CN103068810A - 制备决奈达隆的方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 229960002084 dronedarone Drugs 0.000 title description 14
- 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 14
- -1 di-n-butylamino-3-propoxy Chemical group 0.000 claims abstract description 27
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- 238000006243 chemical reaction Methods 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
- 239000003960 organic solvent Substances 0.000 claims description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 14
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- 206010020772 Hypertension Diseases 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
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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
-
- 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
-
- 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
-
- 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
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Abstract
本发明涉及制备式(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]-甲磺酰胺以及其药用盐的方法,所述方法包括使根据式(II)的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃中的甲基磺酰基中的一个选择性地断裂,以及如有需要,将所得的式(I)的化合物转化为其盐。
Description
技术领域
本发明涉及制备N-[2-正丁基-3-{4-[(3-二-正丁基氨基)-丙氧基]-苯甲酰基}-1-苯并呋喃-5-基]-甲磺酰胺(决奈达隆,dronedarone)以及其药用盐的新方法,以及在该方法中使用的新中间体。
背景技术
式I的决奈达隆用于治疗心血管系统的某些病理变化,首先是治疗心绞痛、高血压、心律不齐和脑血流不足(EP0471609B1)。
目前已知几种用于制备式I的决奈达隆的方法。在一项现有技术方法(EP0471609B1)中,使式IX的2-正丁基-5-硝基-苯并呋喃
与茴香酰氯在弗瑞德-克来福特(Friedel-Crafts)条件下反应,并通过在氯化铝的存在下加热所得的式X的2-正丁基-3-(4-甲氧基-苯甲酰基)-5-硝基-苯并呋喃
得到式XI的2-正丁基-3-(4-羟基-苯甲酰基)-5-硝基-苯并呋喃:
然而,以工业规模利用这种反应步骤会涉及许多困难,因为式X的化合物是致突变的,且氯化铝对于健康是有害的。将所得的式XI的化合物与二-正丁基氨基丙基氯反应得到式XII的2-正丁基-3-[4-(3-二-正丁基氨基-丙氧基)-苯甲酰基]-5-硝基-苯并呋喃:
其中,在用氧化铂催化剂进行还原后得到式XIII的5-氨基-2-正丁基-3-[4-(3-二-正丁基氨基-丙氧基)-苯甲酰基]-苯并呋喃:
最后,使式XIII的化合物进行甲磺酰化得到式I的决奈达隆。
这是线性合成,其中所期望分子的部分是逐步建立起来的,在连续的步骤中使用越来越多复杂的分子,而这是不经济的。
在最后的步骤中,使式XIII的化合物的氨基进行选择性甲磺酰化是困难的,也生成式II的双甲磺酰化2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃衍生物,并且其伴随出现式I的决奈达隆,所述式II为:
根据文献资料,在经过柱色谱纯化后,此方法可得到61.6%的产率,但是此方法是复杂的,不适合于工业应用。
在公开WO0248132的专利申请中描述了另外一个用于制备决奈达隆的方法。这种超收敛(super-convergent)途径由以下步骤所组成:
对式XIV的5-氨基-2-正丁基-苯并呋喃
进行甲磺酰化且所得的式XV的2-正丁基-5-甲基磺酰氨基-苯并呋喃
在弗瑞德-克来福特条件下与式VIII的4-[3-(二-正丁基氨基)丙氧基]-苯甲酰氯的盐酸盐反应
得到式I的决奈达隆的盐酸盐。
在此种方法中,反应步骤的次序有变动,合成反应的一开始是还原以及甲磺酰化步骤。
就反应步骤数量而言,此方法非常简单且有经济效益。然而,其缺点是在最后一个步骤中,决奈达隆的盐酸盐以相当受污染的形式得到。这可以通过在弗瑞德-克来福特反应中存在的二丁基氨基-丙基而解释。在WO02/48132的例子中,其产率为90%,在起初为粗决奈达隆盐酸盐,接着在异丙醇中用氯化氢溶液处理的纯化步骤中,获得纯化的决奈达隆盐酸盐(90%)。这意味着粗决奈达隆盐酸盐的产率是90%,然后纯化步骤的产率是90%。本方法的另外一个缺点是,在弗瑞德-克来福特反应中所使用的反应混合物以及获得的副产物是不溶于水的,因此它们无法通过水相洗涤从系统中移除。
发明内容
申请人的目标是实现用于制备决奈达隆以及其药用盐的新方法,其中本方法避免上述提到已知方法的缺点,并且是有经济效益以及工业可行的。
申请人已经发现,如果使式II的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃的一个甲基磺酰基选择性地断裂,则以良好的产率以及适当的纯度得到式I的决奈达隆,所述式II为:
根据本发明,在醇溶剂中或在醇溶剂混合物中,在碱金属的醇盐的存在下,使式II的化合物的甲基磺酰基中的一个的断裂。至于醇溶剂,可使用甲醇、乙醇或是它们的混合物。至于碱金属的醇盐,可使用甲醇钠、甲醇钾、乙醇钠或乙醇钾。
依据本发明方法的一个实施方案,使式III的2-正丁基-5-二-(甲基磺酰氨基)-苯并呋喃
在弗瑞德-克来福特条件下与茴香酰氯反应,且对所得的式VII的2-正丁基-5-二-(甲基磺酰氨基)-3-(4-甲氧基-苯甲酰基)-苯并呋喃
脱甲基化,且使由此获得的式VI的2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃
与式V的3-二-正丁基氨基丙基氯反应,
以及使所得的式II的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃
的甲基磺酰基中的一个通过上述提到的方法选择性地断裂。
依据本发明方法的另一个实施方案,使式III的2-正丁基-5-(二-甲基磺酰氨基)-苯并呋喃
在弗瑞德-克来福特条件下与式VIII的4-(3-二-正丁基氨基-丙氧基)-苯甲酸的盐酸盐反应,
以及使由此获得的式II的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃
的甲基磺酰基中的一个通过上述提到的方法选择性地断裂。
依据本发明,在惰性有机溶剂中或惰性有机溶剂混合物中进行式III的化合物与茴香酰氯的反应。至于惰性有机溶剂,可使用卤化有机溶剂(二氯甲烷、二氯乙烷、氯苯)。
在路易斯酸的存在下进行式III的化合物与茴香酰氯的反应。至于路易斯酸,可使用最大5个当量的氯化铁(III)或氯化铝。
在惰性有机溶剂中或惰性有机溶剂混合物中进行式VII的化合物的脱甲基化反应。至于惰性有机溶剂,可使用卤化有机溶剂(二氯甲烷、二氯乙烷、氯苯)。
在路易斯酸的存在下进行式VII的化合物的脱甲基化反应。至于路易斯酸,可使用氯化铁(III)或氯化铝。
在20-100°C的温度进行式VII的化合物的脱甲基化反应。
在有机溶剂中或有机溶剂混合物中进行式V以及VI的化合物的反应。至于有机溶剂,可使用低碳原子数的醇类(甲醇、乙醇)或者是低碳原子数的酮类(丙酮、丁酮)。
在具有碱性特征的酸结合剂的存在下实施式V以及VI的化合物的反应。至于具有碱性特征的酸结合剂,可使用无机碳酸盐。
在所使用的溶剂以及溶剂混合物的沸点附近的温度进行式V和VI的化合物的反应。
在惰性有机溶剂中或惰性有机溶剂混合物中进行式III以及VIII的化合物的反应。至于惰性有机溶剂,可使用卤化有机溶剂(二氯甲烷、二氯乙烷、氯苯)。
在路易斯酸的存在下进行式III以及VIII的化合物的反应。至于路易斯酸,可使用氯化铁(III)或氯化铝。
从文献中(EP0471609B1,实施例35以及实施列70)已知由2-正丁基-5-硝基-苯并呋喃制备式II的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃以及式III的2-正丁基-5-二-(甲基磺酰氨基)-苯并呋喃。
式VI的2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃
以及式VII的2-正丁基-5-二-(甲基磺酰氨基)-3-(4-甲氧基-苯甲酰基)-苯并呋喃
为新化合物,且它们从文献是未知的。
具体实施方式
在以下的实施列中说明本发明的进一步详细描述,但并非将本申请的权利要求限制为实施例。
实施例1
N-[2-正丁基-3-{4-[(3-二-正丁基氨基)-丙氧基]-苯甲酰基}-1-苯并呋喃-5-基]-甲磺酰胺(I)
将由5g的钠以及170ml无水乙醇而制得的溶液添加到7g2-正丁基-3-[(二-正丁基氨基)-3-丙氧基)-4-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃(II)中。反应混合物煮沸30分钟后,接着减压蒸发。将30ml二氯甲烷以及50ml水加到残留物中,并且搅拌此混合物20分钟。分离各相。有机相以20ml的水洗涤并蒸发。
产物:油状物(产率:97.9%)。纯度(HPLC):93.1%
产物经其草酸盐纯化(产率:90.3%)。纯度(HPLC):99.5%。
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);4.15ppm(t,J=6.2Hz,2H);7.09(d,J=8.8Hz,2H);7.24ppm(dd,J=8.9;2.2Hz,1H);7.34ppm(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-正丁基-3-{4-[(3-二-正丁基氨基)-丙氧基]-苯甲酰基}-1-苯并呋喃-5-基]-甲磺酰胺(I)
进行实施例1中的方法,其不同处为使用甲醇,而不是乙醇。
纯化后产率:88.6%。纯度(HPLC):99.7%。
实施例3
N-[2-正丁基-3-{4-[(3-二-正丁基氨基)-丙氧基]-苯甲酰基}-1-苯并呋喃-5-基]-甲磺酰胺(I)
进行实施例1中的方法,其不同处为使用钾,而不是钠。
纯化后产率:88.9%。纯度(HPLC):99.5%。
实施例4
N-[2-正丁基-3-{4-[(3-二-正丁基氨基)-丙氧基]-苯甲酰基}-1-苯并呋喃-5-基]-甲磺酰胺(I)
将溶解在220ml无水乙醇中的0.8g钠金属添加至22g含有4%二甲磺酰氨基化合物(II)的未纯化决奈达隆(I)中。反应混合物煮沸30分钟后,接着蒸发。将140ml水以及80ml二氯甲烷加到残留物中,并且搅拌此混合物20分钟。分离各相,接着蒸发二氯甲烷相。粗决奈达隆(I)经其草酸盐纯化。
纯化后产率:93.5%。纯度(HPLC):99.4%。
实施例5
2-正丁基-5-二-(甲基磺酰氨基)-3-(4-甲氧基-苯甲酰基)-苯并呋喃(VII)
使4g2-正丁基-5-二-(甲基磺酰氨基)-苯并呋喃(III)以及2.29g茴香酰氯在搅拌下溶解于20ml二氯甲烷中。溶液冷却至5-10°C以及在此温度在15分钟内将2.16g氯化铁(III)分四份加入。混合物加热至20°C且在该温度搅拌1小时。接着反应混合物加热至40°C,且在此温度于30分钟内加入30ml的水。在此温度分离各相。二氯甲烷相以10ml的水2x10ml的5%碳酸氢钠水溶液以及2x10ml的水洗涤。蒸发二氯甲烷相。
产物:油状物(产率:95.98%)。纯度(HPLC):99.0%。
1H NMR(DMSO-d6):7.86ppm(d,J=8.6Hz,2H);7.80ppm(d,J=8.7Hz,1H);7.55ppm(d,J=1.9Hz,1H);7.51ppm(dd,J=8.7Hz,2.0Hz,1H);7.12ppm(d,J=8.7Hz,2H);3.9ppm(s,3H);3.53ppm(s,6H);2.84ppm(t,J=7.4Hz,2H);1.7ppm(5’,J=7.3Hz,2H);1,27ppm(6’,J=7.4Hz,2H);083ppm(t,J=7.4Hz,3H)
分子质量:[M+H]+计算值:480.1151Da;[M+H]+测量值:480.1142Da。
实施例6
2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃(VI)
使5.3g2-正丁基-5-二-(甲基磺酰氨基)-3-(4-甲氧基-苯甲酰基)-苯并呋喃(VII)在12ml氯苯中溶解。接着在64-66°C将溶液加入至含有4.44g氯化铝以及17ml氯苯的混悬液中,因此在30分钟内加入一半量的溶液以及在3小时内加入另一半。在添加后,混合物在64-66°C搅拌4小时,并在10分钟内在该温度加入25ml的水。仍然热分离各相。氯苯相在65°C与3x25ml的水进行搅拌,分离各相且蒸发有机相。
产物:油状物(产率:94.0%)。纯度(HPLC):99.0%。
1H NMR(DMSO):0.84ppm(t,J=7,4Hz,3H);1.27ppm(6’,J=7.3Hz,2H);1.70ppm(5’,J=7.4Hz,2H);2.85ppm(t,J=7,3Hz,2H);3.53ppm(s,6H);6.93ppm(s,J=8.5Hz,2H);7.50ppm(dd,J=8.6Hz,1.8Hz,1H);7.54ppm(d,J=1.9Hz,1H);7.77ppm(d,J=8.5Hz,2H);7.79ppm(d,J=8.7Hz,1H);10.54ppm(s,1H)
分子质量:[M+H]+计算值:466.0994Da;[M+H]+测量值:466.1001Da。
实施例7
2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃(VI)
依据实施例6中的方法进行,其中不同处为使用二氯乙烷作为溶剂。
纯化后产率:97.0%。纯度(HPLC):99.1%。
实施例8
2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-4-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃(II)
使2g的2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃(V)以及0.88g的(3-二-正丁基氨基)-丙基氯溶解在16ml的丁酮中。将1.75g的碳酸钾加入至溶液中,且反应混合物煮沸8小时。滤出无机盐,用16ml丁酮洗涤。通过蒸发除去溶剂。
产物:油状物(2.56g,产率:93.5%)。纯度(HPLC):99.1%。
1H NMR(DMSO-d6):7.87ppm(d,J=8.8Hz,2H);7.81ppm(d,J=8.8Hz,1H);7.53ppm(d,J=2.3Hz,1H);7.52ppm(dd,J=8.8;2.3Hz,1H);7.12ppm(d,J=8.8Hz,2H);4.21pp(w,2H);3.53ppm(s,6H);3.26ppm(w,2H);3.03ppm(w,4H);2.84ppm(t,J=7.5Hz,2H);2.19ppm(w,2H);1.70ppm(5’,J=7.4Hz,2H);1.68ppm(w,4H);1.36ppm(6’,J=7.0Hz,4H);1.27ppm(6’,J=7.3Hz,2H);0.94ppm(t,J=7.2Hz,6H);0.84ppm(t,J=7.4Hz,3H)
实施例9
2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-4-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃(II)
使2g的2-正丁基-5-二-(甲基磺酰氨基)-苯并呋喃(III)溶解在10ml的二氯甲烷中,并且将1.8g4-(二-正丁基氨基-丙氧基)苯甲酰氯(VIII)的盐酸盐加入至溶液中。混合物冷却至5°C,以及在15分钟内将0.93g氯化铁(III)分四份加入。反应混合物加热至20°C并在此温度搅拌1小时,接着加热至35-40°C以及将16ml的水加至其中。在搅拌30分钟后,分离各相。二氯甲烷相在35-40°C用6ml的水、2x6ml的5%碳酸氢钠水溶液以及2x60ml的水洗涤。蒸发除去二氯甲烷。
产物:油状物(3.5g,产率:95.2%)。纯度(HPLC):89.2%
此产物与实施例8所制备的化合物是相同的。
Claims (15)
2.权利要求1的方法,其特征在于该反应是在有机溶剂中或者有机溶剂混合物中进行的。
3.权利要求1至2中任一项的方法,其特征在于该反应是在碱金属的醇盐的存在下进行的。
4.权利要求1至3中任一项的方法,其特征在于
a)使式III的2-正丁基-5-二-(甲基磺酰氨基)-苯并呋喃与茴香酰氯在路易斯酸存在下反应,所述式III为:
III,以及
b)使所得的式VII的2-正丁基-5-二-(甲基磺酰氨基)-3-(4-甲氧基-苯甲酰基)-苯并呋喃脱甲基化,所述式VII为:
VII,以及
c)使所得的式VI的2-正丁基-3-(4-羟基-苯甲酰基)-5-二-(甲基磺酰氨基)-苯并呋喃与式V的3-(二-正丁基-氨基)-丙基氯反应,所述式VI为:
所述式V为:
以及
d)使所得的式II的2-正丁基-3-[(二-正丁基氨基-3-丙氧基)-苯甲酰基]-5-二-(甲基磺酰氨基)-苯并呋喃的甲基磺酰基中的一个选择性断裂,且如有需要,将所得的式I的化合物转化为其盐,所述式II为:
5.权利要求4的反应步骤b)的方法,其特征在于该反应是在路易斯酸存在下进行的。
6.权利要求4的反应步骤b)的方法,其特征在于该反应在惰性有机溶剂或惰性有机溶剂混合物中进行。
7.权利要求4的反应步骤b)的方法,其特征在于该反应在20-100°C之间的温度进行。
8.权利要求10的方法,其特征在于该反应在所使用的溶剂或者溶剂混合物的沸点附近的温度进行。
9.权利要求4的反应步骤c)的方法,其特征在于该反应在惰性有机溶剂中或惰性有机溶剂混合物中进行。
10.权利要求4的反应步骤c)的方法,其特征在于该反应在具有碱性特征的酸结合剂存在下进行。
12.权利要求4-11的反应步骤a)中任一项或权利要求5的方法,其特征在于氯化铁(III)或氯化铝(III)用作路易斯酸。
13.权利要求4或12的反应步骤a)的方法,其特征在于该反应在惰性有机溶剂中或惰性有机溶剂混合物中进行。
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Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
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HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
HUP1000010A2 (en) | 2010-01-08 | 2011-11-28 | Sanofi Sa | Process for producing dronedarone |
FR2958290B1 (fr) | 2010-03-30 | 2012-10-19 | Sanofi Aventis | Procede de preparation de derives de sulfonamido-benzofurane |
HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
CN102725279A (zh) * | 2010-11-08 | 2012-10-10 | 山东邹平大展新材料有限公司 | 一种盐酸决奈达隆的制备方法 |
HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
WO2012171135A1 (zh) * | 2011-06-13 | 2012-12-20 | 山东邹平大展新材料有限公司 | 一种苯并呋喃化合物、其制备方法及用途 |
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 |
US9221778B2 (en) | 2012-02-13 | 2015-12-29 | 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 |
WO2013178337A1 (en) | 2012-05-31 | 2013-12-05 | Sanofi | Process for preparation of dronedarone by grignard reaction |
TW201536763A (zh) * | 2013-08-27 | 2015-10-01 | Gilead Sciences Inc | 製備決奈達隆或其鹽類之製程 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5223510A (en) * | 1990-08-06 | 1993-06-29 | Sanofi | Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them |
US20060100460A1 (en) * | 2004-11-10 | 2006-05-11 | Pfizer, Inc. | Substituted N-sulfonylaminobenzyl-2-phenoxyacetamide compounds as VR1 receptor agonists |
Family Cites Families (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3577441A (en) | 1967-03-07 | 1971-05-04 | Warner Lambert Pharmaceutical | Nitro substituted benzofurans |
US3657350A (en) | 1967-05-09 | 1972-04-18 | Sterling Drug Inc | Process and compositions |
DE2337396A1 (de) | 1973-07-23 | 1975-02-13 | Hoechst Ag | Verfahren zur herstellung aromatischer 1,3-diketone |
IE45765B1 (en) | 1976-08-19 | 1982-11-17 | Ici Ltd | Triazoles and imidazoles useful as plant fungicides and growth regulating agents |
US4666931A (en) | 1984-12-29 | 1987-05-19 | Kaken Pharmaceutical Co., Ltd. | Benzofuran derivatives useful in treating diabetic complications |
US5066803A (en) | 1989-12-07 | 1991-11-19 | Sterling Drug Inc. | 2- and 3-aminomethyl-6-arylcarbonyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazines |
GB9416219D0 (en) | 1994-08-11 | 1994-10-05 | Karobio Ab | Receptor ligands |
IT1275997B1 (it) | 1995-03-31 | 1997-10-24 | Great Lakes Chemical Italia | Enammine come accelleranti di vulcanizzazione per gomme naturali o sintetiche |
FR2800067B1 (fr) | 1999-10-21 | 2004-12-17 | Rhodia Chimie Sa | Intermediaires de fabrication d'un derive de type benzofurane ou benzothiophene nitre en position 5 et leurs utilisations |
WO2001029019A1 (fr) | 1999-10-21 | 2001-04-26 | Rhodia Chimie | Procede de preparation d'un compose de type benzofurane ou benzothiophene |
FR2813308B1 (fr) | 2000-08-23 | 2005-07-01 | Sanofi Synthelabo | Aminoalkoxybenzoyl-benzofurannes ou benzothiophenes, leur procede de preparation ainsi que les compositions les contenant |
FR2813306B1 (fr) | 2000-08-23 | 2005-10-21 | Sanofi Synthelabo | Aminoalkybenzoyl-benzofurannes ou benzothiophenes, leur procede de preparation et les compositions les contenant |
FR2817864B1 (fr) * | 2000-12-11 | 2003-02-21 | Sanofi Synthelabo | Derive de methanesulfonamido-benzofurane, son procede de preparation et son utilisation comme intermediaire de synthese |
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 |
FR2833259B1 (fr) | 2001-12-10 | 2004-08-27 | Oreal | Procede de preparation de 2-arylbenzofuranes, composes intermediaires, 2-arylbenzofuranes et compositions les comprenant |
DE10237819A1 (de) | 2002-08-19 | 2004-03-04 | Bayer Ag | 5-Nitrobenzofurane |
DE60319158T2 (de) | 2003-07-03 | 2009-02-05 | Aventis Pharmaceuticals Inc. | Pyrazoloisochinolinenderivaten als kinase inhibitoren |
JP2008510742A (ja) | 2004-08-24 | 2008-04-10 | ビーエーエスエフ ソシエタス・ヨーロピア | 高純度の第4級アンモニウム化合物の製造方法 |
WO2006093801A1 (en) | 2005-02-25 | 2006-09-08 | Abbott Laboratories | Thiadiazine derivatives useful as anti-infective agents |
WO2007022501A2 (en) | 2005-08-18 | 2007-02-22 | Microbia, Inc. | Useful indole compounds |
MX2008011227A (es) | 2006-03-03 | 2009-02-10 | Torrent Pharmaceuticals Ltd | Receptores antagonistas de accion nueva y doble en los receptores at1 y eta. |
WO2007133637A2 (en) | 2006-05-10 | 2007-11-22 | Renovis, Inc. | Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same |
GB0611210D0 (en) | 2006-06-07 | 2006-07-19 | Cambrex Karlskoga Ab | Process |
GB0719180D0 (en) | 2007-10-02 | 2007-11-14 | Cambrex Karlskoga Ab | New process |
WO2010038029A1 (en) | 2008-10-02 | 2010-04-08 | Cambrex Karlskoga Ab | New process for preparing diketones and medicaments |
US8143269B2 (en) | 2008-10-03 | 2012-03-27 | Calcimedica, Inc. | Inhibitors of store operated calcium release |
AU2008362639A1 (en) | 2008-10-10 | 2010-04-15 | Lonza Ltd | Process for preparing 2-alkyl-3-aroyl-5-nitro-benzofurans |
PL2417099T3 (pl) | 2009-04-08 | 2016-06-30 | Cambrex Karlskoga Ab | Nowy sposób wytwarzania hydroksyloamin i leki |
UY32582A (es) | 2009-04-28 | 2010-11-30 | Amgen Inc | Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero |
TW201107303A (en) | 2009-05-27 | 2011-03-01 | Sanofi Aventis | Process for the production of benzofurans |
UY32657A (es) | 2009-05-27 | 2010-12-31 | Sanofi Aventis | Procedimiento para la fabricación de productos intermedios de dronedarona |
CN101993427B (zh) | 2009-08-26 | 2012-10-10 | 成都伊诺达博医药科技有限公司 | 一种制备决奈达隆的方法 |
HUP0900759A2 (en) | 2009-12-08 | 2011-11-28 | Sanofi Aventis | Novel process for producing dronedarone |
HUP1000010A2 (en) | 2010-01-08 | 2011-11-28 | Sanofi Sa | Process for producing dronedarone |
BR112012020058A2 (pt) * | 2010-02-10 | 2016-11-01 | Mapi Pharma Ltd | preparação de benzofuranos e uso dos mesmos como intermediários sintéticos. |
IT1398317B1 (it) | 2010-02-23 | 2013-02-22 | Chimico Internaz Spa Lab | Nuovo procedimento per la preparazione del 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 |
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 |
CN101838252B (zh) | 2010-05-27 | 2016-05-04 | 北京德众万全医药科技有限公司 | 2-正丁基-5-取代氨基苯并呋喃及其制备方法 |
HUP1000330A2 (en) | 2010-06-18 | 2011-12-28 | Sanofi Sa | Process for the preparation of dronedarone and the novel intermediates |
WO2012004658A2 (en) | 2010-07-09 | 2012-01-12 | Frichem Private Limited | Process for preparation of n-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]methanesulfonamide, acid addition salts and product thereof |
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 |
WO2012032545A1 (en) | 2010-09-08 | 2012-03-15 | Cadila Healthcare Limited | Processes for preparing dronedarone and its intermediates |
FR2973027A1 (fr) | 2011-03-24 | 2012-09-28 | Sanofi Aventis | Procede de synthese de derives de cetobenzofurane |
HUP1100166A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Reductive amination process for preparation of dronedarone using amine intermediary compound |
HUP1100167A2 (en) | 2011-03-29 | 2012-11-28 | Sanofi Sa | Process for preparation of dronedarone by mesylation |
HUP1100165A2 (en) | 2011-03-29 | 2012-12-28 | Sanofi Sa | Process for preparation of dronedarone by n-butylation |
WO2013014479A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Reductive animation process for preparation of dronedarone using aldehyde intermediary compound |
WO2013014480A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Process for preparation of dronedarone using amide intermediary compound |
WO2013014478A1 (en) | 2011-07-26 | 2013-01-31 | Sanofi | Reductive amination process for preparation of dronedarone using carboxyl intermediary compound |
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 |
US9221778B2 (en) | 2012-02-13 | 2015-12-29 | 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 |
-
2010
- 2010-06-18 HU HU1000330A patent/HUP1000330A2/hu unknown
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2011
- 2011-05-30 TW TW100118793A patent/TW201200506A/zh unknown
- 2011-06-10 BR BR112012032358A patent/BR112012032358A2/pt not_active IP Right Cessation
- 2011-06-10 WO PCT/HU2011/000054 patent/WO2011158050A1/en active Application Filing
- 2011-06-10 MX MX2012014675A patent/MX2012014675A/es not_active Application Discontinuation
- 2011-06-10 CA CA2802918A patent/CA2802918A1/en not_active Abandoned
- 2011-06-10 AU AU2011266805A patent/AU2011266805A1/en not_active Abandoned
- 2011-06-10 SG SG2012090692A patent/SG186260A1/en unknown
- 2011-06-10 KR KR1020137001314A patent/KR20130036282A/ko not_active Application Discontinuation
- 2011-06-10 RU RU2013102259/04A patent/RU2013102259A/ru not_active Application Discontinuation
- 2011-06-10 CN CN2011800400348A patent/CN103068810A/zh active Pending
- 2011-06-10 JP JP2013514790A patent/JP2013528641A/ja not_active Withdrawn
- 2011-06-10 EP EP11730061.6A patent/EP2582685A1/en not_active Withdrawn
- 2011-06-17 AR ARP110102110A patent/AR082006A1/es unknown
-
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- 2012-12-12 US US13/711,891 patent/US9174958B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5223510A (en) * | 1990-08-06 | 1993-06-29 | Sanofi | Alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, process for their preparation and compositions containing them |
US20060100460A1 (en) * | 2004-11-10 | 2006-05-11 | Pfizer, Inc. | Substituted N-sulfonylaminobenzyl-2-phenoxyacetamide compounds as VR1 receptor agonists |
Non-Patent Citations (1)
Title |
---|
何晓清 等.: "盐酸决奈达隆合成路线图解", 《中国医药工业杂志》, vol. 41, no. 2, 10 February 2010 (2010-02-10), pages 148 - 151 * |
Also Published As
Publication number | Publication date |
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TW201200506A (en) | 2012-01-01 |
WO2011158050A1 (en) | 2011-12-22 |
CA2802918A1 (en) | 2011-12-22 |
RU2013102259A (ru) | 2014-07-27 |
MX2012014675A (es) | 2013-01-22 |
SG186260A1 (en) | 2013-01-30 |
US20130109868A1 (en) | 2013-05-02 |
JP2013528641A (ja) | 2013-07-11 |
BR112012032358A2 (pt) | 2016-11-08 |
AU2011266805A1 (en) | 2013-01-10 |
KR20130036282A (ko) | 2013-04-11 |
HU1000330D0 (en) | 2010-08-30 |
US9174958B2 (en) | 2015-11-03 |
HUP1000330A2 (en) | 2011-12-28 |
EP2582685A1 (en) | 2013-04-24 |
AR082006A1 (es) | 2012-11-07 |
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