KR20120070353A - Method of producing related substance of olmesartan medoxomil - Google Patents
Method of producing related substance of olmesartan medoxomil Download PDFInfo
- Publication number
- KR20120070353A KR20120070353A KR1020100131876A KR20100131876A KR20120070353A KR 20120070353 A KR20120070353 A KR 20120070353A KR 1020100131876 A KR1020100131876 A KR 1020100131876A KR 20100131876 A KR20100131876 A KR 20100131876A KR 20120070353 A KR20120070353 A KR 20120070353A
- Authority
- KR
- South Korea
- Prior art keywords
- biphenyl
- propyl
- methyl
- hydroxypropan
- trityl
- Prior art date
Links
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 7
- UQGKUQLKSCSZGY-UHFFFAOYSA-N Olmesartan medoxomil Chemical compound C=1C=C(C=2C(=CC=CC=2)C2=NNN=N2)C=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C UQGKUQLKSCSZGY-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims abstract 5
- 239000000126 substance Substances 0.000 title abstract description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 12
- TZQDBKJBKJIHPR-UHFFFAOYSA-N ethyl 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound CCCC1=NC(C(C)(C)O)=C(C(=O)OCC)N1CC1=CC=C(C=2C(=CC=CC=2)C=2N(N=NN=2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 TZQDBKJBKJIHPR-UHFFFAOYSA-N 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- -1 2-hydroxypropan-2-yl Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000005480 Olmesartan Substances 0.000 claims description 3
- 229960005117 olmesartan Drugs 0.000 claims description 3
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- WBRMIXBFMUWHHX-UHFFFAOYSA-N 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2N(N=NN=2)C(C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 WBRMIXBFMUWHHX-UHFFFAOYSA-N 0.000 abstract 1
- 239000002245 particle Substances 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021068 Western diet Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
-
- 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
-
- 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
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/02—Lithium compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
본 발명은 올메사탄 메독소밀의 유연물질의 제조방법에 관한 것이다.The present invention relates to a method for producing 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 proportion of risk factors for death worldwide. In particular, hypertension is regarded as the main cause of cardiovascular disease, and such cardiovascular and cerebrovascular disease is the number one cause of death in Korea. As advanced countries progress, the market for chronic diseases including hypertension tends to expand instead of shrinking the antibiotic market due to changes in Western diets and improved hygiene.
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 medication. Angiotensin II receptor antagonists are currently receiving the most attention in the hypertension market. Angiotensin II receptor antagonists have a mechanism of reducing blood pressure by relaxing blood vessels by blocking the action of angiotensin II, a substance having vasoconstrictive action.
상기 안지오텐신Ⅱ 수용체 길항제 가운데에서도 올메사탄 메독소밀은 혈압강하 효과가 우수할 뿐만 아니라, 표적장기손상 보호작용 또한 우수하여 현재 가장 높은 점유율을 갖는 고혈압 치료제이다.Among the angiotensin II receptor antagonists, olmesartan medoxomil is not only excellent in lowering blood pressure, but also in protecting against long-term damage to target organs.
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, a related manufacturing method of olmesartan medoxomil, which is a kind of impurity that may be made during the synthesis of raw materials or the manufacture of finished drugs, has not been established, and thus, it is difficult to prove the quality. In addition, there is a problem that the expensive cost is generated when separating through the decomposition of olmesatan medoxomile, there is an advantage that can lower the manufacturing cost when manufacturing the flexible material through synthesis.
본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로서, 올메사탄 메독소밀의 유연물질의 새로운 제조방법을 제공하는 것을 그 목적으로 한다.The present invention has been made to solve the above problems, and an object thereof is to provide a new method for producing a flexible material of olmesartan medoxo mill.
본 발명 올메사탄 메독소밀의 유연물질의 제조방법은 상술한 바와 같은 목적을 달성하기 위하여, Method for producing a flexible material of the olmesatan medoxomill of the present invention, in order to achieve the object as described above,
(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-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -1H-imidazol-5-carboxylate is reacted with lithium hydroxide to react 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl) Synthesizing -1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate, and
(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-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -1H-imidazole-5-carboxylate was synthesized above 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H) Reacting with -tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate
를 포함한다.It includes.
또한, 상기 단계 (A)의 합성은 물 및 다이옥산의 혼합 용매에서 수행될 수 있다.In addition, the synthesis of step (A) can 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 manufacturing method of the flexible material of olmesatan medoxomill of the present invention is an essential material for evaluating the quality of a pharmaceutical product, and it is possible to identify impurities generated during the manufacturing process, thereby enabling the synthesis of high quality products at low cost. have. In addition, there is an advantage that the quality control can be performed at a low cost from the manufacturer of the Olmesartan Medoc Soybean Mill.
도 1은 HPLC 공시험 차트이다.
도 2는 본 발명의 유연물질에 대한 HPLC 차트이다.1 is an 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.First of all, the term 'related substance' in the present specification refers to a kind of impurity that is likely to be produced during raw material synthesis or final drug manufacturing. Such flexible materials should only be contained below the standard in the final pharmaceutical product and are used for quality verification.
본 발명의 반응과정을 정리하면 하기 반응식과 같다.In summary, the reaction process of the present invention is shown in the following reaction formula.
[반응식]
[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.Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl of formula 1 After adding a mixed solvent of purified water and dioxane to the methyl) -1H-imidazole-5-carboxylate, lithium hydroxide was added and reacted at room temperature for 2 hours. The reaction was confirmed by thin layer chromatography, concentrated under reduced pressure to remove the organic solvent, and methylene chloride was added thereto and neutralized with 1N hydrochloric acid solution. The organic layer was separated, dried and concentrated to give 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl). ) Biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate was synthesized.
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.Ethyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate and 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5- I) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate was diluted 1: 1 with tetrahydrofuran solvent and benzenesulfonic acid was added and refluxed for 5 hours. The reaction solution was confirmed by thin layer chromatography, and then concentrated under reduced pressure. Water and dioxane mixed solvents were added to the concentrated residue to dissolve it, potassium hydroxide was added thereto, warmed, and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, followed by extraction with methylene chloride and distilled water. The organic layer was separated, dried, concentrated and separated and purified by column chromatography to obtain the title compound, 1-((2 '). -(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -4- (2- (1-((2 '-(1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -4- (2-hydroxypropan-2-yl) -2-propyl-1H-imidazole-5-carboxy) propan-2-yl) -2-propyl-1H-imidazole-5- Carboxylic acid was obtained.
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, 759.7.1H-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.
MS (m/z) = 875.36 (M+).MS (m / z) = 875.36 (M < + >).
시험예Test Example
하기 분석조건으로 수득된 유연물질을 분석하였다.The analog obtained under the following analytical conditions was analyzed.
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 × 150mm, 5μm
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 buffer and 1400 mL acetonitrile
완충액 : 인산이수소칼륨용액 0.015M (10.2을 물 5L에 녹인 후 인산수용액 0.015M로 pH2.8로 조절)Buffer solution: 0.015M potassium dihydrogen phosphate solution (dissolve 10.2 in 5L of water and adjust the pH to 2.8 with 0.015M aqueous phosphate solution)
유속 : 1.5mL/minFlow rate: 1.5mL / min
상기 분석결과를 도 1과 도 2에 나타내었다.The analysis results are shown in FIGS. 1 and 2.
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.In the above description of the preferred embodiment of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art various modifications without departing from the gist of the present invention 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-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -1H-imidazol-5-carboxylate is reacted with lithium hydroxide to react 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl) Synthesizing -1H-tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate, and
(B) ethyl 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl ) Methyl) -1H-imidazole-5-carboxylate was synthesized above 4- (2-hydroxypropan-2-yl) -2-propyl-1-((2 '-(1-trityl-1H) Reacting with -tetrazol-5-yl) biphenyl-4-yl) methyl) -1H-imidazole-5-carboxylate
Method for producing a flexible material of olmesatan medoxomil comprising a.
상기 단계 (A)의 합성은 물 및 다이옥산의 혼합 용매에서 수행되는 것을 특징으로 하는 올메사탄 메독소밀의 유연물질의 제조방법.The method according to claim 1,
Synthesis of step (A) is a method for producing a flexible material of olmesartan medoxo mill, characterized in that 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,
The reaction of step (B) is a method for producing a flexible material of olmesartan medoxomil, characterized in that is carried out in the presence of tetrahydrofuran and benzenesulfonic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100131876A KR101696851B1 (en) | 2010-12-21 | 2010-12-21 | Method of Producing Related Substance of Olmesartan Medoxomil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100131876A KR101696851B1 (en) | 2010-12-21 | 2010-12-21 | Method of Producing Related Substance of Olmesartan Medoxomil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20120070353A true KR20120070353A (en) | 2012-06-29 |
| KR101696851B1 KR101696851B1 (en) | 2017-01-17 |
Family
ID=46688227
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020100131876A KR101696851B1 (en) | 2010-12-21 | 2010-12-21 | Method of Producing Related Substance of Olmesartan Medoxomil |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101696851B1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650046A (en) * | 2015-01-27 | 2015-05-27 | 吉林修正药业新药开发有限公司 | Synthesis method of olmesartan dimer |
| CN111004223A (en) * | 2020-03-11 | 2020-04-14 | 长沙晨辰医药科技有限公司 | Preparation and separation method of olmesartan medoxomil dimer impurities |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2010
- 2010-12-21 KR KR1020100131876A patent/KR101696851B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104650046A (en) * | 2015-01-27 | 2015-05-27 | 吉林修正药业新药开发有限公司 | Synthesis method of olmesartan dimer |
| CN111004223A (en) * | 2020-03-11 | 2020-04-14 | 长沙晨辰医药科技有限公司 | Preparation and separation method of olmesartan medoxomil dimer impurities |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101696851B1 (en) | 2017-01-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102417830B1 (en) | Novel acid addition salt of 1-(5-(2,4-difluorophenyl)-1-((3-fluorophenyl)sulfonyl)-4-methoxy-1h-pyrrol-3-yl)-n-methylmethanamine | |
| CN109422752B (en) | Compound with functions of inhibiting and degrading Bruton tyrosine protein kinase Btk activity | |
| US9663497B2 (en) | Benzoimidazol-2-yl pyrimidine modulators of the histamine H4 receptor | |
| KR102171120B1 (en) | Substituted 2-thioxo-imidazolidin-4-ones and spiro analogues thereof, active anti-cancer ingredient, pharmaceutical composition, medicinal preparation, method for treating prostate cancer | |
| JP6704422B2 (en) | Quinazoline derivative salt and method for producing the same | |
| EP3177616B1 (en) | Novel routes of synthesis for the preparation of suvorexant | |
| KR101378260B1 (en) | Serotonin and norepinephrine reuptake inhibitor | |
| AU2019224344A1 (en) | Compound having S1P5 receptor agonist activity | |
| KR20120070353A (en) | Method of producing related substance of olmesartan medoxomil | |
| KR101316653B1 (en) | Manufacturing Method Of Hetero Cyclic Compound | |
| KR20140009564A (en) | Pyrazole derivatives useful as aldosterone synthase inhibitors | |
| KR101523264B1 (en) | Method of producing related substance of olmesartan medoxomil | |
| AU2016361026B2 (en) | Method for purifying benzopyran derivative, crystal form thereof, and method for preparing crystal form | |
| KR20200057662A (en) | The derivative compounds of Azilsartan, intermediates thereof, preparation thereof and pharmaceutical composition comprising the same | |
| US9822101B1 (en) | Pyrazole compounds | |
| CN104230909B (en) | A kind of preparation method of Azilsartan | |
| US9371311B2 (en) | Benzoimidazol-2-yl pyrimidine derivatives | |
| RU2207340C2 (en) | Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazole-4-one or its pharmaceutically acceptable salts | |
| CN103328446B (en) | Be used for the treatment of the new 4-Amino-N-hydroxy-benzamide of cancer | |
| KR101009404B1 (en) | Preparation of high purity S-N-1-carboxy-2-methyl-pro-1-phyl-N-pentanoyl-N-[2?-1H-tetrazol-5-ylbiphenyl-4-yl-methyl]amine | |
| KR101897797B1 (en) | Cyclic amino substituted 5-arylfuran-2-carboxamide, preparation method thereof, and pharmaceutical composition for use in preventing or treating Urotensin-Ⅱ receptor activity related diseases containing the same as an active ingredient | |
| EP4073059A1 (en) | Cgrp antigonists useful as tracer compounds for positron emission tomography | |
| WO2003066627A1 (en) | Deuterated spirocyclopentanimidazolinones and the use thereof in the treatment of cardiovascular diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| N231 | Notification of change of applicant | ||
| A201 | Request for examination | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20191231 Year of fee payment: 4 |