JP2922220B2 - Penem recipe - Google Patents
Penem recipeInfo
- Publication number
- JP2922220B2 JP2922220B2 JP1171736A JP17173689A JP2922220B2 JP 2922220 B2 JP2922220 B2 JP 2922220B2 JP 1171736 A JP1171736 A JP 1171736A JP 17173689 A JP17173689 A JP 17173689A JP 2922220 B2 JP2922220 B2 JP 2922220B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- substituted
- ococh
- 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 - Lifetime
Links
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title description 4
- -1 benzoyloxy methyl Chemical group 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 22
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- 229910052709 silver Inorganic materials 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000004332 silver Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910001297 Zn alloy Inorganic materials 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000005949 ozonolysis reaction Methods 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical class C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 claims description 2
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-O Piperidinium(1+) Chemical compound C1CC[NH2+]CC1 NQRYJNQNLNOLGT-UHFFFAOYSA-O 0.000 claims description 2
- 125000005042 acyloxymethyl group Chemical group 0.000 claims description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims 2
- 229910000881 Cu alloy Inorganic materials 0.000 claims 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims 1
- 125000002723 alicyclic group Chemical group 0.000 claims 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- BJDTWVQNEWIULP-RXMQYKEDSA-N (5R)-3-bromo-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound BrC=1S[C@H]2N(C=1)C(C2)=O BJDTWVQNEWIULP-RXMQYKEDSA-N 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- 239000005695 Ammonium acetate Substances 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 235000019257 ammonium acetate Nutrition 0.000 description 3
- 229940043376 ammonium acetate Drugs 0.000 description 3
- 150000002961 penems Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- WOOSCPWOYYLIHS-UHFFFAOYSA-N Oxoamide Chemical compound CNC(=O)CCC(=O)C1=CC=CN=C1 WOOSCPWOYYLIHS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- FZKGLCPKPZBGLX-ROXVQFJHSA-N acetyloxymethyl (5r,6s)-3-(carbamoyloxymethyl)-6-[(1r)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound S1C(COC(N)=O)=C(C(=O)OCOC(C)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 FZKGLCPKPZBGLX-ROXVQFJHSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- REQPQFUJGGOFQL-UHFFFAOYSA-N dimethylcarbamothioyl n,n-dimethylcarbamodithioate Chemical compound CN(C)C(=S)SC(=S)N(C)C REQPQFUJGGOFQL-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- BSWGGJHLVUUXTL-UHFFFAOYSA-N silver zinc Chemical compound [Zn].[Ag] BSWGGJHLVUUXTL-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
【発明の詳細な説明】 本発明は抗菌剤の合成に有用な6−[(1R)−ヒドロ
キシエチル]ペネムの製造方法、その方法に用いる中間
体及びその中間体の製造に関する。The present invention relates to a method for producing 6-[(1R) -hydroxyethyl] penem useful for synthesizing an antibacterial agent, an intermediate used in the method, and production of the intermediate.
さらに詳細には、本発明は、式(I): (式中: Rは a)アルカノイル部分が直鎖もしくは分枝鎖C2〜C10ア
ルカノイル基もしくはC4〜C8シロクアルカノイル基であ
るアルカノイルオキシメチル又は1−(アルカノイルオ
キシ)エチル; b)ベンゾイルオキシメチル又は1−(ベンゾイルオキ
シ)エチル; c)アルコキシルカルボニルオキシメチル又は1−(ア
ルコキシカルボニルオキシ)エチル; d)3−フタリジル; e)5位がC1〜C4アルキル基で置換されているか又は置
換されていない2−オキソ−1,3−ジオキソラン−4−
イル; f)R′がC1〜C4直鎖もしくは分枝鎖アルキル又はベン
ジルである−CH2COOR′; あるいは g)4位がC1〜C4アルキル基で置換されているか又は置
換されていない2−オキソテトラヒドロフラン−5−イ
ルを表わし、 R1は、テトラヒドロフラニル基、あるいは非置換もしく
は置換C1〜C4アルキル基、メチルフェニル基又はメチル
フェノキシメチル基であって、その置換基は以下の基か
ら選択される: (i)カルバモイルオキシ,C1〜C18アルコキシ,カルボ
キシ,又は遊離もしくは保護されたヒドロキシ,及び (ii)非置換もしくは置換及び/又は融合された(fuse
d)ピリジニウム,N−メチルピロリジニウムあるいはピ
ペリジニウムであって、その置換基は上記(i)の基で
あるかあるいはスルホニルオキシ基もしくはカルボキシ
基により置換されているか又は置換されていないC1〜C4
アルキル基であり、 R2は水素原子か又はヒドロキシ保護基を表わす)化合物
の製造方法に関するが、該方法は式(II) (式中R,R1及びR2は上記の意味を有する)の化合物を還
元することを包含する。More specifically, the present invention provides a compound of formula (I): (In wherein: R is a) alkanoyl moiety is a linear or branched C 2 -C 10 alkanoyl or C 4 -C 8 white alkanoyloxymethyl an alkanoyl group or a 1- (alkanoyloxy) ethyl; b) benzoyl oxymethyl or 1- (benzoyloxy) ethyl; c) alkoxycarbonyl oxymethyl or 1- (alkoxycarbonyloxy) ethyl; d) 3- phthalidyl; e) or 5-position is substituted by C 1 -C 4 alkyl group Or unsubstituted 2-oxo-1,3-dioxolan-4-
Yl; it is or a substituted or g) 4-position is substituted by C 1 -C 4 alkyl group; f) R 'is -CH 2 COOR a C 1 -C 4 straight or branched chain alkyl or benzyl' R 1 is a tetrahydrofuranyl group, or an unsubstituted or substituted C 1 -C 4 alkyl group, a methylphenyl group or a methylphenoxymethyl group, wherein the substituent is Selected from the following groups: (i) carbamoyloxy, C 1 -C 18 alkoxy, carboxy, or free or protected hydroxy, and (ii) unsubstituted or substituted and / or fused (fuse
d) pyridinium, a N- methyl pyrrolidinium or piperidinium, C 1 -C its substituent is not or is substituted is substituted by a group in which one or a sulfonyloxy group or carboxy group of the (i) Four
An alkyl group, and R 2 represents a hydrogen atom or a hydroxy protecting group). (Wherein R, R 1 and R 2 have the meanings given above).
アルコキシ部分は、好ましくは1〜6個の炭素原子を
含有し、さらに好ましくは1〜4個の炭素原子を含有す
る。R2、又はR1のヒドロキシ保護部分は、例えばp−ニ
トロベンジルオキシカルボニル基,トリメチルシリル
基,t−ブチルジメチルシリル基,t−ブチルジフェニルシ
リル基,メトキシメチル基,ベンジル基,p−ブロモフェ
ナシル基,トリフェニルメチル基又はテトラヒドロピラ
ニル基であってもよい。The alkoxy moiety preferably contains 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. The hydroxy-protecting moiety of R 2 or R 1 includes, for example, p-nitrobenzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, p-bromophenacyl, It may be a triphenylmethyl group or a tetrahydropyranyl group.
ピリジニウム基,N−メチルピロリジニウム基及びピペ
リジニウム基と融合可能な基の例としては、フェニル
基,及びC5〜C7飽和もしくは不飽和脂環式基又はヘテロ
環式基がある。ヘテロ環式基は、例えば、酸素原子,窒
素原子及びイオウ原子の群から選択される1〜4個のヘ
テロ原子を含有してもよい。ピリジニウム基,N−メチル
ピロリジニウム基及びピペリジニウム基と融合可能な好
ましい基は: である。Pyridinium groups, examples of which can be fused to N- methyl-pyrrolidinium group and piperidinium group, phenyl, and C 5 -C 7 is saturated or unsaturated cycloaliphatic radical, or a heterocyclic group. The heterocyclic group may contain, for example, 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Preferred groups which can be fused with the pyridinium, N-methylpyrrolidinium and piperidinium groups are: It is.
式(I)の化合物の例は、欧州特許出願第88305277.1
号、英国特許出願第2,133,010号及び英国特許出願第2,0
97,786号に記載されている。Examples of compounds of formula (I) are described in European Patent Application No. 88305277.1
No., UK Patent Application No. 2,133,010 and UK Patent Application No. 2,0
No. 97,786.
本発明はまた、式(II)の化合物を提供し、さらに式
(II)の化合物の製造方法をも提供するが、該方法は式
(V): (式中R,R1及びR2は上記の意味を有する)の化合物を環
化することを包含する。The present invention also provides a compound of formula (II), and further provides a method for preparing a compound of formula (II), wherein the method comprises formula (V): (Wherein R, R 1 and R 2 have the meanings given above).
式(III): (式中R,R1及びR2は上記の意味を有する)の化合物のオ
ゾン分解によって式(V)の化合物を製造し得る。Formula (III): The compound of formula (V) may be prepared by ozonolysis of a compound of formula (where R, R 1 and R 2 have the meanings given above).
本発明の方法は、良好な収率で及び高い光学純度の式
(I)のペネムを提供する。この方法は、臭素原子が最
終段階までβ−ラクタム核上に維持されるという点で従
来の技術と異なる。The process of the present invention provides penems of formula (I) in good yield and of high optical purity. This method differs from the prior art in that bromine atoms are maintained on the β-lactam nucleus until the final stage.
水素原子による臭素原子の置換は、本発明方法の初期
段階の他の中間体よりも式(II)の化合物上に於いて関
してより高い立体選択性を伴って進行する。さらに、本
発明方法に関与する中間体は従来報告されたものよりも
より安定で、取り扱い易く、したがって、分解すること
なく保存可能である。The replacement of the bromine atom by a hydrogen atom proceeds with a higher stereoselectivity on the compounds of formula (II) than other intermediates in the earlier stages of the process. Further, the intermediates involved in the process of the present invention are more stable and easier to handle than previously reported, and therefore can be stored without degradation.
ペネム核の好ましい最終の[5R,6S,(1R)]立体化学
を得るためには、式(II)の化合物の立体配置は[5R,6
S,(1R)]である。式(III)の出発物質は、欧州特許
出願第0188247号に記載の6−アミノペニシラン酸から
便宜的に製造可能である。したがって、本発明は、以下
の反応スキームに要約されているように、6−アミノペ
ニシラン酸から直接式(I)の化合物の合成を可能にす
る。To obtain the preferred final [5R, 6S, (1R)] stereochemistry of the penem nucleus, the configuration of the compound of formula (II) is [5R, 6
S, (1R)]. The starting materials of the formula (III) can be conveniently prepared from 6-aminopenicillanic acids as described in European Patent Application 0188247. Thus, the present invention allows the synthesis of compounds of formula (I) directly from 6-aminopenicillanic acid, as summarized in the following reaction scheme.
一般に低温で化合物(III)のオゾン分解によりスキ
ーム中の式(V)の化合物を調製し、さらにクロロホル
ム,ベンゼン,トルエン又はキシレンのような不活性有
機溶剤に溶解したトリエチルホスファイト又はトリメチ
ルホスファイトで一般的に処理することにより化合物
(II)に環化する。In general, the compound of formula (V) in the scheme is prepared by ozonolysis of compound (III) at low temperature and further treated with triethyl phosphite or trimethyl phosphite dissolved in an inert organic solvent such as chloroform, benzene, toluene or xylene. The compound is generally cyclized to a compound (II) by treatment.
上記の環化条件の例は、C.Battistiniら,Tetrahedron
Lett.25,2595,(1984);A.Yoshidaら,Chem.Pharm.Bul
l.31,768,(1983),及びその中の参考文献、並びに米
国特許出願第4,631,150号に詳述されている。Examples of the above cyclization conditions are described in C. Battistini et al., Tetrahedron.
Lett. 25 , 2595, (1984); A. Yoshida et al., Chem. Pharm.
l. 31 , 768, (1983), and references therein, as well as U.S. Patent Application No. 4,631,150.
式(II)の化合物は、接触水素添加又は還元性金属に
よる処理といった任意の適当な方法で化合物(I)に還
元される。好ましくは、亜鉛、又は銅もしくは銀のよう
な別の金属と亜鉛との合金で処理して、(II)からペネ
ム(I)を得る。好ましくは、アンモニウム又は亜鉛カ
ルボキシレート又はハロゲン化物の水性溶液存在下、ア
セトニトリル,エチルエーテール,t−ブチルメチルエー
テル,酢酸エチル,テオラヒドロフラン,アセトン,ク
ロロホルム又は塩化メチレンのような有機溶剤中で反応
を行なう。The compound of formula (II) is reduced to compound (I) by any suitable method, such as catalytic hydrogenation or treatment with a reducing metal. Preferably, treatment with zinc or an alloy of zinc with another metal, such as copper or silver, yields penem (I) from (II). Preferably, the reaction is carried out in an organic solvent such as acetonitrile, ethyl ether, t-butyl methyl ether, ethyl acetate, teorahydrofuran, acetone, chloroform or methylene chloride in the presence of an aqueous solution of ammonium or zinc carboxylate or halide. Perform
反応温度は一般的に−20℃〜+80℃である。反応終了
時、慣用的操作により式(I)のペネムを取り上げる。
必要に応じて、反応粗製物を脱保護し、カラムクロマト
グラフィによって精製する。 The reaction temperature is generally between -20 ° C and + 80 ° C. At the end of the reaction, the penem of formula (I) is taken up by conventional procedures.
If necessary, the reaction crude is deprotected and purified by column chromatography.
式(I)のペネムは抗菌剤である。したがって、これ
らは医薬組成物として処方し得るし、また医薬的に許容
可能な担体又は希釈剤を包含してもよい。The penems of the formula (I) are antimicrobial agents. Thus, they may be formulated as pharmaceutical compositions and may include a pharmaceutically acceptable carrier or diluent.
以下の実施例により本発明をさらに詳しく説明する。 The following examples illustrate the invention in more detail.
実施例1 ブロモペネム(II)の製造(一般的方法) (3S,4R)−1−(1−アセトキシメチルオキシカル
ボニル−2−メチル−1−プロペニル)−4−アシルチ
オ−3−ブロモ−3−[1−(R)−ヒドロキシエチ
ル]−アゼチジン−2−オン(III,R=CH2OCOCH3,R2=
H)を、AlpegianiらJ.Am.Chem.Soc.,107,6398,(198
5)に記載のように、(3S,5R,6S)−6−ブロモ−6−
[1−(R)−ヒドロキシエチル]−ペニシラン酸アセ
トキシメチル(IV,R=CH2OCOCH3)から製造した。Example 1 Preparation of bromopenem (II) (general method) (3S, 4R) -1- (1-acetoxymethyloxycarbonyl-2-methyl-1-propenyl) -4-acylthio-3-bromo-3- [ 1- (R) -Hydroxyethyl] -azetidin-2-one (III, R = CH 2 OCOCH 3 , R 2 =
H) was converted to Alpegiani et al., J. Am. Chem. Soc., 107 , 6398, (198
As described in 5), (3S, 5R, 6S) -6-bromo-6-
Prepared from [1- (R) -hydroxyethyl] -acetoxymethyl penicillanate (IV, R = CH 2 OCOCH 3 ).
粗製物(III)を慣用手順に従ってそのトリメチルシ
リル(TMS)誘導体に変換した。保護されたアゼチジノ
ン(III)(20mmol)を−78℃で乾燥塩化メチレン(300
ml)中に溶解した。Crude (III) was converted to its trimethylsilyl (TMS) derivative according to conventional procedures. The protected azetidinone (III) (20 mmol) was dried at -78 ° C with methylene chloride (300
ml).
同一温度で4〜6時間、この溶液にオゾンを通気し
た。Ozone was bubbled through the solution at the same temperature for 4-6 hours.
反応終了時に、溶液に窒素を通じて過剰のオゾンを除
去し、混合液を0℃とした。この溶液を重亜硫酸ナトリ
ウム(0.2M,2×100ml)で洗浄し、硫酸ナトリウム上で
乾燥した。溶剤を蒸発してオキソアミド(V)を得た
が、これは何ら分解することなく数日間保存可能であっ
た。At the end of the reaction, excess ozone was removed by passing nitrogen through the solution and the mixture was brought to 0 ° C. This solution was washed with sodium bisulfite (0.2 M, 2 × 100 ml) and dried over sodium sulfate. Evaporation of the solvent gave oxoamide (V), which could be stored for several days without any decomposition.
Va(R=CH2OCOCH3,R1=CH2OCONH2,R2=TMS):白色泡
状物;収率80%; 1H−NMRδ(CDCl3):0.2(9H,s,OTMS),1.55(3H,d,CH3
−CH),2.15(3H,s,OCOCH3),4.18(1H,m,H−8),4.82
(2H,AB系,SCOCH2),5.1(2H,br,NH2),5.9(2H,AB系,C
H2OCOCH3),6.23(1H,s,H−5)。 Va (R = CH 2 OCOCH 3 , R 1 = CH 2 OCONH 2, R 2 = TMS): white foam; yield 80%; 1H-NMRδ (CDCl 3) : 0.2 (9H, s, OTMS), 1.55 (3H, d, CH 3
-CH), 2.15 (3H, s , OCOCH 3), 4.18 (1H, m, H-8), 4.82
(2H, AB, SCOCH 2 ), 5.1 (2H, br, NH 2 ), 5.9 (2H, AB, C
H 2 OCOCH 3), 6.23 ( 1H, s, H-5).
Vb(R=CH2OCOOH3,R1=CH2OCH3,R2=TMS),油状物;
収率82%; 1H−NMRδ(CDCl3):0.2(9H,s,OTMS),1.55(3H,d,CH3
CH),2.15(3H,s,OCOCH3),3.5(3H,s,OCH3),4.13−4.
22(3H:SCOCH2及びH−8),5.9(2H,AB系,CH2OCOC
H3),6.22(1H,s,H=5)。 Vb (R = CH 2 OCOOH 3 , R 1 = CH 2 OCH 3, R 2 = TMS), oil;
1H-NMR δ (CDCl 3 ): 0.2 (9H, s, OTMS), 1.55 (3H, d, CH 3)
CH), 2.15 (3H, s , OCOCH 3), 3.5 (3H, s, OCH 3), 4.13-4.
22 (3H: SCOCH 2 and H-8), 5.9 (2H, AB system, CH 2 OCOC
H 3), 6.22 (1H, s, H = 5).
Vc(R=CH2OCOCH3,R1=CH3,R2=TMS),油状物;収率7
5%;1H=NMRδ(CDCl3):0.2(9H,s,OTMS),1.55(3H,
d,CH3−CH),2.15(3H,s,OCOCH3),2.35(3H,s,SOCO
H3),4.12(1H,m,H−8),5.85(2H,AB系,CH2OCOCH3),
6.02(1H,s,H−5)。 Vc (R = CH 2 OCOCH 3 , R 1 = CH 3, R 2 = TMS), oil; yield 7
5%; 1H = NMRδ (CDCl 3 ): 0.2 (9H, s, OTMS), 1.55 (3H,
d, CH 3 -CH), 2.15 (3H, s, OCOCH 3 ), 2.35 (3H, s, SOCO
H 3 ), 4.12 (1H, m, H-8), 5.85 (2H, AB system, CH 2 OCOCH 3 ),
6.02 (1H, s, H-5).
粗製物(V)を乾燥トルエン又はキシレン(70ml)に
溶解した。トリエチルホスファイト(8.7ml,50mmol)を
添加し、この溶液を1〜6時間還流した。反応終了時
に、混合液を20℃に冷却し、リン酸緩衝液(pH=7,3×2
0ml)で洗浄し、硫酸ナトリウム上で乾燥した。溶剤を
蒸発して油状物を得、これをカラムクロマトグラフィー
にかけて精製し、80−保護ブロモペネム(II)を得た。Crude (V) was dissolved in dry toluene or xylene (70 ml). Triethyl phosphite (8.7 ml, 50 mmol) was added and the solution was refluxed for 1-6 hours. At the end of the reaction, cool the mixture to 20 ° C. and add phosphate buffer (pH = 7.3 × 2
0 ml) and dried over sodium sulfate. Evaporation of the solvent gave an oil which was purified by column chromatography to give 80-protected bromopenem (II).
IIa(R=CH2OCOCH3,R1=CH2OCONH2,R2=TMS):黄色油
状物;収率50%; 1H−NMRδ(CDCl3):0.13(9H,s,OTMS),1.28(3H,d,CH
3CH),2.1(3H,s,OCOCH3),4.33(1H,m,H−8),5.0−
5.5(2H,AB系,CH2OCONH2),4.95(2H,br,OCONH2),5.75
(1H,s,H−5),5.85(2H,AB系,CH2OCOCH3)。 IIa (R = CH 2 OCOCH 3 , R 1 = CH 2 OCONH 2, R 2 = TMS): yellow oil; 50% yield; 1H-NMRδ (CDCl 3) : 0.13 (9H, s, OTMS), 1.28 (3H, d, CH
3 CH), 2.1 (3H, s, OCOCH 3), 4.33 (1H, m, H-8), 5.0-
5.5 (2H, AB system, CH 2 OCONH 2), 4.95 (2H, br, OCONH 2), 5.75
(1H, s, H-5 ), 5.85 (2H, AB system, CH 2 OCOCH 3).
IIb(R=CH2OCOCH3,R1=CH2OCH3,R2=TMS):黄色油状
物;収率57%; 1H−NMRδ(CDCl3):0.13(9H,s,OTMS),1.3(3H,d,CH3
CH),2.13(3H,s,OCOCH3),3.4(3H,s,OCH3),4.37(1
H,m,H−8),4.64(2H,AB系,CH2OCH3),5.24(1H,s,H−
5),5.58(2H,AB系,CH2OCOCH3)。IIb (R = CH 2 OCOCH 3 , R 1 CHCH 2 OCH 3 , R 2 TMTMS): yellow oil; yield 57%; 1 H-NMR δ (CDCl 3 ): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH 3
CH), 2.13 (3H, s , OCOCH 3), 3.4 (3H, s, OCH 3), 4.37 (1
H, m, H-8) , 4.64 (2H, AB system, CH 2 OCH 3), 5.24 (1H, s, H-
5), 5.58 (2H, AB system, CH 2 OCOCH 3).
IIc(R=CH2OCOCH3,R1=CH3,R2=TMS):黄色油状物;
収率42%; 1H−NMRδ(CDCl3):0.13(9H,s,OTMS),1.3(3H,d,CH3
CH),2.12(3H,s,OCOCH3),2.4(3H,s,2−CH3),4.35
(1H,m,H−8),5.71(1H,s,H−5),5.85(2H,AB系,CH
2OCOCH3)。IIc (R = CH 2 OCOCH 3 , R 1 = CH 3 , R 2 = TMS): yellow oil;
1H-NMRδ (CDCl 3 ): 0.13 (9H, s, OTMS), 1.3 (3H, d, CH 3)
CH), 2.12 (3H, s , OCOCH 3), 2.4 (3H, s, 2-CH 3), 4.35
(1H, m, H-8), 5.71 (1H, s, H-5), 5.85 (2H, AB system, CH
2 OCOCH 3 ).
上記と同様にして得た、保護された(II)を慣用法に
従って脱保護化し、対応する8−OHブロモペネム(II)
を得た。The protected (II), obtained as described above, is deprotected according to conventional methods and the corresponding 8-OH bromopenem (II)
I got
IIe(R=CH2OCOCH3,R1=CH2OCONH2,R2=H):黄色油
状物;1H−NMRδ(CDCl3):1.3(3H,d,CH3CH),2.13(3
H,s,OCOCH3),2.7(1H,br,OH),4.38(1H,m,H−8),5.
05−5.47(2H,AB系,CH2OCONH2),4.98(2H,br,OCON
H2),5.81(1H,s,H−5),5.87(2H,AB系,CH2OCOC
H3)。IIe (R = CH 2 OCOCH 3 , R 1 2CH 2 OCONH 2 , R 2 HH): yellow oil; 1 H-NMR δ (CDCl 3 ): 1.3 (3H, d, CH 3 CH), 2.13 (3
H, s, OCOCH 3 ), 2.7 (1H, br, OH), 4.38 (1H, m, H-8), 5.
05−5.47 (2H, AB system, CH 2 OCONH 2 ), 4.98 (2H, br, OCON
H 2), 5.81 (1H, s, H-5), 5.87 (2H, AB system, CH 2 OCOC
H 3).
IIf(R=CH2OCOCH3,R1=CH2OCH3,R2=H):黄色油状
物;1H−NMRδ(CDCl3):1.3(3H,d,CH3CH),2.13(3H,
s,OCOCH3),2.6(1H,br,OH),3.4(3H,s,OCH3),4.40
(1H,m,H−8),4.64(2H,AB系,CH2OCH3),5.76(1H,s,
H−5),5.85(2H,AB系,CH2OCOCH3)。IIf (R = CH 2 OCOCH 3 , R 1 CHCH 2 OCH 3 , R 2 HH): yellow oil; 1H-NMR δ (CDCl 3 ): 1.3 (3H, d, CH 3 CH), 2.13 (3H,
s, OCOCH 3 ), 2.6 (1H, br, OH), 3.4 (3H, s, OCH 3 ), 4.40
(1H, m, H-8 ), 4.64 (2H, AB system, CH 2 OCH 3), 5.76 (1H, s,
H-5), 5.85 (2H , AB system, CH 2 OCOCH 3).
IIg(R=CH2OCOCH3,R1=CH3 R2=H):黄色油状物;1
H−NMRδ(CDCl3):1.3(3H,d,CH3CH),2.12(3H,s,OCO
CH3),2.4(3H,s,2−CH3),2.9(1H,br,OH),4.35(1H,
m,H−8),5.75(1H,s,H−5),5.79(2H,AB系,CH2OCOC
H3)。 IIg (R = CH 2 OCOCH 3 , R 1 = CH 3 R 2 = H): yellow oil; 1
H-NMR δ (CDCl 3 ): 1.3 (3H, d, CH 3 CH), 2.12 (3H, s, OCO
CH 3 ), 2.4 (3H, s, 2-CH 3 ), 2.9 (1H, br, OH), 4.35 (1H,
m, H-8), 5.75 (1H, s, H-5), 5.79 (2H, AB system, CH 2 OCOC
H 3).
実施例2 (5R,6S)−2−カルバモイルオキシメチル−6−ブロ
モ−6−[1−(R)−ヒドロキシエチル]−ペネム−
3−カルボン酸アセトキシメチル [(II e):R=CH2OCOCH3;R1=CH2OCONH2;R2=H](88
0mg,2mmol)をアセトニトリル(40ml)中に溶解した。1
M酢酸アンモニウム(10ml,10mmol)及び銀/亜鉛カップ
ル(520mg,0.4%Ag)を添加し、この混合物を20℃で75
分間撹拌した。反応終了時に、混合液を濾過し、酢酸エ
チルで希釈し、食塩水で洗浄した。溶剤を蒸発し、カラ
ムクロマトグラフィー(シリカゲル,エチルエーテル/
酢酸エチル60:40v/v)にかけて精製し、白色固体の(5
R,6S)−2−カルバモイルオキシメチル−6−[1−
(R)−ヒドロキシエチル]−ペネム−3−カルボン酸
アセトキシメチル[(Ie):R=CH2OCOCH3;R1=CH2COCNH
2;R2=H]を得た。収量252mg(35%)。Example 2 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H] (88
(0 mg, 2 mmol) was dissolved in acetonitrile (40 ml). 1
M ammonium acetate (10 ml, 10 mmol) and a silver / zinc couple (520 mg, 0.4% Ag) are added and the mixture is cooled at 20 ° C. to 75 ° C.
Stirred for minutes. At the end of the reaction, the mixture was filtered, diluted with ethyl acetate and washed with brine. The solvent was evaporated and column chromatography (silica gel, ethyl ether /
Purification by ethyl acetate 60:40 v / v) gave a white solid (5
R, 6S) -2-carbamoyloxymethyl-6- [1-
(R) -Hydroxyethyl] -penem- 3 -acetoxymethyl carboxylate [(Ie): R = CH 2 OCOCH 3 ; R 1 = CH 2 COCNH
2 ; R 2 = H]. Yield 252 mg (35%).
1H−NMR(CDCl3):δ1.35(3H,d,CH3CH),1.5−1.8(1
H,br,OH),2.13(3H,s,OCOCH3),3.77(1H,dd,H−6),
4.22(1H,m,H−8),4.82(2H,br,NH2),5.27(2H,AB
系,CH2OCONH2),5.65(1H,d,H−5),5.85(2H,AB系,CH
2OCOCH3)。1H-NMR (CDCl 3 ): δ 1.35 (3H, d, CH 3 CH), 1.5-1.8 (1
H, br, OH), 2.13 (3H, s, OCOCH 3), 3.77 (1H, dd, H-6),
4.22 (1H, m, H- 8), 4.82 (2H, br, NH 2), 5.27 (2H, AB
System, CH 2 OCONH 2), 5.65 (1H, d, H-5), 5.85 (2H, AB system, CH
2 OCOCH 3 ).
実施例3 (5R,6S)−2−カルバモイルオキシメチル−6−ブロ
モ−6−[1−(R)−ヒドロキシエチル]−ペネム−
3−カルボン酸アセトキシメチル [(II e):R=CH2OCOCH3;R1=CH2OCONH2;R2=H](92
4mg,2.1mmol)を95%エタノール(18ml)に溶解した。Example 3 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H] (92
4 mg, 2.1 mmol) was dissolved in 95% ethanol (18 ml).
炭酸カルシウム(420mg,4.2mmol)、及び炭酸カルシ
ウム上に担持した10%パラジウム(40mg,0.228mmol P
d)を添加し、室内で1時間、水素雰囲気下で混合液を
撹拌した。触媒を過し、そのアルコール溶液を酢酸エ
チルで希釈し、食塩水で洗浄して、硫酸ナトリウム上で
乾燥した。溶剤を蒸発し、カラムクロマトグラフィー
(シリカゲル,エチルエーテル/酢酸エチル60:40v/v)
にかけて精製して、(5R,6S)−2−カルバモイルオキ
シメチル−6−[1−(R)−ヒドロキシエチル]−ペ
ネム−3−カルボン酸アセトキシメチル[(I e):R=C
H2OCOCH3;R1=CH2OCONH2;R2=H]を白色固体として得
た。収量258mg(34%)。Calcium carbonate (420 mg, 4.2 mmol) and 10% palladium supported on calcium carbonate (40 mg, 0.228 mmol P
d) was added and the mixture was stirred under a hydrogen atmosphere for 1 hour in a room. The catalyst was removed and the alcohol solution was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. Evaporate the solvent and column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v)
And purified by (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate acetoxymethyl [(Ie): R = C
H 2 OCOCH 3; R 1 = CH 2 OCONH 2; the R 2 = H] was obtained as a white solid. Yield 258 mg (34%).
実施例4 (5R,6S)−2−カルバモイルオキシメチル−6−ブロ
モ−6−[1−(R)−トリメチルシリルオキシエチ
ル]−ペネム−3−カルボン酸アセトキシメチル[(II
a)R:=CH2OCOCH3; R1=CH2OCONH2;R2=TMS](1.02g,2mmol)をアセトニト
リル(40ml)に溶解した。1Mギ酸アンモニウム(10ml,1
0mmol)と活性化亜鉛(260mg,4mmol)とを添加し、この
混合液を20℃で30分間撹拌した。反応終了時、混合液を
過し、酢酸エチルで希釈し、食塩水で洗浄した。溶剤
を蒸発し、カラムクロマトグラフィ−(シリカゲル,エ
チルエーテル/酢酸エチル2:1v/v)にかけて精製して、
(5R,6S)−2−カルバモイルオキシメチル−6−[1
−(R)−トリメチルシリルオキシエチル]−ペネム−
3−カルボン酸アセトキシメチル[(I a):R=CH2OCOC
H3;R1=CH2OCONH2;R2=TMS]を得た。黄色油状物。収量
260mg(30%)。Example 4 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -trimethylsilyloxyethyl] -penem-3-carboxylate acetoxymethyl [(II
a) R: = CH 2 OCOCH 3 ; R 1 = CH 2 OCONH 2 ; R 2 = TMS] (1.02 g, 2 mmol) was dissolved in acetonitrile (40 ml). 1M ammonium formate (10ml, 1
0 mmol) and activated zinc (260 mg, 4 mmol) were added and the mixture was stirred at 20 ° C. for 30 minutes. At the end of the reaction, the mixture was filtered, diluted with ethyl acetate, and washed with brine. The solvent was evaporated and purified by column chromatography (silica gel, ethyl ether / ethyl acetate 2: 1 v / v),
(5R, 6S) -2-carbamoyloxymethyl-6- [1
-(R) -trimethylsilyloxyethyl] -penem-
Acetoxymethyl 3-carboxylate [(Ia): R = CH 2 OCOC
H 3 ; R 1 = CH 2 OCONH 2 ; R 2 = TMS]. Yellow oil. yield
260 mg (30%).
1H−NMR(CDCl3):δ0.13(9H,s,TMS),1.24(3H,d,CH
3CH),2.12(3H,s,OCOCH3),3.70(1H,dd,H−6),4.18
(1H,m,H−8),4.95(2H,br,NH2),5.27(2H,AB系,CH2
OCONH2),5.35(1H,d,H−5),5.83(2H,AB系,CH2OCOCH
3)。1H-NMR (CDCl 3 ): δ 0.13 (9H, s, TMS), 1.24 (3H, d, CH
3 CH), 2.12 (3H, s, OCOCH 3), 3.70 (1H, dd, H-6), 4.18
(1H, m, H-8 ), 4.95 (2H, br, NH 2), 5.27 (2H, AB system, CH 2
OCONH 2 ), 5.35 (1H, d, H-5), 5.83 (2H, AB system, CH 2 OCOCH)
3 ).
実施例5 (5R,6S)−2−メトキシメチル−6−ブロモ−6−
[1−(R)−ヒドロキシルエチル]−ペネム−3−カ
ルボン酸アセトキシメチル[(II f):R=CH2OCOCH3,R1
=CH2OCH3,R2=H](820mg,2mmol)をエチルエーテル
(40ml)に溶解した。1M酢酸アンモニウム(10ml,10mmo
l)と85%亜鉛(615mg,8mmol)とを添加し、その混合液
を室温で2時間撹拌した。反応終了時、混合液を過
し、食塩水で洗浄し、硫酸ナトリウム上で乾燥した。溶
剤を蒸発し、カラムクロマトグラフィー(シリカゲル,
エチルエーテル)にかけて精製して、(5R,6S)−2−
メトキシメチル−6−[1−(R)−ヒドロキシルエチ
ル]−ペネム−3−カルボン酸アセトキシメチル[(I
f):R=CH2OCOCH3,R1=CH2OCH3,R2=H]を得た。油状
物。収量250mg(38%)。Example 5 (5R, 6S) -2-methoxymethyl-6-bromo-6
[1- (R) -hydroxylethyl] -penem-3-acetoxymethyl carboxylate [(IIf): R = CH 2 OCOCH 3 , R 1
= Dissolved CH 2 OCH 3, R 2 = H] (820mg, 2mmol) in ethyl ether (40 ml). 1M ammonium acetate (10ml, 10mmo
l) and 85% zinc (615 mg, 8 mmol) were added and the mixture was stirred at room temperature for 2 hours. At the end of the reaction, the mixture was filtered, washed with brine, and dried over sodium sulfate. The solvent was evaporated and column chromatography (silica gel,
(5R, 6S) -2-
Acetoxymethyl methoxymethyl-6- [1- (R) -hydroxylethyl] -penem-3-carboxylate [(I
f): R = CH 2 OCOCH 3 , R 1 = CH 2 OCH 3 , R 2 = H]. Oil. Yield 250 mg (38%).
1H−NMR(CDCl3):δ1.33(3H,d,CH3CH),2.13(3H,s,
OCOCH3),3.42(3H,s,OCH3),3.72(1H,dd,H−6),4.2
2(1H,m,H−8),4.61(2H,AB系,CH2OCH3),5.62(1H,
d,H−5),5.83(2H,AB系,CH2OCOCH3)。1H-NMR (CDCl 3 ): δ 1.33 (3H, d, CH 3 CH), 2.13 (3H, s,
OCOCH 3 ), 3.42 (3H, s, OCH 3 ), 3.72 (1H, dd, H-6), 4.2
2 (1H, m, H-8), 4.61 (2H, AB system, CH 2 OCH 3 ), 5.62 (1H,
d, H-5), 5.83 (2H, AB system, CH 2 OCOCH 3).
実施例6 (5R,6S)−2−カルバモイルオキシメチル−6−ブロ
モ−6−[1−(R)−ヒドロキシエチル]−ペネム−
3−カルボン酸アセトキシメチル[(II e):=R=CH
2OCOCH3;R1=CH2OCONH2;R2=H](880mg,2mmol)をア
セトニトリル(40ml)に溶解した。1M酢酸亜鉛(10ml,1
0mmol)及び銀−亜鉛カップル(520mg.0.4%銀)を添加
し、その混合液を20℃で40分間撹拌した。反応終了後
に、混合液を過し、酢酸エチルで希釈して、食塩水で
洗浄した。溶剤を蒸発し、カラムクロマトグラフィー
(シリカゲル,エチルエーテル/酢酸エチル60:40v/v)
にかけて精製して、(5R,6S)−2−カルバモイルオキ
シメチル−6−[1−(R)−ヒドロキシエチル]−ペ
ネム−3−カルボン酸アセトキシメチル[(I e):=
R=CH2OCOCH3;R1=CH2OCONH2;R2=H]を白色固体とし
て得た。収量215mg(30%)。Example 6 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
Acetoxymethyl 3-carboxylate [(II e): = R = CH
2 OCOCH 3 ; R 1 CHCH 2 OCONH 2 ; R 2 HH] (880 mg, 2 mmol) was dissolved in acetonitrile (40 ml). 1M zinc acetate (10ml, 1
0 mmol) and a silver-zinc couple (520 mg. 0.4% silver) were added and the mixture was stirred at 20 ° C. for 40 minutes. After completion of the reaction, the mixture was passed through, diluted with ethyl acetate, and washed with brine. Evaporate the solvent and column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v)
And purified by acetoxymethyl (5R, 6S) -2-carbamoyloxymethyl-6- [1- (R) -hydroxyethyl] -penem-3-carboxylate [(Ie): =
R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; to give the R 2 = H] as a white solid. Yield 215 mg (30%).
実施例7 (5R,6S)−2−カルバモイルオキシメチル−6−ブロ
モ−6−[1−(R)−ヒドロキシエチル]−ペネム−
3−カルボン酸アセトキシメチル [(II e):=R=CH2OCOCH3;R1=CH2OCONH2;R2=H]
(880mg,2mmol)をアセトニトリル(40ml)に溶解し
た。Example 7 (5R, 6S) -2-carbamoyloxymethyl-6-bromo-6- [1- (R) -hydroxyethyl] -penem-
3-carboxylic acid acetoxymethyl [(II e): = R = CH 2 OCOCH 3; R 1 = CH 2 OCONH 2; R 2 = H]
(880 mg, 2 mmol) was dissolved in acetonitrile (40 ml).
1Mの塩化アンモニウム(10ml,10mmol)と銀/亜鉛カ
ップル(520mg,0.4%銀)とを添加し、その混合液を20
℃で20分間撹拌した。反応終了後、混合液を過し、酢
酸エチルで希釈して、食塩水で洗浄した。溶剤を蒸発
し、カラムクロマトグラフィー(シリカゲル,エチルエ
ーテル/酢酸エチル60:40v/v)にかけて精製して、(5
R,6S)−2−カルバモイルオキシメチル−6−[1−
(R)−ヒドロキシエチル]−ペネム−3−カルボン酸
アセトキシメチル[(I e):=R=CH2OCOCH3;R1=CH2
OCONH2;R2=H]を白色固体として得た。収量180mg(28
%)。1M ammonium chloride (10 ml, 10 mmol) and a silver / zinc couple (520 mg, 0.4% silver) were added and the mixture was added for 20 minutes.
Stirred at C for 20 minutes. After completion of the reaction, the mixture was passed, diluted with ethyl acetate, and washed with brine. The solvent was evaporated and purified by column chromatography (silica gel, ethyl ether / ethyl acetate 60:40 v / v) to give (5
R, 6S) -2-carbamoyloxymethyl-6- [1-
(R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl [(I e): = R = CH 2 OCOCH 3; R 1 = CH 2
OCONH 2 ; R 2 = H] was obtained as a white solid. Yield 180mg (28
%).
実施例8 (5R,6S)−2−メチル−6−ブロモ−6−[1−
(R)−ヒドロキシエチル]−ペネム−3−カルボン酸
アセトキシメチル[IIg):R=CH2OCOCH3,R1=CH3,R2=
H](760mg,2mmol)を酢酸エチル(40ml)に溶解し
た。1M酢酸アンモニウム(10ml,10mmol)と85%亜鉛(6
15mg,8mmol)とを添加し、その混合液を20℃で3時間撹
拌した。反応終了時、混合液を過し、食塩水で洗浄し
て、硫酸ナトリウム上で乾燥した。溶剤を蒸発し、カラ
ムクロマトグラフィー(シリカゲル,エチルエーテル)
にかけて精製して、(5R,6S)−2−メチル−6−[1
−(R)−ヒドロキシエチル]−ペネム−3−カルボン
酸アセトキシメチル[I g:R=CH2OCOCH3,R1=CH3,R2=
H]を得た。黄色油状物。収量110mg(18%)。Example 8 (5R, 6S) -2-methyl-6-bromo-6- [1-
(R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl [IIg): R = CH 2 OCOCH 3, R 1 = CH 3, R 2 =
H] (760 mg, 2 mmol) was dissolved in ethyl acetate (40 ml). 1 M ammonium acetate (10 ml, 10 mmol) and 85% zinc (6
15 mg, 8 mmol) and the mixture was stirred at 20 ° C. for 3 hours. At the end of the reaction, the mixture was filtered, washed with brine and dried over sodium sulfate. Evaporate the solvent and column chromatography (silica gel, ethyl ether)
And purified by (5R, 6S) -2-methyl-6- [1
- (R) - hydroxyethyl] - penem-3-carboxylic acid acetoxymethyl [I g: R = CH 2 OCOCH 3, R 1 = CH 3, R 2 =
H]. Yellow oil. Yield 110 mg (18%).
1H−NMR(CDCl3):δ1.3(3H,d,CH3CH),2.13(3H,s,O
COCH3),2.38(3H,s,2−CH3),2.80(1H,br,OH),3.80
(1H,dd,H−6),4.20(1H,m,H−8),5.65(1H,d,H−
5),5.85(2H,AB系,CH2OCOCH3)。1H-NMR (CDCl 3 ): δ1.3 (3H, d, CH 3 CH), 2.13 (3H, s, O
COCH 3), 2.38 (3H, s, 2-CH 3), 2.80 (1H, br, OH), 3.80
(1H, dd, H-6), 4.20 (1H, m, H-8), 5.65 (1H, d, H-
5), 5.85 (2H, AB system, CH 2 OCOCH 3).
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭56−65892(JP,A) 特開 昭61−180766(JP,A) 特開 昭63−316784(JP,A) 特開 昭57−99589(JP,A) J.Am.Chem.Soc. (1985),107,pages 6398− 6399 (58)調査した分野(Int.Cl.6,DB名) C07D 499/00 - 499/82 CA(STN) REGISTRY(STN)──────────────────────────────────────────────────続 き Continuation of front page (56) References JP-A-56-65892 (JP, A) JP-A-61-180766 (JP, A) JP-A-63-316784 (JP, A) JP-A-57-658 99589 (JP, A) Am. Chem. Soc. (1985), 107, pages 6398-6399 (58) Fields investigated (Int. Cl. 6 , DB name) C07D 499/00-499/82 CA (STN) REGISTRY (STN)
Claims (12)
ルカノイル基もしくはC4〜C8シクロアルカノイル基であ
るアルカノイルオキシメチル又は1−(アルカノイルオ
キシ)エチル; b)ベンゾイルオキシメチル又は1−(ベンゾイルオキ
シ)エチル; c)アルコキシカルボニルオキシメチル又は1−(アル
コキシカルボニルオキシ)エチル; d)3−フタリジル; e)5位がC1〜C4アルキル基で置換されているか又は置
換されていない2−オキソ−1,3−ジオキソラン−4−
イル; f)R′がC1〜C4直鎖もしくは分枝鎖アルキル又はベン
ジである−CH2COOR′; あるいは g)4位がC1〜C4アルキル基で置換されているか又は置
換されていない2−オキソテトラヒドロフラン−5−イ
ルを表わし、 R1は、テトラヒドロフラニル基、あるいは置換されてい
るか又は置換されていないC1〜C4アルキル基、メチルフ
ェニル基若しくはメチルフェノキシメチル基であって、
置換基は以下の基から選択される: (i)カルバモイルオキシ,C1〜C18アルコキシ,カルボ
キシ,又は遊離もしくは保護されたヒドロキシ,及び (ii)置換されているか又は置換されていないピリジニ
ウム,N−メチルピロリジニウム若しくはピペリジニウム
であって、これらはフェニル基、飽和又は不飽和のC5〜
C7脂環式基又はヘテロ環式基と縮合していてもよく、そ
の置換基が上記(i)の基であるか又はスルホニルオキ
シ基もしくはカルボキシ基により置換されているか又は
置換されていないC1〜C4アルキル基である;及び、 R2は水素原子か又はヒドロキシ保護基を表わす)の化合
物の製造方法であって、式(II) (式中R,R1及びR2は上記の意味を有する) の化合物を還元することを特徴とする前記製造方法。(1) Formula (I): (Wherein R a) alkanoyl moiety is a linear or branched C 2 -C 10 alkanoyl or C 4 -C 8 cycloalkanoyl alkanoyloxymethyl a group or a 1- (alkanoyloxy) ethyl; b) benzoyloxy methyl or 1- (benzoyloxy) ethyl; c) alkoxycarbonyloxymethyl or 1- (alkoxycarbonyloxy) ethyl; d) 3- phthalidyl; e) or 5-position is substituted by C 1 -C 4 alkyl or Unsubstituted 2-oxo-1,3-dioxolan-4-
Yl; it is or a substituted or g) 4-position is substituted by C 1 -C 4 alkyl group; f) R 'is -CH 2 COOR a C 1 -C 4 straight or branched chain alkyl or benzyl' R 1 is a tetrahydrofuranyl group, or a substituted or unsubstituted C 1 -C 4 alkyl group, methylphenyl group or methylphenoxymethyl group; ,
The substituents are selected from: (i) carbamoyloxy, C 1 -C 18 alkoxy, carboxy, or free or protected hydroxy, and (ii) substituted or unsubstituted pyridinium, N - a methyl pyrrolidinium or piperidinium, these phenyl, a saturated or C 5 ~ unsaturated
C 7 may be condensed with an alicyclic group or a heterocyclic group, and the substituent thereof is the group of the above (i), or is substituted or unsubstituted by a sulfonyloxy group or a carboxy group. 1 -C is 4 alkyl group; and to a process for the preparation of compounds of R 2 represents a hydrogen atom or a hydroxy protecting group), the formula (II) Wherein R, R 1 and R 2 have the above-mentioned meanings.
求の範囲第1項記載の方法。2. The method according to claim 1, wherein the reduction is carried out by catalytic hydrogenation.
なう特許請求の範囲第1項記載の方法。3. The method according to claim 1, wherein the reduction is performed by a treatment using a reducing metal.
合金である特許請求の範囲第3項記載の方法。4. The method according to claim 3, wherein the reducing metal is zinc or an alloy of zinc and another metal.
る特許請求の範囲第4項記載の方法。5. The method according to claim 4, wherein the reducing metal is an alloy of zinc and copper or silver.
トロベンジルオキシカルボニル基,トリメチルシリル
基,t−ブチルジメチルシリル基,t−ブチルジフェニルシ
リル基,メトキシメチル基,ベンジル基,p−ブロモフェ
ナシル基,トリフェニルメチル基又はテトラヒドロピラ
ニル基である特許請求の範囲第1項〜第5項のいずれか
一項に記載の方法。6. The method according to claim 1 , wherein the hydroxy-protecting moiety of R 2 or R 1 is p-nitrobenzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methoxymethyl, benzyl, p-nitrobenzyl. The method according to any one of claims 1 to 5, wherein the method is a bromophenacyl group, a triphenylmethyl group, or a tetrahydropyranyl group.
ンモニウム又は亜鉛カルボキシレート又はハロゲン化物
の水性溶液存在下で還元を行なう特許請求の範囲第1項
〜第6項のいずれか一項に記載の方法。7. The method according to claim 1, wherein the reduction is carried out in an organic solvent at a temperature of -20.degree. C. to + 80.degree. C. in the presence of an aqueous solution of ammonium or zinc carboxylate or a halide. A method according to claim 1.
かに定義された式(II)の化合物。8. A compound of formula (II) as defined in any one of claims 1 and 6.
特許請求の範囲第8項に定義された式(II)の化合物の
製造方法。 (式中R,R1及びR2は特許請求の範囲第1項又は第6項に
記載の意味を有する。)9. A process for preparing a compound of formula (II) as defined in claim 8, comprising cyclizing the compound of formula (V). (Wherein R, R 1 and R 2 have the meanings described in claims 1 or 6)
イト又はトリメチルホスファイトを用いて環化を行なう
特許請求の範囲第9項記載の方法。10. The process according to claim 9, wherein the cyclization is carried out using triethyl phosphite or trimethyl phosphite in an inert organic solvent.
を有する) の化合物のオゾン分解により式(V)の化合物を製造す
る特許請求の範囲第9項又は第10項記載の方法。11. Formula (III): (Wherein R, R 1 and R 2 means has according to paragraph 9 claims) Claims 9 or paragraph 10 for preparing a compound of formula (V) by ozonolysis of a compound of The method described in the section.
1項に定義された式(II)の化合物。12. A compound of formula (II) as defined in claim 1 as specified herein.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8815821A GB2220203B (en) | 1988-07-04 | 1988-07-04 | Process for penems |
GB8815821.7 | 1988-07-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0267287A JPH0267287A (en) | 1990-03-07 |
JP2922220B2 true JP2922220B2 (en) | 1999-07-19 |
Family
ID=10639813
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP1171736A Expired - Lifetime JP2922220B2 (en) | 1988-07-04 | 1989-07-03 | Penem recipe |
Country Status (4)
Country | Link |
---|---|
JP (1) | JP2922220B2 (en) |
DE (1) | DE3921830A1 (en) |
GB (1) | GB2220203B (en) |
IT (1) | IT1230959B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69131753T2 (en) * | 1990-08-20 | 2000-05-04 | Suntory Limited, Osaka | ANTIBACTERIAL PENEM ESTER DERIVATIVES |
CA2089366C (en) * | 1990-08-20 | 2001-10-16 | Hiromitsu Iwata | Penem compounds |
JP3148235B2 (en) * | 1990-08-20 | 2001-03-19 | サントリー株式会社 | Antibacterial penem compounds |
-
1988
- 1988-07-04 GB GB8815821A patent/GB2220203B/en not_active Expired - Fee Related
-
1989
- 1989-06-30 IT IT8921055A patent/IT1230959B/en active
- 1989-07-03 JP JP1171736A patent/JP2922220B2/en not_active Expired - Lifetime
- 1989-07-03 DE DE3921830A patent/DE3921830A1/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
J.Am.Chem.Soc.(1985),107,pages 6398−6399 |
Also Published As
Publication number | Publication date |
---|---|
JPH0267287A (en) | 1990-03-07 |
GB2220203A (en) | 1990-01-04 |
GB2220203B (en) | 1991-09-11 |
GB8815821D0 (en) | 1988-08-10 |
DE3921830A1 (en) | 1990-02-22 |
IT8921055A0 (en) | 1989-06-30 |
IT1230959B (en) | 1991-11-08 |
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