JPS6219431B2 - - Google Patents
Info
- Publication number
- JPS6219431B2 JPS6219431B2 JP54164690A JP16469079A JPS6219431B2 JP S6219431 B2 JPS6219431 B2 JP S6219431B2 JP 54164690 A JP54164690 A JP 54164690A JP 16469079 A JP16469079 A JP 16469079A JP S6219431 B2 JPS6219431 B2 JP S6219431B2
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- formula
- mmol
- carboxylic acid
- amino
- 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
Links
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- -1 7-methoxycephem compound Chemical class 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 150000003952 β-lactams Chemical class 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 239000013076 target substance Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 229910021538 borax Inorganic materials 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 235000010339 sodium tetraborate Nutrition 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- 239000004328 sodium tetraborate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical group CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 3
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910004844 Na2B4O7.10H2O Inorganic materials 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
- 235000013736 caramel Nutrition 0.000 description 2
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 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
- 238000001914 filtration Methods 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
- 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
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 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
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- WDRFYIPWHMGQPN-UHFFFAOYSA-N 2-chloroisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Cl)C(=O)C2=C1 WDRFYIPWHMGQPN-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
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-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
- 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
- 229910001730 borate mineral Inorganic materials 0.000 description 1
- 239000010429 borate mineral Substances 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
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling 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
- 239000000706 filtrate Substances 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
- 238000006198 methoxylation reaction Methods 0.000 description 1
- GYQRIAVRKLRQKP-UHFFFAOYSA-N methyl 2-chloro-3-oxobutanoate Chemical compound COC(=O)C(Cl)C(C)=O GYQRIAVRKLRQKP-UHFFFAOYSA-N 0.000 description 1
- NDTWZHURUDSPQV-UHFFFAOYSA-N methyl 2-methyl-3-oxobutanoate Chemical compound COC(=O)C(C)C(C)=O NDTWZHURUDSPQV-UHFFFAOYSA-N 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
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 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
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 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製造方
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、Wは水素原子又は
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製造方法に関する。
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。
一方、C、U、Kim等は7−フエノキシアセト
アミドセフエム化合物にN−クロロスクシンイミ
ドの存在下、メタノールとジクロロメタンの混液
(1:1)を作用させるときは2−メトキシ誘導
体が85%の収率で得られることを報告している
〔Tetrahedon Lett.No.5 409(1978)〕。
本発明者等は、セフエム化合物の7位にメトキ
シ基を導入するべく種々研究を重ねた結果、式
()で表わされるセフエム化合物に、N−ブロ
モスクシンイミドとホウ酸塩の存在下でメタノー
ルを作用させるときは上記C、U、Kim等の報告
に反し、7位にメトキシ基が導入されることを見
出し、本発明を完成した。
即ち、本発明は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ものであ
る。
本発明は式()
(式中、R1、R2、R3、W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N−ハロゲノイミドとホウ酸塩の存在下で
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製造方
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。Wとしては、水素原子又は塩素、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、Z及びWは前記と同じ意味
を表わす。)
更に、式()で表わされる化合物のWが塩素
原子であるものは、式()で表わされる化合物
のWが水素原子であるものに、クロラミンTとホ
ウ酸を作用させることによつても製造できる。
N−ハロゲノイミドとしては、N−クロロスク
シンイミド、N−ブロモスクシンイミド、N−ク
ロロフタルイミド、N−ブロモフタルイミド等の
化合物が挙げられる。
ホウ酸塩としては、ホウ酸ナトリウム、ホウ酸
カリウム、或はホウ酸塩鉱物であるホウ砂等が挙
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N−ハロゲノイミドを1〜
2.5モル程度、通常1〜1.5モル使用する。またホ
ウ酸塩は式()で表わされる化合物1モルに対
し0.5〜10モル程度使用する。例えば、ホウ砂
(Na2B4O7・10H2O)の場合では、0.5〜5モル程
度、通常1〜1.5モル使用する。
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、かか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
工程で製造することができる。
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、残渣にメタノール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、
g、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−メチル−7−(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4.18g(14ミリモ
ル)にアセト酢酸メチル10mlを加え室温で20時間
撹拌する。アセト酢酸メチルを50℃において減圧
下留去し、残渣にエタノール30mlを加えて析出す
る結晶をろ取し、メタノールより再結晶すると白
色結晶4.81g(収率85.4%、m、p、91.5〜92.5
℃)を得る。
IRνKBr naxcm−1
1760(β−ラクタム)、1720(C=O)、1620(C
=C)、1260(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.95(3H、s、−CH3)、2.13(3H、s、−CH3)
3.22、3.44(2H、ABq、J=18Hz、2位H)、
3.61(3H、s、−COOCH3)
4.65(1H、s、【式】)、4.96(1H、d、
6位H、J=4.5Hz)
5.20(1H、q、7位H、J=4.5Hz、J=8Hz)、
5.23(2H、s、【式】)7.33(5H、
s、【式】)、9.10(1H、d、J=8Hz、
−NH−)
参考例 3
3−アセトキシメチル−7−(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1.00g
(3.0ミリモル)にアセト酢酸メチル3gを加え室
温で1夜撹拌する。アセト酢酸メチルを50℃で減
圧下留去するとカラメル状の目的物質1.30g
(100%)を得る。
IRνKBr naxcm−1
1785(β−ラクタム)、1740、1730(C=O)、
1620(C=C)、1260(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.56(9H、s、−C(CH3)3)、1.98(H、s、−
CH3)
2.08(3H、s、−CH3)、3.36(3.55(2H、ABq、
J=18Hz、2位H)
3.62(H、s、−COOCH3)、4.65(1H、s、
【式】)
4.75、5.00(2H、ABq、J=13Hz、−CH2 −
OAc)
4.98(1H、d、J=5Hz、6位H)、3.30(1H、
d、J=5Hz、J=9Hz、7位H)
9.08(1H、d、J=9Hz、−NH−)
参考例 4
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℃におて減圧下留去
し、残渣にエタノール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、6MHz、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 5
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
参考例2で得た3−メチル−7−(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402mg(1.00ミリモル)を無水メタノー
ル13mlに溶かし、クロラミンT(無水)455.3ml
(2.00ミリモル)及びホウ酸136mg(2.20ミリモ
ル)を加え、1.5時間室温で撹拌し、析出した結
晶を氷冷後ろ取すると目的物質234.8mg(53.8
%)を得る。これを酢酸エチルとメタノールの混
液で再結晶するとm、p、137.5〜138℃となる。
参考例 6
3−メチル−7−(3−t−ブトキシ−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2.00g(6.58ミリモ
ル)にアセトン酢酸t−ブチル2.50gを加え室温
で1夜撹拌する。反応混合物にエタノール30mlを
加え析出する結晶をろ取すると目的物質2.77g
(収率94.9%、m、p、165.5〜167.0℃)を得る。
IRνKBr naxcm−1
1785(β−ラクタム)、1740(C=O)、1620(C
=C)、1150(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.45(9H、s、−C(CH3)3)、1.90(H、s、−
CH3)
2.12(3H、s、−CH3)、3.21、3.45(2H、ABq、
J=18Hz、2位H)
4.56(1H、s、
【式】)、4.91(1H、J=4Hz、6位H)
5.21(1H、J=4Hz、J=9Hz、7位H)
5.25(2H、s、【式】)、
7.36(5H、s、【式】)
9.01(1H、d、J=9Hz、−NH−)
参考例 7
3−アセトキシメチル−7−(3−t−ブトキ
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3.28g
(10.0ミリモル)にアセト酢酸−t−ブチルエス
テル1.58g(10.0ミリモル)及びエタノール3.5g
を加え室温にて1夜撹拌する。
溶媒を減圧下留去するとカラメル状の目的物質
4.68g(100%)を得る。
IRνKBr naxcm−1
1790(β−ラクタム)、1750、1730(C=O)
1620(C=C)、1250、1230(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.45(9H、s、−C(CH3)3)
1.55(9H、s、−C(CH3)3)
1.93(3H、s、−CH3)
2.06(3H、s、−CH3)
3.39、3.55(2H、ABq、J=18Hz、2位H)
4.59(1H、s、【式】)
4.92(1H、、J=4.5Hz、6位H)
4.88、5.08(2H、ABq、J=20Hz、−CH2OAc)
5.21(1H、q、J=10Hz、J=4.5Hz、7位H)
9.03(1H、d、J=10Hz、NH)
参考例 8
7−(3−t−ブトキシ−1−メチル−3−オ
キソ−1−プロペニル)アミノ−3−(1−メ
チル−テトラゾール−5−イル)チオメチル−
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−(1−メチル−テトラゾール
−5−イル)チオメチル−3−セフエム−4−カ
ルボン酸t−ブチルエステル816mg(2.13ミリモ
ル)をメタノール5mlに溶かした液にアセト酢酸
t−ブチルエステル337mg(2.13ミリモル)を加
え室温にて1夜撹拌する。
溶媒を減圧下留去するとカラメル状の目的物質
1.10g(100%)を得る。
IRνKBr naxcm−1
1780(β−ラクタム)、1725、1715(C=O)、
1610(C=O)、1270、1250(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.46(9H、s、−C(CH3)3)
1.59(9H、s、−C(CH3)3)
1.90(3H、s、−CH3)、3.93(3H、s、N−
CH3)
4.55(1H、s、【式】)
4.96(1H、d、6位H、J=4.5Hz)
5.30(1H、q、7位H、J=4.5Hz、J=10Hz)
8.95(1H、d、NH、J=8Hz)
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544.6mg(1.25ミリモル)
をジクロロメタン10ml及びメタノール20mlに溶か
し、撹拌下ホウ砂(Na2B4O7・10H2O)620.0mg
(1.63ミリモル)を加えて溶かし、N−ブロモス
クシンイミド244.5mg(1.37ミリモル)を加え室
温で5.5時間撹拌する。溶媒を減圧下留去し、残
渣を酢酸エチル30mlに溶かし、水洗、乾燥後酢酸
エチルをを減圧下留去するとカラメル状物質
612.9mgを得る。これをシリカゲル20gのカラム
を用いシクロヘキサンと酢酸エチルの混液(1:
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341.6mg(58.7%)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−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−メチル−7−(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2で得た3−メチル−7−(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402.1mg(1.00ミリモル)、ホウ砂526.3mg
(1.38ミリモル)及びN−ブロモスクシンイミド
245.6mg(1.38ミリモル)にメタノール60mlを加
えて室温にて1夜撹拌する。溶媒を減圧下留去
し、残査を酢酸エチル20mlに溶かし、不溶分をろ
去し、ろ液を水洗、乾燥後酢酸エチルを減圧下留
去するとカラメル状物質486mg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(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260.2mg(60.2%)を得
る。
IRνKBr naxcm−1
1770(β−ラクタム)、1730(C=O)、1610(C
=C)、1270、1230(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
2.16(3H、s、−CH3)、2.22(3H、s、−CH3)
3.12(2H、s、2位H)、3.36(3H、s、−
OCH3)
3.62(3H、s、−COOCH3)、4.75(1H、s、
【式】)4.90(1H、s、6位H)、5.23
(2H、s、
【式】)、7.33(5H、s、
【式】)、9.53(1H、s、−NH−)
実施例 3
3−アセトキシメチル−7−(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t−ブチルエステルの製造
参考例3で得た3−アセトキシ−7−(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t−
ブチルエステル426.4mg(1.00ミリモル)をメタ
ノール15mlに溶かし、撹拌下ホウ砂495.8mg
(1.30ミリモル)及びN−ブロモスクシンイミド
231.4mg(1.30ミリモル)を加え室温にて3時間
撹拌する。溶媒を減圧下留去し、残渣を酢酸エチ
ルに溶かし、水洗、乾燥後酢酸エチルを減圧下留
去するとカラメル状物質570mg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(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200.0mg(43.8%)を得
る。
IRνKBr naxcm−1
1780(β−ラクタム)、1730(C=O)、1620(C
=C)、1270、1240(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.57(9H、s、−C(CH3)3)、2.07(3H、s、−
CH3)
2.15(3H、s、−CH3)
※(2H、ABq、J=17Hz、2位H)
3.45(3H、s、−OCH3)、3.65(H、s、−
COOCH3)
4.77(1H、s、【式】)
4.83、5.07(2H、ABq、J=13Hz、−CH2 OAc)
4.91(1H、s、6位H)、9.45(1H、s、−NH
−)
※ABqの高磁場の2本線(3.08、3.36ppm)は
明確であるが、低磁場の2本線は3.45ppm(−
OCH3)のシグナルと重なる。
実施例 4
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4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291.0mg(0.70ミリモル)をジク
ロロメタン2ml及びメタノール10mlに溶かし、ホ
ウ砂320.4mg(0.84ミリモル)を含むメタノール
溶液8ml及びN−ブロモスクシンイミド149.5mg
(0.84ミリモル)を加え、室温にて1夜撹拌す
る。溶媒を減圧下留去し、得られる残査をジクロ
ロメタンに溶かし、水洗、乾燥後ジクロロメタン
を減圧下留去するとカラメル状物質を得る。これ
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(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56.0mg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 5
3−メチル−7−(3−t−ブトキシ−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6で得た3−メチル−7−(3−t−ブ
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445.8mg(1.00ミリモル)をジクロ
ロメタン5mlに溶かし、ホウ酸500.0mg(1.31ミ
リモル)を含むメタノール溶液30mlとN−ブロモ
スクシンイミド235.0mg(1.31ミリモル)を加え
室温で1夜撹拌する。溶媒を減圧下留去し、残査
を酢酸エチル30mlに溶かし、水洗、乾燥後酢酸エ
チルを減圧下留去する。残査をシリカゲル60g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アメ状の目的物
質302.0mg(63.5%)を得る。
IRνKBr naxcm−1
1780(β−ラクタム)、1730(C=O)、1620(C
=C)、1140(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.47(9H、s、−C(CH3)3)、2.10(3H、s、−
CH3)
2.22(3H、s、−CH3)、3.14(2H、s、2位
H)
3.40(3H、s、−OCH3)、4.68(1H、s、
【式】)
4.88(1H、s、6位H)、5.25(2H、s、
【式】)
7.35(5H、s、【式】)、
9.47(1H、s、−NH−)
実施例 6
3−アセトキシメチル−7−(3−t−ブトキ
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t−ブチルエステルの製造
参考例7で得た3−アセトキシメチル−7−
(3−t−ブトキシ−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t−ブチルエステル4.68g(10.0ミリモ
ル)にホウ砂(Na2B4O7・10H2O)5.00g(13.1
ミリモル)を含むメタノール溶液300mlとN−ブ
ロモスクシンイミド2.35g(13.2ミリモル)を加
え4時間室温にて撹拌する。溶媒を減圧下留去
し、残渣を酢酸エチル150mlに溶かし、水洗、乾
燥後酢酸エチルを減圧下留去する。残渣をシリカ
ゲル180g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2.70g(54.2%)を得る。
IRνKBr naxcm−1
1790(β−ラクタム)、1750、1730(C=O)、
1620(C=C)、1250、1230(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.45(9H、s、−C(CH3)3)
1.55(9H、s、−C(CH3)3)
2.07(3H、s、−CH3)、2.07(3H、s、−CH3)
3.26、3.53(2H、ABq、J=16Hz、2位H)
3.46(3H、s、−OCH3)
4.69(1H、s、【式】)
4.86(1H、6位H)
4.82、5.02(2H、ABq、J=14Hz、−CH2OAc)
9.38(1H、s、NH)
実施例 7
7(3−t−ブトキシ−1−メチル−3−オキ
ソ−1−プロペニル)アミノ−7−メトキシ−
3−(1−メチル−テトラゾール−5−イル)
チオメチル−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8で得た7−(3−t−ブトキシ−1−
メチル−3−オキソ−1−プロペニル)アミノ−
3−(1−メチル−テトラゾール−5−イル)チ
オメチル−3−セフエム−4−カルボン酸t−ブ
チルエステル657mg(1.25ミリモル)をメタノー
ル20mlに溶かし撹拌下ホウ砂(Na2B4O7・
10H2O)620mg(1.63ミリモル)およびN−ブロ
モスクシンイミド290mg(1.63ミリモル)を加え
1時間室温にて撹拌する。溶媒を減圧下留去し、
残渣を酢酸エチル20mlに溶かし、水洗、乾燥後酢
酸エチルを減圧下留去する。残渣をシリカゲル40
gのカラムを用いn−ヘキサンと酢酸エチルの混
液(3:1V/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531mg(76.6%)を得る。
IRνKBr naxcm−1
1780(β−ラクタム)、1730、1710(C=O)、
1610(C=C)、1270、1250(C−O)
NMRppm〔δ〕(CDCl3、60MHz、TMS)
1.46(9H、s、−C(CH3)3)
1.59(9H、s、−C(CH3)3)
2.06(3H、s、−CH3)
3.45(3H、s、−OCH3)
3.93(3H、s、N−CH3)
4.66(1H、s、【式】)
4.86(1H、s、6位H)
9.40(1H、s、NH) DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 7-methoxycephem compound, more specifically, (In the formula, R 1 represents a lower alkyl group, R 2 and R 3
represents a carboxylic acid protecting group, W represents a hydrogen atom, a halogen atom or a lower alkyl group, and Z represents an organic or inorganic residue. ) 7-
The present invention relates to a method for producing a methoxycephem compound. 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. On the other hand, C, U, Kim et al. reported that when a mixture of methanol and dichloromethane (1:1) was applied to 7-phenoxyacetamidocepheme compound in the presence of N-chlorosuccinimide, 85% of the 2-methoxy derivative was [Tetrahedon Lett. No. 5 409 (1978)] reports that it can be obtained in high yield. As a result of various studies aimed at introducing a methoxy group into the 7-position of a cefem compound, the present inventors discovered that methanol was applied to the cefem compound represented by the formula () in the presence of N-bromosuccinimide and a borate. Contrary to the reports of C, U, Kim et al., the inventors have found that when the methoxy group is introduced into the 7-position, a methoxy group is introduced into the 7-position, and the present invention has been completed. That is, the present invention provides a novel and advantageous method for 7-position methoxylation that is completely different from conventional methods. The present invention is based on the formula () (wherein R 1 , R 2 , R 3 , W and Z have the same meanings as in formula ()) is reacted with methanol in the presence of N-halogenoimide and borate. This is a method for producing a 7-methoxycephem compound represented by the formula (). 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. W is a hydrogen atom or a halogen atom such as chlorine or bromine, or methyl, ethyl, (n
-, iso-) propyl and (n-, iso-, t-)
Examples include lower alkyl groups such as butyl. Examples of Z include a hydrogen atom, acetoxy, carbamoyloxy, heterocyclic thio, such as 1-methyl-1H-tetrazol-5-ylthio, 1,3,4-thiadiazol-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 , Z and W have the same meanings as above.) Furthermore, a compound represented by the formula () in which W is a chlorine atom is a compound represented by the formula () It can also be produced by reacting a compound in which W is a hydrogen atom with chloramine T and boric acid. Examples of the N-halogenimide include compounds such as N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, and N-bromophthalimide. Examples of the borate include sodium borate, potassium borate, and borax which is a borate mineral. In the present invention, the reaction is usually carried out in an inert solvent.
Specifically, dichloromethane, chloroform, ethyl acetate, etc. are often used. Moreover, methanol, which is a reaction raw material, can be used as it is as a solvent. In the present invention, 1 to 1 to 1 mole of N-halogenoimide is added to 1 mole of the cefem compound represented by formula ().
About 2.5 mol, usually 1 to 1.5 mol, is used. Further, the borate is used in an amount of about 0.5 to 10 moles per mole of the compound represented by formula (). For example, in the case of borax ( Na2B4O7.10H2O ), about 0.5 to 5 moles , usually 1 to 1.5 moles, is used. The reaction is carried out at 0 to 40°C, usually at room temperature. After completion of the reaction, it is not necessary to use any special method to separate and purify the target product, 7-methoxycepheme compound represented by formula (), from the reaction mixture, and well-known methods commonly used for such purposes can be used. The objective can be easily achieved by 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 manufactured 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 with 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, -
CH 3 ), 2.20 (3H, s, -CH 3 ) 3.19, 3.41 (2H, ABq, J=18Hz, 2nd H),
3.71 (3H, s, -COOCH 3 ) 4.95 (1H, d, 6th H, J = 4.5Hz), 5.14 (1H,
g, 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-methyl-7-(3-methoxy-1-methyl-3-oxo-1-propenyl)amino-3-
Production of cefem-4-carboxylic acid benzyl ester 7-amino-3-methyl-3-cefem-4-
Add 10 ml of methyl acetoacetate to 4.18 g (14 mmol) of carboxylic acid benzyl ester and stir at room temperature for 20 hours. Methyl acetoacetate was distilled off under reduced pressure at 50°C, 30 ml of ethanol was added to the residue, the precipitated crystals were collected by filtration, and recrystallized from methanol to give 4.81 g of white crystals (yield 85.4%, m, p, 91.5-92.5
℃) is obtained. IRν KBr nax cm −1 1760 (β-lactam), 1720 (C=O), 1620 (C
=C), 1260 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.95 (3H, s, -CH3 ), 2.13 (3H, s, -CH3 ) 3.22, 3.44 (2H, ABq , J=18Hz, 2nd place H),
3.61 (3H, s, -COOCH 3 ) 4.65 (1H, s, [formula]), 4.96 (1H, d, 6th position H, J = 4.5Hz) 5.20 (1H, q, 7th position H, J = 4.5Hz , J=8Hz),
5.23 (2H, s, [Formula]) 7.33 (5H, s, [Formula]), 9.10 (1H, d, J=8Hz, -NH-) Reference example 3 3-acetoxymethyl-7-(3-methoxy-
Production of 1-methyl-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 1.00 g
Add 3 g of methyl acetoacetate to (3.0 mmol) and stir at room temperature overnight. When methyl acetoacetate was distilled off under reduced pressure at 50℃, 1.30g of caramel-like target substance was obtained.
(100%). IRν KBr nax cm −1 1785 (β-lactam), 1740, 1730 (C=O),
1620 (C=C), 1260 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.56 (9H, s, -C( CH3 ) 3 ), 1.98 (H, s, -
CH 3 ) 2.08 (3H, s, -CH 3 ), 3.36 (3.55 (2H, ABq,
J = 18Hz, 2nd H) 3.62 (H, s, -COOCH 3 ), 4.65 (1H, s, [Formula]) 4.75, 5.00 (2H, ABq, J = 13Hz, - CH 2 -
OAc) 4.98 (1H, d, J = 5Hz, 6th H), 3.30 (1H,
d, J=5Hz, J=9Hz, 7th position H) 9.08 (1H, d, J=9Hz, -NH-) Reference example 4 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 benzyl carboxylic acid ester, and the mixture was stirred at room temperature overnight and then at 50° C. for 3 hours. 2-
Methyl methylacetoacetate was distilled off under reduced pressure at 50°C, 30 ml of ethanol was added to the residue, and the precipitated crystals (2.25 g) were recrystallized from methanol to give 1.67 g of white crystals (60.9%, m, p, 118.5-119.5 ℃) is obtained. IRν KBr nax cm −1 1770 (β-lactam), 1720 (C=O), 1600 (C
=C), 1255, 1240 (C-O) NMRppm [δ] ( CDCl3 , 6MHz, 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 5 3-methyl-7-(3-methoxy-1-methyl-2-chloro-3-oxo-1-propenyl)
Production of amino-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(3-methoxy-1-methyl-3-oxo-1-propenyl) obtained in Reference Example 2
Dissolve 402 mg (1.00 mmol) of amino-3-cephem-4-carboxylic acid benzyl ester in 13 ml of anhydrous methanol, and dissolve 455.3 ml of chloramine T (anhydrous).
(2.00 mmol) and 136 mg (2.20 mmol) of boric acid were added, stirred at room temperature for 1.5 hours, and the precipitated crystals were collected after cooling on ice. 234.8 mg (53.8
%). When this is recrystallized from a mixture of ethyl acetate and methanol, m and p become 137.5 to 138°C. Reference example 6 3-methyl-7-(3-t-butoxy-1-methyl-3-oxo-1-propenyl)amino-
Production of 3-cephem-4-carboxylic acid benzyl ester 7-amino-3-methyl-3-cepheme-4-
2.50 g of t-butyl acetone acetate was added to 2.00 g (6.58 mmol) of benzyl carboxylic acid ester, and the mixture was stirred overnight at room temperature. Add 30ml of ethanol to the reaction mixture and filter the precipitated crystals to obtain 2.77g of the target substance.
(yield 94.9%, m, p, 165.5-167.0°C). IRν KBr nax cm −1 1785 (β-lactam), 1740 (C=O), 1620 (C
=C), 1150 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.45 (9H, s, -C( CH3 ) 3 ), 1.90 (H, s, -
CH 3 ) 2.12 (3H, s, -CH 3 ), 3.21, 3.45 (2H, ABq,
J=18Hz, 2nd place H) 4.56 (1H, s, [formula]), 4.91 (1H, J=4Hz, 6th place H) 5.21 (1H, J=4Hz, J=9Hz, 7th place H) 5.25 (2H , s, [Formula]), 7.36 (5H, s, [Formula]) 9.01 (1H, d, J=9Hz, -NH-) Reference example 7 3-acetoxymethyl-7-(3-t-butoxy-1 -Methyl-3-oxo-1-propenyl)amino-3-cephem-4-carboxylic acid t
-Manufacture of butyl ester 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid t-butyl ester 3.28 g
(10.0 mmol), 1.58 g (10.0 mmol) of acetoacetic acid-t-butyl ester and 3.5 g of ethanol.
and stir overnight at room temperature. When the solvent is distilled off under reduced pressure, a caramel-like target substance is obtained.
Obtain 4.68g (100%). IRν KBr nax cm −1 1790 (β-lactam), 1750, 1730 (C=O) 1620 (C=C), 1250, 1230 (C-O) NMRppm [δ] (CDCl 3 , 60MHz, TMS) 1.45 ( 9H, s, -C (CH 3 ) 3 ) 1.55 (9H, s, -C (CH 3 ) 3 ) 1.93 (3H, s, -CH 3 ) 2.06 (3H, s, -CH 3 ) 3.39, 3.55 ( 2H, ABq, J=18Hz, 2nd H) 4.59 (1H, s, [Formula]) 4.92 (1H, J=4.5Hz, 6th H) 4.88, 5.08 (2H, ABq, J=20Hz, -CH 2 OAc) 5.21 (1H, q, J = 10Hz, J = 4.5Hz, 7th position H) 9.03 (1H, d, J = 10Hz, NH) Reference example 8 7-(3-t-butoxy-1-methyl- 3-oxo-1-propenyl)amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-
Preparation of 3-cephem-4-carboxylic acid t-butyl ester 7-amino-3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid t-butyl ester 816 mg (2.13 mmol) 337 mg (2.13 mmol) of t-butyl acetoacetate was added to a solution of 5 ml of methanol, and the mixture was stirred overnight at room temperature. When the solvent is distilled off under reduced pressure, a caramel-like target substance is obtained.
Obtain 1.10g (100%). IRν KBr nax cm −1 1780 (β-lactam), 1725, 1715 (C=O),
1610 (C=O), 1270, 1250 (C-O) NMRppm [δ] (CDCl 3 , 60MHz, TMS) 1.46 (9H, s, -C (CH 3 ) 3 ) 1.59 (9H, s, -C ( CH 3 ) 3 ) 1.90 (3H, s, -CH 3 ), 3.93 (3H, s, N-
CH 3 ) 4.55 (1H, s, [formula]) 4.96 (1H, d, 6th position H, J = 4.5Hz) 5.30 (1H, q, 7th position H, J = 4.5Hz, J = 10Hz) 8.95 (1H , d, NH, J=8Hz) 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 544.6 mg (1.25 mmol)
was dissolved in 10 ml of dichloromethane and 20 ml of methanol, and 620.0 mg of borax (Na 2 B 4 O 7・10H 2 O) was added under stirring.
(1.63 mmol) was added and dissolved, and 244.5 mg (1.37 mmol) of N-bromosuccinimide was added and stirred at room temperature for 5.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 ml of ethyl acetate, washed with water, dried, and the ethyl acetate was distilled off under reduced pressure, leaving a caramel-like substance.
You get 612.9mg. A mixture of cyclohexane and ethyl acetate (1:
1V/V) and purified by column chromatography using the eluate to obtain 341.6 mg (58.7%) of the target substance in caramel form. When this is recrystallized with ethanol, it becomes white crystals, m, p, 129.5
~131.5°C. IRν KBr nax cm −1 1780 (β-cutam), 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 place 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-Methyl-7-(3-methoxy-1- Methyl-3-oxo-1-propenyl)amino-7-
Production of methoxy-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(3-methoxy-1-methyl-3-oxo-1-propenyl) obtained in Reference Example 2
Amino-3-cephem-4-carboxylic acid benzyl ester 402.1 mg (1.00 mmol), borax 526.3 mg
(1.38 mmol) and N-bromosuccinimide
Add 60 ml of methanol to 245.6 mg (1.38 mmol) and stir at room temperature overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in 20 ml of ethyl acetate, the insoluble matter was filtered off, the filtrate was washed with water, and after drying, the ethyl acetate was distilled off under reduced pressure to obtain 486 mg of caramel-like substance. This was developed using a 50 g silica gel column with a mixture of n-hexane and ethyl acetate (2:1 V/V), and purified by column chromatography as the eluent to obtain 260.2 mg (60.2%) of the caramel-like target substance. . IRν KBr nax cm −1 1770 (β-lactam), 1730 (C=O), 1610 (C
=C), 1270, 1230 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 2.16 (3H, s, -CH3 ), 2.22 (3H, s, -CH3 ) 3.12 (2H, s , 2nd H), 3.36 (3H, s, -
OCH 3 ) 3.62 (3H, s, -COOCH 3 ), 4.75 (1H, s, [Formula]) 4.90 (1H, s, H at 6th position), 5.23 (2H, s, [Formula]), 7.33 (5H, s, [Formula]), 9.53 (1H, s, -NH-) Example 3 3-acetoxymethyl-7-(3-methoxy-
Production of 1-methyl-3-oxo-1-propenyl)amino-7-methoxy-3-cephem-4-carboxylic acid t-butyl ester 3-acetoxy-7-(3-methoxy-1 -Methyl-3-oxo-1-propenyl)amino-3-cephem-4-carboxylic acid t-
426.4 mg (1.00 mmol) of butyl ester was dissolved in 15 ml of methanol, and 495.8 mg of borax was stirred.
(1.30 mmol) and N-bromosuccinimide
Add 231.4 mg (1.30 mmol) and stir at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, dried, and the ethyl acetate was distilled off under reduced pressure to obtain 570 mg of a caramel-like substance. This was purified using a 50 g column of silica gel, developed with a mixture of n-hexane and ethyl acetate (2:1 V/V), and purified by column chromatography as the eluent, yielding 200.0 mg (43.8%) of the target substance in the form of a caramel. obtain. IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1620 (C
=C), 1270, 1240 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.57 (9H, s, -C( CH3 ) 3 ), 2.07 (3H, s, -
CH 3 ) 2.15 (3H, s, -CH 3 ) *(2H, ABq, J=17Hz, 2nd H) 3.45 (3H, s, -OCH 3 ), 3.65 (H, s, -
COOCH 3 ) 4.77 (1H, s, [formula]) 4.83, 5.07 (2H, ABq, J=13Hz, -CH2OAc ) 4.91 (1H, s, H at 6th position), 9.45 (1H, s, -NH
-) *The two high magnetic field lines (3.08, 3.36ppm) of ABq are clear, but the two low magnetic field lines are 3.45ppm (-
overlaps with the OCH 3 ) signal. Example 4 Production of 3-methyl-7-(1,2-dimethyl-3-methoxy-3-oxo-1-propenyl)amino-7-methoxy-3-cephem-4-carboxylic acid benzyl ester In Reference Example 4 291.0 mg (0.70 mmol) of the obtained 3-methyl-7-(1,2-dimethyl-3-methoxy-3-oxo-1-propenyl)amino-3-cephem-4-carboxylic acid benzyl ester was added to 2 ml of dichloromethane and methanol. 8 ml of methanol solution containing 320.4 mg (0.84 mmol) of borax dissolved in 10 ml and 149.5 mg of N-bromosuccinimide.
(0.84 mmol) and stirred at room temperature overnight. The solvent is distilled off under reduced pressure, the resulting residue is dissolved in dichloromethane, washed with water, dried, and dichloromethane is distilled off under reduced pressure to obtain a caramel-like substance. This was developed using a 30 g column of silica gel with a mixture of n-hexane and ethyl acetate (2:1 V/V) and purified by column chromatography as the eluent to obtain 56.0 mg of caramel-like target substance. 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, 6th position H), 5.27 (2H, s,
[Formula]) 7.36 (5H, s, [Formula]) 10.10 (1H, s, -NH-) Example 5 3-Methyl-7-(3-t-butoxy-1-methyl-3-oxo-1- propenyl)amino-
Production of 7-methoxy-3-cephem-4-carboxylic acid benzyl ester 3-methyl-7-(3-t-butoxy-1-methyl-3-oxo-1-propenyl)amino-3 obtained in Reference Example 6 -Cefem-4-carboxylic acid benzyl ester (445.8 mg (1.00 mmol)) was dissolved in dichloromethane (5 ml), and 30 ml of methanol solution containing boric acid (500.0 mg (1.31 mmol)) and N-bromosuccinimide (235.0 mg (1.31 mmol)) were added at room temperature. Stir at night. The solvent is distilled off under reduced pressure, the residue is dissolved in 30 ml of ethyl acetate, washed with water, dried, and ethyl acetate is distilled off under reduced pressure. The residue was developed with a mixture of n-hexane and ethyl acetate (4:1 V/V) using a 60 g silica gel column, and purified by column chromatography as the eluent, yielding 302.0 mg (63.5%) of the target substance as a candy. obtain. IRν KBr nax cm −1 1780 (β-lactam), 1730 (C=O), 1620 (C
=C), 1140 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.47 (9H, s, -C( CH3 ) 3 ), 2.10 (3H, s, -
CH 3 ) 2.22 (3H, s, -CH 3 ), 3.14 (2H, s, 2nd H) 3.40 (3H, s, -OCH 3 ), 4.68 (1H, s,
[Formula]) 4.88 (1H, s, 6th position H), 5.25 (2H, s,
[Formula]) 7.35 (5H, s, [Formula]), 9.47 (1H, s, -NH-) Example 6 3-acetoxymethyl-7-(3-t-butoxy-1-methyl-3-oxo- 1-propenyl)amino-7-methoxy-3-cephem-4
-Production of carboxylic acid t-butyl ester 3-acetoxymethyl-7- obtained in Reference Example 7
(3-t-butoxy-1-methyl-3-oxo-
Borax ( Na2B4O7.10H2O ) 5.00g ( 13.1
300 ml of a methanol solution containing 1 mmol) and 2.35 g (13.2 mmol) of N-bromosuccinimide were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 150 ml of ethyl acetate, washed with water, dried, and the ethyl acetate was distilled off under reduced pressure. The residue was developed using a 180 g silica gel column with a mixture of n-hexane and ethyl acetate (4:1 V/V), and purified by column chromatography as the eluent to obtain 2.70 g (54.2%) of the caramel-like target substance. . IRν KBr nax cm −1 1790 (β-lactam), 1750, 1730 (C=O),
1620 (C=C), 1250, 1230 (C-O) NMRppm [δ] (CDCl 3 , 60MHz, TMS) 1.45 (9H, s, -C (CH 3 ) 3 ) 1.55 (9H, s, -C ( CH 3 ) 3 ) 2.07 (3H, s, -CH 3 ), 2.07 (3H, s, -CH 3 ) 3.26, 3.53 (2H, ABq, J=16Hz, 2nd H) 3.46 (3H, s, -OCH 3 ) 4.69 (1H, s, [formula]) 4.86 (1H, H at 6th position) 4.82, 5.02 (2H, ABq, J = 14Hz, -CH 2 OAc) 9.38 (1H, s, NH) Example 7 7 ( 3-tert-butoxy-1-methyl-3-oxo-1-propenyl)amino-7-methoxy-
3-(1-methyl-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid t
-Manufacture of butyl ester 7-(3-t-butoxy-1-obtained in Reference Example 8)
Methyl-3-oxo-1-propenyl)amino-
657 mg (1.25 mmol) of 3-(1-methyl-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid t-butyl ester was dissolved in 20 ml of methanol and mixed with borax (Na 2 B 4 O 7 .
620 mg (1.63 mmol) of 10H 2 O) and 290 mg (1.63 mmol) of N-bromosuccinimide were added, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off under reduced pressure,
The residue was dissolved in 20 ml of ethyl acetate, washed with water and dried, and then the ethyl acetate was distilled off under reduced pressure. Silica gel 40 to remove residue
Developed with a mixture of n-hexane and ethyl acetate (3:1 V/V) using a column (g), and purified by column chromatography as an eluent to obtain 531 mg (76.6%) of the target substance in the form of a caramel. IRν KBr nax cm −1 1780 (β-lactam), 1730, 1710 (C=O),
1610 (C=C), 1270, 1250 (C-O) NMRppm [δ] ( CDCl3 , 60MHz, TMS) 1.46 (9H, s, -C( CH3 ) 3 ) 1.59 (9H, s, -C( CH 3 ) 3 ) 2.06 (3H, s, -CH 3 ) 3.45 (3H, s, -OCH 3 ) 3.93 (3H, s, N-CH 3 ) 4.66 (1H, s, [formula]) 4.86 (1H, s, 6th H) 9.40 (1H, s, NH)
Claims (1)
はカルボン酸保護基を表わし、Wは水素原子又は
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N−ハロゲノイミドとホウ酸塩の存
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、W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製造方法。[Claims] 1 Formula () (In the formula, R 1 represents a lower alkyl group, R 2 and R 3
represents a carboxylic acid protecting group, W represents a hydrogen atom, a halogen atom or a lower alkyl group, and Z represents an organic or inorganic residue. Formula () characterized in that a cefem compound represented by ) is reacted with methanol in the presence of N-halogenoimide and borate. (In the formula, R 1 , R 2 , R 3 , W and Z have the same meanings as in formula ().) A method for producing a 7-methoxycephem compound.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16469079A JPS5687584A (en) | 1979-12-20 | 1979-12-20 | Preparation of 7-methoxycephem compound |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP16469079A JPS5687584A (en) | 1979-12-20 | 1979-12-20 | Preparation of 7-methoxycephem compound |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5687584A JPS5687584A (en) | 1981-07-16 |
JPS6219431B2 true JPS6219431B2 (en) | 1987-04-28 |
Family
ID=15797998
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP16469079A Granted JPS5687584A (en) | 1979-12-20 | 1979-12-20 | Preparation of 7-methoxycephem compound |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5687584A (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
- 1979-12-20 JP JP16469079A patent/JPS5687584A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5687584A (en) | 1981-07-16 |
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