CN102459243A - 奥美沙坦酯制造工艺 - Google Patents
奥美沙坦酯制造工艺 Download PDFInfo
- Publication number
- CN102459243A CN102459243A CN2010800314916A CN201080031491A CN102459243A CN 102459243 A CN102459243 A CN 102459243A CN 2010800314916 A CN2010800314916 A CN 2010800314916A CN 201080031491 A CN201080031491 A CN 201080031491A CN 102459243 A CN102459243 A CN 102459243A
- Authority
- CN
- China
- Prior art keywords
- acid
- technology
- olmesartan
- olmesartan medoxomill
- medoxomill
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 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 11
- 239000002051 C09CA08 - Olmesartan medoxomil Substances 0.000 title claims abstract description 9
- 229960001199 olmesartan medoxomil Drugs 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 48
- 239000012535 impurity Substances 0.000 claims abstract description 23
- 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 66
- 239000005480 Olmesartan Substances 0.000 claims description 65
- 229960005117 olmesartan Drugs 0.000 claims description 65
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- 238000005516 engineering process Methods 0.000 claims description 29
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000003495 polar organic solvent Substances 0.000 claims description 22
- IJOPLMOXIPGJIJ-UHFFFAOYSA-N (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 5-(2-hydroxypropan-2-yl)-2-propyl-3-[[4-[2-(1-trityltetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylate Chemical compound C=1C=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=CC=1CN1C(CCC)=NC(C(C)(C)O)=C1C(=O)OCC=1OC(=O)OC=1C IJOPLMOXIPGJIJ-UHFFFAOYSA-N 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 150000002576 ketones Chemical class 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 230000003197 catalytic effect Effects 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 150000002825 nitriles Chemical class 0.000 claims description 5
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims description 3
- 229940005991 chloric acid Drugs 0.000 claims description 3
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940077239 chlorous acid Drugs 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- 239000000243 solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 7
- 239000003513 alkali Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 2
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940055053 benicar Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 229960002198 irbesartan Drugs 0.000 description 2
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 2
- 229960004773 losartan Drugs 0.000 description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 2
- -1 methyl-propyl Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
- 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 class 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 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明改进了奥美沙坦酯制造工艺,所得奥美沙坦酯不含OLM-酸,消除物和乙酸杂质含量低。
Description
技术领域
本发明改进了奥美沙坦酯(olmesartan medoxomil)制造工艺,所得奥美沙坦酯不含OLM-酸,消除物(eliminate)和乙酸杂质含量低。
技术领域
抗高血压药属于称为“沙坦”的一类血管紧张素II拮抗剂。这包括奥美沙坦(olmesartan)、坎地沙坦(Candesartan)、厄贝沙坦(Irbesartan)、洛沙坦(Losartan)和缬沙坦(Valsartan)。它们是强血管扩张剂,通过阻抑血管紧张素II受体的活性起作用。美国专利5,616,599(‘599专利)记载了奥美沙坦酯,2,3-二羟基-2-丁烯基-4-(1-羟基-1-甲基乙基)-2-丙基-1-[p-(o-1H-四唑-5-基苯基)苄基]咪唑-5-羧酸酯,环2,3-碳酸酯,具有结构式I所示结构:
已知有数种制备奥美沙坦酯的方法,例如以下专利和申请中所述:美国专利5,616,599和5,763,619;美国专利申请公开2005/0119488;2006/0148870;2006/0069141;2006/0074117;2007/0054948;2010/0076200;以及PCT公开WO2006/050922,WO2007/048361和WO 2005/021535,以上均通过引用纳入本申请。
‘599专利记载了一种制备奥美沙坦酯的方法,包括在60℃用70%乙酸水溶液将三苯甲基奥美沙坦酯(MTT)去保护。‘599专利所述方法产生一种凝胶状产物,该产物在工业化工艺中很难处理,并且,该方法的得率较低,所得奥美沙坦酯含2.2%OLM-酸(HPLC面积百分比)。Benicar含0.3%OLM-酸(HPLC面积百分比)。
美国专利公开2006/0069141记载了一种制备奥美沙坦酯的工艺,包括将三苯甲基奥美沙坦酯与酸例如硫酸、水和与水互溶的有机溶剂例如丙酮接触。‘141申请所述方法产生的奥美沙坦酯含约0.89% OLM-酸。
美国专利申请2006/0074117和2010/0076200记载了一种纯化奥美沙坦酯的方法,包括将搅拌奥美沙坦酯的C3-6酮溶液,然后加入水。2006/0074117和2010/0076200申请所述方法所得奥美沙坦酯中的OLM酸少于0.03%。美国专利公开2007/0054948的奥美沙坦酯中OLM-酸少于约0.12%(HPLC面积百分比)。
以上文献中所述方法可能需用大量溶剂来进行最后的纯化,然后进行层析,多次萃取或共沸蒸馏。并且,其中的方法可能需用强腐蚀性的酸或回流条件,这些在工业化生产中很难处理。
所以,需要更好工艺,其简单、经济,能以更高的产率生产杂质含量更低的纯奥美沙坦酯。
发明概述
总的来说,本发明的内容之一是提供制备奥美沙坦酯的工艺。所述工艺包括:a)将催化量的强酸与三苯甲基奥美沙坦酯在弱酸与水混合物中所成的溶液或悬浮液混合;b)分离奥美沙坦酯;c)将步骤(b)所得奥美沙坦酯溶于极性有机溶剂;d)分离纯的晶体奥美沙坦酯。
本发明的实施方式可具有一项或多项以下特征。例如,所述强酸可以是高氯酸,氯酸,亚氯酸,次氯酸,硫酸,亚硫酸,硝酸,磷酸,碳酸,盐酸或三氟乙酸。所述催化量的强酸可以是三苯甲基奥美沙坦酯的约1至1.5摩尔当量。
所述弱酸可以是乙酸。乙酸可含有约1∶1的水。
所述工艺还可以包括在步骤a)中将反应混合物的温度提高至约25℃至35℃。所述工艺还可包括在步骤c)中在约40℃至溶剂回流温度之间加热反应混合物。
所述极性有机溶剂可以是腈,酮或醇。所述极性有机溶剂可以是乙腈、丙酮、乙基甲基酮、2-戊酮、3-戊酮、乙醇或甲醇。
总的来说,本发明还提供一种纯化奥美沙坦酯的工艺。所述工艺包括:a)将不含OLM-酸杂质的奥美沙坦酯溶于极性有机溶剂;和b)分离纯的晶体奥美沙坦酯。
本发明的实施方式可具有一项或多项以下特征。例如,所述工艺还可包括在步骤a)中在约40℃至溶剂回流温度之间加热反应混合物
所述极性有机溶剂可以是腈,酮或醇。所述极性有机溶剂可以是乙腈、丙酮、乙基甲基酮、2-戊酮、3-戊酮、乙醇或甲醇。
总的来说,本发明还提供了不含乙酸和/或OLM-酸的奥美沙坦酯。
总的来说,本发明还提供了OLM-消除物杂质含量低于约0.05%的奥美沙坦酯。
最后,总的来说,本发明还提供了据HPLC面积百分比测算,在RRT 0.34和1.15没有可测质量杂质的奥美沙坦酯。
详细描述
本发明提供改进型奥美沙坦酯制备工艺,包括以下步骤:
a)将三苯甲基奥美沙坦酯的溶液或悬浮液加入弱酸与水混合物;
b)加入催化量的强酸;或者,将三苯甲基奥美沙坦酯加入催化量的强酸、水和弱酸的溶液或悬浮液;
c)分离奥美沙坦酯;
d)将步骤(c)所得奥美沙坦酯溶于极性有机溶剂;
e)分离纯的晶体奥美沙坦酯。
三苯甲基奥美沙坦酯可用已知方法来制备,包括背景部分所引用文献中所述的那些。
可将三苯甲基奥美沙坦酯加入弱酸与水的混合物或两种或更多种酸与水的混合物。
用于制备三苯甲基奥美沙坦酯水溶液或水悬浮液的弱酸可以是有机酸,优选乙酸。水与有机酸例如乙酸的比例优选约2∶1至1∶2,更优选约1∶1。可向所述溶液或悬浮液中添加催化量的强酸。强酸的pH可以为0至4。
合适的强酸包括高氯酸,氯酸,亚氯酸,次氯酸,硫酸,亚硫酸,硝酸,亚硝酸,磷酸,碳酸,盐酸或三氟乙酸。优选硫酸。较好的是,所用催化量的酸是三苯甲基奥美沙坦酯酸的约1-2摩尔当量,更优选约1-1.5摩尔当量,最优选约1摩尔当量。
添加强酸可能需要约10至25分钟。可将反应混合物冷却至约5℃-15℃。可对含三苯甲基奥美沙坦酯的反应混合物搅拌约25分钟至4小时。该去三苯甲基反应可在约0℃至35℃之间的温度进行,优选室温。
优选实施方式中,所述酸或混合酸通过形成沉淀去除三苯基甲醇,但不生成任何奥美沙坦酯的酸成盐。可在分离三苯基甲醇之前添加丙酮,以防生成杂质。较好的是,丙酮的用量约为酸-水混合物体积的1/4。三苯基甲醇沉淀过程中会形成不同的沉淀颗粒,悬浮在悬浮液中,或沉积在溶液所在容器的底部。
可采用诸如过滤或离心等已知方法从溶液中去除三苯基甲醇沉淀。
分离出三苯基甲醇后,在奥美沙坦酯溶液中加入碱。碱在此用于中和所用催化量的酸。合适的碱包括碱金属和碱土金属氢氧化物、碳酸盐和碳酸氢盐。具体如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、碳酸钠、碳酸钾、碳酸钙、碳酸氢钠和碳酸氢钾。优选碳酸钾和碳酸钠。
分离无OLM-酸的奥美沙坦酯粗品包括在与碱接触后用卤化物溶剂萃取反应混合物。
合适的卤化物溶剂的例子包括氯仿、二氯甲烷、二氯乙烷等。优选用二氯甲烷萃取。用已知方法去除溶剂,例如旋真空转蒸发或蒸馏。
溶剂回收后的产物呈油状。将该油状产物溶于水互溶性溶剂,例如二噁烷、四氢呋喃、酮、醇或乙腈。优选乙腈。首次以水互溶性溶剂溶解后对所得产物重复溶解步骤,从而获得不含OLM-酸且杂质含量低的结晶奥美沙坦酯。
另一方面,本发明提供了一种纯化奥美沙坦酯的工艺。所述工艺包括以下步骤:
a)以极性有机溶剂制备无OLM-酸的奥美沙坦酯溶液;
b)分离纯的晶体奥美沙坦酯。
合适的极性有机溶剂包括:腈,酮和醇。优选溶剂有乙腈,丙酮,乙基甲基酮,2-戊酮,3-戊酮,乙醇和甲醇。较好的是,所用极性有机溶剂为酮溶剂,例如丙酮。酮的优选量是至少约4体积酮比约1克固体奥美沙坦酯,更好的是至少约3体积酮比约1克固体奥美沙坦酯,最好至少约2体积酮比约1克固体奥美沙坦酯。
所述工艺可进一步包括加热奥美沙坦酯粗品在极性有机溶剂中的溶解反应。较好的是,将奥美沙坦酯的极性有机溶剂溶液加热至约40℃至回流温度,约50℃至回流温度更好。
可将由此所得溶液冷却至约25℃-35℃。在溶液中加入活性炭处理约20分钟到35分钟。经活性炭处理的溶液用流化床(hyflobed)过滤,然后用极性有机溶剂洗涤。用于洗涤的极性有机溶剂用量优选约0.2至0.4体积的极性有机溶剂,0.2体积更好。所述工艺还包括在35℃-45℃将滤液合并后浓缩为约1体积的总体积。可将浓缩溶液冷却至约15℃至约25℃,并搅拌约3-4小时。
可用各种已知方法回收不含OLM-酸且仅低量消除物和乙酸杂质的纯晶体奥美沙坦酯,例如离心或过滤,过滤可能后续还需用极性有机溶剂洗涤。可用各种干燥方法诸如真空干燥或空气干燥在45℃至55℃干燥所得晶体奥美沙坦酯。
根据优选实施方式之一,本发明工艺所得奥美沙坦酯没有可测知量的乙酸和/或OLM-酸杂质。
本发明实施方式之一提供基本纯的奥美沙坦酯,“基本纯”表示奥美沙坦酯最终产物不含OLM-酸,仅含低量消除物和乙酸杂质。
本发明的另一实施方式提供的基本纯奥美沙坦酯含低于约0.1%的消除物杂质,低于约0.07%更好,最好低于约0.05%。
本发明的另一实施方式提供的基本纯奥美沙坦酯仅含可能构成杂质的低量乙酸杂质。
据本发明的另一实施方式,本发明工艺所得奥美沙坦酯的HPLC纯度高于约99%,高于约99.77%更好。
具体实施方式之一中,据HPLC面积百分比测算,奥美沙坦酯在RRT 0.34和1.15没有可测知量的杂质。
由此所得奥美沙坦酯可与药学上可接受的赋形剂一起用于制备可用于人高血压的药物组合物。
以下将通过实施例来描述本发明的工艺。然而,这些并非对本发明范围的限定。以下实施例的多种变异形式对本领域技术人员来说显而易见。
实施例
实施例1:奥美沙坦酯的制备
将三苯甲基奥美沙坦酯(100gm)加入乙酸与水的混合物(1∶1;400mL),将此悬浮液的温度调至10℃-15℃。在10℃-15℃,用15分钟,向反应混合物中缓慢加入硫酸(12.2gm)(1摩尔当量)。将反应混合物的温度升至25℃-30℃,搅拌45分钟,过滤去除三苯基甲醇。向滤液中加入碳酸钠溶液(25%w/v,100mL),用二氯甲烷(500mL)萃取产物,然后回收溶剂。分离出产物,用乙腈(300mL)重结晶,过滤,洗涤,然后减压干燥,得奥美沙坦酯粗品。
产率:80%
HPLC纯度:99.77%
OLM-酸:未测得
OLM-消除物:0.05%
乙酸含量:未测得
实施例2:奥美沙坦酯的制备
三苯甲基奥美沙坦酯在乙酸和水(1∶1,400mL)及硫酸(12.2gm)(1摩尔当量)中的混合物在25℃-30℃搅拌45-60分钟。过滤去除三苯基甲醇,滤液用乙酸与水的混合物(1∶1,50mL)洗涤。向滤液中加入碳酸钠溶液(25%w/v,100mL),用二氯甲烷(500mL)萃取产物,然后回收溶剂。分离出产物,用乙腈(300mL)重结晶,过滤,洗涤,然后减压干燥,得奥美沙坦酯粗品。
产率:90%
HPLC纯度:99.29%
OLM-酸:未测得
OLM-消除物:0.07%
乙酸含量:未测得
实施例3:奥美沙坦酯(粗品)的纯化
在55℃-60℃将奥美沙坦酯粗品(10gm)溶于丙酮(2000mL),将溶液冷却至45℃。溶液在此温度用活性炭处理30分钟。经活性炭处理的反应混合物在40℃用流化床过滤,并用丙酮(2X 100mL)洗涤。合并滤液,于40℃-45℃浓缩至1000mL总体积,冷却至25℃,在25℃-30℃搅拌2小时。过滤后收集产物,用丙酮(2x 50mL)洗涤,于45℃-50℃减压干燥。
产率:90%
实施例4:奥美沙坦酯杂质情况的测定
用分析化学方法对本发明奥美沙坦酯中的杂质进行了鉴定和定量,据测定,水解杂质,即OLM-酸已完全消除,其它可能的杂质,诸如消除物和甲基丙基类似物杂质已被降至低水平,此为上述物质各自RRT的HPLC分析结果,其中,OLM-酸的RRT为0.34,消除物杂质的为1.23,甲基丙基类似物杂质的为1.15。在一特定实施方式中,据HPLC测定,在RRT 0.34和1.15,奥美沙坦酯没有可测知量的杂质(图1)。
Claims (16)
1.一种制造奥美沙坦酯的工艺,包括:
a)将催化量的强酸与三苯甲基奥美沙坦酯在弱酸与水混合物中形成的溶液或悬浮液混合;
b)分离奥美沙坦酯;
c)将步骤(b)所得奥美沙坦酯溶于极性有机溶剂;和
d)分离纯晶体奥美沙坦酯。
2.如权利要求1所述的工艺,所述强酸包括高氯酸、氯酸、亚氯酸、次氯酸、硫酸、亚硫酸、硝酸、磷酸、碳酸、盐酸或三氟乙酸。
3.如权利要求1所述的工艺,所述催化量的强酸包含三苯甲基奥美沙坦酯的约1-1.5摩尔当量。
4.如权利要求1所述的工艺,所述弱酸包括乙酸。
5.如权利要求4所述的工艺,所述乙酸还包含1∶1的水。
6.如权利要求1所述的工艺,还包括将步骤a)中反应混合物的温度提高至约25-35℃。
7.如权利要求1所述的工艺,还包括在约40℃至溶剂回流温度之间的温度加热步骤c)中的反应混合物。
8.如权利要求1所述的工艺,所述极性有机溶剂包含腈、酮或醇。
9.如权利要求1所述的工艺,所述极性有机溶剂包括乙腈、丙酮、乙基甲基酮、2-戊酮、3-戊酮、乙醇或甲醇。
10.一种纯化奥美沙坦酯的方法,包括:
a)将不含OLM-酸杂质的奥美沙坦酯溶于极性有机溶剂;和
b)分离纯晶体奥美沙坦酯。
11.如权利要求10所述的工艺,还包括在约40℃至溶剂回流温度之间的温度加热步骤a)中的反应混合物。
12.如权利要求10所述的工艺,所述极性有机溶剂包括腈、酮或醇。
13.如权利要求10所述的工艺,所述极性有机溶剂包括乙腈、丙酮、乙基甲基酮、2-戊酮、3-戊酮、乙醇或甲醇。
14.不含乙酸或OLM-酸杂质的奥美沙坦酯。
15.OLM-消除物杂质低于约0.05%的奥美沙坦酯。
16.据HPLC面积百分比测算,在RRT0.34和1.15无可测知量杂质的奥美沙坦酯。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1037DE2009 | 2009-05-20 | ||
IN1037/DEL/2009 | 2009-05-20 | ||
PCT/IB2010/052260 WO2010134052A1 (en) | 2009-05-20 | 2010-05-20 | Process for the preparation of olmesartan medoxomil |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102459243A true CN102459243A (zh) | 2012-05-16 |
Family
ID=42306735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010800314916A Pending CN102459243A (zh) | 2009-05-20 | 2010-05-20 | 奥美沙坦酯制造工艺 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20120184750A1 (zh) |
EP (1) | EP2432777A1 (zh) |
JP (1) | JP2012527446A (zh) |
KR (1) | KR20120046115A (zh) |
CN (1) | CN102459243A (zh) |
AP (1) | AP2011005999A0 (zh) |
AU (1) | AU2010250827A1 (zh) |
BR (1) | BRPI1010969A2 (zh) |
CA (1) | CA2762846A1 (zh) |
EA (1) | EA201171413A1 (zh) |
MX (1) | MX2011012460A (zh) |
WO (1) | WO2010134052A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447208A (zh) * | 2014-11-28 | 2015-03-25 | 山东新华制药股份有限公司 | 从奥美沙坦酯生产废液中回收三苯基甲醇的方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ305129B6 (cs) * | 2010-11-24 | 2015-05-13 | Zentiva, K.S. | (5-Methyl-2-oxo-1,3-dioxol-4-ylmethyl)-4-(1-hydroxy-1-methyl-propyl)-2-propyl-1-[2´-(1H-tetrazol-5-yl)bifenyl-4-yl-methyl]imidazol-5-karboxylát jako nečistota olmesartan medoxomilu a způsob jeho přípravy |
KR101418871B1 (ko) * | 2012-08-28 | 2014-07-17 | 한국과학기술연구원 | 올메사탄 메독소밀의 정제방법 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
CN1976926A (zh) * | 2004-09-02 | 2007-06-06 | 特瓦制药工业有限公司 | 奥美沙坦酯的制备 |
CN101094850A (zh) * | 2005-01-03 | 2007-12-26 | 特瓦制药工业有限公司 | 具有较低水平杂质的奥美沙坦酯 |
CN101094849A (zh) * | 2004-12-30 | 2007-12-26 | 特瓦制药工业有限公司 | 在ph高于2.5的情况下制备奥美沙坦酯的方法 |
WO2008043996A2 (en) * | 2006-10-09 | 2008-04-17 | Cipla Limited | Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69517832T2 (de) | 1994-01-28 | 2000-11-09 | Takeda Chemical Industries, Ltd. | Ein Verfahren zur Herstellung von Tetrazolyl-Verbindungen |
WO2005021535A2 (en) | 2003-08-27 | 2005-03-10 | Zentiva, A.S. | A method of removing the triphenylmethane protecting group |
ITMI20032338A1 (it) | 2003-11-28 | 2005-05-29 | Dinamite Dipharma S P A In Forma A Bbreviata Diph | Composti feniltetrazolici. |
US20070054948A1 (en) | 2004-09-02 | 2007-03-08 | Lilach Hedvati | Purification of olmesartan medoxomil |
CA2575177A1 (en) * | 2004-09-02 | 2006-03-16 | Teva Pharmaceutical Industries Ltd. | Purification of olmesartan medoxomil |
WO2006050922A1 (en) | 2004-11-11 | 2006-05-18 | Lek Pharmaceuticals D.D. | Process for the synthesis of tetrazoles |
CZ299902B6 (cs) | 2005-10-27 | 2008-12-29 | Zentiva, A. S | Zpusob odstranování trifenylmethanové chránicí skupiny u prekurzoru antihypertenzních léciv |
WO2007148344A2 (en) * | 2006-06-19 | 2007-12-27 | Matrix Laboratories Limited | Process for the preparation of olmesartan medoxomil |
-
2010
- 2010-05-20 EA EA201171413A patent/EA201171413A1/ru unknown
- 2010-05-20 AP AP2011005999A patent/AP2011005999A0/xx unknown
- 2010-05-20 AU AU2010250827A patent/AU2010250827A1/en not_active Abandoned
- 2010-05-20 CN CN2010800314916A patent/CN102459243A/zh active Pending
- 2010-05-20 CA CA2762846A patent/CA2762846A1/en not_active Abandoned
- 2010-05-20 US US13/321,231 patent/US20120184750A1/en not_active Abandoned
- 2010-05-20 MX MX2011012460A patent/MX2011012460A/es not_active Application Discontinuation
- 2010-05-20 WO PCT/IB2010/052260 patent/WO2010134052A1/en active Application Filing
- 2010-05-20 BR BRPI1010969A patent/BRPI1010969A2/pt unknown
- 2010-05-20 EP EP10722780.3A patent/EP2432777A1/en not_active Withdrawn
- 2010-05-20 KR KR1020117030196A patent/KR20120046115A/ko not_active Application Discontinuation
- 2010-05-20 JP JP2012511401A patent/JP2012527446A/ja active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5616599A (en) * | 1991-02-21 | 1997-04-01 | Sankyo Company, Limited | Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use |
CN1976926A (zh) * | 2004-09-02 | 2007-06-06 | 特瓦制药工业有限公司 | 奥美沙坦酯的制备 |
CN1993355A (zh) * | 2004-09-02 | 2007-07-04 | 特瓦制药工业有限公司 | 奥美沙坦酯的纯化方法 |
CN101094849A (zh) * | 2004-12-30 | 2007-12-26 | 特瓦制药工业有限公司 | 在ph高于2.5的情况下制备奥美沙坦酯的方法 |
CN101094850A (zh) * | 2005-01-03 | 2007-12-26 | 特瓦制药工业有限公司 | 具有较低水平杂质的奥美沙坦酯 |
WO2008043996A2 (en) * | 2006-10-09 | 2008-04-17 | Cipla Limited | Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447208A (zh) * | 2014-11-28 | 2015-03-25 | 山东新华制药股份有限公司 | 从奥美沙坦酯生产废液中回收三苯基甲醇的方法 |
CN104447208B (zh) * | 2014-11-28 | 2016-08-24 | 山东新华制药股份有限公司 | 从奥美沙坦酯生产废液中回收三苯基甲醇的方法 |
Also Published As
Publication number | Publication date |
---|---|
EA201171413A1 (ru) | 2012-09-28 |
JP2012527446A (ja) | 2012-11-08 |
AU2010250827A1 (en) | 2012-01-19 |
US20120184750A1 (en) | 2012-07-19 |
WO2010134052A1 (en) | 2010-11-25 |
EP2432777A1 (en) | 2012-03-28 |
BRPI1010969A2 (pt) | 2019-01-15 |
CA2762846A1 (en) | 2010-11-25 |
KR20120046115A (ko) | 2012-05-09 |
MX2011012460A (es) | 2012-04-20 |
AP2011005999A0 (en) | 2011-12-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4511550B2 (ja) | オルメサルタンメドキソミルの調製法 | |
CA2707334C (en) | A process for the preparation or purification of olmesartan medoxomil | |
CN103664920B (zh) | 阿奇沙坦中间体及其与阿奇沙坦的制备方法 | |
JP2009527509A5 (zh) | ||
CN109761924B (zh) | 一种改进的缬沙坦反应混合液的后处理方法 | |
KR20080034448A (ko) | 5-치환된 테트라졸의 분리방법 | |
CN102459243A (zh) | 奥美沙坦酯制造工艺 | |
CN102816172A (zh) | 一种头孢孟多酯钠的制备工艺 | |
WO2011036674A1 (en) | A new process for the preparation of olmesartan medoxomil | |
CN102617601A (zh) | 一种头孢地尼的制备方法 | |
CN102234313A (zh) | 一种匹多莫德的合成方法 | |
WO2008111016A1 (en) | Process for the preparation of pure prulifloxacin | |
CN114845713A (zh) | 制备高纯度缬沙坦的方法 | |
US20130190506A1 (en) | Process for olmesartan medoxomil | |
EP2167477B1 (en) | Process for preparing pure valsartan | |
CN104418855A (zh) | 制备帕利哌酮和其中间体的改进的方法 | |
KR100809159B1 (ko) | 로사탄의 개선된 제조방법 | |
CN101328167B (zh) | 一种洛沙坦的制备方法 | |
CN104230909B (zh) | 一种阿齐沙坦的制备方法 | |
CN102863398B (zh) | 一种沙坦类药物中间体的合成方法以及该中间体的应用 | |
CN103304543A (zh) | 一种坎地沙坦酯的制备方法 | |
CN107325092B (zh) | 一种阿奇沙坦的制备新工艺 | |
EP2022790A1 (en) | A process for the preparation or purification of olmesartan medoxomil | |
CN104072490A (zh) | 一种阿奇沙坦关键中间体的制备方法 | |
KR101257272B1 (ko) | 탈보호화 반응을 이용한 고혈압 치료용 비페닐테트라졸 화합물의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120516 |