JPH01216968A - Production of 4-acetyl-beta-lactam derivative - Google Patents
Production of 4-acetyl-beta-lactam derivativeInfo
- Publication number
- JPH01216968A JPH01216968A JP63040750A JP4075088A JPH01216968A JP H01216968 A JPH01216968 A JP H01216968A JP 63040750 A JP63040750 A JP 63040750A JP 4075088 A JP4075088 A JP 4075088A JP H01216968 A JPH01216968 A JP H01216968A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- beta
- acetyl
- group
- lactam
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 150000003462 sulfoxides Chemical class 0.000 claims abstract description 6
- 150000003568 thioethers Chemical class 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 230000002140 halogenating effect Effects 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract 3
- 229910052740 iodine Inorganic materials 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 150000003951 lactams Chemical class 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 18
- 150000001875 compounds Chemical class 0.000 abstract description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 239000000460 chlorine Substances 0.000 abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 abstract 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract 1
- 150000002961 penems Chemical class 0.000 abstract 1
- 239000002132 β-lactam antibiotic Substances 0.000 abstract 1
- 229940124586 β-lactam antibiotics Drugs 0.000 abstract 1
- -1 dimethyl sulfoxide Chemical class 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DPGBHCGFIJENSU-UHFFFAOYSA-N 4-acetylazetidin-2-one Chemical compound CC(=O)C1CC(=O)N1 DPGBHCGFIJENSU-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野〕
本発明は、−数式［Ｉ［［］
（式中、Ｒ１，Ｒｚは一体となってオキソ基を表すか、
Ｒ＋、 ｌ震の一方が水素原子のとき他方は水酸基また
は保護された水酸基を表す Ｒ３は水素原子、アルキル
基、アリール基またはシリル基を示す、）で示される４
−アセチル−β−ラクタム誘導体の製造方法に係わり、
その目的とするところは、医薬中間体として有用な４−
アセチル−β−ラクタム誘導体を工業的に有利な条件で
製造する方法を提供することにある。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to -the formula [I[[] (wherein R1 and Rz together represent an oxo group,
When one of the R+ and l-shapes is a hydrogen atom, the other represents a hydroxyl group or a protected hydroxyl group. R3 represents a hydrogen atom, an alkyl group, an aryl group, or a silyl group.
-Relating to a method for producing an acetyl-β-lactam derivative,
The purpose is to use 4-4, which is useful as a pharmaceutical intermediate.
The object of the present invention is to provide a method for producing acetyl-β-lactam derivatives under industrially advantageous conditions.
４−サセチルーβ−ラクタム誘導体はチェナマイシンに
代表されるカルバペネムまたはペネム系β−ラクタム抗
生物質の鍵合成中間体である光学活性（３Ｒ，４Ｒ，ｌ
’ Ｒ）−４−アセトキシ−３−（１−アルコキシエ
チル）−２−アゼチジノンの合成原料として用いられる
＊ （ＴｅｔｒａｈｅｄｏｒｏｎＬｅｔｔ、、 １３
−、５７５１．１９８６）〔従来の技術〕
従来、−数式［Ｉ１で示される４−（１−ヒドロキシエ
チル）−β−ラクタム化合物から一般式［Ｉ［［］で示
される４−アセチル−β−ラクタム誘導体を製造する方
法としては、ピリジン中で無水クロム酸を用いて酸化す
る方法が知られている。4-Sacetyl-β-lactam derivatives are optically active (3R, 4R,
' R) - Used as a raw material for the synthesis of -4-acetoxy-3-(1-alkoxyethyl)-2-azetidinone* (Tetrahedoron Lett, 13
-, 5751.1986) [Prior Art] Conventionally, - from a 4-(1-hydroxyethyl)-β-lactam compound represented by the formula [I1 to 4-acetyl-β- represented by the general formula [I] A known method for producing lactam derivatives is oxidation using chromic anhydride in pyridine.
（Ｔｅｔｒａｈｅｄｏｒｏｎ Ｌｅｔｔ−＋ ２７．＋
５７５１＋ １９８６）しかし、この方法では反応を
完結させるために過剰の無水クロム酸を用いており、工
業的に実施した場合、未反応の６価クロムの処理に問題
を来すと考えられ有効な工業的製法とは言い難い。(Tetrahedoron Lett-+ 27.+
5751+ 1986) However, this method uses an excess of chromic anhydride to complete the reaction, and if carried out industrially, it would pose a problem in the treatment of unreacted hexavalent chromium, making it difficult to implement it industrially. It is hard to say that it is a perfect manufacturing method.
本発明者らは一般式［Ｉ］で示されるー（１−ヒドロキ
シエチル）−β−ラクタム誘導体から、−数式［■］で
示される４−アセチル−β−ラクタム誘導体への酸化工
程を、安価で廃棄物処理に問題のない酸化剤で実施すべ
く重金属を用いない系での酸化を種々検討した。その結
果、−数式チルスルフィド、メチルフェニルスルフィド
等のスルフィド類またはジメチルスルホキシド等のスル
ホキシド類と反応させた後、トリエチルアミン等の塩基
で処理することにより高収率で酸化反応が進行すること
を見いだし、４−アセチル−β−ラクタム誘導体の新規
合成法として本発明を完成させたものである。The present inventors have demonstrated an inexpensive oxidation process from the -(1-hydroxyethyl)-β-lactam derivative represented by the general formula [I] to the 4-acetyl-β-lactam derivative represented by the formula [■]. We investigated various oxidation systems that do not use heavy metals in order to use oxidizing agents that do not cause problems in waste treatment. As a result, it was found that the oxidation reaction proceeded in high yield by reacting with sulfides such as formula tylsulfide and methylphenylsulfide or sulfoxides such as dimethyl sulfoxide, and then treating with a base such as triethylamine. The present invention has been completed as a new method for synthesizing 4-acetyl-β-lactam derivatives.
本発明において用いられる、−数式［ＩＩ］で示される
ハロゲン化剤とスルフィド類またはスルホキシド類とは
例えばジメチルスルフィドを例にとれば、以下の図に示
されるように化合物［Ａ］で示される錯化合物を形成し
た後、４−（１−ヒドロキシエチル）−β−ラクタム誘
導体と反応し、化合物［Ｂ］で示される中間体を生成す
る。この中間体はトリエチルアミンなどの塩基で処理す
ることにより、効果的に４−アセチル−β−ラクタム誘
導体に変換されるものである。The halogenating agent represented by the formula [II] and the sulfides or sulfoxides used in the present invention include, for example, dimethyl sulfide, which is a complex represented by the compound [A] as shown in the figure below. After forming the compound, it reacts with a 4-(1-hydroxyethyl)-β-lactam derivative to produce an intermediate represented by compound [B]. This intermediate is effectively converted into a 4-acetyl-β-lactam derivative by treatment with a base such as triethylamine.
化合物（Ｂ）
本発明において、原料として用いられる４−（１−ヒド
ロキシエチル）−β−ラクタム誘導体は一般式［Ｉ］で
示される化合物のセラミ体、あるいは光学活性体を表し
、３位の側鎖上のｉｌｌ、 Ｒ”は一体となってオキソ
基を表すか、Ｒ１，Ｒ１の一方が水素原子のとき他方は
水酸基または保護された水酸基を表す、水酸基の保護基
としては、例えばトリメチルシリル、トリエチルシリル
、ｔ−ブチルジメチルシリル、ｔ−ブチルジフェニルシ
リル等のトリアルキルシリル基、例えばメトキシメチル
、メチルチオメチル、ベンジルオキシメチル、１−ブト
キシメチル、（２−メトキシエトキシ）メチル、１−エ
トキシエチル、２−メトキシ−２−プロピル、テトラヒ
ドロピラニル等のアルコキシアルキル基、例えば、ベン
ジル、ｐ−メトキシベンジル、２．４−ジメトキシベン
ジル、Ｏ−ニトロベンジル、Ｐ−ニトロベンジル簀の置
換あるいは無置換モノアリールメチル基、例えば、アセ
チル、ベンゾイル、Ｐ−メトキシベンゾイル、ｐ−ニト
ロベンゾイル等のアシル基、例えば、ベンジルオキシカ
ルボニル、ｐ−メトキシベンジルオキシカルボニル、ｐ
−ニトロベンジルオキシカルボニル基等を例示すること
が出来る。また、Ｒ３は水素原子またはアルキル基、ア
リール基およびシリル基を有する置換基が挙げられるが
、更に詳しくは、アルキル基として、例えばベンジルオ
キシカルボニルメチル、ｐ−ニトロベンジルオキシカル
ボニルメチル、メトキシカルボニルメチル、エトキシカ
ルボニルメチル、ｔ−ブトキシカルボニルメチルのよう
なアルコキシカルボニルメチル基、例えばベンジル、ｐ
−メトキシベンジル、２，４−ジメトキシベンジル、０
−ニトロベンジル、ｐ−−＝−トロベンジルのような置
換あるいは無置換のモノアリールメチル基、例えばジフ
ェニルメチル、ジ−ルーアニーシルメチル、ジ−ｐ−ニ
トロフェニルメチルのような置換あるいは無置換のジア
リールメチル基等を例示することができ、アリール基と
しては、例えばフェニル、ｐ−フェニル、２，４−ジメ
トキシフェニル、ｐ−ニトロフェニル等の置換あるいは
無置換アリール基を例示することができ、シリル基とし
ては、トリメチルシリル、トリエチルシリル、ｔ−ブチ
ルジメチルシリル、を−ブチルジフェニルシリルのよう
なトリ置換シリル基を例示することができる。Compound (B) In the present invention, the 4-(1-hydroxyethyl)-β-lactam derivative used as a raw material represents a ceramide or optically active compound of the compound represented by the general formula [I], and ill and R'' on the chain together represent an oxo group, or when one of R1 and R1 is a hydrogen atom, the other represents a hydroxyl group or a protected hydroxyl group. Examples of protecting groups for hydroxyl groups include trimethylsilyl, triethyl, etc. Trialkylsilyl groups such as silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 1-butoxymethyl, (2-methoxyethoxy)methyl, 1-ethoxyethyl, 2 - Alkoxyalkyl groups such as methoxy-2-propyl and tetrahydropyranyl, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, O-nitrobenzyl, and P-nitrobenzyl, substituted or unsubstituted monoarylmethyl groups, such as acetyl, benzoyl, p-methoxybenzoyl, p-nitrobenzoyl, etc. acyl groups, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p
-Nitrobenzyloxycarbonyl group, etc. can be exemplified. Further, R3 may be a hydrogen atom or a substituent having an alkyl group, an aryl group, or a silyl group, and more specifically, examples of the alkyl group include benzyloxycarbonylmethyl, p-nitrobenzyloxycarbonylmethyl, methoxycarbonylmethyl, Alkoxycarbonylmethyl groups such as ethoxycarbonylmethyl, t-butoxycarbonylmethyl, e.g. benzyl, p
-methoxybenzyl, 2,4-dimethoxybenzyl, 0
- Substituted or unsubstituted monoarylmethyl groups such as -nitrobenzyl, p--=-trobenzyl; substituted or unsubstituted diaryl groups such as diphenylmethyl, di-ruanisylmethyl, di-p-nitrophenylmethyl; Examples of the aryl group include substituted or unsubstituted aryl groups such as phenyl, p-phenyl, 2,4-dimethoxyphenyl, p-nitrophenyl, and silyl groups. Examples include trisubstituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and -butyldiphenylsilyl.
本発明で用いられる一般式［Ｉ１］で示されるハロゲン
化剤には、塩素、臭素、ヨウ素等のハロゲン分子、Ｎ−
クロロスクシンイミド、Ｎ−ブロモスクシンイミド等の
アルキルイミドが例示され、原料化合物に対し通常１〜
１０当量用いられる。The halogenating agent represented by the general formula [I1] used in the present invention includes halogen molecules such as chlorine, bromine, and iodine, N-
Alkylimides such as chlorosuccinimide and N-bromosuccinimide are exemplified;
10 equivalents are used.
また、スルフィド類またはスルホキシド類は、原料化合
物に対し、通常１〜１０当量用いられる。Moreover, sulfides or sulfoxides are usually used in an amount of 1 to 10 equivalents based on the raw material compound.
また、本発明に用いられる溶媒としては、ベンゼン、ト
ルエン、キシレン、ヘキサンなどの炭化水素系溶媒、ク
ロロホルム、ジクロロメタン、四塩化炭素などのハロゲ
ン化炭素溶媒およびジメチルスルホキシド等の溶媒が例
示できる０反応は−５０ ’Ｃ〜０°Ｃにおいて良好に
進行する０反応後の反応液に、反応時の温度に保ったま
まトリエチルアミン等の塩基を加えることにより、−数
式［■］で示される４−アセチル−β−ラクタム誘導体
が生成する。In addition, examples of the solvent used in the present invention include hydrocarbon solvents such as benzene, toluene, xylene, and hexane, halogenated carbon solvents such as chloroform, dichloromethane, and carbon tetrachloride, and solvents such as dimethyl sulfoxide. By adding a base such as triethylamine to the reaction solution after the 0 reaction, which progresses well at -50'C to 0°C, while maintaining the reaction temperature, -4-acetyl- represented by the formula [■] A β-lactam derivative is produced.
反応終了後は反応液を希塩酸で処理した後、水洗、濃縮
等の処理を行うことにより目的化合物である４−アセチ
ル−β−ラクタム誘導体を取り出すことが出来る。After the reaction is completed, the target compound, 4-acetyl-β-lactam derivative, can be extracted by treating the reaction solution with dilute hydrochloric acid, followed by washing with water, concentration, etc.
以下に実施例を挙げて本発明を説明するが、本発明はこ
れらに限定されるものではない、なお、７ｅｔｐａｈｔ
ｌｐｒａＨ
実施例１で示される原料化合物は
Ｌｅｔｔ、、 ２７．５７５１．１９８６の方法によっ
て合成し、実施例２で示される原料化合物はＣｈｅ＋ｍ
、 Ｌｅｔｔ、＋４４５、１９８７の方法によって合成
した。The present invention will be described below with reference to Examples, but the present invention is not limited thereto.
lpraH The raw material compound shown in Example 1 was synthesized by the method of Lett, 27.5751.1986, and the raw material compound shown in Example 2 was synthesized by Che+m
, Lett, +445, 1987.
（実施例１）
Ｎ〜ジクロロクシンイミド１２５．０１！Ｉｇ（０，９
３５ｓｍｏｌ ）をトルエン５ｄに添加し、４０°Ｃに
て完全に溶解した。この溶液を室温まで徐々に冷却し、
ジメチルス！レフイド５８．１■（０，９３６ｍ曽ｏ１
）ヲ添加した。この溶液を直ちにＯ″Ｃまで冷却し、そ
のまま２０分間撹拌した。その後、反応液を一２５°Ｃ
まで冷却しく３Ｓ、４Ｓ、１’ Ｒ，１’ ５）−３
−（１’ −ｔ−ブチルジメチルシリルオキシエチル）
−４−（１”−ヒドロキシエチル）−２−アゼチジノン
６４．０■（０，２３４ｍｏｌ）をトルエン０．９ ｍ
に溶かした溶液を徐々に滴下し、そのまま−２５°Ｃに
て２時間４０分撹拌した。反応液にトリエチルアミン（
１３６μりを加え１５分間撹拌し、その後室温まで戻し
反応液を１規定塩酸１ｄで洗浄した。有機層を飽和食塩
水で水洗後、硫酸マグネシウムで乾燥した。溶媒を減圧
留去した後、得られた残渣をシリカゲルカラム（ジクロ
ロメタン〜ジクロロメタン：アセトン−２０：１）で分
離精製し、（３Ｓ、４Ｓ、１’ Ｒ）−３−（１°
−ｔ−プチルジメチルシリルオキシエチ。(Example 1) N~dichlorouccinimide 125.01! Ig(0,9
35 smol) was added to 5 d of toluene and completely dissolved at 40°C. The solution was gradually cooled to room temperature,
Dimethylsu! Refuid 58.1■ (0,936m so o1
) was added. The solution was immediately cooled to O''C and stirred for 20 minutes.Then, the reaction solution was cooled to -25°C.
Cool until 3S, 4S, 1' R, 1' 5)-3
-(1'-t-butyldimethylsilyloxyethyl)
-4-(1''-hydroxyethyl)-2-azetidinone 64.0 ml (0,234 mol) was added to 0.9 m of toluene.
A solution dissolved in was gradually added dropwise, and the mixture was stirred at -25°C for 2 hours and 40 minutes. Triethylamine (
After adding 136 μl of the mixture and stirring for 15 minutes, the mixture was returned to room temperature and the reaction solution was washed with 1 d of 1N hydrochloric acid. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was separated and purified using a silica gel column (dichloromethane to dichloromethane:acetone-20:1) to give (3S, 4S, 1′ R)-3-(1°
-t-butyldimethylsilyloxyethyl.
ル）−４−アセチル−２−アゼチジノン６０．０■（収
率９５％）を得た。60.0 ml of 4-acetyl-2-azetidinone (yield: 95%) was obtained.
ＨＮＭＲ（ＣＤＣｌ ｓ） δ＝０．１１ （６Ｈ，
ｓ、 （ＣＨｓ）ｚ−Ｓｉ ）＝０．９０ （９）１．
ｓ、 （Ｃ）ＩｘＬ−Ｃ）−１，３１（３１１，ｄ、Ｃ
Ｈｚ）
＝２．２５ （３１１，ｓ、ＣＨｓ）
＝３．０８ （ＬＨ，ｍ、ＣＩ）
＝４．２８ （２Ｈ，ｍ、ＣＩ（Ｘ ２ ）＝６．１９
（ＩＨ，ｂｓ、Ｎｌ
（実施例２）
Ｎ−クロロスクシンイミド５７９．５■（４，３４ｍｍ
ｏｌ ）をトルエン３２ｄに添加し、４０°Ｃにて完全
に溶解した。この溶液を室温まで徐々に冷却し、ジメチ
ルスルフィド４４４μｊ！ （６，０７ｍ＠ｏｌ）を添
加した。この溶液を直ちにＯ′Ｃまで冷却し、そのまま
１５分間撹拌した。その後、反応液を一２５°Ｃまで冷
却しく３３，４Ｓ、１° Ｒ，１″５）−１−（ジ−ｐ
−アユシルメチル）−３−（１’−１−ブチルジメチル
シリルオキシエチル）−４−（１“−ヒドロキシエチル
）−２−アゼチジノン１４４５．１ ｍｇ （２，８９
ｍｍｏｌ）をトルエン３ｄに溶かした溶液を徐々に滴下
し、そのまま−２５°Ｃにて２時間撹拌した０反応液に
トリエチルアミン（６４２μｌ）を加え１５分間撹拌し
、その後室温まで戻、し更に３０分間撹拌して、反応液
を１規定塩酸１Ｉ１１で洗浄した。有機層を飽和食塩水
で水洗後、硫酸マグネシウムで乾燥した。溶媒を減圧留
去した後、得られた残渣をシリカゲルカラム（ジクロロ
メタン〜ジクロロメタン：酢酸エチル−９：１）で分離
精製し、（３Ｓ、４３．１’Ｒ）−夏−（ｐ−ジアニシ
ルメチル）−３−（１−も−ブチルジメチルシリルオキ
シエチル）−４−アセチル−２−アゼチジノン１４０９
．４■（収率９８％）を得た。HNMR (CDCl s) δ=0.11 (6H,
s, (CHs)z-Si)=0.90 (9)1.
s, (C)IxL-C)-1,31(311,d,C
Hz) = 2.25 (311, s, CHs) = 3.08 (LH, m, CI) = 4.28 (2H, m, CI (X 2 ) = 6.19
(IH, bs, Nl (Example 2) N-chlorosuccinimide 579.5cm (4.34mm
ol) was added to 32d of toluene and completely dissolved at 40°C. This solution was gradually cooled to room temperature and dimethyl sulfide was added to 444 μj! (6.07 m@ol) was added. The solution was immediately cooled to O'C and left to stir for 15 minutes. Thereafter, the reaction solution was cooled to -25°C and heated to 33,4S, 1° R, 1″5)
1445.1 mg (2,89
A solution of 3 mmol) dissolved in toluene was gradually added dropwise, and the mixture was stirred for 2 hours at -25°C. Triethylamine (642 μl) was added to the reaction mixture, stirred for 15 minutes, and then returned to room temperature for an additional 30 minutes. After stirring, the reaction solution was washed with 1111 1N hydrochloric acid. The organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was separated and purified using a silica gel column (dichloromethane to dichloromethane:ethyl acetate -9:1) to give (3S, 43.1'R)-summer-(p-dianisylmethyl)- 3-(1-Mo-butyldimethylsilyloxyethyl)-4-acetyl-2-azetidinone 1409
．． 4■ (yield 98%) was obtained.
Ｈ−ＮＭＲ（ＣＤＩ！３） δ −０，０３（３８，
ｓ、（ＣＨｓ）−Ｓｉ ）＝０．０５ （３Ｂ、ｓ、
（ＣＨｉ）−５ｉ ）＝０．８５ （９Ｈ，ｓ、ｃＨ
ｚ）ｓ−Ｃ）−ｔ、ｘｓ （３Ｒ，ｄ、ｃＨｓ）
＝１．７７ （３Ｈ，ｓ、ＣＩ（ｚ）＝２．８８
（１１，ｓ、ＣＨ）
＝３．７２ （６Ｈ１ｓ、Ｃ）ｌｓｏｘ２）−４，１
１（２Ｈ，曽、Ｃｌ１Ｘ２）
−５，７６（１８，蒙、ＣＨ）
−６，７５〜７．２６
（８Ｈ，ｍ、（Ｃ２Ｈ３ＯＭｅ）！ Ｘ２）出願人：財
団法人 和積中央化学研究所間 ： （４３０） 日
本曹達株式会社代理人： 横 山 吉 美H-NMR (CDI!3) δ -0,03 (38,
s, (CHs)-Si)=0.05 (3B, s,
(CHi)-5i)=0.85 (9H,s,cH
z) s-C)-t, xs (3R, d, cHs) = 1.77 (3H, s, CI(z) = 2.88
(11,s,CH) =3.72 (6H1s,C)lsox2)-4,1
1 (2H, Zeng, Cl1X2) -5,76 (18, Meng, CH) -6,75~7.26 (8H, m, (C2H3OMe)! : (430) Nippon Soda Co., Ltd. Agent: Yoshimi Yokoyama
Claims (1)
、Ｒ＾１、Ｒ＾２の一方が水素原子のとき他方は水酸基
または保護された水酸基を表す。Ｒ＾３は水素原子、ア
ルキル基、アリール基またはシリル基を表す。）で表さ
れる４−（１−ヒドロキシエチル）−β−ラクタム誘導
体を、有機溶媒中で一般式［II］ Ｒ＾４Ｘ （式中Ｘは塩素原子、臭素原子あるいはヨウ素原子を表
し、Ｒ＾４はＸを放出しうる基を表す。）で表されるハ
ロゲン化剤及びスルフィド類またはスルホキシド類と反
応させた後、塩基で処理することを特徴とする一般式［
III］ ▲数式、化学式、表等があります▼ （式中Ｒ＾１、Ｒ＾２及びＲ＾３は前記と同じ意味を示
す。）で表される４−アセチル−β−ラクタム誘導体の
製造方法。[Claims] General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 together represent an oxo group, or R^1 and R^2 When one is a hydrogen atom, the other represents a hydroxyl group or a protected hydroxyl group.R^3 represents a hydrogen atom, an alkyl group, an aryl group, or a silyl group. - A lactam derivative represented by the general formula [II] R^4X (wherein, X represents a chlorine atom, a bromine atom, or an iodine atom, and R^4 represents a group capable of releasing X) in an organic solvent. The general formula [characterized by the reaction with a halogenating agent and sulfides or sulfoxides, and then treatment with a base]
III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1, R^2, and R^3 have the same meanings as above.) Method for producing 4-acetyl-β-lactam derivatives .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63040750A JPH01216968A (en) | 1988-02-25 | 1988-02-25 | Production of 4-acetyl-beta-lactam derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63040750A JPH01216968A (en) | 1988-02-25 | 1988-02-25 | Production of 4-acetyl-beta-lactam derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01216968A true JPH01216968A (en) | 1989-08-30 |
Family
ID=12589308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63040750A Pending JPH01216968A (en) | 1988-02-25 | 1988-02-25 | Production of 4-acetyl-beta-lactam derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01216968A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1256572A1 (en) * | 2001-05-10 | 2002-11-13 | Tessenderlo Chemie S.A. | Process for the deprotection of N-substituted azetidones |
-
1988
- 1988-02-25 JP JP63040750A patent/JPH01216968A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1256572A1 (en) * | 2001-05-10 | 2002-11-13 | Tessenderlo Chemie S.A. | Process for the deprotection of N-substituted azetidones |
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