WO2007025481A1

WO2007025481A1 - Process for preparing (s)-n-ethyl-n-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate and tartrate thereof

Info

Publication number: WO2007025481A1
Application number: PCT/CN2006/002246
Authority: WO
Inventors: Dawei Ma; Qiangbiao Pan; Song Pan
Original assignee: Shanghai Aobo Bio-Pharmaceutical Technology Co., Ltd; Shanghai Institute Of Organic Chemistry, Chinese Academy Of Sciences; Zhejiang Huahai Pharmaceutical Co., Ltd.
Priority date: 2005-09-02
Filing date: 2006-09-01
Publication date: 2007-03-08
Also published as: CN1923801A; CN100391938C

Abstract

The present invention relates to a process for preparing (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (i.e. (S)-rivastigmine) ( I ) and tartrate ( II ) thereof, which includes the following steps: reacting 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol ( III ) or its salt with phosgene, diphosgene or triphosgene and obtaining compound ( IV ), followed by reacting with N-methyl-N-ethyl amine and obtaining the compound ( I ). The tartrate ( II ) can be obtained by reacting compound ( I ) with L-(+)-tartaric acid ( V ) . In said process, 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol is prepared from (S)-1-phenethylamine.

Description

(S)-N-乙基 -N-甲基 -3-「1- (二甲氨基)乙基] -氨基甲酸苯酯（ I )及其酒石酸盐（II ) 的制备方法技术领域 Process for preparing (S)-N-ethyl-N-methyl-3-"1-(dimethylamino)ethyl]-carbamic acid phenyl ester (I) and its tartrate (II)

本发明涉及 (S)-N-乙基 -N-甲基 -3- [ 1- (二甲氨基)乙基] -氨基甲酸苯酯（1 )及其酒石酸盐（Π ) 的一种新合成方法。技术背景 The present invention relates to a novel synthesis of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester (1) and its tartrate (Π) method. technical background

阿尔茨海默氏病（简称 AD)是一种由于脑神经细胞死亡而造成的神经性疾病，其症状表现主要是病人记忆和认知能力不同程度丧失，行为活动发生障碍。 Alzheimer's disease (referred to as AD) is a neurological disease caused by the death of brain nerve cells. The symptoms are mainly caused by the loss of memory and cognitive ability of patients and the disorder of behavioral activities.

卡巴拉汀（Rivastigmine, 化学名（S)-N-乙基 -N-甲基 -3- [ 1- (二甲氨基)乙基] -氨基甲酸苯酯）（ I )，及其酒石酸盐（Π )具有如下结构式：

Rivastigmine (chemical name (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester) (I), and its tartrate ( Π ) has the following structural formula:

卡巴拉汀酒石酸盐（II )是一种用于缓解 AD病情发展的有效药物，其作用机理是抑制人脑中的乙酰胆碱酯酶，提高中枢神经介质乙酰胆碱的含量，适用于轻度至中度患者的治疗，可有效改善患者记忆，副作用较少。卡巴拉汀（ I ) 的制备方法如下所述，但是到目前为止无法获得令人满意的结果。 It is an effective drug for relieving the development of AD disease. Its mechanism of action is to inhibit acetylcholinesterase in the human brain and increase the content of acetylcholine in the central nervous system. It is suitable for patients with mild to moderate disease. The treatment can effectively improve the patient's memory with fewer side effects. The preparation method of rivastigmine (I) is as follows, but satisfactory results have not been obtained so far.

美国专利 US 5602176公开了一种方法，是先制备消旋的卡巴拉汀，再与 Ο,Ο'-二对甲苯甲酰基酒石酸单水合物成盐，结晶得到光学纯的 (S) -卡巴拉汀。 U.S. Patent No. 5,602,176 discloses a process for the preparation of racemic rivastigmine which is then salted with hydrazine, Ο'-di-p-toluoyl tartaric acid monohydrate, crystallized to give optically pure (S)-Kabala Ting.

世界专利 WO 2004037771公开了采用间甲氧基苯乙酮为起始原料通过多步反应制备得到消旋的 3-(1-(Ν,Ν-二甲基胺基)乙基) -苯酚，再经拆分纯化得到光学纯的 3-(l-(S)-( ,N- 二甲基胺基)乙基) -苯酚，然后再与 N-甲基 -N-乙基氨基甲酰氯反应制备得到（S) -卡巴拉汀。 World Patent WO 2004037771 discloses the use of m-methoxyacetophenone as a starting material to prepare racemic 3-(1-(indolyl-dimethylamino)ethyl)-phenol by a multi-step reaction. It is purified by resolution to obtain optically pure 3-(l-(S)-(,N-dimethylamino)ethyl)-phenol, which is then reacted with N-methyl-N-ethylcarbamoyl chloride. Get (S) - rivastigmine.

英国专利 GB 2409453公开了采用间羟基苯乙酮为起始原料先与 N-甲基乙基氨基甲酰氯反应，然后转化为消旋的卡巴拉汀，再通过拆,分制得光学纯的（S) -卡巴拉汀。 British Patent GB 2409453 discloses the use of m-hydroxyacetophenone as a starting material for the first reaction with N-methylethylcarbamoyl chloride, followed by conversion to racemic rivastigmine, which is then optically pure by dissection. S) - rivastigmine.

这些拆分方法意味者至少浪费掉 50%的 (R)-异构体，从而使得该方法的总收率低，成本较高。 ' 发明内容 These splitting methods mean that at least 50% of the (R)-isomer is wasted, resulting in a low overall yield and a high cost. ' Summary of the invention

为了克服现有技术的缺陷，本发明提供一种新的制备 (S) - N-乙基 -N-甲基 -3- [ 1- (二甲氨基）乙基] -氨基甲酸苯酯（ I )及其酒石酸盐（ II )的方法，该方法采用化合物（III) 或其盐与光气、双光气或三光气在碱性物质作用下得到化合物（IV)，化合物（IV )不经纯化直接与 N-甲基- N-乙基胺反应制备化合物（ I )，化合物（ I )与 L-(+)-酒石酸（V) 在反应制备其酒石酸盐（11)，具体反应如下， In order to overcome the deficiencies of the prior art, the present invention provides a novel preparation of (S)-N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-carbamic acid phenyl ester (I And a method for the tartrate salt thereof (II), which comprises the compound (IV) by using the compound (III) or a salt thereof and phosgene, diphosgene or triphosgene under a basic substance, and the compound (IV) is not purified. The compound (I) is prepared by directly reacting with N-methyl-N-ethylamine, and the compound (I) is reacted with L-(+)-tartaric acid (V) to prepare the tartrate (11). The specific reaction is as follows.

反应中所采用的碱性物质举例如下：无机碱类（如碳酸钠、碳酸钾、氨基钠、氢化钠、氢化钾）；碱金属醇化合物（如甲醇钠、乙醇钠、叔丁醇钾）；有机碱类（如三乙胺、吡啶、喹啉、二异丙基乙基胺）。反应所采用的溶剂为惰性溶剂，举例如下：如醚（如四氢呋喃、 ***、乙二醇二甲醚、二恶烷)；芳香烃类（如苯、甲苯、二甲苯)；卤代烃（如二氯甲垸、三氯甲垸、二氯乙烷）。反应的温度控制在 0°C到溶剂沸点的温度。制备化合物（ I ) 时采用任意惰性溶剂，低级醇类（如甲醇、乙醇、丙醇、丁醇）；醚类（如四氢呋喃、 ***、乙二醇二甲醚、二恶垸）；芳香烃类（如苯、甲苯、二甲苯）；卤代烃类（如二氯甲垸、三氯甲烷、二氯乙烷）；二甲基甲酰胺，二甲基乙酰胺；酮等。

The basic substances used in the reaction are exemplified as follows: inorganic bases (such as sodium carbonate, potassium carbonate, sodium amide, sodium hydride, potassium hydride); alkali metal alcohol compounds (such as sodium methoxide, sodium ethoxide, potassium t-butoxide); Organic bases (such as triethylamine, pyridine, quinoline, diisopropylethylamine). The solvent used in the reaction is an inert solvent, such as: ether (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as Dichloromethane, trichloromethane, dichloroethane). The temperature of the reaction is controlled at a temperature from 0 ° C to the boiling point of the solvent. The compound ( I ) is prepared by using any inert solvent, lower alcohols (such as methanol, ethanol, propanol, butanol); ethers (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxins); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as dichloromethane, chloroform, dichloroethane); dimethylformamide, dimethylacetamide; ketones, etc.

化合物（IV)和 N-甲基- N-乙基胺反应最好加入碱性物质，以利于反应的进行，可加入的碱性物质举例如下：无机碱类（如碳酸钠、碳酸钾、氨基钠、氢化钠）；碱金属醇化合物类（如甲醇钠、乙醇钠、叔丁醇钾）；有机碱类（如三乙胺、吡啶、喹啉、二异丙基乙基胺）。反应溶剂采用任意惰性溶剂如醚（如四氢呋喃、 ***、乙二醇二甲醚、二恶烷)；芳香烃类（如苯、甲苯、二甲苯）；卤代烃（如二氯甲垸、三氯甲烷、二氯乙烷）；二甲基甲酰胺，二甲基乙酰胺；丙酮等。 The reaction of the compound (IV) with N-methyl-N-ethylamine is preferably carried out by adding a basic substance to facilitate the progress of the reaction. Examples of the basic substance which can be added are as follows: Inorganic bases (e.g., sodium carbonate, potassium carbonate, amino group) Sodium, sodium hydride); alkali metal alcohol compounds (such as sodium methoxide, sodium ethoxide, potassium t-butoxide); organic bases (such as triethylamine, pyridine, quinoline, diisopropylethylamine). The reaction solvent is any inert solvent such as ether (such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane); aromatic hydrocarbons (such as benzene, toluene, xylene); halogenated hydrocarbons (such as dichloromethane, three Methyl chloride, dichloroethane); dimethylformamide, dimethylacetamide; acetone, and the like.

化合物（ I ) 与 L-(+)-酒石酸（V)根据常规的方法制备化合物（11)。 Compound (11) and L-(+)-tartaric acid (V) were prepared according to a conventional method.

本发明中化合物（III)或其盐釆用如下反应得到，方法一： In the present invention, the compound (III) or its salt hydrazine is obtained by the following reaction. method one:

化合物（3) 可以采用众所周知的方法在氨基上引入双甲基，其中包括甲醛 /甲酸、硫酸二甲酯体系。 Compound (3) A bismethyl group can be introduced onto the amino group by a well-known method, including formaldehyde/formic acid, dimethyl sulfate system.

化合物（4)在苯环 3号位选择性引入硝基，可釆用的硝化条件为硝酸 /硫酸体系，为了选择性地在苯环 3号位引入硝基，控制反应中所加入的硝化试剂的用量和反应所釆用的温度，反应的温度不超过 50Ό，优选的不超过 40°C，不同的反应体系、不同的硝化试剂的用量，所控制的最高温度有所不同。 Compound (4) selectively introduces a nitro group at the 3-position of the benzene ring, and the nitrification condition which can be used is a nitric acid/sulfuric acid system. In order to selectively introduce a nitro group at the 3 position of the benzene ring, the nitrification reagent added in the reaction is controlled. The amount used and the temperature at which the reaction is applied, the reaction temperature does not exceed 50 Torr, preferably does not exceed 40 ° C, and the maximum temperature controlled varies depending on the reaction system and the amount of different nitrating reagents.

化合物（5) 中的硝基，可采用常规还原方法，包括催化氢化和化学还原。 The nitro group in the compound (5) can be subjected to a conventional reduction method including catalytic hydrogenation and chemical reduction.

化合物（6) 的重氮化反应，水解可采用常规的方法进行，制得化合物（111)，化合物（III)可根据需要转化为碱盐或者酸盐。 The diazotization reaction of the compound (6), the hydrolysis can be carried out by a conventional method to obtain the compound (111), and the compound (III) can be converted into an alkali salt or an acid salt as needed.

方法二- Method Two-

其中 R为乙酰基、丙酰基、苯甲酰基或者苯乙酰基。 Wherein R is acetyl, propionyl, benzoyl or phenylacetyl.

化合物（4)在苯环 3号位选择性的引入酰基，可以采用的酰化条件为路易斯酸或质子酸存在下的乙酰氯、丙酰氯、笨甲酰氯、苯乙酰氯体系，优选的为乙酰氯、苯甲酰氯、苯乙酰氯体系；为了控制反应在苯环上选择性的引入酰基，酰化反应中所使用的酰化试剂的用量控制在 1摩尔量的化合物（4)釆用 1.1-10.0摩尔量的酰化试剂量，优选的 1.1-2.0 摩尔量。 The compound (4) is selectively introduced into the acyl group at the 3-position of the benzene ring, and the acylation conditions may be acetyl chloride, propionyl chloride, benzoyl chloride, phenylacetyl chloride system in the presence of a Lewis acid or a protic acid, preferably B. Acyl chloride, benzoyl chloride, phenylacetyl chloride system; in order to control the selective introduction of an acyl group on the benzene ring, the acylation test used in the acylation reaction The amount of the agent is controlled to be 1 mole amount of the compound (4), and the amount of the acylating agent is preferably 1.1-10.0 moles, preferably 1.1 to 2.0 moles.

化合物（7) 与 Baeyer- Villager氧化剂在常规 Baeyer-Villager氧化反应体系中反应制备化合物（8)，包括间氯过氧苯甲酸、三氟过氧乙酸体系。 Compound (7) is reacted with Baeyer-Villar oxidant in a conventional Baeyer-Villager oxidation reaction system to prepare compound (8), including m-chloroperoxybenzoic acid, trifluoroperoxyacetic acid system.

化合物（8)在碱性条件下水解或者醇解制得化合物（III)或其盐，化合物（III)可根据需要转化为碱盐或者酸盐。 The compound (8) is hydrolyzed or subjected to alcoholysis under basic conditions to give the compound (III) or a salt thereof, and the compound (III) can be converted into an alkali salt or an acid salt as needed.

上述方法一到方法二中，化合物（3)可先进行硝基或酰基的取代反应，所得到的化合物再与常规的氨甲基化试剂进行反应，其中酰基可为乙酰基、丙酰基、苯甲酰基或者苯乙酰基，所得到的产物进行后续的反应。 In the above method 1 to method 2, the compound (3) may be subjected to a substitution reaction of a nitro group or an acyl group, and the obtained compound is further reacted with a conventional aminomethylating agent, wherein the acyl group may be an acetyl group, a propionyl group or a benzene group. Formyl or phenylacetyl, the resulting product is subjected to subsequent reactions.

方法三： Method three:

III III

化合物（3 ) 可以釆用众所周知的方法在氨基上引入双甲基，其中包括甲醛 /甲酸、硫酸二甲酯体系。 The compound (3) can be introduced into a bismethyl group by a well-known method, including a formaldehyde/formic acid, dimethyl sulfate system.

化合物（4)在苯环 3号位引入磺酸基，可以釆用的磺化试剂为硫酸体系或者氯磺酸体系。为了控制反应在苯环上选择性的引入磺酸基，可以控制反应中所加入的磺化试剂的用量和反应的温度。 The compound (4) is introduced into the sulfonic acid group at the 3-position of the benzene ring, and the sulfonating reagent which can be used is a sulfuric acid system or a chlorosulfonic acid system. In order to control the selective introduction of a sulfonic acid group on the benzene ring, the amount of the sulfonating agent to be added to the reaction and the temperature of the reaction can be controlled.

化合物（9) 采用在强碱作用下熔融制得化合物（111)，反应所采用的强碱可为氢氧化钠和 /或者氢氧化钾。化合物（III)可根据需要转化为碱盐或者酸盐。 The compound (11) is obtained by melting under a strong alkali to obtain a compound (111), and the strong base used in the reaction may be sodium hydroxide and/or potassium hydroxide. The compound (III) can be converted into an alkali salt or an acid salt as needed.

方法四： Method four:

III 化合物（3)在苯环 3号位引入磺酸基，可以釆用的磺化试剂为硫酸体系或者氯磺酸体系。为了控制反应在苯环上选择性的引入磺酸基，控制反应的磺化试剂的用量和反应的温度。 III The compound (3) introduces a sulfonic acid group at the 3-position of the benzene ring, and the sulfonating reagent which can be used is a sulfuric acid system or a chlorosulfonic acid system. In order to control the selective introduction of a sulfonic acid group on the benzene ring, the amount of the sulfonating agent to be reacted and the temperature of the reaction are controlled.

化合物（11 )在强碱作用下熔融制得化合物（12)，反应所釆用的强碱可为氢氧化钠和 /或者氢氧化钾。 Compound (11) is melted by a strong base to obtain compound (12), and the strong base used for the reaction may be sodium hydroxide and/or potassium hydroxide.

化合物（12) 中的氨基，可以采用众所周知的方法在氨基上引入双甲基得到化合物 (III), 包括甲醛 /甲酸体系。 The amino group in the compound (12) can be introduced into the amino group by a well-known method to obtain the compound (III), including a formaldehyde/formic acid system.

化合物（III)可根据需要转化为碱盐或者酸盐。 The compound (III) can be converted into an alkali salt or an acid salt as needed.

本发明合成工艺选择合理，无需进行复杂的拆分纯化，原料来源方便，操作简单，便于获得化学收率髙，光学纯度高，是一种经济的制备化合物（I)及其酒石酸盐（Π) 的方法。 The synthetic process of the invention has reasonable selection, no complicated resolution and purification, convenient source of raw materials, simple operation, convenient chemical yield, high optical purity, and an economical preparation of the compound (I) and its tartrate (Π). Methods.

本发明还提供了一种新的化合物中间体（5)，结构式如下：

The invention also provides a novel compound intermediate (5) having the following structural formula:

本发明又提供了一种新的化合物中间体（6)，结构式如下:

具体实施方式 The invention further provides a novel compound intermediate (6) having the following structural formula:

detailed description

下面结合实施例进一步阐明本发明的内容,这些实施例并非是对本发明范围或精神的限制。 The contents of the present invention are further clarified by the following examples, which are not intended to limit the scope or spirit of the invention.

实施例一 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基氯甲酸酯的制备 Example 1 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

将三光气（15.9 g, 53.5 mmol) 溶于 400 mL 四氢呋喃中，在冰盐浴冷却下加入 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚钠 (25 g， 133.7 mmol), 0°C搅拌 20分钟，然后加热至 55-60°C反应 4小时，用氮气吹走剩余光气，过滤掉氯化钠，浓缩得油状液体（30 g)。不经提纯，直接进入下一步反应。 The triphosgene (15.9 g, 53.5 mmol) was dissolved in 400 mL of tetrahydrofuran, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenolate was added under cooling in an ice salt bath. (25 g, 133.7 mmol), stirred at 0 ° C for 20 minutes, then heated to 55-60 ° C for 4 hours, the remaining phosgene was purged with nitrogen, filtered, and filtered to give an oily liquid (30 g). Without purification, go directly to the next step.

实施例二卡巴拉汀的制备 Example 2 Preparation of rivastigmine

冰水浴冷却下，将实施例一中所得的油状液体 GO g)溶于 200 mL无水***，将此溶液滴加至三乙胺（18.7 mL)、甲基乙基胺（7.9 g， 133.7 mmol)和 300 mL的无水*** 的混合液中。继续在冰水冷却下搅拌 20分钟，然后室温反应过夜。过滤除去三乙胺盐酸盐，用饱和食盐水（2x200 mL)洗涤，无水硫酸钠干燥，浓缩得无色油状液体，减压蒸馏，收集 120-122 °C馏分 (约 0.5毫米汞柱），得卡巴拉汀 (26.8 g, 两步收率 80%)。 The oily liquid GO g obtained in Example 1 was dissolved in 200 mL of anhydrous diethyl ether under ice-cooling, and the solution was added dropwise to triethylamine (18.7 mL), methylethylamine (7.9 g, 133.7 mmol). And a mixture of 300 mL of anhydrous ether. Stirring was continued for 20 minutes while cooling under ice water, and then allowed to react at room temperature overnight. Filtration to remove triethylamine hydrochloride The salt is washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. g, two-step yield 80%).

实施例三 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基氯甲酸酯的制备 Example 3 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

将氢氧化钠（3.18 g， 79.5 mmol)溶于 100 mL乙醇中，慢慢滴加入 3-(l-(S)- (Ν,Ν- 二甲基胺基)乙基) -苯酚盐酸盐 (8 g, 39.7 mmol)的 100 mL乙醇溶液，室温搅拌 1小时后，浓缩蒸干乙醇和水。冰盐浴冷却下，将所得固体慢慢加至三光气（4.7 g, 15.9 mmol) 的四氢呋喃（120 mL)溶液中， 0°C搅拌 20分钟，然后加热至 55-60^QC反应 4小时，氮气吹走剩余光气，过滤掉氯化钠，浓缩得油状液体（9 g)。不经提纯，可直接与甲基乙基胺反应制备卡巴拉汀（操作步骤参照实施例二）。 Sodium hydroxide (3.18 g, 79.5 mmol) was dissolved in 100 mL of ethanol, and 3-(l-(S)-(Ν,Ν-dimethylamino)ethyl)-phenol hydrochloride was slowly added dropwise. (8 g, 39.7 mmol) in 100 mL of ethanol, stirred at room temperature for 1 hour, concentrated and evaporated to dryness ethyl alcohol and water. The resulting solid was slowly added to a solution of triphosgene (4.7 g, 15.9 mmol) in tetrahydrofuran (120 mL), stirred at 0 ° C for 20 min, then heated to 55-60 ^Q C for 4 h. The remaining phosgene was purged with nitrogen, sodium chloride was filtered off, and concentrated to give an oily liquid (9 g). Without purification, rivastigmine can be prepared by directly reacting with methyl ethylamine (refer to Example 2 for the procedure).

实施例四 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基氯甲酸酯的制备 Example 4 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenyl chloroformate

将绝对无水吡啶（8.85 g, 110 mmol)慢慢滴加至 0°C的双光气（ 14.2 mL, 200 mmol) 中，然后滴加 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚（16.5 g, 100 mmol)的无水*** (30 mL) 溶液，滴毕后， 0°C搅拌 1小时，然后升温至室温反应 8小时。减压去除氯化氢气体和多余的光气，再加入 200 mL无水***，过滤，浓缩得油状液体（23 g)。不经提纯，可直接与甲基乙基胺反应制备卡巴拉汀（操作步骤参照实施例二）。 Absolute anhydrous pyridine (8.85 g, 110 mmol) was slowly added dropwise to a double phosgene ( 14.2 mL, 200 mmol) at 0 ° C, then 3-(l-(S)-(N,N- A solution of dimethylamino)ethyl)-phenol (16.5 g, 100 mmol) in dry diethyl ether (30 mL) was evaporated, and then stirred at 0 ° C for 1 hour, then warmed to room temperature for 8 hours. Hydrogen chloride gas and excess phosgene were removed under reduced pressure, and then 200 mL of anhydrous diethyl ether was added, filtered and concentrated to give an oily liquid (23 g). Without purification, rivastigmine can be prepared by directly reacting with methyl ethylamine (refer to Example 2 for the procedure).

实施例五卡巴拉汀酒石酸盐的制备 Example 5 Preparation of rivastigmine tartrate

将卡巴拉汀（2.0 g, 8.0 mmol)和 L-(+)-酒石酸 (1.2 g, 8.0 mmol)溶于 5 mL甲醇中，加热至 60°C，搅拌至澄清，然后将溶液冷却至室温，加入丙酮（约 50 mL)，于 5°C过夜析晶，滤出所析晶体，用丙酮清洗（2x10 mL)， 40 °C真空干燥，得白色晶体卡巴拉汀酒石酸盐 (2.56 g, 80%)。 The rivastigmine (2.0 g, 8.0 mmol) and L-(+)-tartaric acid (1.2 g, 8.0 mmol) were dissolved in 5 mL of methanol, heated to 60 ° C, stirred until clear, then the solution was cooled to room temperature. Acetone (about 50 mL) was added, and the crystals were crystallized at 5 ° C overnight. The crystals were filtered, washed with acetone (2×10 mL), and dried in vacuo at 40 ° C to give white crystals of rivastigmine tartrate (2.56 g, 80%) .

实施例六（S)-N,N-二甲基 -1-苯乙胺的制备 Example 6 Preparation of (S)-N,N-dimethyl-1-phenylethylamine

冰水浴冷却下，在 (5)-1-苯乙胺中（100 g, 0.825 mol) 滴加甲酸（ 129 g, 2.47 mol)，再加入甲醛（162 g， 2.06 mol),然后加热回流 12小时，冷却至室温， 5M盐酸调至 pH=2，然后用 ml乙酸乙酯（3x250 mL)提取除去杂质，水相用 5M NaOH溶液调至 pH=9-10，采用乙酸乙酯（3x400 mL)提取，有机相饱和食盐水洗涤两次，无水硫酸钠干燥，真空除去溶剂，减压蒸馏得无色透明液体（86.1 g， 70%)。 Under ice cooling, add formic acid (129 g, 2.47 mol) in (5)-1-phenylethylamine (100 g, 0.825 mol), add formaldehyde (162 g, 2.06 mol), and then heat to reflux for 12 hours. After cooling to room temperature, 5M hydrochloric acid was adjusted to pH=2, then extracted with ml ethyl acetate (3×250 mL) to remove impurities. The aqueous phase was adjusted to pH=9-10 with 5M NaOH solution and extracted with ethyl acetate (3×400 mL). The organic phase was washed twice with brine, dried over anhydrous sodium sulfate and evaporated.

实施例七硝基取代的 0S)-N,N-二甲基 -1-苯乙胺的制备 Example 7 Preparation of Nitro-substituted 0S)-N,N-Dimethyl-1-phenylethylamine

将 (5 N,N-二甲基小苯乙胺（30 g, 201 mmol) 溶于 150 mL氯仿中，冰水浴冷却下滴加到浓硫酸（52 mL)中，控制溶液温度在 25^QC以下，然后在室温下搅拌 20分钟。滴加浓硝酸（ 15 mL, 221 mmol)和浓硫酸（ 15 mL)的混酸溶液，滴加时控制温度在 30~35^QC 左右。滴毕后将反应液冷却至室温，继续搅拌半小时，然后用 5 N的 NaOH溶液调节 pH 值至 9-10，然后用氯仿（3 x 200 mL)萃取，有机相合并后，用饱和食盐水（2 x 200 mL) 洗涤，无水硫酸钠干燥，浓缩，得黄色油状物（37.1 g， 95%， HPLC显示间位取代的产物含量为 65%)。 (5 N,N-Dimethylacetophenethylamine (30 g, 201 mmol) was dissolved in 150 mL of chloroform, added dropwise to concentrated sulfuric acid (52 mL) under ice-cooling, and the temperature of the solution was controlled at 25 ^Q C. After that, it was stirred at room temperature for 20 minutes. A mixed acid solution of concentrated nitric acid (15 mL, 221 mmol) and concentrated sulfuric acid (15 mL) was added dropwise, and the temperature was controlled at 30 to 35 ^Q C when added dropwise. about. After the completion of the dropwise addition, the reaction solution was cooled to room temperature, stirring was continued for half an hour, and then the pH was adjusted to 9-10 with a 5 N NaOH solution, followed by extraction with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine. (2 x 200 mL) EtOAc (EtOAc m.)

实施例八硝基取代的 (5)-N,N-二甲基 -1-苯乙胺的制备 EXAMPLES Preparation of octanitro substituted (5)-N,N-dimethyl-1-phenylethylamine

将 S)-N,N-二甲基 -1-苯乙胺（20 g, 134 mmol)溶于 50 mL的 CHC1₃中，冰水浴冷却下滴加到浓硫酸 (40 mL)中，保持溶液温度低于室温，然后室温搅拌 20分钟。滴加浓硝酸（11 mL), 滴加过程中保持溶液温度在 30-35^左右。滴毕，反应体系搅拌至室温，用 5 N的 NaOH溶液调节 pH值至 9-10，然后用氯仿（3 x 250 mL)萃取，有机相合并后，用饱和食盐水（2 150 mL)洗涤，无水硫酸钠干燥，浓缩，得黄色油状物（23.5g， 90%, HPLC显示间位取代的产物含量为 63%)。 Dissolve S)-N,N-dimethyl-1-phenylethylamine (20 g, 134 mmol) in 50 mL of CHC1 ₃ and add dropwise to concentrated sulfuric acid (40 mL) with ice-water bath to keep the solution. The temperature was below room temperature and then stirred at room temperature for 20 minutes. Concentrated nitric acid (11 mL) was added dropwise, and the temperature of the solution was maintained at about 30-35^ during the dropwise addition. After the completion of the dropwise addition, the reaction system was stirred to room temperature, and the pH was adjusted to 9-10 with a 5 N NaOH solution, then extracted with chloroform (3×250 mL), and the organic phase was combined and washed with saturated brine (2 150 mL). Dry over anhydrous sodium sulfate and concentrate to give a yellow oil (23.5 g, 90%, HPLC).

实施例九 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯胺的制备 Example 9 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline

将实施例八中所得到的黄色油状物（20 g, 103 minol)溶于 100 mL乙醇中，加热至 50°C, 滴加 SnCl₂.2H₂0 (76.5 g, 339 mmol) 的盐酸（5 N, 240 mL)溶液，滴加过程中保持反应温度为 50〜60^QC，滴加完毕后再于 50^QC反应两小时。减压蒸掉体系中的部分乙醇，用 5 N NaOH溶液调 pH值为 9-10，然后用氯仿 ( 3 200 mL)萃取，有机相合并后，用饱和食盐水（2 X 200 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离得淡黄色油状物 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯胺（9.3 g, 55%)。 The yellow oil (20 g, 103 minol) obtained in Example 8 was dissolved in 100 mL of ethanol, heated to 50 ° C, and SnCl ₂ .2H ₂ 0 (76.5 g, 339 mmol) of hydrochloric acid was added dropwise (5 N, 240 mL) was added dropwise maintaining the reaction temperature during 50~60 ^Q C, after the addition was complete the reaction at 50 ^Q C for two hours. Part of the ethanol in the system was distilled off under reduced pressure, and the pH was adjusted to 9-10 with 5 N NaOH solution, then extracted with chloroform (3 200 mL). The organic phases were combined and washed with brine (2×200 mL). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.)

实施例十 3-(l-(S)-(N，N-二甲基胺基)乙基) -苯酚的制备 Example 10 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

将 17 mL浓 H₂S0₄溶于 50 mL水中，冰水浴冷却下加入 3-(l-(S)-(N,N-二甲基胺基) 乙基) -苯胺（8.1 g, 49.39 mmol), 滴加时保持温度在 25^QC以下，滴加完后继续室温搅拌 30分钟。然后将反应体系用冰盐浴冷却，滴加亚硝酸钠（3.9 g, 56.5 mmol) 的 20 mL水溶液，滴加时保持反应体系温度在 5^QC以下，滴加完毕后，在冰盐浴冷却下继续搅拌 1 小时，得一淡黄色重氮盐溶液。接着，将该淡黄色重氮盐溶液滴加至 120 的 30 mL浓硫酸和 15 mL的水的混合溶液中，控制温度在 120-125^GC，滴加完毕后，冷却至室温，用 5 N的 NaOH溶液中和至 pH值为 9-10，用乙酸乙酯（2 100 mL) 萃取，饱和食盐水 (2 x 50 mL)洗涤，减压蒸干溶剂，柱层析分离，得淡黄色固体 3-(l-(S)- (N,N-二甲基胺基)乙基) -苯酚（6.53 g, 80%)。 17 mL of concentrated H ₂ S0 _{4 was} dissolved in 50 mL of water, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline (8.1 g, 49.39 mmol) was added under ice-cooling. ), keep the temperature below 25 ^Q C during the dropwise addition, and continue to stir at room temperature for 30 minutes after the addition. Then, the reaction system was cooled with an ice salt bath, and a 20 mL aqueous solution of sodium nitrite (3.9 g, 56.5 mmol) was added dropwise. The temperature of the reaction system was kept below 5 ^Q C when added dropwise, and after cooling, it was cooled in an ice salt bath. Stirring was continued for 1 hour to obtain a pale yellow diazonium salt solution. Next, the pale yellow diazonium salt solution is added dropwise to a mixed solution of 120 mL of concentrated sulfuric acid and 15 mL of water at a temperature of 120-125 ^G C. After the dropwise addition is completed, the mixture is cooled to room temperature, and 5 N is used. The NaOH solution was neutralized to a pH of 9-10, extracted with ethyl acetate (2 100 mL), washed with saturated brine (2×50 mL), evaporated and evaporated. 3-(l-(S)-(N,N-Dimethylamino)ethyl)-phenol (6.53 g, 80%).

实施例十一 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚盐酸盐的制备 Example 11 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride

将实施例十中所得的乙酸乙酯萃取液加入 1 N的盐酸（lOO mL) , 室温搅拌半小时，分出水层，有机层再用 1N 的盐酸（50 mL ) 洗涤，合并水层，浓缩得淡黄色固体 3-(l-(S)-(N，N-二甲基胺基)乙基) -苯酚盐酸盐（8.0 g, 80%)。 The ethyl acetate extract obtained in Example 10 was added to 1 N hydrochloric acid (100 mL), and stirred at room temperature for half an hour. The aqueous layer was separated and the organic layer was washed with EtOAc EtOAc (EtOAc) Phenol hydrochloride (8.0 g, 80%).

实施例十二 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚钠的制备 Example 12 Preparation of 3-(1-(S)-(N,N-dimethylamino)ethyl)-phenol sodium

称取钠（0.92 g， 40 mmol)溶解在 100 mL绝对无水乙醇中，然后加入实施例十中所得的 3-(l-(S)- (N,N-二甲基胺基)乙基) -苯酚（6.58 g, 39.9 mmol),室温搅拌半小时，浓缩，得 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚钠（7.45 g, 100%)。 Sodium (0.92 g, 40 mmol) was weighed and dissolved in 100 mL of absolute absolute ethanol, followed by the addition of 3-(l-(S)-(N,N-dimethylamino)ethyl group obtained in Example 10. -Phenol (6.58 g, 39.9 mmol), stirred at room temperature for half an hour, and concentrated to give 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol sodium (7.45 g, 100) %).

实施例十三硝基取代的苯乙胺的制备 Example 13 Preparation of Nitro-Substituted Phenylethylamine

称取 0S)-1-笨乙胺 20 g (165 mmol)溶于 50 mL的 CHC1₃中，冰水浴冷却下，滴加入 35 mL浓硫酸中，滴加时保持温度 25^QC以下，滴毕后室温搅拌 20分钟。滴加 13.5 mL 浓 HN0₃ (d = 1.4)和 13.5 mL浓硫酸配制而成的混酸，滴加时控制温度在 30~35^QC左右。滴毕后将反应液冷却至室温，继续搅拌半小时，然后用 5 N的 NaOH溶液调节 pH值至 9-10，然后用氯仿（3 x 200 niL) 萃取，有机相合并后，用饱和食盐水（2 x 200 mL)洗涤，无水硫酸钠干燥，浓缩，得黄色油状物（24.9 g, 91%, HPLC显示间位取代的产物含量为 64%)。 Weigh 0S)-1-phenylethylamine 20 g (165 mmol) dissolved in 50 mL of CHC1 ₃ , cooled in an ice water bath, added dropwise to 35 mL of concentrated sulfuric acid, and kept at a temperature below 25 ^Q C when dropped. After stirring at room temperature for 20 minutes. The mixed acid prepared by adding 13.5 mL of concentrated HN0 ₃ (d = 1.4) and 13.5 mL of concentrated sulfuric acid was added, and the temperature was controlled to be about 30 to 35 ^Q C during the dropwise addition. After the completion of the dropwise addition, the reaction solution was cooled to room temperature, stirring was continued for half an hour, and then the pH was adjusted to 9-10 with a 5 N NaOH solution, followed by extraction with chloroform (3 x 200 niL), and the organic phase was combined with saturated brine. (2 x 200 mL), EtOAc (EtOAc m.)

实施例十四硝基取代的 (S)-N,N-二甲基 -1-苯乙胺的制备 Example Fourteen Preparation of Nitro-substituted (S)-N,N-Dimethyl-1-phenylethylamine

称取实施例十三所得的黄色油状物（13.3 g, 80 mmol),冰水浴冷却下，加入甲酸（12.6 g, 240 mmol)和甲醛 15.7 g (200 mmol), 加热回流反应 12小时，冷却至室温，用 5N的盐酸调至 pH至 2-3，用乙酸乙酯（3 100 mL)提取除去杂质，水相用 5 N的 NaOH 溶液调至 pH至 9-10，再用乙酸乙酯（3 x 200 mL)提取，有机相合并，用饱和食盐水洗涤（2 x 500 mL)，无水硫酸钠干燥，真空除去溶剂，得黄色油状物（12.4 g， 80%)。 The yellow oil obtained in Example 13 (13.3 g, 80 mmol) was weighed, and then cooled with ice-water bath, and then, formic acid (12.6 g, 240 mmol) and formaldehyde 15.7 g (200 mmol) were added, and the mixture was heated under reflux for 12 hours and cooled to At room temperature, adjust to pH 2-3 with 5N hydrochloric acid, extract with ethyl acetate (3 100 mL) to remove impurities, and adjust the aqueous phase to pH 9-10 with 5 N NaOH solution. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

实施例十五（<S)-N，N-二甲基 -1-苯乙胺的乙酰基化产物的制备 Preparation of the acetylation product of the fifteenth (<S)-N,N-dimethyl-1-phenylethylamine

在一装有冷凝器和氮气入口的 250 mL圆底烧瓶中加入三氯化铝（30.7 g， 230 mmol), 二硫化碳（150 mL)和乙酰氯（3.8 mL， 48 mmol),搅拌下将 (5)-N,N-二甲基 -1-苯乙胺（5.5 g, 37 mmol) 分批加到此混合液中（约 15分钟），再将反应物搅拌 10分钟，然后回流两小时。将反应物冷却，加到冰中充分搅拌，用 5 N的 NaOH水溶液中和体系至 pH为 12，用氯仿（3 x 200 mL)萃取，有机相合并后，用饱和食盐水（2 x l00 mL)洗涤，无水硫酸钠干燥，得到乙酰化产物（5.66 g， 80%) A 250 mL round bottom flask equipped with a condenser and a nitrogen inlet was charged with aluminum trichloride (30.7 g, 230 mmol), carbon disulfide (150 mL) and acetyl chloride (3.8 mL, 48 mmol). -N,N-Dimethyl-1-phenylethylamine (5.5 g, 37 mmol) was added portionwise to this mixture (about 15 min), then the mixture was stirred for 10 min then refluxed for two hours. The reaction was cooled, added to ice and stirred well. The system was neutralized with a 5 N aqueous NaOH solution to pH 12, extracted with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine (2×100 mL) Washed, dried over anhydrous sodium sulfate to give acetylated product (5.66 g, 80%)

实施例十六 0S)-N,N-二甲基 -1-苯乙胺的苯甲酰化产物的制备 Example 16 Preparation of benzoylated product of 0S)-N,N-dimethyl-1-phenylethylamine

在一装有冷凝器和氮气入口的 250 mL圆底烧瓶中加入三氯化铝（15.4 g, 115 mmol) , 二硫化碳（75 mL)和苯甲酰氯（2.1 mL, 24 mmol) , 于 15分钟内将 ( -N,N-二甲基 -1- 苯乙胺（2.7 g, 18 mmol)分批加到此搅拌的混合物中，再将反应物搅拌 10分钟，然后回流两小时。将反应物冷却，加到冰中充分搅拌，用 5 N的 NaOH水溶液中和体系至 pH 为 12，用氯仿（3 x 200 mL) 萃取，有机相合并后，用饱和食盐水（2 x l00 mL)洗涤，无水硫酸钠干燥，经干燥后得到笨甲酰化产物（3.4 g， 75%)。 In a 250 mL round bottom flask equipped with a condenser and a nitrogen inlet, add aluminum trichloride (15.4 g, 115 mmol), carbon disulfide (75 mL) and benzoyl chloride (2.1 mL, 24 mmol) in 15 min. Will (-N,N-dimethyl-1- Phenylethylamine (2.7 g, 18 mmol) was added portionwise to the stirred mixture and the mixture was stirred for 10 min then refluxed for two hours. The reaction was cooled, added to ice and stirred well. The system was neutralized with a 5 N aqueous solution of NaOH to pH 12, extracted with chloroform (3 x 200 mL), and the organic phase was combined with saturated brine (2×100 mL) The mixture was washed with anhydrous sodium sulfate and dried to give the product of the product (3.4 g, 75%).

实施例十七 0S)-N,N-二甲基 -1-苯乙胺的乙酰化产物的 Baeyer-Villager氧化 Example 17 Baeyer-Villager oxidation of the acetylated product of 0S)-N,N-dimethyl-1-phenylethylamine

将实施例十六中所得的 (S)-N，N-二甲基 -1-苯乙胺的乙酰基化产物（6 g, 31.4 mmol) 溶于二氯甲烷（400 mL) 中，加入磷酸二氢钠（4.46 g, 31.4 mmol), 冰水浴冷却下，加入间氯过氧苯甲酸（29.5 g， 55%, 94.2 mmol), 0°C下搅拌 12小时。然后加入饱和 Na₂S0₃ 溶液（lOO mL),室温搅拌 5小时。用饱和碳酸氢钠调节 pH值至 9，用氯仿（3 x 200 mL) 萃取，有机相合并后，饱和食盐水（2 x 200 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 1,2和 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基乙酸酯混合物（5.2 g, 80%)。 The acetylation product of (S)-N,N-dimethyl-1-phenylethylamine obtained in Example 16 (6 g, 31.4 mmol) was dissolved in dichloromethane (400 mL), and phosphoric acid was added. Sodium dihydrogen (4.46 g, 31.4 mmol) was added to m-chloroperoxybenzoic acid (29.5 g, 55%, 94.2 mmol), and the mixture was stirred at 0 ° C for 12 hours. Then a saturated Na ₂ SO ₃ solution (100 mL) was added and stirred at room temperature for 5 hours. The pH was adjusted to 9 with saturated sodium bicarbonate, and extracted with chloroform (3×200 mL). The organic phase was combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate, and concentrated. A mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylacetate (5.2 g, 80%) was obtained.

实施例十八（S)-N,N-二甲基 -1-苯乙胺的苯甲酰化产物的 Baeyer-Villager氧化 Baeyer-Villager oxidation of the benzoylation product of the eighteen (S)-N,N-dimethyl-1-phenylethylamine

(S)-N,N-二甲基 -1-苯乙胺苯甲酰化产物（10.6 g, 41.8 mmol)溶于二氯甲烷（500 mL) 中，加入磷酸二氢钠（5.94 g, 41.8 mmol), 冰水浴冷却下，加入间氯过氧苯甲酸（39.3 g, 55%, 125.4 mmol), 0°C搅拌过夜，然后加入饱和 Na₂S0₃溶液（120 mL)，室温下搅拌 5小时。用饱和碳酸氢钠调节 pH值至 9，用氯仿（3x 300 mL)萃取，有机相合并后，饱和食盐水（2x200 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 1,2和 3-(l-(S)-(N,N- 二甲基胺基)乙基) -苯基苯甲酸酯混合物（5.51 g， 49%) (S)-N,N-Dimethyl-1-phenylethylamine benzoylation product (10.6 g, 41.8 mmol) was dissolved in dichloromethane (500 mL) and sodium dihydrogen phosphate (5.94 g, 41.8 Methanol), with ice-water bath cooling, add m-chloroperoxybenzoic acid (39.3 g, 55%, 125.4 mmol), stir at 0 ° C overnight, then add saturated Na ₂ SO ₃ solution (120 mL) and stir at room temperature for 5 hours . The pH was adjusted to 9 with saturated sodium bicarbonate, and extracted with chloroform (3×300 mL). The organic phase was combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate 2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylbenzoate mixture (5.51 g, 49%)

实施例十九 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚的制备 Example 19 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

称取实施例十七中所得的 1,2和 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基乙酸酯混合物 (5 g, 24.7 mmol), 溶于四氢呋喃（lOO mL) 中，然后加入 NaOH (1.48 g, 37 mmol)的水 ( 10 mL)溶液。室温搅拌 3小时，然后用 NaHC0₃饱和溶液调 pH值至 9,乙酸乙酯 (3x150 mL)萃取，有机相合并，饱和食盐水 (2x150 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚（2.03 g， 51%)。 The mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylacetate obtained in Example 17 (5 g, 24.7 mmol) was weighed. Dissolved in tetrahydrofuran (100 mL), then a solution of NaOH (1.48 g, 37 mmol) in water (10 mL). Was stirred at room temperature for 3 hours and then treated with saturated NaHC0 ₃ solution was adjusted to pH 9, extracted with ethyl acetate (3x150 mL), the organic phases were combined, saturated brine (2x150 mL), dried over anhydrous sodium sulfate, concentrated and column chromatography Isolated to give 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol (2.03 g, 51%).

实施例二十 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚的制备 Example Twenty-three (1-(S)-(N,N-dimethylamino)ethyl)-phenol preparation

称取实施例十八中所得的 1,2和 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯基苯甲酸酯混合物（7 g, 26 mmol)，溶于四氢呋喃（lOO mL) 中，然后加入 NaOH (1.48 g, 37 mmol)的水 ( 10 mL)溶液。室温搅拌 3小时，然后用 NaHC0₃饱和溶液调 pH值至 9，乙酸乙酯 (3x150 mL)萃取，有机相合并，饱和食盐水（2x150 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚（2.10 g， 49%)。实施例二十一（5)-N,N-二甲基 -1-苯乙胺的磺化 The mixture of 1,2 and 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenylbenzoate obtained in Example 18 (7 g, 26 mmol) was weighed. ), dissolved in tetrahydrofuran (100 mL), then a solution of NaOH (1.48 g, 37 mmol) in water (10 mL). Was stirred at room temperature for 3 hours and then treated with saturated NaHC0 ₃ solution was adjusted to pH 9, extracted with ethyl acetate (3x150 mL), the organic phases were combined, saturated brine (2x150 mL), dried over anhydrous sodium sulfate, concentrated and column chromatography Separation gave 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol (2.10 g, 49%). Example sulfonation of twenty-one (5)-N,N-dimethyl-1-phenylethylamine

称取（5 N,N-二甲基小苯乙胺（23 g， 154 mmol) 溶于 150 mL氯仿中，室温下滴入氯磺酸（30.8 mL, 462 mmol), 反应放热，温度很快升至 60°C， 20分钟滴加完，自然冷却至室温。将反应液倾入冰中（300 g)，逐渐升温至 100°C加热 1小时，冷却至室温后，用 5 N的 NaOH溶液调 pH值至 12，将体系中的水旋去，然后用乙醇（500 mL)热提取，热过滤后将所得母液浓缩，得灰白色固体 1,2和 3-(S)-N,N-二甲基 -1-苯乙胺磺酸钠的混合物（30.9 g, 80%)。 Weigh out (5 N,N-dimethyl phenethylamine (23 g, 154 mmol) in 150 mL of chloroform, and add chlorosulfonic acid (30.8 mL, 462 mmol) at room temperature. The reaction is exothermic and the temperature is very high. Rise to 60 ° C, add in 20 minutes, and naturally cool to room temperature. Pour the reaction into ice (300 g), gradually warm to 100 ° C for 1 hour, cool to room temperature, use 5 N NaOH The solution was adjusted to pH 12, the water in the system was spun off, and then extracted with ethanol (500 mL). After hot filtration, the obtained mother liquid was concentrated to give an off-white solid 1, 2 and 3-(S)-N, N- Mixture of sodium dimethyl-1-phenylethyl sulfonate (30.9 g, 80%).

实施例二十二（S)-N,N-二甲基 -1-苯乙胺的磺化 Example 22 Sulfonation of (S)-N,N-Dimethyl-1-phenylethylamine

称取 (5}-N，N-二甲基小苯乙胺（20 g, 134 mmol)溶于 150 mL氯仿中，通 HC1气体至全部成盐，蒸干溶剂，红外烘干，得白色固体 (S)-N,N-二甲基 -1-苯乙胺盐酸盐 (24.9 _g，134 mmol)。 Weigh (5}-N,N-dimethylacetophenethylamine (20 g, 134 mmol) in 150 mL of chloroform, pass HC1 gas to all salt, evaporate the solvent, and dry in the infrared to obtain a white solid. (S)-N,N-Dimethyl-1-phenylethylamine hydrochloride (24.9 _g , 134 mmol).

将氯磺酸（13.4 mL, 201 mmol)加热至 140°C，向其中加入上述所得的 (S -N,W-二甲基 -1-苯乙胺盐酸盐，加料完毕后于 140°C反应一小时。自然冷却至室温，将反应液倾入冰中（300 g)，然后逐渐升温至 100°C加热 1小时，用 5 N的 NaOH溶液调 pH值至 12，将体系中的水减压浓缩掉，然后用热乙醇（500 mL)溶解，热过滤后将所得母液浓缩，得灰白色固体 1,2和 3-(S)-N,N-二甲基 -1-苯乙胺磺酸钠的混合物（30.30 g, 90%) The chlorosulfonic acid (13.4 mL, 201 mmol) was heated to 140 ° C, and the above-obtained (S-N,W-dimethyl-1-phenylethylamine hydrochloride was added thereto at 140 ° C after the addition was completed. After one hour of reaction, naturally cool to room temperature, pour the reaction solution into ice (300 g), then gradually heat up to 100 ° C for 1 hour, adjust the pH to 12 with 5 N NaOH solution, and reduce the water in the system. Concentrated by pressure, then dissolved in hot ethanol (500 mL), and concentrated to give a white solid. 1,2 and 3-(S)-N,N-dimethyl-1-phenylethylamine Mixture of sodium (30.30 g, 90%)

实施例二十三（5)-N,N-二甲基- 苯乙胺的磺化 Example Twenty-three (5)-sulfonation of N,N-dimethyl-phenethylamine

将浓硫酸 (50 g, 500 mmol)加热至 180^DC，加入 (5)-N，N-二甲基 -1-苯乙胺（14.9 g, 100 mmol), 反应液在 180°C反应一小时，自然冷却至室温。将反应液倾入冰中（200 g)，用 5 N的 NaOH溶液调 pH值至 12，将体系中的水减压浓缩掉，然后用热乙醇（350 mL) 溶解，热过滤后将所得母液浓缩，得 1,2和 3-(<S)-N,N-二甲基 -1-苯乙胺磺酸钠的混合物 (21.6 g, 86%)。 Concentrated sulfuric acid (50 g, 500 mmol) was heated to 180 ^D C, (5)-N,N-dimethyl-1-phenylethylamine (14.9 g, 100 mmol) was added, and the reaction mixture was reacted at 180 ° C. Hour, naturally cool to room temperature. The reaction solution was poured into ice (200 g), and the pH was adjusted to 12 with a 5 N NaOH solution. The water in the system was concentrated under reduced pressure and then dissolved in hot ethanol (350 mL). Concentration gave a mixture of 1,2 and 3-(<S)-N,N-dimethyl-1-phenylethylamine sulfonate (21.6 g, 86%).

实施例二十四（5 -1-苯乙胺的磺化 Example 24 (sulfonation of 5-1-phenethylamine)

称取 (S)小苯乙胺（12.1 g, 100 mmol)溶于 150 mL氯仿中，室温下滴入氯磺酸（20.0 mL, 300 mmol), 反应放热，温度很快升至 60°C， 20分钟滴加完，自然冷却至室温。将反应液倾入冰中（ 150 g)，逐渐升温至 100°C加热 1小时，冷却至室温后，用 5 N的 NaOH 溶液调 pH值至 12，将体系中的水减压浓缩掉，然后用热乙醇 GOO mL)提取，热过滤后将所得母液浓缩，得灰白色固体 1,2和 3-(5)- 1-苯乙胺磺酸钠的混合物（20.5 g, 92%)。 (S) Small phenethylamine (12.1 g, 100 mmol) was dissolved in 150 mL of chloroform, and chlorosulfonic acid (20.0 mL, 300 mmol) was added dropwise at room temperature. The reaction was exothermic and the temperature rose rapidly to 60 °C. After 20 minutes, the mixture was cooled and allowed to cool to room temperature. The reaction solution was poured into ice (150 g), gradually heated to 100 ° C for 1 hour, cooled to room temperature, adjusted to pH 12 with 5 N NaOH solution, the water in the system was concentrated under reduced pressure, and then It was extracted with hot ethanol GOO mL), and the resulting mother liquid was concentrated by hot filtration to give a mixture (20.5 g, 92%) of an off-white solid 1,2 and sodium 3-(5)-1-phenylethylamine.

实施例二十五（S)-l-苯乙胺的磺化 Example Twenty-five (S)-l-Phenylethylamine Sulfonation

称取 (S)-l-苯乙胺（24.2 g, 200 mmol)溶于 150 mL氯仿中，通通 HC1气体至全部成盐，蒸千溶剂，红外烘干，得白色固体 (》S)-1-苯乙胺盐酸盐 (31.5 g, 200 mmol)。将氯磺酸（40.0 mL, 600 mmol)加热至 140°C，加入上述所得的 (5)-1-苯乙胺盐酸盐，加料完毕后于 140°C反应一小时，自然冷却至室温。将反应液倾入冰中（350 g)，然后逐渐升温至 100°C加热 1小时，用 5 N的 NaOH溶液调 PH值至 12, 将体系中的水减压浓缩掉，然后用热乙醇（500 mL)提取，热过滤后将所得母液浓缩，得灰白色固体 1,2和 3-0S)- 1-苯乙胺磺酸钠的混合物（41.1 g, 92%)。 Weigh (S)-l-phenethylamine (24.2 g, 200 mmol) in 150 mL of chloroform, and pass HC1 gas to all The salt was evaporated in vacuo to give a white solid ("S)-1-phenylethylamine hydrochloride (31.5 g, 200 mmol). The chlorosulfonic acid (40.0 mL, 600 mmol) was heated to 140 ° C, and the above-obtained (5)-1-phenylethylamine hydrochloride was added. After the addition was completed, the mixture was reacted at 140 ° C for one hour, and then naturally cooled to room temperature. The reaction solution was poured into ice (350 g), then gradually heated to 100 ° C for 1 hour, adjusted to pH 12 with 5 N NaOH solution, and the water in the system was concentrated under reduced pressure, then hot ethanol ( After extraction with 500 mL), the obtained mother liquid was concentrated to give a white solid (1,2) and a mixture of sodium acetophenone sulfonate (41.1 g, 92%).

实施例二十六 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚的制备 Example Twenty-six Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

将实施例二十一、二十二和二十三中所得的 1,2和 3-0S)-N，N-二甲基 -1-苯乙胺磺酸钠的混合物（25.1 g, lOOmmol)和 NaOH (40 g, 1 mol)溶于少量水中（70 mL)，加热至 120 °C 将水蒸干，继续升温至 280 °C，体系进入熔融状态，继续反应 5分钟，停止加热，自然冷却至室温，加水（200 mL)，用 6 N盐酸溶液调 pH至 9，然后用乙酸乙酯（3 χ 200 mL) 萃取，有机相合并后，用饱和食盐水 (2 X 200 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 3-(l-(S)-( ,N-二甲基胺基)乙基) -苯酚（7.93 g, 48%)。 a mixture of 1,2 and 3-0S)-N,N-dimethyl-1-phenylethylamine sulfonate obtained in Examples 21, 22 and 23 (25.1 g, 100 mmol) Dissolve with NaOH (40 g, 1 mol) in a small amount of water (70 mL), heat to 120 °C, evaporate the water, continue to warm to 280 °C, the system enters a molten state, continue the reaction for 5 minutes, stop heating, and naturally cool To the room temperature, add water (200 mL), adjust the pH to 9 with 6 N hydrochloric acid solution, then extract with ethyl acetate (3 χ 200 mL), and then wash the organic phase and wash with saturated brine (2×200 mL). The aqueous sodium sulfate was dried (MgSO4), evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

实施例二十七 3-(l-(S)-胺基乙基) -苯酚的制备 Example 27 Preparation of 3-(l-(S)-aminoethyl)-phenol

将实施例二十四和二十五中所得的 1,2和 3-0SH-苯乙胺磺酸钠（22.3 g, 100 mmol) 和 NaOH (40 g， 1 mol)溶于少量水中（70 mL), 加热至 120 °C将水蒸干，再继续升温至 280°C,体系进入熔融状态，继续反应 5分钟，停止加热，自然冷却至室温，加水（200 mL)，用 6 N盐酸溶液调 pH至 9, 然后用乙酸乙酯（3x 200 mL)萃取，有机相合并后，用饱和食盐水 (2 200 mL)洗涤，无水硫酸钠干燥，浓缩，柱层析分离，得 3-(l-(S)-胺基乙基) -苯酚（7.54 g, 55%)。 The sodium 1,2 and 3-0SH-phenylethyl sulfonate (22.3 g, 100 mmol) and NaOH (40 g, 1 mol) obtained in Examples 24 and 25 were dissolved in a small amount of water (70 mL). ), heated to 120 ° C, evaporated to dryness, and then continued to warm to 280 ° C, the system into a molten state, continue to react for 5 minutes, stop heating, naturally cooled to room temperature, add water (200 mL), adjust with 6 N hydrochloric acid solution The mixture was extracted with ethyl acetate (3×200 mL). The organic phase was combined, washed with saturated brine (2200 mL), dried over anhydrous sodium sulfate, and concentrated. -(S)-Aminoethyl)-phenol (7.54 g, 55%).

实施例二十八 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚的制备 Example 28 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol

称取实施例二十七中所得的 3-(l-(S)-胺基乙基) -苯酚（ 11.0 g, 80 mmol),冰水浴冷却下，加入甲酸（ 12.6 g, 240 mmol)和甲醛 15.7 g (200 mmol), 加热回流反应 12小时，冷却至室温，用 5N的盐酸调至 pH至 2-3，用乙酸乙酯 G x lOO mL)提取除去杂质，水相用 5N的 NaOH溶液调至 pH至 9-10，再用乙酸乙酯（3 x 200 mL)提取，有机相合并，用饱和食盐水洗涤（2 x 500 mL)，无水硫酸钠干燥，真空除去溶剂，得 3-(l-(S)-(N,N- 二甲基胺基)乙基) -苯酚（10.4 g， 79%)。 The 3-(l-(S)-aminoethyl)-phenol (11.0 g, 80 mmol) obtained in Example 27 was weighed, and the formic acid ( 12.6 g, 240 mmol) and formaldehyde were added under ice-cooling. 15.7 g (200 mmol), heated under reflux for 12 hours, cooled to room temperature, adjusted to pH 2-3 with 5N hydrochloric acid, extracted with ethyl acetate G x 100 mL), and the aqueous phase was adjusted with 5 N NaOH solution. The mixture was extracted with ethyl acetate (3×200 mL). The organic layer was combined and washed with brine (2×500 mL). 1-(S)-(N,N-Dimethylamino)ethyl)-phenol (10.4 g, 79%).

实施例二十九 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚盐酸盐的制备 Example 29 Preparation of 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride

将 25.5 mL浓 H₂S0₄溶于 75 mL水中，冰水浴冷却下加入 3-(l-(S)-(N,N-二甲基胺基) 乙基) -苯胺（12.15 g, 74 mmol) , 滴加时保持温度在 25。C以下，滴加完后继续室温搅拌 30分钟。然后将反应体系用冰盐浴冷却，滴加亚硝酸钠（5.85 g, 84.75 mmol) 的 30 mL 水溶液，滴加时保持反应体系温度在 5^QC以下，滴加完毕后，在冰盐浴冷却下继续搅拌 1 小时，得一淡黄色重氮盐溶液。接着，将该淡黄色重氮盐溶液滴加至 120^QC的 30 mL浓硫酸和 15 mL的水的混合溶液中，控制温度在 120-125^QC，滴加完毕后，冷却至室温，用 5 N的 NaOH溶液中和至 pH值为 9-10，用氯仿（3 x 200 mL) 萃取，有机相合并后，用饱和食盐水（2 x 200 mL)洗涤，无水硫酸钠干燥，将体系真空浓缩至约 200 mL，通 HC1 气体 30 分钟。浓缩得淡黄色固体 3-(l-(S)-(N,N-二甲基胺基)乙基) -苯酚盐酸盐 (12.7 g, 85%)。 25.5 mL of concentrated H ₂ S0 _{4 was} dissolved in 75 mL of water, and 3-(l-(S)-(N,N-dimethylamino)ethyl)-aniline (12.15 g, 74 mmol) was added under ice-cooling. ), keep the temperature at 25 when dropping. Below C, continue to stir at room temperature after the addition 30 minutes. Then, the reaction system was cooled with an ice salt bath, and a 30 mL aqueous solution of sodium nitrite (5.85 g, 84.75 mmol) was added dropwise, and the temperature of the reaction system was kept below 5 ^Q C when added dropwise, and after cooling, it was cooled in an ice salt bath. Stirring was continued for 1 hour to obtain a pale yellow diazonium salt solution. Subsequently, the pale yellow diazonium salt solution was added dropwise to 120 ^Q C in 30 mL of concentrated sulfuric acid and a mixed solution of 15 mL of water, controlling the temperature at 120-125 ^Q C, after the addition was complete, cooled to room temperature, 5 N NaOH solution was neutralized to a pH of 9-10, extracted with chloroform (3 x 200 mL), and the organic phases were combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate Concentrate to about 200 mL in vacuo and pass HC1 gas for 30 minutes. Concentration gave 3-(l-(S)-(N,N-dimethylamino)ethyl)-phenol hydrochloride (12.7 g, 85%).

Claims

权利要求 Rights request

1、S)-N-

的制备方法，

(III)的化合物或其盐与光气、双光气或者三光气在碱性物质作用

( IV ), 化合物（IV ) 不经纯化直接与 N-甲基- N-乙基胺反应制备化合物（ I )。 1, S)-N-

Preparation method,

a compound of (III) or a salt thereof and a phosgene, a diphosgene or a triphosgene acting on a basic substance

(IV), Compound (IV) is directly reacted with N-methyl-N-ethylamine without purification to prepare Compound (I).

2、如权利要求 1所述的方法，其中所述式（III)化合物或其盐经如下反应制得_: a.起始原料化合物（3)

与氨甲基化试剂反应，得化合物（4) b.化合物（4) 与硝化试剂反应，得化合物（5) c化合物（5) 与还原试剂反应，得化合物（6)

2. The method according to claim 1, wherein the compound of the formula (III) or a salt thereof is obtained by the following reaction _: a. starting material compound (3)

Reaction with an aminomethylation reagent to obtain a compound (4) b. The compound (4) is reacted with a nitrating reagent to obtain a compound (5) c compound (5) which is reacted with a reducing reagent to obtain a compound (6)

d.化合物（6)与亚硝酸盐在酸性条件下进行重氮化反应，然后水解得到化合物（III); e.根据需要，将化合物（III)转变成相应的碱盐或者酸盐。 d. Compound (6) is subjected to diazotization reaction under acidic conditions with nitrite, followed by hydrolysis to give compound (III); e. Compound (III) is converted to the corresponding base salt or acid salt as needed.

3、权利要求 1所述的方法，其中所述式（III)化合物或其盐经如下反应制得： a.化合物（3 )在氨甲基化条件下反应制备化合物 (4); The method according to claim 1, wherein the compound of the formula (III) or a salt thereof is obtained by the following reaction: a. the compound (3) is reacted under aminomethylation conditions to prepare a compound (4);

b. 化合物（4 ) 与酰化试剂在路易斯酸或质子酸存在下反应制备合物（7 )

b. Compound (4) is reacted with an acylating reagent in the presence of a Lewis acid or a protic acid to prepare a compound (7)

其中 R为乙酰基、丙酰基、苯甲酰基或者苯乙酰基； c.化合物（7)经 Baeyer-Villager氧化制备化合物（8)

，其中 R为乙酰基、丙酰基、苯甲酰基或者苯乙酰基； Wherein R is acetyl, propionyl, benzoyl or phenylacetyl; c. Compound (7) is oxidized by Baeyer-Villager to prepare compound (8)

Wherein R is acetyl, propionyl, benzoyl or phenylacetyl;

d.化合物（8) 经水解得到化合物（ΠΙ); d. Compound (8) is hydrolyzed to give a compound (ΠΙ);

e.根据需要，将化合物（III)转变成相应的碱盐或者酸盐。 e. Conversion of compound (III) to the corresponding base salt or acid salt, as needed.

4、如权利要求 1所述的方法，其中所述化合物（III) 或其盐经如下反应进行， a. 化合物（3 )在氨甲基化条件下反应制得化合物 (4); 4. The method according to claim 1, wherein the compound (III) or a salt thereof is subjected to the following reaction, a compound (3) is reacted under ammonia methylation conditions to obtain a compound (4);

b.化合物（4) 与磺化试剂反应，得化合物（9 ) c化合物（9)在氢氧化钠和 /或氢氧化钾作用下碱

熔得到化合物（III) b. Compound (4) is reacted with a sulfonating reagent to obtain a compound (9) c compound (9) which is alkalized by sodium hydroxide and/or potassium hydroxide.

Melting compound (III)

d.根据需要，将化合物（III)转变成相应的碱盐或者酸盐。 d. Conversion of compound (III) to the corresponding base salt or acid salt, as needed.

5、如权利要求 1所述的方法，其中所述化合物（III)或其盐经如下反应进行， a. 化合物（3 ) 与磺化试剂反应得到化合物（11 ) b.化合物（11 )在氢氧化钠和 /或氢氧化钾存在下碱

熔制得化合物（12) c. 化合物（12)在氨甲基化条件下反应制得化合物（III)

The method according to claim 1, wherein the compound (III) or a salt thereof is subjected to the following reaction: a. the compound (3) is reacted with a sulfonating reagent to obtain a compound (11) b. the compound (11) is hydrogen. Alkali in the presence of sodium oxide and/or potassium hydroxide

Melting compound (12) c. Compound (12) is reacted under aminomethylation conditions to obtain compound (III)

6、如权利要求 2或者 3所述的方法，其中所述化合物（3 )先与硝化试剂引入硝基或酰化试剂反应引入酰基，所得产物再与氨甲基化试剂反应，其中酰基为乙酰基、丙酰基、苯甲酰基或者苯乙酰基。 The method according to claim 2 or 3, wherein the compound (3) is first introduced into a nitro group by introducing a nitrating reagent into a nitro group or an acylating reagent, and the resulting product is further reacted with an aminomethylating reagent, wherein the acyl group is acetyl. Base, propionyl, benzoyl or phenylacetyl.

7、如权利要求 1所述的方法，其中所述碱性物质选自包括碳酸钠、碳酸钾、氨基钠、氢化钠、氢化钾的无机碱类；包括甲醇钠、乙醇钠、叔丁醇钾的碱金属醇化合物；和包括三乙胺、吡啶、喹啉、二异丙基乙基胺的有机碱类。 7. The method of claim 1 wherein said basic material is selected from the group consisting of sodium carbonate, potassium carbonate, sodium amide, sodium hydride, potassium hydride; and sodium methoxide, sodium ethoxide, potassium t-butoxide An alkali metal alcohol compound; and an organic base comprising triethylamine, pyridine, quinoline, diisopropylethylamine.

8、如权利要求 1所述的方法，其中从化合物（IV)制备化合物（ I ) 的反应在碱性物质中进行，所述碱性物质选自包括碳酸钠、碳酸钾、氨基钠、氢化钠的无机碱类；包括甲醇钠、乙醇钠、叔丁醇钾的碱金属醇化合物；和包括三乙胺、吡啶、喹啉、二异丙基乙基胺的有机碱类。 8. The method according to claim 1, wherein the reaction for preparing the compound (I) from the compound (IV) is carried out in a basic substance selected from the group consisting of sodium carbonate, potassium carbonate, sodium amide, sodium hydride Inorganic bases; alkali metal alcohol compounds including sodium methoxide, sodium ethoxide, potassium t-butoxide; and organic bases including triethylamine, pyridine, quinoline, diisopropylethylamine.

9、如权利要求 1所述的方法，从化合物（III )制备化合物（IV) 的反应在惰性溶剂中进行，所述惰性溶剂选自包括四氢呋喃、 ***、乙二醇二甲醚、二恶烷的醚类，包括苯、甲苯、二甲苯的苯类；及丙酮；从化合物（IV)制备化合物（I ) 的反应在惰性溶剂中进行，所述惰性溶剂选自包括甲醇、乙醇、丙醇、丁醇的低级醇；包括四氢呋喃、 ***、乙二醇二甲醚、二恶垸的醚类；包括苯、甲苯、乙苯的苯类；二氯甲烷、三氯甲烷、二氯乙烷的卤代烃类；二甲基甲酰胺；二甲基乙酰胺；及丙酮。 The method according to claim 1, wherein the reaction for preparing the compound (IV) from the compound (III) is carried out in an inert solvent selected from the group consisting of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether and dioxane. Ethers, including benzenes of benzene, toluene, xylene; and acetone; the reaction for preparing compound (I) from compound (IV) is carried out in an inert solvent selected from the group consisting of methanol, ethanol, propanol, Lower alcohol of butanol; ethers including tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxins; benzenes including benzene, toluene, ethylbenzene; halogens of dichloromethane, chloroform, dichloroethane Hydrocarbons; dimethylformamide; dimethylacetamide; and acetone.

10、一种化合物（ I )的酒石酸盐（II )的制备方法，化合物（ I )与 L-(+)-酒石酸 (V) 反应制备化合物（11 )。 A process for producing a tartrate (II) of the compound (I), which is prepared by reacting the compound (I) with L-(+)-tartaric acid (V).

11、一种结构式如下的化合物（5) 11. A compound of the following formula (5)

12、一种结构式如下的化合物（6)

12. A compound of the following formula (6)