JPS6219432B2 - - Google Patents
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- Publication number
- JPS6219432B2 JPS6219432B2 JP54167671A JP16767179A JPS6219432B2 JP S6219432 B2 JPS6219432 B2 JP S6219432B2 JP 54167671 A JP54167671 A JP 54167671A JP 16767179 A JP16767179 A JP 16767179A JP S6219432 B2 JPS6219432 B2 JP S6219432B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- methyl
- carboxylic acid
- compound represented
- mmol
- 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
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- -1 7-methoxycephem compound Chemical class 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 9
- 239000004327 boric acid Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 150000003952 β-lactams Chemical class 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000013076 target substance Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- YADSGOSSYOOKMP-UHFFFAOYSA-N dioxolead Chemical compound O=[Pb]=O YADSGOSSYOOKMP-UHFFFAOYSA-N 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- GYQRIAVRKLRQKP-UHFFFAOYSA-N methyl 2-chloro-3-oxobutanoate Chemical compound COC(=O)C(Cl)C(C)=O GYQRIAVRKLRQKP-UHFFFAOYSA-N 0.000 description 2
- NDTWZHURUDSPQV-UHFFFAOYSA-N methyl 2-methyl-3-oxobutanoate Chemical compound COC(=O)C(C)C(C)=O NDTWZHURUDSPQV-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YEVAUDUCLFERSB-ULUSZKPHSA-N (6r)-4-methoxy-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class C1=CC(OC)S[C@@H]2CC(=O)N21 YEVAUDUCLFERSB-ULUSZKPHSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical group CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 101000933374 Gallus gallus Brain-specific homeobox/POU domain protein 3 Proteins 0.000 description 1
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- UAZSJWADJKHHSJ-CYBMUJFWSA-N benzyl (6R)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(C1=CC=CC=C1)OC(=O)C1=CCS[C@H]2N1C(C2)=O UAZSJWADJKHHSJ-CYBMUJFWSA-N 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- KFCUPNHUPHDVJC-UHFFFAOYSA-N bromine azide Chemical compound BrN=[N+]=[N-] KFCUPNHUPHDVJC-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- YXLVLOWNJCOOAU-UHFFFAOYSA-N methyl 2-ethyl-3-oxobutanoate Chemical compound CCC(C(C)=O)C(=O)OC YXLVLOWNJCOOAU-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】
本発明は７−メトキシセフエム化合物の合成方
法に関し、更に詳細には、式（）
（式中、R1は低級アルキル基を表わし、R2及びR3
はカルボン酸保護基を表わし、Ｙはハロゲン原子
又は低級アルキル基を表わし、Ｚは有機又は無機
残基を表わす。）で表わされる７−メトキシセフ
エム化合物の合成方法に関する。
式（）で表わされる７−メトキシセフエム化
合物は、β−ラクタメースに強い抵抗を有する７
−メトキシセフエム系化合物の合成用中間体とし
て有用な化合物である。
従来、セフエム化合物の７位にメトキシ基を導
入する方法としては、
(a) ７−アミノセフエム化合物をジアゾ化した後
BrN3を作用せしめ、７−アチド−７−ブロモ
セフエム化合物とし、次いでこれにメタノール
を作用させる方法〔Ｊ、Am、Chem、Soc、94
1408（1972）〕。
(b) ７−ベンジリデンアミノセフエム化合物を−
78℃でフエニルリチウムと反応せしめ、次いで
Ｎ−ブロモスクシンイミドを作用せしめて７−
ブロモ体とし、これに酸化銀の存在下でメタノ
ールを作用させる方法〔Tetrahedron
Lett.3505（1973）〕。
(c) ７−（３・５−ジ−ｔ−ブチル−４−ヒドロ
キシベンジリデン）アミノセフエム化合物に二
酸化鉛を作用させ、次いでメタノールを作用さ
せる方法〔Tetrahedron Lett.2705（1975）〕。
(d) ７−スルフエニルアミノセフエム化合物に二
酸化マンガン或はＮ−クロロコハク酸イミドと
塩基を作用せしめて７−スルフエニルイミノセ
フエム化合物とし、次いでこれに−78℃に於て
メトキシリチウムを作用させるか或は室温でパ
ラトルエンスルホン酸水和物の存在下でメタノ
ールを作用させる方法〔特開昭52−122390〕。
等が知られている。
本発明は、これらの従来方法とは全く異なる新
規かつ有利な７位メトキシ化方法を提供するので
ある。
本発明は式（）
（式中、R1、R2、R3、Ｙ及びＺは式（）のそれ
と同じ意味を表わす。）で表わされるセフエム化
合物を式（）
（式中、R4は低級アルキル基を表わし、ｎは０か
ら３までの数を表わし、Ｍはアルカリ金属を表わ
し、Ｘはハロゲン原子を表わす。）で表わされる
化合物とホウ酸の存在下でメタノールと反応させ
ることよりなる式（）で表わされる７−メトキ
シセフエム化合物の合成方法である。
以下に本発明を更に詳細に説明する。
式（）で表わされるセフエム化合物として
は、具体的には、R1としてはメチル又はエチル
等の低級アルキル基、特にメチル基が挙げられ
る。R2のカルボン酸保護基としては、メチル、
エチル、（ｎ−、iso−）プロピル、（ｎ−、iso
−、sec−、ｔ−）ブチル、１・１−ジメチルプ
ロピル、ネオペンチル、メトキシメチル、２・
２・２−トリクロロエチル及びメトキシエトキシ
メチル等のアルキル基、ベンジル、Ｐ−メトキシ
ベンジル、Ｐ−ニトロベンジル及びベンズヒドリ
ル等のアリールアルキル基が挙げられる。R3の
カルボン酸保護基としては、メチル、ｔ−ブチ
ル、ベンジル、Ｐ−メトキシベンジル、Ｐ−ニト
ロベンジル、ベンズヒドリル、メトキシメチル、
２・２・２−トリクロロエチル、トリメチルシリ
ル、メトキシエトキシメチル及びフエナシル等が
挙げられる。Ｙとしては、塩素、臭素等のハロゲ
ン原子又はメチル、エチル、（ｎ−、iso−）プロ
ピル及び（ｎ−、iso−、ｔ−）ブチル等の低級
アルキル基が挙げられる。Ｚとしては、水素原
子、アセトキシ、カルバモイルオキシ、複素環チ
オ、例えば、１−メチル−1H−テトラゾール−
５−イルチオ、１・３・４−チアジアゾール−２
−イルチオ等が挙げられる。
これらの化合物は以下の方法、即ち式（）の
化合物と式（）の化合物を反応させる方法、に
より容易に製造することができる。
（式中、R1、R2、R3、Ｙ及びＺは前記と同じ意味
を表わす。）
式（）で表わされる化合物としては、クロラ
ミンＴ、クロラミンＢ、クロラミンＸ等が挙げら
れる。
本発明は通常不活性溶媒中で反応が行われる。
具体的には、ジクロロメタン、クロロホルム、酢
酸エチル等がよく用いられる。また、反応原料で
あるメタノールをそのまま溶媒として用いること
も出来る。
本発明においては式（）で表わされるセフエ
ム化合物１モルに対し式（）で表わされる化合
物を１〜2.5モル程度、通常１〜1.5モル使用す
る。
また、本発明はホウ酸がなくても反応が進行す
るため、ホウ酸は必ずしも必要でないが、通常式
（）で表わされる化合物１モルに対し0.5〜３モ
ル程度のホウ酸を用いた方が反応がスムーズに進
行する。反応は０〜40℃、通常室温下で行われ
る。
反応終了後、目的物である式（）で表わされ
る７−メトキシセフエム化合物を反応混合物より
分離・精製するには何等格別の方法を用いる必要
はなく、かゝる目的のために通常用いられる周知
の手段、例えば、溶媒留去、溶媒抽出、洗浄、結
晶化、カラムクロマトグラフイー等により容易に
目的を達成することができる。
本発明によれば、式（）で表わされるセフエ
ム化合物より式（）で表わされる７−メトキシ
セフエム化合物を室温下で極めて容易にしかも１
工程で合成することができる。
以下に本発明の参考例及び実施例を示し本発明
を更に詳細に説明する。
参考例 １
３−メチル−７−（３−メトキシ−１−メチル
−２−クロロ−３−オキソ−１−プロペニル）
アミノ−３−セフエム−４−カルボン酸ベンジ
ルエステルの製造
７−アミノ−３−メチル−３−セフエム−４−
カルボン酸ベンジルエステル6.00ｇ（19.7ミリモ
ル）をジクロロメタン40mlに溶かし２−クロロア
セト酢酸メチル6.00ｇ（38.3ミリモル）を加え室
温にて３時間撹拌する。ジクロロメタンを減圧下
留去し、残査にメタノール40mlを加え析出する結
晶をろ取し、酢酸エチルとメタノールの混液で再
結晶すると白色結晶5.44ｇ（収率63.3％、m.
p.137.5〜138℃）を得る。
IRνＫＢｒ ｎａｘcm−１
1770（β−ラクタム）、1720（Ｃ＝Ｏ）、1605（Ｃ
＝Ｃ）、1270、1240（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
2.14（3H、ｓ、−CH3）、2.20（3H、ｓ、−CH3）
3.19、3.41（2H、ABq、Ｊ＝18Hz、２位Ｈ）、
3.71（3H、ｓ、−COOCH3）
4.95（1H、ｄ、６位Ｈ、Ｊ＝4.5Hz）、5.14（1H、
ｑ、７位Ｈ、Ｊ＝4.5Hz、Ｊ＝８Hz）
5.20（2H、ｓ、【式】）、7.34（5H、
ｓ、【式】）
9.55（1H、ｄ、−NH−、Ｊ＝８Hz）
参考例 ２
３−アセトキシメチル−７−（３−メトキシ−
１−メチル−２−クロロ−３−オキソ−１−プ
ロペニル）アミノ−３−セフエム−４−カルボ
ン酸ｔ−ブチルエステルの製造
７−アミノ−３−アセトキシメチル−３−セフ
エム−４−カルボン酸ｔ−ブチルエステル3.85ｇ
（11.7ミリモル）をジクロロメタン３mlに溶か
し、２−クロロアセト酢酸メチル1.78ｇ（11.8ミ
リモル）を加え室温にて１夜撹拌する。ジクロロ
メタンを減圧下留去し、残査をシリカゲル250ｇ
のカラムを用いベンゼンと酢酸エチルの混液
（２：1V／Ｖ）でカラムクロマトグラフイーを行
い精製するとカラメル状物質3.70ｇ（68.5％）を
得る。
IRνＫＢｒ ｎａｘcm−１
1780（β−ラクタム）、1750（Ｃ＝Ｏ）、1720（Ｃ
＝Ｏ）、1600（Ｃ＝Ｃ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
1.51（9H、ｓ、−Ｃ（CH3）3）、2.07（3H、ｓ、−
CH3）
2.22（3H、ｓ、−CH3）、3.38、3.56（2H、ABq、
Ｊ＝19Hz、２位Ｈ）
3.74（3H、ｓ、−COOCH3）、4.68、5.13（2H、
ABq、Ｊ＝13Hz、−CH2 OAc）
5.00（1H、ｄ、Ｊ＝５Hz、６位Ｈ）、5.33（1H、
ｑ、Ｊ＝８Hz、Ｊ＝５Hz、７位Ｈ）
9.54（1H、ｄ、Ｊ＝８Hz、−NH−）
参考例 ３
３−メチル−７−（１・２−ジメチル−３−メ
トキシ−３−オキソ−１−プロペニル）アミノ
−３−セフエム−４−カルボン酸ベンジルエス
テルの製造
７−アミノ−３−メチル−３−セフエム−４−
カルボン酸ベンジルエステル2.00ｇ（6.57ミリモ
ル）に２−メチルアセト酢酸メチル5.00ｇを加え
室温で一夜撹拌後50℃で３時間撹拌する。２−メ
チルアセト酢酸メチルを50℃において減圧下留去
し、残査にエタノール30mlを加えて析出する結晶
（2.25ｇ）をメタノールより再結晶すると白色結
晶1.67ｇ（60.9％、m.p.118.5〜119.5℃）を得
る。
IRνＫＢｒ ｎａｘcm−１
1770（β−ラクタム）、1720（Ｃ＝Ｏ）、1600（Ｃ
＝Ｃ）、1255、1240（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
1.77（3H、ｓ、−CH3）、1.96（3H、ｓ、−CH3）、
2.01（3H、ｓ、−CH3）
3.18、3.39（2H、ABq、Ｊ＝18Hz、２位Ｈ）、
3.63（3H、ｓ、−COOCH3）
4.92（1H、ｄ、Ｊ＝４Hz、６位Ｈ）、5.19（1H、
ｑ、Ｊ＝４Hz、Ｊ＝８Hz、７位Ｈ）
5.22（2H、ｓ、【式】）、7.32（5H、
ｓ、【式】）
9.66（1H、ｄ、Ｊ＝８Hz、−NH−）
参考例 ４
３−メチル−７−（２−エチル−３−メトキシ
−１−メチル−３−オキソ−１−プロペニル）
アミノ−３−セフエム−４−カルボン酸ベンジ
ルエステルの製造
７−アミノ−３−メチル−３−セフエム−４−
カルボン酸ベンジルエステル3.00ｇ（9.86ミリモ
ル）に２−エチルアセト酢酸メチル5.0mlを加え
室温で３日、次いで50℃で５時間撹拌する。反応
混合物にエタノール20mlを加え析出する結晶をろ
取し、メタノール40mlより再結晶すると目的物質
2.01ｇ（m.p.113.0〜115.0℃、収率47.4％）を得
る。
IRνＫＢｒ ｎａｘcm−１
1780（β−ラクタム）、1730（Ｃ＝Ｏ）、1605（Ｃ
＝Ｃ）、1250、1240（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
0.96（3H、ｔ、Ｊ＝７Hz、−CH3 CH3 ）、2.01
（3H、ｓ、−CH3）
2.13（2H、ｑ、Ｊ＝７Hz、−CH2 CH3）、2.14
（3H、ｓ、−CH3）
3.22、3.42（2H、ABq、Ｊ＝18Hz、２位Ｈ）、
3.66（3H、ｓ、−COOCH3）
4.94（1H、ｄ、Ｊ＝４Hz、６位Ｈ）、5.24（1H、
ｑ、Ｊ＝４Hz、Ｊ＝９Hz、７位Ｈ）
5.24（2H、ｓ、【式】）、7.34（5H、
ｓ、【式】）
9.72（1H、ｄ、Ｊ＝９Hz、−NH−）
実施例 １
３−メチル−７−（３−メトキシ−１−メチル
−２−クロロ−３−オキソ−１−プロペニル）
アミノ−７−メトキシ−３−セフエム−４−カ
ルボン酸ベンジルエステルの製造
参考例１で得た３−メチル−７−（３−メトキ
シ−１−メチル−２−クロロ−３−オキソ−１−
プロペニル）アミノ−３−セフエム−４−カルボ
ン酸ベンジルエステル412.2mg（0.944ミリモル）
をジクロロメタン５ml及び無水メタノール55mlに
溶かし、クロラミンＴ（無水）296mg（1.30ミリ
モル）とホウ酸86.5mg（1.40ミリモル）を加え一
夜室温で撹拌する。溶媒を減圧下留去し、残査を
酢酸エチル20mlに溶かし、希NaHCO3水で洗い、
水洗、乾燥後、酢酸エチルを減圧下留去し、残査
にベンゼン15mlを加え不溶分をろ去し、ろ液より
ベンセンを減圧下留去するとカラメル状物質570
mgを得る。これをシリカゲル50ｇのカラムを用
い、ｎ−ヘキサンと酢酸エチルの混液（４：
1V／Ｖ）を展開、溶出液としてカラムクロマト
グラフイーを行い精製するとカラメル状の目的物
質262.3mg（59.6％）を得る。これはエタノール
で再結晶すると白色結晶となりm.p.129.5〜131.5
℃を示す。
IRνＫＢｒ ｎａｘcm−１
1780（β−ラクタム）、1730（Ｃ＝Ｏ）、1600（Ｃ
＝Ｃ）、1270、1230（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
2.25（3H、ｓ、−CH3）、2.36（3H、ｓ、−CH3）
3.13（2H、ｓ、２位Ｈ）、3.40（3H、ｓ、−
OCH3）
3.77（3H、ｓ、−COOCH3）、4.92（1H、ｓ、６
位Ｈ）
5.25（2H、ｓ、【式】）、7.35（5H、
ｓ、【式】）
9.90（1H、ｓ、−NH−）
実施例 ２
３−アセトキシメチル−７−（３−メトキシ−
１−メチル−２−クロロ−３−オキソ−１−プ
ロペニル）アミノ−７−メトキシ−３−セフエ
ム−４−カルボン酸ｔ−ブチルエステルの製造
参考例２で得た３−アセトキシメチル−７−
（３−メトキシ−１−メチル−２−クロロ−３−
オキソ−１−プロペニル）アミノ−３−セフエム
−４−カルボン酸ｔ−ブチルエステル460.9mg
（1.00ミリモル）を無水メタノール50mlに溶か
し、クロラミンＴ（無水）314.2mg（1.38ミリモ
ル）とホウ酸93.8mg（1.52ミリモル）を加え室温
にて５時間撹拌する。溶媒を減圧下留去し、残査
を酢酸エチル15mlに溶かし、希NaHCO3水で洗
い、水洗、乾燥後、酢酸エチルを減圧下留去し、
残査にベンゼン10mlを加え不溶分をろ去し、ろ液
よりベンゼンを減圧下留去するとカラメル状物質
600mgを得る。これをシリカゲル55ｇのカラムを
用いｎ−ヘキサンと酢酸エチルの混液（２：
1V／Ｖ）を展開、溶出液としてカラムクロマト
グラフイーを行い精製するとカラメル状の目的物
質200mg（40.7％）を得る。
IRνＫＢｒ ｎａｘcm-1
1780（β−ラクタム）、1740（Ｃ＝Ｏ）、1600（Ｃ
＝Ｃ）、1260（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
1.57（9H、ｓ、−Ｃ（CH3）3）、2.10（3H、ｓ、−
CH3）
2.34（3H、ｓ、−CH3）、3.29、3.47（2H、ABq、
Ｊ＝18Hz、２位Ｈ）
3.45（3H、ｓ、−OCH3）、3.77（3H、ｓ、−
COOCH3）
4.91（1H、ｓ、６位Ｈ）、4.83、5.06（2H、
ABq、Ｊ＝14Hz、−CH2 OAc）
9.87（1H、ｓ、−NH−）
実施例 ３
３−メチル−７−（１・２−ジメチル−３−メ
トキシ−３−オキソ−１−プロペニル）アミノ
−７−メトキシ−３−セフエム−４−カルボン
酸ベンジルエステルの製造
参考例３で得た３−メチル−７−（１・２−ジ
メチル−３−メトキシ−３−オキソ−１−プロペ
ニル）アミノ−３−セフエム−４−カルボン酸ベ
ンジルエステル1.00ｇ（2.40ミリモル）をジクロ
ロメタン６ml及びメタノール60mlに溶かし、クロ
ラミンＴ（無水）655.9mg（2.88ミリモル）とホ
ウ酸195.8mg（3.17ミリモル）を加え、室温で３
日間撹拌する。溶媒を減圧下留去し、残査を酢酸
エチル30mlに溶解し、水洗、乾燥後、溶媒を減圧
下留去し、残査をシリカゲル50ｇのカラムを用い
ｎ−ヘキサンと酢酸エチルの混液（２：1V／
Ｖ）を展開、溶出液としてカラムクロマトグラフ
イーを行い精製するとカラメル状の目的物質
445.0mg（41.5％）を得る。
IRνＫＢｒ ｎａｘcm−１
1780（β−ラクタム）、1730（Ｃ＝Ｏ）、1600（Ｃ
＝Ｃ）、1255、1230（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
1.81（3H、ｓ、−CH3）、2.16（3H、ｓ、−CH3）
2.23（3H、ｓ、−CH3）、3.14（2H、ｓ、２位
Ｈ）
3.38（3H、ｓ、−OCH3）、3.70（3H、ｓ、−
COOCH3）
4.91（1H、ｓ、６位Ｈ）、5.27（2H、ｓ、
【式】）
7.36（5H、ｓ、【式】）
10.10（1H、ｓ、−NH−）
実施例 ４
３−メチル−７−（２−エチル−３−メトキシ
−１−メチル−３−オキソ−１−プロペニル）
アミノ−７−メトキシ−３−セフエム−４−カ
ルボン酸ベンジルエステルの製造
参考例４で得た３−メチル−７−（２−エチル
−３−メトキシ−１−メチル−３−オキソ−１−
プロペニル）アミノ−３−セフエム−４−カルボ
ン酸ベンジルエステル430.0mg（1.00ミリモル）
をジクロロメタン５ml及びメタノール20mlに溶か
し、クロラミンＴ（無水）250.0mg（1.10ミリモ
ル）及びホウ酸68.0mg（1.10ミリモル）を加え２
日間室温で撹拌する。溶媒を減圧下留去し、残査
をシリカゲル30ｇのカラムを用いｎ−ヘキサンと
酢酸エチルの混液（３：1V／Ｖ）の混液を展
開、溶出液としてカラムクロマトグラフイーを行
い精製すると目的物質109.1mg（23.7％）を得
る。
IRνＫＢｒ ｎａｘcm−１
1780（β−ラクタム）、1730（Ｃ＝Ｏ）、1600（Ｃ
＝Ｃ）、1230（Ｃ−Ｏ）
NMRppm〔δ〕（CDCl3、60MHz、TMS）
0.97（3H、ｔ、Ｊ＝７Hz、−CH2 CH3 ）、2.21
（6H、ｓ、−CH3及び−CH3）
2.27（2H、ｑ、Ｊ＝７Hz、−CH2 CH3）、3.14
（2H、ｓ、２位Ｈ）
3.38（3H、ｓ、−OCH3）、3.69（3H、ｓ、−
COOCH3）
4.91（1H、ｓ、６位Ｈ）、5.26（2H、ｓ、
【式】）
7.36（5H、ｓ、【式】）
10.10（1H、ｓ、−NH−） DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for synthesizing a 7-methoxycepheme compound, more specifically, (In the formula, R 1 represents a lower alkyl group, R 2 and R 3
represents a carboxylic acid protecting group, Y represents a halogen atom or a lower alkyl group, and Z represents an organic or inorganic residue. ) The present invention relates to a method for synthesizing a 7-methoxycephem compound represented by: The 7-methoxycepheme compound represented by the formula () has strong resistance to β-lactamase.
- It is a compound useful as an intermediate for the synthesis of methoxycephem compounds. Conventionally, methods for introducing a methoxy group into the 7-position of a cefem compound include (a) after diazotizing a 7-amino cefem compound;
A method of reacting with BrN3 to form a 7-acydo-7-bromosephem compound, and then reacting with methanol [J, Am, Chem, Soc, 94
1408 (1972)]. (b) 7-benzylidene aminocephem compound -
7-
A method in which methanol is applied to the bromo compound in the presence of silver oxide [Tetrahedron
Lett.3505 (1973)]. (c) A method in which a 7-(3,5-di-t-butyl-4-hydroxybenzylidene) aminocephem compound is reacted with lead dioxide and then with methanol [Tetrahedron Lett. 2705 (1975)]. (d) A 7-sulfenyliminocephem compound is reacted with manganese dioxide or N-chlorosuccinimide and a base to form a 7-sulfenyliminocephem compound, which is then treated with methoxylithium at -78°C. or methanol in the presence of para-toluenesulfonic acid hydrate at room temperature [JP-A-52-122390]. etc. are known. The present invention provides a novel and advantageous method for 7-position methoxylation that is completely different from these conventional methods. The present invention is based on the formula () (In the formula, R 1 , R 2 , R 3 , Y and Z have the same meanings as in the formula ().) A cefem compound represented by the formula () (In the formula, R 4 represents a lower alkyl group, n represents a number from 0 to 3, M represents an alkali metal, and X represents a halogen atom) in the presence of a compound represented by the formula and boric acid. This is a method for synthesizing a 7-methoxycephem compound represented by the formula (), which comprises reacting with methanol. The present invention will be explained in more detail below. Specifically, in the cefem compound represented by formula (), R 1 may be a lower alkyl group such as methyl or ethyl, particularly a methyl group. Carboxylic acid protecting groups for R2 include methyl,
Ethyl, (n-, iso-)propyl, (n-, iso-)
-, sec-, t-)butyl, 1,1-dimethylpropyl, neopentyl, methoxymethyl, 2.
Examples include alkyl groups such as 2,2-trichloroethyl and methoxyethoxymethyl, and arylalkyl groups such as benzyl, P-methoxybenzyl, P-nitrobenzyl and benzhydryl. Carboxylic acid protecting groups for R 3 include methyl, t-butyl, benzyl, P-methoxybenzyl, P-nitrobenzyl, benzhydryl, methoxymethyl,
Examples include 2,2,2-trichloroethyl, trimethylsilyl, methoxyethoxymethyl and phenacyl. Examples of Y include halogen atoms such as chlorine and bromine, or lower alkyl groups such as methyl, ethyl, (n-, iso-)propyl and (n-, iso-, t-)butyl. Z is a hydrogen atom, acetoxy, carbamoyloxy, heterocyclic thio, for example, 1-methyl-1H-tetrazole-
5-ylthio, 1,3,4-thiadiazole-2
-ylthio and the like. These compounds can be easily produced by the following method, ie, a method in which a compound of formula () is reacted with a compound of formula (). (In the formula, R 1 , R 2 , R 3 , Y and Z have the same meanings as above.) Examples of the compound represented by the formula () include chloramine T, chloramine B, and chloramine X. In the present invention, the reaction is usually carried out in an inert solvent.
Specifically, dichloromethane, chloroform, ethyl acetate, etc. are often used. Furthermore, methanol, which is a reaction raw material, can be used as it is as a solvent. In the present invention, the compound represented by formula () is used in an amount of about 1 to 2.5 moles, usually 1 to 1.5 moles, per 1 mole of the cefem compound represented by formula (). In addition, in the present invention, the reaction proceeds even without boric acid, so boric acid is not necessarily necessary, but it is usually better to use about 0.5 to 3 moles of boric acid per mole of the compound represented by formula (). The reaction proceeds smoothly. The reaction is carried out at 0 to 40°C, usually at room temperature. After completion of the reaction, there is no need to use any special method to separate and purify the target compound, 7-methoxycepheme compound represented by formula (), from the reaction mixture, and any method commonly used for such purpose may be used. The purpose can be easily achieved by well-known means such as solvent distillation, solvent extraction, washing, crystallization, column chromatography, etc. According to the present invention, the 7-methoxycephem compound represented by the formula () can be easily converted from the cefem compound represented by the formula () at room temperature, and
It can be synthesized in a process. The present invention will be explained in further detail by showing reference examples and examples of the present invention below. Reference example 1 3-methyl-7-(3-methoxy-1-methyl-2-chloro-3-oxo-1-propenyl)
Production of amino-3-cephem-4-carboxylic acid benzyl ester 7-amino-3-methyl-3-cepheme-4-
6.00 g (19.7 mmol) of benzyl carboxylic acid ester was dissolved in 40 ml of dichloromethane, 6.00 g (38.3 mmol) of methyl 2-chloroacetoacetate was added, and the mixture was stirred at room temperature for 3 hours. Dichloromethane was distilled off under reduced pressure, 40 ml of methanol was added to the residue, the precipitated crystals were collected by filtration, and recrystallized from a mixture of ethyl acetate and methanol, resulting in 5.44 g of white crystals (yield 63.3%, m.
p.137.5-138℃). IRν KBr nax cm −1 1770 (β-lactam), 1720 (C=O), 1605 (C
=C), 1270, 1240 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 2.14 (3H, s, -CH3 ), 2.20 (3H, s, -CH3 ) 3.19, 3.41 (2H , ABq, J=18Hz, 2nd place H),
3.71 (3H, s, -COOCH 3 ) 4.95 (1H, d, 6th H, J = 4.5Hz), 5.14 (1H,
q, 7th H, J = 4.5Hz, J = 8Hz) 5.20 (2H, s, [formula]), 7.34 (5H, s, [formula]) 9.55 (1H, d, -NH-, J = 8Hz) Reference example 2 3-acetoxymethyl-7-(3-methoxy-
Production of 1-methyl-2-chloro-3-oxo-1-propenyl)amino-3-cephem-4-carboxylic acid t-butyl ester 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid t -Butyl ester 3.85g
(11.7 mmol) was dissolved in 3 ml of dichloromethane, 1.78 g (11.8 mmol) of methyl 2-chloroacetoacetate was added, and the mixture was stirred overnight at room temperature. Dichloromethane was distilled off under reduced pressure, and the residue was added to 250 g of silica gel.
Purify the product by column chromatography using a mixed solution of benzene and ethyl acetate (2:1 V/V) to obtain 3.70 g (68.5%) of a caramel-like substance. IRν KBr nax cm −1 1780 (β-lactam), 1750 (C=O), 1720 (C
=O), 1600 (C=C) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.51 (9H, s, -C( CH3 ) 3 ), 2.07 (3H, s, -
CH 3 ) 2.22 (3H, s, -CH 3 ), 3.38, 3.56 (2H, ABq,
J = 19Hz, 2nd place H) 3.74 (3H, s, -COOCH 3 ), 4.68, 5.13 (2H,
ABq, J = 13Hz, - CH 2 OAc) 5.00 (1H, d, J = 5Hz, 6th H), 5.33 (1H,
q, J=8Hz, J=5Hz, 7th position H) 9.54 (1H, d, J=8Hz, -NH-) Reference example 3 3-Methyl-7-(1,2-dimethyl-3-methoxy-3- Production of oxo-1-propenyl)amino-3-cephem-4-carboxylic acid benzyl ester 7-amino-3-methyl-3-cepheme-4-
5.00 g of methyl 2-methylacetoacetate was added to 2.00 g (6.57 mmol) of carboxylic acid benzyl ester, and the mixture was stirred at room temperature overnight and then at 50° C. for 3 hours. Methyl 2-methylacetoacetate was distilled off under reduced pressure at 50°C, 30ml of ethanol was added to the residue, and the precipitated crystals (2.25g) were recrystallized from methanol to give 1.67g of white crystals (60.9%, mp 118.5-119.5°C). ). IRν KBr nax cm −1 1770 (β-lactam), 1720 (C=O), 1600 (C
=C), 1255, 1240 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.77 (3H, s, -CH3 ), 1.96 (3H, s, -CH3 ),
2.01 (3H, s, -CH 3 ) 3.18, 3.39 (2H, ABq, J=18Hz, 2nd H),
3.63 (3H, s, -COOCH 3 ) 4.92 (1H, d, J=4Hz, 6th H), 5.19 (1H,
q, J=4Hz, J=8Hz, 7th H) 5.22 (2H, s, [Formula]), 7.32 (5H, s, [Formula]) 9.66 (1H, d, J=8Hz, -NH-) Reference Example 4 3-Methyl-7-(2-ethyl-3-methoxy-1-methyl-3-oxo-1-propenyl)
Production of amino-3-cephem-4-carboxylic acid benzyl ester 7-amino-3-methyl-3-cepheme-4-
5.0 ml of methyl 2-ethylacetoacetate was added to 3.00 g (9.86 mmol) of benzyl carboxylic acid ester and stirred at room temperature for 3 days and then at 50°C for 5 hours. Add 20ml of ethanol to the reaction mixture, filter the precipitated crystals, and recrystallize from 40ml of methanol to obtain the target substance.
Obtain 2.01 g (mp 113.0-115.0°C, yield 47.4%). IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1605 (C
=C), 1250, 1240 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 0.96 (3H, t, J=7Hz, -CH3CH3 ) , 2.01
(3H, s, −CH 3 ) 2.13 (2H, q, J=7Hz, −CH 2 CH 3 ), 2.14
(3H, s, -CH 3 ) 3.22, 3.42 (2H, ABq, J=18Hz, 2nd H),
3.66 (3H, s, -COOCH 3 ) 4.94 (1H, d, J=4Hz, 6th H), 5.24 (1H,
q, J=4Hz, J=9Hz, 7th H) 5.24 (2H, s, [Formula]), 7.34 (5H, s, [Formula]) 9.72 (1H, d, J=9Hz, -NH-) Implementation Example 1 3-Methyl-7-(3-methoxy-1-methyl-2-chloro-3-oxo-1-propenyl)
Production of amino-7-methoxy-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(3-methoxy-1-methyl-2-chloro-3-oxo-1- obtained in Reference Example 1)
propenyl)amino-3-cephem-4-carboxylic acid benzyl ester 412.2 mg (0.944 mmol)
was dissolved in 5 ml of dichloromethane and 55 ml of anhydrous methanol, 296 mg (1.30 mmol) of chloramine T (anhydrous) and 86.5 mg (1.40 mmol) of boric acid were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, the residue was dissolved in 20 ml of ethyl acetate, washed with dilute NaHCO 3 water,
After washing with water and drying, ethyl acetate was distilled off under reduced pressure, 15 ml of benzene was added to the residue, the insoluble matter was removed by filtration, and the benzene was distilled off from the filtrate under reduced pressure, resulting in a caramel-like substance.
Get mg. Using a column containing 50 g of silica gel, a mixture of n-hexane and ethyl acetate (4:
1V/V) and purified by column chromatography using the eluate to obtain 262.3 mg (59.6%) of the target substance in caramel form. When this is recrystallized with ethanol, it becomes a white crystal with mp129.5~131.5
Indicates °C. IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1600 (C
=C), 1270, 1230 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 2.25 (3H, s, -CH3 ), 2.36 (3H, s, -CH3 ) 3.13 (2H, s , 2nd H), 3.40 (3H, s, -
OCH 3 ) 3.77 (3H, s, -COOCH 3 ), 4.92 (1H, s, 6
Position H) 5.25 (2H, s, [Formula]), 7.35 (5H, s, [Formula]) 9.90 (1H, s, -NH-) Example 2 3-acetoxymethyl-7-(3-methoxy-
Production of 1-methyl-2-chloro-3-oxo-1-propenyl)amino-7-methoxy-3-cephem-4-carboxylic acid t-butyl ester 3-acetoxymethyl-7- obtained in Reference Example 2
(3-methoxy-1-methyl-2-chloro-3-
oxo-1-propenyl)amino-3-cephem-4-carboxylic acid t-butyl ester 460.9mg
(1.00 mmol) was dissolved in 50 ml of anhydrous methanol, 314.2 mg (1.38 mmol) of chloramine T (anhydrous) and 93.8 mg (1.52 mmol) of boric acid were added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 15 ml of ethyl acetate, washed with diluted NaHCO 3 water, washed with water, dried, and ethyl acetate was distilled off under reduced pressure.
Add 10ml of benzene to the residue, filter out the insoluble matter, and distill off the benzene from the filtrate under reduced pressure to obtain a caramel-like substance.
Get 600mg. A mixture of n-hexane and ethyl acetate (2:
1V/V) was developed and purified by column chromatography using the eluate to obtain 200 mg (40.7%) of the caramel-like target substance. IRν KBr nax cm -1 1780 (β-lactam), 1740 (C=O), 1600 (C
=C), 1260 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.57 (9H, s, -C( CH3 ) 3 ), 2.10 (3H, s, -
CH 3 ) 2.34 (3H, s, -CH 3 ), 3.29, 3.47 (2H, ABq,
J = 18Hz, 2nd H) 3.45 (3H, s, -OCH 3 ), 3.77 (3H, s, -
COOCH 3 ) 4.91 (1H, s, 6th H), 4.83, 5.06 (2H,
ABq, J=14Hz, -CH2OAc ) 9.87 (1H, s, -NH-) Example 3 3-Methyl-7-(1,2-dimethyl-3-methoxy-3-oxo-1-propenyl)amino -Production of 7-methoxy-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(1,2-dimethyl-3-methoxy-3-oxo-1-propenyl)amino- obtained in Reference Example 3 Dissolve 1.00 g (2.40 mmol) of 3-cephem-4-carboxylic acid benzyl ester in 6 ml of dichloromethane and 60 ml of methanol, add 655.9 mg (2.88 mmol) of chloramine T (anhydrous) and 195.8 mg (3.17 mmol) of boric acid, and stir at room temperature. 3
Stir for days. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 ml of ethyl acetate, washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was dissolved in a mixture of n-hexane and ethyl acetate (2 :1V/
When V) is developed and purified by column chromatography as the eluate, a caramel-like target substance is obtained.
Obtain 445.0mg (41.5%). IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1600 (C
=C), 1255, 1230 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.81 (3H, s, -CH3 ), 2.16 (3H, s, -CH3 ) 2.23 (3H, s , -CH 3 ), 3.14 (2H, s, 2nd H) 3.38 (3H, s, -OCH 3 ), 3.70 (3H, s, -
COOCH 3 ) 4.91 (1H, s, H at 6th position), 5.27 (2H, s,
[Formula]) 7.36 (5H, s, [Formula]) 10.10 (1H, s, -NH-) Example 4 3-Methyl-7-(2-ethyl-3-methoxy-1-methyl-3-oxo- 1-propenyl)
Production of amino-7-methoxy-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(2-ethyl-3-methoxy-1-methyl-3-oxo-1- obtained in Reference Example 4)
propenyl)amino-3-cephem-4-carboxylic acid benzyl ester 430.0 mg (1.00 mmol)
was dissolved in 5 ml of dichloromethane and 20 ml of methanol, and 250.0 mg (1.10 mmol) of chloramine T (anhydrous) and 68.0 mg (1.10 mmol) of boric acid were added.
Stir at room temperature for days. The solvent was distilled off under reduced pressure, the residue was developed with a mixture of n-hexane and ethyl acetate (3:1 V/V) using a 30 g column of silica gel, and the target substance was purified by column chromatography as the eluent. Obtain 109.1 mg (23.7%). IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1600 (C
=C), 1230 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 0.97 (3H, t, J=7Hz , -CH2CH3 ) , 2.21
(6H, s, -CH3 and -CH3 ) 2.27 (2H, q , J=7Hz, -CH2CH3 ), 3.14
(2H, s, H at 2nd position) 3.38 (3H, s, -OCH 3 ), 3.69 (3H, s, -
COOCH 3 ) 4.91 (1H, s, 6th position H), 5.26 (2H, s,
[Formula]) 7.36 (5H, s, [Formula]) 10.10 (1H, s, -NH-)
Claims (1)
はカルボン酸保護基を表わし、Ｙはハロゲン原子
又は低級アルキル基を表わし、Ｚは有機又は無機
残基を表わす。）で表わされるセフエム化合物を
式（） （式中、R4は低級アルキル基を表わし、ｎは０か
ら３までの数を表わし、Ｍはアルカリ金属を表わ
し、Ｘはハロゲン原子を表わす。）で表わされる
化合物とホウ酸の存在下でメタノールと反応させ
ることを特徴とする式（） （式中、R1、R2、R3、Ｙ及びＺは式（）のそれ
と同じ意味を表わす。）で表わされる７−メトキ
シセフエム化合物の合成方法。[Claims] 1 Formula () (In the formula, R 1 represents a lower alkyl group, R 2 and R 3
represents a carboxylic acid protecting group, Y represents a halogen atom or a lower alkyl group, and Z represents an organic or inorganic residue. ) is a cefem compound represented by the formula () (In the formula, R 4 represents a lower alkyl group, n represents a number from 0 to 3, M represents an alkali metal, and X represents a halogen atom) in the presence of a compound represented by the formula and boric acid. Formula () characterized by reaction with methanol A method for synthesizing a 7-methoxycephem compound represented by the formula (wherein R 1 , R 2 , R 3 , Y and Z have the same meanings as in formula ()).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16767179A JPS5690089A (en) | 1979-12-25 | 1979-12-25 | Synthesis of 7-methoxycephem compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16767179A JPS5690089A (en) | 1979-12-25 | 1979-12-25 | Synthesis of 7-methoxycephem compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5690089A JPS5690089A (en) | 1981-07-21 |
| JPS6219432B2 true JPS6219432B2 (en) | 1987-04-28 |
Family
ID=15854053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16767179A Granted JPS5690089A (en) | 1979-12-25 | 1979-12-25 | Synthesis of 7-methoxycephem compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5690089A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5552542A (en) * | 1995-05-10 | 1996-09-03 | Bristol-Myers Squibb Company | Preparation and use of 7-[(2-carboalkoxy-1-methylethenyl)amino]-3-hydroxymethyl-3-cephem-4-carboxylic acids |
-
1979
- 1979-12-25 JP JP16767179A patent/JPS5690089A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5690089A (en) | 1981-07-21 |
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