TW201331183A - 依伐布雷定（ｉｖａｂｒａｄｉｎｅ）及其與醫藥上可接受酸之加成鹽的新合成方法 - Google Patents
依伐布雷定（ｉｖａｂｒａｄｉｎｅ）及其與醫藥上可接受酸之加成鹽的新合成方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 10
- 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 3
- 230000015572 biosynthetic process Effects 0.000 title abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 239000002253 acid Substances 0.000 title abstract description 5
- 150000003839 salts Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000006268 reductive amination reaction Methods 0.000 claims description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000005576 amination reaction Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- 150000004677 hydrates Chemical class 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 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 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000010970 precious metal Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 238000003833 Wallach reaction Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000504 ivabradine hydrochloride Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 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
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- 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
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
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Abstract
本發明係關於用於合成式(I)之依伐布雷定(ivabradine)：□其與醫藥上可接受酸之加成鹽及其水合物的方法。
Description
本發明係關於一種用於合成式(I)之依伐布雷定(ivabradine)：
或3-{3-[{[(7S)-3,4-二甲氧基二環[4.2.0]辛-1,3,5-三烯-7-基]甲基}(甲基)胺基]丙基}-7,8-二甲氧基-1,3,4,5-四氫-2H-3-苯并氮呯-2-酮，其與醫藥上可接受酸之加成鹽及其水合物的方法。
依伐布雷定及其與醫藥上可接受酸之加成鹽，且更尤其指其鹽酸鹽，具有極其重要之藥理學及醫療特性，尤其指減慢心率特性，使得彼等化合物適用於治療或預防諸如心絞痛、心肌梗塞及相關心律紊亂之心肌缺血之多種臨床病況，且亦適用於包括心律紊亂，尤其室上性心律紊亂之多種病變，以及心臟衰竭。
歐洲專利說明書EP 0 534 859中已描述依伐布雷定及其與醫藥上可接受酸之加成鹽(更尤指其鹽酸鹽)的製備及治療用途。可惜該專利說明書中所述之依伐布雷定合成途徑以僅1%之產率產生預期產物。
歐洲專利說明書EP 1 589 005中已描述另一種基於還原
性胺化反應之依伐布雷定合成途徑。
還原性胺化法為一種有利於製備胺之方法的途徑。因為此方法無需分離所形成之中間物亞胺，所以這種在還原劑存在下進行之醛與胺之間的偶合反應廣泛用於合成在醫藥或農用化學品領域及材料科學中具有價值之化合物。
通常用於進行還原性胺化之程序性方案為：●使用化學計量之量的氫化物供體，諸如硼氫化物(NaBH4、NaBH3CN或NaBH(OAc)3)，●或催化氫化。
氫化物供體之使用會產生許多廢物且試劑本身有毒。
在催化氫化之情況下，還原劑為分子氫之事實無疑具有環境價值。專利說明書EP 1 589 005中描述之合成遵照此第二途徑。
換言之，專利說明書EP 1 589 005描述以式(II)化合物為起始物來合成依伐布雷定鹽酸鹽：
該式(II)化合物在氫氣及鈀催化劑存在下進行催化氫化反應，得到式(III)化合物：
該式(III)化合物不經分離，即在氫氣及鈀催化劑存在下與式(IV)化合物反應：
得到呈鹽酸鹽形式之式(I)之依伐布雷定。
該合成途徑之缺點為使用鈀催化劑。
類似於銠、釕或銥之類同樣用於催化還原性胺化反應之金屬，鈀為一種貴金屬，其有限之可用性及由此帶來之高價格以及毒性限制其適用性。
本申請案描述一種依伐布雷定合成途徑，其使省卻硼氫化物或貴金屬之使用成為可能。
本發明係關於一種用於合成式(I)之依伐布雷定的方法：
其特徵在於式(V)化合物：
與式(VI)化合物：
在三乙胺及甲酸存在下，在溶劑不存在下或在醇溶劑中進行還原性胺化反應。
使用甲酸作為還原劑(洛卡特-瓦拉赫反應(Leuckart-Wallach reaction))有時需要非常高的溫度，可能達到180℃，且常觀察到附帶形成N-甲醯基類型化合物。
用於式(V)化合物與式(VI)化合物之還原性胺化反應中之甲酸的量為每當量醛使用超過1當量，更佳為每當量醛使用2至50當量。
用於式(V)化合物與式(VI)化合物之還原性胺化反應中之三乙胺的量為每當量醛使用超過1當量，更佳為每當量醛使用2至50當量。
式(V)化合物與式(VI)化合物之間的還原性胺化反應之溫度較佳為15℃至100℃，更佳為30℃至100℃。
在可能用於進行式(V)化合物與式(VI)化合物之還原性胺化反應的醇溶劑中，可提及(不含任何限制)乙醇、異丙醇或三氟乙醇。
下文實例說明本發明。
管柱層析純化程序係在70-230篩目矽膠上進行。
1H NMR譜圖係在400 MHz下記錄。
化學位移係以ppm表示(內部參考物：TMS)。
已使用以下縮寫來描述峰：單峰(s)、雙峰(d)、雙二重峰(dd)、三重峰(t)、四重峰(q)、多重峰(m)。
在潔淨且乾燥的舒倫克管(Schlenk tube)中，0.25 mmol 3-(7,8-二甲氧基-2-側氧基-1,2,4,5-四氫-3H-3-苯并氮呯-3-基)丙醛、0.25 mmol[(7S)-3,4-二甲氧基二環[4.2.0]辛-1,3,5-三烯-7-基]-N-甲基甲膠及1 mL(7.4 mmol)三乙胺在周圍溫度下在氬氣氛圍下攪拌1小時。
小心添加113 μL(3 mmol)甲酸且混合物在85℃下加熱18小時。冷卻至周圍溫度後，反應混合物用5 mL 3M氫氧化鈉水溶液稀釋。水相用5 mL乙酸乙酯萃取3次。有機相合併，用飽和NaCl水溶液(10 mL)洗滌，經MgSO4乾燥且在減壓下蒸發。
粗產物在矽膠(溶離劑：戊烷/乙酸乙酯(95/5))上純化，獲得預期產物。
產率=62%
1H NMR(CDCl3)：δ=6.67及6.64(2s,2H)；6.55及6.50(2s,2H)；3.79及3.78(2s,12H)；3.76(s,2H)；3.67(m,2H)；3.45(m,3H)；3.17(dd,1H)；2.99(m,2H)；2.65(m,2H)；2.50(dd,1H)；2.37(t,2H)；2.26(s,3H)；1.72(q,2H)。
Claims (5)
- 一種用於合成式(I)之依伐布雷定(ivabradine)的方法，
- 如請求項1之方法，其中該還原性胺化反應係在溶劑不存在下進行。
- 如請求項1或2中任一項之方法，其中用於該還原性胺化反應中之甲酸的量為每當量醛使用2至50當量。
- 如請求項1或2中任一項之方法，其中用於該還原性胺化反應中之三乙胺的量為每當量醛使用2至50當量。
- 如請求項1或2中任一項之方法，其中該還原性胺化反應之溫度為30℃至100℃。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1103934A FR2984320B1 (fr) | 2011-12-20 | 2011-12-20 | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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|---|---|---|---|---|
| FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
| FR2868775B1 (fr) * | 2004-04-13 | 2008-04-11 | Servier Lab | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-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 |
| 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 |
| FR2870537A1 (fr) * | 2004-05-19 | 2005-11-25 | Servier Lab | Nouveau procede de synthese du (1s)-4,5-dimethoxy-1-(methyl aminomethyl-)-benzocyclobutane et de ses sels d'addition, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| RU2473544C2 (ru) * | 2007-05-30 | 2013-01-27 | Инд-Свифт Лабораториз Лимитед | Способ получения ивабрадина гидрохлорида и его полиморфных модификаций |
| FR2920773B1 (fr) * | 2007-09-11 | 2009-10-23 | Servier Lab | Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| FR2932800B1 (fr) * | 2008-06-20 | 2015-02-20 | Servier Lab | Nouveau procede de synthese de la 7,8-dimethoxy-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 |
| FR2935381B1 (fr) * | 2008-08-29 | 2010-12-17 | Servier Lab | Nouveau procede de resolution des enantiomerees du (3,4-dimethoxy-bicyclo°4.2.0!octa-1,3,5-trien-7-yl)nitrile et application a la synthese de l'ivabradine |
| FR2940287B1 (fr) * | 2008-12-24 | 2010-12-24 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable. |
| FR2941695B1 (fr) * | 2009-02-04 | 2011-02-18 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| ES2440595T3 (es) * | 2009-02-17 | 2014-01-29 | Mallinckrodt Llc | Proceso para la alquilación reductora de normorfinanos |
| ME00986B (me) * | 2009-03-31 | 2012-06-20 | Servier Lab | Novi postupak sinteze ivabradina i njegovih adicionih soli sa farmaceutski prihvatljivom kiselinom |
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