KR100288404B1 - 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same - Google Patents
2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same Download PDFInfo
- Publication number
- KR100288404B1 KR100288404B1 KR1019990001951A KR19990001951A KR100288404B1 KR 100288404 B1 KR100288404 B1 KR 100288404B1 KR 1019990001951 A KR1019990001951 A KR 1019990001951A KR 19990001951 A KR19990001951 A KR 19990001951A KR 100288404 B1 KR100288404 B1 KR 100288404B1
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- chloro
- compound
- benzothiazolyl
- cisapride
- Prior art date
Links
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 title claims abstract description 28
- 229960005132 cisapride Drugs 0.000 title claims abstract description 28
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- PDNWLFDGWYEWPF-UHFFFAOYSA-N O-(1,3-benzothiazol-2-yl) 4-amino-5-chloro-2-methoxybenzenecarbothioate Chemical compound NC1=CC(=C(C(=S)OC=2SC3=C(N2)C=CC=C3)C=C1Cl)OC PDNWLFDGWYEWPF-UHFFFAOYSA-N 0.000 title claims description 16
- -1 2-benzothiazolyl Chemical group 0.000 claims abstract description 10
- RVEATKYEARPWRE-UHFFFAOYSA-N 4-amino-5-chloro-2-methoxybenzoic acid Chemical compound COC1=CC(N)=C(Cl)C=C1C(O)=O RVEATKYEARPWRE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000003849 aromatic solvent Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 150000008065 acid anhydrides Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- DFFWYMMOMUTKOI-UHFFFAOYSA-N 1-(3-chloropropoxy)-4-fluorobenzene Chemical compound FC1=CC=C(OCCCCl)C=C1 DFFWYMMOMUTKOI-UHFFFAOYSA-N 0.000 description 1
- MBGUUFFAYHOGDR-UHFFFAOYSA-N COC1=C(C=C(C=C1N)Cl)C(=O)S Chemical compound COC1=C(C=C(C=C1N)Cl)C(=O)S MBGUUFFAYHOGDR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000000217 alkyl group Chemical class 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/70—Sulfur atoms
Abstract
본 발명은 화합물(II)(4-아미노-5-클로로-2-메톡시벤조산)로부터 신규한 중간체 화합물(III)(2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트)을 합성하고, 이를 화합물(IV)(시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민)와 반응시킴을 특징으로 하는 시사프라이드(I)의 신규한 제조방법을 제공한다.The present invention relates to novel intermediate compound (III) (2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzo) from compound (II) (4-amino-5-chloro-2-methoxybenzoic acid). Ate) and reacted with compound (IV) (cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidineamine) of cisapride (I) It provides a novel manufacturing method.
Description
본 발명은 하기 구조식(I)로 표시되는 시사프라이드의 신규한 제조 방법에 관한 것이다.The present invention relates to a novel process for preparing cisapride represented by the following structural formula (I).
좀 더 구체적으로, 본 발명은 하기 반응식에서 화합물(II)(4-아미노-5-클로로-2-메톡시벤조산)로부터 신규한 중간체인 화합물(III)(2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트)을 합성하고, 이를 화합물(IV)(시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민)와 반응시킴을 특징으로 하는 시사프라이드의 신규한 제조방법에 관한 것이다.More specifically, the present invention relates to a compound (III) (2-benzothiazolyl 4-amino-5, which is a novel intermediate from compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) in the following scheme. -Chloro-2-methoxythiobenzoate) and reacted with compound (IV) (cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidinamine) The present invention relates to a novel process for producing cisapride.
시사프라이드(cisapride)는 위장관 계통의 운동성을 조절함으로써, 그 기능을 정상화시키기 위하여 널리 사용되는 약물이다. 이 화합물 및 이의 제조방법은 유럽특허 제 76530호, 대한민국 특허공고 제 86-1584호 및 제 86-1603호에 공지되어 있다.Cisapride is a drug that is widely used to normalize its function by regulating the motility of the gastrointestinal tract. This compound and its preparation are known from European Patent No. 76530, Korean Patent Publication Nos. 86-1584 and 86-1603.
대한민국 특허공고 제 86-1584호에는 하기 반응도식에서 보듯이, 화합물(II)를 화합물(IV)와 반응시켜서 아미드 결합을 형성시킴으로써 시사프라이드를 합성하는 방법이 개시되어 있다.Korean Patent Publication No. 86-1584 discloses a method for synthesizing cisapride by reacting compound (II) with compound (IV) to form an amide bond, as shown in the following scheme.
이 때 화합물(II)와 화합물(IV)는 상호 직접 반응하기에는 그들 사이의 활성이 크지 않으므로, 화합물(II)를 활성화시켜서 화합물(II-1)로 전환한 다음 화합물(IV)와 반응시키게 되는데, 화합물(II-1)은 화합물(II)를 산할로겐화물 또는 혼성 산무수물로 전환함으로써 얻어진다.At this time, since compound (II) and compound (IV) do not have a large activity between them to directly react with each other, the compound (II) is activated to be converted to compound (II-1) and then reacted with compound (IV). Compound (II-1) is obtained by converting Compound (II) into an acid halide or a mixed acid anhydride.
이 방법에 의하여 활성화된 산할로겐화물을 제조하여 시사프라이드를 합성하고자 할 때에는, 가령, 화합물(II)를 염화티오닐 또는 옥살산염화물 등과 반응시켜서, 우선 4-아미노-5-클로로-2-메톡시벤조일 클로라이드 화합물(II-1a)를 제조하여야 한다. 이 때, 반응 용매로는 반응 조건에 불활성인 것이라면 어떠한 용매나 사용 가능하며, 또한 별도의 용매를 사용하지 않고 과량의 염화티오닐 또는 옥살산염화물 등을 그 자체로서 용매로 사용하여도 된다. 그러나, 이 방법으로 시사프라이드를 합성하고자 할 때에는, 중간체로 얻어지는 화합물(II-1a)의 반응성이 너무 강하기 때문에 화합물(II-1a)가 그 자체에 이미 존재하는 아민 그룹과 부반응물을 생성하는 경우가 많아, 반응에 불순물을 제공하는 요인이 될 수 있으며, 따라서 반응의 수율을 낮출 뿐만 아니라, 원하는 생성물의 정제에도 적지 않은 문제를 일으키게 된다. 이러한 문제 외에도 상기의 반응에서는 사용되는 시약과 반응 후의 부산물이 모두 독성과 부식성이 매우 강한 물질들로서, 이들의 사용과 사후 처리에 신중을 기해야 하는 치명적인 단점을 가지고 있다.When preparing an acid halide activated by this method and synthesizing cisapride, for example, compound (II) is reacted with thionyl chloride or oxalate and the like first to give 4-amino-5-chloro-2-methoxy. A benzoyl chloride compound (II-1a) should be prepared. At this time, any reaction solvent may be used as long as it is inert to the reaction conditions, and an excess of thionyl chloride or oxalate may be used as a solvent by itself without using a separate solvent. However, when it is desired to synthesize cisapride by this method, since the reactivity of compound (II-1a) obtained as an intermediate is too strong, compound (II-1a) produces side reactions with amine groups already present in itself. In many cases, this may be a factor for providing impurities to the reaction, and thus not only lowers the yield of the reaction, but also causes a lot of problems in purifying the desired product. In addition to these problems, both the reagents used and the by-products after the reaction are highly toxic and corrosive, and have a fatal disadvantage in that their use and post-treatment must be carefully considered.
대한민국 특허공고 제 86-1584호에 기술된 화합물(II)를 활성화시키는 또 하나의 방법은 화합물(II)를 활성이 강한 혼성 산무수물의 형태로 전환시켜서 반응에 사용하는 것이다. 혼성 산무수물을 만들기 위하여 흔히 치환된 설포닐 할라이드, 알킬 할로포르메이트 등의 시약을 사용한다. 이렇게하여 얻어지는 혼성 산무수물은 아민(IV)와 반응시켜 원하는 아미드 화합물을 얻을 수 있다. 그러나, 혼성 산무수물은 반응성이 매우 강하여 원하지 않는 부반응물을 생성할 뿐만 아니라, 그 자체로서 불안정하여 수분에 의해서 쉽게 분해되는 문제가 있다.Another method of activating the compound (II) described in Korean Patent Publication No. 86-1584 is to convert the compound (II) into a highly active hybrid acid anhydride and use it in the reaction. Reagents such as substituted sulfonyl halides, alkyl haloformates are often used to make hybrid acid anhydrides. The hybrid acid anhydride thus obtained can be reacted with amine (IV) to obtain the desired amide compound. However, hybrid acid anhydrides are very reactive and not only produce unwanted side reactions, but are also unstable by themselves and easily decomposed by moisture.
이와 같이 화합물(II)를 산할로겐화물이나 혼성 산무수물로 활성화시켜서 시사프라이드를 합성할 때에는, 이들 활성체를 시사프라이드 합성 직전에 제조하여야 할 뿐만 아니라, 사용되는 시약과 반응 부산물의 부식성, 맹독성, 그에 따를 환경 오염 처리 비용, 그리고 화학적 불안정성에 수반되는 제조 및 보관상의 문제점 등이 상존한다.Thus, when synthesizing cisapride by activating compound (II) with an acid halide or a mixed acid anhydride, not only these actives should be prepared immediately before the synthesis of cisapride, but also corrosiveness, toxicity, The costs associated with environmental pollution treatment and manufacturing and storage problems associated with chemical instability remain.
한편, 대한민국 특허공고 제 86-1603호에는 하기 반응도식에서 보듯이, 먼저 아미드 화합물(V)를 합성한 다음에 화합물(VI)로 나타낸 3-(4-플루오로페녹시)프로필클로라이드를 결합시켜서 시사프라이드를 합성하는 다른 방법이 개시되어 있다.Korean Patent Publication No. 86-1603, on the other hand, suggests by first synthesizing an amide compound (V) and then combining 3- (4-fluorophenoxy) propyl chloride represented by compound (VI), as shown in the following scheme. Another method of synthesizing the pride is disclosed.
이 방법에 의해서 시사프라이드를 제조하고자 할 때에도, 역시 화합물(II)의 활성화가 전제가 돼야 화합물(V)를 합성할 수 있게 된다. 따라서, 이 방법의 모든 문제점은 상기에서 이미 제시된 것들과 동일하며, 오히려 반응의 단계가 길어진 단점 외에 특이한 장점을 기대할 수가 없게 된다.When preparing cisapride by this method, compound (V) can be synthesized only when the activation of compound (II) is premised. Therefore, all of the problems of this method are the same as those already presented above, but it is not possible to expect any unique advantages other than the disadvantages of longer reaction stages.
이에, 본 발명자들은 시사프라이드 합성에서의 이러한 제반 문제점들을 개선하고, 생성되는 부산물 제거가 용이하며, 부반응 생성물이 거의 없어 반응의 수율이 높은 방법을 개발하고자 예의 연구노력한 결과, 시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민(IV)와 반응하여 시사프라이드를 합성하는 데에 매우 유용하게 사용할 수 있는 중간체 화합물(III)인 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트를 새로이 합성하여 사용한 결과, 이 화합물(III)이 화합물(IV)와 반응하기에 활성이 적절하여 자체내의 아미노 그룹에 영향을 받지 않기 때문에, 부반응 생성물이 거의 없이 시사프라이드를 효율적으로 제조할 수 있음을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors have diligently researched to develop a method for improving these various problems in the synthesis of cisapride, easily removing the by-products generated, and having a high yield of reaction because there are few side reaction products. 2-benzothiazolyl 4-, an intermediate compound (III) that can be very useful for the synthesis of cisapride by reaction with-(4-fluorophenoxy) propyl] -4-piperidinamine (IV) As a result of the new synthesis and use of amino-5-chloro-2-methoxythiobenzoate, the side reaction was caused by the fact that the compound (III) is suitable for reacting with the compound (IV) and is not affected by the amino group in itself. It was confirmed that the cisapride can be efficiently produced with little product, and the present invention was completed.
결국, 본 발명의 주된 목적은 신규한 시사프라이드의 제조방법을 제공하는 것이다.After all, the main object of the present invention is to provide a novel method for preparing cisapride.
본 발명의 다른 목적은 전기 시사프라이드의 제조방법에 사용되는 중간체인 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트 및 그의 제조방법을 제공하는 것이다.Another object of the present invention is to provide 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate which is an intermediate used in the preparation method of electric cisapride and a preparation method thereof.
본 발명자들은 화합물(II)(4-아미노-5-클로로-2-메톡시벤조산)로부터 유용한 중간체인 화합물(III)(2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트)을 합성하고, 이를 화합물(IV)(시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민)와 반응시켜 시사프라이드를 제조하였다.The present inventors have found that compound (III) (2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzo, which is a useful intermediate from compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) Ate) was synthesized and reacted with compound (IV) (cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidinamine) to prepare cisapride.
이하, 본 발명의 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트 및 그를 이용한 시사프라이드의 제조방법을 공정별로 나누어 보다 구체적으로 설명하고자 한다.Hereinafter, the preparation method of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate and cisapride using the same according to the present invention will be described in more detail.
제 1공정: 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트 제조First Step: Preparation of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate
화합물(II)(4-아미노-5-클로로-2-메톡시벤조산)를 디티오비스벤조티아졸과 반응시켜서, 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트(화합물(III))를 합성한다. 화합물(III)을 합성하기 위해서는 반응에 불활성인 용매 중에서 화합물(II)와 디티오비스벤조티아졸을 활성 매개제인 트리페닐포스핀, 트리에틸아민 등과 같은 적당한 염기를 사용하여 반응시켜야 한다. 반응에 불활성인 용매로는 에틸 아세테이트 등의 에스테르, 테트라히드로퓨란 등의 에테르, 메틸렌클로라이드나 클로로포름 등의 할로겐화알칸, 또는 벤젠, 톨루엔 등의 방향족 용매 등에서 적절히 선택할 수 있으며, 이들 용매를 단독, 또는 두가지 이상의 혼합 용매로서 사용할 수도 있다. 반응은 통상 -10℃ 내지는 50℃ 정도의 범위에서 수행할 수 있으며, 편리하게는 실온에서 수행할 수도 있다. 용매를 적절히 선택하여 반응을 수행하면 반응에 의해서 생성된 화합물(III)을 다른 부생성물의 오염없이 간편하게 여과에 의해서 분리해 낼 수 있다. 합성된 화합물(III)은 안정한 화합물로서 물에 의해 용이하게 분해되지 않으며, 상온에서 공기 중에 보관하여도 쉽게 그 물성이 변하지 않을 정도의 안정성을 가지고 있다. 이 새로운 화합물은 통상의 산할로겐화물이나 혼성 산무수물처럼 활성이 강하지 않아서 자체내의 아미노 그룹에 영향을 받지 않으며, 필요시에는, 가령 다른 아민으로 치환 반응을 일으켜서 아미드 화합물을 만들고자 하는 경우에, 용이하게 원하는 반응을 일으킬 수 있다.Compound (II) (4-amino-5-chloro-2-methoxybenzoic acid) was reacted with dithiobisbenzothiazole to yield 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate ( Compound (III)) is synthesized. To synthesize compound (III), compound (II) and dithiobisbenzothiazole must be reacted with a suitable base such as triphenylphosphine, triethylamine, and the like as an active medium in a solvent inert to the reaction. The solvent inert to the reaction can be appropriately selected from esters such as ethyl acetate, ethers such as tetrahydrofuran, halogenated alkanes such as methylene chloride and chloroform, and aromatic solvents such as benzene and toluene. It can also be used as the above mixed solvent. The reaction can usually be carried out in the range of about −10 ° C. to 50 ° C., and may also be conveniently performed at room temperature. When the reaction is carried out by appropriately selecting a solvent, the compound (III) produced by the reaction can be easily separated by filtration without contamination of other by-products. The synthesized compound (III) is a stable compound, which is not easily decomposed by water, and has a stability such that its physical properties are not easily changed even when stored in air at room temperature. This new compound is not as active as conventional acid halides or hybrid acid anhydrides, and thus is not affected by amino groups in itself, and if necessary, for example, when a substitution reaction is made with another amine to form an amide compound, Can cause the desired reaction.
제 2공정: 시사프라이드의 제조Second Step: Preparation of Cisapride
전기의 합성된 화합물(III)(2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트)을 적당한 불활성인 용매 중에서 화합물(IV)(시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민)와 직접 반응시키면 원하는 아미드 결합을 형성하여 시사프라이드를 생성하게 된다. 이 때, 반응 용매로는 초산 에틸, 초산 메틸 등의 에스테르, 염화메틸렌, 클로로포름 등의 염화탄화수소, 디메틸아세트아미드, 디메틸포름아미드 등의 아미드, 테트라히드로푸란, 디이소프로필에테르 등의 에테르 등에서 적절히 선택할 수 있으며, 이들 용매를 단독, 또는 두가지 이상의 혼합 용매로서 사용할 수도 있다. 반응은 상온에서 용이하게 진행하여 원하는 화합물을 생성하며, 필요에 의해서 가열하거나 냉각할 수도 있다. 바람직한 반응의 온도는 0℃에서 50℃의 사이에서, 보다 바람직하게는 15℃에서 30℃의 사이에서 조정하여 편리하게 반응시킬 수 있다.The previously synthesized compound (III) (2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate) is added to compound (IV) (cis-1- [3- (4) in a suitable inert solvent. Direct reaction with fluorophenoxy) propyl] -4-piperidinamine) results in the formation of the desired amide bond to produce cisapride. In this case, the reaction solvent may be appropriately selected from esters such as ethyl acetate and methyl acetate, hydrocarbon chlorides such as methylene chloride and chloroform, amides such as dimethylacetamide and dimethylformamide, ethers such as tetrahydrofuran and diisopropyl ether, and the like. These solvents may be used alone or as mixed solvents of two or more thereof. The reaction proceeds easily at room temperature to produce the desired compound, which may be heated or cooled as necessary. Preferable reaction temperature can be made to react conveniently by adjusting between 0 degreeC and 50 degreeC, More preferably, between 15 degreeC and 30 degreeC.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 2-벤조티아졸릴 4-아미노-5-클로로-2-메톡시티오벤조에이트 제조Example 1: Preparation of 2-benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate
메틸렌클로라이드 50ml에 트리페닐포스핀 0.42g과 디티오비스벤조티아졸 1.72g을 넣고 실온에서 한 시간동안 교반시켰다. 온도를 10℃로 낮춘 다음, 4-아미노-2-메톡시-5-클로로벤조산 0.992g을 넣고 30분간 교반하였다. 온도를 5℃로 낮춘 다음, 트리에틸아민 0.69ml을 20분간에 걸쳐서 서서히 적가하였다. 이어, 한 시간에 걸쳐서 실온까지 가온한 후, 실온에서 한 시간 동안 교반하였다. 반응액 중에 생성된 물질을 감압 여과하며, 여과된 고체를 5ml의 메틸렌클로라이드, 5ml의 이소프로판올, 그리고 5ml의 에테르의 순으로 세척하였다. 얻어진 고체상의 목적화합물을 40℃의 훈풍으로 하루동안 건조하여, 연한 황색 내지 무색의 고체상인 목적 화합물 1.58g(92%)을 수득하였다.0.42 g of triphenylphosphine and 1.72 g of dithiobisbenzothiazole were added to 50 ml of methylene chloride, and the mixture was stirred at room temperature for one hour. After the temperature was lowered to 10 ° C., 0.992 g of 4-amino-2-methoxy-5-chlorobenzoic acid was added thereto, followed by stirring for 30 minutes. After the temperature was lowered to 5 ° C., 0.69 ml of triethylamine was slowly added dropwise over 20 minutes. Then warmed to room temperature over one hour and then stirred at room temperature for one hour. The material produced in the reaction solution was filtered under reduced pressure, and the filtered solid was washed in order of 5 ml of methylene chloride, 5 ml of isopropanol, and 5 ml of ether. The resultant solid compound was dried in a hot air at 40 ° C. for one day to obtain 1.58 g (92%) of the title compound as a pale yellow to colorless solid.
1H-NMR(DMSO-d6,ppm): 8.12(d, 1H), 7.97(d, 1H), 7.70(s, 1H),7.49(m,2H), 1 H-NMR (DMSO-d 6, ppm): 8.12 (d, 1H), 7.97 (d, 1H), 7.70 (s, 1H), 7.49 (m, 2H),
6.75(b, 2H, NH2), 6.51(s, 1H), 3.93(s, 3H)6.75 (b, 2H, NH 2 ), 6.51 (s, 1H), 3.93 (s, 3H)
융점(℃): 225(분해)Melting Point (℃): 225 (Decomposition)
실시예 2: 시스-4-아미노-5-클로로-N-[1-[3-(4-플루오로페녹시)프로필]-3Example 2: cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3
-메톡시-4-피페리딘일]-2-메톡시벤즈아미드(시사프라이드)의 제조-Methoxy-4-piperidinyl] -2-methoxybenzamide (cisapride)
메틸렌클로라이드 80ml에 시스-1-[3-(4-플루오로페녹시)프로필]-4-피페리딘아민 10g과 2-벤조티아졸릴 4-아미노-2-메톡시-5-클로로티오벤조에이트 12.4g을 넣고 실온에서 한 시간 동안 교반하였다. 반응이 끝난 다음, 반응액에 에탄올로 용해시킨 20% 염산 용액 7.76g을 20분간 적가하고 한 시간동안 교반하였다. 생성된 시사프라이드 염산염의 고체를 감압 여과하고, 10ml의 메틸렌클로라이드로 세척하였다. 얻어진 고체를 수산화나트륨 9.6g을 용해시킨 물 100ml에 넣고, 여기에 메틸렌클로라이드 100ml을 가하여 세 시간 동안 교반시켰다. 유기상을 분리하여 100ml의 물로 세척하고, 10g의 무수 황산마그네슘으로 건조하여 감압 여과한 후 용매를 증발시켰다. 얻어진 증발 잔류물을 메틸이소부틸케톤 90ml에 넣고 환류 교반하여 용해시킨 후에, 메탄올 20ml, 물 3.0ml을 첨가하여 두 시간에 걸쳐 온도를 10℃까지 낮추고 동일한 온도에서 네 시간동안 추가로 교반하여 결정화시켰다. 생성물을 감압 여과하고 40℃의 훈풍으로 하루동안 건조하여 백색 미분 결정상의 일수화물인 목적 화합물 15.9g(93%)을 수득하였다.10 g of cis-1- [3- (4-fluorophenoxy) propyl] -4-piperidineamine and 2-benzothiazolyl 4-amino-2-methoxy-5-chlorothiobenzoate in 80 ml of methylene chloride 12.4g was added and stirred at room temperature for 1 hour. After the reaction, 7.76 g of 20% hydrochloric acid solution dissolved in ethanol was added dropwise to the reaction solution for 20 minutes and stirred for one hour. The solid of the resulting cisapride hydrochloride was filtered under reduced pressure and washed with 10 ml of methylene chloride. The obtained solid was put into 100 ml of water in which 9.6 g of sodium hydroxide was dissolved, and 100 ml of methylene chloride was added thereto, followed by stirring for three hours. The organic phase was separated, washed with 100 ml of water, dried over 10 g of anhydrous magnesium sulfate, filtered under reduced pressure, and the solvent was evaporated. The resulting evaporated residue was dissolved in reflux stirring in 90 ml of methyl isobutyl ketone, and then, 20 ml of methanol and 3.0 ml of water were added to lower the temperature to 10 DEG C over two hours, followed by further stirring at the same temperature for four hours to crystallize. . The product was filtered under reduced pressure and dried for one day with hot air at 40 ° C. to obtain 15.9 g (93%) of the title compound as a monohydrate of white fine crystals.
수분함량: 3.8%Moisture content: 3.8%
1H-NMR(CDCl3, ppm): 8.21(d, 1H), 8.10(s, 1H), 6.95(m, 2H), 6.83(m, 2H), 1 H-NMR (CDCl 3 , ppm): 8.21 (d, 1H), 8.10 (s, 1H), 6.95 (m, 2H), 6.83 (m, 2H),
6.29(s, 1H), 4.38(s, 2H), 4.21(m, 1H), 3.97(m, 2H),6.29 (s, 1H), 4.38 (s, 2H), 4.21 (m, 1H), 3.97 (m, 2H),
3.89(s, 3H), 3.45(m, 1H), 3.43(s, 1H), 3.05(m, 1H),3.89 (s, 3H), 3.45 (m, 1H), 3.43 (s, 1H), 3.05 (m, 1H),
2.80(m, 1H), 2.54(m, 2H), 2.19(m, 2H), 1.98(m, 2H),2.80 (m, 1H), 2.54 (m, 2H), 2.19 (m, 2H), 1.98 (m, 2H),
1.86(m, 1H)1.86 (m, 1 H)
융점(℃): 133도Melting Point (℃): 133 Degrees
이상에서 상세히 설명하고 입증하였듯이, 본 발명은 신규한 2-벤조티아졸릴 4-아미노-2-메톡시-5-클로로티오벤조에이트 및 그를 이용한 시사프라이드의 제조방법을 제공한다. 본 발명의 방법을 사용하면 매우 온화한 반응 조건에서 시사프라이드를 합성할 수 있다. 또한, 본 발명에 의한 반응은 생성되는 부산물도 쉽게 제거가 가능할 뿐만 아니라, 반응이 정량적으로 일어나기 때문에 부반응 생성물이 거의 없고 따라서 반응의 수율도 매우 높다.As described and demonstrated in detail above, the present invention provides a novel 2-benzothiazolyl 4-amino-2-methoxy-5-chlorothiobenzoate and a method for preparing cisapride using the same. Using the method of the present invention it is possible to synthesize cisapride in very mild reaction conditions. In addition, the reaction according to the present invention can not only easily remove the by-products generated, but also there is little side reaction product because the reaction occurs quantitatively, and thus the yield of the reaction is very high.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019990001951A KR100288404B1 (en) | 1999-01-22 | 1999-01-22 | 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019990001951A KR100288404B1 (en) | 1999-01-22 | 1999-01-22 | 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20000051463A KR20000051463A (en) | 2000-08-16 |
| KR100288404B1 true KR100288404B1 (en) | 2001-04-16 |
Family
ID=19572056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019990001951A KR100288404B1 (en) | 1999-01-22 | 1999-01-22 | 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100288404B1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010017625A (en) * | 1999-08-12 | 2001-03-05 | 윤재승 | A Process for Preparing Cisapride |
-
1999
- 1999-01-22 KR KR1019990001951A patent/KR100288404B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20000051463A (en) | 2000-08-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20140128926A (en) | Process for the production of bendamustine alkyl ester, bendamustine, and derivatives thereof | |
| KR100288404B1 (en) | 2-Benzothiazolyl 4-amino-5-chloro-2-methoxythiobenzoate And Process For Preparing Cisapride Employing The Same | |
| EP0727424B1 (en) | Process for the preparation of sulfonylurea derivatives | |
| JP3207018B2 (en) | Method for producing benzylsuccinic acid derivative and intermediate for producing the same | |
| JP3536480B2 (en) | 4,5-Dihalogeno-6-dihalogenomethylpyrimidine and process for producing the same | |
| EP0202625A2 (en) | Process for the preparation of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-beta-(N-benzyl-N-methylamino)-ethyl ester 5-methyl ester and its hydrochloride salt | |
| WO1998032736A1 (en) | Process for producing benzylsuccinic acid derivatives | |
| JPH061776A (en) | Production of substituted pyrazinecarbonitrile | |
| KR100407720B1 (en) | Preparing Method for N-[3-{3-(1-Piperidinylmethyl)phenoxy}propyl]acetoxyacetamide | |
| KR100374405B1 (en) | A new process for amlodipine besylate | |
| CA3214107A1 (en) | New process for the synthesis of 5-{5-chloro-2-[(3s)-3- [(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1h)- carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-carboxylic acid derivatives and its application for the production of pharmaceutical compounds | |
| JPS6152826B2 (en) | ||
| KR100577874B1 (en) | Preparing method for methyl 4-hydroxyiminovenzoate utilizing evaporated residue from DMT preparation | |
| KR100230900B1 (en) | Pyrrolidine derivatives and process for preparing the same | |
| JPS5838261A (en) | Novel 1,3-disubstituted imidazole derivative and its preparation | |
| JPH04360866A (en) | Production of 3-aminopyrrolidines | |
| JPS61218555A (en) | Manufacture of acids substituted with trifluorodichloroethylgroup and zinc compounds | |
| KR970004047B1 (en) | Novel process for the preparation of cephem compound | |
| KR100302349B1 (en) | A process for preparing cisapride | |
| KR100360181B1 (en) | Method of preparing cisapride and an intermediate used therein | |
| KR100483317B1 (en) | METHOD FOR THE PREPARATION OF α-PHENYL-α-PROPOXYBENZENEACETIC ACID 1-METHYL-4-PIPERIDINYL ESTER HYDROCHLORIDE | |
| JP2500316B2 (en) | 1,4,5,8-Tetrakis (halogenomethyl) naphthalene derivative and method for producing the same | |
| JPS61112056A (en) | Imidazole derivative and production thereof | |
| KR100297802B1 (en) | Method for preparing 2- (3-trifluoromethyl) anilinonicotinic acid 2- (N-morpholine) ethyl. | |
| KR910006981B1 (en) | Process for the preparation of carboxylate chlorate roxatidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20040115 Year of fee payment: 5 |
|
| LAPS | Lapse due to unpaid annual fee |