WO2009062377A1 - Résolution de 4,5-diméthoxy-1-(méthylaminométhyl)-benzocyclobutane - Google Patents

Résolution de 4,5-diméthoxy-1-(méthylaminométhyl)-benzocyclobutane Download PDF

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WO2009062377A1
WO2009062377A1 PCT/CN2008/001711 CN2008001711W WO2009062377A1 WO 2009062377 A1 WO2009062377 A1 WO 2009062377A1 CN 2008001711 W CN2008001711 W CN 2008001711W WO 2009062377 A1 WO2009062377 A1 WO 2009062377A1
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tartaric acid
resolution
toluoyl
alcohol
resolving agent
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PCT/CN2008/001711
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English (en)
French (fr)
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Piaoyang Sun
Yongjiang Chen
Guangliang Yu
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Jiangsu Hengrui Medicine Co. Ltd.
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Priority to EP08800667A priority Critical patent/EP2213651B1/en
Priority to US12/742,632 priority patent/US8198485B2/en
Priority to JP2010533411A priority patent/JP5503546B2/ja
Publication of WO2009062377A1 publication Critical patent/WO2009062377A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/06—One of the condensed rings being a six-membered aromatic ring the other ring being four-membered

Definitions

  • the invention provides a method for separating 4, 5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane (indole) mixed intermediate, an important intermediate of ivabradine, Ivabradine intermediate (1S) _4, 5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane (Form I) was obtained.
  • the compound of formula (I) obtained by the process of the present invention can be used in the synthesis of ivaflu
  • Ivabradine and its addition salts with pharmaceutically acceptable acids, especially its hydrochlorides have very valuable pharmacological and therapeutic properties, especially slowing heart rate properties, allowing these compounds to be used for treatment or prevention.
  • Various clinical manifestations of myocardial ischemia such as angina pectoris, myocardial infarction, and associated rhythm disorders, can also be used to treat or prevent various conditions involving rhythm disorders, particularly supraventricular rhythm disorders.
  • Ivabradine is an effective drug for the treatment of myocardial ischemia such as angina pectoris.
  • U.S. Patent Specification No. 5,926, 482 describes a detailed synthetic route for ivabradine, which describes a method for the resolution of a mixed form of (II), which utilizes camphorsulfonic acid to separate the (II) mixed-type spine, thereby A compound of formula (I) is formed.
  • the results obtained by the splitting method are far from satisfactory.
  • the splitting method has a defect of very low yield.
  • the use of camphorsulfonic acid resolution gave the compound of the above formula (I) only in a yield of 4-5%, which resulted in a total yield of only 2-3%.
  • Such low yields inevitably lead to high costs and low efficiency in production.
  • the ee due to the low selectivity of the resolving agent, the ee.
  • the value of the split product is low, and the product needs to undergo multiple recrystallization steps to complete the disintegration process.
  • the disassembly process is cumbersome and unsuitable for industrial production.
  • the chiral purity of the final product is also unsatisfactory.
  • the inventors have extensively and intensively studied and found that, for the commonly used acidic resolving agents, in addition to the selectivity of R-camphorsulfonic acid for the resolution of the ( ⁇ )-type mixed-rotating body, various resolving agent pairs ( ⁇ )
  • the resolution of the mixed-type compound is basically ineffective; some can not effectively form crystal precipitation with the (II) type mixed-rotor in various solvents, such as L-tartaric acid, R-mandelic acid, etc.; Although it can form a crystal precipitate with a ( ⁇ ) type mixed body in a solvent, there is no resolution, and the precipitate is still a mixed form; for example, N-acetyl-L-glutamic acid, L-leucine, and the like.
  • the inventors have intensively studied and found that among the large number of commonly used acidic resolving agents tested, only chiral tartaric acid such as dibenzoyl peroxide protected by benzoyl or substituted benzoyl acylation Tartaric acid (L-DBTA), dibenzoyl-D-tartaric acid (D-DBTA), di-p-toluoyl-L-tartaric acid (L-DTTA) or di-p-toluoyl-D-tartaric acid (D-DTTA)
  • L-DBTA dibenzoyl-D-tartaric acid
  • L-DTTA di-p-toluoyl-L-tartaric acid
  • D-DTTA di-p-toluoyl-D-tartaric acid
  • the invention relates to an important intermediate of ivabradine, 4, 5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane (II) (intermediate amine, mixed-rotation) a method for resolution, comprising the step of salt-resolving and separating the intermediate with an intermediate in an alcohol solvent or an aqueous alcohol solution, wherein the resolving agent is dibenzoyl-L-tartaric acid (L) - DBTA ), dibenzoyl-D-tartaric acid (D-DBTA), di-p-toluoyl-L-tartaric acid (L-DTTA) or di-p-toluoyl-D-tartaric acid (D-DTTA), further preferred Is di-p-toluoyl-L-tartaric acid or di-p-toluoyl-D-tartaric acid, wherein the target product structure obtained is (1S) -4,5-dimethyloxy group represented by the formula (I).
  • the resolution method according to the present invention includes a recrystallization step after salt formation and crystallization.
  • the resolving agent di-p-formyl-L-tartaric acid (L-DTTA) and di-p-toluoyl-D-tartaric acid (D-DTTA) used in the method of the present invention are used singly or in combination.
  • the invention relates to a method of splitting a mixed type II compound.
  • the problem solved by the present invention is to obtain a pharmaceutically acceptable optically pure (I) formula of the above S configuration in an excellent yield by resolution using di-p-toluoyl-L-tartaric acid.
  • the method is characterized in that a mixed body of the formula (II) is added with a chiral resolving acid to form a corresponding salt in a specific solvent to selectively precipitate a crystal of a salt of a chiral intermediate amine which we desire to obtain. .
  • the resolution process of the ( ⁇ )-type mixed-rotator described by the present inventors refers to the crystallization of the acid salt of the (II)-type mixed-rotator and the chiral resolving agent, recrystallization refining, and free extraction (I).
  • the entire process of the intermediate amine if necessary, also includes the addition of a compound of formula (I) and a suitable acid to give an addition salt suitable as a synthetic intermediate for the synthesis of ivabradine.
  • the ( ⁇ )-type mixed-rotation used in the study was prepared according to the method described in U.S. Patent No. 5,928,482.
  • the molar ratio of the intermediate amine to the resolving agent can be 2:1 according to the correspondence of the acid base salt forming reaction; if only the configuration corresponding to us is considered, it can be taken
  • the molar ratio is 4:1; if an equimolar salt is considered to obtain an acid salt, the molar ratio may also be 1:1; and the inventors have found that a higher ratio of the resolving agent is advantageous for the preferred one.
  • the hand rate gives a resolution product of high chiral purity.
  • the molar ratio of the intermediate amine to the resolving agent may be in the range of 5:1 to 1:2, and the preferred ratio is in the range of 2:1 to 1:1. Great help.
  • the resolution process of the (II) mixed compound is carried out in a conventional solvent, preferably
  • the organic solvent is more preferably an alcohol solvent, and the alcohol solvent may be used alone or in combination with other organic solvents.
  • the alcohol solvent used in the method of the present invention includes an alcohol solvent used alone and a mixed solvent mainly composed of an alcohol, and the alcohol solvent is a lower aliphatic alcohol having 3 or less carbon atoms, more preferably ethanol.
  • the alcohol solution is an aqueous ethanol solution.
  • the resolution process of the ( ⁇ ) type mixed body can also be carried out in an aqueous solution of a conventional solvent, more preferably in an aqueous solution of an alcohol, and the ratio of the alcohol to the water can be any, preferably an alcohol solvent. The ratio is between 50% and 100%.
  • the alcohol solvent referred to herein means a lower aliphatic alcohol having 3 or less carbon atoms, and more preferably ethanol.
  • the step of recrystallizing the compound of the formula (I) is sometimes necessary.
  • the process of the separation can generally be carried out at normal temperature, if necessary under heating conditions, and the recrystallization step can generally be carried out under heating, first heating to dissolve the compound of formula (I) in a specific solvent. Then, the process of recrystallization is slowly completed at room temperature.
  • chiral purity is often satisfactory after two recrystallizations, and the ee value is generally above 99%.
  • the process of free intermediate amine is conventional, and the base used for free is preferably sodium hydroxide; the solvent used for extraction is generally selected from hydrophobic organic solvents conventionally used for extraction, preferably toluene, ethyl acetate, dichloromethane, chloroform, etc. More preferred are ethyl acetate and chloroform.
  • the process of forming a salt of (I) is also conventional, and a pharmaceutically acceptable acid salt can be used to facilitate purification and storage, and can also be used directly for feeding.
  • the acid used for salt formation is preferably hydrochloric acid, and the method of salt formation is conventional, and it is easier for a trained professional to do so.
  • the compound of the formula (I) or its addition salt obtained by the process of the invention has a cumulative resolution of up to 80% or more and a chiral purity of more than 99%, and is particularly suitable as a synthetic ivabradine and its pharmacy.
  • a synthetic intermediate which accepts an acid addition salt is particularly suitable as a synthetic ivabradine and its pharmacy.
  • Example 1 (II) Mixture 8.0 g (41.40 sleep 1), dissolve in 350 ml of ethanol, add L-DTTA 4.0 g (10.35 mmol), heat to reflux to clarify, let cool, precipitate a solid, filter, and dry. HPLC analysis. The S configuration accounted for 94.14%.
  • the crude solid of the R configuration was added to 350 mi of ethanol, refluxed to clarify, allowed to cool, and the solid was precipitated, filtered, and dried to yield 7.3 g of the R configuration.
  • the de-split yield of the R configuration split was 60.8%. HPLC analysis of the R configuration accounted for 99.38%.
  • the mother liquor obtained by splitting and recrystallizing in the above-mentioned reverse splitting process is combined and concentrated to dryness After dissolving with sodium hydroxide, extracting with ethyl acetate to obtain 2.6 g of the (II) mixed compound in the S configuration, HPLC analysis of the S configuration accounted for 55.5%, adding 100 ml of ethanol to dissolve, and then adding L-DTTA 5.0 g, heated to reflux to clarify, let cool, precipitate solids, filter, and dry. HPLC analysis of the S configuration accounted for 92.62%.

Description

4, 5-二甲氧基 -1- (甲基氨基甲基） -苯并环丁垸的拆分 技术领域
本发明提供了一种伊伐布雷定的重要中间体 4， 5-二甲氧基- 1- (甲 基氨基甲基） -苯并环丁烷（Π式）混旋体的拆分方法， 得到伊伐布雷 定中间体 （1S ) _4， 5-二甲氧基- 1- (甲基氨基甲基） -苯并环丁垸 （I 式）。
Figure imgf000002_0001
Figure imgf000002_0002
根据本发明的方法制备获得的式 （ I ) 化合物可用于合成伊伐布 中
田疋 o 背景技术
伊伐布雷定及其与药学上可接受的酸的加成盐、特别是其盐酸盐， 具有非常有价值的药理和治疗性能， 尤其是减缓心率的性能， 使这些 化合物可用于治疗或预防心肌局部缺血的各种临床表现， 如心绞痛、 心肌梗塞和伴发的节律紊乱， 而且也可用于治疗或预防各种涉及节律 紊乱特别是室上性节律紊乱的病状。伊伐布雷定是治疗心肌局部缺血如 心绞痛等有效药物。
美国专利说明书 US5296482描述了详细的伊伐布雷定的合成路线， 该专利说明书描述了（II )式混旋体的拆分方法，利用樟脑磺酸对（II ) 式混旋体进行拆分， 从而生成（ I )式化合物。但是该拆分方法所得到 的结果远远不能让人满意， 首先是该拆分方法具有收率非常低的缺陷， 使用樟脑磺酸拆分仅以 4-5%的产率得到上述 （I ) 式化合物， 这就导致 反应总收率只有 2-3%。这样低的产率必然导致生产的高成本和低效率。 另一方面， 由于拆分剂的低选择性， 使得拆分产物的 ee.值较低， 产物 需经过多次重结晶步骤才能完成拆分过程， 拆分工艺操作繁琐， 不适 合于工业化生产， 最终产物的手性纯度也不能令人满意。
鉴于伊伐布雷定及其盐的药用价值， 寻找有效的工业方法， 高效 高收率的通过拆分得到高手性纯度的上述 S构型的 （I ) 式中间体化合 物是十分必要的。 发明内容
本发明人经广泛深入地研究后发现， 对于常用的酸性拆分剂， 除 了 R-樟脑磺酸对 （Π ) 式混旋体的拆分有一定的选择性外， 各种拆分 剂对 （Π ) 式混旋体的拆分基本上是无效的； 有的不能和 （II ) 式混 旋体在各种溶剂中有效地生成结晶沉淀， 如 L-酒石酸， R-扁桃酸等； 有的虽然能够和（Π )式混旋体在溶剂中生成结晶沉淀， 却并无拆分选 择性， 沉淀仍是混旋体； 如 N-乙酰 -L-谷氨酸， L-亮氨酸等。
本发明人经广泛深入地研究后出乎意外地发现， 在所试验的大量 常用酸性拆分剂中， 只有经苯甲酰基或取代苯甲酰基双酰化保护的手 性酒石酸如二苯甲酰 酒石酸 （L- DBTA )、 二苯甲酰- D-酒石酸 ( D-DBTA)、 二对甲苯甲酰 -L-酒石酸 （L- DTTA) 或二对甲苯甲酰 -D-酒 石酸 （D-DTTA) 可使 （S) -构型的胺和 （R) -构型的胺得到有效的分 离。
本发明涉及一种伊伐布雷定的重要中间体 4， 5-二甲氧基- 1- (甲 基氨基甲基） -苯并环丁烷 （II ) (中间体胺， 混旋体） 的拆分方法， 所述方法包括利用拆分剂与所述中间体在醇类溶剂或醇类水溶液中成 盐析晶拆分步骤， 所述拆分剂为二苯甲酰- L-酒石酸 （L- DBTA )、 二苯 甲酰 -D-酒石酸 （D- DBTA )、 二对甲苯甲酰 -L-酒石酸 （L- DTTA)或二对 甲苯甲酰 -D-酒石酸（D-DTTA), 进一步优选为二对甲苯甲酰 -L-酒石酸 或二对甲苯甲酰- D-酒石酸， 其中所得到的目标产物结构为 （I ) 式所 示的 （1S) -4， 5-二甲基氧基 -1- (甲基氨基甲基） -苯并环丁烷。
Figure imgf000004_0001
Figure imgf000004_0002
进一步， 本发明涉及的拆分方法包括在成盐析晶后的重结晶步骤。 本发明方法中所使用的拆分剂二对甲苯甲酰 -L-酒石酸（L- DTTA)和二 对甲苯甲酰 -D-酒石酸 （D-DTTA) 单独使用或联合使用。 具体地说， 本 发明涉及拆分 II式混旋体的方法。 本发明解决的问题是通过使用二对 甲苯甲酰- L-酒石酸拆分， 以优异的产率得到药学上可接受的光学纯的 上述 S构型的 （I ) 式。 该方法的特征在于， 将 （II ) 式的混旋体， 添 加手性拆分剂酸在特定的溶剂中生成相应的盐， 选择性地析出我们希 望得到的手性中间体胺的盐的结晶。
本发明人所述的 （Π ) 式混旋体的拆分过程， 指的是由 （II ) 式 混旋体和手性拆分剂酸成盐析晶、 重结晶精制、 游离萃取得到 （I ) 式 中间体胺的整个过程， 必要的话， 也包括将 （ I ) 式化合物和适当的 酸成盐得到适合于作为合成伊伐布雷定的合成中间体的加成盐的过 程。研究使用的（Π )式混旋体按照美国专利说明书 US5296482描述的 方法制备而得到。
关于拆分剂的用量， 理论上讲， 按酸碱基成盐反应的对应性， 中 间体胺和拆分剂的摩尔比可以是 2: 1 ;如果仅考虑对应我们想要的构型， 可以取摩尔比为 4: 1 ;如果考虑等摩尔成盐得到酸式盐， 也可以取摩尔 比为 1 : 1 ; 而本发明人经过研究后发现， 较高的拆分剂比例有利于以 较理想的手率得到高手性纯度的拆分产物。 一般的讲， 中间体胺和拆 分剂的摩尔比， 合适的范围可以是 5: 1 至 1 : 2， 优选的比例在 2: 1 至 1 : 1, 过量的拆分剂对拆分没有更大的帮助。
所述的 （II ) 式混旋体的拆分过程在常规的溶剂中进行， 优选在 有机溶剂中进行， 所述的有机溶剂更优选为醇类溶剂， 该醇类溶剂可 以单独或者与其他的有机溶剂混合使用。 本发明方法中所使用的醇类 溶剂包括单独使用的醇溶剂以及以醇类为主的混合溶剂， 所述的醇类 溶剂为碳原子数在 3 以下的低级脂肪醇， 更优选乙醇， 所述的醇类溶 液为乙醇水溶液。 更进一步的， （Π ) 式混旋体的拆分过程也可以在常 规的溶剂的水溶液中进行， 更优选在醇类的水溶液中进行， 醇和水的 配比可以是任意的，优选醇类溶剂的比例在 50%〜100%。这里所说的醇 类溶剂指的是含碳原子数在 3以下的低级脂肪醇， 更优选乙醇。
为了提高拆分所得到的（ I )式中间体胺化合物的手性纯度，对（ I ) 式化合物进行重结晶的步骤有时是必要的。 拆分的过程一般可以在常 温下进行， 必要时也可以在加热的条件下进行， 而重结晶的步骤一般 可以在加热的条件下进行， 先加热使 （I ) 式化合物在特定的溶剂中溶 解， 然后在室温条件下缓慢地完成重结晶的过程。 一般来说， 经过二 次重结晶的产物， 手性纯度往往是令人满意的， 其 ee值一般在 99%以 上。
游离中间体胺的过程是常规的， 游离所用的碱优选为氢氧化钠； 萃取所用的溶剂， 一般选用常规用做萃取的疏水有机溶剂， 优选甲苯、 乙酸乙酯、 二氯甲垸和氯仿等， 更优选乙酸乙酯和氯仿。 （ I ) 式化合 物成盐的过程也是常规的， 可以选用药学上可接受的酸成盐以方便纯 化和储存， 也可以直接用于投料。 成盐所用的酸优选盐酸， 成盐采用 的方法是常规的， 对于受过专业训练的业内人士来说， 做到这一点较 为容易。
根据本发明的方法获得的（ I )式化合物或其加成盐具有高达 80% 以上的累积拆分收率和 99%以上的手性纯度，尤其适合作为合成伊伐布 雷定及其与药学上可接受酸的加成盐的合成中间体。 具体实施方式
以下将结合实施例更详细地解释本发明， 本发明的实施例仅用于 说明本发明的技术方案， 并非限定本发明的实质。 实施例 1 (II) 式混旋体 8.0g (41.40睡 1)， 加入 350ml乙醇溶解， 再加 入 L- DTTA 4.0g(10.35mmol), 加热到回流澄清， 放冷， 析出固体， 过 滤， 干燥。 HPLC分析. S构型占 94.14%。
将粗产物固体加入 350ml乙醇中， 回流至澄清， 放冷， 析出固体， 过滤， 干燥得 3.47g(5.99mmol)。 HPLC分析 S构型占 97.19%。 拆分收 率 28.9% (以混旋体中 S构型量计）。 实施例 2
(II) 式混旋体 8.0g (41.40画。1)， 加入 350ml乙醇溶解， 再加 AL-DTTA8.0g(20.7mmol) , 加热到回流澄清， 放冷， 析出固体， 过滤， 干燥。 HPLC分析 S构型占 96.84%
将粗产物固体加入 350ml乙醇中， 回流至澄清， 放冷， 析出固体， 过滤， 干燥得 4.3g(7.42mmol)， 拆分收率 35.8%。 HPLC分析 S构型占 99.87%。 . 实施例 3
(II) 式混旋体 8.0g (41.40隱01)， 加入 350ml乙醇溶解， 再加 入 L- DTTA 16.0g(41.4mmol), 加热到回流澄清， 放冷， 析出固体， 过 滤， 干燥。 HPLC分析 S构型占 94.56%。
将粗产物固体加入 350ml乙醇中， 回流至澄清， 放冷， 析出固体， 过滤， 干燥得一次拆分产物 （I · L-DTTA) 7.4g(12.77隱 ol)， 一次拆 分收率 61.7%。 HPLC分析 S构型占 99.25%。
将上述拆分过程中拆分及重结晶所得的母液合并， 浓缩至干然后 用氢氧化钠游离， 用乙酸乙酯萃取， 得到以 R构型为主的 （Π) 式混 旋体 4.7g， HPLC分析 R构型占 73.5%， 加入 350ml乙醇溶解， 再加入 D-DTTA 14.9g反拆分， 加热到回流澄清， 放冷， 析出固体， 过滤， 干 燥。 HPLC分析 R构型占 94.86%。
将 R构型粗产物固体加入 350mi乙醇中， 回流至澄清， 放冷， 析 出固体， 过滤， 干燥得 R构型拆分物 7.3g。 反拆分得 R构型拆分物得 率 60.8%。 HPLC分析 R构型占 99.38%。
将上述反拆分过程中拆分及重结晶所得的母液合并， 浓缩至干然 后用氢氧化钠游离， 用乙酸乙酯提取得到以 S构型为主的 （II) 式混 旋体 2.6g， HPLC分析 S构型占 55.5%， 加入 100ml乙醇溶解， 再加入 L-DTTA 5.0g, 加热到回流澄清， 放冷， 析出固体， 过滤， 干燥。 HPLC 分析 S构型占 92.62%。
将粗产物固体加入 100ml乙醇中， 回流至澄清， 放冷， 析出固体， 过滤， 干燥得 2.5g(4.31圆 ol)。 HPLC分析 S构型占 99.10%。
将两次正拆分所得到的产物合并， 用氢氧化钠溶液游离， 用乙酸 乙酯萃取， 得到 S 构型的 （I) 式中间体胺化合物 3.3g， 总拆分收率 82.5%0 HPLC分析 S构型占 99.20%。 实施例 4
(II) 式混旋体 8.0g (41.40隱01)， 加入 350ml乙醇溶解， 再加 入 L- DBTA 7.4g (20.7隱 ol)， 加热到回流澄清， 放冷， 析出固体， 过 滤， 干燥。 HPLC分析 R构型占 83.37%。 .
将粗产物固体加入 350ml乙醇中， 回流至澄清， 放冷， 析出固体， 过滤， 干燥得 3.6g。 HPLC分析 R构型占 90.78%。

Claims

权利要求书:
1.一种伊伐布雷定的重要中间体 4， 5-二甲氧基- 1- (甲基氨基甲基） - 苯并环丁垸 （Π ) 的拆分方法， 所述方法包括利用拆分剂与所述中间 体在醇类溶剂或醇类水溶液中成盐析晶拆分步骤， 所述拆分剂为苯甲 酰基或取代苯甲酰基双酰化保护的手性酒石酸， 其中拆分所得到的目 标产物为结构通式（I)所示的 （1S ) -4， 5-二甲基氧基- 1- (甲基氨基 甲基） -苯并环丁烷：
Figure imgf000008_0001
Figure imgf000008_0002
2. 权利要求 1所述的拆分方法，其中所述拆分剂为二苯甲酰 -L-酒石酸， 二苯甲酰- D-酒石酸， 二对甲苯甲酰 -L-酒石酸或二对甲苯甲酰 -D -酒 石酸。
3. 权利要求 1所述的拆分方法， 其中所述拆分剂进一步为二对甲苯甲 酰 -L-酒石酸 （L- DTTA ) 或二对甲苯甲酰- D-酒石酸 （D- DTTA)。
4. 权利要求 1所述的拆分方法， 其中所述拆分方法进一步包括在成盐 析晶后的重结晶步骤。
5. 权利要求 3所述的拆分方法， 其中所使用的拆分剂二对甲苯甲酰 -L- 酒石酸和二对甲苯甲酰 -D-酒石酸单独使用。
6. 权利要求 3所述的拆分方法， 其中所使用的拆分剂二对甲苯甲酰- L - 酒石酸和二对甲苯甲酰 -D-酒石酸联合使用。
7. 权利要求 1所述的拆分方法， 其中所述的醇类溶剂包括单独使用的 醇溶剂以及以醇类为主的混合溶剂。
8. 权利要求 1所述的拆分方法， 其中所述的醇类溶剂为乙醇， 所述的 醇类溶液为乙醇水溶液。
PCT/CN2008/001711 2007-11-16 2008-10-10 Résolution de 4,5-diméthoxy-1-(méthylaminométhyl)-benzocyclobutane WO2009062377A1 (fr)

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EP08800667A EP2213651B1 (en) 2007-11-16 2008-10-10 Resolution of 4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane
US12/742,632 US8198485B2 (en) 2007-11-16 2008-10-10 Resolution of 4,5-dimethoxy-1-(methylaminomenthyl)-benzocyclobutane
JP2010533411A JP5503546B2 (ja) 2007-11-16 2008-10-10 ４，５−ジメトキシ−１−（メチルアミノメチル）−ベンゾシクロブタンの分離

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WO2010072409A1 (en) * 2008-12-22 2010-07-01 Krka, D. D., Novo Mesto Process for preparation of ivabradine
WO2011098582A2 (en) 2010-02-12 2011-08-18 Krka, D.D., Novo Mesto Novel forms of ivabradine hydrochloride
CN103781767A (zh) * 2011-08-01 2014-05-07 化学实验室国际股份公司 伊伐布雷定及其合成中间体的制备方法
US10221141B2 (en) 2015-06-03 2019-03-05 Urquima, S.A. Method for the preparation of highly pure ivabradine base and salts thereof

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CN102070470A (zh) * 2010-11-05 2011-05-25 天津药物研究院 制备s(-)2-(n-正丙基)胺基-5-甲氧基四氢萘的方法
FR2986804A1 (fr) * 2012-02-09 2013-08-16 Servier Lab Procede de synthese enzymatique de l'acide (7s) 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene 7-carboxylique ou de ses esters, et application a la synthese de l'ivabradine et de ses sels
CN102827080B (zh) * 2012-09-12 2014-03-19 江苏宇田生物医药科技有限公司 一种伊伐布雷定的合成方法及其中间产物
CN103848789B (zh) * 2012-11-29 2016-05-18 江苏恒瑞医药股份有限公司 一种伊伐布雷定的制备方法
CN114324714B (zh) * 2021-01-05 2023-06-30 海南鑫开源医药科技有限公司 (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷盐酸盐的检测方法

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