KR100663167B1 - Process for preparing itopride hydrochloride - Google Patents
Process for preparing itopride hydrochloride Download PDFInfo
- Publication number
- KR100663167B1 KR100663167B1 KR1020050101614A KR20050101614A KR100663167B1 KR 100663167 B1 KR100663167 B1 KR 100663167B1 KR 1020050101614 A KR1020050101614 A KR 1020050101614A KR 20050101614 A KR20050101614 A KR 20050101614A KR 100663167 B1 KR100663167 B1 KR 100663167B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- dimethylaminoethoxy
- phenyl
- methyl
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- QQQIECGTIMUVDS-UHFFFAOYSA-N N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 QQQIECGTIMUVDS-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 229960005302 itopride Drugs 0.000 title abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- ZTOUXLLIPWWHSR-UHFFFAOYSA-N n-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide;hydron;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 ZTOUXLLIPWWHSR-UHFFFAOYSA-N 0.000 claims abstract description 6
- HPFKOFNYNQMWEF-UHFFFAOYSA-N chloro-dihydroxy-sulfanylidene-$l^{5}-phosphane Chemical compound OP(O)(Cl)=S HPFKOFNYNQMWEF-UHFFFAOYSA-N 0.000 claims abstract description 4
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- DAUAQNGYDSHRET-UHFFFAOYSA-N 3,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1OC DAUAQNGYDSHRET-UHFFFAOYSA-N 0.000 claims description 9
- GPVDHNVGGIAOQT-UHFFFAOYSA-N Veratric acid Natural products COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- KMJJJTCKNZYTEY-UHFFFAOYSA-N chloro-diethoxy-sulfanylidene-$l^{5}-phosphane Chemical compound CCOP(Cl)(=S)OCC KMJJJTCKNZYTEY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 20
- 239000002699 waste material Substances 0.000 abstract description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- -1 activated phosphorus ester Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- BAUUVNZBTHKSTL-UHFFFAOYSA-M potassium;3,4-dimethoxybenzoate Chemical compound [K+].COC1=CC=C(C([O-])=O)C=C1OC BAUUVNZBTHKSTL-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VIOBGCWEHLRBEP-UHFFFAOYSA-N 3,4-dimethoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1OC VIOBGCWEHLRBEP-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
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
본 발명은 하기 화학식 1의 N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-디메톡시벤즈아미드 염산의 신규 제조방법에 관한 것이다.The present invention relates to a novel process for preparing N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide hydrochloride of formula (1).
상기 화학식 화합물은 일반명 염산 이토프리드(Itopride Hydrochloride)로 통용되는 기능성 소화불량으로 인한 소화기증상에 유용한 약물로 이용되며 이를 제조하는 종래기술은 유럽특허 제 306827 및 대한민국 특허공고 제 1994-0000058 에 명시 되어있다. 이들 특허에 따르면 하기 반응식 I에 나타난 바와 같이 화학식 2의 3,4-디메톡시안식향산을 화학식 3의 산염화물 혹은 혼합산 무수물로 전환하고 화학식 4의 4-[2-(디메톡시아미노에톡시)벤질아민을 반응시켜 화학식 5의 N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-디메톡시벤즈아미드를 생성 시키고 에탄올 및 염 산을 사용하여 상기 화학식 1을 제조한다.The chemical compound is used as a drug useful for digestive symptoms due to functional dyspepsia, commonly known as Itopride Hydrochloride, and the prior art for preparing the same is described in European Patent No. 306827 and Korean Patent Publication No. 1994-0000058. have. According to these patents, the 3,4-dimethoxybenzoic acid of formula (2) is converted to an acid chloride or mixed acid anhydride of formula (3) and 4- [2- (dimethoxyaminoethoxy) benzylamine of formula (4) To react N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide of Chemical Formula 5 to prepare Chemical Formula 1 using ethanol and hydrochloric acid.
그러나 상기 방법은 출발물질 화학식 2의 화합물인 3,4-디메톡시안식향산에서 화학식 3의 화합물인 3,4-디메톡시벤조일 클로라이드의 제조가 까다롭고 티오닐클로라이드 사용에 따른 유독가스인 SO2 및 HCl 가스를 배출하여 공해문제를 야기 시킴으로 해서 대량 생산 시 현장에서 다루기가 까다롭고 생산시설의 부식 등 문제점이 있다. 반응조건 역시 고온에서 진행하여 고 품질의 최종 생성물을 얻기가 어려운 문제가 있다. 또한 에칠클로로포메이트 혹은 피바로일클로라이드등을 사용하여 혼합산 무수물을 제조 시 반응조건이 까다롭고 -20℃의 저온에서 반응을 행하여야 하는 등의 문제점이 따른다.However, the above method is difficult to prepare 3,4-dimethoxybenzoyl chloride of the compound of formula 3 in 3,4-dimethoxybenzoic acid, the compound of formula 2, and SO 2 and HCl, which are toxic gases according to thionyl chloride. It is difficult to deal with in the field during mass production, and there is a problem such as corrosion of production facilities because it causes pollution problem by releasing gas. The reaction conditions are also difficult to obtain a high quality final product by proceeding at high temperatures. In addition, the reaction conditions are difficult to prepare a mixed acid anhydride using ethylchloroformate or pivaloyl chloride, etc., and the reaction must be carried out at a low temperature of -20 ℃.
본 발명자들은 상기 특허에서 제시되는 문제점들을 해결하기 위해 3,4-디메톡시안식향산을 염기와 반응시킨 후 디알킬 클로로포스페이트 혹은 O,O-디알킬 클로로티오포스페이트를 사용하여 안식향산의 활성화된 인 에스테르 유도체를 제조하 고 이어서 치환반응에 의해 용이하게 화학식 1의 화합물을 제조하는 방법을 확립하였다. 본 발명은 반응공정이 온화하고 반응 후 생성되는 폐액이 적은 환경친화적인 제조방법이 특징이다. 또한 본 발명은 -5℃ 정도의 온도에서 반응을 진행하여 불순물의 함유량이 적고 제품의 품질도 매우 우수하며 대량생산에도 용이하다.The present inventors have reacted 3,4-dimethoxybenzoic acid with a base and then using dialkyl chlorophosphate or O, O-dialkyl chlorothiophosphate to solve the problems presented in the above patent. To prepare a compound of formula (1) easily by the substitution reaction was then established. The present invention is characterized by an environmentally friendly method of producing a mild reaction process and less waste fluid generated after the reaction. In addition, the present invention proceeds the reaction at a temperature of about -5 ℃, the content of impurities is small, the product quality is also very good and easy to mass production.
본 발명은 하기 화학식 1의 N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-디메톡시벤즈아미드 염산의 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for preparing N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide hydrochloric acid of formula (1).
[화학식 1][Formula 1]
본 발명의 제조방법을 하기 반응식 2에 보다 상세히 설명하면 다음과 같다.The preparation method of the present invention will be described in more detail in Scheme 2 below.
여기서 R' 는 O 또는 S 이며 R1, R2는 -OCH3, -OC2H5 , -OC6H5 에서 선택될 수 있다.Wherein R 'is O or S and R 1 , R 2 may be selected from -OCH 3 , -OC 2 H 5 , -OC 6 H 5 .
상기 반응식에서 화학식 2의 3,4-디메톡시안식향산에 염기를 반응시켜서 해당되는 음이온인 화학식 6의 화합물을 얻는다. 이때 반응온도는 -30~30℃, 바람직하게는 -10~10℃에서, 1~3시간 동안 화학식 7의 화합물인 디알킬 클로로포스페이트 또는 O,O-디알킬 클로로티오포스페이트를 1.0~1.5당량을 반응시켜서 해당하는 안식향산의 활성화된 인 에스테르인 화학식 8을 제조한다. 여기에 동 온도범위에서 화 학식 4인 4-[2-(디메톡시아미노에톡시)벤질아민을 1.0~1.2 당량을 1~3시간 동안 반응시켜 상기 화학식 5의 화합물인 N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-메톡시벤즈아미드를 얻고 이를 알코올 용매 하에 염산을 투입하여 반응온도 0~50℃에서 0.5~24시간 동안 반응시켜 목적화합물인 화학식 1의 염산 이토프리드를 제조한다.In the above scheme, a base is reacted with 3,4-dimethoxybenzoic acid of Formula 2 to obtain a compound of Formula 6, which is a corresponding anion. At this time, the reaction temperature is -30 ~ 30 ℃, preferably -10 ~ 10 ℃, 1.0 to 1.5 equivalents of dialkyl chlorophosphate or O, O-dialkyl chlorothiophosphate of the compound of formula (7) for 1 to 3 hours Reaction produces a formula (8) which is an activated phosphorus ester of the corresponding benzoic acid. In the same temperature range, 4- [2- (dimethoxyaminoethoxy) benzylamine represented by Chemical Formula 4 was reacted for 1.0 to 1.2 equivalents for 1 to 3 hours to form N-[[4- ( 2-dimethylaminoethoxy) phenyl] methyl] -3,4-methoxybenzamide was obtained by adding hydrochloric acid under an alcohol solvent to react for 0.5 to 24 hours at a reaction temperature of 0 to 50 ° C. Hydrochloride hydrochloride is prepared.
안식향산의 음이온 제조에 사용하는 염기로는 알카리 금속, 트리에틸아민, 디에틸아민, 피리딘, 디이소프로필아민, 디이소프로필에틸아민, 테트라메틸구아니딘 또는 이들을 2종 이상 혼합하여 얻어지는 혼합 염기등을 사용할 수 있다.Alkali metal, triethylamine, diethylamine, pyridine, diisopropylamine, diisopropylethylamine, tetramethylguanidine, or a mixed base obtained by mixing two or more thereof may be used as a base used for the preparation of anion of benzoic acid. Can be.
활성화인 에스테르인 화학식 8의 제조에 사용되는 용매로는 테드라하이드로퓨란, 아세토니트릴, 클로로포름, 에틸아세테이트, 디클로로메탄 등으로 이루어진 군으로부터 선택되는 용매 또는 이들을 2종 이상 혼합하여 얻어지는 혼합용매를 사용할 수 있다.As a solvent used in the preparation of the general formula (8), which is an activating ester, a solvent selected from the group consisting of tetradrafuran, acetonitrile, chloroform, ethyl acetate, dichloromethane, or the like, or a mixed solvent obtained by mixing two or more thereof may be used. have.
화학식 7로 표시되는 화합물로서는 디에칠 클로로포스페이트 혹은 O,O-디에틸 클로로티오포스페이트를 사용할 수 있으며, 생성된 화학식 8로 표시되는 산 에스테르는 별도로 분리함이 없이 다음 반응에 이용하는 것이 바람직하다.Diethyl chlorophosphate or O, O-diethyl chlorothiophosphate may be used as the compound represented by the formula (7), and the acid ester represented by the formula (8) is preferably used for the next reaction without being separated.
상기 반응에서 화학식 1을 제조하는 데 있어서 사용하는 알코올 용매는 이소프로판올, 에탄올, 메탄올 등을 포함하는 저급알코올 및 이들을 2종 이상 혼합하여 얻어지는 혼합용매를 예로 들 수 있으며 염산은 액체상태의 염산 혹은 염산 가스를 사용할 수 있으나 일반적으로 액체상태의 염산 수용액을 사용함이 바람직하다.Examples of the alcohol solvent used in preparing the chemical formula 1 in the reaction include lower alcohols including isopropanol, ethanol, methanol, and the like, and a mixed solvent obtained by mixing two or more thereof. Hydrochloric acid may be a liquid hydrochloric acid or hydrochloric acid gas. In general, it is preferable to use an aqueous hydrochloric acid solution.
하기 실시 예는 본 발명을 보다 구체적으로 설명하는 것이며 본 발명의 범위 를 제한하는 것은 아니다.The following examples illustrate the invention in more detail and do not limit the scope of the invention.
실시예Example 1 : 3,4- 1: 3,4- 디메톡시안식향산Dimethoxy benzoic acid 포타슘염Potassium salt 제조 Produce
반응기에 정제수 60mL, 이소프로판올 150mL, 수산화칼륨 7.8g, 3,4-디메톡시안식향산 20g을 투입하고 가온 용해한다. 반응액을 30분간 교반하고 상온으로 냉각하다. 생성된 결정을 여과하고 정제수 5mL와 이소프로판올 20mL 혼합액으로 세척한다. 진공 건조한다.60 mL of purified water, 150 mL of isopropanol, 7.8 g of potassium hydroxide, and 20 g of 3,4-dimethoxybenzoic acid were added to the reactor and dissolved by heating. The reaction solution is stirred for 30 minutes and cooled to room temperature. The resulting crystals are filtered and washed with 5 mL of purified water and 20 mL of isopropanol. Vacuum dry.
수득량 : 20.6g (수율: 85.2%)Yield: 20.6 g (yield: 85.2%)
실시예Example 2 : N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-메톡시벤즈아미드의 제조 2: Preparation of N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-methoxybenzamide
디클로로메탄 용매 90mL에 3,4-디메톡시안식향산 18.1g, 트리에틸아민 11.1g을 투입한다. 질소 충진하에서 -5~-10℃로 냉각한다. 디에틸 클로로포스페이트 15.9mL를 1.0시간에 걸쳐 적가한다. 동 온도에서 1시간 교반하고 4-[2-(디메톡시아미노에톡시)벤질아민 15g을 디클로로메탄 30mL에 용해한 액을 적가한다. 반응완료 후 정제수 70mL를 투입하고 층분리한다. 분리한 유기층에 정제수 120mL와 6N 염산 14mL를 투입한다. 수층을 분리하고 디클로로메탄 120mL를 투입한다. 수층을 분리하고 디클로로메탄 120mL와 6N 수산화나트륨 수용액 13mL를 투입한다. 분리한 유기층을 무수황산마그네슘으로 탈수하고 여과한 후 여액을 농축한다. 생성된 결정을 에탄올과 이소프로필에테르에서 재결정화 하고 진공 건조한다.18.1 g of 3,4-dimethoxybenzoic acid and 11.1 g of triethylamine were added to 90 mL of a dichloromethane solvent. Cool to -5 ~ -10 ℃ under nitrogen filling. 15.9 mL diethyl chlorophosphate was added dropwise over 1.0 hour. After stirring for 1 hour at the same temperature, a solution of 15 g of 4- [2- (dimethoxyaminoethoxy) benzylamine dissolved in 30 mL of dichloromethane is added dropwise. After completion of the reaction, add 70 mL of purified water and separate the layers. 120 mL of purified water and 14 mL of 6N hydrochloric acid were added to the separated organic layer. Separate the aqueous layer and add 120 mL of dichloromethane. Separate the aqueous layer and add 120 mL of dichloromethane and 13 mL of 6N aqueous sodium hydroxide solution. The separated organic layer was dehydrated with anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The resulting crystals are recrystallized in ethanol and isopropyl ether and dried in vacuo.
수득량 : 23.5g (수율: 84.9%)Yield: 23.5 g (yield: 84.9%)
MP : 110.5℃MP: 110.5 ℃
실시예Example 3 : N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-메톡시벤즈아미드의 제조 3: Preparation of N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-methoxybenzamide
디클로로메탄 용매 120mL에 3,4-디메톡시안식향산 포타슘염 29.6g을 투입한다. 질소 충진하에서 -10℃로 냉각한다. 디에틸 클로로포스페이트 21.2mL를 1.0시간에 걸쳐 적가한다. 동 온도에서 1시간 교반하고 4-[2-(디메톡시아미노에톡시)벤질아민 20g을 디클로로메탄 35mL에 용해한 액을 적가한다. 반응완료 후 과정은 실시예1과 동일하게 시행한다.29.6 g of 3,4-dimethoxybenzoic acid potassium salt was added to 120 mL of dichloromethane solvent. Cool to -10 ° C under nitrogen charge. 21.2 mL of diethyl chlorophosphate was added dropwise over 1.0 hour. After stirring for 1 hour at the same temperature, a solution of 20 g of 4- [2- (dimethoxyaminoethoxy) benzylamine dissolved in 35 mL of dichloromethane is added dropwise. After completion of the reaction was carried out in the same manner as in Example 1.
수득량 : 41.9g (수율: 87.0%)Yield: 41.9 g (Yield: 87.0%)
MP : 110.8℃MP: 110.8 ℃
실시예Example 4 : N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-메톡시벤즈아미드의 제조 4: Preparation of N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-methoxybenzamide
디클로로메탄 용매 60mL에 3,4-디메톡시안식향산 12.1g, 트리에틸아민 7.44g을 투입한다. 질소 충진하에서 -5~-10℃로 냉각한다. O,O-디에틸 클로로티오포스페이트 23mL를 서서히 적가한다. 동일 온도에서 1시간 교반하고 4-[2-(디메톡시아미노에톡시)벤질아민 10g을 디클로로메탄 30mL에 용해한 액을 적가한다. 반응완료 후 과정은 실시예 1과 동일하게 시행한다.12.1 g of 3,4-dimethoxybenzoic acid and 7.44 g of triethylamine were added to 60 mL of dichloromethane solvent. Cool to -5 ~ -10 ℃ under nitrogen filling. 23 mL of O, O-diethyl chlorothiophosphate was slowly added dropwise. After stirring for 1 hour at the same temperature, a solution of 10 g of 4- [2- (dimethoxyaminoethoxy) benzylamine dissolved in 30 mL of dichloromethane is added dropwise. After completion of the reaction was carried out in the same manner as in Example 1.
수득량 : 20.2g (수율: 84.8%)Yield: 20.2 g (yield: 84.8%)
MP : 111.2℃MP: 111.2 ° C
실시예Example 5 : N-[[4-(2- 5: N-[[4- (2- 디메틸아미노에톡시Dimethylaminoethoxy )) 페닐Phenyl ]] 메틸methyl ]-3,4-] -3,4- 메톡시벤즈아미드Methoxybenzamide 염산의 제조 Preparation of Hydrochloric Acid
에탄올 56mL에 실시예 2의 N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-메톡시벤즈아미드 14.5g와 염산 15.2g을 투입하고 용해한다. 1시간 교반하고 감압 농축한다. 농축잔사에 에탄올 10mL를 투입하여 재 농축하고 생성된 결정을 에탄올과 이소프로필에테르를 사용하여 재결정화 한다.14.5 g of N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-methoxybenzamide and 15.2 g of hydrochloric acid of Example 2 were added and dissolved in 56 mL of ethanol. Stir for 1 hour and concentrate under reduced pressure. 10 mL of ethanol was added to the concentrated residue, and the resultant was re-condensed. The resulting crystals were recrystallized using ethanol and isopropyl ether.
수득량 : 14.8g (수율: 92.6%)Yield: 14.8 g (yield: 92.6%)
MP : 194.6℃MP: 194.6 ℃
H1 NMR (CDCl3, ppm): 2.28(s, 6H), 2.67(t,2H), 3.70(s,6H), 4.01(t, 2H), 4.50(s, 2H), 6.70(m, 2H), 6.90(m,1H), 7.01(m, 2H), 7.40(m, 2H)H 1 NMR (CDCl 3 , ppm): 2.28 (s, 6H), 2.67 (t, 2H), 3.70 (s, 6H), 4.01 (t, 2H), 4.50 (s, 2H), 6.70 (m, 2H ), 6.90 (m, 1H), 7.01 (m, 2H), 7.40 (m, 2H)
실시예Example 6 : N-[[4-(2-디메틸아미노에톡시)페닐]메틸]-3,4-디메톡시벤즈아미드 염산의 제조 6: Preparation of N-[[4- (2-dimethylaminoethoxy) phenyl] methyl] -3,4-dimethoxybenzamide hydrochloric acid
디클로로메탄 용매 90mL에 3,4-디메톡시안식향산 18.1g, 트리에틸아민 11.1g을 투입한다. 질소 충진하에서 -5~-10℃로 냉각한다. 디에틸 클로로포스페이트 15.9mL를 1.0시간에 걸쳐 적가한다. 동 온도에서 1시간 교반하고 4-[2-(디메톡시아미노에톡시)벤질아민 15g을 디클로로메탄 30mL에 용해한 액을 적가한다. 반응완료 후 정제수 70mL를 투입하고 층 분리한다. 분리한 유기층에 정제수 120mL와 6N 염산 14mL를 투입한다. 수층을 분리하고 디클로로메탄 120mL를 투입한다. 수층을 분리하고 디클로로메탄 120mL와 6N 수산화나트륨 수용액 13mL를 투입한다. 분리한 유기층을 감압 농축한다. 농축잔사에 에탄올 70mL와 염산 19g을 투입하고 용해한다. 1시간 교반하고 감압 농축한다. 생성된 결정을 에탄올과 이소프로필에테르를 사용하여 재결정화 한다.18.1 g of 3,4-dimethoxybenzoic acid and 11.1 g of triethylamine were added to 90 mL of a dichloromethane solvent. Cool to -5 ~ -10 ℃ under nitrogen filling. 15.9 mL diethyl chlorophosphate was added dropwise over 1.0 hour. After stirring for 1 hour at the same temperature, a solution of 15 g of 4- [2- (dimethoxyaminoethoxy) benzylamine dissolved in 30 mL of dichloromethane is added dropwise. After completion of the reaction, add 70 mL of purified water and separate the layers. 120 mL of purified water and 14 mL of 6N hydrochloric acid were added to the separated organic layer. Separate the aqueous layer and add 120 mL of dichloromethane. Separate the aqueous layer and add 120 mL of dichloromethane and 13 mL of 6N aqueous sodium hydroxide solution. The separated organic layer is concentrated under reduced pressure. Dissolve 70 mL of ethanol and 19 g of hydrochloric acid in the concentrated residue. Stir for 1 hour and concentrate under reduced pressure. The resulting crystals are recrystallized using ethanol and isopropyl ether.
수득량: 33.7g (수율: 85.9%)Yield: 33.7 g (yield: 85.9%)
MP : 194.7℃MP: 194.7 ℃
H1 NMR (CDCl3, ppm): 2.28(s, 6H), 2.67(t,2H), 3.70(s,6H), 4.01(t, 2H), 4.50(s, 2H), 6.70(m, 2H), 6.90(m,1H), 7.01(m, 2H), 7.40(m, 2H)H 1 NMR (CDCl 3 , ppm): 2.28 (s, 6H), 2.67 (t, 2H), 3.70 (s, 6H), 4.01 (t, 2H), 4.50 (s, 2H), 6.70 (m, 2H ), 6.90 (m, 1H), 7.01 (m, 2H), 7.40 (m, 2H)
본 발명은 염산 이토프리드를 보다 안정적이고 효율적으로 제조하는 방법에 관한 것으로, 반응이 용이하고 환경오염성이 적으며 높은 수율과 제품순도가 우수한 장점이 있다. 또한 본 발명은 각 중간 단계를 별도로 분리함이 없이 in situ 로 반응을 진행함으로써 보다 효율적이며 저렴하게 제조할 수 있는 장점이 있다.The present invention relates to a method for producing more stable and efficient etopri hydrochloride, has the advantages of easy reaction, less environmental pollution, high yield and excellent product purity. In addition, the present invention has the advantage that can be produced more efficiently and inexpensively by proceeding the reaction in situ without separating each intermediate step separately.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020050101614A KR100663167B1 (en) | 2005-10-27 | 2005-10-27 | Process for preparing itopride hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020050101614A KR100663167B1 (en) | 2005-10-27 | 2005-10-27 | Process for preparing itopride hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR100663167B1 true KR100663167B1 (en) | 2007-01-02 |
Family
ID=37866525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020050101614A KR100663167B1 (en) | 2005-10-27 | 2005-10-27 | Process for preparing itopride hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR100663167B1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100836528B1 (en) | 2007-07-25 | 2008-06-10 | 주식회사 휴온스 | Process of manufacturing itopride hydrochloride |
| KR100967341B1 (en) | 2008-04-01 | 2010-07-05 | 주식회사 이매진 | Process for preparing a synthetic intermediate of carbapenems |
| KR101508565B1 (en) | 2008-05-27 | 2015-04-03 | 이범찬 | Novel method for preparing itopride and the intermediate obtained from the method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0259548A (en) * | 1988-08-24 | 1990-02-28 | Hokuriku Seiyaku Co Ltd | Amide compound |
| KR940000058B1 (en) * | 1987-09-05 | 1994-01-05 | 호쿠리쿠 세이야쿠 가부시키가이샤 | Amide campounds, process for preparing the same and composition for activating gastric motor function containing the same |
-
2005
- 2005-10-27 KR KR1020050101614A patent/KR100663167B1/en not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR940000058B1 (en) * | 1987-09-05 | 1994-01-05 | 호쿠리쿠 세이야쿠 가부시키가이샤 | Amide campounds, process for preparing the same and composition for activating gastric motor function containing the same |
| JPH0259548A (en) * | 1988-08-24 | 1990-02-28 | Hokuriku Seiyaku Co Ltd | Amide compound |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100836528B1 (en) | 2007-07-25 | 2008-06-10 | 주식회사 휴온스 | Process of manufacturing itopride hydrochloride |
| KR100967341B1 (en) | 2008-04-01 | 2010-07-05 | 주식회사 이매진 | Process for preparing a synthetic intermediate of carbapenems |
| KR101508565B1 (en) | 2008-05-27 | 2015-04-03 | 이범찬 | Novel method for preparing itopride and the intermediate obtained from the method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI709567B (en) | Methods for preparing anti-viral nucleotide analogs | |
| KR20100105852A (en) | An improved process to prepare treprostinil, the active ingredient in remodulin® | |
| RU2646760C2 (en) | Improved method of preparing the 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethyl pyridine-2-amine | |
| US9701613B2 (en) | Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same | |
| JP5390617B2 (en) | Purification method of adefovir dipivoxil | |
| EP3498695B1 (en) | Method for synthesizing 3-(difluoromethyl)-1-methyl-1h-pyrazole-4-carboxylic acid | |
| KR100663167B1 (en) | Process for preparing itopride hydrochloride | |
| JP2015523375A (en) | Process for producing 2-cyanophenylboronic acid and its ester | |
| JP5622842B2 (en) | Method for producing alkylamine derivative | |
| NO328627B1 (en) | Process for the preparation of iopamidol and the novel intermediates therein | |
| KR20100116644A (en) | Method for preparing combretastatin | |
| KR20140044373A (en) | Manufacture of a triiodinated contrast agent | |
| CN101939289A (en) | Novel process for the preparation of vorinostat | |
| KR101327866B1 (en) | Improved process for preparing Mitiglinide calcium salt | |
| JP2009518380A (en) | Preparation of 2-chloroethoxy-acetic acid-N, N-dimethylamide | |
| WO2021020998A1 (en) | Method for producing roxadustat | |
| JP3822901B1 (en) | (2S) -3- (4- {2- [Amino] -2-oxoethoxy} phenyl) -2-ethoxypropanoic acid derivative production method | |
| KR20150041280A (en) | Method for the preparation of Mitiglinide Calcium Dihydrate | |
| CN102659713A (en) | Preparation method for cefdinir side-chain acid active ester | |
| JP2013512883A (en) | Method for preparing combretastatin derivatives | |
| JPH06220001A (en) | 3-imino-3-alkoxypropionic acid lactates and their tautomeric acylic acid lactates | |
| KR20100079285A (en) | A method for preparing crotonic acid derivatives | |
| KR100667673B1 (en) | Process for preparing phenyl alanine derivatives | |
| KR100726890B1 (en) | Synthesis of Thiophene Based Units for Metal Chelation | |
| KR20070082985A (en) | Preparation method of oseltamivir |
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: 20120217 Year of fee payment: 6 |
|
| LAPS | Lapse due to unpaid annual fee |