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KR900002874B1 - Process for preparing acyl ureido penicillin derivatives - Google Patents

Process for preparing acyl ureido penicillin derivatives Download PDF

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Publication number
KR900002874B1
KR900002874B1 KR1019870005495A KR870005495A KR900002874B1 KR 900002874 B1 KR900002874 B1 KR 900002874B1 KR 1019870005495 A KR1019870005495 A KR 1019870005495A KR 870005495 A KR870005495 A KR 870005495A KR 900002874 B1 KR900002874 B1 KR 900002874B1
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general formula
thioester
process according
formula
preparation
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KR1019870005495A
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Korean (ko)
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KR880013947A (en
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김돈기
이기홍
김지한
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보령제약 주식회사
김승호
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C07D499/10—Modification of an amino radical directly attached in position 6
    • C07D499/12—Acylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/70—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with hetero rings as additional substituents on the carbon chain

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Acylureido penicillin derivs. of formula (I) are prepd. by reacting akylenediisocyanate of formula OCN-(CH2)n-NCO with thiol of formula (II) in an inert solvent to obtain thioester of formula (III), and reacting (III) with 6-substd.-amino penicillane acid of formula (IV) in a polar solvent. (I) are useful as antibiotic agents.

Description

아실우레이도 페니실린 유도체의 제조방법Method for preparing acyl ureido penicillin derivative

본 발명은 항생제로서 유효한 다음 일반식(1)의 아실우레이도 페니실린과 이들의 약제학적으로 허용되는 이들 염의 새로운 제조 방법에 관한 것이다.The present invention relates to acylureido penicillin of the following general formula (1) and pharmaceutically acceptable salts thereof, which are effective as antibiotics.

Figure kpo00001
Figure kpo00001

상기 식에서 R1은 페닐 또는 하이드록시페닐이고, R2는 수소, 나트륨, 칼륨, 칼슘 또는 트리에틸아민이고, n은 2, 3 또는 4이다.Wherein R 1 is phenyl or hydroxyphenyl, R 2 is hydrogen, sodium, potassium, calcium or triethylamine, and n is 2, 3 or 4.

본 발명의 새로운 제조방법은 특정한 중간체를 경유하여서 되는 제조방법에서 반응공정, 공정조건이 편리, 용이하고, 수율이 향상되며 그리고 대량생산에 적합하다. 6-아실아미드측쇄의

Figure kpo00002
-위치에 아실우레이도기를 갖는 페니실린 유도체들은 이미 보고되어 있는데, 관련 문헌으로서 예를 들면, 벨기에 왕국 특허 제767,648호, 독일연방공화국 특허 제 2,025,415와, 동 제 2,104,579 호 , 남아프리카공화국 특허 제7,103,274호 및 미합중국 특허 제3,933,795호 등을 들 수 있다.The novel production method of the present invention is convenient, easy to process, improved yield, and suitable for mass production in the production process via a specific intermediate. Of 6-acylamide side chains
Figure kpo00002
Penicillin derivatives having an acylureido group at the position have already been reported, for example, in the Kingdom of Belgium Patent 767,648, German Patent 2,025,415, 2,104,579, South African Patent 7,103,274 and U.S. Patent No. 3,933,795 and the like.

지금까지 알려진 문헌에 의한 제법은 일반적으로 독성이 강하고 취급하기 어려운 물질인 포스겐 가스를 출발물질로서 사용하여 중간체인 1-클로로카보닐-이미다졸리딘-2-온을 제조한 다음 이것을 페니실린 유도체와 반응시켜 목적하는 화합물을 제조하거나, 또는 D-(-)-

Figure kpo00003
-(이미다졸리딘-2-온-1-일)카보닐아미 노페닐 아세트산이나 D-(-)-
Figure kpo00004
-[(이미다졸리딘-2-온-1-일)카보닐아미노]-(p-하이드록시)-페닐아세트산과 아실화제를 사용하여 6-아미노페니실린산과 반응시켜 목적하는 화합물을 제조하는 방법들이 기술되어 있다.The preparations known to date are generally prepared using the phosgene gas, which is generally a highly toxic and difficult to handle, as a starting material to produce the intermediate 1-chlorocarbonyl-imidazolidin-2-one and then the penicillin derivative. Reaction to produce the desired compound, or D-(-)-
Figure kpo00003
-(Imidazolidin-2-one-1-yl) carbonylaminophenyl acetic acid or D-(-)-
Figure kpo00004
-[(Imidazolidin-2-one-1-yl) carbonylamino]-(p-hydroxy) -phenylacetic acid and acylating agent to react with 6-aminophenicylic acid to produce the desired compound Are described.

본 발명은 독성이 강하고 취급하기에 위험한 포스겐을 사용하지 않으며, 상기 문헌에 보고된 카보닐 클로라이드와는 전혀 다른 알킬렌 디이소시아네이트와 같은 출발물질을 사용하여 일반식(1)의 아실우레이도 페니실린 유도체를 보다 경제적으로 제조하는 방법에 관한 것이고 또한 보존이 용이한 중간체의 물질을 경유하는 신규한 제조방법에 관한 것이다.The present invention does not use phosgene, which is highly toxic and dangerous to handle, and uses a starting material such as alkylene diisocyanate which is completely different from the carbonyl chloride reported in the literature, and the acylureido penicillin derivative of the general formula (1) It relates to a method for producing more economically and to a novel method for producing via intermediate material which is easy to preserve.

본 발명의 방법에 따라 일반식(Ⅰ)의 화합물은 다음과 같이 제조한다 : 하기 일반식(Ⅱ)의 알킬렌디이소시아네이트를 동당량 또는 이 이하의 하기 일반식(Ⅲ)의 티올과 트리에틸렌디아민 또는 N-메틸모르포린 등의 촉매존재 또는 부재하에 디옥산 테트라하이드로푸란, 아세톤, 아세토니트릴, 메틸렌틀로라이드, 메틸에틸케톤, 벤젠과 같은 극성 또는 비극성 유기 용매중에서 -10℃ 내지 환류온도에서 30분 내지 4시간 동안 반응시켜 중간체인 하기일반식(Ⅳ)의 티오에스테르를 수득하고, 이와같이 수득한 하기 일반식(Ⅳ)의 티오에스테르를 하기 일반식(Ⅴ)의 6-치환-아미노 페니실란산과 반응시켜 원하는 목적물질인 일반식(Ⅰ)의 아실 우레이도페니실린 유도체를 얻는다.According to the method of the present invention, the compound of general formula (I) is prepared as follows: Equivalent alkylene diisocyanate of general formula (II) is equivalent to or less than thiol and triethylenediamine of general formula (III) 30 minutes at -10 ° C to reflux temperature in polar or nonpolar organic solvents such as dioxane tetrahydrofuran, acetone, acetonitrile, methylenetride, methyl ethyl ketone, benzene in the presence or absence of a catalyst such as N-methylmorpholine And reacted for 4 hours to obtain a thioester of the following general formula (IV) as an intermediate, and reacting the thioester of the following general formula (IV) with 6-substituted-amino penicsilane acid of the following general formula (V). To obtain an acyl ureidophenicillin derivative of the general formula (I).

Figure kpo00005
Figure kpo00005

상기 일반식에서, R1,R2및 n은 상술한 바와 같다. 일반식(Ⅱ)의 알킬렌 디이소시아네이트는 일반적으로 미합중국 특허 제3,017,420호, 미합중국 특허 제3,118,925호 등에 기재된 바와 같은 공지된 방법에 의하여 제조한다. 그러므로 본 발명은 종래에는 전혀 사용된바 없는 알킬렌디이소시아네이트를 출발물질로 사용하여 보다 경제적으로 목적하는 일반식(Ⅰ)의 아실우레이도 페니실린 유도체를 제조할 수 있는 획기적인 방법을 제공한다.In the general formula, R1, R2 and n are as described above. Alkylene diisocyanates of formula (II) are generally prepared by known methods as described in US Pat. No. 3,017,420, US Pat. No. 3,118,925, and the like. Therefore, the present invention provides a breakthrough method for producing an acylureido penicillin derivative of general formula (I), which is more economically desired, using alkylene diisocyanate, which has never been used before, as a starting material.

본 발명의 새로운 제조방법은 또한 중간제품인 일반식(Ⅳ)의 티오에스테르의 높은 반응성에 착안하여 이 발명의 목적을 위해 특별히 티오에스테르를 제조하는 것이다. 또한 본 중간제품인 일반식(Ⅳ)의 티오에스테르는 새로운 아실화제인 동시에 안정하여 장기간 보존도 가능하다.The new production process of the present invention also focuses on the high reactivity of the thioesters of general formula (IV), which are intermediate products, to prepare thioesters specifically for the purpose of this invention. In addition, the thioester of the general formula (IV), which is the intermediate product, is a new acylating agent and is stable and can be stored for a long time.

본 발명은 이어서 일반식(Ⅳ)의 티오에스테르와 일반식(Ⅴ)의 6-치환-아미노페니실란산을 극성 요매 또는 비극성 용매중에서, 바람직하기는 물과 다른 극성용매의 혼합액중에서 반응시켜서 목적하는 화합물인 일반식(Ⅰ) 아실우레이도아미도 페니실린 유도체를 제조하면 종래의 중간체를 경유하지 않는 것 보다 반응성이 높으며 수율이 향상된다.The present invention is then reacted with a thioester of general formula (IV) and 6-substituted-aminophenic silane acid of general formula (V) in a polar solvent or nonpolar solvent, preferably in a mixed solution of water and another polar solvent. The preparation of the compound of general formula (I) acylureidoamido penicillin derivatives is more reactive and improves yield than not via conventional intermediates.

다음은 본 발명의 실시예로서 보다 상세히 설명하고저 하는 것이며 본 발명은 제한하는 것은 아니다.The following is an example of the present invention to be described in more detail, but the present invention is not limited.

[실시예 1]Example 1

가) 아세톤 50ml에 2.8g(25밀리몰)의 에틸렌 디이소시아네이트를 가하고, 이어서 0.01g의 트리에틸렌 디아민을 가한다. 온도를 올려 환류시키고 여기에 아세톤 50ml 에 3.4g(20밀리몰)의 2-머캅토벤조티아졸을 현탁시킨 액을 2시간 이상에 걸쳐 서서히 적하시키고, 적하 완료된 반응액은 환류온도에서 30분간 더 교반시켜 반응을 완결시킨다.A) 2.8 g (25 mmol) of ethylene diisocyanate is added to 50 ml of acetone, followed by 0.01 g of triethylene diamine. The temperature was raised to reflux, and a solution of 3.4 g (20 mmol) of 2-mercaptobenzothiazole suspended in 50 ml of acetone was slowly added dropwise over 2 hours, and the reaction solution was further stirred at reflux for 30 minutes. To complete the reaction.

과량의 아세톤을 감압하에 제거한 다음, 다시 아세톤으로 재결정하고 여과한후 테트라하이드로푸란 소량으로 세정하고 40℃에서 감압하게 건조하여 5.01g의 무색 결정인 N-(2-벤조티아졸일 티오카보닐)-아미다졸리딘-2온을 얻는다.Excess acetone was removed under reduced pressure, then recrystallized with acetone, filtered, washed with a small amount of tetrahydrofuran and dried under reduced pressure at 40 ° C. to give 5.01 g of colorless crystals N- (2-benzothiazolyl thiocarbonyl)- Obtain amidazolidin-2one.

융점 : 216 내지 219℃Melting Point: 216 ~ 219 ℃

I.R(KBr) : 3275, 1740, 1665cm-1 IR (KBr): 3275, 1740, 1665 cm -1

나) 20%의 수분이 함유된 테트라하이드로푸란 20ml에 0.4g(1밀리몰)의 6-[D(-)-

Figure kpo00006
-아미노페닐아세트아미도] 페니실란산 3수화물을 가하고 냉각하여 5℃를 유지시키고 0.1N 수산화나트륨액을 서서히 적하하여 용해시켜 pH 7.5내지 8.2로 맞춘후에 실온으로 올리고, 0.6g(2.2밀리몰)의 가)에서 제조한 화합물을 15ml의 테트라하이드로푸란 및 15ml의 아세톤에 현탁시킨 다음 적하한다. 이때 pH는 0.1N 수산화나트륨액으로 7.5 내지 8.7로 맞춘다.B) 0.4 g (1 mmol) of 6- [D (-)-in 20 ml of tetrahydrofuran containing 20% water.
Figure kpo00006
-Aminophenylacetamido] peniclanic acid trihydrate was added and cooled to maintain 5 ° C. 0.1N sodium hydroxide solution was slowly added dropwise to dissolve it, adjusted to pH 7.5 to 8.2, and then raised to room temperature. 0.6 g (2.2 mmol) of The compound prepared in a) is suspended in 15 ml of tetrahydrofuran and 15 ml of acetone and then added dropwise. At this time, the pH is adjusted to 7.5 to 8.7 with 0.1N sodium hydroxide solution.

반응의 종결을 위해서 액의 온도를 상승시켜 환류온도에서 약 20분간 유지시킨 후 냉각한다. 실온으로 냉각된 반응액에 증류수 30ml를 가하고 50℃ 이하에서 감압하에 테트라하이드로푸란 및 아세톤을 제거한다.약 5℃로 냉각하여 과량의 미반응물로서 잔류하는 가)의 화합물을 여과제거한후 이 여액을 5℃ 이하로 유지시키면서 0.1N-염산용액으로 pH를 1.5로 유지시키면 흰색의 결정이 석출된다.In order to terminate the reaction, the temperature of the liquid is raised and maintained at reflux for about 20 minutes and then cooled. 30 ml of distilled water was added to the reaction solution cooled to room temperature, and tetrahydrofuran and acetone were removed under reduced pressure at 50 ° C. or lower. The mixture was cooled to about 5 ° C., and the filtrate was filtered off. When the pH is maintained at 1.5 with 0.1 N hydrochloric acid solution while keeping it at 5 ° C or lower, white crystals are precipitated.

다시 이 온도에서 30분간 교반한후에 여과하고 소량의 에틸아세테이트로 세정한후 40℃에서 감압하게 건조하여 0.39g의 D-(-)--(이미다졸리딘-2-온-1-일-카보닐아미노)-벤질페니실린을 얻는다.The mixture was stirred at this temperature for 30 minutes, filtered, washed with a small amount of ethyl acetate, dried at 40 ° C. under reduced pressure, and then 0.39 g of D-(-)- -(Imidazolidin-2-one-1-yl-carbonylamino) -benzylphenicillin is obtained.

융점 : 146 내지 168℃(분해)Melting Point: 146-168 ° C (Decomposition)

I.R(KBr) : 3300, 1800, 1745, 1705, 1660cm-1 IR (KBr): 3300, 1800, 1745, 1705, 1660 cm -1

Claims (5)

하기 일반식(Ⅱ)의 알킬렌디이소시아네이트와 하기 일반식(Ⅲ) 티올을 촉매존재 또는 부재하에 불활성용매내에서 반응시켜 일반식(Ⅳ)의 티오에스테르를 수득하고, 이 티오에스테르를 하기 일반식(Ⅴ)의 6-치환-아미노 페니실란산과 극성 또는 비극성 용매중에서 반응시켜 일반식(Ⅰ)의 아실우레이도 페니실린 유도체를 제조하는 방법.The alkylene diisocyanate of the following general formula (II) and the following general formula (III) thiol are reacted in an inert solvent in the presence or absence of a catalyst to obtain a thioester of the general formula (IV), and the thioester is converted into the following general formula ( A process for preparing an acylureido penicillin derivative of the general formula (I) by reacting 6-substituted-amino penicsilane acid of V) in a polar or nonpolar solvent.
Figure kpo00008
Figure kpo00008
Figure kpo00009
Figure kpo00009
 상기 일반식에서, R1은 페닐 또는 하이드록시페닐기이고, R2는 수소, 나트륨, 칼륨, 칼슘 또는 트리에틸아민이고, n은 2,3 또는 4이다.In the general formula, R 1 is a phenyl or hydroxyphenyl group, R 2 is hydrogen, sodium, potassium, calcium or triethylamine, and n is 2, 3 or 4. 제 1 항에 있어서, 일반식(Ⅳ)의 티오에스테르의 제조시에 사용되는 촉매는 트리에틸렌 디아민 또는 N-메틸모르포린인 방법.The process according to claim 1, wherein the catalyst used in the preparation of the thioester of general formula (IV) is triethylene diamine or N-methylmorpholine. 제 1 항에 있어서, 일반식(Ⅳ)의 티오에스테르의 제조시에 사용되는 반응용매는 불활성의 극성 또는 비극성 용매인 방법.The process according to claim 1, wherein the reaction solvent used in the preparation of the thioester of general formula (IV) is an inert polar or nonpolar solvent. 제 3 항에 있어서, 불활성의 극성 또는 비극성 용매로서 디옥산, 테트라하이드로푸란, 아세톤, 아세토니트릴, 메틸렌클로라이드, 메틸에틸케톤, 벤젠을 단독 또한 혼합 용매로 사용하는 방법.4. The process according to claim 3, wherein dioxane, tetrahydrofuran, acetone, acetonitrile, methylene chloride, methylethylketone, benzene alone and as mixed solvents are used as inert polar or nonpolar solvents. 제 1 항에 있어서, 일반식(Ⅳ)의 티오에스테르의 제조시 반응온도는 -10℃ 내지 환류온도에서 실시하는 방법.The process according to claim 1, wherein the reaction temperature in the preparation of the thioester of general formula (IV) is carried out at -10 ° C to reflux temperature.
KR1019870005495A 1987-05-30 1987-05-30 Process for preparing acyl ureido penicillin derivatives KR900002874B1 (en)

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