JPH0258271B2 - - Google Patents
Info
- Publication number
- JPH0258271B2 JPH0258271B2 JP58013076A JP1307683A JPH0258271B2 JP H0258271 B2 JPH0258271 B2 JP H0258271B2 JP 58013076 A JP58013076 A JP 58013076A JP 1307683 A JP1307683 A JP 1307683A JP H0258271 B2 JPH0258271 B2 JP H0258271B2
- Authority
- JP
- Japan
- Prior art keywords
- ampicillin
- dioxolen
- mol
- formula
- general formula
- 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
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 13
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical class O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 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 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000411 inducer Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- 229960000723 ampicillin Drugs 0.000 description 20
- 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 20
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- -1 ampicillin ester Chemical class 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- 229960003311 ampicillin trihydrate Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- GWFALVUXAGYMHR-UHFFFAOYSA-N 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1CBr GWFALVUXAGYMHR-UHFFFAOYSA-N 0.000 description 3
- PVDNUJWCLUDTSE-UHFFFAOYSA-N 4-(bromomethyl)-5-phenyl-1,3-dioxol-2-one Chemical compound O1C(=O)OC(C=2C=CC=CC=2)=C1CBr PVDNUJWCLUDTSE-UHFFFAOYSA-N 0.000 description 3
- HXXOPVULXOEHTK-UHFFFAOYSA-N 4-methyl-1,3-dioxol-2-one Chemical compound CC1=COC(=O)O1 HXXOPVULXOEHTK-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000012474 bioautography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- GZMPBWRVQSXAJR-UHFFFAOYSA-N 4,5-bis(bromomethyl)-1,3-dioxol-2-one Chemical compound BrCC=1OC(=O)OC=1CBr GZMPBWRVQSXAJR-UHFFFAOYSA-N 0.000 description 2
- 101100460146 Arabidopsis thaliana NEET gene Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000031891 intestinal absorption Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- FVTBEDLKPPVXNH-UHFFFAOYSA-N 3-bromo-7-hydroxy-4-methylchromen-2-one Chemical compound C1=C(O)C=CC2=C1OC(=O)C(Br)=C2C FVTBEDLKPPVXNH-UHFFFAOYSA-N 0.000 description 1
- QYIOFABFKUOIBV-UHFFFAOYSA-N 4,5-dimethyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1C QYIOFABFKUOIBV-UHFFFAOYSA-N 0.000 description 1
- KFZJRSPXJHVSCX-UHFFFAOYSA-N 4-(bromomethyl)-1,3-dioxol-2-one Chemical compound BrCC1=COC(=O)O1 KFZJRSPXJHVSCX-UHFFFAOYSA-N 0.000 description 1
- JODXHEZZVYDUPS-UHFFFAOYSA-N 4-methyl-5-phenyl-1,3-dioxol-2-one Chemical compound O1C(=O)OC(C=2C=CC=CC=2)=C1C JODXHEZZVYDUPS-UHFFFAOYSA-N 0.000 description 1
- VMAJRFCXVOIAAS-UHFFFAOYSA-N 4-phenyl-1,3-dioxol-2-one Chemical compound O1C(=O)OC=C1C1=CC=CC=C1 VMAJRFCXVOIAAS-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
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010019160 Pancreatin Proteins 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
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- ZKUKMWMSYCIYRD-ZXFNITATSA-N lenampicillin Chemical compound O1C(=O)OC(COC(=O)[C@H]2C(S[C@H]3N2C([C@H]3NC(=O)[C@H](N)C=2C=CC=CC=2)=O)(C)C)=C1C ZKUKMWMSYCIYRD-ZXFNITATSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940055695 pancreatin Drugs 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
- 238000005192 partition Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 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 1
- 229960002780 talampicillin Drugs 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 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
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は医薬品のプロドラツグ用修飾剤として
有用な新規１，３−ジオキソレン−２−オン誘導
体の製造法に関する。
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（バイオアベ
ラビリテイー）の不良等のために、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、又こ
のような欠点を改善する方法の１つとして化学的
修飾によるプロドラツグがある。
例えば腸管吸収率の低い薬物を化学的に部分修
飾して腸管吸収を行め、生体内で化学的・生物学
的作用により元の薬物に復元せしめて、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の
化学的安定性、生体内での元の薬物への復元性、
あるいは修飾基がもたらす副作用等の点で未だ満
足の域に達していない。
本発明は、特に医薬品のプロドラツグ用の修飾
剤として有用かつ新規な一般式［］で示される
１，３−ジオキソレン−２−オン誘導体の製造法
を提供するものである。
［式中、R1は水素原子、低級アルキル基又はフ
エニル基を示し、R2は水素原子であるか又はR2
はR1と一緒になつて−（CH2）3−を形成している］
一般式［］で示される１，３−ジオキソレン
−２−オン誘導体は、いずれも文献未記載の新規
化合物であり、具体的を挙げると４−ブロモメチ
ル−１，３−ジオキソレン−２オン、４−ブロモ
メチル−５−メチル−１，３−ジオキソレン−２
−オン、４−ブロモメチル−５−フエニル−１，
３−ジオキソレン−２−オン、３−ブロモ−１，
２−カルボニルジオキシシクロヘキセン等であ
る。これら１，３−ジオキソレン−２−オン誘導
体は、いずれもカルボン酸類、チオカルボン酸
類、フエノール類等と容易に反応して対応するエ
ステル型化合物およびエーテル型化合物を生成す
るが、これらエステル型化合物およびエーテル型
化合物は中性および酸性媒質中で安定であり、又
通常の化学反応におけるアルカリ加水分離条件下
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に安定であ
つて、しかも生体内酵素の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。
例えばカルボン酸基を持つペニシリン類と一般
式［］で示される１，３−ジオキソレン−２−
オン誘導体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内では安定
であつて、腸管から容易に吸収されると共に生体
内で容易に加水分解されて元のペニシリンに復元
する。このように、一般式［］で示される１，
３−ジオキソレン−２−オン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。な
お、カルボン酸類およびフエノール類と該１，３
−ジオキソレン−２−誘導体から導かれるエステ
ル類およびエーテル類は、前述のとおり中性媒質
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、該１，３−ジオキソレン−２−オン誘導体は
化学反応における保護基の導入試薬としても有用
である。
以下に該１，３−ジオキソレン−２−オン誘導
体の有用性を示す実験データーを挙げる。
［経口投与時の血中濃度］
１ 供試化合物
Ａ アンピシリン（５−メチル−２−オキソ−
１，３−ジオキソレン−４−イル）メチルエ
ステル塩酸塩（後述の参考例３に従つてアン
ピシリン三水和物と４−ブロモメチル−５−
メチル−１，３−ジオキソレン−２−オンと
から合成した。）
Ｂ アンピシリンフタリジルエステル塩酸塩
（公知のアンピシリンエステル、対照化合物）
Ｃ アンピシリン三水化物（対照化合物）
２ 試験方法
一夜絶食した４週令マウス（ddY系、体重約
20ｇ、一群５匹）にアンピシリン換算50.0mg／
Kg相当の供試化合物（アンピシリン換算で濃度
５mg／mlの水溶液約0.2ml）を経口投与し、経
時的に採血して血清中のアンピシリン濃度をバ
イオアツセイ法によつて測定し、各供試化合物
の血清中アンピシリン濃度の相対比を求めた。
３ 結果
The present invention relates to a method for producing a novel 1,3-dioxolen-2-one derivative useful as a modifier for pharmaceutical prodrugs. Some pharmaceuticals have high pharmacological activity, but
There are some drugs that cannot fully demonstrate their usefulness as pharmaceuticals due to chemical instability or poor bioavailability, and there are no methods to improve these drawbacks. One type of drug is a prodrug based on chemical modification. For example, a drug with a low rate of intestinal absorption can be partially modified chemically to achieve intestinal absorption, and then restored to its original form in the body through chemical and biological actions, thereby allowing the original pharmacological activity of the drug to be expressed. It is. Various modification groups have been proposed for this purpose, but the chemical stability of prodrugs using them, the ability to revert to the original drug in vivo,
Alternatively, the level of satisfaction has not yet been reached in terms of side effects caused by the modifying group. The present invention provides a method for producing a novel 1,3-dioxolen-2-one derivative represented by the general formula [], which is particularly useful as a modifier for pharmaceutical prodrugs. [In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R 2 is a hydrogen atom or R 2
is combined with R 1 to form -(CH 2 ) 3 -] The 1,3-dioxolen-2-one derivatives represented by the general formula [] are all new compounds that have not been described in any literature. , Specifically, 4-bromomethyl-1,3-dioxolene-2one, 4-bromomethyl-5-methyl-1,3-dioxolene-2
-one, 4-bromomethyl-5-phenyl-1,
3-dioxolen-2-one, 3-bromo-1,
2-carbonyldioxycyclohexene and the like. All of these 1,3-dioxolen-2-one derivatives easily react with carboxylic acids, thiocarboxylic acids, phenols, etc. to produce corresponding ester-type compounds and ether-type compounds. type compounds are stable in neutral and acidic media, and are relatively stable in alkaline media corresponding to intestinal fluids, although they are easily hydrolyzed under alkaline hydrolysis conditions in common chemical reactions. Furthermore, in the presence of in vivo enzymes, it is easily hydrolyzed and restored to its original compound. For example, penicillins having a carboxylic acid group and 1,3-dioxolene-2-
Reaction of the on derivative produces the corresponding ester, which is stable in gastric and intestinal fluids, easily absorbed from the intestinal tract, and easily hydrolyzed in vivo to restore the original penicillin. In this way, 1, represented by the general formula [ ],
3-Dioxolen-2-one derivatives are particularly useful as modifiers for pharmaceutical prodrugs. In addition, carboxylic acids and phenols and the 1,3
Esters and ethers derived from -dioxolene-2- derivatives are stable in neutral and acidic media as described above, but are easily hydrolyzed under normal alkaline hydrolysis conditions. , 3-dioxolen-2-one derivatives are also useful as reagents for introducing protective groups in chemical reactions. Experimental data showing the usefulness of the 1,3-dioxolen-2-one derivatives are listed below. [Blood concentration upon oral administration] 1 Test compound A Ampicillin (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl ester hydrochloride (ampicillin trihydrate and 4-bromomethyl-5-according to Reference Example 3 described below)
It was synthesized from methyl-1,3-dioxolen-2-one. ) B Ampicillin phthalidyl ester hydrochloride (known ampicillin ester, control compound) C Ampicillin trihydrate (control compound) 2 Test method 4-week-old mice fasted overnight (ddY strain, body weight approx.
Ampicillin equivalent: 50.0mg/20g, 5 animals per group)
Kg equivalent of the test compound (approximately 0.2 ml of an aqueous solution with a concentration of 5 mg/ml in terms of ampicillin) was orally administered, blood was collected over time, and the ampicillin concentration in the serum was measured by a bioassay method. The relative ratio of serum ampicillin concentrations was determined. 3 Results
【表】
第１表から明らかなように、該１，３−ジオ
キソレン−２−オン誘導体から誘導されたアン
ピシリンエステル(A)は、容易に吸収されて生体
内で元のアンピシリンに復元し、アンピシリン
(C)および公知のアンピシリンエステル(B)に比し
長時間にわたり高い血中アンピシリン濃度を示
す。
［酸性物質（人工胃液に該当）中での加水分解］
１ 供試化合物 前記ＡおよびＢ
２ 試験方法
1000ml中に食塩2.0ｇ、10％塩酸24ml、ペプ
シン3.2ｇを含む酸性媒質（PH1.2）に供試化合
物を溶解し、37℃に振盪しつつ経時的にサンプ
リングして逆相分配カラムを用いた高速液体ク
ロマト法により、各供試化合物のピーク高の減
少からその加水分解率を求めた。
３ 結果[Table] As is clear from Table 1, the ampicillin ester (A) derived from the 1,3-dioxolen-2-one derivative is easily absorbed and restored to the original ampicillin in vivo.
(C) and the known ampicillin ester (B) show higher blood ampicillin concentration over a longer period of time. [Hydrolysis in acidic substance (corresponding to artificial gastric fluid)] 1 Test compound A and B above 2 Test method Acidic medium (PH1.2) containing 2.0 g of common salt, 24 ml of 10% hydrochloric acid, and 3.2 g of pepsin in 1000 ml. The hydrolysis rate of each test compound was determined from the decrease in peak height by high-performance liquid chromatography using a reversed-phase partition column by dissolving the test compound and sampling over time while shaking at 37°C. . 3 Results
【表】
第２表に示すとおり、酸性媒質中ではＡはＢ
に比し遥かに安定である。
［塩基性媒質（人工腸液に該当）中での加水分
解］
１ 供試化合物 前記ＡおよびＢ
２ 試験方法
1000ml中に燐酸二ナトリウム35.8ｇ、10％塩
酸6.0ml、パンクレアチン2.8ｇを含む塩基性媒
質（PH7.5）中に供試化合物を溶解し、前記の
酸性媒質の場合と同様にして、各供試化合物の
加水分解率を求めた。
３ 結果[Table] As shown in Table 2, A is B in acidic medium.
It is much more stable than . [Hydrolysis in basic medium (corresponding to artificial intestinal fluid)] 1 Test compound A and B above 2 Test method Basic solution containing 35.8 g of disodium phosphate, 6.0 ml of 10% hydrochloric acid, and 2.8 g of pancreatin in 1000 ml A test compound was dissolved in a medium (PH7.5), and the hydrolysis rate of each test compound was determined in the same manner as in the case of the acidic medium. 3 Results
【表】
第３表に示すように、塩基性媒質中ではＡは
Ｂに比し安定である。
［その他］
前記Ａの毒性（LD50）をマウス（４週令ddY
系）を用いて調べた結果は次のとおりである。
経口投与＞5000mg／Kg、腹腔内投与1430mg／
Kg、静脈内投与557mg／Kg。
以上のとおり該１，３−ジオキソレン−２−オ
ン誘導体は医薬のプロドラツグ用修飾剤として極
めて有用であるが、かかる有用性は従来の知見か
らは全く予測し得ないところである。
すなわち、本発明の出発原料である４−メチル
−５−フエニル−１，３−ジオキソレン−２−オ
ン、４，５−ジメチル−１，３−ジオキソレン−
２−オン等がリービツヒズ・アンナレン・デル・
ヘミー、第764巻、116〜124頁（1972年）、テトラ
ヘドロン・レターズ、1972年、1701〜1704頁およ
び米国特許第3020290号公報に開示されているが、
それらから導かれる一般式［］で示される該
１，３−ジオキソレン−２−オン誘導体について
は何等の記載もない。又、リービツヒズ・アンナ
レン・デル・ヘミー、1977年、27〜32頁には、
４，５−ジメチル−１，３−ジオキソレン−２−
オン1.0モルに対して2.0モルのＮ−ブロモコハク
酸イミドを用いてブロム化することによる重合体
製造用中間原料である４，５−ビス（ブロモメチ
ル）−１，３−ジオキソレン−２−オンの製造法
が記載されているが、本発明における一般式
（）の１，３−ジオキソレン−２−オン誘導体
およびその製法に関しては具体的な記載がない
し、又、該化合物の用途に関しても何らの示唆も
ない。
本発明の１，３−ジオキソレン−２−オン誘導
体の製造法は、一般式
［式中、R1、R2は前記に同じ］
で示される化合物に、室温もしくは一般には加熱
条件下のラジカル発生条件下で、化合物［］
1.0モルに対し、0.8〜1.2モルのＮ−ブロモコハク
酸イミドを反応させることによつて達せられる。
出発原料である一般式［］の化合物は、例え
ばリービツヒズ・アンナレン・デル・ヘミー、第
764巻、116〜124頁（1972年）、テトラヘドロン・
レターズ、1972年、1701〜1704頁、および米国特
許第3020290号公報等に開示されている公知の方
法に従つて合成することができる。
一般式［］で示される原料とＮ−ブロモコハ
ク酸イミドとの反応を進めるために、反応中紫外
線を照射するか、或は反応液に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
ラジカル誘起剤を用いる。反応溶媒は、原料の性
質等に応じて適当なものが選択され、例えば塩化
メチレン、クロロホルム、四塩化炭素、四塩化エ
チレン、ベンゼン等の非プロトン性不活性溶媒が
挙げられる。
以下実施例および参考例を挙げて本発明を具体
的に説明する。
実施例 １
４−ブロモメチル−５−フエニル−１，３−ジ
オキソレン−２−オンの製造；
４−メチル−５−フエニル−１，３−ジオキソ
レン−２−オン（リービツヒズ・アンナレン・デ
ル・ヘミー、第764巻、116〜124頁、1972年に従
つて合成した）2.4ｇ（0.0136モル）を四塩化炭
素150mlに溶解し、これに2.9ｇ（0.0162モル）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、90分間
加熱還流した。反応液を半量まで濃縮し不溶物を
濾別し、濾液を濃縮し残渣をベンゼンとシクロヘ
キサンの混液から再結晶し無色針状結晶、融点
90.5〜91.5℃の目的物2.3ｇ（収率66％）を得た。
元素分析、分子式C10H7BrO3：理論値（％）
Ｃ、47.09：Ｈ、2.77：Br、31.33。実験値（％）
Ｃ、47.22：Ｈ、2.64：Br、31.29。IR（KBr、ν
cm-1）：1825付近（カルボニル）。NMR（CCl4）
δ（ppm）：4.35（−CH2Br、ｓ）、7.40（ベンゼン
環、ｓ）
実施例 ２
４−ブロモメチル−５−メチル−１，３−ジオ
キソレン−２−オンの製造：
４，５−ジメチル−１，３−ジオキソレン−２
−オン（テトラヘドロン・レターズ、1972年、
1701〜1704頁に従つて合成した）3.42ｇ（0.003
モル）を四塩化炭素150mlに溶解し、これに5.34
ｇ（0.03モル）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、15分間加熱還流した。反応液を半量まで
濃縮し不溶物を濾去した後、濾液を濃縮した。シ
ラツプ状の残渣を減圧蒸留し無色液体、沸点115
〜120℃／５mmHgの目的物4.2ｇ（収率73％）を
得た。
元素分析、分子式C5H5BrO3：理論値（％）：
Ｃ、31.12：Ｈ、2.61：Br、41.40、実験値（％）：
Ｃ、31.30：Ｈ、2.49：Br、41.31、IR（ニート、
νcm-1）：1825付近（カルボニル）
NMR（CCl4）δ（ppm）：2.10（−CH3、ｓ）、
4.10（−CH2Br、ｓ）
実施例 ３
４−ブロモメチル−１，３−ジオキソレン−２
−オンの製造：
４−メチル−１，３−ジオキソレン−２−オン
（米国特許第3020290号に従つて合成した）8.6ｇ
（0.086モル）を四塩化炭素200mlに溶解し、これ
に17.8ｇ（0.1モル）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90分間加熱還流した。以下実施例２
と同様に処理して無色液体、沸点94℃／３mmHg
の目的物5.2ｇ（収率33.6％）を得た。
元素分析、分子式C4H3BrO3：理論値（％）：
Ｃ、26.84：Ｈ、1.69：Br、44.65、実験値（％）：
Ｃ、26.94：Ｈ、1.66：Br、44.60。IR（ニート、
νcm-1）：1830付近（カルボニル）
NMR（CCl4）δ（ppm）：4.10（−CH2Br、ｓ）、
7.00（＝CH−Ｏ−、ｓ）
実施例 ４
３−ブロモ−１，２−カルボニルジオキシシク
ロヘキセンの製造：
１，２−カルボニルジオキシシクロヘキセン
（テトラヘドロン・レターズ。1972年、1701〜
1704頁に従つて合成した）2.15ｇ（0.015モル）
を四塩化炭素80mlに溶解し、これに2.3ｇ（0.013
モル）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20
分間加熱還流した。反応液を冷後濾過し、濾液を
低温で濃縮し目的の粗生成物（淡褐色液体）3.2
ｇを得た。IR（ニート、νcm-1）：1825付近（カ
ルボニル）NMR（CDCl3）δ（ppm）：5.0
｜
（＝Ｃ−CH−Br、ｍ）、1.3〜3.0（環状
｜
水素、ｍ）
この目的物の粗生成物は不安定であるので、単
離精製することなくアンピシリンと反応させてア
ンピシリンエステルを得た（参考例１参照）。
参考例 １
アンピシリン三水和物500mgをジメチルホルム
アミド６mlに分散させ、これに重炭酸カリウム
125mgを加えて０℃に冷却し、更にベンズアルデ
ヒド0.25mlを加えて０℃で2.5時間撹拌した。次
に重炭酸カリウム125mgと３−ブロモ−１，２−
カルボニルジオキシシクロヘキセン250mg（実施
例４で得た粗生成物）を加え更に０℃で３時間撹
拌した。反応終了後、反応液を氷水中に注ぎ込
み、析出する固型物を酢酸エチル30mlで抽出し、
有機層を水20mlで３回洗浄し、無水硫酸マグネシ
ウムで乾燥した後、酢酸エチルを減圧下留去し黄
色シラツプを得た。
上記の様にして得られたシラツプ状残渣をアセ
トニトリル４mlに溶解し希塩酸でPH2.0に調整し
０℃で30分間撹拌した。これに水10mlを加え減圧
下アセトニトリルを留去し、水層を酢酸エチルで
くりかえし洗浄した後、食塩を飽和させ、析出す
る油状物質を塩化メチレン50mlで抽出し、飽和食
塩水で洗浄した。塩化メチレン溶液を無水硫酸ナ
トリウムで乾燥した後半量まで濃縮し、イソプロ
ピルアルコール30mlを加え再び減圧濃縮すると淡
黄色固体が得られた。
この固体を濾取しイソプロピルアルコール、エ
ーテルで洗浄しアンピシリン（２，３−カルボニ
ルジオキシ−２−シクロヘキセニル）エステル塩
酸塩の無色無定型固体256mgを得た。融点140℃
（分解）。IR（KBr、νcm-1）：1830、1780、1750
（カルボニル）、1690（アミド）
上記アンピシリンエステル塩酸塩を40％マウス
血液中で37℃で10分間インキユベートしたのちバ
イオオートグラフイーを実施したところ、該エス
テルは全てアンピシリンに転化している事が判つ
た。
参考例 ２
参考例１と同様にして、アンピシリン三水和物
と４−ブロモメチル−５−フエニル−１，３−ジ
オキソレン−２−オンからアンピシリン（５−フ
エニル−２−オキソ−１，３−ジオキソレン−４
−イル）メチルエステル塩酸塩を得た。
収率46.4％、無色無定型固体、融点140℃（分
解）。IR（KBr、νcm-1）：1830、1785、1760（カ
ルボニル）、1690（アミド）
このアンピシリン（５−フエニル−２−オキソ
−１，３−ジオキソレン−４−イル）メチルエス
テル塩酸塩を40％マウス血液中で37℃で５分間イ
ンキユベートしたのちバイオオートグラフイーを
実施したところ該エステルは全てアンピシリンに
転化している事が判つた。
参考例 ３
参考例１と同様にして、アンピシリン三水和物
と４−ブロモメチル−５−メチル−１，３−ジオ
キソレン−２−オンからアンピシリン（５−メチ
ル−２−オキソ−１，３−ジオキソレン−４−イ
ル）メチルエステル塩酸塩を得た。
収率50.6％、無色無定型固体。
融点141℃より着色し始め145℃で発泡する。
IR（KBr、νcm-1）：1825、1785、1750（カルボニ
ル）、1690（アミド）
このアンピシリン（５−メチル−２−オキソ−
１，３−ジオキソレン−４−イル）メチルエステ
ル塩酸塩を40％マウス血液中で37℃に５分間イン
キユベートしたのちバイオオートグラフイーを実
施したところ該エステルは全てアンピシリンに転
化している事が判つた。[Table] As shown in Table 3, A is more stable than B in a basic medium. [Others] The toxicity (LD 50 ) of the above A was measured in mice (4 weeks old ddY
The results of the investigation using the system) are as follows. Oral administration > 5000mg/Kg, intraperitoneal administration 1430mg/
Kg, intravenous administration 557 mg/Kg. As described above, the 1,3-dioxolen-2-one derivatives are extremely useful as modifiers for pharmaceutical prodrugs, but such usefulness could not be predicted from conventional knowledge. That is, 4-methyl-5-phenyl-1,3-dioxolene-2-one, 4,5-dimethyl-1,3-dioxolene-
2-on et al.
Hemy, Vol. 764, pp. 116-124 (1972), Tetrahedron Letters, 1972, pp. 1701-1704, and U.S. Pat. No. 3,020,290.
There is no description whatsoever about the 1,3-dioxolen-2-one derivatives derived from them and represented by the general formula []. Also, in Liebitz His Annalen der Hemy, 1977, pp. 27-32,
4,5-dimethyl-1,3-dioxolene-2-
Production of 4,5-bis(bromomethyl)-1,3-dioxolen-2-one, an intermediate raw material for polymer production, by bromination using 2.0 mol of N-bromosuccinimide per 1.0 mol of 4,5-bis(bromomethyl)-1,3-dioxolen-2-one Although the method is described, there is no specific description regarding the 1,3-dioxolen-2-one derivative of the general formula () in the present invention and its manufacturing method, nor is there any suggestion regarding the use of the compound. do not have. The method for producing the 1,3-dioxolen-2-one derivative of the present invention is based on the general formula [In the formula, R 1 and R 2 are the same as above] The compound [
This can be achieved by reacting 0.8 to 1.2 moles of N-bromosuccinimide to 1.0 mole. The starting material, a compound of the general formula [ ], is used, for example, as described in
Volume 764, pp. 116-124 (1972), Tetrahedron.
It can be synthesized according to known methods disclosed in Letters, 1972, pp. 1701-1704, and US Pat. No. 3,020,290. In order to proceed with the reaction between the raw material represented by the general formula [] and N-bromosuccinimide, ultraviolet rays are irradiated during the reaction, or α,α'-azobisisobutyronitrile, benzoyl peroxide is added to the reaction solution. Use a radical inducer such as An appropriate reaction solvent is selected depending on the properties of the raw materials, and examples thereof include aprotic inert solvents such as methylene chloride, chloroform, carbon tetrachloride, ethylene tetrachloride, and benzene. The present invention will be specifically explained below with reference to Examples and Reference Examples. Example 1 Preparation of 4-bromomethyl-5-phenyl-1,3-dioxolen-2-one; 764, pp. 116-124, 1972) was dissolved in 150 ml of carbon tetrachloride, and 2.9 g (0.0162 mol) of N-bromosuccinimide and a catalytic amount of α ，
α'-Azobisisobutyronitrile was added, and the mixture was heated under reflux for 90 minutes. Concentrate the reaction solution to half its volume, filter out insoluble matter, concentrate the filtrate, and recrystallize the residue from a mixture of benzene and cyclohexane to obtain colorless needle-like crystals, melting point.
2.3 g (yield 66%) of the target product was obtained at 90.5-91.5°C. Elemental analysis , molecular formula C10H7BrO3 : Theoretical value (%)
C, 47.09: H, 2.77: Br, 31.33. Experimental value (%)
C, 47.22: H, 2.64: Br, 31.29. IR(KBr, ν
cm -1 ): around 1825 (carbonyl). NMR ( CCl4 )
δ (ppm): 4.35 (-CH 2 Br, s), 7.40 (benzene ring, s) Example 2 Production of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one: 4,5-dimethyl -1,3-dioxolene-2
-On (Tetrahedron Letters, 1972,
3.42 g (0.003
mol) in 150 ml of carbon tetrachloride, and add 5.34
g (0.03 mol) of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added and heated to reflux for 15 minutes. After concentrating the reaction solution to half its volume and removing insoluble materials by filtration, the filtrate was concentrated. The syrup-like residue is distilled under reduced pressure to produce a colorless liquid with a boiling point of 115.
4.2g (yield 73%) of the target product was obtained at ~120°C/5mmHg. Elemental analysis, molecular formula C5H5BrO3 : Theoretical value (%) :
C, 31.12:H, 2.61:Br, 41.40, experimental value (%):
C, 31.30:H, 2.49:Br, 41.31, IR (NEET,
νcm -1 ): around 1825 (carbonyl) NMR (CCl 4 ) δ (ppm): 2.10 (-CH 3 , s),
4.10( -CH2Br ,s) Example 3 4-bromomethyl-1,3-dioxolene-2
Preparation of -one: 8.6 g 4-methyl-1,3-dioxolen-2-one (synthesized according to U.S. Pat. No. 3,020,290)
(0.086 mol) was dissolved in 200 ml of carbon tetrachloride, and 17.8 g (0.1 mol) of N-bromosuccinimide and a catalytic amount of α,α'-azobisisobutyronitrile were added thereto and heated under reflux for 90 minutes. Example 2 below
Treated in the same manner as colorless liquid, boiling point 94℃/3mmHg
5.2 g (yield 33.6%) of the desired product was obtained. Elemental analysis , molecular formula C4H3BrO3 : Theoretical value (%):
C, 26.84:H, 1.69:Br, 44.65, experimental value (%):
C, 26.94:H, 1.66:Br, 44.60. IR (NEET,
νcm -1 ): around 1830 (carbonyl) NMR (CCl 4 ) δ (ppm): 4.10 (-CH 2 Br, s),
7.00 (=CH-O-, s) Example 4 Production of 3-bromo-1,2-carbonyldioxycyclohexene: 1,2-carbonyldioxycyclohexene (Tetrahedron Letters. 1972, 1701-
2.15 g (0.015 mol) synthesized according to page 1704
was dissolved in 80 ml of carbon tetrachloride, and 2.3 g (0.013
mol) of N-bromosuccinimide and a catalytic amount of α,α′-azobisisobutyronitrile were added.
The mixture was heated to reflux for a minute. After cooling the reaction solution, filter it, and concentrate the filtrate at low temperature to obtain the desired crude product (light brown liquid) 3.2
I got g. IR (neat, νcm -1 ): around 1825 (carbonyl) NMR (CDCl 3 ) δ (ppm): 5.0 | (=C-CH-Br, m), 1.3-3.0 (cyclic | hydrogen, m) This target object Since the crude product was unstable, it was reacted with ampicillin without isolation and purification to obtain ampicillin ester (see Reference Example 1). Reference example 1 500 mg of ampicillin trihydrate was dispersed in 6 ml of dimethylformamide, and potassium bicarbonate was added to it.
125 mg was added and cooled to 0°C, and further 0.25 ml of benzaldehyde was added and stirred at 0°C for 2.5 hours. Next, 125 mg of potassium bicarbonate and 3-bromo-1,2-
250 mg of carbonyldioxycyclohexene (crude product obtained in Example 4) was added, and the mixture was further stirred at 0°C for 3 hours. After the reaction was completed, the reaction solution was poured into ice water, and the precipitated solid was extracted with 30 ml of ethyl acetate.
The organic layer was washed three times with 20 ml of water, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure to obtain a yellow syrup. The syrup-like residue obtained as above was dissolved in 4 ml of acetonitrile, the pH was adjusted to 2.0 with diluted hydrochloric acid, and the mixture was stirred at 0°C for 30 minutes. To this was added 10 ml of water, and the acetonitrile was distilled off under reduced pressure. The aqueous layer was washed repeatedly with ethyl acetate, then saturated with common salt, and the precipitated oily substance was extracted with 50 ml of methylene chloride and washed with saturated brine. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated to half the volume, added with 30 ml of isopropyl alcohol, and concentrated again under reduced pressure to obtain a pale yellow solid. This solid was collected by filtration and washed with isopropyl alcohol and ether to obtain 256 mg of a colorless amorphous solid of ampicillin (2,3-carbonyldioxy-2-cyclohexenyl) ester hydrochloride. Melting point 140℃
(Disassembly). IR (KBr, νcm -1 ): 1830, 1780, 1750
(Carbonyl), 1690 (amide) When the above ampicillin ester hydrochloride was incubated in 40% mouse blood at 37°C for 10 minutes and bioautography was performed, it was found that all of the ester was converted to ampicillin. Ivy. Reference Example 2 In the same manner as in Reference Example 1, ampicillin (5-phenyl-2-oxo-1,3-dioxolene) was prepared from ampicillin trihydrate and 4-bromomethyl-5-phenyl-1,3-dioxolene-2-one. -4
-yl) methyl ester hydrochloride was obtained. Yield 46.4%, colorless amorphous solid, melting point 140°C (decomposed). IR (KBr, νcm -1 ): 1830, 1785, 1760 (carbonyl), 1690 (amide) This ampicillin (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl ester hydrochloride at 40% After incubation in mouse blood for 5 minutes at 37°C, bioautography revealed that all of the ester was converted to ampicillin. Reference Example 3 In the same manner as in Reference Example 1, ampicillin (5-methyl-2-oxo-1,3-dioxolene) was prepared from ampicillin trihydrate and 4-bromomethyl-5-methyl-1,3-dioxolene-2-one. -4-yl) methyl ester hydrochloride was obtained. Yield 50.6%, colorless amorphous solid. It begins to color at the melting point of 141℃ and foams at 145℃.
IR (KBr, νcm -1 ): 1825, 1785, 1750 (carbonyl), 1690 (amide) This ampicillin (5-methyl-2-oxo-
When 1,3-dioxolen-4-yl) methyl ester hydrochloride was incubated in 40% mouse blood at 37°C for 5 minutes and bioautography was performed, it was found that all of the ester was converted to ampicillin. Ivy.
Claims (1)
エニル基を示し、R2は水素原子であるか又はR2
はR1と一緒になつて−（CH2）3−を形成している） で示される化合物の１モルに対して、ラジカル発
生条件下で0.8〜1.2モルのＮ−ブロモコハク酸イ
ミドを、反応せしめることを特徴とする一般式 （式中、R1、R2は前記に同じ。） で示される１，３−ジオキソレン−２−オン誘導
体の製造法。 ２ 反応を非プロトン性不活性有機溶媒中で行う
特許請求の範囲第１項に記載の製造法。 ３ 反応をラジカル誘起剤の存在下もしくは紫外
線照射下に行う特許請求の範囲第１項乃至第２項
のいずれかに記載の製造法。[Claims] 1. General formula (In the formula, R 1 represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R 2 is a hydrogen atom or R 2
is combined with R 1 to form -(CH 2 ) 3 -) 0.8 to 1.2 mol of N-bromosuccinimide is reacted with 1 mol of the compound represented by R 1 under radical generating conditions. General formula characterized by forcing (In the formula, R 1 and R 2 are the same as above.) A method for producing a 1,3-dioxolen-2-one derivative represented by the following formula. 2. The production method according to claim 1, wherein the reaction is carried out in an aprotic inert organic solvent. 3. The production method according to any one of claims 1 to 2, wherein the reaction is carried out in the presence of a radical inducer or under ultraviolet irradiation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58013076A JPS58150585A (en) | 1983-01-29 | 1983-01-29 | Preparation of 1,3-dioxolen-2-one derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58013076A JPS58150585A (en) | 1983-01-29 | 1983-01-29 | Preparation of 1,3-dioxolen-2-one derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP55058510A Division JPS6019908B2 (en) | 1980-04-30 | 1980-04-30 | 1,3-dioxolen-2-one derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58150585A JPS58150585A (en) | 1983-09-07 |
| JPH0258271B2 true JPH0258271B2 (en) | 1990-12-07 |
Family
ID=11823061
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58013076A Granted JPS58150585A (en) | 1983-01-29 | 1983-01-29 | Preparation of 1,3-dioxolen-2-one derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58150585A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5874677A (en) * | 1981-10-30 | 1983-05-06 | Kanebo Ltd | Preparation of brominated 1,3-dioxolene-2-ones |
-
1983
- 1983-01-29 JP JP58013076A patent/JPS58150585A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58150585A (en) | 1983-09-07 |
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