JPS626552B2 - - Google Patents
Info
- Publication number
- JPS626552B2 JPS626552B2 JP53085814A JP8581478A JPS626552B2 JP S626552 B2 JPS626552 B2 JP S626552B2 JP 53085814 A JP53085814 A JP 53085814A JP 8581478 A JP8581478 A JP 8581478A JP S626552 B2 JPS626552 B2 JP S626552B2
- Authority
- JP
- Japan
- Prior art keywords
- ethylidenephthalide
- ampicillin
- phthalide
- derivative
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- FLOWXWKOKRXGBR-UHFFFAOYSA-N 3-ethylidene-2-benzofuran-1-one Chemical class C1=CC=C2C(=CC)OC(=O)C2=C1 FLOWXWKOKRXGBR-UHFFFAOYSA-N 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 11
- 229960000723 ampicillin Drugs 0.000 description 11
- -1 3-(2-chloroethylidene) phthalide Chemical compound 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- XLDBFJIFFFXPHV-UHFFFAOYSA-N 3-(2-bromoethylidene)-2-benzofuran-1-one Chemical compound C1=CC=C2C(=CCBr)OC(=O)C2=C1 XLDBFJIFFFXPHV-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229960002780 talampicillin Drugs 0.000 description 4
- SOROUYSPFADXSN-SUWVAFIASA-N talampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OC2C3=CC=CC=C3C(=O)O2)(C)C)=CC=CC=C1 SOROUYSPFADXSN-SUWVAFIASA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003607 modifier Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- 229960003311 ampicillin trihydrate Drugs 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000031891 intestinal absorption Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000002925 chemical effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000005633 phthalidyl group Chemical group 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 150000003573 thiols Chemical class 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
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は医薬品のプロドラツグ用修飾剤あるい
は化学反応に於ける保護基試薬として有用な新規
3−エチリデンフタリド誘導体に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 3-ethylidenephthalide derivatives useful as modifiers for prodrugs of pharmaceuticals or protecting group reagents in chemical reactions.
医薬品の中には、高い薬理活性を有しながら、
化学的な不安定性や生物学的利用率の低さなどの
ために医薬品としての有用性を充分に発揮し得な
いものがあり、このような欠点を改善する方法の
一つとしてプロドラツグに導くという手法があ
る。この手法は、例えば腸管吸収率の低い薬物を
化学的に部分修飾して腸管吸収率を高め、生体内
で化学的・生物学的作用により元の薬物に復元さ
せ、その薬物本来の薬理活性を発現させるやり方
である。従来から、この目的のために種々の修飾
基が提案されているが、それらを用いたプロドラ
ツグは、その化学的安定性、生体内での元の薬物
への復元性の点で未だ充分とは云い難い。 Some pharmaceuticals have high pharmacological activity, but
There are some drugs that cannot fully demonstrate their usefulness as pharmaceuticals due to chemical instability or low bioavailability, and one way to improve these drawbacks is to develop prodrugs. There is a method. This method involves, for example, chemically partially modifying a drug with a low rate of intestinal absorption to increase its rate of intestinal absorption, and restoring it to the original drug in the body through chemical and biological effects, thereby enhancing the drug's original pharmacological activity. This is the way to make it manifest. Various modifying groups have been proposed for this purpose, but prodrugs using these groups are still insufficient in terms of their chemical stability and ability to revert back to the original drug in vivo. Hard to say.
本発明は、特に上記プロドラツグ用修飾剤とし
て有用であり、また化学反応に於ける保護基試薬
としても有用な一般式()
(式中、Xはハロゲン原子を示す。)
で示される新規3−エチリデンフタリド誘導体を
提供するものである。 The present invention is particularly useful as a modifier for the above-mentioned prodrugs, and also useful as a protecting group reagent in chemical reactions. (In the formula, X represents a halogen atom.) A novel 3-ethylidenephthalide derivative represented by the following is provided.
本発明の3−エチリデンフタリド誘導体()
は、いずれも文献未記載の新規化合物であり、具
体的には、3−(2−ブロモエチリデン)フタリ
ド、3−(2−クロロエチリデン)フタリドおよ
び3−(2−ヨードエチリデン)フタリドが挙げ
られる。 3-ethylidenephthalide derivative of the present invention ()
are all new compounds that have not been described in literature, and specific examples include 3-(2-bromoethylidene) phthalide, 3-(2-chloroethylidene) phthalide, and 3-(2-iodoethylidene) phthalide. .
本発明の3−エチリデンフタリド誘導体()
は、アルコール類、チオール類、フエノール類お
よびカルボン酸等と容易に反応して夫々エーテル
型およびエステル型化合物を生成するが、これら
エーテル型およびエステル型化合物は中性および
酸性媒質中で安定であり、また通常の化学反応に
於けるアルカリ加水分解条件下では容易に加水分
解されるにかかわらず、腸液に相当するアルカリ
性媒質中では比較的安定であつて、しかも生体内
酵素存在下では容易に加水分解されて元の化合物
に復元する。 3-ethylidenephthalide derivative of the present invention ()
easily reacts with alcohols, thiols, phenols, carboxylic acids, etc. to produce ether and ester compounds, respectively, but these ether and ester compounds are stable in neutral and acidic media. Although it is easily hydrolyzed under alkaline hydrolysis conditions in normal chemical reactions, it is relatively stable in an alkaline medium equivalent to intestinal fluid, and is easily hydrated in the presence of enzymes in vivo. It is broken down and restored to its original compound.
例えば、カルボキシル基を有するペニシリン類
と3−エチリデンフタリド誘導体()とを反応
させると対応するエステルが生成し、このエステ
ルは胃液および腸液中では安定であり腸管から吸
収されたのちに、生体内酵素存在下容易に加水分
解され元のペニシリン類に復元する。 For example, when a penicillin having a carboxyl group is reacted with a 3-ethylidenephthalide derivative (3-ethylidenephthalide), a corresponding ester is produced. Easily hydrolyzed in the presence of enzymes to restore the original penicillins.
このように、本発明の3−エチリデンフタリド
誘導体()は特に医薬品のプロドラツグ用修飾
剤として有用である。 Thus, the 3-ethylidenephthalide derivative () of the present invention is particularly useful as a modifier for pharmaceutical prodrugs.
また、前述のとおり本発明の3−エチリデンフ
タリド誘導体()から導かれるエーテル型およ
びエステル型化合物は、中性および酸性媒質中で
安定であるが、通常のアルカリ加水分解条件下で
は容易に加水分解を受けるので、本発明の3−エ
チリデンフタリド誘導体()は化学反応に於け
る保護基試薬としても有用である。 Furthermore, as mentioned above, the ether type and ester type compounds derived from the 3-ethylidenephthalide derivative () of the present invention are stable in neutral and acidic media, but are easily hydrated under normal alkaline hydrolysis conditions. Since it undergoes decomposition, the 3-ethylidenephthalide derivative () of the present invention is also useful as a protecting group reagent in chemical reactions.
次に、本発明の3−エチリデンフタリド誘導体
()の有用性を示す具体例を挙げる。 Next, specific examples showing the usefulness of the 3-ethylidenephthalide derivative () of the present invention will be given.
アンピシリンに3−エチリデンフタリド誘導体
()を反応させると、次式で示されるアンピシ
リン フタリジリデンエチルエステル塩酸塩が得
られる。 When ampicillin is reacted with a 3-ethylidenephthalide derivative (), ampicillin phthalidylidene ethyl ester hydrochloride represented by the following formula is obtained.
上記ペニシリンエステルをマウスに経口投与
し、10分後の血中アンピシリン濃度を測定したと
ころ、同力価のアンピシリン3水和物を経口投与
した場合に比べ、約4倍の血中アンピシリン濃度
を示した。しかも上記ペニシリンエステルは、従
来の、同様のエステル類、例えば、アンピシリン
をフタリジル基で修飾したアンピシリン フタリ
ジルエステル塩酸塩(塩酸タランピシリン)に比
して、非酵素的な安定性の面でも優れていた。即
ち、アンピシリン フタリジリデンエチルエステ
ル塩酸塩と塩酸タランピシリンとのリン酸緩衝液
〔PH8.0(37℃)〕中での安定性を調べたところ、
アンピシリン フタリジリデンエチルエステル塩
酸塩の加水分解半減期は約100分であるのに対し
て、比較した塩酸タランピシリンのそれは10分以
下であつた。 When the above penicillin ester was orally administered to mice and the blood ampicillin concentration was measured 10 minutes later, the blood ampicillin concentration was approximately 4 times higher than when the same potency of ampicillin trihydrate was orally administered. Ta. Moreover, the above penicillin ester was superior in terms of non-enzymatic stability compared to conventional similar esters, such as ampicillin phthalidyl ester hydrochloride (talampicillin hydrochloride), which is ampicillin modified with a phthalidyl group. . That is, when the stability of ampicillin phthalidylidene ethyl ester hydrochloride and talampicillin hydrochloride in a phosphate buffer [PH8.0 (37°C)] was investigated,
The hydrolytic half-life of ampicillin phthalidylidene ethyl ester hydrochloride was approximately 100 minutes, whereas that of talampicillin hydrochloride was less than 10 minutes.
本発明の3−エチリデンフタリド誘導体()
は3−エチリデンフタリド()に、
これに対して通常等モルないしは過剰のハロゲ
ン化剤を、不活性溶媒中加熱条件下あるいは室温
に於いて、ラジカル発生条件下で反応させること
によつて得られる。 3-ethylidenephthalide derivative of the present invention ()
is 3-ethylidenephthalide (), On the other hand, it is usually obtained by reacting equimolar or excess halogenating agents under radical generation conditions in an inert solvent under heating conditions or at room temperature.
ハロゲン化剤としては、塩素、臭素、N−ブロ
モフタル酸イミド、N−ブロモコハク酸イミド等
が挙げられる。 Examples of the halogenating agent include chlorine, bromine, N-bromophthalimide, N-bromosuccinimide, and the like.
ラジカルを発生させるためには、反応中紫外線
を照射するか、α・α′−アゾビスイソブチロニ
トリル、過酸化ベンゾイルのようなラジカル発生
剤を用い、更に両者を併用してもよい。 In order to generate radicals, ultraviolet rays may be irradiated during the reaction, or a radical generator such as α·α'-azobisisobutyronitrile or benzoyl peroxide may be used, or both may be used in combination.
不活性溶媒としては、塩化メチレン、クロロホ
ルム、四塩化炭素、四塩化エチレン、二塩化エチ
レン、ベンゼンあるいはこれらの混合溶媒等が挙
げられる。 Examples of the inert solvent include methylene chloride, chloroform, carbon tetrachloride, ethylene tetrachloride, ethylene dichloride, benzene, and a mixed solvent thereof.
また、3−(2−ヨードエチリデン)フタリド
は、上記の方法で得られる3−(2−ブロモエチ
リデン)フタリドまたは3−(2−クロロエチリ
デン)フタリドに、常法に従つて沃化ナトリウム
又は沃化カリウムを作用させて得ることができ
る。 In addition, 3-(2-iodoethylidene) phthalide can be obtained by adding sodium iodide or iodine to 3-(2-bromoethylidene) phthalide or 3-(2-chloroethylidene) phthalide obtained by the above method. It can be obtained by the action of potassium chloride.
次に実施例および参考例を挙げて、本発明を更
に具体的に説明する。 Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.
実施例
3−(2−ブロモエチリデン)フタリドの製
造:
3−エチリデンフタリド〔Chem.Ber.、32、
958(1899)に従つて合成した。〕52.5gを四塩化
炭素1500mlに溶解し、これに67.0gのN−ブロモ
コハク酸イミドおよび触媒量のα・α′−アゾビ
スイソブチロニトリルを加え紫外線照射下40時間
加熱還流した。生成したコハク酸イミドをろ別
し、ろ液を減圧下濃縮し、析出した結晶をろ取し
て3−(2−ブロモエチリデン)フタリド53gを
淡黄色針状結晶として得た。Example 3 - Preparation of (2-bromoethylidene) phthalide: 3-ethylidene phthalide [Chem.Ber., 32 ,
958 (1899). ] 52.5 g was dissolved in 1500 ml of carbon tetrachloride, 67.0 g of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added thereto, and the mixture was heated under reflux for 40 hours under ultraviolet irradiation. The generated succinimide was filtered off, the filtrate was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 53 g of 3-(2-bromoethylidene) phthalide as pale yellow needle-like crystals.
融点:106〜108℃
IR(KBr):1780(C=0)、1685(エキソオレ
フイン)cm-1
NMR(CDCl3)δ:4.3(2H、d、J=8.0Hz、−
CH2Br)、5.7(1H、t、J=8.0Hz、=CH−)、
7.5(4H、m、ベンゼン環)
元素分析値(C10H7BrO2として):
計算値(%) C、50.24;H、2.95;
Br、33.42
実測値(%) C、50.23;H、3.09;
Br、33.13
参考例
アンピリシン フタリジデンエチルエステル塩
酸塩の製造:
アンピシリン三水和物510mgをジメチルホルム
アミド5ml中に懸濁後、炭酸水素カリウム125mg
を加え0℃に冷却した。これにベンズアルデヒド
0.25mlを滴下し0〜5℃で3.5時間撹拌した。次
いで、炭酸水素カリウム145mg、3−(2−ブロモ
エチリデン)フタリド350mgを加え更に0〜5℃
で3時間撹拌した。反応液を氷水中に加え析出し
た固体を酢酸エチルで抽出し、水洗後、無水硫酸
ナトリウムで乾燥した。減圧下に溶媒を留去して
油状のN−ベンジリデンアンピシリン フタリジ
リデンエチルエステル520mgを得た。Melting point: 106-108°C IR (KBr): 1780 (C = 0), 1685 (exo-olefin) cm -1 NMR (CDCl 3 ) δ: 4.3 (2H, d, J = 8.0Hz, -
CH 2 Br), 5.7 (1H, t, J=8.0Hz, =CH−),
7.5 (4H, m, benzene ring) Elemental analysis value (as C 10 H 7 BrO 2 ): Calculated value (%) C, 50.24; H, 2.95;
Br, 33.42 Actual value (%) C, 50.23; H, 3.09;
Br, 33.13 Reference example Production of ampicillin phthalididene ethyl ester hydrochloride: After suspending 510 mg of ampicillin trihydrate in 5 ml of dimethylformamide, 125 mg of potassium hydrogen carbonate was added.
was added and cooled to 0°C. In this, benzaldehyde
0.25 ml was added dropwise and stirred at 0 to 5°C for 3.5 hours. Next, 145 mg of potassium hydrogen carbonate and 350 mg of 3-(2-bromoethylidene) phthalide were added, and the mixture was further heated at 0 to 5°C.
The mixture was stirred for 3 hours. The reaction solution was added to ice water, and the precipitated solid was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 520 mg of oily N-benzylidene ampicillin phthalidylidene ethyl ester.
次いで、得られたN−ベンジリデンアンピシリ
ンフタリジリデンエチルエステル520mgをアセト
ニトリル3mlに溶解し、1N−塩酸2mlを加え5
℃で30分間撹拌した。反応混合物を減圧下に濃縮
後、水6mlを加え、酢酸エチルで洗浄し、食塩を
加えて塩化メチレンで抽出した。有機層を飽和食
塩水で洗浄後、無水硫酸ナトリウムで乾燥した。
減圧下に溶媒を濃縮し、析出した結晶をろ取して
アンピシリン フタリジリデンエチルエステル塩
酸塩230mgを白色無定形結晶として得た。 Next, 520 mg of the obtained N-benzylidene ampicillin phthalidylidene ethyl ester was dissolved in 3 ml of acetonitrile, and 2 ml of 1N-hydrochloric acid was added thereto.
Stirred at ℃ for 30 minutes. After the reaction mixture was concentrated under reduced pressure, 6 ml of water was added, washed with ethyl acetate, added with common salt, and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was concentrated under reduced pressure, and the precipitated crystals were collected by filtration to obtain 230 mg of ampicillin phthalidylidene ethyl ester hydrochloride as white amorphous crystals.
融点145〜155℃(分解)Melting point 145-155℃ (decomposition)
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8581478A JPS5513221A (en) | 1978-07-13 | 1978-07-13 | 3-ethylidene phthalide derivative and its preparation |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8581478A JPS5513221A (en) | 1978-07-13 | 1978-07-13 | 3-ethylidene phthalide derivative and its preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5513221A JPS5513221A (en) | 1980-01-30 |
JPS626552B2 true JPS626552B2 (en) | 1987-02-12 |
Family
ID=13869321
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP8581478A Granted JPS5513221A (en) | 1978-07-13 | 1978-07-13 | 3-ethylidene phthalide derivative and its preparation |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5513221A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5921692A (en) * | 1982-07-29 | 1984-02-03 | Sankyo Co Ltd | Orally administrable penem compound and its preparation |
JPH084016B2 (en) * | 1987-03-18 | 1996-01-17 | 株式会社ユアサコーポレーション | Charge control system for lead-acid batteries |
-
1978
- 1978-07-13 JP JP8581478A patent/JPS5513221A/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5513221A (en) | 1980-01-30 |
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