JPH0124156B2 - - Google Patents
Info
- Publication number
- JPH0124156B2 JPH0124156B2 JP61211209A JP21120986A JPH0124156B2 JP H0124156 B2 JPH0124156 B2 JP H0124156B2 JP 61211209 A JP61211209 A JP 61211209A JP 21120986 A JP21120986 A JP 21120986A JP H0124156 B2 JPH0124156 B2 JP H0124156B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- substituted
- cephem
- carbamoyloxymethyl
- carboxylic acid
- 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
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 13
- 229930186147 Cephalosporin Natural products 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 229940124587 cephalosporin Drugs 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000003573 thiols Chemical class 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000001780 cephalosporins Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- -1 carbamoyloxymethyl group Chemical group 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 9
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ZJIANJKJAAXAOC-CLZZGJSISA-N (6r,7r)-7-amino-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(COC(N)=O)=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 ZJIANJKJAAXAOC-CLZZGJSISA-N 0.000 description 1
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- AFBBKYQYNPNMAT-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium-3-thiolate Chemical compound SC=1N=CNN=1 AFBBKYQYNPNMAT-UHFFFAOYSA-N 0.000 description 1
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- 229930184397 7-Methoxycephalosporin Natural products 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 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
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005109 alkynylthio group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000003209 petroleum derivative Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
本発明は３位にカルバモイルオキシメチル基を
有する７−アシルアミノセフアロスポリン化合物
の３位を置換チオメチル基に変換する新規な方法
に関するものである。
７−アシルアミノセフアロスポリン化合物は抗
菌性物質として極めて多数の種類が製造されてい
る。そしてセフアロスポリンの３位がチアジアゾ
ールチオメチル基、テトラゾールチオメチル基等
の複素環チオメチル基で置換された化合物に有効
な抗菌性を示すものが見いだされている。そこ
で、セフアロスポリン化合物の３位を複素環チオ
メチル基で置換する方法が多く知られている。セ
フアロスポリン化合物の３位がアセトキシメチル
基であるものを複素環チオール類と反応させて置
換する方法としては「セフアロスポリン及びペニ
シリン 化学及び生物学」エドウイン・Ｈ・フイ
ン編158〜159頁、特公昭39−17936、特公昭49−
45880、特開昭50−154287号公報等がある。又、
３位がカルバモイルオキシメチル基であるものを
複素環チオール類と反応させて置換する方法とし
ては、特開昭50−83383号公報等がある。しかし、
上記何れ方法においても水あるいは含水有機溶媒
中PH６〜７で行う方法である。しかしながら、こ
れらの方法によると得られる生成物の収率は悪
く、工業的に有利な方法とはいえない。特に近時
７位にメトキシ基を有するセフアロスポリン化合
物が開発され、それらの中には広い範囲の菌に対
しすぐれた抗菌力を有する化合物が発表されてい
る。これらの化合物はセフエム核の３位に置換チ
オメチル基をもつものが多く、かつ、これらの化
合物の合成にはセフアマイシンＣを原料とする場
合が多い。しかるにセフアマイシンＣは３位がカ
ルバモイルオキシメチル基であるため、この基を
置換チオメチル基に変換する必要がある。しかる
に上記の如く従来までの方法は収率が悪くこれら
化合物の製造上の一つの欠陥となつていた。最
近、水又は含水有機溶媒を用いずに有機溶媒中三
弗化硼素もしくはその錯化合物の存在下セフアロ
スポリン化合物の３位のカルバモイルオキシメチ
ル基を置換チオメチル基に変換する方法が発表さ
れた。（特開昭53−98987）しかし、この方法にお
いても三弗化硼素化合物を用いるため７−メトキ
シセフアロスポリン化合物を使用すると同化合物
が分解し目的物と得ることができない。
そこで、本発明者等は上記変換について研究を
重ねた所、意外にも水を用いずに、しかも何の触
媒も使用せずに７−アシルアミノ−３−カルバモ
イルオキシメチルセフアロスポリン化合物を置換
チオール化合物とただ加熱するだけで３位のカル
バモイルオキシメチル基が置換チオメチル基に変
換することを見い出し本発明を完成した。
本発明は
一般式
（式中、Ｒは水素原子又はアシル基、Ｘは水素原
子又はアルコキシ基を示す。）
を有する７−アシルアミノ（又はアミノ）−３−
カルバモイルオキシメチルセフアロスポラン酸類
又はそのカルボキシル基における誘導体、又はそ
れらの塩に一般式
R″SH （）
（式中、R″は置換又は非置換複素環基或いは基
The present invention relates to a novel method for converting the 3-position of a 7-acylaminocephalosporin compound having a carbamoyloxymethyl group at the 3-position into a substituted thiomethyl group. A large number of types of 7-acylaminocephalosporin compounds are produced as antibacterial substances. Compounds in which the 3-position of cephalosporin is substituted with a heterocyclic thiomethyl group such as a thiadiazole thiomethyl group or a tetrazole thiomethyl group have been found to exhibit effective antibacterial properties. Therefore, many methods are known in which the 3-position of a cephalosporin compound is substituted with a heterocyclic thiomethyl group. A method for substituting a cephalosporin compound in which the 3-position is an acetoxymethyl group by reacting it with a heterocyclic thiol is described in "Cephalosporin and Penicillin Chemistry and Biology" edited by Edwin H. Huynh, pp. 158-159, Japanese Patent Publication No. 39-1989. 17936, Special Publication Showa 49-
45880, Japanese Unexamined Patent Publication No. 154287/1987, etc. or,
A method for substituting a compound having a carbamoyloxymethyl group at the 3-position by reacting with a heterocyclic thiol is disclosed in JP-A-50-83383. but,
In any of the above methods, the reaction is carried out in water or a water-containing organic solvent at pH 6 to 7. However, the yield of the product obtained by these methods is poor, and it cannot be said that these methods are industrially advantageous. In particular, cephalosporin compounds having a methoxy group at the 7-position have recently been developed, and among these compounds, compounds having excellent antibacterial activity against a wide range of bacteria have been announced. Many of these compounds have a substituted thiomethyl group at the 3-position of the cefem nucleus, and cefamycin C is often used as a raw material for the synthesis of these compounds. However, since cefamycin C has a carbamoyloxymethyl group at the 3-position, it is necessary to convert this group to a substituted thiomethyl group. However, as mentioned above, the conventional methods have poor yields, which is one drawback in the production of these compounds. Recently, a method has been announced for converting the carbamoyloxymethyl group at the 3-position of a cephalosporin compound into a substituted thiomethyl group in the presence of boron trifluoride or its complex compound in an organic solvent without using water or a water-containing organic solvent. (JP-A-53-98987) However, since this method also uses a boron trifluoride compound, if a 7-methoxycephalosporin compound is used, the compound decomposes and the desired product cannot be obtained. Therefore, the present inventors conducted repeated research on the above conversion, and surprisingly, they converted 7-acylamino-3-carbamoyloxymethylcephalosporin compound into substituted thiol without using water or any catalyst. The present invention was completed by discovering that the carbamoyloxymethyl group at the 3-position can be converted to a substituted thiomethyl group simply by heating the compound. The present invention has the general formula (In the formula, R represents a hydrogen atom or an acyl group, and X represents a hydrogen atom or an alkoxy group.) 7-acylamino (or amino)-3-
Carbamoyloxymethylcephalosporanic acids, their carboxyl group derivatives, or salts thereof have the general formula R″SH () (wherein R″ is a substituted or unsubstituted heterocyclic group or group).
【式】を示す。）
を有するチオール類を無水条件下セフアロスポリ
ン誘導体の３倍量以下の溶媒の存在下で加熱する
ことによつて 一般式
（式中、Ｒ、R″、Ｘは先と同一意義を有す。）
を有する７−アシルアミノ（又はアミノ）−３−
置換チオメチルセフアロスポリン化合物を操作簡
易にかつ収率よく製造する方法である。
本発明の出発物質として用いる前記一般式
（）で示される化合物は7β−アミノ−7α−アル
コキシ−３−カルバモイルオキシメチル−３−セ
フエム−４−カルボン酸、7β−アミノ−３−カ
ルバモイルオキシメチル−３−セフエム−４−カ
ルボン酸、7β−アシルアミノ−7α−アルコキシ
−３−カルバモイルオキシメチル−３−セフエム
−４−カルボン酸及び7β−アシルアミノ−３−
カルバモイルオキシメチル−３−セフエム−４−
カルボン酸及びそれらの化合物のカルボキシル基
における誘導体又はそれらの塩である。これらの
化合物のアシル基は本反応に直接関与しない部分
であるから如何なるアシル基でもよい。例えば、
置換アセチル基、置換バレリル基、置換ベンゾイ
ル基等である。置換アセチル基の置換基としては
アミノ基、置換アミノ基、カルボキシル基、スル
ホニル基、水酸基、複素環基、複素環チオ基、複
素環オキシ基、置換アルキルチオ基、アルキニル
チオ基等であり、置換バレリル基の置換基として
はアミノ基、置換アミノ基、カルボキシル基等で
あり、置換ベンゾイル基の置換基としてはアミノ
基、水酸基、スルホ基である。特に本発明は7α
−アルコキシセフアロスポリン化合物の３位のカ
ルバモイルオキシメチル基を置換チオメチル基に
変換するに最も適した方法であるから、7β−ア
シルアミノ−7α−アルコキシ−３−カルバモイ
ルオキシメチル−３−セフエム−４−カルボン酸
が用いられる。例えばセフアマイシンＣ、7β−
（Ｄ−5′−Ｎ−イソブトキシカルボニルアミノ−
5′−カルボキシバレルアミド）−7α−メトキシ−
３−カルバモイルオキシメチル−３−セフエム−
４−カルボン酸、7β−（Ｄ−5′−Ｎ−ｐ−ニトロ
ベンゾイルアミノ−5′−カルボキシバレルアミ
ド）−7α−メトキシ−３−カルバモイルオキシメ
チル−３−セフエム−４−カルボン酸、7β−チ
エニルアセトアミド−7α−メトキシ−３−カル
バモイルオキシメチル−３−セフエム−４−カル
ボン酸、7β−（イミダゾール−２−イル）チオア
セトアミド−7α−メトキシ−３−カルバモイル
オキシメチル−３−セフエム−４−カルボン酸、
7β−（１，３，４−チアジアゾール−２−イル）
チオアセトアミド−7α−メトキシ−３−カルバ
モイルオキシメチル−３−セフエム−４−カルボ
ン酸、7β−（６−イソオキサゾリルオキシ）アセ
トアミド−7α−メトキシ−３−カルバモイルオ
キシメチル−３−セフエム−４−カルボン酸、
7β−プロパルギルチオアセトアミド−7α−メト
キシ−３−カルバモイルオキシメチル−３−セフ
エム−４−カルボン酸、7β−シアノメチルチオ
アセトアミド−7α−メトキシ−３−カルバモイ
ルオキシメチル−３−セフエム−４−カルボン
酸、7β−（５−メチル−１，３，４−チアジアゾ
ール−２−イル）チオアセトアミド−7α−メト
キシ−３−カルバモイルオキシメチル−３−セフ
エム−４−カルボン酸、7β−（１，２，４−トリ
アゾール−4H−３−イル）チオアセトアミド−
7α−メトキシ−３−カルバモイルオキシメチル
−３−セフエム−４−カルボン酸等及びそれらの
化合物のカルボキシル基における誘導体又は塩が
本方法に好適な出発物質である。
（）式におけるカルボキシル基の誘導体とし
ては次の様なものがあげられる。
(i) エステル類としてはメチル、エチル、プロピ
ル、イソプロピル、ブチル、tert−ブチル、メ
トキシエチル、エトキシメチル、フエノキシメ
チル、メチルチオメチル、フエニルチオチル、
ジメチルアミノエチル、ジエチルアミノエチ
ル、フエナシル、ｐ−ブロモフエナシル、アセ
トキシメチル、ピバロイルオキシメチル、ベン
ゾイルオキシメチル、１，１−ジアセチルアル
キルメタンスルホニルエチル、トルエンスルホ
ニルエチル、トリクロロエチル、シアノメチ
ル、フタルイミドメチルのような置換基を有す
るか、有しないアルキルエステル、その他シク
ロアルキルエステル、シクロアルケニルエステ
ル、トリメチルシリルエステル等反応に影響し
ないすべてを含み
(ii) アミド類としては反応に影響されない通常の
すべてのアミドを含む、又
(iii) 酸無水物類としては本反応に不活性な有機
酸、または無機酸との混合酸無水物又はカルボ
キシル基とヒドロキシコハク酸イミド、Ｎ−ヒ
ドロキシフタルイミド、ジアルキルヒドロキシ
ルアミン、オキシム等との無水物をあげること
ができる。
本発明に用いる前記一般式（）で示されるチ
オール類はチオウレア類、或いは置換又は非置換
複素環チオールである。後者のチオール類の複素
環基としては一般にセフアロスポリン系化合物の
３位に置換されている複素環チオメチル基の複素
環基であり、例えば窒素原子１乃至４個を有する
５又は６員複素環基、酸素原子１個、窒素原子１
乃至２個を有する５又は６員複素環基、硫黄原子
１個、窒素原子１乃至２個を有する５又は６員複
素環基等であり、これらの複素環基には１乃至３
個のアルキル基等が置換されていてもよい。代表
的な例をあげると１−メチル−５−メルカプトテ
トラゾール、５−メチル−２−メルカプト−１，
３，４−チアジアゾール、３−メルカプト−１，
２，４−トリアゾール等である。
本発明の反応は前記一般式（）で示される７
−アシルアミノ（又はアミノ）−３−カルバモイ
ルオキシメチルセフアロスポリン化合物と一般式
（）で示されるチオール類を混合し、無水の条
件下セフアロスポリン誘導体の３倍量以下の溶媒
の存在下で加熱するのみで容易に反応は進行し、
前記一般式（）で示される７−アシルアミノ
（又はアミノ）−３−置換チオメチルセフアロスポ
リン化合物が得られる。加熱温度は内温50乃至
150℃、好適には70乃至100℃であり、溶媒として
例えばトルエン、キシレン、石油系炭化水素が用
いられる。反応時間は通常数秒乃至数十分であ
る。反応生成物は常法によつて反応混合物から採
取される。例えば反応終了後、生成物を溶媒にと
かし不純物を除去し、濃縮乾燥する。更に精製す
る場合はクロマトグラフイー等の適宜の精製手段
を用いる。
本発明によつて得られる化合物は前記一般式
（）で示される７−アシルアミノ（又はアミノ）
−３−置換チオメチルセフアロスポリン化合物、
７−アシルアミノ（又はアミノ）−３−置換チオ
メチルセフアロスポラン酸又はそのカルボキシル
基における誘導体、又はそれらの塩であつて、
7β−（イミダゾール−２−イル）チオアセトアミ
ド−7α−メトキシ−３−（１−メチル−1H−テト
ラゾール−５−イル）チオメチル−３−セフエム
−４−カルボン酸、7β−（１，３，４−チアジア
ゾール−２−イル）チオアセトアミド−7α−メ
トキシ−３−（１−メチル−1H−テトラゾール−
５−イル）チオメチル−３−セフエム−４−カル
ボン酸、7β−（５−イソオキサゾリルオキシ）ア
セトアミド−7α−メトキシ−３−（１−メチル−
1H−テトラゾール−５−イル）チオメチル−３
−セフエム−４−カルボン酸、7β−プロパルギ
ルチオアセトアミド−7α−メトキシ−３−（１−
メチル−1H−テトラゾール−５−イル）チオメ
チル−３−セフエム−４−カルボン酸、7β−シ
アノメチルチオアセトアミド−7α−メトキシ−
３−（１−メチル−1H−テトラゾール−５−イ
ル）チオメチル−３−セフエム−４−カルボン
酸、7β−（５−メチル−１，３，４−チアジアゾ
ール−２−イル）チオアセトアミド−7α−メト
キシ−３−（１−メチル−1H−テトラゾール−５
−イル）チオメチル−３−セフエム−４−カルボ
ン酸等は抗菌性物質として公知なものであり、又
7β−（Ｄ−5′−Ｎ−イソブトキシカルボニルアミ
ノ−5′−カルボキシバレルアミド）−7α−メトキ
シ−３−（１−メチル−1H−テトラゾール−５−
イル）チオメチル−３−セフエム−４−カルボン
酸、7β−（Ｄ−5′−Ｎ−ｐ−ニトロベンゾイルア
ミノ−5′−カルボキシルバレルアミド）−7α−メ
トキシ−３−（１−メチル−1H−テトラゾール−
５−イル）チオメチル−３−セフエム−４−カル
ボン酸は前記の如き抗菌性物質の中間体として有
用なものである。
次に本発明の実施例を示す。
実施例 １
7β−（Ｄ−5′−Ｎ−イソブトキシカルボニルア
ミノ−5′−カルボキシバレルアミド）−7α−メト
キシ−３−カルバモイルオキシメチル−３−セフ
エム−４−カルボン酸1.0ｇに２−メチル−５−
メルカプト−１，３，４−チアジアゾール1.0ｇ
及びトルエン３mlを加え油浴上浴温115〜120℃に
10分加熱する。冷却後エーテル20mlを加えよくか
きまぜ油状物を粉末化せしめ集し、エーテルで
洗滌後乾燥すると1.0ｇの7β−（Ｄ−5′−Ｎ−イソ
ブトキシカルボニルアミノ−5′−カルボキシバレ
ルアミド）−7α−メトキシ−３−（２−メチル−
１，３，４−チアジアゾール−５−イル）チオメ
チル−３−セフエム−４−カルボン酸が得られ
る。
nmr、CD3OD、ppm値
1.08、1.18（二重線6H）、1.6〜2.6（多重線7H）、
2.76（一重線3H）、3.57（一重線3H）、5.11（一重線
1H）[Formula] is shown. ) by heating thiols having the general formula (In the formula, R, R″, and X have the same meanings as above.) 7-acylamino (or amino)-3-
This is a method for producing substituted thiomethylcephalosporin compounds with simple operation and high yield. The compounds represented by the general formula () used as starting materials in the present invention are 7β-amino-7α-alkoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-amino-3-carbamoyloxymethyl- 3-cephem-4-carboxylic acid, 7β-acylamino-7α-alkoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 7β-acylamino-3-
Carbamoyloxymethyl-3-cephem-4-
Carboxylic acids and their derivatives at the carboxyl group or salts thereof. Since the acyl group of these compounds is a moiety that does not directly participate in this reaction, any acyl group may be used. for example,
These include a substituted acetyl group, a substituted valeryl group, a substituted benzoyl group, and the like. Substituents for the substituted acetyl group include an amino group, a substituted amino group, a carboxyl group, a sulfonyl group, a hydroxyl group, a heterocyclic group, a heterocyclic thio group, a heterocyclic oxy group, a substituted alkylthio group, an alkynylthio group, etc. Substituents for the group include an amino group, substituted amino group, carboxyl group, etc., and substituents for the substituted benzoyl group include an amino group, a hydroxyl group, and a sulfo group. In particular, the present invention is 7α
-7β-acylamino-7α-alkoxy-3-carbamoyloxymethyl-3-cephem-4- since it is the most suitable method for converting the 3-carbamoyloxymethyl group of the alkoxycephalosporin compound into a substituted thiomethyl group. Carboxylic acids are used. For example, cefamycin C, 7β-
(D-5'-N-isobutoxycarbonylamino-
5′-carboxyvaleramide)-7α-methoxy-
3-carbamoyloxymethyl-3-cephem-
4-carboxylic acid, 7β-(D-5'-N-p-nitrobenzoylamino-5'-carboxyvaleramide)-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β- Thienylacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(imidazol-2-yl)thioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4- carboxylic acid,
7β-(1,3,4-thiadiazol-2-yl)
Thioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(6-isoxazolyloxy)acetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4 -carboxylic acid,
7β-propargylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-cyanomethylthioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(5-Methyl-1,3,4-thiadiazol-2-yl)thioacetamide-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, 7β-(1,2,4- triazol-4H-3-yl)thioacetamide-
7α-Methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and the like and derivatives or salts of these compounds at the carboxyl group are suitable starting materials for this process. Examples of carboxyl group derivatives in formula () include the following. (i) Esters include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, methoxyethyl, ethoxymethyl, phenoxymethyl, methylthiomethyl, phenylthiothyl,
Such as dimethylaminoethyl, diethylaminoethyl, phenacyl, p-bromophenacyl, acetoxymethyl, pivaloyloxymethyl, benzoyloxymethyl, 1,1-diacetylalkylmethanesulfonylethyl, toluenesulfonylethyl, trichloroethyl, cyanomethyl, phthalimidomethyl It includes all the alkyl esters with or without substituents, other cycloalkyl esters, cycloalkenyl esters, trimethylsilyl esters, etc. that do not affect the reaction (ii) Amides include all the usual amides that are not affected by the reaction, (iii) Acid anhydrides include organic acids inert to this reaction, mixed acid anhydrides with inorganic acids, or anhydrides with carboxyl groups and hydroxysuccinimide, N-hydroxyphthalimide, dialkylhydroxylamine, oxime, etc. I can give things away. The thiols represented by the general formula () used in the present invention are thioureas or substituted or unsubstituted heterocyclic thiols. The latter heterocyclic group of thiols is generally a heterocyclic thiomethyl group substituted at the 3-position of a cephalosporin compound, such as a 5- or 6-membered heterocyclic group having 1 to 4 nitrogen atoms, 1 oxygen atom, 1 nitrogen atom
5- or 6-membered heterocyclic groups having 1 to 2 atoms, 5- or 6-membered heterocyclic groups having 1 to 2 nitrogen atoms, etc., and these heterocyclic groups have 1 to 3 atoms.
Alkyl groups, etc. may be substituted. Representative examples include 1-methyl-5-mercaptotetrazole, 5-methyl-2-mercapto-1,
3,4-thiadiazole, 3-mercapto-1,
2,4-triazole and the like. The reaction of the present invention is represented by the general formula () 7
-Acylamino (or amino)-3-carbamoyloxymethyl cephalosporin compound and thiols represented by the general formula () are mixed and heated under anhydrous conditions in the presence of a solvent not more than three times the amount of the cephalosporin derivative. The reaction progresses easily with
A 7-acylamino (or amino)-3-substituted thiomethylcephalosporin compound represented by the general formula () is obtained. Heating temperature is internal temperature 50 to
The temperature is 150°C, preferably 70 to 100°C, and the solvent used is, for example, toluene, xylene, or petroleum hydrocarbon. The reaction time is usually several seconds to several tens of minutes. The reaction product is collected from the reaction mixture in a conventional manner. For example, after the reaction is completed, the product is dissolved in a solvent to remove impurities, and then concentrated and dried. For further purification, appropriate purification means such as chromatography are used. The compound obtained by the present invention is a 7-acylamino (or amino) compound represented by the above general formula ().
-3-substituted thiomethylcephalosporin compounds,
7-acylamino (or amino)-3-substituted thiomethylcephalosporanic acid or a derivative thereof at the carboxyl group, or a salt thereof,
7β-(imidazol-2-yl)thioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(1,3,4 -thiadiazol-2-yl)thioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(5-isoxazolyloxy)acetamide-7α-methoxy-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid, 7β-propargylthioacetamide-7α-methoxy-3-(1-
Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-cyanomethylthioacetamide-7α-methoxy-
3-(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(5-methyl-1,3,4-thiadiazol-2-yl)thioacetamide-7α- Methoxy-3-(1-methyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-carboxylic acid, etc. are known as antibacterial substances, and
7β-(D-5′-N-isobutoxycarbonylamino-5′-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(D-5'-N-p-nitrobenzoylamino-5'-carboxylvaleramide)-7α-methoxy-3-(1-methyl-1H- Tetrazole
5-yl)thiomethyl-3-cephem-4-carboxylic acid is useful as an intermediate for antibacterial substances such as those mentioned above. Next, examples of the present invention will be shown. Example 1 1.0 g of 7β-(D-5'-N-isobutoxycarbonylamino-5'-carboxyvaleramide)-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 2-methyl -5-
Mercapto-1,3,4-thiadiazole 1.0g
Add 3 ml of toluene and raise the oil bath temperature to 115-120℃.
Heat for 10 minutes. After cooling, add 20 ml of ether and stir well to turn the oil into a powder, collect, wash with ether and dry to obtain 1.0 g of 7β-(D-5′-N-isobutoxycarbonylamino-5′-carboxyvaleramide)-7α. -methoxy-3-(2-methyl-
1,3,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained. nmr, CD 3 OD, ppm value 1.08, 1.18 (duplex 6H), 1.6~2.6 (multiplet 7H),
2.76 (single line 3H), 3.57 (single line 3H), 5.11 (single line
1H)
Claims (1)
水素原子又はアルコキシ基を示す。）を有する７
−アシルアミノ（又はアミノ）−３−カルバモイ
ルオキシメチルセフアロスポラン酸類又はそのカ
ルボキシル基における誘導体、又はそれらの塩に 一般式 R″SH （式中、R″は置換又は非置換複素環基或いは基
−Ｃ（＝NH）NH2を示す。）を有するチオール類
を無水条件下セフアロスポリン誘導体の３倍量以
下の溶媒の存在下で加熱することを特徴とする 一般式 （式中、Ｒ、Ｘ、R″は先と同一意義を有する。）
を有する７−アシルアミノ（又はアミノ）−３−
置換チオメチルセフアロスポリン化合物もしくは
そのカルボキシル基における誘導体又はそれらの
塩の製法。 ２ ７−アシルアミノ−３−カルバモイルセフア
ロスポラン酸化合物が 一般式 （式中、Ｒは水素原子又はアシル基を示し、Ｘは
アルコキシ基を示す。）である特許請求の範囲第
１項記載の方法。[Claims] 1. General formula (In the formula, R represents a hydrogen atom or an acyl group, and X represents a hydrogen atom or an alkoxy group.)
-Acylamino (or amino)-3-carbamoyloxymethylcephalosporanic acids or their carboxyl group derivatives, or salts thereof with the general formula R″SH (wherein R″ is a substituted or unsubstituted heterocyclic group or group- A general formula characterized by heating thiols having C(=NH) NH2 ) under anhydrous conditions in the presence of a solvent in an amount not more than three times the amount of the cephalosporin derivative. (In the formula, R, X, and R″ have the same meanings as above.)
7-acylamino (or amino)-3- having
A process for producing a substituted thiomethylcephalosporin compound or a derivative at its carboxyl group or a salt thereof. 2 7-acylamino-3-carbamoylcephalosporanic acid compound has the general formula (In the formula, R represents a hydrogen atom or an acyl group, and X represents an alkoxy group.) The method according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21120986A JPS62281881A (en) | 1986-09-08 | 1986-09-08 | Production of 3-substituted thiomethylcephalosporin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21120986A JPS62281881A (en) | 1986-09-08 | 1986-09-08 | Production of 3-substituted thiomethylcephalosporin derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11689878A Division JPS5543043A (en) | 1978-09-22 | 1978-09-22 | Preparation of 3-substituted thiomethylcephalosporin derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62281881A JPS62281881A (en) | 1987-12-07 |
| JPH0124156B2 true JPH0124156B2 (en) | 1989-05-10 |
Family
ID=16602134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21120986A Granted JPS62281881A (en) | 1986-09-08 | 1986-09-08 | Production of 3-substituted thiomethylcephalosporin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62281881A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53130689A (en) * | 1977-03-07 | 1978-11-14 | Lilly Co Eli | Novel process for preparing cephalospoline |
-
1986
- 1986-09-08 JP JP21120986A patent/JPS62281881A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53130689A (en) * | 1977-03-07 | 1978-11-14 | Lilly Co Eli | Novel process for preparing cephalospoline |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62281881A (en) | 1987-12-07 |
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