 | ??＞25 | ??＞25 | ???12.5 | ??＞25 | ??＞25 | ??12.5 | ??＞25 |
| ????A33 | ??12.5 | ????25 | ???12.5 | ??＞25 | ??＞25 | ??＞25 | ????25 | ????25 | ??＞25 | ??＞25 | ????25 | ?????25 | ????25 | ????25 | ????25 | ??＞25 |
| ????A34 | ??6.25 | ＞6.25 | ???0.78 | ＞6.25 | ＞6.25 | ??0.78 | ??0.39 | ??0.39 | ??6.25 | ??6.25 | ??0.78 | ??0.195 | ??0.78 | ??0.78 | ??0.195 | ??1.56 |
| ????A35 | ??3.13 | ??6.25 | ???3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ??3.13 | ??3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ???6.25 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 |
| ????A36 | ??1.56 | ??12.5 | ???1.56 | ????25 | ??＞25 | ????25 | ??6.25 | ??12.5 | ??＞25 | ??＞25 | ??＞25 | ?????25 | ????25 | ????25 | ???12.5 | ??＞25 |
| ????A37 | ??12.5 | ??12.5 | ???12.5 | ??＞25 | ??＞25 | ??＞25 | ??＞25 | ??＞25 | ??＞25 | ??＞25 | ??＞25 | ???＞25 | ??＞25 | ??＞25 | ?????25 | ??＞25 |
| ????B1 | ??＞25 | ??＞25 | ???6.25 | ??＞25 | ??＞25 | ??0.78 | ??0.39 | ??0.78 | ??0.78 | ??1.56 | ??0.78 | ???0.78 | ??0.78 | ??0.78 | ???0.39 | ??0.78 |
| ????B2 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ＞6.25 | ??0.78 | ??0.39 | ??0.39 | ??1.56 | ??1.56 | ??0.78 | ??0.195 | ??1.56 | ??1.56 | ???0.39 | ??0.78 |
| ????B3 | ＞6.25 | ＞6.25 | ???3.13 | ＞6.25 | ＞6.25 | ??0.78 | ?0.788 | ??0.39 | ??1.56 | ??3.13 | ??0.78 | ??0.195 | ??1.56 | ??1.56 | ???0.39 | ??1.56 |
| ????B4 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 1.56 | 1.56 | 1.56 | 6.25 | ＞6.25 | 1.56 | 0.39 | 1.56 | 3.13 | 0.78 | 3.13 |
| ????B5 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 1.56 | 6.25 | ＞6.25 | 3.13 | 0.78 | 3.13 | 3.13 | 0.78 | 3.13 |
| ????B6 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | ?6.25 | 6.25 | 0.78 | 6.25 |
| ????B7 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 |
| ????B8 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 3.13 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | 6.25 | 6.25 | 1.56 | ＞6.25 |
| ????B9 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 |
| ????B10 | 1.56 | 3.13 | 0.78 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 0.78 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 3.13 | 3.13 | 1.56 | ＞6.25 |
| ????B11 | ＞25 | ＞25 | 6.25 | ＞25 | ＞25 | 6.25 | 3.13 | 3.13 | 6.25 | ＞25 | 6.25 | 3.13 | 3.13 | 3.13 | 3.13 | 6.25 |
| ????B12 | ＞25 | ＞25 | 6.25 | ＞25 | ＞25 | 12.5 | 6.25 | 6.25 | ＞25 | ＞25 | 12.5 | 6.25 | 12.5 | 12.5 | 6.25 | 25 |
| ????B13 | 25 | ＞25 | 12.5 | ＞25 | ＞25 | ＞25 | 25 | 25 | ＞25 | ＞25 | ＞25 | 25 | ＞25 | ＞25 | 25 | ＞25 |
| ????B14 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 6.25 | 6.25 | 6.25 | ＞6.25 | ＞6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 | 6.25 |
| ????B15 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????B16 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 1.56 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 3.13 | 6.25 | 1.56 | ＞6.25 |
| ????B17 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 | ＞6.25 | 1.56 | 0.39 | 0.39 | ＞6.25 | ＞6.25 | 3.13 | 0.195 | 0.39 | 0.78 | 0.195 | ＞6.25 |
| ????B18 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 3.13 | 3.13 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | 1.56 | 6.25 | 0.78 | ＞6.25 |
| ????B19 | ＞25 | ＞25 | 6.25 | ＞25 | ＞25 | 6.25 | 3.13 | 3.13 | 25 | ＞25 | 6.25 | 6.25 | 6.25 | 6.25 | 3.13 | 12.5 |
| ????B20 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 6.25 | 3.13 | 1.56 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | 3.13 | 3.13 | 1.56 | ＞6.25 |
| ????B21 | ＞25 | ＞25 | 25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | 25 | ＞25 |
| ????B22 | ＞6.25 | ＞6.25 | 0.39 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????B23 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????B24 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 | ＞25 |
| ????B25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????B26 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 0.78 | 6.25 | ＞6.25 | 1.56 | 0.78 | 3.13 | 3.13 | 0.78 | 6.25 |
| ????C1 | ＞6.25 | ＞6.05 | 1.56 | ＞6.25 | ＞6.25 | 0.39 | 0.195 | 0.195 | 0.78 | 1.56 | 0.39 | 0.049 | 0.195 | 0.195 | ??0.195 | ?0.39 |
| ????C2 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 0.78 | 0.39 | 0.39 | 1.56 | 6.25 | 1.56 | 0.195 | 0.78 | 1.56 | ??0.39 | ?1.56 |
| ????C3 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | 3.13 | 0.78 | 0.39 | 0.39 | 1.56 | 6.25 | 0.78 | 0.195 | 0.78 | 0.78 | ??0.39 | ?1.56 |
| ????C4 | 3.13 | ＞6.25 | 0.39 | ＞6.25 | ＞6.25 | 0.195 | 0.098 | 0.049 | 0.39 | 0.78 | 0.195 | 0.049 | 0.195 | 0.195 | ??0.049 | ?0.39 |
| ????C5 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 0.39 | 0.39 | 0.39 | 3.13 | 6.25 | 1.56 | 0.78 | 0.78 | 0.78 | ??0.39 | ?1.56 |
| ????C6 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 1.56 | 6.25 | ＞6.25 | 3.13 | 0.78 | 3.13 | 3.13 | ??0.78 | ?6.25 |
| ????C7 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 1.56 | 0.78 | 0.78 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 1.56 | 1.56 | ??0.78 | ?3.13 |
| ????C8 | 1.56 | 1.56 | 0.098 | ＞6.25 | 3.13 | ＞6.25 | 0.78 | 0.39 | ＞6.25 | ＞6.25 | ＞6.25 | 0.78 | ＞6.25 | ＞6.25 | ??0.78 | ?＞6.25 |
| ????C9 | 0.098 | 0.098 | ≤0.049 | 6.25 | 6.25 | 6.25 | 0.195 | 0.195 | ＞6.25 | ＞6.25 | ＞6.25 | 0.195 | ＞6.25 | ＞6.25 | ??0.098 | ?＞6.25 |
| ????C10 | 1.56 | 3.13 | 0.195 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ??6.25 | ?＞6.25 |
| ????C1?1 | 0.78 | 0.78 | 0.049 | 1.56 | 6.25 | 1.56 | 0.78 | 0.78 | 6.25 | 6.25 | 3.13 | 0.78 | 1.56 | 1.56 | ??0.78 | ?＞6.25 |
| ????C12 | 0.098 | 0.195 | ≤0.049 | 0.78 | ＞6.25 | 1.56 | 0.195 | 0.195 | ＞6.25 | ＞6.25 | 3.13 | 0.195 | 1.56 | 1.56 | ??0.39 | ?＞6.25 |
| ????C13 | 0.78 | 3.13 | 0.098 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | 0.78 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ??1.56 | ?＞6.25 |
| ????C14 | 3.13 | 3.13 | 0.195 | ＞6.25 | 1.56 | ＞6.25 | 6.25 | 1.56 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ??3.13 | ?＞6.25 |
| ????C15 | 0.78 | 0.78 | 0.195 | 1.56 | 3.13 | 0.78 | 0.78 | 0.195 | 6.25 | 6.25 | 3.13 | 0.39 | 1.56 | 1.56 | ??0.78 | ?6.25 |
| ????C16 | 1.56 | 0.78 | 0.39 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 0.39 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 1.56 | 0.78 | ??0.78 | ?＞6.25 |
| ????C17 | 6.25 | ＞6.25 | 0.78 | ＞6.25 | ＞6.25 | 0.39 | 0.195 | 0.39 | 0.78 | 1.56 | 0.39 | 0.049 | 0.39 | 0.78 | ??0.098 | ?0.78 |
| ????C18 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 | ＞6.25 | 0.78 | 0.39 | 0.78 | 0.56 | 6.25 | 0.78 | 0.195 | 0.78 | 0.78 | ??0.39 | ?1.56 |
| ????C19 | 6.25 | ＞6.25 | 0.78 | ＞6.25 | ＞6.25 | 3.13 | 1.56 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | 0.78 | 6.25 | 6.25 | ??3.13 | ?＞6.25 |
| ????C20 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ??＞6.25 | ?＞6.25 |
| ????C21 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ??＞6.25 | ?＞6.25 |
| ????C22 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ??＞6.25 | ?＞6.25 |
| ????C23 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ??＞6.25 | ?＞6.25 |
| ????C24 | ＞6.25 | ＞6.25 | 6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 |
| ????C25 | ＞6.25 | ＞6.25 | 1.56 | ?＞6.25 | ＞6.25 | 6.25 | 1.56 | 1.56 | ＞6.25 | ＞6.25 | 3.13 | 0.78 | 1.56 | 3.13 | 1.56 | 6.25 |
| ????C26 | ＞6.25 | ＞6.25 | 6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????C27 | 3.13 | ＞6.25 | 0.78 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????C28 | 6.25 | ＞6.25 | 0.39 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????C29 | ＞6.25 | ＞6.25 | 3.13 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????C30 | 3.13 | 3.13 | 0.39 | ?＞6.25 | 3.13 | 6.25 | 6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 |
| ????C31 | 3.13 | 6.25 | 3.13 | ?6.25 | 6.25 | ＞6.25 | 6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 |
| ????C32 | 3.13 | 3.13 | 0.39 | ?6.25 | 3.13 | 6.25 | 3.13 | 1.56 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 6.25 | 6.25 | 1.56 | ＞6.25 |
| ????D1 | 3.13 | ＞6.25 | 3.13 | ?＞6.25 | ＞6.25 | 0.195 | 0.098 | 0.098 | 0.39 | 0.78 | 0.39 | 0.098 | 0.195 | 0.098 | ≤0.049 | 0.195 |
| ????D2 | 3.13 | 3.13 | 0.39 | ?6.25 | ＞6.25 | ≤0.049 | ≤0.049 | ≤0.049 | 0.195 | 0.78 | 0.098 | ≤0.049 | ≤0.049 | ≤0.049 | ≤0.049 | 0.195 |
| ????D3 | 0.195 | 0.78 | ≤0.049 | ?＞6.25 | ＞6.25 | ＞6.25 | 1.56 | 1.56 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 |
| ????D4 | ＞6.25 | ＞6.25 | 3.13 | ?＞6.25 | ＞6.25 | 0.78 | 0.39 | 0.39 | 1.56 | 6.25 | 0.78 | 0.195 | 0.78 | 0.39 | 0.39 | 1.56 |
| ????D5 | ＞6.25 | ＞6.25 | 3.13 | ?＞6.25 | ＞6.25 | 0.78 | 0.78 | 0.78 | 3.13 | ＞6.25 | 6.25 | 0.39 | 1.56 | 1.56 | 0.78 | 3.13 |
| ????D6 | ＞6.25 | ＞6.25 | 1.56 | ?＞6.25 | ＞6.25 | 6.25 | 3.13 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 1.56 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 |
| ????D7 | ＞6.25 | ＞6.25 | ＞6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D8 | ＞6.25 | ＞6.25 | ＞6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D9 | ＞6.25 | ＞6.25 | ＞6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D10 | ＞6.25 | ＞6.25 | 6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 |
| ????D11 | ＞6.25 | ＞6.25 | 3.13 | ?＞6.25 | 6.25 | 6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | 1.56 | 6.25 | ＞6.25 | 1.56 | ＞6.25 |
| ????D12 | ＞6.25 | ＞6.25 | ＞6.25 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | 6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D13 | 3.13 | ＞6.25 | 0.78 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D14 | ＞6.25 | ＞6.25 | 0.78 | ?＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D15 | ＞6.25 | ＞6.25 | ??3.13 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 | ＞6.25 |
| ????D16 | ??6.25 | ??6.25 | ??3.13 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ??6.25 | ?6.25 |
| ????D17 | ??3.13 | ??3.13 | ??0.78 | ＞6.25 | ＞6.25 | ??0.78 | ??0.195 | ??0.78 | ??6.25 | ??3.13 | ??0.78 | ??0.195 | ??0.78 | ??0.78 | ??0.39 | ?1.56 |
| ????D18 | ??6.25 | ??6.25 | ??0.78 | ＞6.25 | ＞6.25 | ??1.56 | ??0.39 | ??0.39 | ??6.25 | ??3.13 | ??0.78 | ??0.39 | ??0.78 | ??1.56 | ??0.195 | ??1.56 |
Embodiment
All melting point compounds of the present invention are measured with the capillary melting point determination instrument, nucleus magnetic resonance is by Bruke AM-400 type nmr determination, with TMS is interior mark, mass spectrum is measured with Finnign-MAT212 type mass spectrograph, ultimate analysis is measured by Carlo Erba1106 type automatic elemental analyzer, and specific rotatory power is measured by Perkin Elmer P-341 polarimeter.The HNMR data of target compound see Table 7～10.
The column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces (200-300 order), and thin layer chromatography board is the HSF-254 type that sesame handle of the Big Dipper experiment chemical plant, Yantai produces, and anhydrous response is all at N
2Carry out under the protection.
Embodiment 1
1-cyclopropyl-6,8-two fluoro-7-amine methyl isophthalic acids, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is Va) synthetic:
With (11.8g, 33.5mmol) 1-cyclopropyl-6,8-two fluoro-7-nitre methyl isophthalic acids, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is IVa) is dissolved in 500ml ethanol and the 250ml ethylene glycol monomethyl ether, add 20 gram Raney nickels, hydrogenation hydrogenation 24h under room temperature 10atm.Filter, washing with alcohol, filtrate decompression concentrates, add HCl/ ethanol and regulate pH＜3, the evaporated under reduced pressure solvent, resistates is with recrystallizing methanol, separate out solid filtering, join in sodium carbonate solution and the methylene dichloride miscellany and stir, layering, water layer is with twice of dichloromethane extraction, organic phase merges, successively with water, saturated NaCl solution washing, MgSO
4Drying, evaporated under reduced pressure solvent get Va (5.1g, 48%).mp：168-172℃，HNMR(DMSO-d
6)，δppm，8.52(s，1H，2-H)，7.82(d，J＝9.2Hz，1H，5-H)，6.88(br，NH
2)，4.20-4.31(m，4H，2CH
2)，3.99(m，1H，CH)，1.28(t，J＝7.2Hz，3H，CH
3)，1.17(br，4H，CH
2CH
2).EIMS(m/z)322(M
+)，277(M-OCH
2CH
3)，250(M-COOEt+1)。
In like manner, with 1-ethyl-6,8-two fluoro-7-nitre methyl isophthalic acids, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is IVb) substitutes IVa, can obtain 1-ethyl-6,8-two fluoro-7-amine methyl isophthalic acids, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is Vb).
Embodiment 2
1-cyclopropyl-6,8-two fluoro-7-piperidino methyls-1, (code name is VI to 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester
1) synthetic:
Will (216mg, 0.67mmol) Va be with (166mg, 0.7mmol) dibromo pentane is woven in the 50ml acetonitrile, adds that (back flow reaction 8h boils off solvent for 250mg, 1.8mmol) salt of wormwood.Add entry and methylene dichloride layering, water layer is with dichloromethane extraction twice, and organic phase merges, successively with water, and saturated NaCl solution washing, MgSO
4Drying, the pressure reducing and steaming solvent, resistates gets VI through column chromatography (petrol ether/ethyl acetate is a developping agent at 1: 1)
1(165mg, 63%).mp：152-155℃，HNMR(CDCl
3)，δppm，8.60(s，1H，2-H)，7.99(d，J＝8.8Hz，1H，5-H)，4.39(t，J＝7.2Hz，2H，OCH
2)，3.91-3.97(m，1H，CH)，3.81(s，2H，NCH
2Ar)，2.51(br，4H，2NCH
2)，1.60(br，4H，2CH
2)，1.41(t，J＝6.8Hz，5H，CH
2+CH
3)，1.27(m，2H，cyclopropy1-H)，1.13(br，2H，cyclopropyl-H).EIMS(m/z)390(M
+)，345，278，235，192，98.。
Embodiment 3
Adopt the identical method of embodiment 2, but replace above-mentioned Va, can obtain 1-ethyl-6 with Vb, 8-two fluoro-7-piperidino methyls-1, (code name is VI to 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester
2): (47%), mp:161-164 ℃,
1HNMR (CDCl
3), δ ppm, 8.59 (s, 1H, 2-H), 7.99 (d, J=8.8Hz, 1H, 5-H), 4.39 (t, J=7.2Hz, 2H, OCH
2), 3.94 (br, 3H, NCH+NCH
2Ar), 2.65 (br, 4H, 2NCH
2), 1.81 (br, 4H, 2CH
2), 1.41 (t, J=6.8Hz, 3H, CH
3), 1.21 (m, 2H, cyclopropyl-H), 1.13 (br, 2H, cyclopropyl-H) .EIMS (m/z) 376 (M
+), 356,331,278,235,215,173,98.
Embodiment 4
1-cyclopropyl-6,8-two fluoro-7-piperidino methyls-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid (code name is A23) synthetic:
With (150mg, 0.38mmol) VI
1Be dissolved among 3: 1 the HOAc/HCl, backflow 3h, solvent evaporated gets A23 (98mg, 64%) with 95% ethyl alcohol recrystallization, promptly obtains target product A23.Physicochemical constant sees Table 3.
Embodiment 5
With the same method of embodiment 4, but with VI
2Replace VI
1, can obtain 1-cyclopropyl-6,8-two fluoro-7-Pyrrolidine ylmethyls-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid (code name is A22).Physicochemical constant sees Table 3.
Embodiment 6
1-cyclopropyl-6,8-two fluoro-7-formyl radicals-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (VIIa) synthetic:
(10g, 28.5mmol) IVa and 200ml methyl alcohol are mixed, splash into KOH (4.78g, methyl alcohol 84mmol) (285ml) solution under the cryosel cooling.Dripping off the back stirred 30 minutes.Add frozen water refrigerative Na
2B
4O
7Water (15g) (100ml) solution splashes into KMnO
4(3.0g, water 19mmol) (750ml) solution drips process temperature and is controlled between-10～-5 ℃, drips off back equality of temperature reaction 2h, reaction mixture is by the thin layer filtered through silica gel, layer of silica gel washes twice with amount of ethyl acetate, and water is saturated with sodium-chlor, ethyl acetate extraction 5 times, merge organic phase, and with water, saturated NaCl solution washing, MgSO
4Drying, the evaporated under reduced pressure solvent, crude product gets VIIa (6.1g, 66%) with acetone recrystallization.
Adopt and use the same method; respectively with 1-ethyl-6; 8-two fluoro-7-nitre methyl isophthalic acids; 4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is IVb); (S)-9-fluoro-3-methyl isophthalic acid 0-nitre methyl-7-oxygen-2; 3-dihydro-7H-pyridine [1; 2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is IVc); or 9-fluoro-3-methyl isophthalic acid 0-nitre methyl-7-oxygen-2; 3-dihydro-7H-pyridine [1; 2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is IVd) substitutes IVa; can obtain intermediate 1-ethyl-6; 8-two fluoro-7-formyl radicals-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is VIIb); (S)-and 9-fluoro-3-methyl isophthalic acid 0-formyl radical-7-oxygen-2,3-dihydro-7H-pyridine [1; 2; 3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is VIIc) and 9-fluoro-3-methyl isophthalic acid 0-formyl radical-7-oxygen-2,3-dihydro-7H-pyridine [1; 2; 3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester VIId (code name is VIId), physicochemical constant sees Table 1.
Embodiment 7
1-cyclopropyl-6,8-two fluoro-7-methylols-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester VIIIa
Will (6.0g, 18.7mmol) VIIa dissolves in the 500ml methyl alcohol, and the frozen water cooling adds (0.35g, 9.3mmol) sodium borohydride, equality of temperature reaction 1h down in batches.Add 5ml acetone, stir half an hour, the pressure reducing and steaming solvent, resistates adds entry, the ethyl acetate layering, water layer merges organic layer with ethyl acetate extraction twice, and with water, saturated NaCl solution washing, MgSO
4Drying, the pressure reducing and steaming solvent, residual solid gets VIIIa (4.7g, 78%) with ethyl alcohol recrystallization.mp：168-170℃，
1HNMR(CDCl
3，δppm)：8.57(s，1H，2H)，7.91(dd，J＝9.2Hz，1H，5-H)，4.89(s，2H，CH
2(OH))，4.39(q，J＝7.2Hz，2H，OCH
2)，3.91(m，1H，NCH)，1.40(t，J＝7.2Hz，3H，CH
3)，1.25-1.27(m，2H，CH
2)，1.14-1.19(m，2H，CH
2)；
Substitute VIIa with VIIb, VIIc and VIId respectively, adopting uses the same method can obtain 1-ethyl-6,8-two fluoro-7-methylols-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is VIIIb), (S)-9-fluoro-3-methyl isophthalic acid 0-methylol-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is VIIIc) and 9-fluoro-3-methyl isophthalic acid 0-methylol-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is VIIId).VIIIb：
1HNMR(CDCl
3)δppm：8.41(s，1H，2-H)，8.01(d，J＝11.2Hz，1H，5-H)，4.90(s，2H，CH
2(OH))，4.38-4.43(m，4H)，1.54(t，J＝6.8Hz，3H)，1.41(t，J＝7.2Hz，3H)。
Embodiment 8
1-cyclopropyl-6,8-two fluoro-7-brooethyls-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester IXa
Will (4.7g, 14.6mmol) VIIIa is dissolved in the 150ml methylene dichloride, the frozen water cooling, the adding phosphorus tribromide (1.37ml, 14.6mmol).Equality of temperature reaction 4h adds the methylene dichloride dilution, successively with saturated sodium bicarbonate, and water and saturated NaCl washing, MgSO
4Drying boils off solvent and gets IXa (5.0g, 89%).Not purified next step reaction of direct input of product.
Respectively with VIIIb, VIIIc and VIIId substitute VIIIa, adopt and use the same method, can obtain 1-ethyl-6,8-two fluoro-7-brooethyls-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid ethyl ester (code name is IXb), (S)-and 9-fluoro-3-methyl isophthalic acid 0-brooethyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is IXc) and 9-fluoro-3-methyl isophthalic acid 0-brooethyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (code name is IXd).
Embodiment 9
1-cyclopropyl-6,8-two fluoro-7-morpholinyl methyl-1,4-dihydro-4-oxygen-quinoline-3-carboxylic acid hydrochloride (A24)
Will (350mg, 0.9mmol) IXa is dissolved in the acetonitrile, adds (187mg, 2.1mmol) morpholine and (0.32g, 2.3mmol) salt of wormwood, stirring at room 4h, boil off acetonitrile, resistates is with water, the ethyl acetate layering, and water layer is with twice of ethyl acetate extraction, merge organic phase, organic phase is successively with water, saturated common salt water washing, MgSO
4Drying boils off solvent.Add 4: 1 HOAc/HCl 8ml, backflow 3h boils off solvent, and resistates gets A24 (200mg, two step yields amount to 51%) with 95% ethyl alcohol recrystallization.
Adopt and use the same method, substitute IXa with IXb, IXc and IXd respectively, can obtain code name is A28～A34, B11～B13, and B19～B26, C17～C19, the target compound of C25～C29 is in the physicochemical constant tabulation 3～6.
Embodiment 10
9-fluoro-3-methyl isophthalic acid 0-methylamino methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [synthesizing of 1,4] benzoxazine-6-carboxylic acid hydrochloride (D1):
With concentration is (0.39g, 1mmol) the 25ml acetonitrile solution of IXd slowly drips in the 50ml acetonitrile solution of methylamine (15ml), stir 2h after dripping off, pressure reducing and steaming solvent and excess amine, resistates adds water, the methylene dichloride layering, water merges organic layer, successively with water with dichloromethane extraction twice, saturated NaCl washing, MgSO
4Drying boils off solvent, adds 4: 1 HOAc/HCl 8ml, and backflow 3h boils off solvent, and resistates gets D1 (163mg, 43%) with 95% ethyl alcohol recrystallization.
Adopt and use the same method, substitute IXd with IXa, IXb, IXc respectively and can obtain target compound A2～A8, A25～A27, B2～B8, B14～B18, C1～C7, C20～C24, D2 and D7～D10 are in physicochemical constant row and table 3～6.
Embodiment 11
(S)-and 9-fluoro-3-methyl isophthalic acid 0-[N-ethyl-3-chloro-4-fluoroanilino] methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [synthesizing of 1,4] benzoxazine-6-carboxylic acid (C30):
Will (421mg, 1.1mmol) (140mg 1.2mmol) is woven in the 40ml acetonitrile IXc and N-ethyl-3-chloro-4-fluoro-aniline, adding salt of wormwood (280mg, 2mmol), backflow 4h, boil off solvent, get target compound C30 (228mg, 49%) through similar hydrolysis and aftertreatment.
Adopt and use the same method, substitute IXc, can obtain target compound A35 and C31, physicochemical constant tabulation 3～6 with IXa.
Embodiment 12
1-cyclopropyl-6,8-two fluoro-7-(3-chloro-4-fluoroanilino) methyl isophthalic acid, 4-dihydro-4-oxygen-quinoline-3-carboxylic acid (A13) synthetic:
Will (0.35g, 1.1mmol) VIIa is dissolved in the 20ml ethanol, and (160mg, 1.1mmol), reflux 1h is as cold as room temperature, adds 50ml methyl alcohol and a small amount of methyl violet, adds NaBH again to add 3-chloro-4-fluoroaniline
3CN (80mg, 1.29mmol), it is blue that system becomes, and in reaction process, repeatedly splashes into HCl/ methyl alcohol, so that blueness is taken off, stirred overnight at room temperature boils off solvent, and resistates adds water, the methylene dichloride layering, water merges organic layer with dichloromethane extraction twice, successively with water, and saturated NaCl washing, MgSO
4Drying boils off solvent, and add 4: 1HOAc/HCl8ml, backflow 3h boils off solvent, gets target compound A13 (289mg, 63%) with ethanol/ethylene glycol monomethyl ether recrystallization.
Adopt and use the same method, substitute VIIa with VIIb, VIIc or VIId respectively, can obtain target compound A9～A21, B9, B10, C8～C16 and D3 are in physicochemical constant row and table 3～6.
Embodiment 13
(S)-and 9-fluoro-3-methyl isophthalic acid 0-[N-methyl-4-fluoroanilino] methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [synthesizing of 1,4] benzoxazine-6-carboxylic acid (C31):
With ((222mg 1.7mmol) is woven in the ethanol para-fluoroaniline, and reflux 1h is cooled to room temperature, adds a small amount of methyl violet, adds NaBH again for 0.51g, 1.6mmol) VIIc
3CN (100mg, 1.6mmol), it is blue that system becomes, and in reaction process, repeatedly splashes into HCl/ methyl alcohol, so that blueness is taken off, room temperature reaction spends the night, and adds formaldehyde 0.5ml and NaBH
3CN (100mg, 1.6mmol).Repeatedly splash into HCl/ methyl alcohol, so that blueness is taken off, room temperature reaction 6h boils off solvent, and resistates adds entry, the ethyl acetate layering, and water layer merges organic layer again with ethyl acetate extraction twice, successively with water, saturated NaCl washing, MgSO
4Drying boils off solvent and gets solid, and crude product gets C31 (0.306g, 45%) through similar hydrolysis and aftertreatment, and physicochemical constant sees Table 5.
Claims (18)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530091A (en) * | 2014-12-23 | 2015-04-22 | 河南大学 | Chiral 3,3'-methylene-dioxazine (thiazine)-fluoroquinolone derivative as well as preparation method and application thereof |
| CN108285469A (en) * | 2018-03-15 | 2018-07-17 | 遵义医学院 | A kind of anti-microbial type Carbostyril derivative and its preparation method and application |
| WO2020163816A1 (en) * | 2019-02-08 | 2020-08-13 | Frequency Therapeutics, Inc. | Quinolin-4-one and 4(1h)-cinnolinone compounds and methods of using same |
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2002
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104530091A (en) * | 2014-12-23 | 2015-04-22 | 河南大学 | Chiral 3,3'-methylene-dioxazine (thiazine)-fluoroquinolone derivative as well as preparation method and application thereof |
| CN108285469A (en) * | 2018-03-15 | 2018-07-17 | 遵义医学院 | A kind of anti-microbial type Carbostyril derivative and its preparation method and application |
| WO2020163816A1 (en) * | 2019-02-08 | 2020-08-13 | Frequency Therapeutics, Inc. | Quinolin-4-one and 4(1h)-cinnolinone compounds and methods of using same |
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