JP3747329B2 - Method for producing 3-aminoazetidinone derivative - Google Patents
Method for producing 3-aminoazetidinone derivative Download PDFInfo
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- JP3747329B2 JP3747329B2 JP22077095A JP22077095A JP3747329B2 JP 3747329 B2 JP3747329 B2 JP 3747329B2 JP 22077095 A JP22077095 A JP 22077095A JP 22077095 A JP22077095 A JP 22077095A JP 3747329 B2 JP3747329 B2 JP 3747329B2
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- 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
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Description
【0001】
【発明の属する技術分野】
本発明は、一般式(5)で示される3−アミノアゼチジノン誘導体及びその塩の新規製造法に関するものである。
本発明で製造される一般式(5)で示される3−アミノアゼチジノン誘導体は、各種セファロスポリン系抗生物質の合成中間体となり得る重要な既知の化合物である。例えば、下記の一般式(6)
【0002】
【化6】
【0003】
(式中、R2 は前記と同義である。)に示されるようなセファロスポリン系抗生物質の重要な合成中間体となり、医薬製造産業上の利用価値は極めて高い。
【0004】
【従来の技術】
本発明に係る一般式(5)で表される誘導体の既知類似化合物としては、例えば特開昭58−85894号公報及び特開昭59−164771号公報に示されている。それらの化合物はいずれも下記一般式(7)
【0005】
【化7】
【0006】
(式中、R1 、R2 、R3 は前記と同義である。)で示され、アミノ基がアシル基で保護された型を取っている。従って、本発明に係る一般式(5)で表される3−アミノアゼチジノン誘導体を得るのに、後に脱アシル化を行わなければならず工業的に有利でない。
更に、一般式(5)で表される3−アミノアゼチジノン誘導体の既知の合成反応としては、例えば、特開平5−78373号公報及び特開平5−65268号公報(反応式A)、特開平3−147539号公報及び特開平5−51361号公報(反応式B)が挙げられる。
【0007】
【化8】
【0008】
【化9】
【0009】
反応式Aは、各反応ごとに生成物を単離する必要があり、また、反応式(B)では、本発明に係る一般式(5)で表される3−アミノアゼチジノン誘導体を得るには、改めてアゼチジノンの3位の側鎖を切断する必要があり、いずれも工業的に有利でない。
【0010】
【発明が解決しようとする課題】
本発明者らは、上記事実に鑑み、上記一般式(5)で表される3−アミノアゼチジノン誘導体及びその塩を高収率で製造する方法を鋭意研究を行った結果、一般式(1)で表されるアゼチジノン誘導体に有機溶媒中、塩化水素捕集剤の存在下五塩化リンと反応させて得られる一般式(2)で表されるイミノクロル体が、その反応液のままの状態で塩素化剤と反応し、高収率で塩素化イミノクロル体を生成すること、更には、その反応液にアルコ−ルを反応させ、生成する塩素化イミノエ−テル体を加水分解させることにより、簡便な連続操作により高収率で3−アミノアゼチジノン誘導体及びその塩を製造することができることを知見し、本発明を完成させた。
【0011】
【課題を解決するための手段】
即ち、本発明は、下記の一般式(1)
【0012】
【化10】
【0013】
(式中、R1 は、置換又は置換基を有しないアリ−ル基、アリ−ルメチル基又はアリ−ルオキシメチル基を示し、R2 はカルボキシル基の保護基を示し、R3 は置換又は置換基を有しないアリール基を示す)で表されるアゼチジノン誘導体を有機溶媒中塩化水素捕集剤の存在下、五塩化リンと反応させて、下記の一般式(2)
【0014】
【化11】
【0015】
(式中、R1 、R2 、R3 は前記と同義である。)で表されるイミノクロル体を生成させる第一工程、次いで該イミノクロル体を塩素化剤と反応させて、下記の一般式(3)
【化12】
【0016】
(式中、R1 、R2 、R3 は前記と同義である。)で表される塩素化イミノクロル体を生成させる第二工程、次いで該生成物にアルコ−ルを反応させて下記一般式(4)
【0017】
【化13】
【0018】
(式中、R1 、R2 、R3 は前記と同義、R4 はアルキル基、1又は複数のヒドロキシル基を有するアルキル基を示す。)で表される塩素化イミノエ−テル体を生成させる第三工程、次いで該塩素化イミノエ−テル体を加水分解する第四工程よりなることを特徴とする下記の一般式(5)
【0019】
【化14】
【0020】
(式中、R2 、R3 は前記と同義である。)で表される3−アミノアゼチジノン誘導体及びその塩の新規製造法に関するものである。
以下、本発明を詳細に説明する。
本発明に係る一般式(5)で表される3−アミノアゼチジノン誘導体及びその塩の製造法は、上記のように基本的には、四つの反応工程からなる。その特徴とするところは、反応式上では4つの工程を経るも、各反応ごとの生成物を単離精製することなく、結局のところ出発原料の脱アシル化と塩素化を連続的に行えることにある。
なお、本発明の製造方法において、第2工程の塩素化反応をせずに脱アシル化を行って得られる下記一般式(12)
【0021】
【化15】
【0022】
(式中、R2 、R3 は前記と同義である。)で表される化合物の塩素化を行っても本発明の目的物はほとんど得られない。
本発明において出発原料として用いられる一般式(1)のアゼチジノン誘導体は、例えば特開昭50−129590号公報、特開昭59−164771号公報及び特開平5−51361号公報に示され、各種セファロスポリン系抗生物質の重要な合成中間体として既に既知の化合物である。
【0023】
本発明において、一般式(1)に示す化合物のうちR1 の具体例としては、例えばフェニル基、トリル基、p−クロロフェニル基、p−ニトロフェニル基、p−メトキシフェニル基等の置換もしくは置換基を有しないアリ−ル基、ベンジル基、トリルメチル基、ナフチルメチル基、p−メトキシベンジル基、p−ニトロベンジル基、フェニルジクロロメチル基等の置換もしくは置換基を有しないアリ−ルメチル基、フェノキシメチル基、p−クロロフェノキシメチル基、p−ニトロフェノキシメチル基等の置換もしくは置換基を有しないアリ−ルオキシメチル基を挙げることができる。
【0024】
R2 のカルボン酸保護基としては、例えばメチル基、エチル基、プロピル基、ブチル基、tert- ブチル基、2、2、2-トリクロロエチル基、2−クロロエチル基等のハロゲンを含むことのある低級アルキル基、ベンジル基、p−ニトロベンジル基、p−メトキシベンジル基、3、4、5-トリメトキシベンジル基、ジフェニルメチル基等の置換もしくは置換基を有しないアリ−ルメチル基、フェニル基、p−メトキシフェニル基等の置換もしくは置換基を有しないアリ−ル基を挙げることができる。
【0025】
R3 の具体例としては、例えばフェニル基、トリル基、キシリル基、p−メトキシフェニル基、p−ニトロフェニル基、p−クロロフェニル基等の置換もしくは置換基を有しないアリ−ル基を挙げることができる。
第一工程は、一般式(1)で表されるアゼチジノン誘導体を有機溶媒中塩化水素捕集剤の存在下、五塩化リンと反応させて、一般式(2)で表されるイミノクロル体を生成させる工程である。
【0026】
本発明で使用される有機溶媒は低級ハロゲン化炭化水素、芳香族炭化水素、ジ低級アルキルエーテル、環状エーテル、低級ジアルコキシエタン、脂肪族アミド等が挙げられ、これらの中から選ばれる1種叉は2種以上の混合溶媒として用いられる。例えばクロロホルム、ジクロルメタン、ジクロルエタン、四塩化炭素等の低級ハロゲン化炭化水素、ベンゼン、クロルベンゼン等の芳香族炭化水素、ジエチルエーテル、ジメチルエーテル等のジ低級アルキルエーテル、テトラヒドロフラン、ジオキサン等の環状エーテル、1、2ージメトキシエタン、1、2ージエトキシエタン、1、2ージブトキシエタン、1、2ージベンジルオキシエタン等の低級ジアルコキシエタン、ジメチルホルムアミド等の脂肪族アミド等が挙げられる。
塩化水素捕集剤としては、例えばピリジン、ピコリン、トリエチルアミン等の第三級アミン、プロピレンオキサイド、ブチレンオキサイド等のエポキシド類、炭酸ソ−ダ、炭酸カルシウム、重炭酸ソ−ダ等のアルカリ金属の炭酸塩等が挙げられる。
【0027】
第一工程における反応条件は、原料の物性、溶媒の種類および塩化水素捕集剤によって異なるが、反応温度は通常−30〜10℃、好ましくは−2〜4℃であり、反応時間は通常0.5〜10時間、好ましくは1〜3時間である。
化合物(1)のアゼチジノン誘導体に対する五塩化リンと塩化水素捕集剤の使用量は特に制限されないが、通常化合物(1)に対して五塩化リンが1〜5倍モル、好ましくは1〜3倍モル、塩化水素捕集剤が1〜10倍モル、好ましくは1〜3倍モルが適当である。
【0028】
次に、第二工程は、上記で得られたイミノクロル体の反応液を有機溶媒中塩素化剤を反応させて一般式(3)で示される塩素化イミノクロル体を生成させる工程である。
塩素化剤としては、例えば塩素ガス、t−BuOCl、Cl2O等を挙げることができる。塩素ガスは、ガス状または不活性有機溶媒、例えば四塩化炭素、ジクロルメタン、クロロホルム等の低級ハロゲン化炭化水素の溶液として反応せることもできる。
塩素化剤の使用量は特に制限されないが、通常化合物(1)に対して1〜5倍モル、好ましくは1〜2倍モルが適当である。
なお、本工程の塩素化は、一般式(2)のメチル基を上記塩素化剤で塩素化するものであるが、前工程で使用している五塩化リンではこの塩素化が進まない。
【0029】
この第二工程では、有機溶媒を用いることにより一般式(2)に示されるイミノクロル体を更に塩化水素捕集剤を用いることなく、容易に塩素化を行うことができ、また低温下で反応を行わせることにより一般式(3)に示される塩素化イミノクロル体を高収率で得ることができる。
この工程で使用される有機溶媒は、前記に挙げたものと同様であるが、低級ハロゲン化炭化水素、芳香族炭化水素、ジ低級アルキルエーテル、環状エーテル、脂肪族アミドからなる群から選ばれる1種叉は2種以上の有機溶媒が好ましく、特に、低級ハロゲン化炭化水素と環状エーテルの混合溶媒が好ましく、通常ジクロルメタン1(容)に対してジオキサン1〜3(容)、好ましくはジオキサン2(容)の混合溶媒が最適である。
【0030】
この工程での反応温度は通常−15〜−40℃、好ましくは−20℃以下である。反応温度が−20℃以上では一般式(3)で示される目的化合物の生成以外に他のクロル体が副生し易い。例えば、R1 がアリールメチル基の場合は、更に塩素化が進み、3位のメチル基が塩素化された下記一般式(13)、(14)で
【0031】
【化16】
【0032】
【化17】
【0033】
(式中、R2 、R3 は前記と同義である。)表される副生成物等が主に生成され易くなる。もっとも、一般式(13)及び(14)で表される化合物であっても、後のアルコール処理及び加水分解により本発明に係る一般式(5)で表される3−アミノアゼチジノン誘導体及びその塩にすることも可能である。
【0034】
次に、第三工程は、上記で得られた塩素化イミノクロル体の反応液とアルコ−ルを反応させて下記一般式(4)で表される塩素化イミノエ−テル体を生成させる反応である。
使用するアルコ−ルとしては、例えばメタノ−ル、エタノ−ル、n−プロパノ−ル、n−ブタノ−ル等の低級アルコ−ル、エチレングリコ−ル、プロピレングリコ−ル、グリセリン等の多価アルコ−ル等が挙げられる。
反応条件は、アルコ−ルの種類によって異なるが、反応温度は通常−50〜50℃、好ましくは−30〜20℃であり、反応時間は通常0.5〜24時間、好ましくは0.5〜10時間である。
アルコ−ルの使用量は特に制限されないが、通常化合物(1)に対して10〜100V/W 、好ましくは10〜50V/Wが適当である。
【0035】
次に、第四工程は、前工程で得られた一般式(4)で表される塩素化イミノエ−テル体反応液を加水分解させて、本発明に係る目的物である3−アミノアゼチジノン誘導体及びその塩を得る工程である。
反応生成物は、前工程で得られた反応液に水を反応させることにより得ることができる。反応時間は通常0.5〜5時間、好ましくは0.5〜1時間である。
反応温度は室温以下であればよいが、生成物の分解を抑えるためになるべく低温で反応させることが好ましい。
反応終了後、疎水性溶媒、例えばジクロルメタン、1、2-ジクロルメタン、クロロホルム、四塩化炭素、ベンゼン、クロルベンゼン、酢酸エチル、ギ酸エチル、ジクロルエタン、エトキシアセテート等の抽出溶媒を加えて抽出した有機層を水層と分離する。
【0036】
更に、分離した有機層を、水で洗浄した後、例えば無水硫酸マグネシウム、無水硫酸ナトリウム等で脱水する。その後室温以下の温度で濃縮して3−アミノアゼチジノン誘導体の塩酸塩を得る。
また、pHを中性付近にすることにより3−アミノアゼチジノン誘導体の遊離アミノ化合物を得ることもでき、無機酸及び有機酸、例えば硫酸、燐酸等の無機酸、トシル酸、ベンゼンスルホン酸等の有機酸と更に反応させることによりそれらの酸に相当する塩として得ることも可能である。
このようにして製造される本発明の化合物は、通常の分離精製手段により容易に単離精製することができるが、一般式(6)で示される化合物に誘導するのに本発明の化合物を精製することなしにおこなうことも可能であり、工業的に有利である。
【0037】
【発明の実施の形態】
以下に本発明の実施の形態を、実施例により詳細に説明する。
実施例1
[p-メトキシベンジル-2-(3-アミノ-4-ベンゼンスルホニルチオ-2-アゼチジノン-1-イル)-3-クロロメチル-3-ブテノエート]の製造
(第一工程)
撹拌器付き0.5リットル容の4つ口フラスコを窒素置換して、五塩化リン15g(0.072M)とジクロルメタン100mlを仕込み、30〜35℃で溶解後、−2〜−5℃まで冷却し、ピリジン5.87g(0.073M)をゆっくり滴下する。−2〜−5℃で約20分間反応後、p-メトキシベンジル-2-(3-フェニルアセトアミト゛-4-ベンゼンスルホニルチオ-2-アゼチジノン-1-イル)-3-メチル-3-ブテノエート20g(0.033M)を加える。反応はほぼ2時間(1〜2時間)で完結し、イミノクロル体を得た。
【0038】
(第二工程)
得られたイミノクロル体反応溶液を−20℃まで冷却し、ジオキサン200mlを加え、−20℃以下の温度で7.9%塩素含有ジクロルメタン36g(塩素含有量2.86g=0.04M)を滴下後、−20℃以下の温度で0.5時間撹拌反応し、塩素化イミノクロル体を得た。
【0039】
(第三工程)
別に用意した撹拌器付き1リットル容の4つ口フラスコを窒素置換して、脱水メタノール400mlを仕込み、−20℃まで冷却後、上記で得られた塩素化イミノクロル体反応液を一気に加えて、約0℃で1〜2時間反応し、塩素化イミノエーテル体を得た。
【0040】
(第四工程)
上記で得られた塩素化イミノエーテル反応液を−10℃まで冷却し、蒸留水140mlを加え、−10〜0℃の温度で約20分間反応後、ジクロルメタン100mlで抽出した。更に、その有機層を無水硫酸ナトリウムで脱水後、濃縮し、アミノアゼチジノンの淡黄色混合液を得た。
得られた混合液をイソプロピルアルコールから晶析し、乾燥した後、淡黄色固体16.3gを得た。NMR、MS、IR等の機器分析により、p−メトキシベンジル−2−(3−アミノ−4−ベンゼンスルホニルチオ−2−アゼチジン−1−イル)−3−クロロメチル−3−ブテノエート・塩酸塩であることを確認した。収率は89%であった。
【0041】
(1)400 MHz 1H-NMR δppm (DMSO:CDCl3 1:1)
3.81(s、3H、OMe)
4.06(d、1H、-CH2Cl、J=16.0Hz)、4.39(d、1H、-CH2Cl、J=16.0Hz)
4.29(s、1H、-CH(-COO-)-C)
4.98(s、1H、=C=CH2)、5.01(s、1H、=C=CH2)
5.14(d、1H、-OCH2-、J=16.0Hz)、5.20(d.1H、-OCH2-、J=16.0Hz)
5.24(d、1H、ラクタム、J=4.0Hz)、6.01(d、1H、ラクタム、J=4.0Hz)
6.94(d、2H、J=8.0Hz)、7.32(d、2H、J=8.0Hz)
7.59(t、2H、J=8.0Hz)、7.71(t、1H、J=8.0Hz)
7.84(d、2H、J=8.0Hz)
(2)MS(FAB): 511 m/z(M+H)+
(3)IR(KBr):ν3400、2950、2840、1785、1740、1515、1330、1245、1 170、1140、580 cm-1
【0042】
実施例2
[p-メトキシベンジル-2-(3-アミノ-4-ベンゼンスルホニルチオ-2-アゼチジノン-1-イル)-3-クロロメチル-3-ブテノエート]の製造
(第一工程)
撹拌器付き100ml容の4つ口フラスコを窒素置換して、五塩化リン3.5g(0.017M)とジクロルメタン24mlを仕込み、30〜35℃で溶解後、−2〜−5℃まで冷却し、ピリジン1.35g(0.017M)をゆっくり滴下する。−2〜−5℃で約20分間反応後、p−メトキシベンジル−2−(3−フェニルアセトアミド−4−ベンゼンスルホニルチオ−2−アゼチジノン−1−イル)−3−メチル−3−ブテノエート5.0g(0.0084M)を加える。反応はほぼ2時間(1〜2時間)で完結し、イミノクロル体を得た。
【0043】
(第二工程)
得られたイミノクロル体反応溶液を−20℃まで冷却し、ジクロルメタンに対して2倍容量のジオキサン48mlを加え、−20℃以下で7.9%塩素含有のジクロルメタン10.0g(塩素含有量0.8g=0.011M)を滴下後、0℃で0.5時間撹拌反応し、塩素化イミノクロル体を得た。
【0044】
(第三工程)
別に用意した撹拌器付きの0.5リットル容の4つ口フラスコを窒素置換して、脱水メタノール100mlを仕込み、−20℃に冷却した後、塩素化イミノクロル体反応液を一気に加え、約0℃で1時間熟成反応をおこなって、塩素化イミノエーテル体を得た。
【0045】
(第四工程)
得られた塩素化イミノエーテル体反応液を−10℃に冷却し、純水35mlを添加し、20分間反応後、ジクロルメタンで抽出し、重ソウ水で冷却、水洗後、その有機層を無水硫酸マグネシウム10gで脱水乾燥後、濃縮し、黄色混合液を得た。
得られた黄色混合液を順相(Wako gel C-300、450g)カラムクロマトグラフィーにより酢酸エチルで不純物を除き、メタノールで目的物を含むフラクションを回収した。回収した液を濃縮し、逆相(COSMOSIL 75C18、500g)クロマトグラフィーによるアセトニトリル:水=1:1の溶剤で精製した結果、1.9gの黄色液体を得た。NMR、MS、IRの機器分析によりフリーのp−メトキシベンジル−2−(3−アミノ−4−ベンゼンスルホニルチオ−2−アゼチジノン−1−イル)−3−クロロメチル−3−ブテノエートであることを確認した。収率は45%であった。
【0046】
(1)300 MHz 1H-NMR δppm (DMSO:CDCl3)
3.78(s、3H、OMe)
4.07(d、2H、-CH2Cl)
4.64(d、1H、ラクタム、J=4.8Hz)
4.93(s、1H、-CH(-COO-)-C)
5.09(d、1H、-OCH2-、J=12.0Hz)、5.13(d、1H、-OCH2-、J=12.0Hz)
5.16(s、1H、=C=CH2)、5.29(d、1H、=C=CH2)
5.69(d、1H、ラクタム、J=4.8Hz)
6.90(d、2H、J=9.6Hz)、7.29(d、2H、J=9.6Hz)
7.52(t、2H、J=9.8Hz)、7.63(t、1H、J=9.8Hz)
7.88(d、2H、J=9.8Hz)
(2)MS(FAB):511 m/z(M+H)+
(3)IR(neat):ν3400、2960、1780、1740、1615、1520、1445、1372 1330、1250、1175、1145、1075、590 cm-1
【0047】
実施例3
[p-メトキシベンジル-2-(3-アミノ-4-ベンゼンスルホニルチオ-2-アゼ
チジノン-1-イル)-3-クロロメチル-3-ブテノエート]の製造
実施例1の第二工程のジオキサンの代わりにジメチルホルムアミド200mlを使用した他は、実施例1と同様に行った結果、黄色混合液を得た。
得られた黄色混合液を実施例1と同様に晶析し、塩酸塩として11.7gを得た。収率は64%であった。
【0048】
【発明の効果】
以上詳述したように、本発明の製造法によれば、3−アミノアゼチジノン誘導体及びその塩を簡便な操作で連続的に高収率で得ることができる。
その特徴とするところは、各反応ごとの生成物を単離精製することなく、脱アシル化工程中で、脱アシル化と塩素化を連続的に行うことにあり、工業的に有利である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel process for producing a 3-aminoazetidinone derivative represented by the general formula (5) and a salt thereof.
The 3-aminoazetidinone derivative represented by the general formula (5) produced in the present invention is an important known compound that can be a synthetic intermediate of various cephalosporin antibiotics. For example, the following general formula (6)
[0002]
[Chemical 6]
[0003]
(In the formula, R 2 has the same meaning as described above.) It becomes an important synthetic intermediate of a cephalosporin antibiotic as shown in the above, and its utility value in the pharmaceutical production industry is extremely high.
[0004]
[Prior art]
Known similar compounds of the derivative represented by the general formula (5) according to the present invention are disclosed in, for example, JP-A-58-85894 and JP-A-59-164771. These compounds are all represented by the following general formula (7)
[0005]
[Chemical 7]
[0006]
(Wherein R 1 , R 2 and R 3 have the same meanings as described above), and the amino group is protected with an acyl group. Therefore, in order to obtain the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention, deacylation must be performed later, which is not industrially advantageous.
Furthermore, as a known synthesis reaction of the 3-aminoazetidinone derivative represented by the general formula (5), for example, JP-A-5-78373 and JP-A-5-65268 (Reaction Formula A), No. 3-147539 and JP-A-5-51361 (Reaction Formula B).
[0007]
[Chemical 8]
[0008]
[Chemical 9]
[0009]
In the reaction formula A, it is necessary to isolate the product for each reaction, and in the reaction formula (B), the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention is obtained. Need to cleave the side chain at the 3-position of azetidinone again, which is not industrially advantageous.
[0010]
[Problems to be solved by the invention]
In view of the above facts, the present inventors conducted extensive research on a method for producing the 3-aminoazetidinone derivative represented by the general formula (5) and a salt thereof in a high yield. As a result, the general formula (1 The iminochlor compound represented by the general formula (2) obtained by reacting the azetidinone derivative represented by formula (2) with phosphorus pentachloride in an organic solvent in the presence of a hydrogen chloride scavenger remains in the reaction solution. By reacting with a chlorinating agent to produce a chlorinated iminochlor form in a high yield, and further by reacting the reaction solution with alcohol and hydrolyzing the resulting chlorinated imino ether form, It was discovered that a 3-aminoazetidinone derivative and a salt thereof can be produced in a high yield by simple continuous operation, and the present invention was completed.
[0011]
[Means for Solving the Problems]
That is, the present invention provides the following general formula (1)
[0012]
[Chemical Formula 10]
[0013]
(In the formula, R 1 represents an aryl group, an arylmethyl group or an aryloxymethyl group having no substituent or a substituent, R 2 represents a protecting group for a carboxyl group, and R 3 represents a substituted or a substituent. An azetidinone derivative represented by formula (2) is reacted with phosphorus pentachloride in the presence of a hydrogen chloride scavenger in an organic solvent.
[0014]
Embedded image
[0015]
(Wherein R 1 , R 2 and R 3 have the same meanings as described above), the first step of producing the iminochlor body represented by the following formula, the iminochlor body is then reacted with a chlorinating agent, and the following general formula (3)
Embedded image
[0016]
(Wherein R 1 , R 2 and R 3 have the same meanings as described above), a second step of producing a chlorinated iminochlor compound represented by the following formula, and then reacting the product with alcohol to give the following general formula (4)
[0017]
Embedded image
[0018]
(Wherein R 1 , R 2 , and R 3 are as defined above, and R 4 represents an alkyl group and an alkyl group having one or more hydroxyl groups). The following general formula (5), characterized in that it comprises a third step and then a fourth step of hydrolyzing the chlorinated imino ether.
[0019]
Embedded image
[0020]
(Wherein R 2 and R 3 have the same meanings as described above), and relates to a novel process for producing a 3-aminoazetidinone derivative represented by the formula:
Hereinafter, the present invention will be described in detail.
The production method of the 3-aminoazetidinone derivative represented by the general formula (5) and the salt thereof according to the present invention basically includes four reaction steps as described above. It is characterized by four steps in the reaction formula, but after all the starting material can be continuously deacylated and chlorinated without isolating and purifying the product of each reaction. It is in.
In the production method of the present invention, the following general formula (12) obtained by deacylation without the chlorination reaction in the second step.
[0021]
Embedded image
[0022]
(In the formula, R 2 and R 3 have the same meanings as described above.) Even if chlorination of the compound represented by the formula is carried out, the object of the present invention is hardly obtained.
Examples of the azetidinone derivative of the general formula (1) used as a starting material in the present invention are shown in, for example, JP-A-50-129590, JP-A-59-164771, and JP-A-5-51361. It is already known as an important synthetic intermediate for sporin antibiotics.
[0023]
In the present invention, specific examples of R 1 in the compound represented by the general formula (1) include substitution or substitution of phenyl group, tolyl group, p-chlorophenyl group, p-nitrophenyl group, p-methoxyphenyl group and the like. An aryl group having no substituent, an benzyl group, a tolylmethyl group, a naphthylmethyl group, a p-methoxybenzyl group, a p-nitrobenzyl group, a phenyldichloromethyl group, or an arylmethyl group having no substituent or a substituent, phenoxy Examples thereof include an aryloxymethyl group having no substituent or a substituent such as a methyl group, a p-chlorophenoxymethyl group, and a p-nitrophenoxymethyl group.
[0024]
Examples of the carboxylic acid protecting group for R 2 may include halogens such as a methyl group, an ethyl group, a propyl group, a butyl group, a tert-butyl group, a 2,2,2-trichloroethyl group, and a 2-chloroethyl group. A lower alkyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a 3,4,5-trimethoxybenzyl group, a diphenylmethyl group or a substituted or unsubstituted arylmethyl group, a phenyl group, Examples include substituted or unsubstituted aryl groups such as a p-methoxyphenyl group.
[0025]
Specific examples of R 3 include substituted or unsubstituted aryl groups such as phenyl group, tolyl group, xylyl group, p-methoxyphenyl group, p-nitrophenyl group, and p-chlorophenyl group. Can do.
In the first step, an azetidinone derivative represented by the general formula (1) is reacted with phosphorus pentachloride in the presence of a hydrogen chloride scavenger in an organic solvent to produce an iminochlor form represented by the general formula (2). It is a process to make.
[0026]
Examples of the organic solvent used in the present invention include lower halogenated hydrocarbons, aromatic hydrocarbons, di-lower alkyl ethers, cyclic ethers, lower dialkoxyethanes, aliphatic amides, and the like. Is used as a mixed solvent of two or more. For example, lower halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride, aromatic hydrocarbons such as benzene and chlorobenzene, di-lower alkyl ethers such as diethyl ether and dimethyl ether, cyclic ethers such as tetrahydrofuran and dioxane, 1, Examples thereof include lower dialkoxyethanes such as 2-dimethoxyethane, 1,2-diethoxyethane, 1,2-dibutoxyethane, and 1,2-dibenzyloxyethane, and aliphatic amides such as dimethylformamide.
Examples of the hydrogen chloride scavenger include tertiary amines such as pyridine, picoline and triethylamine, epoxides such as propylene oxide and butylene oxide, carbonates of alkali metals such as soda carbonate, calcium carbonate and soda bicarbonate. Examples include salts.
[0027]
The reaction conditions in the first step vary depending on the physical properties of the raw materials, the type of solvent and the hydrogen chloride scavenger, but the reaction temperature is usually −30 to 10 ° C., preferably −2 to 4 ° C., and the reaction time is usually 0. 0.5 to 10 hours, preferably 1 to 3 hours.
Although the usage-amount of phosphorus pentachloride and a hydrogen chloride scavenger with respect to the azetidinone derivative of compound (1) is not particularly limited, phosphorus pentachloride is usually 1 to 5 times mol, preferably 1 to 3 times mol of compound (1). The molar amount of the hydrogen chloride scavenger is 1 to 10 times, preferably 1 to 3 times.
[0028]
Next, the second step is a step of producing a chlorinated iminochlor body represented by the general formula (3) by reacting the iminochlor body reaction liquid obtained above with a chlorinating agent in an organic solvent.
Examples of the chlorinating agent include chlorine gas, t-BuOCl, Cl 2 O, and the like. Chlorine gas can also be reacted as a solution in gaseous or inert organic solvents such as lower halogenated hydrocarbons such as carbon tetrachloride, dichloromethane and chloroform.
The amount of the chlorinating agent is not particularly limited, but is usually 1 to 5 times mol, preferably 1 to 2 times mol for the compound (1).
The chlorination in this step is to chlorinate the methyl group of the general formula (2) with the chlorinating agent, but this chlorination does not proceed with phosphorus pentachloride used in the previous step.
[0029]
In this second step, by using an organic solvent, the iminochlor compound represented by the general formula (2) can be easily chlorinated without using a hydrogen chloride scavenger, and the reaction can be performed at a low temperature. By carrying out, a chlorinated iminochlor compound represented by the general formula (3) can be obtained in high yield.
The organic solvent used in this step is the same as that described above, but is selected from the group consisting of lower halogenated hydrocarbons, aromatic hydrocarbons, di-lower alkyl ethers, cyclic ethers, and aliphatic amides. The seed fork is preferably two or more organic solvents, particularly preferably a mixed solvent of a lower halogenated hydrocarbon and a cyclic ether, and usually dioxane 1 to 3 (volume), preferably dioxane 2 (volume) with respect to dichloromethane 1 (volume). The mixed solvent is optimal.
[0030]
The reaction temperature in this step is usually −15 to −40 ° C., preferably −20 ° C. or lower. When the reaction temperature is −20 ° C. or higher, other chloro compounds are easily produced as a by-product in addition to the production of the target compound represented by the general formula (3). For example, when R 1 is an arylmethyl group, the chlorination further proceeds, and the methyl group at the 3-position is chlorinated by the following general formulas (13) and (14):
Embedded image
[0032]
Embedded image
[0033]
(In the formula, R 2 and R 3 have the same meanings as described above.) The by-products and the like represented are easily generated mainly. However, even in the compounds represented by the general formulas (13) and (14), the 3-aminoazetidinone derivative represented by the general formula (5) according to the present invention and the compound thereof are obtained by subsequent alcohol treatment and hydrolysis. It can also be made into a salt.
[0034]
Next, the third step is a reaction in which the chlorinated iminochlor form reaction solution obtained above is reacted with an alcohol to produce a chlorinated imino ether form represented by the following general formula (4). .
Examples of the alcohol used include lower alcohols such as methanol, ethanol, n-propanol and n-butanol, and polyvalent polyols such as ethylene glycol, propylene glycol and glycerin. Examples include alcohol.
The reaction conditions vary depending on the type of alcohol, but the reaction temperature is usually -50 to 50 ° C, preferably -30 to 20 ° C, and the reaction time is usually 0.5 to 24 hours, preferably 0.5 to 0.5 hours. 10 hours.
The amount of alcohol used is not particularly limited, but is usually 10 to 100 V / W, preferably 10 to 50 V / W, relative to compound (1).
[0035]
Next, a 4th process hydrolyzes the chlorinated imino ether body reaction liquid represented by General formula (4) obtained at the previous process, and is 3-amino azetidinone which is the target object which concerns on this invention. This is a step of obtaining a derivative and a salt thereof.
The reaction product can be obtained by reacting water with the reaction solution obtained in the previous step. The reaction time is usually 0.5 to 5 hours, preferably 0.5 to 1 hour.
The reaction temperature may be room temperature or lower, but the reaction is preferably performed at a temperature as low as possible in order to suppress decomposition of the product.
After completion of the reaction, the organic layer extracted by adding an extraction solvent such as a hydrophobic solvent such as dichloromethane, 1,2-dichloromethane, chloroform, carbon tetrachloride, benzene, chlorobenzene, ethyl acetate, ethyl formate, dichloroethane, ethoxyacetate, etc. Separate from the aqueous layer.
[0036]
Further, the separated organic layer is washed with water and then dehydrated with anhydrous magnesium sulfate, anhydrous sodium sulfate, or the like. Thereafter, the mixture is concentrated at room temperature or lower to obtain a hydrochloride of the 3-aminoazetidinone derivative.
Moreover, free amino compounds of 3-aminoazetidinone derivatives can also be obtained by adjusting the pH to near neutral, such as inorganic acids and organic acids such as inorganic acids such as sulfuric acid and phosphoric acid, tosylic acid, benzenesulfonic acid and the like. It can also be obtained as a salt corresponding to these acids by further reaction with an organic acid.
The compound of the present invention thus produced can be easily isolated and purified by ordinary separation and purification means, but the compound of the present invention is purified to be derived into the compound represented by the general formula (6). It is possible to carry out without doing this, which is industrially advantageous.
[0037]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, embodiments of the present invention will be described in detail with reference to examples.
Example 1
Production of [p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] (first step)
A 0.5-liter four-necked flask equipped with a stirrer was purged with nitrogen, charged with 15 g (0.072 M) of phosphorus pentachloride and 100 ml of dichloromethane, dissolved at 30 to 35 ° C., and then cooled to −2 to −5 ° C. Then, 5.87 g (0.073 M) of pyridine is slowly added dropwise. After reacting at −2 to −5 ° C. for about 20 minutes, 20 g of p-methoxybenzyl-2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-methyl-3-butenoate ( 0.033M). The reaction was completed in about 2 hours (1-2 hours) to obtain an iminochlor form.
[0038]
(Second step)
The obtained iminochlor form reaction solution was cooled to −20 ° C., 200 ml of dioxane was added, and 36 g of 7.9% chlorine-containing dichloromethane (chlorine content 2.86 g = 0.04 M) was added dropwise at a temperature of −20 ° C. or lower. The mixture was reacted with stirring at a temperature of −20 ° C. or lower for 0.5 hour to obtain a chlorinated iminochlor.
[0039]
(Third process)
Separately, a 1-liter four-necked flask equipped with a stirrer was purged with nitrogen, charged with 400 ml of dehydrated methanol, cooled to −20 ° C., and then the chlorinated iminochlor reaction solution obtained above was added all at once. Reaction was performed at 0 ° C. for 1 to 2 hours to obtain a chlorinated imino ether.
[0040]
(Fourth process)
The chlorinated imino ether reaction solution obtained above was cooled to −10 ° C., 140 ml of distilled water was added, and the reaction was carried out at a temperature of −10 to 0 ° C. for about 20 minutes, followed by extraction with 100 ml of dichloromethane. Further, the organic layer was dehydrated with anhydrous sodium sulfate and concentrated to obtain a light yellow mixed liquid of aminoazetidinone.
The obtained mixture was crystallized from isopropyl alcohol and dried to obtain 16.3 g of a pale yellow solid. By instrumental analysis such as NMR, MS and IR, p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidin-1-yl) -3-chloromethyl-3-butenoate hydrochloride I confirmed that there was. The yield was 89%.
[0041]
(1) 400 MHz 1 H-NMR δppm (DMSO: CDCl 3 1: 1)
3.81 (s, 3H, OMe)
4.06 (d, 1H, -CH 2 Cl, J = 16.0Hz), 4.39 (d, 1H, -CH 2 Cl, J = 16.0Hz)
4.29 (s, 1H, -CH (-COO-)-C)
4.98 (s, 1H, = C = CH 2), 5.01 (s, 1H, = C = CH 2)
5.14 (d, 1H, -OCH 2 -, J = 16.0Hz), 5.20 (d.1H, -OCH 2 -, J = 16.0Hz)
5.24 (d, 1H, lactam, J = 4.0Hz), 6.01 (d, 1H, lactam, J = 4.0Hz)
6.94 (d, 2H, J = 8.0Hz), 7.32 (d, 2H, J = 8.0Hz)
7.59 (t, 2H, J = 8.0Hz), 7.71 (t, 1H, J = 8.0Hz)
7.84 (d, 2H, J = 8.0Hz)
(2) MS (FAB): 511 m / z (M + H) +
(3) IR (KBr): ν3400, 2950, 2840, 1785, 1740, 1515, 1330, 1245, 1170, 1140, 580 cm −1
[0042]
Example 2
Production of [p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] (first step)
A 100 ml four-necked flask equipped with a stirrer was purged with nitrogen, charged with 3.5 g (0.017 M) of phosphorus pentachloride and 24 ml of dichloromethane, dissolved at 30 to 35 ° C., and then cooled to −2 to −5 ° C. 1.35 g (0.017 M) of pyridine is slowly added dropwise. After reaction at −2 to −5 ° C. for about 20 minutes, p-methoxybenzyl-2- (3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl) -3-methyl-3-butenoate Add 0 g (0.000084 M). The reaction was completed in about 2 hours (1-2 hours) to obtain an iminochlor form.
[0043]
(Second step)
The resulting iminochlorate reaction solution was cooled to −20 ° C., 48 ml of dioxane having a volume twice that of dichloromethane was added, and 10.0 g of dichloromethane containing 7.9% chlorine at −20 ° C. or less (the chlorine content was 0.00). 8 g = 0.011 M) was added dropwise, followed by stirring reaction at 0 ° C. for 0.5 hour to obtain a chlorinated iminochlor form.
[0044]
(Third process)
Separately, a 0.5 liter four-necked flask equipped with a stirrer was purged with nitrogen, charged with 100 ml of dehydrated methanol, cooled to −20 ° C., and then the chlorinated iminochlor reaction solution was added all at once. A aging reaction was carried out for 1 hour to obtain a chlorinated imino ether.
[0045]
(Fourth process)
The obtained chlorinated imino ether reaction liquid was cooled to −10 ° C., added with 35 ml of pure water, reacted for 20 minutes, extracted with dichloromethane, cooled with sodium bicarbonate water, washed with water, and the organic layer was dried over anhydrous sulfuric acid. After dehydrating and drying with 10 g of magnesium, the mixture was concentrated to obtain a yellow mixture.
The obtained yellow mixture was subjected to normal phase (Wako gel C-300, 450 g) column chromatography to remove impurities with ethyl acetate, and the fraction containing the desired product was recovered with methanol. The collected liquid was concentrated and purified by reverse phase (COSMOSIL 75C18, 500 g) chromatography with a solvent of acetonitrile: water = 1: 1 to obtain 1.9 g of a yellow liquid. It was found to be free p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate by instrumental analysis of NMR, MS and IR. confirmed. The yield was 45%.
[0046]
(1) 300 MHz 1 H-NMR δppm (DMSO: CDCl 3 )
3.78 (s, 3H, OMe)
4.07 (d, 2H, -CH 2 Cl)
4.64 (d, 1H, lactam, J = 4.8Hz)
4.93 (s, 1H, -CH (-COO-)-C)
5.09 (d, 1H, -OCH 2 -, J = 12.0Hz), 5.13 (d, 1H, -OCH 2 -, J = 12.0Hz)
5.16 (s, 1H, = C = CH 2), 5.29 (d, 1H, = C = CH 2)
5.69 (d, 1H, lactam, J = 4.8Hz)
6.90 (d, 2H, J = 9.6Hz), 7.29 (d, 2H, J = 9.6Hz)
7.52 (t, 2H, J = 9.8Hz), 7.63 (t, 1H, J = 9.8Hz)
7.88 (d, 2H, J = 9.8Hz)
(2) MS (FAB): 511 m / z (M + H) +
(3) IR (neat): ν 3400, 2960, 1780, 1740, 1615, 1520, 1445, 1372 1330, 1250, 1175, 1145, 1075, 590 cm −1
[0047]
Example 3
Preparation of [p-methoxybenzyl-2- (3-amino-4-benzenesulfonylthio-2-azetidinone-1-yl) -3-chloromethyl-3-butenoate] In place of dioxane in the second step of Example 1 As a result of carrying out in the same manner as in Example 1 except that 200 ml of dimethylformamide was used, a yellow mixed solution was obtained.
The obtained yellow mixed liquid was crystallized in the same manner as in Example 1 to obtain 11.7 g as a hydrochloride. The yield was 64%.
[0048]
【The invention's effect】
As described above in detail, according to the production method of the present invention, a 3-aminoazetidinone derivative and a salt thereof can be continuously obtained in a high yield by a simple operation.
The characteristic feature is that the deacylation and chlorination are continuously carried out in the deacylation step without isolating and purifying the product of each reaction, which is industrially advantageous.
Claims (2)
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JPH0967339A (en) | 1997-03-11 |
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