JPS5899486A - Preparation of cephalosporin derivative - Google Patents
Preparation of cephalosporin derivativeInfo
- Publication number
- JPS5899486A JPS5899486A JP19516281A JP19516281A JPS5899486A JP S5899486 A JPS5899486 A JP S5899486A JP 19516281 A JP19516281 A JP 19516281A JP 19516281 A JP19516281 A JP 19516281A JP S5899486 A JPS5899486 A JP S5899486A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- reacted
- acid
- carboxylic acid
- caustic
- 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.)
- Granted
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- Cephalosporin Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は1−ム0ムを出発原料とし、その3位及びT位
の変換反応に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention uses 1-muom as a starting material and relates to a conversion reaction at the 3-position and the T-position.
一般KT−ムCムの3位およびT位を変換してより強力
な抗菌剤に一導する方法は数多く報告されて□いるが、
本発明者らは特Kl−ハロメチル体の合成法について種
々検討した結果1次の工程を連続的に実施する事により
、効率よく目的物を合成し得る事を見出し本発明を完成
した。Many methods have been reported to convert the 3- and T-positions of the general KT-mu to create more powerful antibacterial agents.
The present inventors have conducted various studies on methods for synthesizing specific Kl-halomethyl compounds, and as a result have found that the desired product can be synthesized efficiently by carrying out the first step continuously, and have completed the present invention.
00H (式中%Rはアシル基、Xはハロゲン原子を示す。) 次に各工11について詳細に説明する。00H (In the formula, %R represents an acyl group, and X represents a halogen atom.) Next, each process 11 will be explained in detail.
第一工程
? −Aoムもしくはその1−アシルアミノ体の3位ア
セトキシメチル基なヒドロキシメチル基に変換する方法
としては、酵素的に又は苛性アルカリを使用して加水分
解する方法が報告されている。酵素的な方法としてはベ
ルギー特許第・71@12号に記載されているような小
麦胚エステラーゼまたはりゾピュム属のエステラーゼを
用いる方法、興国特許第1116222号の明細書に記
載されているようなオレンジの果皮から得られるエステ
ラーゼを用いる方法婢が知られている。First step? As a method for converting the acetoxymethyl group at the 3-position of -Aom or its 1-acylamino derivative into a hydroxymethyl group, enzymatic hydrolysis or hydrolysis using caustic alkali has been reported. Enzymatic methods include methods using wheat embryo esterase or Rhizopyum esterase as described in Belgian Patent No. 71@12, and orange esterase as described in the specification of Kokoku Patent No. 1116222. A method using esterase obtained from the pericarp of the fruit is known.
又苛性アルカリ水溶液中で水解する方法としてはTh@
Journal of Antibiotics vo
l N4 、11・・(lqlll)K記載されている
ような2t1%苛性ソーダ水溶液中で反応させる方法が
報告され【いる。Also, as a method of water dissolution in a caustic alkali aqueous solution, Th@
Journal of Antibiotics vo
A method of reacting in a 2t1% caustic soda aqueous solution as described above has been reported.
これらの方法めうち、前者は酵素へ調製および反応後そ
れらの除去等操作上難点を有し、後者は苛性アルカリ等
の強塩基を使用するため、!−ラクタム積の開裂を伴い
収率が低下するという欠点がある。本発明者らはこの苛
性アルカリによる氷解反応の際低級アルコールを加える
と意外にもこの反一応が非常に促進され、従つ【反応時
間を短縮する事が出来、!−ツクタム濃の開裂をかなり
防ぎ得る事がわかった。この際−使用する低級アルコー
ルはメタノール、エタノールンn−プ四パノールなどで
、好ましくはメタノ−1ルである。また、苛性ソーダ、
苛性カリなどの使用する苛性アルカリのモル比は1−ム
0ムに対し1〜2モル比であるが、好ましくは苛性ソー
ダを用いて1.0 !i〜1. Sモル比である。又反
応温度は−SO℃〜室温で進行するが、好ましくは一り
0℃〜O0である。反応一時間は数分乃至数十分で終了
する。Among these methods, the former has operational difficulties such as preparing the enzyme and removing it after the reaction, and the latter uses a strong base such as caustic alkali. -There is a drawback that the yield is reduced due to cleavage of the lactam product. The present inventors found that when a lower alcohol was added during the ice-melting reaction using caustic alkali, this reaction was surprisingly accelerated, and thus the reaction time could be shortened! - It was found that the cleavage of tscutam concentrate can be significantly prevented. The lower alcohol used in this case is methanol, ethanol, tetrapanol, etc., preferably methanol. Also, caustic soda,
The molar ratio of the caustic alkali used, such as caustic potash, is 1 to 2 molar ratios to 1.0 m, preferably 1.0 to 1.0 m, using caustic soda. i~1. S molar ratio. The reaction temperature is -SO°C to room temperature, preferably 0°C to 00°C. The one hour reaction is completed in several minutes to several tens of minutes.
このよう忙して得られたT−ア建ハI−ヒドロキシメチ
ルー3−セフェム−4−カルボン酸は単離する事なく通
常のT−ア建ノセファ四スポリン誘導体のアシル化反応
の条件下においてアシル化を行う事が出来る。このよう
なアシル化剤の種類としては一般にセファロスポリン系
化合物に使用されているカルボン酸の反応性誘導体であ
れば特に制限はないが、好ましくはフェノオキV酢酸又
)W 2− (2−ホルム又は2−クロロアセチルアミ
ノチアゾール)−4−イル2−(シン)メトキシイミノ
酢酸などの反応性誘導体1例えば酸ハライド又はビール
ス、マイヤーm向導体として反応せしめ、得られた1−
アシルアミノ−3−ヒドロキシ/?ルー3−セフェム−
4−カルボン酸は通常の方法により単離し得る。すなわ
ち反応終了後液性を酸性とし、適当な溶媒例えば酢酸エ
チルで抽出し、濃縮すれば容易に単離出来る。The thus obtained T-a-denocepha I-hydroxymethyl-3-cephem-4-carboxylic acid was acylated under the conditions of the usual acylation reaction of T-a-denocephatetrasporin derivatives without isolation. It is possible to perform conversion. The type of such acylating agent is not particularly limited as long as it is a reactive derivative of carboxylic acid that is generally used in cephalosporin compounds, but preferably phenox-V acetic acid or) W 2- (2-form or reactive derivatives such as 2-chloroacetylaminothiazol)-4-yl 2-(syn)methoxyiminoacetic acid 1 such as acid halides or viruses, reacted as Mayer m-directing conductors, and the resulting 1-
Acylamino-3-hydroxy/? Lou 3 - Cephem -
4-carboxylic acids can be isolated by conventional methods. That is, after the reaction is completed, the solution can be easily isolated by making the liquid acidic, extracting with a suitable solvent such as ethyl acetate, and concentrating.
第二工程
前工程で得られた1−アジルアイノ−3−ヒドロキフ体
の3位をハロメチル体に変換する方法としては、特公昭
1t−47@78号−+l@3FyK記載されている方
法によれば、4位カルボキシ、ル基を脱離可能なエステ
ル、例えばジフェニルメチル、β、/、β−トリクロロ
エチル、c−フfル基で保護し、クロル化反応終了後エ
ステル部分を脱離して目的物を単離しているが、このよ
うな方法は工程が長くなり、操作法も煩給となり工業的
に有利な方法とはいえない。本発明者らは1−アシルア
オフ−3−ヒドロキシメチル−3−セフェム−4−カル
ボン酸にチオニルクロライドのようなりロル化剤を作用
せしめたところ、3−ヒドロキシメチル基のみが優先的
にクロル化を受ける事を見出した。The method for converting the 3-position of the 1-azilaino-3-hydroxy compound obtained in the pre-step of the second step into the halomethyl compound is according to the method described in Japanese Patent Publication No. Sho 1t-47@78-+l@3FyK. , the 4-position carboxy group is protected with a removable ester such as diphenylmethyl, β, /, β-trichloroethyl, c-fur group, and after the chlorination reaction is completed, the ester moiety is removed to obtain the desired product. However, such a method is not industrially advantageous because the process is long and the operation method is laborious. The present inventors exposed 1-acylaof-3-hydroxymethyl-3-cephem-4-carboxylic acid to a chlorating agent such as thionyl chloride, and found that only the 3-hydroxymethyl group was preferentially chlorinated. I found something to accept.
本反応におけるハロゲン化剤としては、チオニルクロラ
イド、チオニルブロマイド、三臭化燐1.五塩化燐等が
あげられるが、チオニルクロライドが好ましい。反応温
度は一り0℃〜室温であるがo−icが好fしい0反応
時間は30分乃至1時間である0反応終了後[1を留去
し。Examples of halogenating agents in this reaction include thionyl chloride, thionyl bromide, and phosphorus tribromide. Examples include phosphorus pentachloride, but thionyl chloride is preferred. The reaction temperature is 0° C. to room temperature, but the preferred reaction time for O-IC is 30 minutes to 1 hour. After the reaction is complete, 1 is distilled off.
不溶性の溶媒を加えて却晶性粉末として単離するか、又
は適当な塩基を加1Gカルボン酸の塩とし曵単離する事
が出来る。It can be isolated as a crystalline powder by adding an insoluble solvent, or it can be isolated as a salt of 1G carboxylic acid with a suitable base.
このようにし【本発明の方法によって得られた。1−ア
ジルアミノ−3−ハロメチル−3−セフェム−4−カル
ボン酸はセファロスポリン系抗生物質の中間体として有
用である。例えばメタノール、エタノールを作用せしめ
%3−メトキシメチル、3−エト中ジメチル体のよ5な
3−アルコキシメチル体に、又メチルメルカプタン、S
−メルカプト−1−メチル−1H−テトラゾールのよう
なメルカプタン類を作用させて相当する3−置換メルカ
プトメチル体に、又ア(ン類を作用させて相当する3−
ア建ツメチル体にそれぞれ誘導する事が出来る。Thus obtained by the method of the present invention. 1-Adylamino-3-halomethyl-3-cephem-4-carboxylic acid is useful as an intermediate for cephalosporin antibiotics. For example, by reacting methanol or ethanol, %3-methoxymethyl, 5-alkoxymethyl forms such as dimethyl form in 3-ethyl alcohol, or methyl mercaptan, S
The corresponding 3-substituted mercaptomethyl compound is reacted with a mercaptan such as -mercapto-1-methyl-1H-tetrazole, and the corresponding 3-substituted mercaptomethyl compound is reacted with a (an).
It is possible to induce each of the two methyl forms.
次に実施例をあげて本発明を具体的に説明するが、これ
ら実施例ならびに参考例はなんら本発明を制限するもの
ではない。Next, the present invention will be specifically explained with reference to Examples, but these Examples and Reference Examples are not intended to limit the present invention in any way.
実施例1゜
(1−1)
T−ムOム 44#に水1・e−及びメタノールS・−
を加え一5cK冷却し、よく攪拌しながらIM−苛性ソ
ーダ水溶液tWO−を徐々に満願する。Example 1゜(1-1) T-mu Omu 44#, water 1.e- and methanol S.-
was added, cooled to 15 cK, and IM-caustic soda aqueous solution tWO- was gradually added while stirring well.
内容物は溶解し均一な溶液となる。均一の溶液となって
から、更に1N−苛性ソーダ水溶1[40−を加え、同
温度で10分攪拌を続け、ついでフェノキシアセチルク
ロライドをIO−のアセトンにとかしたS液を満願し、
同時に!O−苛性苛性ソーダ上満願し1反応液のpHな
7.!i −11に保つようKする。満願に約11公費
した。更に%i分攪拌し、酢酸エチル200−を加え、
塩IIっ*1EOpHヶ、。え調製オ、。酢酸8.ヤ。The contents dissolve and become a homogeneous solution. After it became a homogeneous solution, 1N aqueous sodium hydroxide solution 1 [40] was added, and stirring was continued for 10 minutes at the same temperature.
at the same time! The pH of the reaction solution is 7. ! K to keep it at i -11. Approximately 11 yen of public funds were spent on the full petition. Stir further for %i minutes, add 200% of ethyl acetate,
Salt II*1 EOpH. Preparation o. Acetic acid8. Ya.
を分離し、水層な酢酸エチルで抽出する。抽出液を合し
、S媒を減圧議縮すると、結晶が析出する。、これをP
集し酢酸エチルで洗浄後乾燥する。r液を更に濃縮する
と少量の結晶が析出するので同様KP集乾燥して、合計
4LNIの3−ヒドロキシメチル−1β−フェノキシア
セドア瑠ドー3−セフェム−4−カルボン酸が得うtt
。Separate and extract the aqueous layer with ethyl acetate. When the extracts are combined and the S medium is condensed under reduced pressure, crystals are precipitated. , this is P
Collect, wash with ethyl acetate, and dry. When the R solution is further concentrated, a small amount of crystals precipitates, so KP is similarly collected and dried to obtain a total of 4LNI of 3-hydroxymethyl-1β-phenoxyacedorudo-3-cephem-4-carboxylic acid.
.
た。収率82−
MMRδ (DM80−−ツL6− OD Ol−M
) 冨 till (2]ヨ【 、 a 、 コヒ
位CJ ) e 4mm (2Hg 8 m ”位on
、 ) 、 41@(I H、@ 、 0Oi1100
) 、 S、00 (、11! e a # J ”
5Hsi、IQH)、 L11@(11,d4sJc”
s*ll Hg ) # 41 ”−7,4(S H#
!a #)i=ニルプロト7 ) 、 #T@ (I
H、A 、 J x= 15 Hz e N1り(ト
4 )
3−ヒドロキシメチル−1β−フェノキシアセドア(ビ
ー3−セフェム−4−カルメン酸11のテトラヒドロフ
ランS−のけん濁液に氷塩冷下チオニルクロライド&宜
−を加え、15分間攪拌後、反応液に酢酸エチルを加え
、水洗(×3)する。無水硫酸マグネシウムで乾燥後溶
媒を留去して、粉末状の目的化合物(L@jを得た。Ta. Yield 82-MMRδ (DM80--T L6-ODOl-M
) Tomi (2) Yo [, a, CJ) e 4mm (2Hg 8m” on
, ) , 41@(I H, @ , 0Oi1100
), S, 00 (, 11! e a # J”
5Hsi, IQH), L11@(11,d4sJc”
s*ll Hg) #41”-7,4(S H#
! a #)i=nilprot7), #T@(I
H, A, J After adding thionyl chloride & chloride and stirring for 15 minutes, ethyl acetate was added to the reaction solution and washed with water (x3). After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the target compound (L@j) in the form of a powder. I got it.
WMR(ODOj暴) δ :S、・o(zu、 ム
Bq 、 Δ δ =04@ ppm 、 J ml@
Hg 、 2位CI!1) # 4!i4 (2”
N8、s位011 ) * 40 (2H* I 、
OOHmOO) 。WMR (ODOj violent) δ:S,・o(zu, MUBq, Δ δ =04@ppm, J ml@
Hg, 2nd place CI! 1) #4! i4 (2”
N8, s position 011) * 40 (2H * I,
OOHmOO).
5.11(口1 # & 、 J w= i Il+
、 @位11 ) 、 LTO(IH,14,Jffl
、象!i Htx # 1位B) I ll−7−7,
4(l H、m 、)z=ニルプ謔トン) 、 1LO
7CI HM 6 e J −L!i Hsi )カル
ボン酸
(2−1)
TI−アミノセファロスポラン酸t(+IIのメタノー
ルlll−と水t@−中のけん濁液に−10〜−SCに
冷却下■−苛性ソーダ水溶液ILImを満願し、S分間
同温度で攪拌後、アセトンSO−を加える。一方オキシ
塩化すン龜s4−と菖9M−ジメチルホルムア々ド1■
−との混合物を40℃、1時間攪拌して得た試薬を酢酸
エチルsI−にけん濁し、これKl−(!−ホルムアミ
ノー4−チアゾリル)l−(シン)−メトキシインノ酢
酸&41を加え、室温で暴分間攪拌し、均一なアシル化
試薬を調製する。このアシル化試薬を先の1−アミノセ
ファロスポラン酸加水時間水冷下攪拌後、水、酢酸エチ
ルを加え、水層な分離する。水層に酢酸エチル−テトラ
ヒトミフッy(2:1)混合溶媒(250−)を加え、
この混合物KIN塩酸を加えpH15として有機層を分
離する。水層なさらに酢酸エチル−テトラヒドロフラン
(!it)で抽出後、抽出液を合し、無水硫酸マグネシ
ウムで乾燥後、s液を濃縮し、析出する粉末なr取し【
、目的化合物を得た。収量1m、1 tt (−11−
)。5.11 (mouth 1 # & , J w= i Il+
, @11), LTO(IH,14,Jffl
,elephant! i Htx #1st place B) I ll-7-7,
4(l H, m,)z=Nirup 謔TON), 1LO
7CI HM 6 e J-L! i Hsi) Carboxylic acid (2-1) TI-Aminocephalosporanic acid t(+II) in methanol lll- and water t@- in a suspension under cooling to -10 to -SC ■-Aqueous caustic soda solution ILIm was added to the suspension. After stirring at the same temperature for S minutes, acetone SO- is added.Meanwhile, acetone SO- and irises 9M-dimethylformade 1
The reagent obtained by stirring the mixture with - at 40°C for 1 hour was suspended in ethyl acetate sI-, and Kl-(!-formamino-4-thiazolyl)l-(syn)-methoxyinnoacetic acid &41 was added thereto. Stir for a minute at room temperature to prepare a homogeneous acylation reagent. After stirring this acylating reagent under water cooling for the above-mentioned 1-aminocephalosporanic acid hydration period, water and ethyl acetate were added to separate the aqueous layer. Add ethyl acetate-tetrachloromethane (2:1) mixed solvent (250-) to the aqueous layer,
Add KIN hydrochloric acid to this mixture to adjust the pH to 15 and separate the organic layer. The aqueous layer is further extracted with ethyl acetate-tetrahydrofuran (!IT), the extracts are combined, dried over anhydrous magnesium sulfate, the S solution is concentrated, and the precipitated powder is collected.
, the target compound was obtained. Yield 1m, 1tt (-11-
).
MMR(DM&0−di) J j Ll@ (2H*
a m 2位cHt)elllo (F−11、s
s 0OIIl) e 41g (2H* I 、 1
位OBI ) e 10F (t II * eL e
J m I HM * @ 位H) #11!(目’
# a、a、 J冨1 、 UI Hg 、 7位H
)。MMR (DM&0-di) J j Ll@ (2H*
a m 2nd position cHt) ello (F-11, s
s 0OIIl) e 41g (2H*I, 1
position OBI) e 10F (t II * eL e
J m I HM * @ place H) #11! (eye'
# a, a, J Tomi 1, UI Hg, 7th place H
).
!!M< N > m s、s唱 (I II
w & j J 脇 a、I 11m
、 リ)。! ! M < N > m s, s chant (I II
w & j J side a, I 11m
, li).
%2・(t n 、 s 、 !00 )。%2・(tn, s, !00).
(宜−2)
TI−(2−(2−ホルムア建ノー4−チアゾリル)−
1−(シン)−メトキシイミノアセトアミド〕−3−ヒ
ドロキシメチル−3−七フエムー4−カルボン酸(1,
S29 )のテトラヒドロフラン(S Osg)けん濁
液に氷塩冷下、チオニルクロライド(1宜!−)を加え
、混合物を内温O〜5℃に保ち1.1時間攪拌する。沈
澱物をP去し、F液を濃縮して、粉末状の目的化合物(
1,211N )を得た。(Yi-2) TI-(2-(2-forma-4-thiazolyl)-
1-(syn)-methoxyiminoacetamide]-3-hydroxymethyl-3-7femu-4-carboxylic acid (1,
To a suspension of S29) in tetrahydrofuran (S Osg), thionyl chloride (1 y!-) is added under ice-salt cooling, and the mixture is stirred for 1.1 hours while keeping the internal temperature at 0 to 5°C. The precipitate was removed by P and the F solution was concentrated to obtain the powdered target compound (
1,211N) was obtained.
WMR(DM80−414) a :龜11 (2H@
brs s 2位C1l、 ) 、 SJI (1m
l 、 a 、 001s) 、 48m (2Hl、
3位ONり 、 11m (目l 、 ll 、 J
ym l II 。WMR (DM80-414) a: 11 (2H@
brs s 2nd place C1l, ), SJI (1m
l, a, 001s), 48m (2Hl,
3rd place ONri, 11m (eyes L, ll, J
ym l II.
6位H) * IJI (I M、 6 Am J W
S s KI Hz )*T、32 (%Beamン
狂)、川(11!−参!1−(、)、11@1(SR,
、a、Jgtsn塵 。6th place H) * IJI (I M, 6 Am J W
S s KI Hz ) * T, 32 (% Beam fanatic), river (11!-san!1-(,), 11@1 (SR,
,a,Jgtsndust.
Mり a 118 (I II 、 s 、 二00
)。Mri a 118 (I II, s, 200
).
錆例1゜
3−クロルメチル−1β−フェノキシアセトアミド−3
−セフェム−4−カルボン[QIO#のメタノール3−
溶液に三弗化ボロン・エーテラート(今ヤピラリー1滴
)を加え室温で1時間攪拌後、酢酸エチルで5すめ、水
洗する。酢酸エチル層を10%重1水と振り混ぜ、カル
ボン酸を水層に移す。水層に酢酸エチルを加え、8M塩
酸を加えpHz、s K して、カルボン酸を再度酢酸
エチルで抽出する。抽出液を無水硫酸マグネシウムで乾
燥し、溶媒を留去して、粉末状の目的化合物(rL*1
1)を得た。Rust example 1゜3-chloromethyl-1β-phenoxyacetamide-3
-cephem-4-carvone [QIO# methanol 3-
Add boron trifluoride etherate (1 drop of chloride) to the solution and stir at room temperature for 1 hour, then rinse with ethyl acetate for 5 minutes and then wash with water. Shake the ethyl acetate layer with 10% sodium chloride water and transfer the carboxylic acid to the aqueous layer. Ethyl acetate was added to the aqueous layer, 8M hydrochloric acid was added, the pH was adjusted to s K , and the carboxylic acid was extracted again with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the target compound in powder form (rL*1
1) was obtained.
MMRCODOIm)δ+ LX@ (* II 、
a 、 00Mg) 。MMRCODOIm) δ+ LX@ (* II,
a, 00Mg).
&42 (I H* brs 、 2位cJ1t )
s tie (2Hes、s位”2 ) s 452
(2III # I * oou、oo ) e4.1
! (目! 、 (1、J wg l ilz 、・位
a ) 、 1Lys (I H、Aa、 JzI 、
L5Bm 、 1位” ) e 1F −L3(SH
,m、7zxル基プロトン) # 7.1@ (1m
、 s 、 M! )。&42 (I H* brs, 2nd place cJ1t)
s tie (2Hes, s position"2) s 452
(2III #I * oou, oo) e4.1
! (Eye!, (1, J wg lilz, ・place a), 1Lys (I H, Aa, JzI,
L5Bm, 1st place") e 1F -L3(SH
, m, 7zx group proton) #7.1@ (1m
, s, M! ).
参考例2
8−クロルメチル−Tβ−フェノキシアセトアミド−3
−セフェム−4−カルボン@asayとS−メルカプト
−1−メチル−1R−テトラ酢酸エチルを加え、沈澱物
をr去し、FII中のカルボン酸を10−重曹水で抽出
する。抽出水溶液を酢酸エチルで洗浄後、8M塩酸でp
H11にして析出するカルボン酸を酢酸エチルで抽出す
る。抽出液を無水硫酸マグネシウムで乾燥後濃縮し約2
−になったらジイソプロピルエーテルを加え、析出する
粉末状の目的物をP取した。Reference example 2 8-chloromethyl-Tβ-phenoxyacetamide-3
-Cephem-4-carvone@asay and ethyl S-mercapto-1-methyl-1R-tetraacetate are added, the precipitate is removed, and the carboxylic acid in FII is extracted with 10-aqueous sodium bicarbonate. After washing the extracted aqueous solution with ethyl acetate, it was diluted with 8M hydrochloric acid.
The carboxylic acid precipitated in H11 is extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to about 2
When the temperature reached -, diisopropyl ether was added and the precipitated powdery target product was collected.
収量8.41 #
NMR(DM80−44)δ : &1@ (2H、
# 、 2位CIIg)*&@4 (I II 、
s s IJ−OHa )−t two (2II
、 # 13位0H2) s 4@0 (2if 、
s # 0011200 ) 、 LQ・(口1 、
(1、J−5H&6位” ) # 5.II (口16
dm JxS 、 11.I Hg 、 1位H)
、 LT −T、S (Sa、m、)z=ニルプロトン
) $ 11.all (S H。Yield 8.41 #NMR (DM80-44) δ: &1@(2H,
#, 2nd place CIIg) * & @4 (I II,
s s IJ-OHa )-t two (2II
, #13th place 0H2) s 4@0 (2if,
s #0011200), LQ・(mouth 1,
(1, J-5H & 6th place) #5.II (mouth 16
dm JxS, 11. I Hg, 1st place H)
, LT -T,S (Sa, m,)z=nyl proton) $ 11. all (SH.
6、 J W 11 Hg * NH) *特許出願人
三共株式会社
代理人 弁理士樫出庄治6. J W 11 Hg * NH) *Patent applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashide
Claims (1)
)を低級アルコールの存在下、苛性アルカリ水fII液
と反応せしめ、1−アミノ−3−ヒト四キシメチル−3
−セフェム−4−カルボン駿とし、ついでアシルハライ
ドと反応せしめることを特徴とする一般式 (式中、Rはアシル基な示す。) を有するセフ了りスポリン誘導体の製法。 2.1−ア々ノセファロスポラン酸(1−ムGA )を
低級アルコールの存在下、苛性アルカリ水溶液と反応せ
しめ、1−アミノ−1−ヒドロキシメチル−3−セフェ
ム−4−カルボン酸とし、つい−でアシルハライドと反
応せしめ。 得られた1、−アジルア々ノー1−にド驕キシメチルー
3−セフェム−4−カルボン酸ヲハロゲン化剤と反応せ
しめることを特徴とする一般式 (式中、aはアシル基、Xはハロゲン原子を示す、)を
有するセファロスポリン卿導体の製法。 龜 一般式 (式中、Rはアシル基を示す。) を有する化合物をハロゲン化剤と反応せしめることを特
徴とする特許 (式中、Rは前述したものと同意義を示し、Xはハロゲ
ン原子を示す。) を有するセファロスポリン誘導体の製法。[Claims] 1, 1-Aminocephalosborane (rllcT-muam) is reacted with caustic alkaline water fII in the presence of a lower alcohol to produce 1-amino-3-human tetraxymethyl-3.
1. A method for producing a cephalosporin derivative having the following general formula (wherein R represents an acyl group): 2.1-Aranocephalosporanic acid (1-muGA) was reacted with an aqueous caustic alkali solution in the presence of a lower alcohol to form 1-amino-1-hydroxymethyl-3-cephem-4-carboxylic acid, and then − to react with acyl halide. The obtained 1,-azilaano 1- is reacted with a halogenating agent to form a dooxymethyl-3-cephem-4-carboxylic acid having a general formula (wherein a is an acyl group and X is a halogen atom). A method for producing a cephalosporin conductor having the following properties: A patent characterized in that a compound having the general formula (wherein R represents an acyl group) is reacted with a halogenating agent (wherein R represents the same meaning as described above, and X represents a halogen atom) A method for producing a cephalosporin derivative having the following.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP19516281A JPS5899486A (en) | 1981-12-04 | 1981-12-04 | Preparation of cephalosporin derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP19516281A JPS5899486A (en) | 1981-12-04 | 1981-12-04 | Preparation of cephalosporin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5899486A true JPS5899486A (en) | 1983-06-13 |
JPH0354108B2 JPH0354108B2 (en) | 1991-08-19 |
Family
ID=16336454
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP19516281A Granted JPS5899486A (en) | 1981-12-04 | 1981-12-04 | Preparation of cephalosporin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5899486A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0204517A2 (en) * | 1985-05-30 | 1986-12-10 | Shionogi & Co., Ltd. | Hydroxymethylcephem compounds and their preparation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5112635A (en) * | 1974-07-19 | 1976-01-31 | Japan Storage Battery Co Ltd | NATORIUM UDENCHI |
JPS52102289A (en) * | 1976-02-23 | 1977-08-27 | Takeda Chem Ind Ltd | Synthesis of cephalosporin derivatives |
-
1981
- 1981-12-04 JP JP19516281A patent/JPS5899486A/en active Granted
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5112635A (en) * | 1974-07-19 | 1976-01-31 | Japan Storage Battery Co Ltd | NATORIUM UDENCHI |
JPS52102289A (en) * | 1976-02-23 | 1977-08-27 | Takeda Chem Ind Ltd | Synthesis of cephalosporin derivatives |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0204517A2 (en) * | 1985-05-30 | 1986-12-10 | Shionogi & Co., Ltd. | Hydroxymethylcephem compounds and their preparation |
Also Published As
Publication number | Publication date |
---|---|
JPH0354108B2 (en) | 1991-08-19 |
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