JPH0236186A - Production of pivmecillinam - Google Patents
Production of pivmecillinamInfo
- Publication number
- JPH0236186A JPH0236186A JP63187129A JP18712988A JPH0236186A JP H0236186 A JPH0236186 A JP H0236186A JP 63187129 A JP63187129 A JP 63187129A JP 18712988 A JP18712988 A JP 18712988A JP H0236186 A JPH0236186 A JP H0236186A
- Authority
- JP
- Japan
- Prior art keywords
- reacted
- afford
- aminopenicillanic acid
- potassium carbonate
- mecillinam
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- NPGNOVNWUSPMDP-UTEPHESZSA-N chembl1650818 Chemical compound N(/[C@H]1[C@@H]2N(C1=O)[C@H](C(S2)(C)C)C(=O)OCOC(=O)C(C)(C)C)=C\N1CCCCCC1 NPGNOVNWUSPMDP-UTEPHESZSA-N 0.000 title 1
- 229960004212 pivmecillinam Drugs 0.000 title 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 12
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 claims abstract description 8
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims abstract description 8
- -1 halomethyl pivalate Chemical compound 0.000 claims abstract description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 229950010765 pivalate Drugs 0.000 claims abstract 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 11
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 7
- 229940024554 amdinocillin Drugs 0.000 abstract description 5
- BWWVAEOLVKTZFQ-ISVUSNJMSA-N chembl530 Chemical compound N(/[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)=C\N1CCCCCC1 BWWVAEOLVKTZFQ-ISVUSNJMSA-N 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract 3
- 239000002798 polar solvent Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はピプメシリナム（Ｐｉｖｍｅｃｉｌｌｉｎａｍ
）の工業的製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to Pivmecillinum (Pivmecillinum).
) concerning industrial manufacturing methods.
ピプメシリナムは次式（Ｉ）
（Ｉ）
で表わされる、化学名ビパロイロキシメチル・６−Ｃ（
ヘキサヒドロ−１１−１−アゼピン−１−イル）−メチ
レンアミノクーペニシラネートの抗生物質でめシ、現在
臨床において広く使用されている。Pipmecillinum is represented by the following formula (I) (I), and its chemical name is biparoyloxymethyl 6-C (
Hexahydro-11-1-azepin-1-yl)-methyleneaminocoupenicilate is an antibiotic that is currently widely used in clinical practice.
従来、これを製造する方法としては、６−アミノペニシ
ラン酸のピパロイロキシメチルエステルにクロロ−Ｎ、
Ｎ−へキサメチレンフォルムイミニウムクロライドを反
応させる方法が知られているが（特公昭５１−８９５５
号）、この方法はＳ ６−アミノペニシラン酸のビパロ
イロキシメチルエステルが不安定でるるという欠点がめ
った。Conventionally, the method for producing this is to add chloro-N,
A method of reacting N-hexamethylene formiminium chloride is known (Japanese Patent Publication No. 51-8955).
(No.), this method often had the disadvantage that the biparoyloxymethyl ester of S 6-aminopenicillanic acid was unstable.
この欠点を解決するために、次式（ｉｔ）（ＩＩ）
で表わされるメシリナムをビバロイロキシメテルエステ
ル化する方法が提案された。しかし、この方法も、メシ
リナムを得るために、６−アミノペニシラン酸のエステ
ルカラメシリナムのエステルヲ製造し、更にそのエステ
ルを脱離するという長い工程を必要とし、工業的方法と
しては満足し得るものではなかった。In order to solve this drawback, a method of converting mecillinum represented by the following formula (it) (II) into a bivaloyloxy methester was proposed. However, this method also requires a long process of producing an ester of 6-aminopenicillanic acid ester caramecillinum and then eliminating the ester in order to obtain mecillinam, and is not satisfactory as an industrial method. It wasn't something.
斯かる実情において、本発明者は上記問題点を解決せん
と鋭意研究を行った結果、６−アミノペニシラン酸から
一挙に高収率でメシリナム（■）を得ることに成功し、
本発明を完成した。Under these circumstances, the present inventor conducted intensive research to solve the above problems, and as a result, succeeded in obtaining mecillinum (■) from 6-aminopenicillanic acid in a high yield all at once.
The invention has been completed.
すなわち、本発明は、６−アミノペニシラン酸と次式（
ＬＬ［）
で表わされる１−へキサメチレンイミンカルボキサアル
デヒドジメチルアセタールとを、アルコール溶媒中、冷
却下に反応せしめてメシリナム［有］）となし、次いで
これに炭酸カリウムの存在下ハロメチルピバレートを反
応せしめてピプメシリナム（Ｉ）ｔ−製造する方法でる
る。That is, the present invention combines 6-aminopenicillanic acid with the following formula (
1-hexamethyleneiminecarboxaldehyde dimethyl acetal represented by LL[) is reacted with 1-hexamethyleneimine carboxaldehyde dimethyl acetal in an alcohol solvent under cooling to form mecillinam [A], which is then reacted with halomethylpivalate in the presence of potassium carbonate. This is a method for producing pipmecillinum (I) by reacting the following.
本発明の第一工程は、６−アミノペニシラン酸をメタノ
ール等のアルコールに分散シ、５℃〜−１０ｃ１好まし
くは０〜５℃の温度で、これに１−ヘキサメチレンイミ
ンカルｌキサアルデヒドジメチルアセタール（１１１）
を滴下し、同温度で３〜５時間反応させることによって
実施される。In the first step of the present invention, 6-aminopenicillanic acid is dispersed in an alcohol such as methanol, and 1-hexamethyleneimine calxaaldehyde dimethyl Acetal (111)
is added dropwise and reacted at the same temperature for 3 to 5 hours.
第二工程は、公知の方法、例えば、メシリナム（１０４
−Ｎ、Ｎ−ジメチルホルムアミド等の極性非プロトン溶
媒（メシリナムの４〜１０倍量用いる）に溶解し、これ
に炭酸カリウム及びクロロ又はブロモメチルビバレート
を滴下して反応させる方法によって実施される。The second step is carried out using a known method, for example, mecillinum (104
-N,N-Dimethylformamide or the like is dissolved in a polar aprotic solvent (4 to 10 times the amount of mecillinam is used), and potassium carbonate and chloro or bromomethyl bivalate are added dropwise thereto to react.
反応温度は０〜２５℃、反応時間は１０〜２０時間が好
ましい。The reaction temperature is preferably 0 to 25°C and the reaction time is preferably 10 to 20 hours.
成上の如く、本発明によれば、短い工程で高収率にてピ
ブメシリナムを製造することができる。As described above, according to the present invention, pivmecillinum can be produced in a high yield in a short process.
次に実施例を挙げて説明する。 Next, an example will be given and explained.
実施例１
６−アミノペニシラン酸２６．７ ｔ ｆメタノール１
０６−に分散させ、０〜５℃に冷却し、これに１−ヘキ
サメチレンイミンカルｌキサアルデヒドジメチルアセタ
ール２９．４ ｔを滴下する。同温度で５時間攪拌して
反応を完結させる。反応液をヂ遇し、Ｆ液を減圧濃縮し
、残留物にメチルエチルケトン（ゾエテルエーチルでも
よい）を加えて結晶化させ、メシリナム３４．１ ？
（収率８５％）を得た。Example 1 6-aminopenicillanic acid 26.7 t f methanol 1
06-, cooled to 0 to 5°C, and 29.4 t of 1-hexamethyleneimine calxaaldehyde dimethyl acetal was added dropwise thereto. The reaction was completed by stirring at the same temperature for 5 hours. The reaction solution was treated, solution F was concentrated under reduced pressure, and methyl ethyl ketone (or zoether ether may be used) was added to the residue to crystallize it, resulting in mecillinum 34.1?
(yield 85%).
実施例２
メシリナム３４．１ ｔを５借賃のＮ、Ｎ−ジメチルホ
ルムアミドに溶解し、５℃以下に冷却し、これに炭酸カ
リウム１＆８を及びクロロメチルビバレート２０．５
ｆを滴下し、０〜２５℃で２０時間反応を行う。反応液
に氷８２ｆｔ−入れると結晶が析出する。この結晶をア
セトン３７０−に浴かして脱色し、これを５Ｃ以下の水
３７０−に圧加し、析出する白色結晶ｔ−Ｆ取して、ピ
ブメシリナム３Ｌ４？（収率６８％）を得た。融点１２
０〜１２１℃、比旋光匿〔α〕賃＝２２８〜２３４以上Example 2 34.1 t of mecillinum was dissolved in 5 t of N,N-dimethylformamide, cooled to below 5°C, potassium carbonate 1 & 8 and 20.5 t of chloromethyl bivalate were dissolved.
f was added dropwise, and the reaction was carried out at 0 to 25°C for 20 hours. When 82 ft of ice is added to the reaction solution, crystals are precipitated. The crystals were decolorized by bathing them in acetone 370-, and then they were pressed into 5C or less water 370-, and the precipitated white crystals t-F were collected. (yield 68%). melting point 12
0-121℃, specific rotation [α] ratio = 228-234 or more
Claims (1)
ンカルボキサアルデヒドジメチルアセタールとを、アル
コール溶媒中、冷却下に反応せしめてメシリナムとなし
、次いでこれに炭酸カリウムの存在下ハロメチルピバレ
ートを反応せしめることを特徴とするピブメシリナムの
製造法。1,6-aminopenicillanic acid and 1-hexamethyleneimine carboxaldehyde dimethyl acetal are reacted in an alcohol solvent under cooling to give mecillinum, which is then reacted with halomethyl pivalate in the presence of potassium carbonate. A method for producing pivmecillinum, which is characterized by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63187129A JPH0236186A (en) | 1988-07-27 | 1988-07-27 | Production of pivmecillinam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63187129A JPH0236186A (en) | 1988-07-27 | 1988-07-27 | Production of pivmecillinam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0236186A true JPH0236186A (en) | 1990-02-06 |
Family
ID=16200628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63187129A Pending JPH0236186A (en) | 1988-07-27 | 1988-07-27 | Production of pivmecillinam |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0236186A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007109483A (en) * | 2005-10-12 | 2007-04-26 | Chugoku Electric Power Co Inc:The | Voltage indicator |
-
1988
- 1988-07-27 JP JP63187129A patent/JPH0236186A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007109483A (en) * | 2005-10-12 | 2007-04-26 | Chugoku Electric Power Co Inc:The | Voltage indicator |
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