CN102666522A - 决奈达隆的新的制备方法 - Google Patents
决奈达隆的新的制备方法 Download PDFInfo
- Publication number
- CN102666522A CN102666522A CN2010800580717A CN201080058071A CN102666522A CN 102666522 A CN102666522 A CN 102666522A CN 2010800580717 A CN2010800580717 A CN 2010800580717A CN 201080058071 A CN201080058071 A CN 201080058071A CN 102666522 A CN102666522 A CN 102666522A
- Authority
- CN
- China
- Prior art keywords
- formula
- salt
- compound
- butyl
- cumarone
- 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 25
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 229960002084 dronedarone Drugs 0.000 title description 7
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 229910052728 basic metal Inorganic materials 0.000 claims description 11
- 150000003818 basic metals Chemical class 0.000 claims description 11
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 claims description 10
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 7
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 229910003002 lithium salt Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 229920004449 Halon® Polymers 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- -1 alkali metal salt Chemical class 0.000 claims description 3
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 abstract 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 abstract 1
- 239000000047 product Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 229960002919 dronedarone hydrochloride Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- HACDESLXZXBASP-UHFFFAOYSA-N CCCCc1cc2cc(NS(C)(=O)=O)ccc2[o]1 Chemical compound CCCCc1cc2cc(NS(C)(=O)=O)ccc2[o]1 HACDESLXZXBASP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 0 CCCCN(CCCC)CC*(C)Oc(cc1)ccc1C(Cl)=O Chemical compound CCCCN(CCCC)CC*(C)Oc(cc1)ccc1C(Cl)=O 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052784 alkaline earth metal Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000010953 base metal Substances 0.000 description 1
- CSCFNOKJIMTZSC-UHFFFAOYSA-N benzoyl chloride;hydrochloride Chemical compound Cl.ClC(=O)C1=CC=CC=C1 CSCFNOKJIMTZSC-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000012679 convergent method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种式(I)的N-[2-正丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺的新的制备方法及该制备方法的新中间体。
Description
本发明涉及一种式I的N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺(决奈达隆(Dronedarone))及其可药用盐的新的制备方法和该制备方法的新中间体。
式I的决奈达隆用于治疗心血管系统的某些病理性变化，具体用于治疗心绞痛、高血压、心律不齐及脑血液循环不足(EP 0471609B1)。
存在几种用于制备式I的决奈达隆的已知方法。公开号WO 02/48132的专利申请公开了下列的超汇集方法(super-convergent method)：
将式IV的5-氨基-2-丁基-苯并呋喃甲磺酰化，
并在Friedel-Crafts条件下，将所得式II的2-丁基-5-甲磺酰胺基-苯并呋喃与式III的4-[3-(二丁基氨基)丙氧基]-苯甲酰氯盐酸盐反应，
以获得式I的决奈达隆盐酸盐。
此方法在反应步骤数方面非常简单经济。然而，其缺点在于最后步骤中获得实质上被污染形式的决奈达隆盐酸盐。此可解释为Friedel-Crafts反应中二丁基氨基-丙基的存在。在公开实施例中产率为90%，在纯化步骤期间，首先，纯化粗品决奈达隆盐酸盐，然后接着用氯化氢异丙醇溶液进行处理，获得经纯化的决奈达隆盐酸盐(90%)。
该方法的另一个缺点在于Friedel-Crafts反应中所用的反应物及所得副产物不溶于水，因此无法通过水洗从系统中去除。
该方法的另一个缺点在于5-氨基-2-丁基苯并呋喃IV的甲磺酰化期间，被双甲磺酰化的衍生物总是以反应副产物形式出现。通过重结晶纯化，其产率为78.5%。
我们的目标在于设计出一种决奈达隆及其可药用盐的新的制备方法，该方法避免上述缺点并且为经济的和适于工业应用。
我们已经发现若在方法制备中，在Friedel-Crafts条件下，取代2-丁基-5-甲磺酰胺基-苯并呋喃II，而以其碱金属或碱土金属盐与式III的4-[3-(二丁基氨基)丙氧基]-苯甲酰氯盐酸盐反应，则可避免上述缺点。
根据本发明，通过文献(WO 02/48132)已知方法，将式IV的5-氨基-2-丁基-苯并呋喃甲磺酰化，
且
将得到的式II的2-丁基-5-甲磺酰胺基-苯并呋喃与合适的碱金属或碱土金属盐反应，
获得式II化合物的各自的碱金属或碱土金属盐，
然后如上所述，将其在Friedel-Crafts条件下与式III的4-[3-(二丁基氨基)丙氧基]-苯甲酰氯盐酸盐反应，获得式I的N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺，其任选地转化成其盐或从其盐游离。
根据本发明的方法的优点在于式IV化合物的甲磺酰化期间，所形成的副产物将不会妨碍下一步反应步骤，因为向所得反应混合物中加入碱金属或碱土金属盐溶液，而该所需式II化合物的碱金属或碱土金属盐将溶解并留在水相中。
通过选择合适的反应条件，可以获得所需纯度和产率的式I化合物，不形成副产物，且仅小百分比的未反应起始原料可能留在反应混合物中，其可以容易地通过水洗除去并可重复使用。
根据本发明的一个实施方式，将式II化合物的碱金属盐与式III化合物反应。术语碱金属包括锂、钠或钾。
式II化合物的锂、钠或钾盐通过将式II的2-丁基-5-甲磺酰胺基-苯并呋喃与合适的碱金属氢氧化物(氢氧化锂、氢氧化钠、氢氧化钾)反应而制得。
根据本发明的另一个实施方式，将式II化合物的碱土金属盐与式III化合物反应。术语碱土金属包括镁或钙。式II的2-丁基-5-甲磺酰胺基-苯并呋喃的镁或钙盐通过将式II的2-丁基-5-甲磺酰胺基-苯并呋喃先与碱金属氢氧化物(氢氧化锂或氢氧化钾)反应，然后与合适的碱土金属卤化物(氯化钙、溴化钙、氯化镁、溴化镁)反应而制得。
根据本发明的优选方式，式II化合物的碱金属或碱土金属盐与式III化合物的反应在惰性有机溶剂或惰性有机溶剂的混合物中进行。可使用卤化烃(二氯甲烷、二氯乙烷、氯苯)或它们的混合物作为惰性有机溶剂。
根据本发明的优选方式，式II化合物的碱金属或碱土金属盐与式III化合物的反应在Friedel-Crafts催化剂(氯化铁(III)、氯化铝)的存在下进行。
根据本发明的优选方式，式II化合物的碱金属或碱土金属盐与式III化合物的反应在10-100℃的温度进行。
式II的2-丁基-5-甲磺酰胺基-苯并呋喃及其通过甲磺酰化式IV的5-氨基-2-丁基-苯并呋喃的制备方法已知于文献(WO 02/48132)中。
该方法中所用的式III的4-[3-(二丁基氨基)丙氧基]-苯甲酰氯盐酸盐及其制备方法已知于文献(WO 02/48078)中。
式II化合物的锂盐IIa、钠盐IIb、钾盐IIc、镁盐IId及钙盐IIe为新化合物，无法从文献获知。
本发明的其它细节由下列实施例说明，但不将权利要求限制在这些实例中。
实施例
实施例1
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
向由5.2克的2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb和20毫升的二氯甲烷制成的悬浮液中，加入含6.29克的4-{3-(二丁基氨基)丙氧基}苯甲酰氯盐酸盐III的25毫升的二氯甲烷溶液。搅拌反应混合物30分钟，在5-10℃于15分钟内加入3.57克的氯化铁(III)，并在20-25℃搅拌反应混合物2小时。在40℃于10分钟内将20毫升的水加入混合物中，并分离各相。伴随搅拌用15毫升的水清洗二氯甲烷相，然后用15毫升的5%碳酸氢钠溶液清洗。蒸发二氯甲烷相。
获得9.8克(98%)黄色油。
通过HPLC获得的纯度：98.6%。
1H NMR(DMSO)：0.8-0.9ppm(m,9H);1.2-1.5ppm(m,10H);1.67ppm(5’,2H);1.87ppm(5’,2H);2.38ppm(t,J=7.2Hz,4H);2.57ppm(m,2H);2.81ppm(t,J=7.5Hz,2H);2.91ppm(S,3H);9.51ppm(t,J=6.2Hz,2H);7.09ppm(d,J=8.8Hz,2H);7.24ppm(dd,J=8.9,2.2Hz,1H);7.38ppm(d,J=2,1Hz,1H);7.65ppm(d,J=8.8Hz,1H);7.81ppm(d,J=8.8Hz,2H)。
实施例2
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但使用氯苯取代二氯甲烷。
产率：97.8%。
通过HPLC获得的纯度：98.4%。
实施例3
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但区别在于使用等量的2-丁基-5-甲磺酰胺基-苯并呋喃钾盐IIc取代2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb。所得物质与实施例1的产物相同。
产率：99.1%。
通过HPLC获得的纯度：98.4%。
实施例4
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但区别在于使用等量的2-丁基-5-甲磺酰胺基-苯并呋喃锂盐IIa取代2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb。所得物质与实施例1的产物相同。
产率：98.1%。
通过HPLC获得的纯度：98.7%。
实施例5
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但区别在于使用等量的2-丁基-5-甲磺酰胺基-苯并呋喃镁盐IIe取代2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb。所得物质与实施例1的产物相同。
产率：97.8%
通过HPLC获得的纯度：99.0%。
实施例6
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但区别在于使用等量的2-丁基-5-甲磺酰胺基-苯并呋喃钙盐IId取代2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb。所得物质与实施例1的产物相同。
产率：97.7%。
通过HPLC获得的纯度：97.6%。
实施例7
N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺I
进行如实施例1所述操作，但使用2.93克的氯化铝取代氯化铁(III)。
所得物质与实施例1的产物相同。
产率：89.9%
通过HPLC获得的纯度：96.1%
实施例8
2-丁基-5-甲磺酰胺基-苯并呋喃锂盐IIa
在搅拌下将2.23克的2-丁基-5-甲磺酰胺基-苯并呋喃II加入至含0.20克氢氧化锂的5毫升水溶液中。在室温搅拌反应混合物1小时，然后保持在5-10℃共8小时。收集沉淀的白色物质，用1毫升的5℃的水洗涤，并在70℃干燥。
产物的质量：1.7克(74.5%)。
熔点：252.1-253.7℃。
元素分析：C:51.98%,H:5.79%,N:4.61%,S:10.44%,Li:2.41%
(计算值:C:57.1%,H:5.86%,N:5.13%,S:11.7%,Li:2.56%)。
实施例9
2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb
将2.12克的2-丁基-5-甲磺酰胺基-苯并呋喃II加入至含1克氢氧化锂的75毫升水溶液中。将所得悬浮液温热至70℃，然后将其冷却至20℃并在5-10℃搅拌1小时。过滤产物，在真空中干燥的。
产物的质量：2.04克(89.0%)。
熔点：226.3-228.9℃。
元素分析：C:59.9%,H:5.63%,N:5.16%,S:11.14%,Na:7.2%
(计算值:C:59.98%,H:5.54%,N:4.84%,S:11.07%,Na:7.94%)。
实施例10
2-丁基-5-甲磺酰胺基-苯并呋喃钠盐IIb
进行如实施例9所述操作，但将40毫升的水用于反应中。所得物质与实施例9的产物相同。
产率：95.0%。
实施例11
2-丁基-5-甲磺酰胺基-苯并呋喃钾盐IIc
将2.12克的2-丁基-5-甲磺酰胺基-苯并呋喃II加入至含1克85%氢氧化锂的25毫升水溶液中。在室温搅拌反应混合物1小时，然后在5℃搅拌2小时。过滤产物，在真空中干燥。
产物的质量：2.0克(82.0%)。
熔点：103.2-105.7℃。
元素分析：C:50.37%,H:5.16%,N:4.54%,S:9.53%,K:12.0%
(计算值:C:51.07%,H:5.24%,N:4.58%,S:10.47%,K:12.8%)。
实施例12
2-丁基-5-甲磺酰胺基-苯并呋喃钾盐IIc
进行如实施例11所述操作，但将10毫升的水用于反应中。所得物质与实施例11的产物相同。
产率：94.0%。
实施例13
2-丁基-5-甲磺酰胺基-苯并呋喃钙盐IIe
将2.0克的2-丁基-5-甲磺酰胺基-苯并呋喃II加入至含0.5克的85%氢氧化钾的20毫升水溶液中。搅拌反应混合物30分钟。向所得溶液中，于10分钟内加入溶于5毫升水中的0.89克氯化钙。将所得悬浮液在20-25℃搅拌1小时，然后在5℃搅拌2小时。过滤产物并干燥。
产物的质量：1.8克(86.1%)。
熔点：103.4-105.7℃。
元素分析：C:51.74%,H:5.50%,N:4.55%,S:10.29%,Ca:5.8%
(计算值:C:54.47%,H:5.58%,N:4.89%,S:11.17%,Ca:6.99%)。
实施例14
2-丁基-5-甲磺酰胺基-苯并呋喃钙盐IIe
进行如实施例13所述操作，但将15毫升的水(取代20毫升)用于反应中。所得物质与实施例13的产物相同。
产率：92.0%。
实施例15
2-丁基-5-甲磺酰胺基-苯并呋喃镁盐IId
将1.6克的2-丁基-5-甲磺酰胺基-苯并呋喃II加入至含0.28克的85%氢氧化钾的16毫升水溶液中。搅拌反应混合物30分钟。向所得溶液中，于10分钟内加入溶于5毫升水中的0.76克氯化镁。将所得悬浮液在20-25℃搅拌1小时，然后在5℃搅拌2小时。过滤产物并干燥。
产量：1.4克(83.8%)。
熔点：高于270℃。
元素分析：C:51.74%,H:5.50%,N:4.55%,S:10.29%,Mg:4.8%
(计算值:C:56.0%,H:5.74%,N:5.03%,S:11.49%,Mg:4.36%)。
实施例16
2-丁基-5-甲磺酰胺基-苯并呋喃镁盐IId
进行如实施例15所述操作，但将10毫升的水(取代16毫升)用于反应中。所得物质与实施例15的产物相同。
产率：93.7%。
Claims (13)
1.一种制备式I的N-[2-丁基-3-{4-[(3-二丁基氨基)丙氧基]苯甲酰基}-1-苯并呋喃-5-基]甲磺酰胺及其可药用盐的方法，
其特征在于在催化剂的存在下，将式II化合物的碱金属或碱土金属盐与式III的4-[3-(二丁基氨基)丙氧基]-苯甲酰氯盐酸盐反应，
且任选地将式I化合物转化成其盐或从其盐游离。
2.如权利要求1的方法，其特征在于该碱金属包括锂、钠或钾，且该碱土金属包括镁或钙。
3.如权利要求1-2中任一项的方法，其特征在于式II化合物与式III化合物的反应在惰性溶剂或它们的混合物中进行。
4.如权利要求3的方法，其特征在于应用卤化烃作为惰性溶剂。
5.如权利要求4的方法，其特征在于使用二氯甲烷、二氯乙烷、氯苯或它们的混合物作为卤化烃。
6.如权利要求1-5中任一项的方法，其特征在于使用氯化铁(III)或氯化铝作为催化剂。
7.如权利要求1-6中任一项的方法，其特征在于该反应在10-100℃的温度进行。
8.式II的2-丁基-5-甲磺酰胺基-苯并呋喃的碱金属或碱土金属盐
9.权利要求8的式II化合物的锂盐IIa、钠盐IIb、钾盐IIc、镁盐IId及钙盐IIe。
10.一种制备权利要求8-9中任一项的式II化合物的碱金属盐的方法，其特征在于将式II化合物与合适的碱金属氢氧化物反应
11.如权利要求10的方法，其特征在于该碱金属氢氧化物包括氢氧化锂、氢氧化钠或氢氧化钾。
12.一种制备权利要求8-9中任一项的式II化合物的碱土金属盐的方法，其特征在于将式II化合物先与氢氧化锂或氢氧化钾反应，然后与合适的碱土金属卤化物反应
13.如权利要求12的方法，其特征在于该碱土金属卤化物包括氯化镁、溴化镁、氯化钙或溴化钙。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP1000010 | 2010-01-08 | ||
| HU1000010A HUP1000010A2 (en) | 2010-01-08 | 2010-01-08 | Process for producing dronedarone |
| PCT/HU2010/000143 WO2011083346A1 (en) | 2010-01-08 | 2010-12-15 | New process for the preparation of dronedarone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102666522A true CN102666522A (zh) | 2012-09-12 |
Family
ID=89989488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800580717A Pending CN102666522A (zh) | 2010-01-08 | 2010-12-15 | 决奈达隆的新的制备方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US8658809B2 (zh) |
| EP (1) | EP2521720B1 (zh) |
| JP (1) | JP2013516451A (zh) |
| KR (1) | KR20120115365A (zh) |
| CN (1) | CN102666522A (zh) |
| AR (1) | AR079843A1 (zh) |
| AU (1) | AU2010340786A1 (zh) |
| BR (1) | BR112012016448A2 (zh) |
| CA (1) | CA2786218A1 (zh) |
| HU (1) | HUP1000010A2 (zh) |
| IL (1) | IL220523A0 (zh) |
| MX (1) | MX2012007897A (zh) |
| RU (1) | RU2012133967A (zh) |
| SG (1) | SG182405A1 (zh) |
| TW (1) | TW201139399A (zh) |
| UY (1) | UY33168A (zh) |
| WO (1) | WO2011083346A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450124A (zh) * | 2013-08-30 | 2013-12-18 | 江苏九九久科技股份有限公司 | 决奈达隆合成方法 |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
| FR2957079B1 (fr) | 2010-03-02 | 2012-07-27 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| FR2958290B1 (fr) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | Procede de preparation de derives de sulfonamido-benzofurane |
| FR2958291B1 (fr) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | Procede de preparation de derives d'amino-benzofurane |
| HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
| FR2962731B1 (fr) | 2010-07-19 | 2012-08-17 | Sanofi Aventis | Procede de preparation de derives d'amino-benzoyl-benzofurane |
| FR2963006B1 (fr) | 2010-07-21 | 2013-03-15 | Sanofi Aventis | Procede de preparation de derives de nitro-benzofurane |
| HUP1000386A2 (en) | 2010-07-22 | 2012-05-29 | Sanofi Sa | Novel process for producing dronedarone |
| HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
| HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
| FR2983198B1 (fr) | 2011-11-29 | 2013-11-15 | Sanofi Sa | Procede de preparation de derives de 5-amino-benzoyl-benzofurane |
| EP2617718A1 (en) | 2012-01-20 | 2013-07-24 | Sanofi | Process for preparation of dronedarone by the use of dibutylaminopropanol reagent |
| WO2013121235A2 (en) | 2012-02-13 | 2013-08-22 | Sanofi | Process for preparation of dronedarone by removal of hydroxyl group |
| US9249119B2 (en) | 2012-02-14 | 2016-02-02 | Sanofi | Process for the preparation of dronedarone by oxidation of a sulphenyl group |
| US9382223B2 (en) | 2012-02-22 | 2016-07-05 | Sanofi | Process for preparation of dronedarone by oxidation of a hydroxyl group |
| US9238636B2 (en) | 2012-05-31 | 2016-01-19 | Sanofi | Process for preparation of dronedarone by Grignard reaction |
| EP2963869A4 (en) | 2013-02-26 | 2016-09-28 | Nec Corp | COMMUNICATION SYSTEM, SWITCH, CONTROL APPARATUS, CONTROL CHANNEL CONFIGURATION METHOD AND PROGRAM |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1479735A (zh) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | 甲基磺酰胺基-苯并呋喃衍生物,它的制备方法与它作为合成中间体的应用 |
| CN101153012A (zh) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | 一种决奈达隆关键中间体的新的制备方法 |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2665444B1 (fr) | 1990-08-06 | 1992-11-27 | Sanofi Sa | Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant. |
| GB9416219D0 (en) | 1994-08-11 | 1994-10-05 | Karobio Ab | Receptor ligands |
| FR2817865B1 (fr) | 2000-12-11 | 2005-02-18 | Sanofi Synthelabo | Derive aminoalkoxybenzoyle sous forme de sel, son procede de preparation et son utilisation comme intermediaire de synthese |
| IL146389A0 (en) | 2001-11-08 | 2002-07-25 | Isp Finetech Ltd | Process for the preparation of dronedarone |
| FR2833262A1 (fr) | 2001-12-06 | 2003-06-13 | Rhodia Chimie Sa | Procede de monosulfonylation d'un compose de type aminobenzofuranne ou aminobenzothiophene |
| DE10237819A1 (de) | 2002-08-19 | 2004-03-04 | Bayer Ag | 5-Nitrobenzofurane |
| UY32657A (es) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | Procedimiento para la fabricación de productos intermedios de dronedarona |
| UY32656A (es) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | Procedimiento para producir benzofuranos |
| FR2957079B1 (fr) | 2010-03-02 | 2012-07-27 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| FR2958290B1 (fr) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | Procede de preparation de derives de sulfonamido-benzofurane |
| FR2958289B1 (fr) | 2010-03-30 | 2012-06-15 | Sanofi Aventis | Procede de preparation de derives de 3-ceto-benzofurane |
| FR2958291B1 (fr) | 2010-04-01 | 2013-07-05 | Sanofi Aventis | Procede de preparation de derives d'amino-benzofurane |
| HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
| FR2962731B1 (fr) | 2010-07-19 | 2012-08-17 | Sanofi Aventis | Procede de preparation de derives d'amino-benzoyl-benzofurane |
| FR2963006B1 (fr) | 2010-07-21 | 2013-03-15 | Sanofi Aventis | Procede de preparation de derives de nitro-benzofurane |
| HUP1000386A2 (en) | 2010-07-22 | 2012-05-29 | Sanofi Sa | Novel process for producing dronedarone |
| FR2973027A1 (fr) | 2011-03-24 | 2012-09-28 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
| HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
| HUP1100166A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Reductive amination process for preparation of dronedarone using amine intermediary compound |
| HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
-
2010
- 2010-01-08 HU HU1000010A patent/HUP1000010A2/hu unknown
- 2010-12-15 CN CN2010800580717A patent/CN102666522A/zh active Pending
- 2010-12-15 MX MX2012007897A patent/MX2012007897A/es not_active Application Discontinuation
- 2010-12-15 KR KR1020127020680A patent/KR20120115365A/ko not_active Application Discontinuation
- 2010-12-15 JP JP2012547552A patent/JP2013516451A/ja not_active Withdrawn
- 2010-12-15 WO PCT/HU2010/000143 patent/WO2011083346A1/en active Application Filing
- 2010-12-15 RU RU2012133967/04A patent/RU2012133967A/ru not_active Application Discontinuation
- 2010-12-15 CA CA2786218A patent/CA2786218A1/en not_active Abandoned
- 2010-12-15 BR BRBR112012016448-1A patent/BR112012016448A2/pt not_active IP Right Cessation
- 2010-12-15 EP EP10809330.3A patent/EP2521720B1/en active Active
- 2010-12-15 SG SG2012050118A patent/SG182405A1/en unknown
- 2010-12-15 AU AU2010340786A patent/AU2010340786A1/en not_active Abandoned
-
2011
- 2011-01-06 AR ARP110100030A patent/AR079843A1/es unknown
- 2011-01-07 TW TW100100566A patent/TW201139399A/zh unknown
- 2011-01-07 UY UY0001033168A patent/UY33168A/es not_active Application Discontinuation
-
2012
- 2012-06-20 IL IL220523A patent/IL220523A0/en unknown
- 2012-06-29 US US13/537,930 patent/US8658809B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1479735A (zh) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | 甲基磺酰胺基-苯并呋喃衍生物,它的制备方法与它作为合成中间体的应用 |
| CN101153012A (zh) * | 2006-09-29 | 2008-04-02 | 北京德众万全药物技术开发有限公司 | 一种决奈达隆关键中间体的新的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| ANDRÁS VARRÓ，ET AL.: "Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart:comparison with amiodarone", 《BRITISH JOURNAL OF PHARMACOLOGY》, vol. 133, no. 5, 31 December 2001 (2001-12-31), pages 625 - 634 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103450124A (zh) * | 2013-08-30 | 2013-12-18 | 江苏九九久科技股份有限公司 | 决奈达隆合成方法 |
| CN103450124B (zh) * | 2013-08-30 | 2016-03-09 | 江苏九九久科技股份有限公司 | 决奈达隆合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| AR079843A1 (es) | 2012-02-22 |
| TW201139399A (en) | 2011-11-16 |
| JP2013516451A (ja) | 2013-05-13 |
| IL220523A0 (en) | 2012-08-30 |
| BR112012016448A2 (pt) | 2015-09-01 |
| HU1000010D0 (en) | 2010-03-01 |
| MX2012007897A (es) | 2012-08-01 |
| EP2521720A1 (en) | 2012-11-14 |
| HUP1000010A2 (en) | 2011-11-28 |
| EP2521720B1 (en) | 2014-03-12 |
| WO2011083346A1 (en) | 2011-07-14 |
| UY33168A (es) | 2011-08-31 |
| US20120330036A1 (en) | 2012-12-27 |
| KR20120115365A (ko) | 2012-10-17 |
| CA2786218A1 (en) | 2011-07-14 |
| RU2012133967A (ru) | 2014-02-20 |
| AU2010340786A1 (en) | 2012-07-26 |
| US8658809B2 (en) | 2014-02-25 |
| SG182405A1 (en) | 2012-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102666522A (zh) | 决奈达隆的新的制备方法 | |
| JP3526581B2 (ja) | シタロプラムの製造方法 | |
| CN103562195A (zh) | 通过n-丁基化制备决奈达隆的方法 | |
| CN103562196A (zh) | 使用胺中间体化合物制备决奈达隆的还原胺化方法 | |
| CN102741238A (zh) | 制备决奈达隆的新方法 | |
| CN103228639A (zh) | 用于制备决奈达隆的新方法 | |
| CN102875440B (zh) | 3-（4-氯丁基）-5-氰基吲哚的制备方法 | |
| PL196956B1 (pl) | Sposób wytwarzania 3-alkanoilo- i 3-alkiloindoli | |
| CN108467355A (zh) | (r)-4-羟基-2-氧代-1-吡咯烷乙酰胺的制备方法 | |
| CN101247806B (zh) | 用于制备苯并咪唑化合物的SNAr方法 | |
| CN1680374A (zh) | 含哌嗪环化合物的新型合成和结晶方法 | |
| CN111170881B (zh) | 一种布瓦西坦中间体的制备方法 | |
| CN103274948A (zh) | 西那卡塞的制备方法 | |
| CN106748884B (zh) | 一种比卡鲁胺中间体的制备方法 | |
| CN111349052B (zh) | 一种枸橼酸莫沙必利的合成方法 | |
| CN109824537B (zh) | 一种n-(3-乙酰基-2-羟基苯基)乙酰胺的制备方法 | |
| CN112979507A (zh) | 一种茜素磺酸酯的合成方法 | |
| KR100486320B1 (ko) | 5,11-디히드로-6에이치-디벤즈[비,이]아제핀-6-온의제조방법 | |
| CN116217564A (zh) | 一种阿哌沙班杂质的制备方法 | |
| CN104151276A (zh) | 一种盐酸决奈达隆代谢杂质的制备方法 | |
| CN110092749A (zh) | 一种抗抑郁药nsi189及其磷酸盐的合成方法 | |
| WO2009119086A1 (ja) | ９－ヒドロキシメチル－シクロヘプタ［ｂ］ピリジン－３－カルボン酸エステル誘導体の製造方法 | |
| CN105753836A (zh) | 一种预防骨质疏松症药物的制备方法 | |
| CN1566078A (zh) | N－（1－s－乙氧羰基－3－苯基丙基）－s－丙氨酸的制备方法 | |
| JPH01106850A (ja) | Ｎ−アシル−ｎ−アルキル−２，６−ジアルキル−３−クロロアニリンの製造方法 |
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: 20120912 |