JP2919910B2 - Optically active quinolone carboxylic acid derivative - Google Patents
Optically active quinolone carboxylic acid derivativeInfo
- Publication number
- JP2919910B2 JP2919910B2 JP2124640A JP12464090A JP2919910B2 JP 2919910 B2 JP2919910 B2 JP 2919910B2 JP 2124640 A JP2124640 A JP 2124640A JP 12464090 A JP12464090 A JP 12464090A JP 2919910 B2 JP2919910 B2 JP 2919910B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- carbon atoms
- reduced pressure
- under reduced
- residue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 85
- -1 acetoxymethyl group Chemical group 0.000 claims description 57
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 150000003248 quinolines Chemical group 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 116
- 239000000243 solution Substances 0.000 description 93
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 83
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 66
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
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- 238000006243 chemical reaction Methods 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 229910052739 hydrogen Inorganic materials 0.000 description 32
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
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- 238000001914 filtration Methods 0.000 description 17
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- BAYYCLWCHFVRLV-UHFFFAOYSA-N 1-ethyl-7-[3-(ethylaminomethyl)pyrrolidin-1-yl]-6,8-difluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C1C(CNCC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CC)C2=C1F BAYYCLWCHFVRLV-UHFFFAOYSA-N 0.000 description 12
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
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- 238000001816 cooling Methods 0.000 description 10
- 238000000921 elemental analysis Methods 0.000 description 10
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 8
- 229940125797 compound 12 Drugs 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
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- 241001465754 Metazoa Species 0.000 description 7
- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000007868 Raney catalyst Substances 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- 229910000564 Raney nickel Inorganic materials 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 6
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- 239000000843 powder Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 206010028470 Mycoplasma infections Diseases 0.000 description 4
- 206010040047 Sepsis Diseases 0.000 description 4
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 201000003146 cystitis Diseases 0.000 description 4
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 150000007660 quinolones Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
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- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 3
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- BUQMHUKZYMREQT-UHFFFAOYSA-N n-(pyrrolidin-3-ylmethyl)ethanamine Chemical compound CCNCC1CCNC1 BUQMHUKZYMREQT-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明は医薬、動物薬、水産用薬、保存剤として有用
な抗菌性化合物に関し、さらにこの化合物を有効成分と
して含有する抗菌剤に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to an antibacterial compound useful as a medicine, an animal drug, a marine medicine, and a preservative, and further relates to an antibacterial agent containing this compound as an active ingredient.
＜技術の背景＞ キノロンカルボン酸系合成抗菌薬において、キノリン
骨格の７位相当位に３−メチルアミノピロリジン類を置
換基として有する化合物が強い抗グラム陽性菌活性を示
したことが記載されており（特開昭59−67279号或は特
開昭60−241773号）、これらの代表的な化合物として、
コード名CI−934及びPD−117558等の化合物が知られて
いる。<Technical Background> It is described that among quinolone carboxylic acid-based synthetic antibacterial drugs, compounds having 3-methylaminopyrrolidines as substituents at the 7-position equivalent of the quinoline skeleton exhibited strong anti-gram-positive bacterial activity. (JP-A-59-67279 or JP-A-60-241773).
Compounds with code names CI-934 and PD-117558 are known.
上記二化合物の７位置換基である３−（エチルアミノ
メチル）ピロリジンは、ピロリジン環の３位が不斉炭素
であり異性体の混合物のラセミ体であった。この各々の
光学活性体には、本質的に抗菌活性に差がないとされて
いる（J.Med.Chem.，30,1711−1715（1987））。 3- (ethylaminomethyl) pyrrolidine, which is a substituent at the 7-position of the above two compounds, was a racemic mixture of isomers at the 3-position of the pyrrolidine ring with an asymmetric carbon. It is said that each of these optically active substances has essentially no difference in antibacterial activity ( J. Med. Chem. , 30 , 1711-1715 (1987)).
本発明者は、３−アミノメチルピロリジン類のアミノ
メチル側鎖の１位の炭素原子に低級アルキル基を導入し
た３−（１−アミノアルキル）ピロリジンをキノリン骨
格の７位相当位に導入することにより、光学活性体間で
抗菌活性に差を生じること、またこれらのうちの最も強
い活性を示す光学活性体は上記のCI−934はもとよりPD
−117558に比べ抗菌性が著しく増強されることを見出し
た（特開昭63−166876号公報）。The present inventors have introduced 3- (1-aminoalkyl) pyrrolidine in which a lower alkyl group has been introduced into the 1-position carbon atom of the aminomethyl side chain of 3-aminomethylpyrrolidine, at the 7-position equivalent of the quinoline skeleton. Causes a difference in the antibacterial activity between the optically active substances, and among these, the optically active substance showing the strongest activity is not only the above-mentioned CI-934 but also PD
It has been found that the antibacterial property is remarkably enhanced as compared with -117558 (JP-A-63-166876).
一方、CI−934を含む6,8−ジフルオロキノロン誘導体
はいずれもマウスを用いた光毒性試験で極めて強い光毒
性を示し、これらの誘導体を医薬として使用することを
強く懸念させた。On the other hand, all 6,8-difluoroquinolone derivatives including CI-934 showed extremely strong phototoxicity in a phototoxicity test using mice, and there was a strong concern that these derivatives could be used as drugs.
6,8−ジフルオロキノロン誘導体の強い光毒性反応の
原因を明確にし、光毒性を大幅に減じた、あるいは光毒
性反応を示さずかつ強い抗菌活性を有する化合物を獲得
する為、CI−934（１−エチル−７−（３−エチルアミ
ノメチル−１−ピロリジニル）−6,8−ジフルオロ−４
−オキソキノリン−３−カルボン酸）を用いて光毒性反
応を詳細に検討した。In order to clarify the cause of the strong phototoxic reaction of the 6,8-difluoroquinolone derivative and to obtain a compound having significantly reduced phototoxicity or exhibiting no phototoxicity and having strong antibacterial activity, CI-934 (1) -Ethyl-7- (3-ethylaminomethyl-1-pyrrolidinyl) -6,8-difluoro-4
-Oxoquinoline-3-carboxylic acid) was used to investigate the phototoxic reaction in detail.
CI−934の水溶液に紫外線を照射すると経時的に分解
反応が起り、ほぼ一原子分のフッ素イオンが検出される
こと、更に主な分解生産物は、キノリン骨格１位のエチ
ル基が８位で閉環した三環性化合物であることを確認し
た。Irradiation of an aqueous solution of CI-934 with ultraviolet light causes a decomposition reaction with time, and almost one atom of fluorine ion is detected. In addition, the main decomposition product is that the ethyl group at the 1st position of the quinoline skeleton is at the 8th position. It was confirmed that the compound was a closed ring tricyclic compound.
＜本発明の構成＞ 本発明は、一般式 （式中、R1は、置換基を有することもあるアリール基、
置換基を有することもあるヘテロアリール基、置換基を
有することもある炭素数３〜６の環状アルキル基、炭素
数１〜６のアルキル基、炭素数２〜６のアルケニル基、
炭素数１〜６のハロゲノアルキル基、炭素数１〜６のア
ルコキシ基、または炭素数１〜６のアルキルアミノ基を
意味し、 R2は、置換基を有することもあるアミノ基、水素原子、
水酸基、炭素数１〜６のアルコキシ基、またはハロゲン
原子を意味し、 R3は、炭素数１〜６のアルキル基を意味し、 R4は、水酸基、ハロゲン原子、もしくはフェニル基で置
換されていることもある炭素数１〜６のアルキル基、水
素原子、アシル基、アルキルオキシカルボニル基、また
はアラルキルオキシカルボニル基を意味し、 Ｑは、Ｃ−R5を意味し、 R5は、炭素数１〜６のアルキル基、または炭素数１〜６
のアルコキシ基を意味し、 R6は、水素原子、または炭素数１〜６のアルキル基を意
味する。また、R1はR5および／またはR6と共に環状構造
を形成してもよく、この環は酸素原子、窒素原子、硫黄
原子を含むこともあり、さらに炭素数１〜６のアルキル
基、ハロゲノアルキル基などで置換されていてもよい。<Structure of the present invention> (Wherein, R 1 is an aryl group which may have a substituent,
A heteroaryl group which may have a substituent, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,
A halogenoalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms, R 2 represents an amino group which may have a substituent, a hydrogen atom,
A hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom, R 3 represents an alkyl group having 1 to 6 carbon atoms, and R 4 is substituted with a hydroxyl group, a halogen atom, or a phenyl group. also alkyl group having 1 to 6 carbon atoms that have a hydrogen atom, and means an acyl group, an alkyloxycarbonyl group or an aralkyloxycarbonyl group,, Q means a C-R 5, R 5 is the number of carbon atoms 1 to 6 alkyl groups or 1 to 6 carbon atoms
R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 1 may form a cyclic structure with R 5 and / or R 6 , and this ring may contain an oxygen atom, a nitrogen atom, a sulfur atom, and further has an alkyl group having 1 to 6 carbon atoms, It may be substituted with an alkyl group or the like.
Ｚは、水素原子、炭素数１〜６のアルキル基、炭素数１
〜６のアルコキシアルキル基、炭素数１〜６のアルキル
鎖のフェニルアルキル基、フェニル基、アセトキシメチ
ル基、ピバロイルオキシメチル基、エトキシカルボニル
オキシ基、コリン基、ジメチルアミノエチル基、５−イ
ンダニル基、フタリジニル基、５−置換−２−オキソ−
1,3−ジオキソール−４−イルメチル基、または３−ア
セトキシ−２−オキソブチル基を意味する。） で表わされるキノロン誘導体及びその塩に関する。Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 1 carbon atom
-C6 alkoxyalkyl group, C1-C6 alkyl chain phenylalkyl group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl Group, phthalidinyl group, 5-substituted-2-oxo-
It means a 1,3-dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. ) And a salt thereof.
さらに本発明は、以下の各々にも関する：キノリン骨
格の７位相当位が３−（Ｒ）−［１−（Ｓ）−アミノエ
チル］−１−ピロリジニル基で置換されたキノロンカル
ボン酸誘導体である上記の化合物及びその塩；キノリン
骨格の７位相当位が３−（Ｒ）−［１−（Ｓ）−アミノ
プロピル］−１−ピロリジニル基で置換されたキノロン
カルボン酸誘導体である上記の化合物及びその塩；キノ
リン骨格の７位相当位が３−（Ｒ）−［１−（Ｓ）−第
三級ブトキシカルボニルアミノエチル］１−ピロリジニ
ル基で置換されたキノロンカルボン酸誘導体である上記
の化合物及びその塩；キノリン骨格の７位相当位が３−
（Ｒ）−［１−（Ｓ）−第三級ブトキシカルボニルアミ
ノプロピル］−１−ピロリジニル基で置換されたキノロ
ンカルボン酸誘導体である上記の化合物及びその塩；上
記に記載の化合物を有効成分として含有する抗菌剤； 等である。The present invention further relates to each of the following: a quinolone carboxylic acid derivative in which the 7-position equivalent of the quinoline skeleton is substituted with a 3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl group. Certain of the above compounds and salts thereof; the above compound, which is a quinolone carboxylic acid derivative in which the 7-position equivalent of the quinoline skeleton is substituted with a 3- (R)-[1- (S) -aminopropyl] -1-pyrrolidinyl group And a salt thereof; the above compound, which is a quinolonecarboxylic acid derivative in which the 7-position equivalent of the quinoline skeleton is substituted with a 3- (R)-[1- (S) -tert-butoxycarbonylaminoethyl] 1-pyrrolidinyl group And a salt thereof, wherein the 7-position equivalent of the quinoline skeleton is 3-
(R)-[1- (S) -tert-butoxycarbonylaminopropyl] -1-quinolonecarboxylic acid derivative substituted with a pyrrolidinyl group, the above-mentioned compound and a salt thereof; the above-mentioned compound as an active ingredient Antibacterial agents to be contained;
本発明化合物の置換基について述べると、R1はエチル
基、イソプロピル基、第三級ブチル基等の低級アルキル
基類、２−フルオロエチル基等のハロゲノアルキル基
類、ビニル基、イソプロペニル基等の低級アルケニル基
類、シクロプロピル基、シス−２−メチルシクロプロピ
ル基、２−gem−ジハロゲノシクロプロピル基等の、置
換基を有することもある環状アルキル基、４−フルオロ
フェニル基、2,4−ジフルオロフェニル基、２−フルオ
ロ−４−ピリジル基等の、置換基を有することもあるア
リール基またはヘテロアリール基、メトキシ基、エトキ
シ基等のアルコキシ基等、そしてメチルアミノ基、エチ
ルアミノ基等のアルキルアミノ基等がよい。これらのう
ちではエチル基、２−フルオロエチル基、ビニル基、シ
クロプロピル基、シス−２−メチルシクロプロピル基、
４−フルオロフェニル基、2,4−ジフルオロフェニル
基、２−フルオロ−４−ピリジル基、メトキシ基、メチ
ルアミノ基等が好ましい。As for the substituents of the compound of the present invention, R 1 is a lower alkyl group such as an ethyl group, an isopropyl group or a tertiary butyl group, a halogenoalkyl group such as a 2-fluoroethyl group, a vinyl group, an isopropenyl group or the like. Lower alkenyl groups, cyclopropyl group, cis-2-methylcyclopropyl group, 2-gem-dihalogenocyclopropyl group and the like, a cyclic alkyl group which may have a substituent, 4-fluorophenyl group, 2, Aryl or heteroaryl groups which may have a substituent, such as a 4-difluorophenyl group and a 2-fluoro-4-pyridyl group; alkoxy groups such as a methoxy group and an ethoxy group; and a methylamino group and an ethylamino group And the like. Among these, an ethyl group, a 2-fluoroethyl group, a vinyl group, a cyclopropyl group, a cis-2-methylcyclopropyl group,
Preferred are a 4-fluorophenyl group, a 2,4-difluorophenyl group, a 2-fluoro-4-pyridyl group, a methoxy group, a methylamino group and the like.
R2は水素原子や、アミノ基、メチルアミノ基、エチル
アミノ基、イソプロピルアミノ基、ジメチルアミノ基、
ジエチルアミノ基等の非置換、又は置換アミノ基類、水
酸基、メトキシ基、エトキシ基等のアルコキシ基類、ハ
ロゲン原子等がよい。R 2 is a hydrogen atom, an amino group, a methylamino group, an ethylamino group, an isopropylamino group, a dimethylamino group,
Preferred are unsubstituted or substituted amino groups such as a diethylamino group, alkoxy groups such as a hydroxyl group, a methoxy group and an ethoxy group, and halogen atoms.
R3としてはメチル基、エチル基、イソプロピル基等の
低級アルキル基がよく、このうちではメチル基及びエチ
ル基がよい。R 3 is preferably a lower alkyl group such as a methyl group, an ethyl group and an isopropyl group, and among them, a methyl group and an ethyl group are preferred.
R4は水素原子またはメチル基、エチル基、イソプロピ
ル基等のアルキル基類、２−ヒドロキシエチル基や２−
フルオロエチル基等の置換アルキル基類、第三級ブトキ
シカルボニル基、2,2,2−トリクロロエトキシカルボニ
ル基等のアルコキシカルボニル基類、ベンジルオキシカ
ルボニル基、パラメトキシベンジルオキシカルボニル
基、パラニトロベンジルオキシカルボニル基等のアラル
キルオキシカルボニル基類、アセチル基、メトキシアセ
チル基、トリフルオロアセチル基、クロロアセチル基、
ピバロイル基、ホルミル基、ベンゾイル基等のアシル基
類、第三級ブチル基、ベンジル基、パラニトロベンジル
基、パラメトキシベンジル基、トリフェニルメチル基等
のアルキル基類等を例示することができる。R 4 is a hydrogen atom or an alkyl group such as a methyl group, an ethyl group, or an isopropyl group, a 2-hydroxyethyl group,
Substituted alkyl groups such as fluoroethyl group, tertiary butoxycarbonyl group, alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxy Aralkyloxycarbonyl groups such as carbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group,
Examples include acyl groups such as pivaloyl group, formyl group, and benzoyl group, and alkyl groups such as tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, and triphenylmethyl group.
R5は、メチル基、エチル基、イソプロピル基等のアル
キル基類、メトキシ基、エトキシ基等のアルコキシ基類
を挙げることができる。Examples of R 5 include alkyl groups such as a methyl group, an ethyl group, and an isopropyl group, and alkoxy groups such as a methoxy group and an ethoxy group.
R6は水素原子またはメチル基、エチル基、プロピル基
等のアルキル基類がよい。R1はR5またはR6と、あるいは
R5及びR6と共に環状構造を形成しても良い。この場合に
形成される環の大きさは４〜７員環の範囲がよく、５ま
たは６員環が特に好ましい。また、ここで形成される環
は窒素原子、酸素原子、硫黄原子等を含んでいてもよ
く、さらに単結合だけでなく、二重結合を含む場合もあ
り、芳香化していてもよい。このようにして形成される
キノロン母核構造の例を次に示す。R 6 is preferably a hydrogen atom or an alkyl group such as a methyl group, an ethyl group, or a propyl group. R 1 is R 5 or R 6 or
A cyclic structure may be formed together with R 5 and R 6 . The size of the ring formed in this case is preferably in the range of 4 to 7-membered ring, and 5- or 6-membered ring is particularly preferable. The ring formed here may contain a nitrogen atom, an oxygen atom, a sulfur atom, or the like, and may contain not only a single bond but also a double bond, and may be aromatized. Examples of the quinolone core structure thus formed are shown below.
キノロンの３位（相当位）のカルボン酸部分は遊離の
酸でもよく、またエステル様構造となっていてもよい。
カルボン酸部分がエステル様構造であるキノロン誘導体
は合成中間体やプロドラッグとして有用である。例え
ば、アルキルエステル類やベンジルエステル類、アルコ
キシアルキルエステル類、フェニルアルキルエステル類
及びフェニルエステル類は合成中間体として有用であ
る。 The carboxylic acid moiety at the 3-position (equivalent position) of the quinolone may be a free acid or may have an ester-like structure.
Quinolone derivatives in which the carboxylic acid moiety has an ester-like structure are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthetic intermediates.
また、プロドラッグとして用いられる形態としては、
生体内で容易に切断されて遊離体のカルボン酸を生成す
るようなエステル様置換基であり、例えば、アセトキシ
メチルエステル、ピバロイルオキシメチルエステル、コ
リンエステル、ジメチルアミノエチルエステル、５−イ
ンダニルエステル及びフタリジニルエステル、５−置換
−２−オキソ−1,3−ジオキソール−４−イルメチルエ
ステルそして３−アセトキシ−２−オキソブチルエステ
ル等のオキソアルキルエステルを、そしてエトキシカル
ボニルオキシ基とから導かれる酸無水物等を例示するこ
とができる。In addition, as a form used as a prodrug,
Ester-like substituents which are easily cleaved in vivo to generate free carboxylic acids, such as acetoxymethyl ester, pivaloyloxymethyl ester, choline ester, dimethylaminoethyl ester, and 5-indaniline Esters and phthalidinyl esters, oxoalkyl esters such as 5-substituted-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester, and from ethoxycarbonyloxy groups. Acid anhydrides and the like can be exemplified.
本発明化合物の、キノリン骨格の７位相当位の３−
（１−アミノアルキル）メチルピロリジン部分は、アミ
ノアルキル側鎖部分のアミノ基の結合した炭化水素原子
が不斉炭素である。またこの側鎖が結合しているピロリ
ジンの３位も不斉炭素である。よって、３−（１−アミ
ノアルキル）ピロリジン部分に由来するだけでも４種類
の立体異性体のキノロン誘導体が存在することになる。
これらの異性体はジアステレオマーの関係であり、物理
定数の異なる化合物であるので混合物のままでは医薬と
しての応用は困難である。3- of the compound of the present invention corresponding to the 7-position of the quinoline skeleton
In the (1-aminoalkyl) methylpyrrolidine moiety, the hydrocarbon atom to which the amino group of the aminoalkyl side chain is bonded is an asymmetric carbon. The 3-position of pyrrolidine to which this side chain is bonded is also an asymmetric carbon. Therefore, four types of stereoisomeric quinolone derivatives exist only from the 3- (1-aminoalkyl) pyrrolidine moiety.
These isomers are diastereomers, and are compounds having different physical constants, so that it is difficult to apply them as a pharmaceutical as a mixture.
本発明者は単一のジアステレオマーの３−（１−アミ
ノアルキル）ピロリジン類の合成法の開発に成功した。
そしてこのピロリジンを用いて単一のジアステレオマー
のキノロン誘導体を得ることに成功した。The present inventor has succeeded in developing a method for synthesizing a single diastereomeric 3- (1-aminoalkyl) pyrrolidine.
Using this pyrrolidine, we succeeded in obtaining a single diastereomeric quinolone derivative.
すなわち、光学活性なアミノ酸を光学活性なシントン
として用い、かつ、マイケル反応の立体を制御すること
により、（Ｓ）−アミノ酸の（Ｓ）−アラニンまたは
（Ｓ）−２−アミノ酪酸から（3R,1′Ｓ）ピロリジン体
を、（Ｒ）−アミノ酸の（Ｒ）−２−アミノ酪酸から
（3S,1′Ｒ）ピロリジン体を各々高選択的に合成するこ
とに成功した。また同じ配位のピロリジンを（Ｒ）−ア
ラニンからも導くことが出来よう。In other words, by using an optically active amino acid as an optically active synthon and controlling the stereochemistry of the Michael reaction, the (3R, 1 ′S) pyrrolidine was successfully synthesized from (R) -amino acid (R) -2-aminobutyric acid with high selectivity for (3S, 1′R) pyrrolidine. The same coordination pyrrolidine could also be derived from (R) -alanine.
今回合成したピロリジンの３位での配位の確認は次の
ようにして行った。４−［１−アミノエチル］−１−ベ
ンジル−２−ピロリドン Ａ（dl体）を（Ｓ）−トシル
プロリンアミドへ導いた後に光学分割し、異性体の一方
の化合物Ｂの絶対構造をＸ線解析によって（4R,1′Ｓ）
であると決定した。この化合物Ｂを加水分解後、第３級
ブトキシカルボニル化して得た化合物Ｄが今回（Ｓ）−
アラニンより合成した化合物と一致（融点、施光度、1H
−NMR）した。Confirmation of the coordination at the 3-position of the pyrrolidine synthesized this time was performed as follows. 4- [1-aminoethyl] -1-benzyl-2-pyrrolidone A (dl body) (S) - optically resolved after that led to the tosyl prolinamide, X-rays the absolute structure of one of the compounds B isomers By analysis (4R, 1'S)
Was determined. The compound D obtained by hydrolyzing this compound B and then tertiary butoxycarbonylating is (S)-
Consistent with compounds synthesized from alanine (melting point, light intensity, 1 H
-NMR).
本発明化合物は強い抗菌作用を有することから人体、
動物、及び魚類用の医薬として或は農薬、食品の保存剤
として使用することができる。 Since the compound of the present invention has a strong antibacterial action,
It can be used as a medicine for animals and fish, or as a pesticide and food preservative.
本発明化合物を人体用の医薬として使用する場合、投
与量は成人一日当たり50mgから1g、好ましくは100mgか
ら300mgの範囲である。When the compound of the present invention is used as a medicine for the human body, the dose ranges from 50 mg to 1 g, preferably from 100 mg to 300 mg per adult per day.
また動物用としての投与量は、投与の目的（治療或は
予防）、処置すべき動物の種類や大きさ、感染した病原
菌の種類、程度によって異なるが、一日量として一般的
には動物の体重1kg当たり1mgから200mg、好ましくは5mg
から100mgの範囲である。The dosage for animals may vary depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally used as a daily dose. 1 mg to 200 mg per kg of body weight, preferably 5 mg
To the range of 100mg.
この一日量を一日１回、あるいは２〜４回に分けて投
与する。また一日量は必要によっては上記の量を超えて
もよい。This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above-mentioned amount if necessary.
本発明化合物は各種の感染症の原因となる広範囲の微
生物類に対して活性であり、これらの病原体によって引
き起こされる疾病を治療し、予防し、または軽減するこ
とができる。The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases, and can treat, prevent or reduce the diseases caused by these pathogens.
本発明化合物が有効なバクテリア類又はバクテリア様
微生物類としてブドウ球菌属、化膿レンサ球菌、溶血レ
ンサ球菌、脹球菌、肺炎球菌、ペプトストレプトコッカ
ス属、淋菌、大腸菌、シトロバクター属、シゲラ属、肺
炎桿菌、エンテロバクター属、セラチア属、プロテウス
属、緑膿菌、インフルエンザ菌、アシネトバクター属、
カンピロバクター属、トラコーマクラミジア等を例示す
ることができる。Staphylococci, S. pyogenes, hemolytic streptococci, staphylococci, pneumococci, peptostreptococcus, gonococci, Escherichia coli, citrobacter, shigella, pneumococci as bacteria or bacteria-like microorganisms against which the compounds of the present invention are effective. , Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter,
Campylobacter, Chlamydia trachomatis and the like can be exemplified.
またこれらの病原体によって引き起こされる疾病とし
ては、毛嚢炎、せつ、よう、丹毒、蜂巣炎、リンパ管
（節）炎、ひょう痕、皮下腫瘍、汗腺炎、集簇性ざ瘡、
感染性粉瘤、肛門周囲腫瘍、乳腺炎、外傷・熱傷・手術
創などの表在性二次感染、咽喉頭炎、急性気管支炎、扁
桃炎、慢性気管支炎、気管支拡張症、びまん性汎細気管
支炎、慢性呼吸疾患の二次感染、肺炎、腎盂腎炎、膀胱
炎、前立腺炎、副***、淋菌性尿道炎、非淋菌性尿道
炎、胆のう炎、胆管炎、細菌性赤痢、腸炎、子宮付属器
炎、子宮内感染、バルトリン腺炎、眼瞼炎、表粒腫、涙
嚢炎、瞼板腺炎、角膜潰瘍、中耳炎、副鼻腔炎、歯周組
織炎、歯冠周囲炎、顎炎、腹膜炎、心内膜炎、敗血症、
髄膜炎、皮膚感染症等を例示することができる。Diseases caused by these pathogens include folliculitis, cough, syphilis, erysipelas, cellulitis, lymphatic (node) inflammation, hail marks, subcutaneous tumors, sweat glanditis, acne condensate,
Infectious nodules, perianal tumors, mastitis, superficial secondary infections such as trauma, burns and surgical wounds, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse pandemic Bronchitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterus Appendicitis, intrauterine infection, Bartholin's adenitis, blepharitis, epithelioma, lacrimal cystitis, tarsal adenitis, corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis , Endocarditis, sepsis,
Meningitis, skin infections and the like can be exemplified.
また動物の感染症の原因となる各種の微生物、例えば
エシナリキア属、サルモネラ属、パスツレラ属、ヘモフ
ィルス属、ボルデララ属、スタヒロコッカス属、マイコ
プラズマ属等に有効である。It is also effective against various microorganisms which cause infectious diseases in animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Borderara, Staphylococcus, Mycoplasma and the like.
具体的な疾病名を例示すると鳥類では大腸菌症、ひな
白痢、鶏パラチフス症、家禽コレラ、伝染性コリーザ、
ブドウ球菌症、マイコプラズマ感染症等、豚では大腸菌
性、サルモネラ症、パスツレラ症、ヘモフィルス感染
症、萎縮性鼻炎、滲出性表皮炎、マイコプラズマ感染症
等、牛では大腸菌症、サルモネラ症、出血性敗血症、マ
イコプラズマ感染症、牛肺疫、***炎等、犬では大腸菌
性敗血症、サルモネラ感染症、出血性敗血症、子宮蓄膿
症、膀胱炎等、そして猫では滲出性胸膜炎、膀胱炎、慢
性鼻炎、ヘモフィルス感染症、仔猫の下痢、マイコプラ
ズマ感染症等を挙げることができる。Illustrative disease names include avian diseases such as colibacillosis, chick dysentery, chicken paratyphoid, poultry cholera, infectious coryza,
Staphylococci, mycoplasma infection, etc., Escherichia coli, salmonellosis, pasteurellosis, hemophilus infection, atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc. in pigs, E. coli, salmonellosis, hemorrhagic sepsis, etc. Mycoplasma infection, bovine lung disease, mastitis, etc., E. coli sepsis, salmonella infection, hemorrhagic sepsis, pyometra, cystitis, etc. in dogs, and exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection in cats, Kittens include diarrhea, mycoplasma infection and the like.
本発明化合物からなる抗菌製剤は投与法に応じ適当な
製剤を選択し、通常用いられている各種製剤の調製法に
て調製できる。本発明化合物を主剤とする抗菌製剤の剤
型としては例えば錠剤、散剤、顆粒剤、カプセル剤や、
溶液剤、シロップ剤、エリキシル剤、油性ないし水性の
懸濁液等を経口用製剤として例示できる。The antimicrobial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation according to the administration method and using a preparation method for various preparations which are generally used. As the dosage form of the antimicrobial preparation containing the compound of the present invention as a main component, for example, tablets, powders, granules, capsules,
Solutions, syrups, elixirs, oily or aqueous suspensions, and the like can be exemplified as oral preparations.
注射剤としては製剤中に安定剤、防腐剤、溶解補助剤
を使用することもあり、これらの補助剤を含むこともあ
る溶液を容器に収納後、凍結乾燥等によって固形製剤と
して用時調製の製剤としても良い。また一投与量を容器
に収納しても良く、また多投与量を同一の容器に収納し
ても良い。Injectables may use stabilizers, preservatives, and solubilizing agents in the formulation.After storing the solution that may contain these adjuvants in a container, freeze-dry etc. to prepare a solid formulation at the time of use. It may be a formulation. One dose may be stored in a container, or multiple doses may be stored in the same container.
また外用製剤として溶液剤、懸濁液、乳濁液、軟膏、
ゲル、クリーム、ローション、スプレー等を例示でき
る。Also as external preparations solutions, suspensions, emulsions, ointments,
Examples include gels, creams, lotions, sprays and the like.
固形製剤としては活性化合物とともに製剤学上許容さ
れている添加物を含み、例えば充填剤類や増量剤類、結
合剤類、崩壊剤類、溶解促進剤類、湿潤剤類、潤滑剤類
等を必要に応じて選択して混合し、製剤化することがで
きる。Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants and the like. They can be selected and mixed as needed to form a formulation.
液体製剤としては溶液、懸濁液、乳液剤等を挙げるこ
とができるが添加剤として懸濁化剤、乳化剤等を含むこ
ともある。Liquid preparations include solutions, suspensions, emulsions and the like, but may also contain suspending agents, emulsifiers and the like as additives.
本発明化合物を動物に投与する方法としては直接ある
いは飼料中に混合して経口的に投与する方法、また溶液
とした後、直接もしくは飲水、飼料中に添加して経口的
に投与する方法、注射によって投与する方法等を例示す
ることができる。The method of administering the compound of the present invention to an animal may be a method of orally administering it directly or by mixing it in a feed, or a method of orally administering a solution, and then directly or by adding it to drinking water or a feed, or injection. Can be exemplified.
本発明化合物を動物に投与するための製剤としては、
この分野に於いて通常用いられている技術によって適宜
散剤、細粒剤、可溶散剤、シロップ剤、溶液剤、あるい
は注射剤とすることができる。次に製剤処方例を示す。As a preparation for administering the compound of the present invention to an animal,
Powders, fine granules, dissolvable powders, syrups, solutions, or injections can be appropriately prepared by techniques generally used in this field. Next, formulation examples are shown.
製剤例1.（カプセル剤）： 実施例４の化合物 100.0mg コーンスターチ 23.0mg CMCカルシウム 22.5mg ハイドロキプロピルシメチルセルロース 3.0mg ステアリン酸マグネシウム 1.5mg 総計 150.0mg 製剤例2.（溶液剤）： 実施例４の化合物 １〜10g 酢酸又は水酸化ナトリウム 0.5〜2g パラオキシ安息香酸エチル 0.1g 精製水 88.9〜98.4g 計 100g 製剤例3.（飼料混合用散剤）： 実施例４の化合物 １〜10g コーンスターチ 98.5〜89.5g 軽質無水ケイ酸 0.5g 計 100g 次に本発明を実施例と参考例により説明するが、本発
明はこれに限定されるものではない。なお参考例には、
光学活性なピロリジン類を合成する反応を示した。また
反応式を抗菌活性の表の次に示した。Formulation Example 1. (Capsule): Compound of Example 4 100.0 mg Cornstarch 23.0 mg CMC Calcium 22.5 mg Hydroxypropyl simethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg Formulation Example 2. (Solution): Example 4 Compound 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl paraoxybenzoate 0.1 g Purified water 88.9 to 98.4 g Total 100 g Formulation Example 3. (powder for mixing feed): Compound 1 to 10 g of Example 4 Corn starch 98.5 to 89.5 g Light anhydrous silicic acid 0.5 g Total 100 g Next, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto. In the reference example,
A reaction for synthesizing optically active pyrrolidines was shown. The reaction formula is shown below the table of antibacterial activity.
光学活性な目的化合物の抗菌活性の試験方法は二本化
学療法学会指定の標準法に準じて行い、その結果を表１
にMIC（μg/ml）で示した。The test method for the antibacterial activity of the optically active target compound was performed in accordance with the standard method specified by the Japanese Society of Bimodal Chemotherapy, and the results are shown in Table 1.
MIC (μg / ml).
参考例1.（Ｓ）エチル ４−第三級ブトキシカルボニル
アミノ−３−オキソペンタノエート ２ マグネシウム1.32g、四塩化炭素4ml、エタノール23ml
を混合し室温で２時間撹拌した。ここに、マロン酸モノ
エチルエステル15.8gとテトラヒドロフラン（以下、THF
と略す）80mlの混合物を滴下し、室温で30分撹拌した。
溶媒を減圧留去して残留物をTHF 115mlに溶解した。Reference Example 1. (S) Ethyl 4-tert-butoxycarbonylamino-3-oxopentanoate 1.32 g of magnesium, 4 ml of carbon tetrachloride, 23 ml of ethanol
And stirred at room temperature for 2 hours. Here, 15.8 g of malonic acid monoethyl ester and tetrahydrofuran (hereinafter THF)
80 ml of the mixture was added dropwise, and the mixture was stirred at room temperature for 30 minutes.
The solvent was distilled off under reduced pressure, and the residue was dissolved in 115 ml of THF.
Ｎ−第三級ブトキシカルボニル−Ｌ−アラニン12.5g
をTHF 115mlに溶解し、N,N′−カルボニルジイミダゾー
ル11.4gを加え室温で30分撹拌した。これに上記のTHF溶
液を滴下し室温で１時間撹拌した。溶媒を減圧留去して
残留物を10％クエン酸水溶液とベンゼンの混合物に分配
した。有機層を分離して水洗後、無水硫酸ナトリウムで
乾燥して溶媒を減圧留去し15.5gの無色油状の標記化合
物を得た。1 H−NMR（CDCl3）δppm:1.28（3H,t,J＝7Hz）,1.35（3
H,d,J＝7Hz）,1.45（9H,s）,3.55（2H,s）,4.20（2H,q,
J＝7Hz）,4.1−4.4（1H,broad）,4.9−5.2（1H,broad） 参考例2.4−（Ｓ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−ハイドロキシペンタノエート ３ 化合物２、15.5gをエタノール80mlに溶解して氷冷下
で水素化ホウ素ナトリウム1.20gを加え同温度で１時間
撹拌した。反応液に水100mlを加え20分撹拌後、溶媒を
減圧留去した。残留物をクロロホルムで抽出し抽出液を
水洗し、無水硫酸ナトリウムで乾燥後溶媒を減圧留去
し、14.4gの無色油状の標記の化合物を得た。1 H−NMR（CDCl3）δppm:1.08（3H,t,J＝7Hz）,1.22（3
H,d,J＝7Hz）,1.40（9H,s）,2.3−2.55（2H,m）,3.1−
3.5（1H,m）,3.5−3.9（1H,m）,4.12（2H,q,J＝7Hz）,
4.6−4.9（1H,m） 参考例3.4−（Ｓ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−メタンスルホニルオキシペンタノエ
ート ４ 化合物３、14.5gをピリジン40mlに溶解し、メタンス
ルホニルクロリド8gを加え室温で18時間撹拌した。反応
液を氷水に加えて撹拌し、ベンゼンで抽出した。有機層
を10％クエン酸水溶液、水で洗い、無水硫酸ナトリウム
で乾燥して溶媒を減圧留去し、18.4gの黄色油状の標記
化合物を得た。1 H−NMR（CDCl3）δppm:1.18（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.45（9H,s）,2.64−2.74（2H,m）,3.06
（3H,s）,3.7−4.0（1H,m）,4.16（2H,q,J＝7Hz）,4.6
−4.9（1H,m）,5.0−5.3（1H,m） 参考例4.（Ｓ）−エチル ４−第三級ブトキシカルボニ
ルアミノ−２−ペンテノエート ５ 化合物４、18.4gをクロロホルム100mlに溶解し、1,8
−ジアザビシクロ［5,4,0］−７−ウンデセン（以下DBU
と略す）8.3gを加えて室温で３時間撹拌した。反応液を
10％クエン酸水溶液、水で洗い無水硫酸ナトリウムで乾
燥後溶媒を減圧留去した。残留物をシリカゲル600mlの
カラムに付し、ベンゼン−酢酸エチル（6:1）の混合溶
媒で溶出し10.3gの無色油状の標記化合物を得た。12.5 g of N-tert-butoxycarbonyl-L-alanine
Was dissolved in 115 ml of THF, 11.4 g of N, N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 30 minutes. The above THF solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was partitioned between a 10% aqueous citric acid solution and a mixture of benzene. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 15.5 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.28 (3H, t, J = 7 Hz), 1.35 (3
H, d, J = 7Hz), 1.45 (9H, s), 3.55 (2H, s), 4.20 (2H, q,
J = 7 Hz), 4.1-4.4 (1H, broad), 4.9-5.2 (1H, broad) Reference Example 2.4- (S) -Ethyl 4-tert-butoxycarbonylamino-3-hydroxypentanoate 3 Compound 2, 15.5 g was dissolved in 80 ml of ethanol, and 1.20 g of sodium borohydride was added thereto under ice cooling, followed by stirring at the same temperature for 1 hour. After 100 ml of water was added to the reaction solution and stirred for 20 minutes, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 14.4 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.08 (3H, t, J = 7 Hz), 1.22 (3
H, d, J = 7Hz), 1.40 (9H, s), 2.3−2.55 (2H, m), 3.1−
3.5 (1H, m), 3.5-3.9 (1H, m), 4.12 (2H, q, J = 7Hz),
4.6-4.9 (1H, m) Reference Example 3.4- (S) -Ethyl 4-tert-butoxycarbonylamino-3-methanesulfonyloxypentanoate 4 14.5 g of Compound 3 is dissolved in 40 ml of pyridine, and methanesulfonyl chloride is dissolved. 8 g was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was added to ice water, stirred, and extracted with benzene. The organic layer was washed with a 10% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 18.4 g of the title compound as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.18 (3H, t, J = 7 Hz), 1.28 (3
(H, t, J = 7Hz), 1.45 (9H, s), 2.64-2.74 (2H, m), 3.06
(3H, s), 3.7−4.0 (1H, m), 4.16 (2H, q, J = 7Hz), 4.6
-4.9 (1H, m), 5.0-5.3 (1H, m) Reference Example 4. (S) -Ethyl 4-tert-butoxycarbonylamino-2-pentenoate 5 Compound 4, 18.4 g was dissolved in chloroform 100 ml, 1,8
-Diazabicyclo [5,4,0] -7-undecene (hereinafter referred to as DBU
8.3 g) and the mixture was stirred at room temperature for 3 hours. Reaction solution
After washing with a 10% aqueous citric acid solution and water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was applied to a 600 ml column of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (6: 1) to obtain 10.3 g of the title compound as a colorless oil.
［α］Ｄ−26.0゜（ｃ＝1.20,クロロホルム）1 H−NMR（CDCl3）δppm:1.25（3H,d,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.45（9H,s）,4.19（2H,q,J＝7Hz）,3.9
−4.8（2H,m）,5.89（1H,dd,J＝２＆17Hz）,6.88（1H,d
d,J＝５＆17Hz） 参考例5.（Ｓ）−エチル ４−第三級ブトキシカルボニ
ルアミノ−３−ニトロメチルペンタノエート ６ 化合物５、10.3gをニトロメタン50mlに溶解し1,1,3,3
−テトラメチルグアニジン1.5gを加え室温で２日間撹拌
した後、ニトロメタンを減圧留去した。残留物をクロロ
ホルムに溶解し、10％クエン酸水溶液、水で洗った後無
水硫酸ナトリウムで乾燥した。溶媒を減圧留去し12.34g
の黄色油状の標記化合物を得た。1 H−NMR（CDCl3）δppm:1.21（3H,d,J＝7Hz）,1.27（3
H,t,J＝7Hz）,1.44（9H,s）,2.40−2.54（2H,m）,2.60
−2.90（1H,m）,3.70−3.96（1H,m）,4.16（2H,q,J＝7H
z）,4.0−4.3（1H,broad）,4.52（2H,d,J＝6Hz）， 参考例6.4−（Ｒ）−［１−（Ｓ）−第三級ブトキシカ
ルボニルアミノエチル］−２−ピロリドン ７ 化合物６、45.6gをメタノール800mlに溶解してラネー
ニッケル30mlと共に水素雰囲気下、室温で24時間撹拌し
た。ラネーニッケルを濾去して濾液を減圧留去した。残
留物をエタノールで結晶化し、26.8gの淡黄色結晶を得
た。これを酢酸エチルで再結晶し20.7gの無色結晶の標
記化合物を得た。1 H−NMR（CDCl3）δppm:1.16（3H,d,J＝7Hz）,1.44（9
H,s）,2.04−2.56（2H,m）,3.16−3.46（2H,m）,3.46−
3.8（1H,m）,4.32−4.46（1H,broad）,6.7−6.9（1H,br
oad） 参考例7.1−ベンジル−４−（Ｒ）−［１−（Ｓ）−第
三級ブトキシカルボニルアミノエチル］−２−ピロリド
ン ８ 化合物７、1.14gをN,N−ジメチルホルムアミド30mlに
溶解し50％水素化ナトリウム240mgを加え30分間撹拌し
た。ここにベンジルクロリド633mgを加え室温で24時間
撹拌した。反応液を減圧乾固し残留物を酢酸エチル−ベ
ンゼン（1:1）の混合溶媒100mlで抽出した。抽出液を水
洗後無水硫酸ナトリウムで乾燥し溶媒を減圧留去した。
残留物をイソプロピルエーテルで再結晶し460mgの標記
化合物の無色結晶を得た。[Α] D -26.0 ゜ (c = 1.20, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 1.25 (3H, d, J = 7 Hz), 1.28 (3
H, t, J = 7Hz), 1.45 (9H, s), 4.19 (2H, q, J = 7Hz), 3.9
-4.8 (2H, m), 5.89 (1H, dd, J = 2 & 17Hz), 6.88 (1H, d
d, J = 5 & 17Hz) Reference Example 5. (S) -Ethyl 4-tert-butoxycarbonylamino-3-nitromethylpentanoate 6 10.3 g of Compound 5 was dissolved in 50 ml of nitromethane to prepare 1,1,3,3.
After adding 1.5 g of tetramethylguanidine and stirring at room temperature for 2 days, nitromethane was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. 12.34 g of solvent was distilled off under reduced pressure
The title compound was obtained as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.21 (3H, d, J = 7 Hz), 1.27 (3
(H, t, J = 7Hz), 1.44 (9H, s), 2.40-2.54 (2H, m), 2.60
−2.90 (1H, m), 3.70−3.96 (1H, m), 4.16 (2H, q, J = 7H
z), 4.0-4.3 (1H, broad), 4.52 (2H, d, J = 6 Hz), Reference Example 6.4- (R)-[1- (S) -tert-butoxycarbonylaminoethyl] -2-pyrrolidone 7 45.6 g of the compound 6 was dissolved in 800 ml of methanol and stirred with 30 ml of Raney nickel at room temperature under a hydrogen atmosphere for 24 hours. Raney nickel was removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was crystallized from ethanol to give 26.8 g of pale yellow crystals. This was recrystallized from ethyl acetate to obtain 20.7 g of the title compound as colorless crystals. 1 H-NMR (CDCl 3 ) δ ppm: 1.16 (3H, d, J = 7 Hz), 1.44 (9
H, s), 2.04-2.56 (2H, m), 3.16-3.46 (2H, m), 3.46-
3.8 (1H, m), 4.32-4.46 (1H, broad), 6.7-6.9 (1H, br
oad) Reference Example 7.1 1-benzyl-4- (R)-[1- (S) -tert-butoxycarbonylaminoethyl] -2-pyrrolidone 8 1.14 g of compound 7 was dissolved in 30 ml of N, N-dimethylformamide. 240 mg of 50% sodium hydride was added and stirred for 30 minutes. Thereto was added 633 mg of benzyl chloride, and the mixture was stirred at room temperature for 24 hours. The reaction solution was dried under reduced pressure, and the residue was extracted with 100 ml of a mixed solvent of ethyl acetate-benzene (1: 1). The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was recrystallized from isopropyl ether to give 460 mg of the title compound as colorless crystals.
融点:120−130℃ ［α］Ｄ−31.5゜（ｃ＝0.59,クロロホルム）1 H−NMR（CDCl3）δppm:1.10（3H,d,J＝7Hz）,1.40（9
H,s）,2.1−2.6（2H,m）,2.9−3.4（2H,m）,3.4−3.8
（1H,m）,4.1−4.5（1H,m）,4.44−（2H,AB−q,J＝16H
z）,7.28（5H,s） 参考例8.1−ベンジル−４−（Ｒ）−［１−（Ｓ）−ア
ミノエチル］−２−ピロリドン ９ 化合物８、19.0gをトリフルオロ酢酸100mlに溶解し、
室温で１時間撹拌した。反応液を減圧乾固して残留物を
水100mlに溶解した。1N水酸化ナトリウム水溶液中で中
和し、クロロホルムで抽出した。抽出液を無水硫酸ナト
リウムで乾燥した後溶媒を減圧留去し12.8gの無色油状
の標記化合物を得た。1 H−NMR（CDCl3）δppm:1.05（3H,d,J＝7Hz）,1.24（2
H,broad s）,2.0−2.6（3H,m）,2.6−3.0（1H,m）,3.0
−3.5（2H,m）,4.45（2H,s）,7.28（5H,s） 参考例9.1−ベンジル−３−（Ｒ）］−［１−（Ｓ）−
第三級ブトキシカルボニルアミノエチル］−ピロリジン
11 水素化リチウムアルミニウム10g、THF、600mlの混合
物に化合物９、12.8gとTHF、100mlの溶液を滴下した後1
8時間加熱還流した。反応液を氷冷し、水50mlを滴下後
不溶物を濾去した。濾液に２−（第三級ブトキシカルボ
ニルオキシイミノ）−フェニルアセトニトリル（以下、
Boc−ONと略す）14.4gを加え室温で１日撹拌した。反応
液を減圧乾固して濾液をクロロホルムで抽出した。抽出
液を５％水酸化ナトリウム水溶液、水で洗った後無水硫
酸ナトリウムで乾燥し溶媒を減圧留去した。残留物をシ
リカゲル200gのカラムに付し、酢酸エチル−ベンゼン
（2:1）の混合溶媒で抽出し12.6gの無色油状の標記化合
物を得た。Melting point: 120-130 ° C [α] D −31.5 ゜ (c = 0.59, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 1.10 (3H, d, J = 7 Hz), 1.40 (9
H, s), 2.1-2.6 (2H, m), 2.9-3.4 (2H, m), 3.4-3.8
(1H, m), 4.1-4.5 (1H, m), 4.44- (2H, AB-q, J = 16H
z), 7.28 (5H, s) Reference Example 8.1 1-benzyl-4- (R)-[1- (S) -aminoethyl] -2-pyrrolidone 9 19.0 g of Compound 8 was dissolved in 100 ml of trifluoroacetic acid,
Stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure, and the residue was dissolved in 100 ml of water. Neutralized in a 1N aqueous sodium hydroxide solution and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 12.8 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.05 (3H, d, J = 7 Hz), 1.24 (2
H, broad s), 2.0-2.6 (3H, m), 2.6-3.0 (1H, m), 3.0
-3.5 (2H, m), 4.45 (2H, s), 7.28 (5H, s) Reference Example 9.1-benzyl-3- (R)]-[1- (S)-
Tertiary butoxycarbonylaminoethyl] -pyrrolidine
11 To a mixture of lithium aluminum hydride 10 g, THF, 600 ml was added dropwise a solution of compound 9, 12.8 g and THF, 100 ml.
The mixture was heated under reflux for 8 hours. The reaction solution was ice-cooled, 50 ml of water was added dropwise, and insolubles were removed by filtration. The filtrate is treated with 2- (tert-butoxycarbonyloxyimino) -phenylacetonitrile (hereinafter, referred to as “phenylacetonitrile”)
14.4 g was added and the mixture was stirred at room temperature for 1 day. The reaction solution was dried under reduced pressure, and the filtrate was extracted with chloroform. The extract was washed with a 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a column of 200 g of silica gel, and extracted with a mixed solvent of ethyl acetate-benzene (2: 1) to obtain 12.6 g of the title compound as a colorless oil.
［α］Ｄ−14.95゜（ｃ＝1.23,クロロホルム）1 H−NMR（CDCl3）δppm:1.17（3H,d,J＝7Hz）,1.45（9
H,s）,1.6−2.8（7H,m）,3.4−3.6（1H,m）,3.58（2H,A
B−q,J＝14Hz）,5.3−5.7（1H,broad）,7.29（5H,s） 参考例10.3−（Ｒ）−［１−（Ｓ）−第三級ブトキシカ
ルボニルアミノエチル］−ピロリジン 12 化合物11、3.1gを５％パラジウム−炭素（水分50％）
3gを触媒としてエタノール100ml中で４気圧の水素雰囲
気下で、タングステンランプで照射しながら４時間振盪
した。触媒を濾去し濾液を濃縮乾固して2.1gの無色油状
の標記化合物を得た。放置すると炭酸塩として結晶化し
た。エーテルで結晶を洗浄して濾取し1.75gの無色結晶
の標記化合物を得た。[Α] D -14.95 ゜ (c = 1.23, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 1.17 (3H, d, J = 7 Hz), 1.45 (9
H, s), 1.6-2.8 (7H, m), 3.4-3.6 (1H, m), 3.58 (2H, A
Bq, J = 14 Hz), 5.3-5.7 (1H, broad), 7.29 (5H, s) Reference Example 10.3- (R)-[1- (S) -tert-butoxycarbonylaminoethyl] -pyrrolidine 12 3.1 g of compound 11, 5% palladium-carbon (water 50%)
The mixture was shaken for 4 hours while irradiating with a tungsten lamp under a hydrogen atmosphere of 4 atm in 100 ml of ethanol using 3 g as a catalyst. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to obtain 2.1 g of the title compound as a colorless oil. Upon standing, it crystallized as carbonate. The crystals were washed with ether and collected by filtration to give 1.75 g of the title compound as colorless crystals.
融点:186−188℃ ［α］Ｄ−7.09゜（ｃ＝0.705,エタノール） 参考例11.L−α−第三級ブトキシカルボニルアミノ酪酸
14 Ｌ−α−アミノ酪酸5.0g、トリエチルアミン10ml、50
％含水ジオキサン60mlの混合物にBoc−ON13.1gを加え室
温で24時間撹拌した。反応液に水75mlと酢酸エチル100m
lを加えた。水層を分離して酢酸エチル100mlで洗い、10
％クエン酸水溶液で酸性とした。酸性エチル（200ml×
２）で抽出し、有機層を水で洗った。有機層を無水硫酸
ナトリウムで乾燥後溶媒を減圧留去して10.0gの無色油
状の標記化合物を得た。Melting point: 186-188 ° C [α] D -7.09 ゜ (c = 0.705, ethanol) Reference Example 11. L-α-tert-butoxycarbonylaminobutyric acid
14 L-α-aminobutyric acid 5.0 g, triethylamine 10 ml, 50
13.1 g of Boc-ON was added to a mixture of 60 ml of water-containing dioxane and stirred at room temperature for 24 hours. 75 ml of water and 100 m of ethyl acetate in the reaction solution
l was added. Separate the aqueous layer and wash with 100 ml of ethyl acetate, 10
Acidified with aqueous citric acid solution. Acidic ethyl (200ml ×
Extracted in 2), and the organic layer was washed with water. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 10.0 g of the title compound as a colorless oil.
参考例12.（Ｓ）−エチル ４−第三級ブトキシカルボ
ニルアミノ−３−オキソヘキサノエート 15 マグネシウム0.98g、四塩化炭素3ml、エタノール25ml
を混合し２時間撹拌した。ここにマロン酸モノエチルエ
ステル11.7g、THF 60mlの混合物を滴下し、30分間撹拌
した。溶媒を減圧留去し残留物をTHF 85mlに溶解した。Reference Example 12. (S) -Ethyl 4-tert-butoxycarbonylamino-3-oxohexanoate 15 Magnesium 0.98 g, carbon tetrachloride 3 ml, ethanol 25 ml
And stirred for 2 hours. A mixture of malonic acid monoethyl ester (11.7 g) and THF (60 ml) was added dropwise thereto, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in 85 ml of THF.
化合物14、10.0gをTHF 110mlに溶解しN,N′−カルボ
ニルジイミダゾール8.49gを加え30分撹拌した。これに
上記のTHF溶液を滴下して１時間撹拌した。溶媒を減圧
留去し残留物を10％クエン酸水溶液とベンゼンの混合物
に分配した。有機層を分離して水洗した後無水硫酸ナト
リウムで乾燥し、溶媒を減圧留去して11.9gの無色油状
の標記化合物を得た。1 H−NMR（CDCl3）δppm:1.92（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.44（9H,s）,1.4−2.1（2H,m）,3.54（2
H,s）,4.22（2H,q,J＝7Hz）,4.9−5.2（1H,broad） 参考例13.4−（Ｓ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−ハイドロキシヘキサノエート16 化合物15、11.9gをエタノール50mlに溶解して氷冷下
で水素化ホウ素ナトリウム1.0gを加え同温度で１時間撹
拌した。反応液に水100mlを加え20分撹拌した後溶媒を
減圧留去した。残留物をクロロホルムで抽出し、抽出液
を水洗後無水硫酸ナトリウムで乾燥した。溶媒を減圧留
去し8.27gの無色油状の標記化合物を得た。1 H−NMR（CDCl3）δppm:0.95（3H,t,J＝7Hz）,1.27（3
H,t,J＝7Hz）,1.45（9H,s）,1.3−1.8（2H,m）,2.44−
2.60（2H,m）,2.7−3.2（1H,broad）,3.3−3.7（1H,
m）,3.9−4.1（1H,m）,4.17（2H,m,J＝7Hz）,4.4−4.8
（1H,broad）， 参考例14.4−（Ｓ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−メタンスルホニルオキシヘキサノエ
ート 17 化合物16、8.27gをピリジン30mlに溶解しメタンスル
ホニルクロリド5mlを加え室温で24時間撹拌した。反応
液を氷水に加え撹拌しベンゼンで抽出した。有機層を10
％クエン酸水溶液、水で洗い無水硫酸ナトリウムで乾燥
後溶媒を減圧留去して9.74gの黄色油状の標記化合物を
得た。1 H−NMR（CDCl3）δppm:0.97（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.45（9H,s）,1.3−1.8（2H,m）,2.6−2.
9（2H,m）,3.05（3H,s）,3.5−3.9（1H,m）,4.18（2H,
q,J＝7Hz）,4.2−4.8（2H,m）,4.96−5.24（1H,m） 参考例15.（Ｓ）−エチル ４−第三級ブトキシカルボ
ニルアミノ−２−ヘキセノエート 18 化合物17、9.7gをクロロホルム120mlに溶解し、DBU5.
2gを加えて室温で２時間撹拌した。反応液を10％クエン
酸水溶液、水で洗い無水硫酸ナトリウムで乾燥後溶媒を
減圧留去した。残留物をシリカゲル250gのカラムに付
し、ベンゼン−酢酸エチル（6:1）の混合溶媒で溶出し
7.15gの無色油状の標記化合物を得た。Compound 14, 10.0 g was dissolved in THF 110 ml, N, N'-carbonyldiimidazole 8.49 g was added, and the mixture was stirred for 30 minutes. The above THF solution was added dropwise thereto, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was partitioned between a 10% aqueous citric acid solution and a mixture of benzene. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 11.9 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 1.92 (3H, t, J = 7 Hz), 1.28 (3
H, t, J = 7Hz), 1.44 (9H, s), 1.4−2.1 (2H, m), 3.54 (2
H, s), 4.22 (2H, q, J = 7 Hz), 4.9-5.2 (1H, broad) Reference Example 13.4- (S) -Ethyl 4-tert-butoxycarbonylamino-3-hydroxyhexanoate 16 compound 15 and 11.9 g were dissolved in 50 ml of ethanol, and 1.0 g of sodium borohydride was added under ice-cooling, followed by stirring at the same temperature for 1 hour. After adding 100 ml of water to the reaction solution and stirring for 20 minutes, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 8.27 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.95 (3H, t, J = 7 Hz), 1.27 (3
H, t, J = 7Hz), 1.45 (9H, s), 1.3-1.8 (2H, m), 2.44-
2.60 (2H, m), 2.7-3.2 (1H, broad), 3.3-3.7 (1H,
m), 3.9-4.1 (1H, m), 4.17 (2H, m, J = 7Hz), 4.4-4.8
(1H, broad), Reference Example 14.4- (S) -Ethyl 4-tert-butoxycarbonylamino-3-methanesulfonyloxyhexanoate 17 8.27 g of compound 16 was dissolved in 30 ml of pyridine, and 5 ml of methanesulfonyl chloride was added. Stirred at room temperature for 24 hours. The reaction solution was added to ice water, stirred and extracted with benzene. 10 organic layers
The extract was washed with a 10% aqueous citric acid solution and water and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 9.74 g of the title compound as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.97 (3H, t, J = 7 Hz), 1.28 (3
H, t, J = 7 Hz), 1.45 (9H, s), 1.3-1.8 (2H, m), 2.6-2.
9 (2H, m), 3.05 (3H, s), 3.5−3.9 (1H, m), 4.18 (2H, m
q, J = 7 Hz), 4.2-4.8 (2H, m), 4.96-5.24 (1H, m) Reference Example 15. (S) -Ethyl 4-tert-butoxycarbonylamino-2-hexenoate 18 Compound 17, 9.7 g was dissolved in 120 ml of chloroform, and DBU5.
2 g was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with a 10% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a silica gel 250 g column, and eluted with a benzene-ethyl acetate (6: 1) mixed solvent.
7.15 g of the title compound were obtained as a colorless oil.
［α］Ｄ−15.5゜（ｃ＝0.88,クロロホルム）1 H−NMR（CDCl3）δppm:0.94（3H,t,J＝7Hz）,1.30（3
H,t,J＝7Hz）,1.46（9H,s）,1.3−1.9（2H,m）,4.0−4.
4（1H,m）,4.22（2H,q,J＝7Hz）,5.96（1H,d,J＝16H
z）,6.92（1H,dd,J＝16＆5Hz） 参考例16.4−（Ｓ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−ニトロメチルヘキサノエート19 化合物18、7.15gをニトロメタン24mlに溶解し、1,1,
3,3−テトラメチルグアニジン1.6mlを加え室温で２日間
撹拌した後、ニトロメタンを減圧留去した。残留物をク
ロロホルムに溶解し10％クエン酸水溶液、水で洗った後
無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して7.
70gの黄色油状の標記化合物を得た。1 H−NMR（CDCl3）δppm:0.96（3H,t,J＝7Hz）,1.26（3
H,t,J＝7Hz）,1.44（9H,s）,1.2−1.5（2H,m）,2.44−
2.60（2H,m）,2.7−3.0（1H,m）,3.5−3.9（1H,m）,4.2
0（2H,q,J＝7Hz）,4.3−4.6（1H,broad）,4.54（2H,d,J
＝6Hz） 参考例17.4−（Ｒ）−［１−（Ｓ）−第三級ブトキシカ
ルボニルアミノプロピル］−２−ピロリドン 20 化合物19、7.7gをメタノール200mlに溶解しラネーニ
ッケル10mlと共に水素雰囲気下、室温で３日間撹拌し
た。ラネーニッケルを濾去し濾液を減圧留去した。残留
物をエタノールで結晶化し4.3gの淡黄色結晶の標記化合
物を得た。[Α] D -15.5 ゜ (c = 0.88, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.94 (3H, t, J = 7 Hz), 1.30 (3
H, t, J = 7Hz), 1.46 (9H, s), 1.3-1.9 (2H, m), 4.0-4.
4 (1H, m), 4.22 (2H, q, J = 7Hz), 5.96 (1H, d, J = 16H
z), 6.92 (1H, dd, J = 16 & 5 Hz) Reference Example 16.4- (S) -Ethyl 4-tert-butoxycarbonylamino-3-nitromethylhexanoate 19 Compound 18, 7.15 g was dissolved in nitromethane 24 ml. , 1,1,
After 1.6 ml of 3,3-tetramethylguanidine was added and the mixture was stirred at room temperature for 2 days, nitromethane was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure 7.
70 g of the title compound were obtained as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.96 (3H, t, J = 7 Hz), 1.26 (3
H, t, J = 7Hz), 1.44 (9H, s), 1.2-1.5 (2H, m), 2.44-
2.60 (2H, m), 2.7-3.0 (1H, m), 3.5-3.9 (1H, m), 4.2
0 (2H, q, J = 7 Hz), 4.3-4.6 (1H, broad), 4.54 (2H, d, J
Reference Example 17.4- (R)-[1- (S) -tert-butoxycarbonylaminopropyl] -2-pyrrolidone 20 Compound 19 (7.7 g) was dissolved in methanol (200 ml) and mixed with Raney nickel (10 ml) under a hydrogen atmosphere at room temperature. For 3 days. Raney nickel was removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was crystallized from ethanol to give 4.3 g of the title compound as pale yellow crystals.
融点:165−171℃1 H−NMR（CDCl3）δppm:0.95（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.45（9H,s）,1.3−1.7（2H,m）,2.4−2.
6（2H,m）,2.7−3.0（1H,m）,3.45−3.95（1H,m）,4.17
（2H,q,J＝7Hz）,4.1−4.3（1H,m）,4.49（2H,d,J＝6H
z） 参考例18.1−ベンジル−４−（Ｒ）−［１−（Ｓ）−ア
ミノプロピル］−２−ピロリドン 22 化合物20、4.3gをN,N−ジメチルホルムアミド80mlに
溶解し50％水素化ナトリウム850mgを加え室温で30分間
撹拌した。ここにベンジルクロリド2,42gを加え室温で2
4時間撹拌した。反応液を減圧乾固して残留物を酢酸エ
チル−ベンゼン（1:1）の混合溶媒100mlで抽出した。抽
出液を水洗後、無水硫酸ナトリウムで乾燥して溶媒を減
圧留去した。Melting point: 165-171 ° C 1 H-NMR (CDCl 3 ) δ ppm: 0.95 (3H, t, J = 7 Hz), 1.28 (3
H, t, J = 7 Hz), 1.45 (9H, s), 1.3-1.7 (2H, m), 2.4-2.
6 (2H, m), 2.7-3.0 (1H, m), 3.45-3.95 (1H, m), 4.17
(2H, q, J = 7Hz), 4.1-4.3 (1H, m), 4.49 (2H, d, J = 6H
z) Reference Example 18.1-Benzyl-4- (R)-[1- (S) -aminopropyl] -2-pyrrolidone 22 Compound 20, 4.3 g was dissolved in N, N-dimethylformamide 80 ml and 50% sodium hydride 850 mg was added and the mixture was stirred at room temperature for 30 minutes. To this, add 2,42 g of benzyl chloride and add
Stir for 4 hours. The reaction solution was dried under reduced pressure, and the residue was extracted with 100 ml of a mixed solvent of ethyl acetate-benzene (1: 1). The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
残留物をトリフルオロ酢酸50mlに溶解し、室温で１時
間撹拌した。反応液を減圧乾固し残留物を水100mlに溶
解した。これを1N水酸化ナトリウム水溶液で中和してク
ロロホルムで抽出した。抽出液を無水硫酸ナトリウムで
乾燥して溶媒を減圧留去し3.21gの無色結晶の標記化合
物を得た。The residue was dissolved in 50 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure, and the residue was dissolved in 100 ml of water. This was neutralized with a 1N aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 3.21 g of the title compound as colorless crystals.
［α］Ｄ＋0.84゜（ｃ＝0.610,クロロホルム）1 H−NMR（CDCl3）δppm:0.92（3H,t,J＝7Hz）,1.26（2
H,s）,1.0−1.7（2H,s）,2.1−2.7（4H,m）,3.0−3.5
（2H,m）,4.44（2H,AB−q,J＝14Hz）,7.28（5H,s） 参考例19.1−ベンジル−３−（Ｒ）−［１−（Ｓ）−第
三級ブトキシカルボニルアミノプロピル］−ピロリジン
24 水素化リチウムアルミニウム3.0g、THF、200mlの混合
物に化合物22、3.19g、THF、40mlの溶液を滴下した後18
時間加熱還流した。反応液を氷冷し、水15mlを滴下後不
溶物を濾去した。濾液にBoc−ON 3.38gを加えて室温で
１日撹拌した。反応液を減圧乾固し濾液をクロロホルム
で抽出した。抽出液を５％水酸化ナトリウム水溶液、水
で洗浄して無水硫酸ナトリウムで乾燥し、溶媒を減圧留
去した。残留物をシリカゲル50gのカラムに付し、クロ
ロホルムとメタノール（9:1）の混合溶媒で溶出して2.8
5gの無色油状の標記化合物を得た。[Α] D +0.84 ゜ (c = 0.610, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.92 (3H, t, J = 7 Hz), 1.26 (2
H, s), 1.0-1.7 (2H, s), 2.1-2.7 (4H, m), 3.0-3.5
(2H, m), 4.44 (2H, AB-q, J = 14 Hz), 7.28 (5H, s) Reference Example 19.1-benzyl-3- (R)-[1- (S) -tert-butoxycarbonylamino Propyl] -pyrrolidine
24 To a mixture of lithium aluminum hydride 3.0 g, THF, 200 ml was added dropwise a solution of compound 22, 3.19 g, THF, 40 ml 18
Heated to reflux for an hour. The reaction solution was ice-cooled, 15 ml of water was added dropwise, and insolubles were removed by filtration. 3.38 g of Boc-ON was added to the filtrate, and the mixture was stirred at room temperature for 1 day. The reaction solution was dried under reduced pressure, and the filtrate was extracted with chloroform. The extract was washed with a 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a 50 g column of silica gel, and eluted with a mixed solvent of chloroform and methanol (9: 1) to give 2.8.
5 g of the title compound were obtained as a colorless oil.
［α］Ｄ−30.4゜（ｃ＝1.11,クロロホルム）1 H−NMR（CDCl3）δppm:0.84（3H,d,J＝7Hz）,1.38（9
H,s）,1.2−1.5（2H,m）,1.9−2.7（7H,m）,3.1−3.5
（1H,m）,3.52（2H,AB−q,J＝13Hz）,5.1−5.4（1H,bro
ad）,7.23（5H,s） 参考例20.3−（Ｒ）−［１−（Ｓ）−第三級ブトキシカ
ルボニルアミノプロピル］−ピロリジン 25 化合物24、2.85gを５％パラジウム−炭素（水分50
％）3gを触媒としエタノール50ml中で４気圧の水素雰囲
気下、タングスンランプで照射しながら４時間振盪し
た。触媒を濾去し濾液を濃縮乾固し1.86gの無色油状の
標記化合物を得た。放置すると炭酸塩として結晶化し
た。エーテルで結晶を洗浄して濾取し1.59gの淡黄色結
晶の標記化合物を得た。[Α] D −30.4 ゜ (c = 1.11, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.84 (3H, d, J = 7 Hz), 1.38 (9
H, s), 1.2-1.5 (2H, m), 1.9-2.7 (7H, m), 3.1-3.5
(1H, m), 3.52 (2H, AB-q, J = 13Hz), 5.1-5.4 (1H, bro
ad), 7.23 (5H, s) Reference Example 20.3- (R)-[1- (S) -tert-butoxycarbonylaminopropyl] -pyrrolidine 25 Compound 24, 2.85 g was treated with 5% palladium-carbon (water content 50%).
%) As a catalyst and shaken for 4 hours in 50 ml of ethanol under a hydrogen atmosphere of 4 atm while irradiating with a Tungsung lamp. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to obtain 1.86 g of the title compound as a colorless oil. Upon standing, it crystallized as carbonate. The crystals were washed with ether and collected by filtration to obtain 1.59 g of the title compound as pale yellow crystals.
融点:186−190℃ ［α］Ｄ−21.03゜（ｃ＝0.725,エタノール） 参考例21.D−α−第三級ブトキシカルボニルアミノ酪酸
26 Ｄ−α−アミノ酪酸5.0g、トリエチルアミン10ml、50
％含水ジオキサン60mlの混合物にBoc−ON 13.1gを加え
室温で24時間撹拌した。反応液に水75mlと酢酸エチル10
0mlを加えた。水層を分離して酢酸エチル100mlで洗浄し
水層を10％クエン酸水溶液で酸性とした。酢酸エチル
（200ml×２）で抽出して抽出液を水で洗った。抽出液
を無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し9.75
gの無色油状の標記化合物を得た。Melting point: 186-190 ° C [α] D -21.03 ゜ (c = 0.725, ethanol) Reference Example 21 D-α-tert-butoxycarbonylaminobutyric acid
26 D-α-aminobutyric acid 5.0 g, triethylamine 10 ml, 50
13.1 g of Boc-ON was added to a mixture of 60 ml of water-containing dioxane and stirred at room temperature for 24 hours. 75 ml of water and ethyl acetate 10
0 ml was added. The aqueous layer was separated and washed with 100 ml of ethyl acetate, and the aqueous layer was acidified with a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate (200 ml × 2), and the extract was washed with water. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
g of the title compound were obtained as a colorless oil.
参考例22.（Ｒ）−エチル ４−第三級ブトキシカルボ
ニルアミノ−３−オキソヘキサノエート 27 マグネシウム0.96g、四塩化炭素3ml、エタノール24ml
を混合し室温で１時間撹拌した。ここにマロン酸モノエ
チルエステル11.4g、THF 58mlの混合物を滴下し、室温
で１時間撹拌した。溶媒を減圧留去し残留物をTHF 85ml
に溶解した。化合物 26、9.75gをTHF 110mlに溶解し、
N,N′−カルボニルイミダゾール8.28gを加え室温で30分
撹拌した。これに上記のTHF溶液を滴下し室温で24時間
撹拌した。溶媒を減圧留去し残留物を10％クエン酸水溶
液とベンゼンの混合物に分配した。有機層を分離して水
洗し、有機層を無水硫酸ナトリウムで乾燥し、溶媒を減
圧留去して12.1gの無色油状の標記化合物を得た。1 H−NMR（CDCl3）δppm:0.93（3H,t,J＝7Hz）,1.27（3
H,t,J＝7Hz）,1.45（9H,s）,1.4−2.0（2H,m）,3.53（2
H,s）,4.20（2H,q,J＝7Hz）,4.1−4.3（1H,m）,5.0−5.
2（1H,m） 参考例23.4−（Ｒ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−ハイドロキシヘキサノエート28 化合物27、12.1gをエタノール50mlに溶解して氷冷下
で水素化ホウ素ナトリウム1.0gを加え同温度で２時間撹
拌した。反応液に水300mlを加え20分撹拌した後溶液を
減圧留去した。残留物をクロロホルムで抽出し、抽出液
を水洗後無水硫酸ナトリウムで乾燥し溶媒を減圧留去し
た。残留物をシリカゲルカラムに付し、ベンゼン−酢酸
エチル（6:1）の混合溶媒で溶出し10.0gの無色油状物を
得た。1 H−NMR（CDCl3）δppm:0.96（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.42（9H,s）,1.3−1.8（2H,m）,2.4−2.
6（2H,m）,3.1−3.0（1H,m）,3.7−4.1（1H,m）,4.20
（2H,q,J＝7Hz）,4.3−4.7（1H,m） 参考例24.4−（Ｒ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−メタンスルホニルオキシヘキサノエ
ート 94 化合物28、10.0gをピリジン30mlに溶解し、氷冷下で
メタンスルホニルクロリド5mlを加え30分撹拌した後室
温で２時間撹拌した。反応液を氷水に加え撹拌後ベンゼ
ンで抽出した。有機層を10％クエン酸水溶液、水で洗い
無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して1
2.8gの黄色油状の標記の化合物を得た。1 H−NMR（CDCl3）δppm:0.98（3H,t,J＝7Hz）,1.28（3
H,t,J＝7Hz）,1.45（9H,s）,1.3−1.8（2H,m）,2.6−2.
9（2H,m）,3.06（3H,s）,3.5−3.9（1H,m）,4.17（2H,
q,J＝7Hz）,4.2−4.8（1H,m）,4.96−5.24（1H,m） 参考例25.（Ｒ）−エチル ４−第三級ブトキシカルボ
ニルアミノ−２−ヘキセノエート 30 化合物29、12.8gをクロロホルム150mlに溶解しDBU6.6
gを加え室温で24時間撹拌した。反応液を10％クエン酸
水溶液、水で洗い無水硫酸ナトリウムで乾燥後溶媒を減
圧留去した。Reference Example 22 (R) -ethyl 4-tert-butoxycarbonylamino-3-oxohexanoate 27 0.96 g of magnesium, 3 ml of carbon tetrachloride, 24 ml of ethanol
And stirred at room temperature for 1 hour. A mixture of malonic acid monoethyl ester (11.4 g) and THF (58 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with 85 ml of THF.
Was dissolved. Dissolve 9.75 g of compound 26 in 110 ml of THF,
8.28 g of N, N'-carbonylimidazole was added and the mixture was stirred at room temperature for 30 minutes. The above THF solution was added dropwise thereto, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the residue was partitioned between a 10% aqueous citric acid solution and a mixture of benzene. The organic layer was separated and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 12.1 g of the title compound as a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.93 (3H, t, J = 7 Hz), 1.27 (3
H, t, J = 7Hz), 1.45 (9H, s), 1.4−2.0 (2H, m), 3.53 (2
H, s), 4.20 (2H, q, J = 7 Hz), 4.1-4.3 (1H, m), 5.0-5.
2 (1H, m) Reference Example 23.4- (R) -Ethyl 4-tert-butoxycarbonylamino-3-hydroxyhexanoate 28 Compound 27, 12.1 g was dissolved in 50 ml of ethanol and borohydride was added under ice-cooling. 1.0 g of sodium was added and the mixture was stirred at the same temperature for 2 hours. After adding 300 ml of water to the reaction solution and stirring for 20 minutes, the solution was distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a silica gel column and eluted with a mixed solvent of benzene-ethyl acetate (6: 1) to obtain 10.0 g of a colorless oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.96 (3H, t, J = 7 Hz), 1.28 (3
H, t, J = 7 Hz), 1.42 (9H, s), 1.3-1.8 (2H, m), 2.4-2.
6 (2H, m), 3.1-3.0 (1H, m), 3.7-4.1 (1H, m), 4.20
(2H, q, J = 7 Hz), 4.3-4.7 (1H, m) Reference Example 24.4- (R) -Ethyl 4-tert-butoxycarbonylamino-3-methanesulfonyloxyhexanoate 94 Compound 28, 10.0 g Was dissolved in 30 ml of pyridine, 5 ml of methanesulfonyl chloride was added under ice cooling, and the mixture was stirred for 30 minutes and then at room temperature for 2 hours. The reaction solution was added to ice water, stirred and extracted with benzene. The organic layer was washed with a 10% aqueous citric acid solution and water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure.
2.8 g of the title compound were obtained as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.98 (3H, t, J = 7 Hz), 1.28 (3
H, t, J = 7 Hz), 1.45 (9H, s), 1.3-1.8 (2H, m), 2.6-2.
9 (2H, m), 3.06 (3H, s), 3.5-3.9 (1H, m), 4.17 (2H, m
q, J = 7 Hz), 4.2-4.8 (1 H, m), 4.96-5.24 (1 H, m) Reference Example 25. (R) -Ethyl 4-tert-butoxycarbonylamino-2-hexenoate 30 Compound 29, 12.8 g in 150 ml of chloroform and DBU6.6
g was added and stirred at room temperature for 24 hours. The reaction solution was washed with a 10% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
残留物をシリカゲル200gのカラムに付しベンゼン−酢
酸エチル（6:1）の混合溶媒で溶出し8.94gの無色油状の
標記化合物を得た。The residue was applied to a column of 200 g of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (6: 1) to give 8.94 g of the title compound as a colorless oil.
［α］Ｄ−16.5゜（ｃ＝1.24,クロロホルム）1 H−NMR（CDCl3）δppm:0.95（3H,t,J＝7Hz）,1.29（3
H,t,J＝7Hz）,1.45（9H,s）,1.4−1.7（2H,m）,4.19（2
H,q,J＝7Hz）,4.0−4.3（1H,m）,4.3−4.6（1H,m）,5.8
9（1H,dd,J＝16＆1.5Hz） 6.84（1H,dd,J＝16＆5.2Hz） 参考例26.4−（Ｒ）−エチル ４−第三級ブトキシカル
ボニルアミノ−３−ニトロメチルヘキサノエート31 化合物30、8.94gをニトロメタン30mlに溶解し1,1,3,3
−テトラメチルグアニジン2.9mlを加え室温で２日間撹
拌した。ニトロメタンを減圧留去して残留物をクロロホ
ルムに溶解し、10％クエン酸水溶液、水で洗った後無水
硫酸ナトリウムで乾燥した。溶媒を減圧留去し10.3gの
黄色油状の標記化合物を得た。1 H−NMR（CDCl3）δppm:0.96（3H,t,J＝7Hz）,1.27（3
H,t,J＝7Hz）,1.44（9H,s）,1.3−1.7（2H,m）,2.40−
2.56（2H,m）,2.72−2.98（1H,m）,3.44−3.94（1H,
m）,4.16（2H,q,J＝7Hz）,4.1−4.3（1H,m）,4.51（2H,
d,J＝6Hz） 参考例27.4−（Ｓ）−［１−（Ｒ）−第三級ブトキシカ
ルボニルアミノプロピル］−２−ピロリドン 32 化合物31、10.3gをメタノール200mlに溶解してラネー
ニッケル20mlと共に水素雰囲気下、室温で３日間撹拌し
た。ラネーニッケルを濾去し濾液を減圧留去した。残留
物をエタノールで結晶化し5.5gの淡黄色結晶の標記化合
物を得た。[Α] D -16.5 ゜ (c = 1.24, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.95 (3H, t, J = 7 Hz), 1.29 (3
H, t, J = 7Hz), 1.45 (9H, s), 1.4-1.7 (2H, m), 4.19 (2
H, q, J = 7Hz), 4.0-4.3 (1H, m), 4.3-4.6 (1H, m), 5.8
9 (1H, dd, J = 16 & 1.5Hz) 6.84 (1H, dd, J = 16 & 5.2Hz) Reference Example 26.4- (R) -Ethyl 4-tert-butoxycarbonylamino-3-nitromethylhexanoate 31 Compound 9, 8.94 g was dissolved in nitromethane 30 ml, 1,1,3,3
-2.9 ml of tetramethylguanidine was added and the mixture was stirred at room temperature for 2 days. Nitromethane was distilled off under reduced pressure, and the residue was dissolved in chloroform, washed with a 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 10.3 g of the title compound as a yellow oil. 1 H-NMR (CDCl 3 ) δ ppm: 0.96 (3H, t, J = 7 Hz), 1.27 (3
H, t, J = 7Hz), 1.44 (9H, s), 1.3-1.7 (2H, m), 2.40-
2.56 (2H, m), 2.72 to 2.98 (1H, m), 3.44 to 3.94 (1H,
m), 4.16 (2H, q, J = 7Hz), 4.1-4.3 (1H, m), 4.51 (2H,
d, J = 6 Hz) Reference Example 27.4- (S)-[1- (R) -tert-butoxycarbonylaminopropyl] -2-pyrrolidone 32 Compound 31, 10.3 g was dissolved in methanol 200 ml, and hydrogen was mixed with Raney nickel 20 ml. The mixture was stirred at room temperature for 3 days under an atmosphere. Raney nickel was removed by filtration, and the filtrate was distilled off under reduced pressure. The residue was crystallized from ethanol to obtain 5.5 g of the title compound as pale yellow crystals.
融点:163−170℃1 H−NMR（CDCl3）δppm:0.96（3H,t,J＝7Hz）,1.46（9
H,s）,1.1−1.5（2H,m）,2.08−2.80（2H,m）,2.3−2.7
（1H,m）,3.14−3.70（3H,m）,5.9−6.3（1H,m） 参考例28.1−ベンジル−４−（Ｓ）−［１−（Ｒ）−ア
ミノプロピル］−２−ピロリドン 33 化合物32、5.5gをN,N−ジメチルホルムアミド100mlに
溶解して50％水素化ナトリウム1.09gを加え室温で30分
間撹拌した。ここへベンジルクロリド2.87gを加えて室
温で24時間撹拌した。反応液を減圧乾固し残留物を酢酸
エチル−ベンゼン（1:1）の混合溶媒100mlで抽出した。
抽出液を水洗後、無水硫酸ナトリウムで乾燥し溶媒を減
圧留去した。Melting point: 163-170 ° C. 1 H-NMR (CDCl 3 ) δ ppm: 0.96 (3H, t, J = 7 Hz), 1.46 (9
H, s), 1.1-1.5 (2H, m), 2.08-2.80 (2H, m), 2.3-2.7
(1H, m), 3.14-3.70 (3H, m), 5.9-6.3 (1H, m) Reference Example 28.1-Benzyl-4- (S)-[1- (R) -aminopropyl] -2-pyrrolidone 33 5.5 g of Compound 32 was dissolved in 100 ml of N, N-dimethylformamide, and 1.09 g of 50% sodium hydride was added, followed by stirring at room temperature for 30 minutes. 2.87 g of benzyl chloride was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction solution was dried under reduced pressure, and the residue was extracted with 100 ml of a mixed solvent of ethyl acetate-benzene (1: 1).
The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
残留物をトリフルオロ酢酸50mlに溶解し、室温で１時
間撹拌した。反応液を減圧乾固して残留物を水100mlに
溶解した。これを1N水酸化ナトリウム水溶液で中和後ク
ロロホルムで抽出した。抽出液を無水硫酸ナトリウムで
乾燥して溶媒を減圧留去し3.59gの無色結晶の標記化合
物を得た。The residue was dissolved in 50 ml of trifluoroacetic acid and stirred at room temperature for 1 hour. The reaction solution was dried under reduced pressure, and the residue was dissolved in 100 ml of water. This was neutralized with a 1N aqueous sodium hydroxide solution and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 3.59 g of the title compound as colorless crystals.
［α］Ｄ＋0.90゜（ｃ＝1.11クロロホルム）1 H−NMR（CDCl3）δppm:0.92（3H,t,J＝7Hz）,1.27（2
H,s）,1.0−1.7（2H,s）,2.1−2.7（4H,m）,3.0−3.5
（2H,m）,4.45（2H,AB−q,J＝14Hz）,7.28（5H,s） 参考例29.1−ベンジル−３−（Ｓ）−［１−（Ｒ）−第
三級ブトキシカルボニルアミノプロピル］−ピロリジン
34 水素化リチウムアルミニウム3.0g、THF、200mlの混合
物に化合物33、3.96gとTHF、40mlの溶液を滴下した後18
時間加熱還流した。反応液を氷冷して水15mlを滴下した
後、不溶物を濾去した。濾液にBco−ON 4.2gを加え室温
で３時間撹拌した。反応液を減圧乾固し残留物をクロロ
ホルムで抽出した。抽出液を５％水酸化ナトリウム水溶
液、水で洗った後無水硫酸ナトリウムで乾燥して溶媒を
減圧留去した。残留物をシリカゲル50gのカラムに付し
クロロホルムとメタノール（95.5）の混合溶媒で溶出し
3.20gの無色油状の標記化合物を得た。[Α] D +0.90 ゜ (c = 1.11 chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.92 (3H, t, J = 7 Hz), 1.27 (2
H, s), 1.0-1.7 (2H, s), 2.1-2.7 (4H, m), 3.0-3.5
(2H, m), 4.45 (2H, AB-q, J = 14 Hz), 7.28 (5H, s) Reference Example 29.1-benzyl-3- (S)-[1- (R) -tert-butoxycarbonylamino Propyl] -pyrrolidine
34 A solution of 3.96 g of compound 33 and 40 ml of THF was added dropwise to a mixture of 3.0 g of lithium aluminum hydride and 200 ml of THF.
Heated to reflux for an hour. The reaction solution was ice-cooled, 15 ml of water was added dropwise, and insolubles were removed by filtration. 4.2 g of Bco-ON was added to the filtrate, and the mixture was stirred at room temperature for 3 hours. The reaction solution was dried under reduced pressure, and the residue was extracted with chloroform. The extract was washed with a 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to a 50 g column of silica gel and eluted with a mixed solvent of chloroform and methanol (95.5).
3.20 g of the title compound were obtained as a colorless oil.
［α］Ｄ−30.3゜（ｃ＝1.28,クロロホルム）1 H−NMR（CDCl3）δppm:0.84（3H,d,J＝7Hz）,1.39（9
H,s）,1.2−1.5（2H,m）,1.9−2.7（7H,m）,3.1−3.5
（1H,m）,3.51（2H,AB−q,J＝13Hz）,5.1−5.4（1H,
m）,7.23（5H,s） 参考例30.3−（Ｓ）−［１−（Ｒ）−第三級ブトキシカ
ルボニルアミノプロピル］−ピロリジン 35 化合物34、3.2gを５％パラジウム−炭素（水分50
％）、2.1gを触媒としてエタノール90ml中で４気圧の水
素雰囲気下でタングステンランプで照射しながら４時間
振盪した。触媒を濾去して濾液を濃縮乾固し2.0gの無色
油状の標記化合物を得た。放置すると炭酸塩として結晶
化した。エーテルで結晶を洗浄して濾取し1.64gの淡黄
色結晶の標記化合物を得た。[Α] D −30.3 ゜ (c = 1.28, chloroform) 1 H-NMR (CDCl 3 ) δ ppm: 0.84 (3H, d, J = 7 Hz), 1.39 (9
H, s), 1.2-1.5 (2H, m), 1.9-2.7 (7H, m), 3.1-3.5
(1H, m), 3.51 (2H, AB-q, J = 13Hz), 5.1-5.4 (1H,
m), 7.23 (5H, s) Reference Example 3 0.3- (S)-[1- (R) -tert-butoxycarbonylaminopropyl] -pyrrolidine 35 Compound 34, 3.2 g was treated with 5% palladium-carbon (water content 50%).
%) And 2.1 g of a catalyst, and shaken for 4 hours in 90 ml of ethanol while irradiating with a tungsten lamp under a hydrogen atmosphere of 4 atm. The catalyst was removed by filtration, and the filtrate was concentrated to dryness to obtain 2.0 g of the title compound as a colorless oil. Upon standing, it crystallized as carbonate. The crystals were washed with ether and collected by filtration to give 1.64 g of the title compound as pale yellow crystals.
融点:187−190℃ ［α］Ｄ＋21.41゜（ｃ＝0.813,エタノール） 実施例1.10−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］−１−ピロリジニル］−９−フルオロ−３−（Ｓ）
−メチル−2,3−ジヒドロ−７−オキソ−7H−ピリド
［1,2,3−de］［1,4］−ベンズオキサジン−６−カルボ
ン酸 37 8,9−ジフルオロ−３−（Ｓ）−メチル−2,3−ジヒド
ロ−７−オキソ−7H−ピリド［1,2,3−de］［1,4］ベン
ズオキサジン−６−カルボン酸BF2キレート36、300mg、
化合物12、790mg、トリエチルアミン500mg、ジメチルス
ルホキシド61mlを混合し室温で２時間撹拌した。反応液
を減圧濃縮し残留物に90％メタノール50ml、トリエチル
アミン1mlを加え12時間加熱還流した。反応液を減圧濃
縮後、残留物をクロロホルムで抽出して抽出液を10％ク
エン酸水溶液、水で洗い無水硫酸ナトリウムで乾燥して
溶媒を減圧留去した。Melting point: 187-190 ° C [α] D + 21.41 ° (c = 0.913, ethanol) Example 1.10- [3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl] -9- Fluoro-3- (S)
-Methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] -benzoxazine-6-carboxylic acid 37 8,9-difluoro-3- (S) -Methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid BF 2 chelate 36, 300 mg,
Compound 12, 790 mg, triethylamine 500 mg, and dimethyl sulfoxide 61 ml were mixed and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and 50% of 90% methanol and 1 ml of triethylamine were added to the residue, and the mixture was heated under reflux for 12 hours. After the reaction solution was concentrated under reduced pressure, the residue was extracted with chloroform. The extract was washed with a 10% aqueous citric acid solution and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
残留物にトリフルオロ酢酸10mlを加えて室温で30分撹
拌した。反応液を減圧濃縮し残留物に水5mlを加え結晶
を濾取した。この結晶を1N水酸化ナトリウム水溶液に溶
解した後、1N塩酸でpH7.5としクロロホルムで抽出し
た。クロロホルム層を無水硫酸ナトリウムで乾燥後溶媒
を減圧留去した。残留物をエタノールで再結晶し160mg
の黄色結晶の標記化合物を得た。10 ml of trifluoroacetic acid was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, 5 ml of water was added to the residue, and the crystals were collected by filtration. The crystals were dissolved in a 1N aqueous sodium hydroxide solution, adjusted to pH 7.5 with 1N hydrochloric acid, and extracted with chloroform. After the chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to 160 mg.
The title compound was obtained as yellow crystals.
融点:242−244℃ ［α］Ｄ−150.4゜（ｃ＝0.23,0.1N−NaOH） 元素分析値:C19H22FN3O4として 計算値 C 60.79 H 5.91 N 11.19 分析値 C 60.50 H 6.22 N 11.05 参考例31.7−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］１−ピロリジニル］−１−シクロプロピル−６−フ
ルオロ−1,4−ジヒドロ−４−オキソキノリン−３−カ
ルボン酸 38 １−シクロプロピル−6,7−ジフルオロ−1,4−ジヒド
ロ−４−オキソキノリン−３−カルボン酸300mg、化合
物12、500mg、トリエチルアミン1ml、アセトニトリル15
mlを混合し４時間加熱還流した。反応液を減圧濃縮し、
残留物をクロロホルムで抽出し抽出液を10％クエン酸水
溶液、水で洗った。無水硫酸ナトリウムで乾燥後、溶媒
を減圧留去し融点252−255℃の７−［３−（Ｒ）−［１
−（Ｓ）−第３級ブトキシカルボニルアミノエチル］−
１−ピロリジニル］−１−シクロプロピル−６−フルオ
ロ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸の無色結晶を得た。Melting point: 242-244 ° C [α] D -150.4 ゜ (c = 0.23, 0.1N-NaOH) Elemental analysis: Calculated for C 19 H 22 FN 3 O 4 C 60.79 H 5.91 N 11.19 Analysis C 60.50 H 6.22 N 11.05 Reference Example 31.7- [3- (R)-[1- (S) -aminoethyl] 1-pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid 38 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 300 mg, compound 12, 500 mg, triethylamine 1 ml, acetonitrile 15
Then, the mixture was heated and refluxed for 4 hours. The reaction solution was concentrated under reduced pressure,
The residue was extracted with chloroform, and the extract was washed with a 10% aqueous citric acid solution and water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 7- [3- (R)-[1
-(S) -tert-butoxycarbonylaminoethyl]-
[1-Pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as colorless crystals.
これにトリフルオロ酢酸10mlを加え室温で20分間撹拌
した。反応液を減圧濃縮し残留物を1N水酸化ナトリウム
水溶液に溶解し、塩酸でpH7.4としクロロホルムで抽出
した。抽出液を無水硫酸ナトリウムで乾燥して溶媒を減
圧留去し、残留物をエタノールで再結晶して270mgの無
色結晶の標記化合物を得た。To this was added 10 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a 1N aqueous solution of sodium hydroxide, adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 270 mg of the title compound as colorless crystals.
融点:236−241℃ ［α］Ｄ−47.6゜（ｃ＝0.42,0.1N NaOH） 元素分析値C19H22FN3O3として 計算値 C 63.50 H 6.17 N 11.69 分析値 C 63.21 H 6.35 N 11.55 実施例2.7−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］−１−ピロリジニル］−１−エチル−６−フルオロ
−８−メトキシ−1,4−ジヒドロ−４−オキソキノリン
−３−カルボン酸 39 １−エチル−6,7−ジフルオロ−８−メトキシ−1,4−
ジヒドロ−４−オキソキノリン−３−カルボン酸350m
g、化合物12、500mg、トリエチルアミン300ml、アセト
ニトリル10mlを混合し18時間加熱還流した。反応液を減
圧濃縮して残留物をクロロホルムで抽出し抽出液を10％
クエン酸水溶液、水で洗った。これを無水硫酸ナトリウ
ムで乾燥して溶媒を減圧留去した。Melting point: 236-241 ° C [α] D −47.6 ° (c = 0.42, 0.1N NaOH) Elemental analysis value calculated as C 19 H 22 FN 3 O 3 C 63.50 H 6.17 N 11.69 Analysis value C 63.21 H 6.35 N 11.55 Example 2.7- [3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl] -1-ethyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid 39 1-ethyl-6,7-difluoro-8-methoxy-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 350m
g, compound 12, 500 mg, triethylamine 300 ml, and acetonitrile 10 ml were mixed and heated under reflux for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with chloroform.
Washed with citric acid aqueous solution and water. This was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.
残留物にトリフルオロ酢酸5mlを加えて20分間撹拌し
た。反応液を減圧濃縮し、残留物を1N水酸化ナトリウム
水溶液に溶解して塩酸でpH7.4としクロロホルムで抽出
した。抽出液を無水硫酸ナトリウムで乾燥後溶媒を減圧
留去した。残留物をエタノールで再結晶して210mgの無
色結晶の標記化合物を得た。5 ml of trifluoroacetic acid was added to the residue and stirred for 20 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a 1N aqueous sodium hydroxide solution, adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 210 mg of the title compound as colorless crystals.
融点:215℃ ［α］Ｄ−146.9゜（ｃ＝0.358,0.1N−NaOH） 元素分析値:C19H22FN3O4・1/2H2Oとして 計算値 C 59.06 H 6.52 N 10.87 分析値 C 58.95 H 6.35 N 11.85 参考例32.5−アミノ−７−［３−（Ｒ）−［１−（Ｓ）
−アミノエチル］−１−ピロリジニル］−１−エチル−
6,8−ジフルオロ−４−オキソキノリン−３−カルボン
酸 40 ５−アミノ−１−エチル−6,7,8−トリフルオロ−４
−オキソキノリン−３−カルボン酸1.0g、化合物12、1.
0g、トリエチルアミン3.0g、アセトニトリル70mlを混合
して３時間加熱還流した。反応液を減圧濃縮し、残留物
にエタノールを加え結晶を濾取した。これをオリフルオ
ロ酢酸30mlに溶解し室温で30分撹拌して減圧濃縮した。
残留物に水10mlを加えた後1N水酸化ナトリウム水溶液を
加えて残留物を溶解して不溶物を濾去した。濾液を塩酸
でpH7.4としクロロホルムで抽出した。抽出液を無水硫
酸ナトリウムで乾燥後溶媒を減圧留去して残留物をエタ
ノールで再結晶し、500mgの黄色結晶の標記化合物を得
た。Melting point: 215 ° C [α] D -146.9 ゜ (c = 0.358, 0.1 N-NaOH) Elemental analysis: Calculated as C 19 H 22 FN 3 O 4 1/2 H 2 O C 59.06 H 6.52 N 10.87 Analysis C 58.95 H 6.35 N 11.85 Reference Example 32.5-Amino-7- [3- (R)-[1- (S)
-Aminoethyl] -1-pyrrolidinyl] -1-ethyl-
6,8-difluoro-4-oxoquinoline-3-carboxylic acid 40 5-amino-1-ethyl-6,7,8-trifluoro-4
-Oxoquinoline-3-carboxylic acid 1.0 g, compound 12, 1.
0 g, triethylamine 3.0 g and acetonitrile 70 ml were mixed and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the crystals were collected by filtration. This was dissolved in 30 ml of trifluoroacetic acid, stirred at room temperature for 30 minutes, and concentrated under reduced pressure.
After adding 10 ml of water to the residue, a 1N aqueous sodium hydroxide solution was added to dissolve the residue, and the insoluble matter was removed by filtration. The filtrate was adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to obtain 500 mg of the title compound as yellow crystals.
融点:227−229℃ ［α］Ｄ−169.0゜（ｃ＝0.84,0.1N−NaOH） 元素分析値:C18H22F2N4O3として 計算値 C 56.84 H 5.83 N 14.72 分析値 C 56.78 H 5.80 N 14.60 実施例3.7−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］−１−ピロリジニル］−６−フルオロ−１−フルオ
ロエチル−８−メトキシ−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸 42 6,7−ジフルオロ−１−フルオロエチル−８−メトキ
シ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸260mg、化合物12、450mg、トリエチルアミン400m
g、アセトニトリル20mlを混合し18時間加熱還流した。
溶媒を減圧留去し、残留物をクロロホルムに溶解して10
％クエン酸水溶液、水で洗い無水硫酸ナトリウムで乾燥
後減圧乾固した。Melting point: 227-229 ° C [α] D- 169.0 ゜ (c = 0.84, 0.1 N-NaOH) Elemental analysis: Calculated for C 18 H 22 F 2 N 4 O 3 C 56.84 H 5.83 N 14.72 Analysis C 56.78 H 5.80 N 14.60 Example 3.7- [3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl] -6-fluoro-1-fluoroethyl-8-methoxy-1,4-dihydro- 4-oxoquinoline-3-carboxylic acid 42 6,7-difluoro-1-fluoroethyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 260 mg, compound 12, 450 mg, triethylamine 400 m
g and acetonitrile (20 ml) were mixed and heated under reflux for 18 hours.
The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform.
% Citric acid aqueous solution and water, dried over anhydrous sodium sulfate, and then dried under reduced pressure.
残留物をシリカゲルカラムに付してクロロホルム−メ
タノール（95:5）の混合溶媒で溶出し187mgの無色結晶
の７−［３−（Ｒ）−［１−（Ｓ）−第３級ブトキシカ
ルボニルアミノエチル］−１−ピロリジニル］−６−フ
ルオロ−１−フルオロエチル−８−メトキシ−1,4−ジ
ヒドロ−４−オキソキノリン−３−カルボン酸41、187m
gを得た。これをトリフルオロ酢酸5mlに溶解し室温で20
分撹拌後減圧乾固した。残留物に水5mlを加え1N水酸化
ナトリウム水溶液でpH12とし、クロロホルムで洗浄し
た。水層を塩酸でpH7.6としてクロロホルムで抽出し、
抽出液を無水硫酸ナトリウムで乾燥した。溶媒を減圧留
去して残留物をアンモニア水−エタノールで再結晶し、
60mgの標記化合物の無色結晶を得た。The residue was applied to a silica gel column and eluted with a mixed solvent of chloroform-methanol (95: 5) to elute 187 mg of 7- [3- (R)-[1- (S) -tert-butoxycarbonylamino] colorless crystal. Ethyl] -1-pyrrolidinyl] -6-fluoro-1-fluoroethyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 41, 187 m
g was obtained. Dissolve this in 5 ml of trifluoroacetic acid and add
After stirring for minutes, the mixture was dried under reduced pressure. To the residue was added 5 ml of water, adjusted to pH 12 with a 1N aqueous solution of sodium hydroxide, and washed with chloroform. The aqueous layer was adjusted to pH 7.6 with hydrochloric acid and extracted with chloroform,
The extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol,
60 mg of colorless crystals of the title compound were obtained.
融点:220−223℃ ［α］Ｄ−149.0℃（ｃ＝0.208,0.1N−NaOH） 元素分析値:C19H23N3O4・1/2H2Oとして 計算値 C 56.43 H 5.98 N 10.39 分析値 C 56.11 H 6.00 N 10.33 実施例4.7−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］−１−ピロリジニル］−１−シクロプロピル−６−
フルオロ−８−メトキシ−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸 43 １−シクロプロピル−6,7−ジフルオロ−８−メトキ
シ−1,4−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸BF2キレート100mg、化合物12、100mg、トリエチル
アミン60mg、ジメチルスルホキシド5mlを混合し、室温
で16.5時間撹拌した。反応液を減圧濃縮し、残留物に80
％メタノール15ml、トリエチルアミン300mgを加え６時
間加熱還流した。反応液を減圧濃縮して残留物をクロロ
ホルムで抽出した。抽出液を10％クエン酸水溶液、水で
洗い無水硫酸ナトリウムで乾燥した。溶媒を減圧乾固し
100mgの淡黄色粉末の７−［３−（Ｒ）−［１−（Ｓ）
−第３級ブトキシカルボニルアミノエチル］−１−ピロ
リジニル］−１−シクロプロピル−６−フルオロ−８−
メトキシ−1,4−ジヒドロ−４−オキソキノリン−３−
カルボン酸を得た。Melting point: 220-223 ° C [α] D −149.0 ° C (c = 0.208, 0.1N-NaOH) Elemental analysis: Calculated as C 19 H 23 N 3 O 4 .1 / 2H 2 O C 56.43 H 5.98 N 10.39 Analytical value C 56.11 H 6.00 N 10.33 Example 4.7- [3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl] -1-cyclopropyl-6-
Fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 43 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3- 100 mg of carboxylic acid BF 2 chelate, 100 mg of compound 12, 60 mg of triethylamine, and 5 ml of dimethyl sulfoxide were mixed and stirred at room temperature for 16.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was concentrated to 80
15 ml of methanol and 300 mg of triethylamine were added, and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with a 10% aqueous citric acid solution and water and dried over anhydrous sodium sulfate. Evaporate the solvent under reduced pressure
7- [3- (R)-[1- (S) of 100 mg of pale yellow powder
-Tert-butoxycarbonylaminoethyl] -1-pyrrolidinyl] -1-cyclopropyl-6-fluoro-8-
Methoxy-1,4-dihydro-4-oxoquinoline-3-
A carboxylic acid was obtained.
これをトリフルオロ酢酸6mlに溶解し室温で15分撹拌
した後減圧乾固し、残留物を塩酸に溶解した。これをク
ロロホルムで洗浄し、水層を氷冷下、水酸化ナトリウム
水溶液でpH12としクロロホルムで洗浄した。水層を塩酸
でpH6.7としてクロロホルムで抽出し、抽出液を無水硫
酸ナトリウムで乾燥した。溶液を減圧留去して残留物を
アンモニア水−エタノールで再結晶し、44mgの標記化合
物の無色結晶を得た。This was dissolved in 6 ml of trifluoroacetic acid, stirred at room temperature for 15 minutes, and dried under reduced pressure, and the residue was dissolved in hydrochloric acid. This was washed with chloroform, and the aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution under ice-cooling and washed with chloroform. The aqueous layer was adjusted to pH 6.7 with hydrochloric acid, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solution was evaporated under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 44 mg of the title compound as colorless crystals.
融点:188−190℃ ［α］Ｄ−167℃（ｃ＝0.270,0.1N−NaOH） 参考例33.7−［３−（Ｒ）−［１−（Ｓ）−アミノエチ
ル］−１−ピロリジニル］−６−フルオロ−１−（2,4
−ジフルオロフェニル）−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸 44 6,7−ジフルオロ−１−（2,4−ジフルオロフェニル）
−1,4−ジヒドロ−４−オキソキノリン−３−カルボン
酸400mg、化合物12、500mg、トリエチルアミン400mg、
アセトニトリル20mlを混合し1.5時間加熱還流した。反
応液を減圧濃縮し、残留物をクロロホルムに溶解して10
％クエン酸水溶液、水で洗い無水硫酸ナトリウムで乾燥
後減圧留去した。残留物をイソプロピルエーテルで結晶
化して得られた７−［３−（Ｒ）−［１−（Ｓ）−第３
級ブトキシカルボニルアミノエチル］−１−ピロリジニ
ル］−６−フルオロ−１−（2,4−ジフルオロフェニ
ル）−1,4−ジヒドロ−４−オキソキノリン−３−カル
ボン酸の結晶520mgをトリフルオロ酢酸10mlに溶解して
室温で20分撹拌した。反応液を減圧乾固し残留物を塩酸
に溶解した。これをクロロホルムで洗浄し、水層を氷冷
下、水酸化ナトリウム水溶液でpHとしてクロロホルムで
洗浄した。水層を塩酸でpH7.3とした後クロロホルムで
抽出し、抽出液を無水硫酸ナトリウムで乾燥した。溶媒
を減圧留去して残留物をアンモニア水−エタノールで再
結晶し、270mgの標記化合物の無色結晶を得た。Melting point: 188-190 ° C [α] D -167 ° C (c = 0.270, 0.1N-NaOH) Reference Example 33.7- [3- (R)-[1- (S) -aminoethyl] -1-pyrrolidinyl]- 6-fluoro-1- (2,4
-Difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 44 6,7-difluoro-1- (2,4-difluorophenyl)
1,4-dihydro-4-oxoquinoline-3-carboxylic acid 400 mg, compound 12, 500 mg, triethylamine 400 mg,
20 ml of acetonitrile was mixed and heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in chloroform.
% Citric acid aqueous solution and water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 7- [3- (R)-[1- (S) -third obtained by crystallizing the residue with isopropyl ether.
Butoxycarbonylaminoethyl] -1-pyrrolidinyl] -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (520 mg) was treated with trifluoroacetic acid (10 ml). And stirred at room temperature for 20 minutes. The reaction solution was dried under reduced pressure, and the residue was dissolved in hydrochloric acid. This was washed with chloroform, and the aqueous layer was washed with chloroform after adjusting the pH to pH with an aqueous sodium hydroxide solution under ice-cooling. The aqueous layer was adjusted to pH 7.3 with hydrochloric acid, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 270 mg of colorless crystals of the title compound.
融点:250−252℃ ［α］Ｄ−46.95゜（ｃ＝0.230,1N−NaOH） 実施例34.（−）−７−［３−（Ｒ）−［１−（Ｓ）−
アミノプロピル］−１−ピロリジニル］−１−エチル−
6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン
−３−カルボン酸45 １−エチル−6,7,8−トリフルオロ−1,4−ジヒドロ−
４−オキソキノリン−３−カルボン酸150mg、化合物2
5、150mg、トリエチルアミン0.5ml、アセトニトリル15m
lを混合し16時間加熱還流した。反応液を減圧濃縮し、
残留物をクロロホルムに溶解して10％クエン酸水溶液、
水で洗浄し、無水硫酸ナトリウムで乾燥後溶媒を減圧留
去した。Melting point: 250-252 ° C [α] D -46.95 ° (c = 0.230, 1N-NaOH) Example 34. (−)-7- [3- (R)-[1- (S)-
Aminopropyl] -1-pyrrolidinyl] -1-ethyl-
6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 45 1-ethyl-6,7,8-trifluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 150 mg, compound 2
5, 150mg, triethylamine 0.5ml, acetonitrile 15m
were mixed and heated under reflux for 16 hours. The reaction solution was concentrated under reduced pressure,
The residue was dissolved in chloroform and 10% aqueous citric acid solution was added.
After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
残留物をトリフルオロ酢酸10mlに溶解し室温で15分間
撹拌した。反応液を減圧乾固して残留物を水10mlに懸濁
し、濃酸塩を加えて溶液としてクロロホルムで洗浄し
た。水層を氷冷下水酸化ナトリウム水溶液でpH12としク
ロロホルムで洗浄した。水層を塩酸でpH7.3としクロロ
ホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥
して溶媒を減圧留去し、残留物をアンモニア水−エタノ
ールで再結晶して138mgの無色結晶の標記化合物を得
た。The residue was dissolved in 10 ml of trifluoroacetic acid and stirred at room temperature for 15 minutes. The reaction solution was dried under reduced pressure, the residue was suspended in 10 ml of water, concentrated salt was added, and the solution was washed with chloroform. The aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution under ice cooling, and washed with chloroform. The aqueous layer was adjusted to pH 7.3 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 138 mg of the title compound as colorless crystals.
融点:215−216℃ ［α］Ｄ−164.22゜（ｃ＝0.218,1N−NaOH） 元素分析値:C19H23F2N3O3・1/2H2Oとして 計算値 C 58.75 H 6.23 N 10.82 分析値 C 58.70 H 6.21 N 11.13 参考例35.（＋）−７−［３−（Ｓ）−［１−（Ｒ）−
アミノプロピル］−１−ピロリジニル］−１−エチル−
6,8−ジフルオロ−1,4−ジヒドロ−４−オキソキノリン
−３−カルボン酸46 １−エチル−6,7,8−トリフルオロ−1,4−ジヒドロ−
４−オキソキノリン−３−カルボン酸150mg、化合物3
5、150mg、トリエチルアミン0.5ml、アセトニトリル15m
lを混合し19時間加熱還流した。反応液を減圧濃縮し、
残留物をクロロホルムに溶解して10％クエン酸水溶液、
水で洗浄し、無水硫酸ナトリウムで乾燥後溶媒を減圧留
去した。Melting point: 215-216 ° C [α] D -164.22 ゜ (c = 0.218, 1N-NaOH) Elemental analysis: C 19 H 23 F 2 N 3 O 3 1/2 H 2 O Calculated value C 58.75 H 6.23 N 10.82 Analytical value C 58.70 H 6.21 N 11.13 Reference Example 35. (+)-7- [3- (S)-[1- (R)-
Aminopropyl] -1-pyrrolidinyl] -1-ethyl-
6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 46 1-ethyl-6,7,8-trifluoro-1,4-dihydro-
4-oxoquinoline-3-carboxylic acid 150 mg, compound 3
5, 150mg, triethylamine 0.5ml, acetonitrile 15m
were mixed and heated under reflux for 19 hours. The reaction solution was concentrated under reduced pressure,
The residue was dissolved in chloroform and 10% aqueous citric acid solution was added.
After washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
残留物をトリフルオロ酢酸10mlに溶解し室温で20分間
撹拌した。反応液を減圧乾固して残留物を水15mlに懸濁
し、濃塩酸を加えて溶液としてクロロホルムで洗浄し
た。水層を氷冷下に水酸化ナトリウム水溶液でpH13と
し、クロロホルムで洗浄した。水層を塩酸でpH13とし、
クロロホルムで洗浄した。水層を塩酸でpH7.3としてク
ロロホルムで抽出した。抽出液を無水硫酸ナトリウムで
乾燥して溶媒を減圧留去し、残留物をアンモニア水−エ
タノールで再結晶して127mgの無色結晶の標記化合物を
得た。The residue was dissolved in 10 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The reaction solution was dried under reduced pressure, the residue was suspended in 15 ml of water, concentrated hydrochloric acid was added, and the solution was washed with chloroform. The aqueous layer was adjusted to pH 13 with an aqueous sodium hydroxide solution under ice cooling, and washed with chloroform. The aqueous layer was adjusted to pH 13 with hydrochloric acid,
Washed with chloroform. The aqueous layer was adjusted to pH 7.3 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 127 mg of the title compound as colorless crystals.
融点:216−217℃ ［α］Ｄ＋153.58゜（ｃ＝0.293,1N−NaOH） 元素分析値:C19H23F2N3O3・1/2H2Oとして 計算値 C 58.75 H 6.23 N 10.82 分析値 C 59.12 H 6.59 N 11.18 参考例36.（−）−７−［３−（Ｒ）−［１−（Ｓ）−
アミノプロピル］−１−ピロリジニル］−１−シクロプ
ロピル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸 47 １−シクロプロピル−6,7,8−トリフルオロ−1,4−ジ
ヒドロ−４−オキソキノリン−３−カルボン酸200mg、
化合物25、200mg、トリエチルアミン0.5ml、アセトニト
リル15mlを混合し16時間加熱還流した。反応液を冷却
し、析出した結晶を濾取して７−［３−（Ｒ）−［１−
（Ｓ）−第３級ブトキシカルボニルアミノプロピル］−
１−ピロリジニル］−１−シクロプロピル−6,8−ジフ
ルオロ−1,4−ジヒドロ−４−オキソキノリン−３−カ
ルボン酸を得た。Melting point: 216-217 ° C [α] D +153.58 ゜ (c = 0.293, 1N-NaOH) Elemental analysis: Calculated as C 19 H 23 F 2 N 3 O 3 .1 / 2H 2 O C 58.75 H 6.23 N 10.82 Analytical value C 59.12 H 6.59 N 11.18 Reference Example 36. (-)-7- [3- (R)-[1- (S)-
Aminopropyl] -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 47 1-cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg,
Compound 25 (200 mg), triethylamine (0.5 ml) and acetonitrile (15 ml) were mixed and heated under reflux for 16 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration and treated with 7- [3- (R)-[1-
(S) -tert-butoxycarbonylaminopropyl]-
[1-Pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.
これをトリフルオロ酢酸10mlに溶解し室温で20分間撹
拌した。反応液を減圧乾固して残留物を水10mlに懸濁
し、1N水酸化ナトリウム水溶液を加えて溶解し（pH 1
2）、クロロホルムで洗浄した。水層を塩酸でpH7.3とし
てクロロホルムで抽出した。抽出液を無水硫酸ナトリウ
ムで乾燥して溶媒を減圧留去し、残留物をアンモニア水
−エタノールで再結晶して175mgの無色結晶の標記化合
物を得た。This was dissolved in 10 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The reaction solution was dried under reduced pressure, the residue was suspended in 10 ml of water, and dissolved by adding a 1N aqueous sodium hydroxide solution (pH 1
2), and washed with chloroform. The aqueous layer was adjusted to pH 7.3 with hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to obtain 175 mg of the title compound as colorless crystals.
融点:216−218℃ ［α］Ｄ−174.07゜（ｃ＝0.378,0.1N−NaOH） 元素分析値:C20H23F2N3O3・1/4H2Oとして 計算値 C 60.67 H 5.98 N 10.61 分析値 C 60.63 H 6.15 N 10.60 参考例37.（＋）−７−［３−（Ｓ）−［１−（Ｒ）−
アミノプロピル］−１−ピロリジニル］−１−シクロプ
ロピル−6,8−ジフルオロ−1,4−ジヒドロ−４−オキソ
キノリン−３−カルボン酸 48 １−シクロプロピル−6,7,8−トリフルオロ−1,4−ジ
ヒドロ−４−オキソキノリン−３−カルボン酸200mg、
化合物35、200mg、トリエチルアミン0.5ml、アセトニト
リル15mlを混合し18時間加熱還流した。反応液を冷却
し、析出した結晶を濾取して７−［３−（Ｓ）−［１−
（Ｒ）−第３級ブトキシカルボニルアミノプロピル］−
１−ピロリジニル］−１−シクロプロピル−6,8−ジフ
ルオロ−1,4−ジヒドロ−４−オキソキノリン−３−カ
ルボン酸を得た。Melting point: 216-218 ° C [α] D −174.07 ゜ (c = 0.378, 0.1N-NaOH) Elemental analysis: Calculated as C 20 H 23 F 2 N 3 O 3 .1 / 4H 2 O C 60.67 H 5.98 N 10.61 Analytical value C 60.63 H 6.15 N 10.60 Reference Example 37. (+)-7- [3- (S)-[1- (R)-
Aminopropyl] -1-pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 48 1-cyclopropyl-6,7,8-trifluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 200 mg,
Compound 35 (200 mg), triethylamine (0.5 ml), and acetonitrile (15 ml) were mixed and heated under reflux for 18 hours. The reaction solution was cooled, and the precipitated crystals were collected by filtration and treated with 7- [3- (S)-[1-
(R) -tert-butoxycarbonylaminopropyl]-
[1-Pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.
これをトリフルオロ酢酸10mlに溶解し室温で30分間撹
拌した。反応液を減圧乾固し残留物に水10mlを加え1N水
酸化ナトリウム水溶液でpH11としクロロホルムで洗浄し
た。水層を塩酸でpH7.1としクロロホルムで抽出した。
抽出液を無水硫酸ナトリウムで乾燥して溶媒を減圧留去
し、残留物をアンモニア水−エタノールで再結晶し162m
gの無色結晶の標記化合物を得た。This was dissolved in 10 ml of trifluoroacetic acid and stirred at room temperature for 30 minutes. The reaction solution was dried under reduced pressure, 10 ml of water was added to the residue, and the mixture was adjusted to pH 11 with a 1N aqueous sodium hydroxide solution and washed with chloroform. The aqueous layer was adjusted to pH 7.1 with hydrochloric acid and extracted with chloroform.
The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous ammonia-ethanol to give 162 m
g of the title compound were obtained as colorless crystals.
融点:218−220℃ ［α］Ｄ＋174.46゜（ｃ＝0.235,0.1N−NaOH） 元素分析値:C20H23F2N3O3・H2Oとして 計算値 C 58.67 H 6.15 N 10.26 分析値 C 58.57 H 6.26 N 10.24 参考例38.（＋）−７−［３−（Ｒ）−［１−（Ｓ）−
アミノエチル］−１−ピロリジニル］−1,4−ジヒドロ
−６−フルオロ−１−（２−メチル−２−プロピル）−
４−オキソ−1,8−ナフチリジン−３−カルボン酸49 化合物12、180mgとジクロロメタン6ml、トリフルオロ
酢酸4mlを混合し、室温で50分撹拌した後溶媒を減圧留
去した。残留物にアセトニトリル10ml、エチル７−クロ
ロ−1,4−ジヒドロ−６−フルオロ−１−（２−メチル
−２−プロピル）−４−オキソ−1,8−ナフチリジン−
３−カルボキシレート208mg、トリエチルアミン2mlを加
えて１時間加熱還流した。冷後溶媒を減圧留去し、残留
物に水を加えて析出晶を集め、水、エーテルで洗浄し、
融点151−154℃のエチル７−［３−（Ｒ）−［１−
（Ｓ）−アミノエチル］−１−ピロリジニル］−1,4−
ジヒドロ−６−フルオロ−１−（２−メチル−２−プロ
ピル）−４−オキソ−1,8−ナフチリジン−３−カルボ
キシレートの白色粉末304mgを得た。Melting point: 218-220 ° C [α] D +174.46 ゜ (c = 0.235, 0.1 N-NaOH) Elemental analysis: Calculated as C 20 H 23 F 2 N 3 O 3 .H 2 O C 58.67 H 6.15 N 10.26 Analytical value C 58.57 H 6.26 N 10.24 Reference example 38. (+)-7- [3- (R)-[1- (S)-
Aminoethyl] -1-pyrrolidinyl] -1,4-dihydro-6-fluoro-1- (2-methyl-2-propyl)-
4-oxo-1,8-naphthyridine-3-carboxylic acid 49 180 mg of Compound 12, 6 ml of dichloromethane and 4 ml of trifluoroacetic acid were mixed, stirred at room temperature for 50 minutes, and the solvent was distilled off under reduced pressure. 10 ml of acetonitrile was added to the residue, and ethyl 7-chloro-1,4-dihydro-6-fluoro-1- (2-methyl-2-propyl) -4-oxo-1,8-naphthyridine-
208 mg of 3-carboxylate and 2 ml of triethylamine were added, and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were collected, washed with water and ether,
Ethyl 7- [3- (R)-[1-
(S) -aminoethyl] -1-pyrrolidinyl] -1,4-
304 mg of white powder of dihydro-6-fluoro-1- (2-methyl-2-propyl) -4-oxo-1,8-naphthyridine-3-carboxylate was obtained.
このエチルエステル300mgと水2ml、1N水酸化ナトリウ
ム水溶液2mlを混合し、１時間加熱還流した。冷後、水5
mlを加え、0.25N塩酸でpHを7.2に調整して析出晶を集
め、水、エーテル、エタノールにて洗浄した。エタノー
ルとアンモニア水から再結晶し無色針状晶140mgを得
た。300 mg of this ethyl ester, 2 ml of water and 2 ml of a 1N aqueous sodium hydroxide solution were mixed, and the mixture was refluxed for 1 hour. After cooling, water 5
Then, the pH was adjusted to 7.2 with 0.25N hydrochloric acid, and the precipitated crystals were collected and washed with water, ether and ethanol. Recrystallization from ethanol and aqueous ammonia gave 140 mg of colorless needles.
融点:228−230℃ ［α］Ｄ＋7.5゜（ｃ＝0.268,1N NaOH） 元素分析値:C19H25FN4O3として 計算値 C 60.63 H 6.69 N 14.88 分析値 C 60.38 H 6.88 N 14.70 合成した目的のキノロン誘導体は抗菌試験の結果、キ
ノリン骨格の７位相当位のピロリジン置換基については
（3R,1′Ｓ）配位のものが強い抗菌活性を示した。Melting point: 228-230 ° C [α] D +7.5 ゜ (c = 0.268, 1N NaOH) Elemental analysis: Calculated for C 19 H 25 FN 4 O 3 C 60.63 H 6.69 N 14.88 Analysis C 60.38 H 6.88 N 14.70 As a result of antibacterial test, the synthesized quinolone derivative showed that the pyrrolidine substituent at the 7-position equivalent of the quinoline skeleton had a strong (3R, 1 ′S) -coordinated antibacterial activity.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 401/04 C07D 498/06 ＣＡ，ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. 6 , DB name) C07D 401/04 C07D 498/06 CA, REGISTRY (STN)
Claims (6)
置換基を有することもあるヘテロアリール基、置換基を
有することもある炭素数３〜６の環状アルキル基、炭素
数１〜６のアルキル基、炭素数２〜６のアルケニル基、
炭素数１〜６のハロゲノアルキル基、炭素数１〜６のア
ルコキシ基、または炭素数１〜６のアルキルアミノ基を
意味し、 R2は、置換基を有することもあるアミノ基、水素原子、
水酸基、炭素数１〜６のアルコキシ基、またはハロゲン
原子を意味し、 R3は、炭素数１〜６のアルキル基を意味し、 R4は、水酸基、ハロゲン原子、もしくはフェニル基で置
換されていることもある炭素数１〜６のアルキル基、水
素原子、アシル基、アルキルオキシカルボニル基、また
はアラルキルオキシカルボニル基を意味し、 Ｑは、Ｃ−R5を意味し、 R5は、炭素数１〜６のアルキル基、または炭素数１〜６
のアルコキシ基を意味し、 R6は、水素原子、または炭素数１〜６のアルキル基を意
味する。また、R1はR5および／またはR6と共に環状構造
を形成してもよく、この環は酸素原子、窒素原子、硫黄
原子を含むもともあり、さらに炭素数１〜６のアルキル
基、ハロゲノアルキル基などで置換されていてもよい。 Ｚは、水素原子、炭素数１〜６のアルキル基、炭素数１
〜６のアルコキシアルキル基、炭素数１〜６のアルキル
鎖のフェニルアルキル基、フェニル基、アセトキシメチ
ル基、ピバロイルオキシメチル基、エトキシカルボニル
オキシ基、コリン基、ジメチルアミノエチル基、５−イ
ンダニル基、フタリジニル基、５−置換−２−オキソ−
1,3−ジオキソール−４−イルメチル基、または３−ア
セトキシ−２−オキソブチル基を意味する。） で表わされるキノロン誘導体及びその塩(1) General formula (Wherein, R 1 is an aryl group which may have a substituent,
A heteroaryl group which may have a substituent, a cyclic alkyl group having 3 to 6 carbon atoms which may have a substituent, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,
A halogenoalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms, R 2 represents an amino group which may have a substituent, a hydrogen atom,
A hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom, R 3 represents an alkyl group having 1 to 6 carbon atoms, and R 4 is substituted with a hydroxyl group, a halogen atom, or a phenyl group. also alkyl group having 1 to 6 carbon atoms that have a hydrogen atom, and means an acyl group, an alkyloxycarbonyl group or an aralkyloxycarbonyl group,, Q means a C-R 5, R 5 is the number of carbon atoms 1 to 6 alkyl groups or 1 to 6 carbon atoms
R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 1 may form a cyclic structure together with R 5 and / or R 6 , and this ring may contain an oxygen atom, a nitrogen atom, a sulfur atom, and may further have an alkyl group having 1 to 6 carbon atoms, a halogeno group. It may be substituted with an alkyl group or the like. Z is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 1 carbon atom
-C6 alkoxyalkyl group, C1-C6 alkyl chain phenylalkyl group, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyloxy group, choline group, dimethylaminoethyl group, 5-indanyl Group, phthalidinyl group, 5-substituted-2-oxo-
It means a 1,3-dioxol-4-ylmethyl group or a 3-acetoxy-2-oxobutyl group. And a salt thereof.
［１−（Ｓ）−アミノエチル］−１−ピロリジニル基で
置換されたキノロンカルボン酸誘導体である請求項
（１）に記載の化合物及びその塩2. The quinoline skeleton in which the 7-position equivalent is 3- (R)-
The compound according to claim 1, which is a quinolone carboxylic acid derivative substituted with [1- (S) -aminoethyl] -1-pyrrolidinyl group, and a salt thereof.
［１−（Ｓ）−アミノプロピル］−１−ピロリジニル基
で置換されたキノロンカルボン酸誘導体である請求項
（１）に記載の化合物及びその塩。3. The quinoline skeleton in which the 7-position equivalent is 3- (R)-
The compound according to claim 1, which is a quinolonecarboxylic acid derivative substituted with [1- (S) -aminopropyl] -1-pyrrolidinyl group, and a salt thereof.
［１−（Ｓ）−第三級ブトキシカルボニルアミノエチ
ル］−１−ピロリジニル基で置換されたキノロンカルボ
ン酸誘導体である請求項（１）に記載の化合物及びその
塩4. The quinoline skeleton in which the 7-position equivalent is 3- (R)-
The compound according to claim 1, which is a quinolonecarboxylic acid derivative substituted with [1- (S) -tert-butoxycarbonylaminoethyl] -1-pyrrolidinyl group, and a salt thereof.
［１−（Ｓ）−第三級ブトキシカルボニルアミノプロピ
ル］−１−ピロリジニル基で置換されたキノロンカルボ
ン酸誘導体である請求項（１）に記載の化合物及びその
塩5. The quinoline skeleton in which the position corresponding to the 7-position is 3- (R)-
The compound according to claim 1, which is a quinolonecarboxylic acid derivative substituted with [1- (S) -tert-butoxycarbonylaminopropyl] -1-pyrrolidinyl group, and a salt thereof.
して含有する抗菌剤6. An antibacterial agent comprising the compound according to claim 1 as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1-123366 | 1989-05-17 | ||
| JP12336689 | 1989-05-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0372476A JPH0372476A (en) | 1991-03-27 |
| JP2919910B2 true JP2919910B2 (en) | 1999-07-19 |
Family
ID=14858809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2124640A Expired - Fee Related JP2919910B2 (en) | 1989-05-17 | 1990-05-15 | Optically active quinolone carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2919910B2 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5258528A (en) * | 1990-11-30 | 1993-11-02 | Warner-Lambert Company | Individual stereoisomers of pyrrolidine methanamines substituted on the ring nitrogen by a 1-phenylethyl group |
| EP0550016A1 (en) * | 1991-12-31 | 1993-07-07 | Korea Research Institute Of Chemical Technology | Novel quinolone carboxylic acid derivatives and processes for preparing same |
| WO1994014794A1 (en) * | 1992-12-28 | 1994-07-07 | Yoshitomi Pharmaceutical Industries, Ltd. | 8-methoxyquinolonecarboxylic acid derivative |
| CA2152828A1 (en) * | 1993-03-16 | 1994-07-07 | Shin-Ichi Uesato | 8-methoxy-quinolonecarboxylic acid derivatives |
| KR960702437A (en) * | 1993-05-06 | 1996-04-27 | 로렌스 티. 웰츠 | Optically active 3- (1- (alkylamino)) alkyl pyrrolidine (OPTICALLY ACTIVE 3- (1-ALKYLAMINO) ALKYL PYRROLIDINES |
| US6140510A (en) * | 1993-05-06 | 2000-10-31 | Pharmacia & Upjohn Company | Optically active 3-(1-(carbamoyl))alkyl-2-oxo-pyrrolidines and optically active 3-(1-(alkylamido))alkyl-2-oxo-pyrrolidines |
| US7186855B2 (en) | 2001-06-11 | 2007-03-06 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
-
1990
- 1990-05-15 JP JP2124640A patent/JP2919910B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JPH0372476A (en) | 1991-03-27 |
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