KR101696851B1 - Method of Producing Related Substance of Olmesartan Medoxomil - Google Patents
Method of Producing Related Substance of Olmesartan Medoxomil Download PDFInfo
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- KR101696851B1 KR101696851B1 KR1020100131876A KR20100131876A KR101696851B1 KR 101696851 B1 KR101696851 B1 KR 101696851B1 KR 1020100131876 A KR1020100131876 A KR 1020100131876A KR 20100131876 A KR20100131876 A KR 20100131876A KR 101696851 B1 KR101696851 B1 KR 101696851B1
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- C—CHEMISTRY; METALLURGY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- C—CHEMISTRY; METALLURGY
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- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/02—Lithium compounds
Abstract
본 발명은 올메사탄 메독소밀의 유연물질의 제조방법에 관한 것이다. 본 발명 올메사탄 메독소밀의 유연물질의 제조방법은 약학 제품의 품질을 평가하기에 필수적인 물질로서, 제조과정을 거치면서 발생하는 불순물의 양이 적어 수율이 높고, 저렴한 제조 비용을 통해 공급이 가능하며, 입자도 조절이 용이하여 제조가 용이한 장점이 있다.The present invention relates to a process for preparing a flexible material of olmesartan medoxomil. INDUSTRIAL APPLICABILITY The method for producing a flexible material of olmesatan medoxomil is an essential material for evaluating the quality of a pharmaceutical product, and it is possible to supply the material through a manufacturing process with a low yield of the impurity and a low production cost , And it is easy to control the particle size, which is advantageous in manufacturing.
Description
본 발명은 올메사탄 메독소밀의 유연물질의 제조방법에 관한 것이다.The present invention relates to a process for preparing a flexible material of olmesartan medoxomil.
전세계적으로 사망에 대한 위험인자 중에서 가장 높은 비율을 차지하는 것은 혈압이다. 특히 고혈압은 심장혈관질환의 주요 원인으로 지목되는데, 이러한 심·뇌혈관질환은 우리나라 사망원인 중 1위를 차지한다. 선진국으로 진행될수록 서구식 식생활 변화와 위생상태의 개선 등으로 항생제 시장은 축소하는 대신 고혈압 등을 포함한 만성 질환 시장은 확대되는 경향을 가진다.Blood pressure is the highest rate of death among all risk factors worldwide. In particular, hypertension is a major cause of cardiovascular disease, which is the leading cause of death in Korea. As the market progresses to advanced countries, the market for antibiotics will be reduced and the market for chronic diseases including hypertension will be expanded due to changes in Western food and improvement of sanitary conditions.
혈압 관리에 있어 가장 중요한 수단은 약물이다. 현재 고혈압 치료제 시장은 안지오텐신Ⅱ 수용체 길항제가 가장 주목받고 있다. 안지오텐신Ⅱ 수용체 길항제는 혈관 수축 작용을 가진 물질인 안지오텐신Ⅱ의 작용을 막아 혈관을 이완시켜 혈압을 떨어뜨리는 기전을 갖는다.The most important means of managing blood pressure is drugs. Currently, angiotensin II receptor antagonists are attracting the most attention in hypertension treatment market. Angiotensin II receptor antagonist has a mechanism to slow blood pressure by relaxing the action of angiotensin II, which is a substance with vasoconstrictor action.
상기 안지오텐신Ⅱ 수용체 길항제 가운데에서도 올메사탄 메독소밀은 혈압강하 효과가 우수할 뿐만 아니라, 표적장기손상 보호작용 또한 우수하여 현재 가장 높은 점유율을 갖는 고혈압 치료제이다.Of the angiotensin II receptor antagonists, olmesatan medoxomil is not only superior in blood pressure lowering effect, but also has excellent protecting effect against target organ damage, and is the highest hypertension treatment agent currently having the highest occupancy rate.
그러나, 원료 합성 또는 완제의약품 제조과정 중 만들어질 가능성이 있는 일종의 불순물인 올메사탄 메독소밀의 유연물질 (related substance)에 대해서는 별도의 제조방법이 확립되지 않아, 품질의 입증이 어려운 문제점이 있었다. 뿐만 아니라 올메사탄 메독소밀의 분해를 통해 분리할 경우 고가의 비용이 발생하는 문제점이 있는데 합성을 통해 유연물질을 제조할 경우 제조비용을 낮출수 있는 장점이 있다. However, there has been a problem that it is difficult to prove the quality of a related substance of olmesartan medoxomil, which is a kind of impurities that may be produced during synthesis of raw materials or in the production of finished medicines, since a separate manufacturing method is not established. In addition, there is a problem in that expensive disadvantages arise when the oligosaccharide is decomposed through the decomposition of the medoxomel, which is advantageous in that manufacturing cost can be lowered when a flexible material is manufactured through synthesis.
본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로서, 올메사탄 메독소밀의 유연물질의 새로운 제조방법을 제공하는 것을 그 목적으로 한다.Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a novel process for producing a flexible material of olmesatan medoxomil.
본 발명 올메사탄 메독소밀의 유연물질의 제조방법은 상술한 바와 같은 목적을 달성하기 위하여, According to the present invention, there is provided a process for preparing a soft substance of olmesatan medoxomil,
(A) 에틸 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 수산화 리튬과 반응시켜 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 합성하는 단계, 및 (A) Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl- ) Methyl) -1H-imidazole-5-carboxylate was reacted with lithium hydroxide to give 4- (2-hydroxypropan-2- -1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate,
(B) 에틸 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 상기 합성된 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트와 반응시키는 단계(B) Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl- ) Methyl) -1H-imidazole-5-carboxylate was prepared from 4- (2-hydroxypropan-2-yl) Yl) methyl) -1H-imidazole-5-carboxylate in step
를 포함한다..
또한, 상기 단계 (A)의 합성은 물 및 다이옥산의 혼합 용매에서 수행될 수 있다.In addition, the synthesis of step (A) may be carried out in a mixed solvent of water and dioxane.
또한, 상기 단계 (B)의 반응은 테트라 하이드로 퓨란 및 벤젠술폰산의 존재 하에서 수행될 수 있다.In addition, the reaction of step (B) may be carried out in the presence of tetrahydrofuran and benzenesulfonic acid.
본 발명 올메사탄 메독소밀의 유연물질의 제조방법은 약학 제품의 품질을 평가하기에 필수적인 물질로서, 제조과정을 거치면서 발생하는 불순물의 확인이 가능하여 저렴한 비용으로 높은 품질의 제품합성이 가능한 장점이 있다. 또한, 올메사탄 메독소밀 정 완제 제조사 입장에서도 저렴한 비용으로 품질관리를 할 수 있는 장점이 있다. The method of the present invention for producing a flexible material of olmesatan medoxomil is an essential material for evaluating the quality of a pharmaceutical product, and it is possible to identify impurities generated during the manufacturing process, and thus it is possible to synthesize a high quality product at low cost have. In addition, there is an advantage in that quality control can be performed at a low cost even in the case of a manufacturer of Olmeta Satin Medoxine.
도 1은 HPLC 공시험 차트이다.
도 2는 본 발명의 유연물질에 대한 HPLC 차트이다.Figure 1 is a HPLC blank test chart.
2 is an HPLC chart for the flexible material of the present invention.
이하, 본 발명의 바람직한 실시예에 대하여 상세히 설명한다. 또한, 하기의 설명에서는 구체적인 구성요소 등과 같은 많은 특정사항들이 설명되어 있는데, 이는 본 발명의 보다 전반적인 이해를 돕기 위해서 제공된 것일 뿐 이러한 특정 사항들 없이도 본 발명이 실시될 수 있음은 이 기술분야에서 통상의 지식을 가진 자에게는 자명하다 할 것이다. 그리고, 본 발명을 설명함에 있어서, 관련된 공지 기능 혹은 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Hereinafter, preferred embodiments of the present invention will be described in detail. In the following description, numerous specific details, such as specific elements, are set forth in order to provide a thorough understanding of the present invention, and it is to be understood that the present invention may be practiced without these specific details, It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.
먼저 본 명세서에서 용어 '유연물질 (related substance)'은 원료 합성 또는 완제의약품 제조과정중 만들어질 가능성이 있는 일종의 불순물을 가리킨다. 이러한 유연물질은 최종 약학 제품에 기준 이하로만 함유되어야 하며 품질 입증에 사용되는 물질이다.The term " related substance " is used herein to refer to a kind of impurities that may be produced during synthesis of raw materials or in the manufacture of finished pharmaceutical products. Such a substance is a substance that should be contained in the final pharmaceutical product only below the reference level and used for quality assurance.
본 발명의 반응과정을 정리하면 하기 반응식과 같다.The reaction scheme of the present invention can be summarized as the following reaction scheme.
[반응식]
[Reaction Scheme]
실시예Example
화학식 1의 에틸 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트에 정제수와 다이옥산의 혼합 용매를 가한 후 수산화리튬을 가하고 상온에서 2 시간 반응하였다. 박막 크로마토그래피로 반응의 종결을 확인하고 감압 농축하여 유기용매를 제거한 후 염화 메틸렌을 가하고 1 N 염산 용액으로 중화하였다. 유기층을 분리하여 건조, 농축하여 화학식 2의 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 합성하였다.(2 '- (1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -1H-imidazole-5-carboxylate was added a mixed solvent of purified water and dioxane, lithium hydroxide was added, and the mixture was reacted at room temperature for 2 hours. The reaction was terminated by thin layer chromatography, and the organic solvent was removed by concentration under reduced pressure. Methylene chloride was added to the reaction mixture and neutralized with 1 N hydrochloric acid solution. The organic layer was separated, dried and concentrated to obtain 4- (2-hydroxypropan-2-yl) -2-propyl- ) Biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate.
에틸 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트와 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 1 : 1 로 테트라 하이드로 퓨란 용매에 희석한 후 벤젠술폰산을 첨가하고 5 시간 환류하였다. 반응액을 박막 크로마토그래피로 확인 후 감압 농축하였다. 농축된 잔사에 물과 다이옥산 혼합용매를 가하여 용해한 후 수산화칼륨을 첨가하고 가온하여 2 시간 교반하였다. 반응이 완료된 후 감압 농축하여 용매를 제거하고 염화메틸렌과 증류수를 가하여 추출하고 유기층을 분리하여 건조, 농축 후 컬럼 크로마토그래피로 분리 정제하여 화학식 3을 거쳐 목적화합물인 화학식 4의 1-((2'-(1H-테트라졸-5-일)비페닐-4-일)메틸)-4-(2-(1-((2'-(1H-테트라졸-5-일)비페닐-4-일)메틸)-4-(2-히드록시프로판-2-일)-2-프로필-1H-이미다졸-5-카르복소)프로판-2-일)-2-프로필-1H-이미다졸-5-카르복실산을 얻었다.Yl) methyl) -2-propyl- 1 - ((2 '- (1 -trityl-1H- tetrazol-5-yl) biphenyl- (2 '- (1-trityl-1H-tetrazol-5-yl) Yl) methyl) -1H-imidazole-5-carboxylate was diluted 1: 1 in tetrahydrofuran solvent, benzenesulfonic acid was added, and the mixture was refluxed for 5 hours. The reaction solution was confirmed by thin layer chromatography and then concentrated under reduced pressure. To the concentrated residue, a mixed solvent of water and a dioxane was added and dissolved. Potassium hydroxide was added, and the mixture was warmed and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was extracted with methylene chloride and distilled water. The organic layer was separated, dried, concentrated and purified by column chromatography to obtain 1 - Yl) methyl) -4- (2- (1 - ((2'- (1H-tetrazol-5-yl) Yl) -2-propyl-lH-imidazol-5-yl) - < / RTI & Carboxylic acid.
1H-NMR (DMSO-d6, δ) : 7.676~7.403(m, 8H), 7.017~5.852(m, 8H), 5.586(s, 2H), 5.499(s, 2H), 2.548~2.446(m, 4H), 1.822(s, 6H), 1.542~1.474(m, 10H), 0.833~0.754(m, 6H). IR (KBr, cm-1) : 3396.8, 2968.0, 1704.4, 1632.8, 1461.0, 1383.1, 1158.4, 759.7.(M, 8H), 5.586 (s, 2H), 5.499 (s, 2H), 2.548-2.446 (m, 4H ), 1.822 (s, 6H), 1.542-1.447 (m, 10H), 0.833-0.754 (m, 6H). IR (KBr, cm-1): 3396.8, 2968.0, 1704.4, 1632.8, 1461.0, 1383.1, 1158.4, 759.7.
MS (m/z) = 875.36 (M+).MS (m / z) = 875.36 (M < + >).
시험예Test Example
하기 분석조건으로 수득된 유연물질을 분석하였다.The resulting flexible material was analyzed under the following analysis conditions.
HPLC : Waters - Millenium HPLC: Waters - Millenium
- Detector : 486 - Detector: 486
- Autosampler : 717plus - Autosampler: 717plus
- Pump : 600Controller - Pump: 600Controller
컬럼 : Waters Xterra C8 4.6× 150mm, 5μmColumn: Waters Xterra C8 4.6 x 150 mm, 5 m
이동상 Mobile phase
이동상 A : 완충액 1700mL와 아세토니트릴 300mL를 혼합한 액Mobile phase A: A mixture of 1700 mL of buffer and 300 mL of acetonitrile
이동상 B : 완충액 600mL와 아세토니트릴 1400mL를 혼합한 액Mobile phase B: A mixture of 600 mL of buffer and 1400 mL of acetonitrile
완충액 : 인산이수소칼륨용액 0.015M (10.2을 물 5L에 녹인 후 인산수용액 0.015M로 pH2.8로 조절)Buffer: 0.015 M potassium dihydrogen phosphate solution (10.2 dissolved in 5 L water and adjusted to pH 2.8 with 0.015 M aqueous phosphoric acid solution)
유속 : 1.5mL/minFlow rate: 1.5 mL / min
상기 분석결과를 도 1과 도 2에 나타내었다.The results of the analysis are shown in FIGS. 1 and 2. FIG.
이상에서는 본 발명의 바람직한 실시예에 대해서 설명하였으나, 본 발명은 상술한 특정의 실시예에 한정되지 아니하며, 당해 기술분야에서 통상의 지식을 가진 자라면 본원 발명의 요지를 벗어남이 없이 다양한 변형 실시가 가능함은 물론이다. 따라서, 본 발명의 범위는 위의 실시예에 국한해서 해석되어서는 안되며, 후술하는 특허청구범위 뿐만 아니라 이 특허청구범위와 균등한 것들에 의해 정해져야 할 것이다.While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Of course it is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.
Claims (3)
(B) 에틸 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트를 상기 합성된 4-(2-히드록시프로판-2-일)-2-프로필-1-((2'-(1-트리틸-1H-테트라졸-5-일)비페닐-4-일)메틸)-1H-이미다졸-5-카르복실레이트와 반응시키는 단계
를 포함하는 올메사탄 메독소밀의 유연물질의 제조방법.(A) Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl- ) Methyl) -1H-imidazole-5-carboxylate was reacted with lithium hydroxide to give 4- (2-hydroxypropan-2- -1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate,
(B) Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl- ) Methyl) -1H-imidazole-5-carboxylate was prepared from 4- (2-hydroxypropan-2-yl) Yl) methyl) -1H-imidazole-5-carboxylate in step
≪ / RTI > wherein the method comprises the steps of:
상기 단계 (A)의 합성은 물 및 다이옥산의 혼합 용매에서 수행되는 것을 특징으로 하는 올메사탄 메독소밀의 유연물질의 제조방법.The method according to claim 1,
Wherein the synthesis of step (A) is carried out in a mixed solvent of water and dioxane.
상기 단계 (B)의 반응은 테트라 하이드로 퓨란 및 벤젠술폰산의 존재 하에서 수행되는 것을 특징으로 하는 올메사탄 메독소밀의 유연물질의 제조방법.
The method according to claim 1,
Wherein the reaction of step (B) is carried out in the presence of tetrahydrofuran and benzenesulfonic acid.
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| WO2008020453A2 (en) | 2006-08-17 | 2008-02-21 | Unichem Laboratories Limited | A process for the preparation of a novel crystalline polymorph of aripiprazole |
| WO2008043996A2 (en) | 2006-10-09 | 2008-04-17 | Cipla Limited | Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil |
| WO2009122440A1 (en) | 2008-03-31 | 2009-10-08 | Torrent Pharmaceuticals Ltd. | PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE |
| WO2010026255A1 (en) | 2008-09-05 | 2010-03-11 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing olmesartan medoxomil intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008020453A2 (en) | 2006-08-17 | 2008-02-21 | Unichem Laboratories Limited | A process for the preparation of a novel crystalline polymorph of aripiprazole |
| WO2008043996A2 (en) | 2006-10-09 | 2008-04-17 | Cipla Limited | Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil |
| WO2009122440A1 (en) | 2008-03-31 | 2009-10-08 | Torrent Pharmaceuticals Ltd. | PROCESS FOR THE PREPARATION OF 2-ACETOXY-5-(α -CYCLOPRPYLCARBONYL -2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2-C]PYRIDINE |
| WO2010026255A1 (en) | 2008-09-05 | 2010-03-11 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for preparing olmesartan medoxomil intermediate |
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