CN1332951C - 合成1，3－二氢－2h－3－苯并氮杂䓬－2－酮化合物的方法以及其应用 - Google Patents
合成1，3－二氢－2h－3－苯并氮杂䓬－2－酮化合物的方法以及其应用 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 15
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 9
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 6
- 239000002253 acid Substances 0.000 title abstract description 8
- WUYVQJOTPXVUIS-UHFFFAOYSA-N 1,3-dihydro-3-benzazepin-2-one Chemical class C1=CNC(=O)CC2=CC=CC=C21 WUYVQJOTPXVUIS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 238000010189 synthetic method Methods 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- NTVCIOGUJHBVBO-UHFFFAOYSA-N 4,5-dihydro-3h-dioxepine Chemical compound C1COOC=CC1 NTVCIOGUJHBVBO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- CZLMRJZAHXYRIX-UHFFFAOYSA-N 1,3-dioxepane Chemical group C1CCOCOC1 CZLMRJZAHXYRIX-UHFFFAOYSA-N 0.000 abstract description 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000005595 deprotonation Effects 0.000 description 4
- 238000010537 deprotonation reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000002152 aqueous-organic solution Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229960000504 ivabradine hydrochloride Drugs 0.000 description 1
- HLUKNZUABFFNQS-ZMBIFBSDSA-N ivabradine hydrochloride Chemical compound Cl.C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 HLUKNZUABFFNQS-ZMBIFBSDSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
Abstract
本发明涉及合成式(I)化合物的方法以及在合成伊伐布雷定及其可药用酸加成盐和水合物方面的应用，其中R<sub>1</sub>和R<sub>2</sub>可以相同或不同，各自代表直链或支链的(C<sub>1</sub>-C<sub>8</sub>)烷氧基或者和连接它们的碳原子一起形成1，3-二噁烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
Description
技术领域
本发明涉及一种合成1，3-二氢-2H-3-苯并氮杂-2-酮化合物的方法，及其在合成伊伐布雷定(ivabradine)和其可药用酸加成盐方面的应用。
更具体地说，本发明涉及一种式(I)化合物的合成方法：
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
根据本发明获得的式(I)化合物可用于合成式(II)的伊伐布雷定：
或3-{3-[{[(7S)-3，4-二甲氧基二环[4.2.0]辛-1，3，5-三烯-7-基]甲基}(甲基)氨基]-丙基}-7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯并氮杂-2-酮，以及它们的可药用酸加成盐和水合物。
背景技术
伊伐布雷定和其可药用酸加成盐，尤其是其盐酸盐，具有非常重要的药理学和治疗学性质，尤其是具有减慢心律的性质，从而可使这些化合物用于治疗或预防各种临床上的心肌局部缺血情况，例如心绞痛，心肌梗塞和相关节律紊乱，也包括涉及节律紊乱的各种病理学，尤其是室上性节律紊乱。
伊伐布雷定及其可药用酸加成盐(尤其是其盐酸盐)的制备和治疗用途，已描述在欧洲专利EP0534859的说明书中。
在上述专利说明书中描述了伊伐布雷定盐酸盐的合成，其中以式(III)化合物为原料，
通过在叔丁醇钾存在下，在二甲亚砜中用1-溴-3-氯丙烷烷基化式(IV)化合物，获得式(III)化合物的方法已描述在出版物J.Med.Chem 1990，Vol.33(5)，1496-1504中，同时也记载在专利EP0204349的说明书中。
专利EP0204349的说明书中也描述了一种通过使用3-氯丙醛的二乙缩醛在上述相同条件下(叔丁醇钾，二甲亚砜)烷基化式(IV)化合物获得式(Ia)的二乙缩醛的方法。
使用强碱如叔丁醇钾是酰胺官能团脱质子化所需要的常见条件。
然而，醇盐，尤其是叔丁醇钾，具有吸水性极强的缺点，这使它们的储藏复杂并在工业规模上难以使用。
通常用于酰胺官能团脱质子化的另一种试剂是氢化钠，其在二甲基甲酰胺中使用。
但是，对氢化钠和二甲基甲酰胺而言，除了其也具有高吸水性的事实之外，还有一个主要的缺点是在较低的温度下容易爆炸。
因此，由于伊伐布雷定及其盐的药学价值，寻找一种能以良好收率同时避免使用吸水性试剂而获得式(I)的1，3-二氢-2H-3-苯并氮杂-2-酮的有效方法是势在必行的。
发明内容
申请人发现式(IV)化合物和溴化物的烷基化反应能在氢氧化钠、氢氧化钾、氨水溶液、碳酸盐或碳酸氢盐，尤其钠、钾或铯的碳酸盐或碳酸氢盐的存在下进行，这些试剂易于处理，尤其适合工业规模的应用。
这一事实令人吃惊，因为这与在内酰胺中通常所观察到的情形是相反的，内酰胺的脱质子化通常需要使用更强的碱。
更具体地说，本发明涉及合成式(I)化合物的方法，
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷，该方法的特征在于在有机或含水有机溶剂中，在选自氢氧化钠、氢氧化钾、氨水溶液、碳酸盐或碳酸氢盐的碱存在下用式(V)化合物：
其中R1和R2的定义如上且X代表离去基团，
烷基化式(IV)化合物：
分离后得到式(I)化合物。
在离去基团中可提到的是(非限制性的)卤原子，优选溴原子，以及基团甲苯磺酸酯基、甲磺酸酯基和三氟甲磺酸酯基。
“含水有机溶剂”应理解是指水和有机溶剂的混合物。
在本发明方法中所能使用的有机溶剂中，可提到的是(非限制性的)N-甲基吡咯烷酮(NMP)、二甲基甲酰胺(DMF)和二甲亚砜(DMSO)。
本发明方法中优选的有机溶剂是N-甲基吡咯烷酮。本发明方法中优选的含水有机溶剂是水和N-甲基吡咯烷酮的混合物。
氢氧化钠和氢氧化钾可以固体形式或水溶液或有机溶液的形式使用。
当碱为氢氧化钠时，优选使用水溶液形式。
优选每摩尔式(IV)化合物使用氢氧化钠的量为1-2摩尔。
在氢氧化钠的存在下，反应温度优选20-100℃。
优选的碳酸盐或碳酸氢盐是钠、钾或铯的碳酸盐或碳酸氢盐。
在碳酸钠或碳酸钾存在下，反应温度优选高于80℃。
根据本发明，优选使用的式(V)化合物是其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的这些化合物。
其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的式(I)化合物是新产品，该新产品能在化学或制药工业上作为有用的合成中间体，所有这些形成了本发明的一个整体部分。
本发明方法所获得的式(I)化合物作为合成伊伐布雷定及其可药用酸加成盐的合成中间体尤其有利。
例如，将式(I)化合物催化氢化得到相应的式(VII)的氢化化合物：
其中R1和R2如同在式(I)中的定义，
将式(VII)的二缩醛经过脱质子化得到式(VIII)的醛：
然后将其和(7S)-3，4-二甲氧基二环[4.2.0]辛-1，3，5-三烯-7-基]-N-甲基甲胺在还原胺化条件下反应得到伊伐布雷定。
具体实施方式
下面以实施例的形式描述本发明。
实施例1：3-[2-(1，3-二氧杂环戊烷-2-基)-乙基]-7，8-二甲氧基-1，3-二氢-2H-3-苯并氮杂-2-酮-在氢氧化钠存在下的合成
将100g 7，8-二甲氧基-1，3-二氢-2H-3-苯并氮杂-2-酮、200ml N-甲基吡咯烷酮和115g 2-(2-溴乙基)-1，3-二氧戊环放进反应器，然后将反应混合物的温度升到40℃并加入71g 30％的氢氧化钠溶液，同时维持反应温度在40℃。然后将混合物加热到60℃并搅拌2小时；接着在60℃下倒入400ml水中，冷却反应混合物到20℃，一小时后冷却到2℃。滤出所获得的沉淀，洗涤并干燥。所得标题化合物的产率为87％。
实施例2：3-[2-(1，3-二氧杂环戊烷-2-基)-乙基]-7，8-二甲氧基-1，3-二氢-2H-3-苯并氮杂-2-酮-在碳酸钾存在下的合成
将100g 7，8-二甲氧基-1，3-二氢-2H-3-苯并氮杂-2-酮、250ml N-甲基吡咯烷酮和180.4g碳酸钾放进反应器并在130℃下搅拌该混合物3小时。然后在剧烈搅拌下于130℃以2小时的间隔分三次加入2-(2-溴乙基)-1，3-二氧戊环(90.8g，40.7g和16.3g)。反应恢复至室温后，化合物通过用水沉淀得以分离，冷却，过滤并干燥。所获得标题化合物的产率为80％。
Claims (10)
1.合成式(I)化合物的方法：
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷，其中，在N-甲基吡咯烷酮中，在选自氢氧化钠的水溶液、碳酸钠或碳酸钾的碱存在下用式(V)化合物
其中R1和R2定义如上，X代表离去基团，
烷基化式(IV)化合物：
分离后得到式(I)化合物。
2.根据权利要求1的合成方法，其中使用的是其中X代表卤原子或甲苯磺酸酯、甲磺酸酯或三氟甲磺酸酯基团的式(V)化合物。
3.根据权利要求2的合成方法，其中使用的是其中X代表溴原子的式(V)化合物。
4.根据权利要求1-3任一项的合成方法，其中所使用的碱是氢氧化钠水溶液形式。
5.根据权利要求4的合成方法，其中氢氧化钠的量是每摩尔式(IV)化合物为1-2摩尔。
6.根据权利要求4的合成方法，其中反应温度为20-100℃。
7.根据权利要求1-3任一项的合成方法，其中使用碳酸钠或碳酸钾。
8.根据权利要求7的合成方法，其中反应温度高于80℃。
9.根据权利要求1-3任一项的合成方法，其中使用的是其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的式(V)化合物。
10.合成伊伐布雷定、其药学上可接受的盐及其水合物的方法，其中按照权利要求1的方法将式(IV)化合物转变成式(I)的中间体化合物，然后将式(I)的中间体化合物转变成伊伐布雷定，任选将伊伐布雷定转化成其药学上可接受的盐或其水合物。
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| Application Number | Priority Date | Filing Date | Title |
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| FR0403829 | 2004-04-13 | ||
| FR0403829A FR2868776B1 (fr) | 2004-04-13 | 2004-04-13 | Nouveau procede de synthese de derives de la 1,3-dihydro- 2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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| CN1683342A CN1683342A (zh) | 2005-10-19 |
| CN1332951C true CN1332951C (zh) | 2007-08-22 |
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| EP (1) | EP1589014B1 (zh) |
| JP (2) | JP4511970B2 (zh) |
| KR (1) | KR100636500B1 (zh) |
| CN (1) | CN1332951C (zh) |
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| AT (1) | ATE375339T1 (zh) |
| AU (1) | AU2005200860B2 (zh) |
| BR (1) | BRPI0500478B8 (zh) |
| CA (1) | CA2496721C (zh) |
| CY (1) | CY1107101T1 (zh) |
| DE (1) | DE602005002776T2 (zh) |
| DK (1) | DK1589014T3 (zh) |
| EA (1) | EA007744B1 (zh) |
| ES (1) | ES2294652T3 (zh) |
| FR (1) | FR2868776B1 (zh) |
| GE (1) | GEP20074137B (zh) |
| HK (1) | HK1079776A1 (zh) |
| HR (1) | HRP20070503T3 (zh) |
| MA (1) | MA27599A1 (zh) |
| ME (1) | ME01402B (zh) |
| MX (1) | MXPA05003695A (zh) |
| MY (1) | MY141223A (zh) |
| NO (1) | NO329438B1 (zh) |
| NZ (1) | NZ538327A (zh) |
| PL (1) | PL1589014T3 (zh) |
| PT (1) | PT1589014E (zh) |
| RS (1) | RS50546B (zh) |
| SG (1) | SG116573A1 (zh) |
| SI (1) | SI1589014T1 (zh) |
| UA (1) | UA81772C2 (zh) |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2868776B1 (fr) * | 2004-04-13 | 2008-04-18 | Servier Lab | Nouveau procede de synthese de derives de la 1,3-dihydro- 2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| WO2008146308A2 (en) | 2007-05-30 | 2008-12-04 | Ind-Swift Laboratories Limited | Process for the preparation of ivabradine hydrochloride and polymorph thereof |
| ES2402765T3 (es) | 2008-12-22 | 2013-05-08 | Krka, D.D., Novo Mesto | Procedimiento de preparación de ivabradina |
| SI2902384T1 (en) | 2010-02-12 | 2018-03-30 | Krka, D.D., Novo Mesto | The form of ivabradine hydrochloride |
| FR2956401B1 (fr) * | 2010-02-17 | 2012-02-03 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2984320B1 (fr) * | 2011-12-20 | 2013-11-29 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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| EP0065229A1 (de) * | 1981-05-19 | 1982-11-24 | Dr. Karl Thomae GmbH | Neue Benzazepinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel |
| US4490369A (en) * | 1981-05-19 | 1984-12-25 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Benzazepine derivatives, their pharmaceutical compositions and method of use |
| US4737495A (en) * | 1985-06-01 | 1988-04-12 | Dr. Karl Tomae, Gmbh | (2H)-3-benzazepin-2-ones, their pharmaceutical compositions and their pharmaceutical uses |
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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| DE3242599A1 (de) * | 1982-11-18 | 1984-05-24 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue benzazepinderivate, ihre herstellung und ihre verwendung als arzneimittel |
| DE3418270A1 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue aminotetralinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| DE3519735A1 (de) * | 1985-06-01 | 1986-12-04 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue heteroaromatische aminderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| DE3717561A1 (de) * | 1987-05-25 | 1988-12-08 | Thomae Gmbh Dr K | Indol-, isochinolin- und benzazepinderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
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| JPH0495078A (ja) * | 1990-08-08 | 1992-03-27 | Nippon Shoji Kk | ピリミドン誘導体の製造法、そのための中間体 |
| TW279860B (zh) * | 1993-11-12 | 1996-07-01 | Ciba Geigy Ag | |
| FR2868776B1 (fr) * | 2004-04-13 | 2008-04-18 | Servier Lab | Nouveau procede de synthese de derives de la 1,3-dihydro- 2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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| EP0065229A1 (de) * | 1981-05-19 | 1982-11-24 | Dr. Karl Thomae GmbH | Neue Benzazepinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel |
| US4490369A (en) * | 1981-05-19 | 1984-12-25 | Dr. Karl Thomae Gesellschaft Mit Beschrankter Haftung | Benzazepine derivatives, their pharmaceutical compositions and method of use |
| US4737495A (en) * | 1985-06-01 | 1988-04-12 | Dr. Karl Tomae, Gmbh | (2H)-3-benzazepin-2-ones, their pharmaceutical compositions and their pharmaceutical uses |
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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