KR100286639B1 - Process for preparing iopromide - Google Patents
Process for preparing iopromide Download PDFInfo
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- KR100286639B1 KR100286639B1 KR1019990011106A KR19990011106A KR100286639B1 KR 100286639 B1 KR100286639 B1 KR 100286639B1 KR 1019990011106 A KR1019990011106 A KR 1019990011106A KR 19990011106 A KR19990011106 A KR 19990011106A KR 100286639 B1 KR100286639 B1 KR 100286639B1
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- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229960002603 iopromide Drugs 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
- 239000011630 iodine Substances 0.000 claims abstract description 7
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims abstract description 6
- KBZFDRWPMZESDI-UHFFFAOYSA-N 5-aminobenzene-1,3-dicarboxylic acid Chemical compound NC1=CC(C(O)=O)=CC(C(O)=O)=C1 KBZFDRWPMZESDI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 230000003472 neutralizing effect Effects 0.000 abstract description 2
- HYGGDKPPAGGKNN-UHFFFAOYSA-N 5-acetamido-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound CC(=O)NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I HYGGDKPPAGGKNN-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- ROJNTQLNMWYIQO-UHFFFAOYSA-N 2,4,6-triiodo-5-[(2-methoxyacetyl)amino]benzene-1,3-dicarbonyl chloride Chemical compound COCC(=O)NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I ROJNTQLNMWYIQO-UHFFFAOYSA-N 0.000 description 4
- JEZJSNULLBSYHV-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I JEZJSNULLBSYHV-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- -1 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid halides Chemical class 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- JNFLSZPZYOMFNP-UHFFFAOYSA-M [K+].[I-].Cl.Cl Chemical compound [K+].[I-].Cl.Cl JNFLSZPZYOMFNP-UHFFFAOYSA-M 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- WOMTYMDHLQTCHY-UHFFFAOYSA-N 3-methylamino-1,2-propanediol Chemical compound CNCC(O)CO WOMTYMDHLQTCHY-UHFFFAOYSA-N 0.000 description 2
- FBJVWRITWDYUAC-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I FBJVWRITWDYUAC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UQPKNHUDABGWHM-UHFFFAOYSA-N 2,4,6-triiodo-5-[(2-methoxyacetyl)amino]benzene-1,3-dicarboxylic acid Chemical compound COCC(=O)NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I UQPKNHUDABGWHM-UHFFFAOYSA-N 0.000 description 1
- KQEBGRLRYABJRL-UHFFFAOYSA-N 3-aminopropane-1,2-diol;hydrochloride Chemical compound [Cl-].[NH3+]CC(O)CO KQEBGRLRYABJRL-UHFFFAOYSA-N 0.000 description 1
- BCBIXNWEWWQJST-UHFFFAOYSA-N ClICl Chemical compound ClICl BCBIXNWEWWQJST-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019988 mead Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- C07C2527/06—Halogens; Compounds thereof
- C07C2527/08—Halides
- C07C2527/10—Chlorides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2527/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- C07C2527/14—Phosphorus; Compounds thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명은 명세서중의 반응식 1에 따라 이오프로마이드를 제조함에 있어서, 화학식 5의 5-아미노이소프탈산과 KICl2를 반응시키는 공정 1을 촉매량의 요오드 존재하에 수행하고, 화학식 2의 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산클로라이드를 2,3-디하이드록시프로필아민과 반응시키는 공정 4에서 HCl의 중화제로 트리에틸아민을 사용함을 특징으로 하는 이오프로마이드의 신규한 제조방법에 관한 것이다.In the present invention, in preparing iopromide according to Scheme 1, step 1 of reacting 5-aminoisophthalic acid of formula 5 with KICl 2 in the presence of a catalytic amount of iodine is carried out, and 5-methoxy of formula 2 Novel of iopromide characterized by the use of triethylamine as a neutralizing agent of HCl in step 4 of reacting acetylamino-2,4,6-triiodoisophthalic acid chloride with 2,3-dihydroxypropylamine It relates to a manufacturing method.
Description
본 발명은 5-아미노이소프탈산으로부터 이오프로마이드를 제조하는 개량된 방법에 관한 것이다.The present invention relates to an improved process for preparing iopromide from 5-aminoisophthalic acid.
X-ray 조영제로서 널리 사용되고 있는 이오프로마이드의 공지된 제조방법으로는 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산할라이드를 3-아미노-1,2-프로판디올과 3-메틸아미노-1,2-프로판디올을 염기성 물질 존재하에 디메틸포름아미드 용매중에서 아미드화반응시켜 제조하는 독일 쉐링(Schering)사의 방법(USP 4,364,921)이 알려져 있고, 기타 이오프로마이드의 정제방법이나 제조중간체인 5-아미노-2,4,6-트리요오도이소프탈산의 합성법에 대한 연구가 활발히 진행되어 왔다(참조: J. Org. Chem., 1994, 59, 1344; J. Am. Chem. Soc., 1952, 74, 4365).Known methods for preparing iopromide that are widely used as X-ray contrast agents include 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid halides with 3-amino-1,2-propanediol and 3 The method of Schering, Germany (USP 4,364,921), which is prepared by amidation of -methylamino-1,2-propanediol in a dimethylformamide solvent in the presence of a basic substance, is known. Research has been actively conducted on the synthesis of the intermediate 5-amino-2,4,6-triiodoisophthalic acid (J. Org. Chem., 1994, 59, 1344; J. Am. Chem. Soc ., 1952, 74, 4365).
그러나, 이러한 공지방법들은 제조과정에서 여러번의 여과와 건조공정이 요구될 뿐아니라 반응부산물인 요오드로 인한 공해문제가 심각하게 대두되어 왔으며, 그런 복잡한 과정으로 인한 수율의 저하를 초래하였다.However, these known methods not only require several filtration and drying processes in the manufacturing process, but also have caused serious pollution problems due to reaction by-products of iodine, resulting in lowered yields due to such complex processes.
이에, 본 발명자들은 위와 같은 공지방법들을 단계별로 나누어 각 공정의 반응조건을 여러가지로 변화시키며 비교연구하였으며, 그 결과 혁신적인 공정의 단순화와 수율의 향상을 확인하고 본 발명을 완성하게 되었다.Thus, the present inventors divided the above known methods into stages and compared and studied the reaction conditions of each process in various ways. As a result, the present invention confirmed the simplification of the innovative process and the improvement of the yield and completed the present invention.
하기 화학식 1의 이오프로마이드의 공지된 제조방법으로서 대표적인 방법은 하기 반응식 1과 같이 나타낼 수 있다.As a known method for preparing iopromide of Formula 1, a representative method may be represented by the following Scheme 1.
그런데, 상기 반응식 1에 따른 제조방법에서 하기 화학식 5의 화합물에 KICl2를 반응시켜 하기 화학식 4의 화합물을 제조하는 제 1 공정의 요오드화 반응은 하기 반응식 2에 따라 제조되는 KICl2를 사용하게 되는데, 이중 이염화요오드 음이온이 하기 반응식 3과 같은 평형상태를 이루게되어 반응계에 요오드가 생성되어 유리됨으로써 이염화요오도의 유효농도가 감소하게 된다.However, in the preparation method according to Scheme 1, the iodide reaction of the first step of preparing the compound of Formula 4 by reacting KICl 2 with the compound of Formula 5 is performed using KICl 2 prepared according to Scheme 2 below. The iodine dichloride anion is in an equilibrium state as shown in Scheme 3 below, and iodine is generated and released in the reaction system, thereby reducing the effective concentration of iodine dichloride.
이러한 현상을 방지하기 위하여 반응액중에 과량의 HCl을 가하면 평형이 왼쪽으로 치우쳐 이염화요오드 음이온의 농도는 증가시킬 수 있는 반면, 과도한 산의 존재로 인하여 방향족 친전자 치환반응의 반응기질인 5-아미노이소프탈산이 양성화되어 반응성이 떨어지게 된다. 따라서, 본 발명자들은 반응액중의 이염화요오드이온 농도를 적절히 유지시킬 수 있는 방법을 개발하고자 노력하였으며, 그 결과 반응계내에 촉매량의 I2를 첨가하면 이러한 목적을 달성할 수 있고, 결국 화학식 5의 화합물로부터 용이하게 화학식 4의 화합물로 요오드화 반응을 수행할 수 있음을 발견하였다.To prevent this phenomenon, the addition of excess HCl to the reaction liquid can cause the equilibrium to be shifted to the left, increasing the concentration of iodine dichloride anion, whereas 5-amino, which is a reactive group of aromatic electrophilic substitution reaction due to the presence of excessive acid. Isophthalic acid is protonated, resulting in poor reactivity. Therefore, the present inventors have tried to develop a method capable of properly maintaining the concentration of iodide ion in the reaction solution, and as a result, the addition of a catalytic amount of I2 in the reaction system can achieve this purpose, and eventually the compound of formula 5 It was found from the above that the iodide reaction can be easily carried out with the compound of the formula (4).
이와 같이 촉매량의 요오드를 첨가하는 경우 화학식 4 화합물의 수율을 종래 85%에서 96% 이상으로 상승시킬 수 있으며, 이러한 수율의 향상은 쉽게 예상하기 어려웠던 것이다. 따라서, 본 발명의 특징은 화학식 5의 출발화합물에 KICl2와 함께 촉매량의 I2를 첨가함으로써 생성된 화학식 4 화합물의 생산수율을 향상시킨 점에 있다.As such, when the catalytic amount of iodine is added, the yield of the compound of Formula 4 may be increased from 85% to 96% or more, and the improvement in yield is difficult to predict easily. Therefore, a feature of the present invention is that the production yield of the compound of formula 4 produced by adding a catalytic amount of I 2 together with KICl 2 to the starting compound of formula 5 is improved.
본 발명의 또다른 특징은 상기 반응식 1에 따른 공지의 제조방법에서 제조공정 4의 개량에 있다. 즉, 하기 화학식 2의 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산클로라이드를 화학식 1의 이오프로마이드로 전환시키는 공정 4의 과정은 먼저 2,3-디하이드록시프로필아민과 반응시키는 단계 1 및 2,3-디하이드록시-N-메틸프로필아민과 반응시키는 단계 2로 나뉘어질 수 있는데(하기 반응식 4 참조), 이때 이오프로마이드의 전구체 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산 (2,3-디하이드록시프로필)아미드 클로라이드(이하, 'p-IOP'라 한다)를 합성하는 단계 1에서 기존에 HCl의 중화제로서 사용하여온 트리부틸아민 대신에 트리에틸아민을 사용함으로써 전구체 p-IOP를 정제하지 않고 바로 단계 2를 수행할 수 있게 된 것이다. 특히, 전구체 p-IOP는 강한 흡습성을 가진 물질이어서 신속한 정제가 요구되었으므로 현장에 적용하기에 많은 애로점이 있었는데, 본 발명에 따르면 이러한 정제과정을 생략할 수 있으므로 공정의 간편화 및 전체수율의 향상에 많은 진척을 이루었다.Another feature of the present invention lies in the improvement of manufacturing process 4 in a known production method according to Scheme 1 above. That is, the process of step 4 of converting 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid chloride of the following Chemical Formula 2 into iopromide of Chemical Formula 1 is first performed by 2,3-dihydroxypropylamine. Can be divided into step 1 and 2, reacting with 2,3-dihydroxy-N-methylpropylamine (see Scheme 4 below), wherein the precursor 5-methoxyacetylamino-2 of iopromide Tributylamine, which has been used as a neutralizer of HCl in step 1 for synthesizing, 4,6-triiodoisophthalic acid (2,3-dihydroxypropyl) amide chloride (hereinafter referred to as 'p-IOP') By using triethylamine instead, step 2 can be carried out directly without purifying the precursor p-IOP. In particular, since the precursor p-IOP was a material having strong hygroscopicity and required rapid purification, there were many difficulties in applying it to the field. According to the present invention, since this purification process can be omitted, the process can be simplified and the overall yield is improved. Progress has been made.
따라서, 본 발명은 상기 반응식 1에 따라 화학식 1의 이오프로마이드를 제조함에 있어서, 화학식 5의 5-아미노이소프탈산과 KICl2를 반응시키는 공정 1을 촉매량의 요오드 존재하에 수행하고, 화학식 2의 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산클로라이드를 2,3-디하이드록시프로필아민과 반응시키는 공정 4에서 HCl의 중화제로 트리에틸아민을 사용함을 특징으로 하는 방법을 제공함을 목적으로 한다.Therefore, in the preparation of the iopromide of Chemical Formula 1 according to Scheme 1, step 1 of reacting 5-aminoisophthalic acid of Chemical Formula 5 with KICl 2 in the presence of a catalytic amount of iodine, Provided is a process characterized by using triethylamine as a neutralizing agent of HCl in step 4, in which methoxyacetylamino-2,4,6-triiodoisophthalic acid chloride is reacted with 2,3-dihydroxypropylamine. For the purpose.
상기 본 발명에 따른 특징적인 공정 이외에 기타 공정들은 공지의 방법에 따라 수행할 수 있는데, 예를들어 공정 2는 화학식 4의 5-아미노-2,4,6-트리요오도이소프탈산을 티오닐클로라이드와 반응시켜 하기 화학식 3의 산할라이드를 합성하는 과정으로서, 합성상의 난점은 없으나 산업화에 다른 페기물의 처리나 환경유해 기체의 배출을 최소화하는 방법으로 최소량의 티오닐클로라이드를 사용하는 반응조건이 필요하다.In addition to the characteristic process according to the present invention, other processes may be carried out according to a known method, for example, process 2 may include 5-amino-2,4,6-triiodoisophthalic acid of formula 4 as thionyl chloride. It is a process of synthesizing an acid halide of Chemical Formula 3 by reacting with, and there is no difficulty in synthesis, but a reaction condition using a minimum amount of thionyl chloride is required in order to minimize the discharge of other wastes or environmentally harmful gases for industrialization. .
기존에는, 상기 공정 2에서 용매없이 과량의 티오닐클로라이드만을 사용하거나, 반응용매로서 DMF 또는 DMA 등을 사용하면서 과량의 티오닐클로라이드를 사용하여 왔으나, 이는 고가의 티오닐클로라이드를 과량으로 사용하여야 한다는 점 이외에도 회수, 재사용이 어려운 용매를 사용하는 문제점이 있다. 따라서, 본 발명에서는 최소량의 티오닐클로라이드를 사용하면서 저렴하고 재사용이 용이한 에틸아세테이트를 용매로 사용하는 공정을 새로이 확립하였는데, 이 방법에 따라 에틸아세테이트를 용매로 사용하게 되면 생성물의 재결정화에도 이용할 수 있어서 95%의 우수한 회수율로 재결정할 수 있었다.Conventionally, in the process 2, only an excess of thionyl chloride is used without a solvent or an excess of thionyl chloride is used while using DMF or DMA as a reaction solvent, but it is necessary to use an expensive thionyl chloride in an excess amount. In addition to this point, there is a problem of using a solvent that is difficult to recover and reuse. Therefore, the present invention has newly established a process using ethyl acetate as a solvent while using a minimum amount of thionyl chloride as a solvent. According to this method, when ethyl acetate is used as a solvent, it can be used for recrystallization of a product. It could be recrystallized with an excellent recovery rate of 95%.
또한, 메톡시아세트산을 사용하여 아미드화 반응을 수행하는 공정 3에서는 기존의 방법과 달리 오염화인(PCl5)을 촉매로 사용하는 새로운 방법을 이용하였다.In addition, in step 3 of performing amidation reaction using methoxyacetic acid, a new method using phosphorus pentachloride (PCl 5 ) as a catalyst was used.
반응이 완료된 후, 목적하는 이오프로마이드를 순수한 상태로 수득하기 위하여 여러 가지 분리정제방법, 예를들어 재결정 또는 크로마토그래피 방법을 수행할 수 있다.After the reaction is completed, various separation and purification methods such as recrystallization or chromatography may be performed to obtain the desired iopromide in a pure state.
이하, 본 발명을 하기 실시예에 의거하여 보다 구체적으로 설명한다. 그러나, 이들 실시예는 본 발명에 대한 이해를 돕기위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.
실시예 1: 이염화요오드칼륨 용액(2.1M KlCl2용액)의 합성Example 1 Synthesis of Potassium Iodide Dichloride Solution (2.1M KlCl 2 Solution)
요오드산 칼륨 75.0g(0.35mol), 염화칼륨 42.0g(0.56 mol), 촉매량의 요오드 1g 및 물 90㎖의 혼합액에 진한염산 10㎖(0.1mol)를 가하고 잘 교반하여 백색의 분산혼합액을 제조하였다. 이 분산액을 기계식 교반기로 격렬하게 교반하면서 요오드화칼륨 116.6g(0.07mol)을 물 100㎖에 녹인 수용액과 진한염산(conc. HCl, 180㎖, 1.8mol)을 동시에 천천히 가하면 엷은 노란색의 분산액으로 되면서 점차 진한 노란색의 용액으로 되었다. 이때 요오드화칼륨 용액은 검은색의 요오드가 생성되지 않도록하는 정도의 속도로 가하며 약 1-2 시간이 소요된다. 혼합물을 계속해서 교반하여 진한 검붉은색의 용액을 제조하고 상온에서 30분 정도 더 교반한 후 전체용액의 부피가 500㎖로 되도록 물을 가하여 2.1M 이염화요오드칼륨(KlCl2) 용액을 수득하였다.To the mixture of potassium iodide 75.0 g (0.35 mol), potassium chloride 42.0 g (0.56 mol), catalytic amount of iodine 1 g and 90 ml of water, 10 ml (0.1 mol) of concentrated hydrochloric acid was added and stirred to prepare a white dispersion mixture. The mixture was vigorously stirred with a mechanical stirrer and slowly added an aqueous solution of 116.6 g (0.07 mol) of potassium iodide in 100 ml of water and concentrated hydrochloric acid (conc. HCl, 180 ml, 1.8 mol) simultaneously to form a pale yellow dispersion. It became a dark yellow solution. At this time, potassium iodide solution is added at a speed such that black iodine is not produced, and takes about 1-2 hours. The mixture was continuously stirred to prepare a dark red solution. After stirring for 30 minutes at room temperature, water was added so that the volume of the total solution was 500 ml to obtain 2.1 M potassium iodide dichloride (KlCl 2 ) solution. .
실시예 2: 5-아미노-2,4,6-트리요오도이소프탈산의 합성Example 2: Synthesis of 5-amino-2,4,6-triiodoisophthalic acid
물 1,250㎖에 5-아미노이소프탈산 30.84g(0.16mol)을 분산시켜 연한 황토색의 분산액을 제조하였다. 여기에 촉매량의 요오드(1g)를 가한 다음 가열하여 60℃로 유지하였다. 이 분산액에 실시예 1에서 수득한 이염화요오드칼륨 용액 250㎖ (2.1M)를 1시간에 걸쳐 적하하고 60℃에서 10시간동안 반응시켰다. 생성된 엷은 갈색의 분산액을 상온으로 냉각시키고 다시 빙욕에서 냉각시킨 후 여과하였다. 젖은 고체생성물을 더이상의 여액이 흘러나오지 않을 때까지 공기건조시킨 후, 수산화칼륨 수용액(0.66M, 300㎖)에 용해시키고 활성탄을 3.0g 가하고 pH를 7.0으로 내린 후 탈색하여 여과하고, 물(20㎖×2)로 활성탄을 세척하였다. 여액을 격렬하게 교반하면서 진한 염산을 천천히 가하여 pH를 1.0-2.0으로 조절하였다. 혼합물을 0∼5℃에서 냉각시킨 후 여과하고 얻어진 고체를 60℃에서 진공건조시켜 엷은 갈색의 고체상 표제화합물 86.0g(수율 96%)을 수득하였다.30.84 g (0.16 mol) of 5-aminoisophthalic acid was dispersed in 1,250 ml of water to prepare a light yellow dispersion. A catalytic amount of iodine (1 g) was added thereto, followed by heating to maintain 60 ° C. 250 ml (2.1M) of potassium iodide dichloride solution obtained in Example 1 was added dropwise to this dispersion over 1 hour, and reacted at 60 degreeC for 10 hours. The resulting pale brown dispersion was cooled to room temperature, again cooled in an ice bath and filtered. The wet solid product was air dried until no more filtrate flowed out, dissolved in potassium hydroxide solution (0.66 M, 300 mL), 3.0 g of activated charcoal was added, the pH was lowered to 7.0, decolorized and filtered, and water (20 The activated charcoal was washed with ml × 2). The pH was adjusted to 1.0-2.0 by slowly adding concentrated hydrochloric acid while stirring the filtrate vigorously. The mixture was cooled at 0-5 [deg.] C., filtered and the solid obtained was vacuum dried at 60 [deg.] C. to give 86.0 g (96% yield) of a pale brown solid title compound.
13C NMR(75MHz, DMSO) δ 170.3, 150.5, 147.4, 77.4, 70.7 13 C NMR (75 MHz, DMSO) δ 170.3, 150.5, 147.4, 77.4, 70.7
실시예 3: 5-아미노-2,4,6-트리요오도이소프탈산 클로라이드의 합성Example 3: Synthesis of 5-amino-2,4,6-triiodoisophthalic acid chloride
실시예 2에서 수득한 5-아미노-2,4,6-트리요오도이소프탈산 65.01g(0.116 mol)을 에틸아세테이트 420㎖에 분산시켰다. 분산액에 티오닐클로라이드 55.2g (0.46mol)을 천천히 가하고 생성된 혼합액을 3-4시간동안 가열환류시킨 후 상온으로 냉각시켰다. 과잉의 티오닐클로라이드와 용매를 증류로 제거하고, 증류 잔류물에 에틸아세테이트 135㎖을 가한 다음 다시 감압증류하여 휘발성분을 완전히 제거하였다. 증발 잔류물에 에틸아세테이트 940㎖을 가하여 녹인 후 포화 중탄산나트륨 수용액 1.12ℓ로 세척하고 다시 포화 중탄산나트륨 수용액 0.6ℓ로 세척한 후 유기층을 분리하였다. 분리된 유기층을 무수 탄산칼륨-무수 황산마그네슘(1:1, w/w) 혼합건조제 20g으로 건조시키고 여과하여 투명한 여액을 얻었다. 여액중의 용매를 감압(730 mmHg)하에 천천히 증발시키면서 결정화한 후 여과하고 수득된 결정을 약 20g의 n-헥산으로 세척하였다. 50℃에서 진공건조시켜 일차생성물(52.4g, 수율 80%)를 얻었다. 전단계에서 수득한 여액에 대해 다시 상기 과정을 되풀이하여 이차 생성물(13.2g, 15%, 전체수율 95%)을 수득하였다.65.01 g (0.116 mol) of 5-amino-2,4,6-triiodoisophthalic acid obtained in Example 2 was dispersed in 420 ml of ethyl acetate. 55.2 g (0.46 mol) of thionyl chloride was slowly added to the dispersion, and the resulting mixture was heated to reflux for 3-4 hours and then cooled to room temperature. Excess thionyl chloride and solvent were removed by distillation, and 135 ml of ethyl acetate was added to the distillation residue, followed by distillation under reduced pressure to completely remove volatile components. 940 ml of ethyl acetate was added to the evaporated residue, followed by dissolution. The mixture was washed with 1.12 L of saturated aqueous sodium bicarbonate solution and again with 0.6 L of saturated aqueous sodium bicarbonate solution, and then the organic layer was separated. The separated organic layer was dried over 20 g of anhydrous potassium carbonate-anhydrous magnesium sulfate (1: 1, w / w) mixed desiccant and filtered to obtain a clear filtrate. The solvent in the filtrate was crystallized while slowly evaporating under reduced pressure (730 mmHg), filtered and the obtained crystals were washed with about 20 g of n-hexane. Vacuum drying at 50 ° C. gave the primary product (52.4 g, 80% yield). The procedure was repeated again for the filtrate obtained in the previous step to give a secondary product (13.2 g, 15%, 95% overall yield).
13C NMR(75MHz, CDCl3) δ 168.5, 150.5, 149.2, 84.9, 79.1 13 C NMR (75 MHz, CDCl 3 ) δ 168.5, 150.5, 149.2, 84.9, 79.1
실시예 4: 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산클로라이드의 합성Example 4: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid chloride
메톡시아세트산 12.09g(34mol)에 메틸렌클로라이드 34㎖를 가하여 용해시킨 후 빙욕중에서 냉각시켰다. 반응액을 교반하면서 PCl527.79g을 1시간에 걸쳐 천천히 가하고 -20℃에서 40분간 교반하였다. 무색투명한 반응액에 실시예 3에서 수득한 5-아미노-2,4,6-트리요오도이소프탈산 클로라이드 20.26g(0.033mol)을 DMF에 녹여서 적하한 다음 -20℃에서 2시간동안 교반하였다. 반응액을 840㎖의 증류수에 천천히 가하여 흰색고체를 생성시킨 후, 이를 여과하고 다시 약 500㎖의 증류수에 현탁시켜 교반하고 여과하였다. 수득된 고체를 50℃에서 진공건조시켜 표제화합물 15.96g(수율 70%)을 수득하였다.Methylene chloride (34 ml) was added to 12.09 g (34 mol) of methoxyacetic acid, dissolved, and cooled in an ice bath. While stirring the reaction solution, 27.79 g of PCl 5 was slowly added over 1 hour, followed by stirring at −20 ° C. for 40 minutes. To a colorless transparent reaction solution, 20.26 g (0.033 mol) of 5-amino-2,4,6-triiodoisophthalic acid chloride obtained in Example 3 was dissolved in DMF, added dropwise, and stirred at -20 ° C for 2 hours. The reaction solution was slowly added to 840 ml of distilled water to form a white solid, which was then filtered, suspended in about 500 ml of distilled water, stirred and filtered. The solid obtained was dried in vacuo at 50 ° C. to give 15.96 g (yield 70%) of the title compound.
13C NMR(75MHz, 아세톤-d6) δ 60.2, 72.8, 83.0, 98.4, 146.0, 151.6, 169.1, 169.8 13 C NMR (75 MHz, Acetone-d 6 ) δ 60.2, 72.8, 83.0, 98.4, 146.0, 151.6, 169.1, 169.8
실시예 5: 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산[(2,3-디하이드록시-N-메틸프로필)-(2,3-디하이드록시프로필)]디아미드(이오프로마이드)의 합성Example 5: 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-dihydroxypropyl)] dia Synthesis of Mead (Iopromide)
실시예 4에서 수득한 5-메톡시아세틸아미노-2,4,6-트리요오도이소프탈산 클로라이드 15.13g(0.023mol)에 아세톤 60㎖를 가하여 용해시킨 후 -10℃에서 교반하였다. 반응액에 3-아미노-1,2-프로판디올 2.06g(0.023mol)을 아세톤 30㎖에 용해시킨 용액을 가한다음 트리에틸아민 2.33g(0.023mol)을 1시간에 걸쳐 천천히 적하하였다. -10℃에서 2시간동안 교반한 후 다시 3-메틸아미노-1,2-프로판디올 2.38g(0.023mol)을 아세톤 30㎖에 용해시킨 용액을 가한 다음 트리에틸아민 2.33g(0.023mol)을 1시간에 걸쳐 천천히 적가하였다. 반응액을 -10℃에서 2시간동안 교반한 후 다시 상온에서 2시간동안 교반한다음 반응용매의 양이 절반으로 될 때까지 농축시켰다. 농축시킨 반응액을 메틸렌클로라이드 600㎖에 교반하면서 천천히 가하여 흰 고체 현탁액을 수득한 후, 이를 여과하여 생성물을 분리시킨 다음 감압하에 건조시켰다. 건조된 고체를 증류수 100㎖에 용해시킨 후 pH를 7로 조정하고 활성탄 2g을 가하여 50℃에서 1시간동안 탈색시켰다. 여과에 의하여 활성탄을 제거하고 여액을 앰버라이드(Amberite) XAD-4 400㎖에 통과시킨 후 여액을 감압증류하여 흰색 고체의 표제화합물 9.87g(수율 55%)을 수득하였다.60 ml of acetone was added to 15.13 g (0.023 mol) of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid chloride obtained in Example 4, and dissolved, followed by stirring at -10 ° C. A solution obtained by dissolving 2.06 g (0.023 mol) of 3-amino-1,2-propanediol in 30 ml of acetone was added to the reaction solution, and then 2.33 g (0.023 mol) of triethylamine was slowly added dropwise over 1 hour. After stirring at −10 ° C. for 2 hours, a solution of 2.38 g (0.023 mol) of 3-methylamino-1,2-propanediol dissolved in 30 ml of acetone was added thereto, followed by addition of 2.33 g (0.023 mol) of triethylamine. Slowly added dropwise over time. The reaction solution was stirred at −10 ° C. for 2 hours, and then stirred at room temperature for 2 hours, and then concentrated until the amount of the reaction solvent was halved. The concentrated reaction solution was slowly added to 600 ml of methylene chloride while stirring to obtain a white solid suspension, which was then filtered to separate the product and dried under reduced pressure. The dried solid was dissolved in 100 ml of distilled water, the pH was adjusted to 7, and 2 g of activated carbon was added to decolorize at 50 ° C. for 1 hour. The activated carbon was removed by filtration and the filtrate was passed through 400 ml of Amberber XAD-4, and the filtrate was distilled under reduced pressure to yield 9.87 g (yield 55%) of the title compound as a white solid.
1H-NMR(300MHz, D2O) δ 2.35(d, 4H), 2.75-3.60(m, 12H), 3.58(s, 3H), 4.12(s, 2H) 1 H-NMR (300 MHz, D 2 O) δ 2.35 (d, 4H), 2.75-3.60 (m, 12H), 3.58 (s, 3H), 4.12 (s, 2H)
13C NMR(75MHz, D2O) δ 37.7, 42.2, 50.3, 60.0, 63.6, 64.0, 69.4, 69.7, 71.2, 89.1, 97.6, 142.5, 148.4, 148.5, 149.6, 172.1, 172.3, 172.5 13 C NMR (75 MHz, D 2 O) δ 37.7, 42.2, 50.3, 60.0, 63.6, 64.0, 69.4, 69.7, 71.2, 89.1, 97.6, 142.5, 148.4, 148.5, 149.6, 172.1, 172.3, 172.5
상기 설명한 바와 같은 본 발명의 제조방법에 따르면 X-ray 조영제로서 많이 사용되고 있는 이오프로마이드가 효과적으로 제조될 수 있다.According to the production method of the present invention as described above, the iopromide which is widely used as an X-ray contrast agent can be effectively produced.
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| KR20000075115A (en) * | 1999-05-28 | 2000-12-15 | 강재헌 | The New Method about Removal of 5-Acetamido-2,4,6-triiodoisophthaloyl dichloride in Iopamidol intermediate |
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| CN103570580B (en) * | 2012-08-08 | 2015-04-01 | 北京京卫信康医药科技发展有限公司 | Preparation method of high-purity iopromide |
| KR101520187B1 (en) * | 2013-10-25 | 2015-05-13 | 주식회사 대웅제약 | A method for preparation of an intermediate of iopromide |
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