JPH0330589B2 - - Google Patents
Info
- Publication number
- JPH0330589B2 JPH0330589B2 JP57090427A JP9042782A JPH0330589B2 JP H0330589 B2 JPH0330589 B2 JP H0330589B2 JP 57090427 A JP57090427 A JP 57090427A JP 9042782 A JP9042782 A JP 9042782A JP H0330589 B2 JPH0330589 B2 JP H0330589B2
- Authority
- JP
- Japan
- Prior art keywords
- methylene chloride
- trans
- azetidinone
- phenylthio
- solvent
- 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
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- -1 halogenophenyl Chemical group 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 4
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- JMHDYNZNHIVGRM-RXMQYKEDSA-N (5R)-4-oxa-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical class O1C=CN2[C@H]1CC2=O JMHDYNZNHIVGRM-RXMQYKEDSA-N 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- HEKGSEIAAGMGPL-UHFFFAOYSA-N (z)-3-diazonio-4-[(4-nitrophenyl)methoxy]-4-oxobut-2-en-2-olate Chemical compound CC(=O)C(\[N+]#N)=C(\[O-])OCC1=CC=C([N+]([O-])=O)C=C1 HEKGSEIAAGMGPL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical class O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NQCLICVUMRWNPH-UHFFFAOYSA-N 1-ethyl-4-phenylsulfanylazetidin-2-one Chemical compound C1C(=O)N(CC)C1SC1=CC=CC=C1 NQCLICVUMRWNPH-UHFFFAOYSA-N 0.000 description 1
- UMKYUYPCLWYRGF-UHFFFAOYSA-N 1-phenylsulfanylazetidin-2-one Chemical compound C1(=CC=CC=C1)SN1C(CC1)=O UMKYUYPCLWYRGF-UHFFFAOYSA-N 0.000 description 1
- YEKPNMQQSPHKBP-UHFFFAOYSA-N 2-methyl-6-nitrobenzoic anhydride Chemical compound CC1=CC=CC([N+]([O-])=O)=C1C(=O)OC(=O)C1=C(C)C=CC=C1[N+]([O-])=O YEKPNMQQSPHKBP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- CCNPODNTPSUUSU-UHFFFAOYSA-N C(C=CC)(=S)OC1=CC=CC=C1 Chemical compound C(C=CC)(=S)OC1=CC=CC=C1 CCNPODNTPSUUSU-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 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
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【発明の詳細な説明】
本発明は次の一般式で示されるアゼチジノン誘
導体の製法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an azetidinone derivative represented by the following general formula.
（式中R1は低級アルキルまたはフタルイミド
を意味し、R2はフエニルまたは置換フエニル例
えばハロゲノフエニル、メトキシフエニル、ニト
ロフエニル、トリル等を意味し、R3は窒素原子
の保護基例えばテトラヒドロピラニル、三級ブチ
ルジメチルシリル等を意味し、R4は接触還元で
除去できるカルボキシル基の保護基例えばベンジ
ル、ｐ−ニトロベンジル、ｐ−メトキシベンジ
ル、２，４−ジメトキシベンジル等を意味し、
R5は低級アルキルを意味する。）
本発明の方法は次の反応式で示すことができ
る。 (In the formula, R 1 means lower alkyl or phthalimide, R 2 means phenyl or substituted phenyl such as halogenophenyl, methoxyphenyl, nitrophenyl, tolyl, etc., and R 3 represents a nitrogen atom protecting group such as tetrahydropyranyl, butyldimethylsilyl, etc., and R 4 means a carboxyl group protecting group that can be removed by catalytic reduction, such as benzyl, p-nitrobenzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, etc.
R 5 means lower alkyl. ) The method of the present invention can be represented by the following reaction formula.
すなわち、本発明は、アゼチジノン−４−チオ
ール誘導体（）にα−ジアゾ−β−オキソ脂肪
酸エステル（）を反応させて中間体（）から
分子内転位を経て２−アゼチジノン誘導体（）
を製造する方法である。 That is, the present invention involves reacting an azetidinone-4-thiol derivative () with an α-diazo-β-oxo fatty acid ester () to produce a 2-azetidinone derivative () through intramolecular rearrangement from the intermediate ().
This is a method of manufacturing.
この反応を行なうには、化合物（）と化合物
（）を無極性溶媒、例えばベンゼンと塩化メチ
レンの混合溶媒（３：１〜１：１程度）中、酢酸
ロジウムの如き触媒の存在下100℃以下で数時間
加熱すればよい。反応液は通常の後処理、例えば
シリカゲルカラムクロマトグラフイー等で処理し
目的物を得ることができる。 To carry out this reaction, compound () and compound () are mixed in a nonpolar solvent, such as a mixed solvent of benzene and methylene chloride (approximately 3:1 to 1:1), in the presence of a catalyst such as rhodium acetate, at temperatures below 100°C. Just heat it for a few hours. The reaction solution can be subjected to a conventional post-treatment such as silica gel column chromatography to obtain the desired product.
本発明方法によつて得られるアゼチジノン誘導
体（）は１−オキサペネム誘導体合成の中間体
になり得るとともに、新しいβ−ラクタム系抗菌
物質であるモノバクタム誘導体（３−アシルアミ
ノ−２−オキソアゼチジン−１−スルホン酸類）
の合成中間体でもある。 Azetidinone derivatives () obtained by the method of the present invention can be used as intermediates for the synthesis of 1-oxapenem derivatives, and monobactam derivatives (3-acylamino-2-oxoazetidine-1-sulfonic acids), which are new β-lactam antibacterial substances, can be used as intermediates for the synthesis of 1-oxapenem derivatives. )
It is also a synthetic intermediate.
すなわち、化合物（）をアセトン中ラネーニ
ツケルで処理して脱硫し、次いで窒素原子の保護
基R3を酸処理により除去し、R1がフタルイミド
基の場合は公知の方法でアミノ基へ変換し、米国
特許4172875または4293555の方法により閉環し、
アミノ基を修飾し、さらにカルボキシル基の保護
基をパラジウム−炭、酸化白金等を用いて接触還
元して除去するか、R1がアルキル基の場合は上
記米国特許の方法により閉環し、カルボキシル基
の保護基を同様に除去すると１−オキサペネム誘
導体が得られる。 That is, the compound () is desulfurized by treating it with Raney nickel in acetone, then the protecting group R 3 for the nitrogen atom is removed by acid treatment, and when R 1 is a phthalimide group, it is converted to an amino group by a known method. The ring is closed by the method of patent 4172875 or 4293555,
Modify the amino group and remove the protective group for the carboxyl group by catalytic reduction using palladium-charcoal, platinum oxide, etc., or if R 1 is an alkyl group, close the ring by the method described in the above US patent to remove the carboxyl group. When the protecting group of is similarly removed, the 1-oxapenem derivative is obtained.
また、R1がフタルイミドである化合物（）
を酸処理して保護基R3が除去し、必要に応じて
ラネーニツケル処理で脱硫し、カルボキシル基の
保護基を除去後公知の方法（特開昭56−125362号
参照）によりスルホン化を行なうことによりモノ
バクタム誘導体に導くことができる。 Also, compounds where R 1 is phthalimide ()
is treated with acid to remove the protective group R 3 , desulfurized if necessary by Raney nickel treatment, and after removing the protective group of the carboxyl group, sulfonation is performed by a known method (see JP-A-56-125362). can lead to monobactam derivatives.
次に実施例および参考例を挙げて説明する。 Next, examples and reference examples will be given and explained.
実施例 １
ｐ−ニトロベンジル３−〔トランス−１−（２−
テトラヒドロピラニル）−３−エチル−２−オ
キソ−４−アゼチジニルオキシ〕−２−フエニ
ルチオクロトネートの製造
トランス−１−（２−テトラヒドロピラニル）−
３−エチル−４−フエニルチオ−２−アゼチジノ
ン330mgをベンゼン10mlおよび塩化メチレン12ml
の混液に溶解する。これにｐ−ニトロベンジル
α−ジアゾアセトアセテート300mgをベンゼン10
mlおよび塩化メチレン12mlの混液に溶解して加
え、さらに触媒量の酢酸ロジウムを加え、室温で
10分間撹拌後70〜80℃で４時間加熱還流する。反
応終了後溶媒を留去し残渣をシリカゲルカラムク
ロマトに付し塩化メチレン−アセトンで精製し、
標記トランス体474mgを油状物として得る。同時
に副生成物シス体を油状物として13mg得る。Example 1 p-Nitrobenzyl 3-[trans-1-(2-
Production of trans-1-(2-tetrahydropyranyl)-3-ethyl-2-oxo-4-azetidinyloxy]-2-phenylthiocrotonate
330 mg of 3-ethyl-4-phenylthio-2-azetidinone was added to 10 ml of benzene and 12 ml of methylene chloride.
Dissolve in a mixture of To this, p-nitrobenzyl
α-Diazoacetoacetate 300mg to benzene 10
ml and methylene chloride, add a catalytic amount of rhodium acetate, and stir at room temperature.
After stirring for 10 minutes, the mixture is heated to reflux at 70-80°C for 4 hours. After the reaction, the solvent was distilled off and the residue was purified with silica gel column chromatography using methylene chloride-acetone.
474 mg of the title trans isomer was obtained as an oil. At the same time, 13 mg of the by-product cis isomer was obtained as an oily substance.
トランス体
IRνCHCl3 nax：1760，1700（Ｃ＝０），1345（NO2）c
m
-1
NMRδ（CDCl3）：
1.01（1.8H，ｔ，Ｊ＝6.28Hz，CH2CH〜3）
1.04（1.2H，ｔ，Ｊ＝6.28Hz，CH2CH〜3）
2.57（1.8H，ｓ，Me）
2.63（1.2H，ｓ，Me）
3.06（1H，dt，Ｊ＝1.43Hz，C3−Ｈ）
5.17（2H，ｓ，CH〜2Ar）
5.44（0.6H，ｄ，Ｊ＝1.4Hz，C4−Ｈ）
5.63（0.4H，ｄ，Ｊ＝1.4Hz，C4−Ｈ）
シス体
IRνCHCl3 nax：1765，1695（Ｃ＝０），1350（NO2）c
m
-1
NMRδ（CDCl3）：
1.00（3H，ｔ，Ｊ＝7.14Hz，CH2CH〜3）
3.22（1H，dt，Ｊ＝4.85and8Hz，C3−Ｈ）
5.16（2H，ｓ，CH〜2Ar）
5.99（1H，ｄ，Ｊ＝4.85Hz，C4−Ｈ）
実施例 ２
ｐ−ニトロベンジル３−〔トランス−１−（三級
ブチルジメチルシリル）−３−エチル−２−オ
キソ−４−アゼチジニルオキシ〕−２−フエニ
ルチオクロトネートの製造
トランス−１−（三級ブチルジメチルシリル）−
３−エチル−４−フエニルチオ−２−アゼチジノ
ン260mgをベンゼン20mlおよび塩化メチレン５ml
の混液に溶解する。これに、ｐ−ニトロベンジル
α−ジアゾアセトアセテート213mgをベンゼン20
mlおよび塩化メチレン５mlの混液に溶解して加え
てから触媒量の酢酸ロジウムを加え、室温で10分
間撹拌後70〜80℃で1.5時間加熱還流する。反応
終了後溶媒を留去し残渣をシリカゲルカラムクロ
マトに付し塩化メチレン−アセトンで精製して標
記トランス体360mgを油状物として得る。Trans form IRν CHCl3 nax : 1760, 1700 (C=0), 1345 (NO 2 ) c
m
-1 NMRδ (CDCl 3 ): 1.01 (1.8H, t, J = 6.28Hz, CH 2 CH ~ 3 ) 1.04 (1.2H, t, J = 6.28Hz, CH 2 CH ~ 3 ) 2.57 (1.8H, s , Me) 2.63 (1.2H, s, Me) 3.06 (1H, dt, J = 1.43Hz, C 3 − H) 5.17 (2H, s, CH~ 2 Ar) 5.44 (0.6H, d, J = 1.4Hz , C 4 -H) 5.63 (0.4H, d, J = 1.4Hz, C 4 -H) Cis form IRν CHCl3 nax : 1765, 1695 (C = 0), 1350 (NO 2 ) c
m
-1 NMRδ ( CDCl3 ): 1.00 (3H, t, J=7.14Hz, CH2CH ~ 3 ) 3.22 (1H, dt, J=4.85and8Hz, C3 -H) 5.16 (2H, s, CH~ 2 Ar) 5.99 (1H, d, J = 4.85Hz, C 4 -H) Example 2 p-nitrobenzyl 3-[trans-1-(tert-butyldimethylsilyl)-3-ethyl-2-oxo-4- Production of azetidinyloxy]-2-phenylthiocrotonate trans-1-(tert-butyldimethylsilyl)-
260 mg of 3-ethyl-4-phenylthio-2-azetidinone was added to 20 ml of benzene and 5 ml of methylene chloride.
Dissolve in a mixture of To this, 213 mg of p-nitrobenzyl α-diazoacetoacetate was added to 20 mg of benzene.
ml of methylene chloride and 5 ml of methylene chloride, then add a catalytic amount of rhodium acetate, stir at room temperature for 10 minutes, and then heat under reflux at 70-80°C for 1.5 hours. After the reaction was completed, the solvent was distilled off, and the residue was subjected to silica gel column chromatography and purified with methylene chloride-acetone to obtain 360 mg of the title trans-isomer as an oil.
IRνCHCl3 nax：1760，1700（Ｃ＝０）1350（NO2）cm
-1
NMRδ（CDCl3）：
0.2（6H，ｓ，Si（Me）2）
0.9（9H，ｓ，SiC（Me）3）
2.5（3H，ｓ，Me）
3.0（1H，dt，Ｊ＝1.4and8.3Hz，C3−Ｈ）
5.07（2H，ｓ，CH〜2Ar）
5.20（0.6H，ｄ，Ｊ＝1.4Hz，C4−Ｈ）
5.37（0.4H，ｄ，Ｊ＝1.4Hz，C4−Ｈ）
実施例 ３
ｐ−ニトロベンジル３−〔トランス−１−（２−
テトラヒドロピラニル）−３−フタルイミド−
２−オキソ−４−アゼチジニルオキシ〕−２−
フエニルチオクロトネートの製造
トランス−１−（２−テトラヒドロピラニル）−
３−フタルイミド−４−フエニルチオ−２−アゼ
チジノン102mgおよびｐ−ニトロベンジル２−ジ
アゾアセトアセテート120mgを無水ベンゼン15ml
と無水塩化メチレン５mlの混合溶媒に溶解する。
これに触媒量の酢酸ロジウムを室温で加え、70〜
80℃に約３時間加熱する。溶媒を留去し、シリカ
ゲルカラムクロマトグラフイーに付し、塩化メチ
レン−アセトン（98：２）溶出物として標記の化
合物114mgを得る。 IRν CHCl3 nax : 1760, 1700 (C=0) 1350 (NO 2 ) cm
-1 NMRδ (CDCl 3 ): 0.2 (6H, s, Si(Me) 2 ) 0.9 (9H, s, SiC(Me) 3 ) 2.5 (3H, s, Me) 3.0 (1H, dt, J=1.4and8 .3Hz, C 3 -H) 5.07 (2H, s, CH ~ 2 Ar) 5.20 (0.6H, d, J = 1.4Hz, C 4 -H) 5.37 (0.4H, d, J = 1.4Hz, C 4 -H) Example 3 p-nitrobenzyl 3-[trans-1-(2-
Tetrahydropyranyl)-3-phthalimide-
2-oxo-4-azetidinyloxy]-2-
Production of phenylthiocrotonate trans-1-(2-tetrahydropyranyl)-
102 mg of 3-phthalimido-4-phenylthio-2-azetidinone and 120 mg of p-nitrobenzyl 2-diazoacetoacetate were added to 15 ml of anhydrous benzene.
and 5 ml of anhydrous methylene chloride.
Add a catalytic amount of rhodium acetate to this at room temperature, and
Heat to 80℃ for about 3 hours. The solvent was distilled off and the residue was subjected to silica gel column chromatography to obtain 114 mg of the title compound as an eluate with methylene chloride-acetone (98:2).
IRνCHCl3 naxcm-1：1780，1720（Ｃ＝０）
NMR（CDCl3）ppm：
2.50（3H，ｓ，Me）
5.07（2H，ｓ，CH2Ar）
5.26（1H，1ikes，C3−HorC4−Ｈ）
5.9and6.07（each0.5H，ｄ，Ｊ＝1.5Hz，C3−
HorC4−Ｈ）
7.0〜8.2（14H，ｍ，14XArH）
参考例 １
トランス−３−エチル−４−フエニルチオ−２
−アゼチジノン1.6ｇおよび３，４−ジヒドロピ
ラン800mgを塩化メチレン30mlに溶解し氷冷下触
媒量のｐ−トルエンスルホン酸を加え12時間撹拌
する。次いで重曹水で中和し、塩化メチレンで抽
出する。抽出液を硫酸ナトリウムで乾燥後シリカ
ゲルカラムクロマトグラフイーに付し、塩化メチ
レン−アセトン（99／１〜98／2w／ｗ）溶出物
としてトランス−１−テトラヒドロピラニル−３
−エチル−４−フエニルチオ−２−アゼチジノン
1.93ｇを得る。 IRν CHCl3 nax cm -1 : 1780, 1720 (C=0) NMR (CDCl 3 ) ppm: 2.50 (3H, s, Me) 5.07 (2H, s, CH 2 Ar) 5.26 (1H, 1ikes, C 3 −HorC 4 −H) 5.9and6.07(each0.5H, d, J=1.5Hz, C 3 −
HorC 4 -H) 7.0-8.2 (14H, m, 14XArH) Reference example 1 trans-3-ethyl-4-phenylthio-2
- 1.6 g of azetidinone and 800 mg of 3,4-dihydropyran are dissolved in 30 ml of methylene chloride, and a catalytic amount of p-toluenesulfonic acid is added under ice cooling, followed by stirring for 12 hours. Then, it is neutralized with aqueous sodium bicarbonate and extracted with methylene chloride. After drying the extract with sodium sulfate, it was subjected to silica gel column chromatography, and trans-1-tetrahydropyranyl-3 was obtained as a methylene chloride-acetone (99/1 to 98/2 w/w) eluate.
-ethyl-4-phenylthio-2-azetidinone
Obtain 1.93g.
IRνCHCl3 naxcm-1：1765（Ｃ＝０）
NMR（CDCl3）ppm：
0.97および1.00（each3H，ｔ，Ｊ＝7.2Hz，−
CH3）
2.94（1H，ｍ，C3−Ｈ）
4.73および4.86（each1H，ｄ，Ｊ＝2.6Hz，C4
−Ｈ）
7.22〜7.63（5H，ｍ，ArH×５）
参考例 ２
トランス−３−エチル−４−フエニルチオ−２
−アゼチジノン1.1ｇを無水テトラヒドロフラン
10mlに溶解し、−78゜に冷却下ｎ−ブチルリチウム
340mgを加え約10分撹拌後、三級ブチルジメチル
シリルクロライド801mgの無水テトラヒドロフラ
ン５ml溶液をゆつくり滴下し、２〜３時間を要し
て室温にもどす。塩化メチレンで抽出し硫酸ナト
リウムで乾燥後溶媒を留去する。残渣をシリカゲ
ルカラムクロマトグラフイーに付し、塩化メチレ
ン−アセトン（99／１〜98／２）溶出物としてト
ランス−１−（三級ブチルジメチルシリル）−３−
エチル−４−フエニルチオ−２−アゼチジノン
1.5ｇを得る。 IRν CHCl3 nax cm -1 : 1765 (C = 0) NMR (CDCl 3 ) ppm: 0.97 and 1.00 (each3H, t, J = 7.2Hz, -
CH 3 ) 2.94 (1H, m, C 3 −H) 4.73 and 4.86 (each1H, d, J = 2.6Hz, C 4
-H) 7.22 to 7.63 (5H, m, ArH x 5) Reference example 2 trans-3-ethyl-4-phenylthio-2
- 1.1 g of azetidinone in anhydrous tetrahydrofuran
Dissolve n-butyllithium in 10ml and cool to -78°.
After adding 340 mg and stirring for about 10 minutes, a solution of 801 mg of tertiary butyldimethylsilyl chloride in 5 ml of anhydrous tetrahydrofuran was slowly added dropwise, and the mixture was allowed to return to room temperature over 2 to 3 hours. After extraction with methylene chloride and drying over sodium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography, and trans-1-(tert-butyldimethylsilyl)-3- was eluted with methylene chloride-acetone (99/1 to 98/2).
Ethyl-4-phenylthio-2-azetidinone
Obtain 1.5g.
IRνCHCl3 naxcm-1：1740（Ｃ＝０）
NMR（CDCl3）ppm：
0.23（6H，ｓ，−SiMe2）
0.9（9H，ｓ，Si−tertBU）
1.5（2H，ｑ，Ｊ＝6.6Hz，−CH2−）3.0（1H，
ｄ，ｔ，Ｊ＝2and7Hz，C3−Ｈ）
4.37（1H，ｄ，Ｊ＝２Hz，C4−Ｈ）
7.16（5H，ｍ，5XArH）
参考例 ３
メタノール20mlに金属ナトリウム98mgおよびフ
エニルメルカプタン0.6mlを溶解し、これに４−
アセトキシ−３−フタルイミド−２−アゼチジノ
ン1.16ｇのメタノール20ml溶液を氷冷下で加え、
室温で約３時間撹拌する。溶媒を留去後塩化メチ
レンを加え水洗し、硫酸ナトリウムで乾燥する。
溶媒を留去後シリカゲルカラムクロマトグラフイ
ーで精製し、塩化メチレン−アセトン（95／５）
溶出物としてトランス−３−フタルイミド−４−
フエニルチオ−２−アゼチジノン880mgを得る。 IRν CHCl3 nax cm -1 : 1740 (C = 0) NMR (CDCl 3 ) ppm: 0.23 (6H, s, -SiMe 2 ) 0.9 (9H, s, Si-tertBU) 1.5 (2H, q, J = 6.6Hz , −CH 2 −) 3.0 (1H,
d, t, J = 2and7Hz, C 3 -H) 4.37 (1H, d, J = 2Hz, C 4 -H) 7.16 (5H, m, 5XArH) Reference example 3 98 mg of sodium metal and 0.6 phenyl mercaptan in 20 ml of methanol ml and add 4-
A solution of 1.16 g of acetoxy-3-phthalimido-2-azetidinone in 20 ml of methanol was added under ice cooling.
Stir at room temperature for about 3 hours. After distilling off the solvent, add methylene chloride, wash with water, and dry with sodium sulfate.
After distilling off the solvent, it was purified by silica gel column chromatography and purified with methylene chloride-acetone (95/5).
trans-3-phthalimide-4- as eluent
880 mg of phenylthio-2-azetidinone are obtained.
IRνCHCl3 naxcm-1：1795，1780および1730（Ｃ＝０）
NMR（CDCl3）ppm：
5.10および5.28（each1H，ｄ，Ｊ＝３Hz，C3
−HandC4−Ｈ）
6.8（1H，broads，NH）
7.4（5H，ｍ，5XArH，）
7.8（4H，ｍ，4XArH）
このものの100mgを無水塩化メチレン５mlに溶
解し、これに３，４−ジヒドロピラン30mgを加え
る。 IRν CHCl3 nax cm -1 : 1795, 1780 and 1730 (C = 0) NMR (CDCl 3 ) ppm: 5.10 and 5.28 (each1H, d, J = 3Hz, C 3
-HandC 4 -H) 6.8 (1H, broads, NH) 7.4 (5H, m, 5XArH,) 7.8 (4H, m, 4XArH) Dissolve 100 mg of this in 5 ml of anhydrous methylene chloride, and add 3,4-dihydro Add 30 mg of pyran.
さらに触媒量のｐ−トルエンスルホン酸を加え
て24時間撹拌し、飽和重曹水を加えて塩化メチレ
ンで抽出する。抽出液を水洗し、硫酸ナトリウム
で乾燥し、溶媒留去後シリカゲルカラムクロマト
グラフイーに付し、塩化メチレン−アセトン
（99／１〜98／２）溶出物としてトランス−４−
フエニルチオ−３−フタルイミド−１−テトラヒ
ドロピラニル−２−アゼチジノン102mgを得る。 Further, a catalytic amount of p-toluenesulfonic acid is added and the mixture is stirred for 24 hours, saturated aqueous sodium bicarbonate is added, and the mixture is extracted with methylene chloride. The extract was washed with water, dried over sodium sulfate, and subjected to silica gel column chromatography after distilling off the solvent to obtain trans-4-
102 mg of phenylthio-3-phthalimido-1-tetrahydropyranyl-2-azetidinone are obtained.
IRνCHCl3 naxcm-1：1770および1720（Ｃ＝０）
NMR（CDCl3）ppm：
5.03（1H，ｄ，Ｊ＝2.5Hz，C3−HorC4−Ｈ）
5.26および5.33（each0.5H，ｄ，Ｊ＝2.5Hz，
C3−HorC4−Ｈ）
7.2〜7.9（9H，ｍ，9XArH） IRν CHCl3 nax cm -1 : 1770 and 1720 (C = 0) NMR (CDCl 3 ) ppm: 5.03 (1H, d, J = 2.5Hz, C 3 -HorC 4 -H) 5.26 and 5.33 (each0.5H, d , J=2.5Hz,
C 3 −HorC 4 −H) 7.2 to 7.9 (9H, m, 9XArH)
Claims (1)
テルを反応させることを特徴とする式 で表わされる化合物の製法。ただし、R1は低級
アルキルまたはフタルイミドを、R2はフエニル
または置換フエニルを、R3は窒素原子の保護基
を、R4は接触還元で除去し得る保護基を、R5は
低級アルキルを意味する。[Claims] 1 formula The compound represented by the formula A formula characterized by reacting an α-diazo-β-oxo fatty acid ester represented by A method for producing a compound represented by However, R 1 means lower alkyl or phthalimide, R 2 means phenyl or substituted phenyl, R 3 means a protecting group for the nitrogen atom, R 4 means a protecting group that can be removed by catalytic reduction, and R 5 means lower alkyl. do.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57090427A JPS58206582A (en) | 1982-05-27 | 1982-05-27 | Preparation of azetidinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57090427A JPS58206582A (en) | 1982-05-27 | 1982-05-27 | Preparation of azetidinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58206582A JPS58206582A (en) | 1983-12-01 |
| JPH0330589B2 true JPH0330589B2 (en) | 1991-04-30 |
Family
ID=13998300
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57090427A Granted JPS58206582A (en) | 1982-05-27 | 1982-05-27 | Preparation of azetidinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58206582A (en) |
-
1982
- 1982-05-27 JP JP57090427A patent/JPS58206582A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58206582A (en) | 1983-12-01 |
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