JPH0215088A - Novel method for preparing 7-amino-3-heterocyclic ring-substituted thiomethyl-3-cephem-4-carboxylic acid - Google Patents
Novel method for preparing 7-amino-3-heterocyclic ring-substituted thiomethyl-3-cephem-4-carboxylic acidInfo
- Publication number
- JPH0215088A JPH0215088A JP16245788A JP16245788A JPH0215088A JP H0215088 A JPH0215088 A JP H0215088A JP 16245788 A JP16245788 A JP 16245788A JP 16245788 A JP16245788 A JP 16245788A JP H0215088 A JPH0215088 A JP H0215088A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- amino
- compound
- cephem
- heterocyclic ring
- 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
- 238000000034 method Methods 0.000 title claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- -1 thiol compound Chemical class 0.000 claims abstract description 4
- 150000002148 esters Chemical class 0.000 claims abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007086 side reaction Methods 0.000 abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- OKZIUSOJQLYFSE-UHFFFAOYSA-N difluoroboron Chemical compound F[B]F OKZIUSOJQLYFSE-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業−１−のｆり用分野〕
本発明は、セファロスポラン酸系抗生物質を製造する際
に必須な３位置換ヂオール体の製造方法に関するもので
ある。DETAILED DESCRIPTION OF THE INVENTION [Field of Industry-1-] The present invention relates to a method for producing a 3-substituted diol which is essential for producing cephalosporanic acid antibiotics.
従来、セファロスポラン酸系抗生物質の３位を１η換チ
オ一ル体とするための技術としては、７位に置換基が化
合（、ているしのには炭酸水素ナトリウトを使用するの
が通常であり、置換基を仔さない遊離のアミノ基の場合
は特公昭６０−２２７１８の如き二弗化硼素らしくはそ
の錯化合物、特公昭６０−２７６７７の如き溶媒の６在
下での硫酸、ハ〔７ゲノ硫酸、過塩素酸、アルキル、ア
リールスルツイーン酸、スズ、亜鉛のハロゲン化物又は
その錯化合物、特公昭５９３５９１５の如き溶媒不存在
下の硫酸を用いる方法が知られていた。Conventionally, the technology for converting the 3-position of cephalosporanic acid antibiotics into a 1η-substituted thioyl compound has been to combine a substituent at the 7-position (and usually use sodium bicarbonate for the substitution). In the case of a free amino group without a substituent, boron difluoride is a complex compound thereof as described in Japanese Patent Publication No. 60-22718, sulfuric acid in the presence of a solvent as described in Japanese Patent Publication No. 60-27677, Methods using sulfuric acid in the absence of a solvent have been known, such as 7genosulfuric acid, perchloric acid, alkyl and arylsultzienic acids, tin and zinc halides or complex compounds thereof, and Japanese Patent Publication No. 5935915.
〔発明が解決（２ようとする問題点〕
炭酸水素ナトリウムを用いる方法は簡便であり、試薬ら
安価ではあるか、７位か遊離のアミノ基の場合は使用か
できない上、収率的にも不／ｌ化足であり、溶媒存在下
に於ける硫酸を使用・ｒるときけ溶媒が（ｌε酸と反応
ずろなど条件設定が円錐てあ−た。又、硫酸単独で使用
する方法は溶媒が存在しないため実際の工場での実施は
後処理を含めて困難であり、三弗化硼素なとを用いる方
法は加熱丁で２時間をかけるときは好収率で得られるが
、加熱すると６色が強くなり脱色操作か繁雑となる上、
？Ｈ度を下げた時は反応が遅くなり７〜８時間ら反応時
間が必要となるなど従来の方法には６々に不４：４な点
か多かった。[Problem to be solved by the invention (2)] The method using sodium hydrogen carbonate is simple and inexpensive, and it can only be used in the case of a free amino group at the 7-position, and the yield is low. When using sulfuric acid in the presence of a solvent, the conditions such as reaction time with lε acid were set conically.Also, the method using sulfuric acid alone Since there is no fluorine, it is difficult to implement it in an actual factory, including post-treatment, and the method using boron trifluoride gives a good yield when heated for 2 hours, but when heated, 6 The color becomes stronger and the bleaching process becomes complicated, and
? When the H degree is lowered, the reaction slows down and requires a reaction time of 7 to 8 hours, which is why conventional methods have many disadvantages.
本発明片らは、１ニ場での実施に当っては収率か良好で
あ−）て乙副反応での生成物及びそれらによる着色が最
ら問題となることに鑑み、副反応が少く、目的生成物の
純度の高い製造方法を求め、従来の方法を追試すると共
に新１．い縮合剤の開発について研究を進めていたとこ
ろ、従来知られていなかったテ１へラフルオロホウ酸の
Ｉｔ（ヒ合物が、上記を満足する化合物であることを見
い出し、本発明を完成したしのである。The products of the present invention have good yields when carried out in one place, and considering that the products in the side reactions and the coloring caused by them are the most problematic, the side reactions are small. In search of a method for producing the desired product with high purity, we conducted additional trials on the conventional method and developed a new method. While conducting research on the development of a new condensing agent, we discovered that the previously unknown compound of Te1-herafluoroboric acid (H) is a compound that satisfies the above requirements, and completed the present invention. be.
錯化合物を作る物質としてはジエチルエーテル、ジイソ
プロピルエーテル、ノブデルエーテルの如きアルキルエ
ーテル類及び酢酸が好適であったが、同じアルギルエー
テルでもツメデルエーテルは明らかにその効果か劣った
。Alkyl ethers such as diethyl ether, diisopropyl ether, nobdel ether, and acetic acid were suitable as substances for forming complex compounds, but even among the same argyl ethers, tumedel ether was clearly less effective.
本発明による縮合剤を使用するときは無水の状態で使用
する必要かあるか、温度は１５〜２０°Ｃの室温での使
用が可能であり、約１時間で反応は殆ど完了する。温和
な条件での反応であるので副反応が少く、そのため生成
物に着色がなく生成物の純度が極めて高いのが特長であ
る。When using the condensing agent according to the present invention, it is necessary to use it in an anhydrous state or it can be used at room temperature of 15 to 20°C, and the reaction is almost completed in about 1 hour. Since the reaction is carried out under mild conditions, there are few side reactions, so the product is characterized by no coloration and extremely high purity.
本発明による目的生成物はそのまま７位を変換すること
によってｆＩｉケのセファロスポラン酸系抗生物質の製
造か可能であり極めて白゛用である。The desired product according to the present invention can be used to produce fIi cephalosporanic acid antibiotics by directly converting the 7-position, and is extremely useful for white purposes.
以下、本発明を実施例によって具体的に説明する。Hereinafter, the present invention will be specifically explained with reference to Examples.
実施例１
酢酸１０．ｍｌに７−アミツセフアロスボラン酸２．７
２ｇ、５−メルカプト−１−メチル川１（−テトラゾー
ル１１６ｇを加え、１５°Ｃでテトラフルオローテル酸
・ジエチルエーテル８ｍｌを加え１８〜２０℃で１時間
：３０分１ｆｋ拌した。反応溶液を水２２ｇに注ぎ、水
１０ｍ１で洗浄ののら、２８％アンモニア水でｐ ｌ−
１を・１０とし、水冷下に１時間攪拌ののし沈澱をろ取
した。得た沈澱を水５０ｍ１で２回、アセトノ５０ｍ１
で１回洗浄ののちアノケーク−中で減圧下に乾燥し白色
粉末の７ アミノ−３−（Ｉ−メチル−Ｉ Ｈ−テトラ
ゾール−５イル）チ臼メチル；３−セフェム４ カルホ
ン酸３．０５ｇ（純度９８５％）を得た。Example 1 Acetic acid 10. 2.7 7-amitusephalosboranic acid per ml
2g, 5-mercapto-1-methylkawa 1(-tetrazole) 116g were added, and at 15°C, 8ml of tetrafluoroteric acid diethyl ether was added and stirred at 18-20°C for 1 hour: 30 minutes.The reaction solution was diluted with water. After washing with 10 ml of water, rinse with 28% ammonia water.
The mixture was stirred for 1 hour under water cooling, and the precipitate was collected by filtration. The obtained precipitate was diluted with 50 ml of water twice and 50 ml of acetonate was added.
After washing once with water and drying under reduced pressure in an anoke, a white powder of 7-amino-3-(I-methyl-IH-tetrazol-5yl)thiomethyl; 3.05 g of 3-cephem4 carbonic acid ( A purity of 985% was obtained.
融点（分解） ２０３〜２０６°Ｃ
実施例２
テトラフルオロポウ酸・ジエチルエーテルの代りにテト
ラゾルオ〔Ｊホウ酸・ジブチルエーテル８ｍｌを用いる
他は実施例Ｉと同様に操作り、２．９３ｇ（純度９８０
％）の実施例１と同一物を得た。Melting point (decomposition) 203-206°C Example 2 The same procedure as in Example I was performed except that 8 ml of tetrazol[J boric acid/dibutyl ether was used instead of tetrafluoroporic acid/diethyl ether, and 2.93 g (purity 980
%) identical to that of Example 1 was obtained.
実施例３
テトラフルオロ
オ〔ＪΣ１：つ酸・フイツグ〔ｌピルエーテル８ｍｌを
用いる他は実施例１と同様に操作し３．ＩＯｇ（純度９
８．５％）の実施例１と同一物を得ｌこ、。Example 3 The procedure was carried out in the same manner as in Example 1, except that 8 ml of tetrafluoro[JΣ1: oxalic acid and phyl ether was used.3. IOg (purity 9
8.5%) identical to Example 1 was obtained.
実施例・１
テトラフルオロポウ酸・ジエチルエーテルの代りにテ）
・ラフルオ〔Ｊホウ酸・酢酸６ｍｌを用いる他は実施例
１と同様に操作し２８６ｇ（純度９５２％）の実、憔例
１と同一物を得た。Example 1 Tetrafluoropouic acid/diethyl ether (Te) instead of diethyl ether
・Rafluo [J The same procedure as in Example 1 was performed except that 6 ml of boric acid/acetic acid was used to obtain 286 g (purity 952%) of fruits, which were the same as in Example 1.
Claims (3)
そのエステル誘導体をテトラフルオロホウ酸の錯化合物
の存在下に一般式Ｒ−ＳＨ（式中Ｒは複素環残基を示す
）で表されるチオール化合物と反応させることを特徴と
する７−アミノ−３−複素環置換チオメチル−３−セフ
ェム−４−カルボン酸又はその塩乃至そのエステル誘導
体の製造方法。(1) 7-Amino-cephalosboranic acid or its salt or ester derivative is expressed by the general formula R-SH (wherein R represents a heterocyclic residue) in the presence of a complex compound of tetrafluoroboric acid. A method for producing 7-amino-3-heterocyclic-substituted thiomethyl-3-cephem-4-carboxylic acid, a salt thereof, or an ester derivative thereof, the method comprising reacting with a thiol compound.
、ジイソプロピルエーテル又は酢酸である特許請求の範
囲第１項の製造方法。(2) The manufacturing method according to claim 1, wherein the complex compound is diethyl ether, dibutyl ether, diisopropyl ether, or acetic acid.
の製造方法。(3) The manufacturing method according to claim 1, wherein the reaction is carried out in the presence of a solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16245788A JPH0215088A (en) | 1988-07-01 | 1988-07-01 | Novel method for preparing 7-amino-3-heterocyclic ring-substituted thiomethyl-3-cephem-4-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16245788A JPH0215088A (en) | 1988-07-01 | 1988-07-01 | Novel method for preparing 7-amino-3-heterocyclic ring-substituted thiomethyl-3-cephem-4-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0215088A true JPH0215088A (en) | 1990-01-18 |
Family
ID=15754978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16245788A Pending JPH0215088A (en) | 1988-07-01 | 1988-07-01 | Novel method for preparing 7-amino-3-heterocyclic ring-substituted thiomethyl-3-cephem-4-carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0215088A (en) |
-
1988
- 1988-07-01 JP JP16245788A patent/JPH0215088A/en active Pending
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