WO2008124969A1 - Preparation method of rivastigmine and its intermediates - Google Patents

Preparation method of rivastigmine and its intermediates Download PDF

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WO2008124969A1
WO2008124969A1 PCT/CN2007/001248 CN2007001248W WO2008124969A1 WO 2008124969 A1 WO2008124969 A1 WO 2008124969A1 CN 2007001248 W CN2007001248 W CN 2007001248W WO 2008124969 A1 WO2008124969 A1 WO 2008124969A1
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formula
compound
compound represented
base
reaction
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PCT/CN2007/001248
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Chinese (zh)
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Guanghui Tian
Yi Zhu
Jingshan Shen
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Topharman Shanghai Co., Ltd.
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Priority to PCT/CN2007/001248 priority Critical patent/WO2008124969A1/en
Priority to CN2007800525506A priority patent/CN101707952B/en
Publication of WO2008124969A1 publication Critical patent/WO2008124969A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a process for the preparation of rivastigmine and an intermediate thereof.
  • Rivas tigmine also known as rivastigmine
  • (S) - N-ethyl-N-methyl-3-(1-(dimethylamino)ethyl]amino Phenyl formate a drug developed by Novartis Pharmaceuticals Ltd. for the treatment of Alzheimer's disease, achieves therapeutic goals by selectively inhibiting acetylcholinesterase in the cerebral cortex and hippocampus.
  • ethylmethylcarbamoyl chloride is reacted with dimethylaminoethylphenol to obtain a racemic product, which is then separated by (+) -0, ( ⁇ -di-p-toluoyl-(D)-tartaric acid to obtain S. Configuration compound.
  • WO2005061446 discloses another preparation method in which mainly 3-acetylphenol is subjected to condensation, reduction, methylation, and then re-cleared with ethylmethylcarbamoyl chloride to obtain S-type rivastigmine.
  • WO03101917 discloses the reaction of dimethylaminoethylphenol with hydrazine-ethyl-hydrazine-methyl-4-nitrobenzamide to give the product, also using (+)-o, (-di-p-toluoyl-) (D) - Tartaric acid Perform the split.
  • WO2004037771 discloses a process for first reacting a reaction intermediate dimethylaminoethylphenol with S-(+)-camphorsulfonic acid to obtain a product of the S configuration, followed by reaction with ethylmethylcarbamoyl chloride to obtain a product.
  • CN1486973 also uses dimethylaminoethylphenol and ethylmethylcarbamoyl chloride in the S configuration to give rivastigmine with higher optical purity.
  • the present invention provides a process for preparing rivastigmine, and also provides a novel compound intermediate for the preparation of rivastig.
  • the novel method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production.
  • the present invention provides a process for producing a compound of the formula (1), which is obtained by reacting a compound represented by the formula (2) with CH 3 X or CH 3 CH 2 X in the presence of a base.
  • X is a suitable leaving group
  • R is a methyl group or an ethyl group; when R is a methyl group, it reacts with CH 3 CH 2 X; and when R is an ethyl group, it reacts with CH 3 X.
  • the X is preferably a halogen, and more preferably Cl, Br or I.
  • the base is a metal salt of an alcohol or an amine, a metal hydride, a hydroxide, a metal oxide, or a carbon
  • the acid salt hydrogencarbonate, preferably sodium hydrogen or potassium carbonate.
  • the reaction is carried out in an organic solvent.
  • the organic solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide, 1, 4-dioxane, One of 1,2-dichloroethane or a mixture of any ratio thereof.
  • the compound represented by the formula (2) is obtained by resolution of a compound represented by the formula (3) or an optically active compound represented by the formula (7).
  • R is a methyl group or an ethyl group.
  • the resolving agent is S - (+) - camphorsulfonic acid or (+) - 0, ( ⁇ - di-p-toluene) Formyl-(D)-tartaric acid;
  • the solvent is methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, one of water or a mixture thereof.
  • the compound of the formula (2) can be obtained by reacting a compound of the formula (7) with a compound of the formula (7) and a compound of the formula (5) or a compound of the formula (6).
  • reaction solvent is benzene, toluene, dichloromethane or chloroform
  • reaction temperature is 30 ° C - 120 ° C, preferably 50 ° C - 100 .
  • the reaction of the compound of the formula (7) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1, 2 a mixture of dichloroacetamidine, tetrahydrofuran, I, 4 -dioxane, 1,2-dichloroethane or any ratio thereof;
  • the base is a metal hydride, hydroxide, metal oxide , carbonate, bicarbonate, organic base or a combination thereof.
  • the organic base is an organic amine, a metal salt of an amine, or a combination thereof.
  • the compound represented by the formula (3) is obtained by reacting a compound represented by the formula (4).
  • the method is as follows: a compound represented by the formula (4) is obtained by reacting a compound represented by the formula (5), or a compound represented by the formula (4) with a compound of the formula (6).
  • R is a methyl group or an ethyl group.
  • reaction solvent is tetrahydrofuran, DMF, benzene, toluene, dichloromethane, chloroform, and the reaction temperature is 30 ° C - 120 ° C, preferably 60 . C - 100 ° C.
  • the reaction of the compound of the formula (4) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, One of 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or a mixture thereof in any ratio; the base is a metal hydride, a hydroxide, Metal oxides, carbonates, bicarbonates, organic bases or combinations thereof.
  • the organic base is an organic amine, a metal salt of an amine, or a combination thereof.
  • the present invention also provides a compound of the formula (2):
  • R is an ethyl group.
  • the invention also provides a compound represented by formula (3)
  • R is an ethyl group.
  • the compound of the structural formula (4) according to the present invention can be referred to the literature (Journal of East China Normal University, Nature Scientific version, 2001, 1, 61-65), the method is as follows:
  • the method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production. Detailed ways
  • the invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention.
  • the technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
  • the solvents or reagents used in the tests were produced by Sinopharm Chemical Reagent Co., Ltd. unless otherwise indicated; the NMR spectra were performed on a Varian Mercury 300 instrument, and all spectra were consistent with the predicted structure, and the characteristic peaks were represented by conventional abbreviations. : s, single peak; d, doublet; t, triplet; q, quartet; m, multiplet.
  • Room temperature means 20 - 25 °C.
  • Methyl chloride diluted R is a compound of the formula (6) (N-methylcarbamoyl chloride) 9.77 g (0.105 fflol) was slowly added dropwise to the above solution, and the addition was completed, and the mixture was returned to room temperature and stirred for 2 hours.
  • Example 1 Preparation of compound 11. lg (0.05 mol), dissolved in llOmL methanol, added D (+) 10- 10-camphorsulfonic acid 12. lg (0.053 mol), heated at 60 ° C for 2 hours, returned to room temperature, Ethyl acetate (50 mL) was added to precipitate a solid, and the obtained solid was filtered, and then recrystallized three times with methanol/ethyl acetate, and dried at 50 ° C for 2 hours, weighing 7.3 g of product, dissolved in 20 mL of water, sodium hydroxide 0.64 g (0.016 mol), stirring at room temperature for 30 minutes, adding 100 mL of dichloromethane, separating the liquid, and washing the dichloromethane phase three times with 60 mL of distilled water, and evaporating the solvent under reduced pressure to obtain the formula (2) wherein R is a methyl group.
  • Example 2 The compound of Example 2, lg (4.5 mmol), was dissolved in 10 mL of THF, and potassium carbonate (0.35 g (5.0 lb ol) was added thereto, and 0.54 g (5.0 leg ol) of bromoacetone was slowly added dropwise thereto, and the mixture was heated at 80 ° C for 1.5 hours. After returning to room temperature, most of the THF was evaporated under reduced pressure. The product was obtained by adding 30 mL of dichloromethane, and washed with 5 mL of distilled water. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the compound of formula (1).
  • R is a compound of the formula (3) (ethyl carbamate 3- [1-(dimethylamino)ethyl]phenyl ester) Preparation
  • the compound of the formula (1) ((S) - N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid benzene is a compound represented by the formula (2) wherein R is an ethyl group.

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Abstract

The present invention provides a preparation method of rivastigmine and its intermediates. The present invention provides a preparation method of the formula (1) compound by reacting the formula (2) compound with CH3X or CH3CH2X in the presence of base, wherein X is a suitable leaving-group; R is methyl or ethyl; when R is methyl, the formula (2) compound is reacted with CH3CH2X; when R is ethyl, the formula (2) compound is reacted with CH3X. The preparation method according to the invention does not utilize ethylmethylcarbamoylchloride.

Description

一种制备利伐斯的明的方法及其中间体 技术领域  Method for preparing rivastigmine and intermediate thereof
本发明涉及一种制备利伐斯的明的方法及其中间体。  The present invention relates to a process for the preparation of rivastigmine and an intermediate thereof.
背景技术 Background technique
利伐斯的明（Rivas t igmine , 又称作卡巴拉汀）的化学名称是： （S) - N- 乙基 - N-甲基- 3- [1- (二甲氨基）乙基]氨基甲酸苯酯 , 是由诺华（Novar t i s) 制药有限公司开发的一种用于治疗阿尔茨海默症的药物， 其通过选择性抑 制大脑皮层及海马区的乙酰胆碱酯酶， 达到治疗目的。 FDA于 2000年 4月 批准上巿。 其结构如图 1所示：  The chemical name of Rivas tigmine (also known as rivastigmine) is: (S) - N-ethyl-N-methyl-3-(1-(dimethylamino)ethyl]amino Phenyl formate, a drug developed by Novartis Pharmaceuticals Ltd. for the treatment of Alzheimer's disease, achieves therapeutic goals by selectively inhibiting acetylcholinesterase in the cerebral cortex and hippocampus. The FDA approved the captain in April 2000. Its structure is shown in Figure 1:
Figure imgf000003_0001
Figure imgf000003_0001
DE 3805744公开了其合成方法:  DE 3805744 discloses its synthesis method:
Figure imgf000003_0002
Figure imgf000003_0002
方法中利用了乙基甲基氨基甲酰氯与二甲氨基乙基苯酚反应得到消旋 产物， 然后用（+) -0, (Κ -二对甲苯甲酰- (D) -酒石酸拆分得到 S构型化合物。  In the method, ethylmethylcarbamoyl chloride is reacted with dimethylaminoethylphenol to obtain a racemic product, which is then separated by (+) -0, (Κ-di-p-toluoyl-(D)-tartaric acid to obtain S. Configuration compound.
WO2005061446公开了另一种制备方法，主要是 3-乙酰基苯酚经过缩合， 还原， 甲基化， 然后与乙基甲基氨甲酰氯再拆分得到 S构型利伐斯的明。  WO2005061446 discloses another preparation method in which mainly 3-acetylphenol is subjected to condensation, reduction, methylation, and then re-cleared with ethylmethylcarbamoyl chloride to obtain S-type rivastigmine.
WO03101917公开了利用二甲氨基乙基苯酚与 Ν -乙基 -Ν -甲基 -4-硝基苯 甲酰胺反应， 得到产物， 同样采用了（+)-o, ( -二对甲苯甲酰 - (D) -酒石酸 进行拆分。 WO03101917 discloses the reaction of dimethylaminoethylphenol with hydrazine-ethyl-hydrazine-methyl-4-nitrobenzamide to give the product, also using (+)-o, (-di-p-toluoyl-) (D) - Tartaric acid Perform the split.
WO2004037771公开了首先利用 S- (+) -樟脑磺酸将反应中间体二甲氨基 乙基苯酚拆分得到 S构型的产物, 然后与乙基甲基氨甲酰氯反应得到产物 的方法。  WO2004037771 discloses a process for first reacting a reaction intermediate dimethylaminoethylphenol with S-(+)-camphorsulfonic acid to obtain a product of the S configuration, followed by reaction with ethylmethylcarbamoyl chloride to obtain a product.
CN1486973同样是利用 S构型的二甲氨基乙基苯酚与乙基甲基氨甲酰氯 得到较高光学纯度的利伐斯的明。  CN1486973 also uses dimethylaminoethylphenol and ethylmethylcarbamoyl chloride in the S configuration to give rivastigmine with higher optical purity.
现有方法中大都釆用了乙基甲基氨甲酰氯， 乙基甲基氨甲酰氯的制备 操作手续复杂， 化学稳定性较差， 对反应条件和设备要求较高， 因此， 制 备成本高， 在工业化生产中有一定的局限性。 发明内容  Most of the existing methods use ethyl methylcarbamoyl chloride. The preparation process of ethyl methylcarbamoyl chloride is complicated, the chemical stability is poor, and the reaction conditions and equipment are high. Therefore, the preparation cost is high. There are certain limitations in industrial production. Summary of the invention
为了解决现有技术中存在的上述问题, 本发明提供一种制备利伐斯的 明的方法， 还提供制备利凡斯的新化合物中间体。 本发明提供的制备利伐 斯的明的新方法， 没有使用制备成本高、 化学稳定性差的乙基甲基氨甲酰 氯， 降低了制备成本， 在工业生产中具有很大的应用价值。  In order to solve the above problems in the prior art, the present invention provides a process for preparing rivastigmine, and also provides a novel compound intermediate for the preparation of rivastig. The novel method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production.
本发明的技术方案如下：  The technical solution of the present invention is as follows:
本发明提供一种制备式（1)所示化合物的方法， 由式（2)所示化合物与 CH3X或 CH3CH2X在碱存在条件下反应。 The present invention provides a process for producing a compound of the formula (1), which is obtained by reacting a compound represented by the formula (2) with CH 3 X or CH 3 CH 2 X in the presence of a base.
Figure imgf000004_0001
Figure imgf000004_0001
其中： X为合适的离去基团； R为甲基或乙基； R为甲基时， 与 CH3CH2X 反应； R为乙基时， 与 CH3X反应。 Wherein: X is a suitable leaving group; R is a methyl group or an ethyl group; when R is a methyl group, it reacts with CH 3 CH 2 X; and when R is an ethyl group, it reacts with CH 3 X.
所述 X优选卤素， 进一步优选为 Cl、 Br或 I。  The X is preferably a halogen, and more preferably Cl, Br or I.
所述碱为醇或胺的金属盐、 金属氢化物、 氢氧化物、 金属氧化物、 碳 酸盐、 碳酸氢盐， 优选为钠氢或碳酸钾。 The base is a metal salt of an alcohol or an amine, a metal hydride, a hydroxide, a metal oxide, or a carbon The acid salt, hydrogencarbonate, preferably sodium hydrogen or potassium carbonate.
作为更进一步优化， 所述反应在有机溶剂中进行。 所述有机溶剂为苯、 甲苯、 二甲苯、 ***、 二氯甲烷、 氯仿、 1，2 -二氯乙烷、 四氢呋喃、 Ν, Ν- 二甲基甲酰胺、 1， 4 -二氧六环、 1， 2-二氯乙烷中的一种或其任意比混合物。  As a further optimization, the reaction is carried out in an organic solvent. The organic solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, hydrazine, hydrazine-dimethylformamide, 1, 4-dioxane, One of 1,2-dichloroethane or a mixture of any ratio thereof.
上述反应中， 所述式 （2 )所示化合物由式（3)所示化合物拆分制得， 或由光学活性的式（7)所示化合物制得。  In the above reaction, the compound represented by the formula (2) is obtained by resolution of a compound represented by the formula (3) or an optically active compound represented by the formula (7).
Figure imgf000005_0001
Figure imgf000005_0001
R为甲基或乙基。  R is a methyl group or an ethyl group.
由式（3)所示化合物拆分制得式 ( 2 )所示化合物的反应过程中, 拆分 剂为 S - (+) -樟脑磺酸或 （+ ) - 0, (Τ -二对甲苯甲酰 - (D) -酒石酸； 溶剂为甲 醇、 乙醇、 乙酸乙酯、 丙酮、 四氢呋喃、 水中的一种或其混合物。  During the reaction of the compound represented by the formula (3) to obtain a compound of the formula (2), the resolving agent is S - (+) - camphorsulfonic acid or (+) - 0, (Τ - di-p-toluene) Formyl-(D)-tartaric acid; the solvent is methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, one of water or a mixture thereof.
由式（7)所示化合物制得式（2 )所示化合物的方法是， 式（7)所示化合 物与式（5) 所示化合物或式（6)所示化合物反应制得。  The compound of the formula (2) can be obtained by reacting a compound of the formula (7) with a compound of the formula (7) and a compound of the formula (5) or a compound of the formula (6).
式（7)所示化合物与式 （5 )所示化合物反应过程， 反应溶剂为苯、 甲 苯， 二氯甲烷或三氯甲烷， 反应温度为 30°C - 120°C , 优选 50°C - 100 。  The reaction process of the compound of the formula (7) with the compound of the formula (5), the reaction solvent is benzene, toluene, dichloromethane or chloroform, the reaction temperature is 30 ° C - 120 ° C, preferably 50 ° C - 100 .
式（7)所示化合物与式 ( 6 )所示化合物反应过程， 在碱存在的惰性溶 剂中进行， 所述惰性溶剂为苯、 甲苯、 二甲苯、 ***、 二氯甲烷、 氯仿、 1, 2-二氯乙垸、 四氢呋喃、 I, 4-二氧六环、 1, 2-二氯乙烷中的一种或其任 意比混合物； 所述碱为金属氢化物、 氢氧化物、 金属氧化物、 碳酸盐、 碳 酸氢盐、 有机碱或其组合。 所述有机碱为有机胺类、 胺的金属盐或其组合。 The reaction of the compound of the formula (7) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1, 2 a mixture of dichloroacetamidine, tetrahydrofuran, I, 4 -dioxane, 1,2-dichloroethane or any ratio thereof; the base is a metal hydride, hydroxide, metal oxide , carbonate, bicarbonate, organic base or a combination thereof. The organic base is an organic amine, a metal salt of an amine, or a combination thereof.
所述式 (3)所示化合物由式 (4)所示化合物反应制得
Figure imgf000005_0002
方法如下： 式（4)所示化合物与式 （5)所示化合物反应制得， 或式（4) 所示化合物与式 (6)反应制得。
Figure imgf000006_0001
The compound represented by the formula (3) is obtained by reacting a compound represented by the formula (4).
Figure imgf000005_0002
The method is as follows: a compound represented by the formula (4) is obtained by reacting a compound represented by the formula (5), or a compound represented by the formula (4) with a compound of the formula (6).
Figure imgf000006_0001
R为甲基或乙基。  R is a methyl group or an ethyl group.
式（4)所示化合物与式 (5)所示化合物反应过程， 反应溶剂为四氢呋 喃、 DMF、 苯、 甲苯、 二氯甲烷、 三氯甲烷， 反应温度为 30°C - 120°C, 优 选 60。C - 100°C。  The reaction process of the compound of the formula (4) with the compound of the formula (5), the reaction solvent is tetrahydrofuran, DMF, benzene, toluene, dichloromethane, chloroform, and the reaction temperature is 30 ° C - 120 ° C, preferably 60 . C - 100 ° C.
式（4)所示化合物与式 (6)所示化合物反应过程, 在碱存在的惰性溶 剂中进行， 所述惰性溶剂为苯、 甲苯、 二甲苯、 ***、 二氯甲垸、 三氯甲 烷、 1,2-二氯乙烷、 四氢呋喃、 1,4-二氧六环、 1， 2-二氯乙烷中的一种或 其任意比混合物; 所述碱为金属氢化物、 氢氧化物、 金属氧化物、 碳酸盐、 碳酸氢盐、 有机碱或其组合。  The reaction of the compound of the formula (4) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base, and the inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, One of 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane or a mixture thereof in any ratio; the base is a metal hydride, a hydroxide, Metal oxides, carbonates, bicarbonates, organic bases or combinations thereof.
所述有机碱为有机胺类、 胺的金属盐或其组合。  The organic base is an organic amine, a metal salt of an amine, or a combination thereof.
本发明还提供一种式 (2)所示化合物：  The present invention also provides a compound of the formula (2):
Figure imgf000006_0002
Figure imgf000006_0002
R为乙基。  R is an ethyl group.
本发明还提供一种式 ( 3)所示化合  The invention also provides a compound represented by formula (3)
Figure imgf000006_0003
Figure imgf000006_0003
R为乙基。  R is an ethyl group.
本发明所涉及结构式 (4)化合物可以参照文献（华东师范大学学报自然 科学版， 2001, 1， 61-65)制得, 方法如下: The compound of the structural formula (4) according to the present invention can be referred to the literature (Journal of East China Normal University, Nature Scientific version, 2001, 1, 61-65), the method is as follows:
2)Raney Ni/EtOH2) Raney Ni/EtOH
Figure imgf000007_0001
Figure imgf000007_0001
本发明所涉及结构式 (5)化合物和结构式（6)化合物均可以商购得到。 本 发 明 所 涉 及 结 构 式 （7) 化 合 物 可 以 参 照 文 献 (J. Chem. Soc, 1932, 2513-2519)得到。  Both the compound of the structural formula (5) and the compound of the formula (6) according to the present invention are commercially available. The structure (7) compound referred to in the present invention can be obtained by reference to the literature (J. Chem. Soc, 1932, 2513-2519).
本发明实现的技术效果如下：  The technical effects achieved by the present invention are as follows:
本发明提供的制备利伐斯的明的方法， 没有使用制备成本高、 化学稳 定性差的乙基甲基氨甲酰氯， 降低了制备成本， 在工业生产中具有很大的 应用价值。 具体实施方式  The method for preparing rivastigmine provided by the invention does not use ethylmethylcarbamoyl chloride which is high in preparation cost and poor in chemical stability, and reduces the preparation cost, and has great application value in industrial production. Detailed ways
本发明通过以下实施例进一步说明， 以下实施例仅用于更具体说明本 发明的优选实施方式， 不用于对本发明的技术方案进行限定。 上述本发明 的技术方案均为可实现本发明目的之技术方案。 即以下实施例所釆用温度 和试剂， 均可用上文所述相应温度和试剂替代以实现本发明之目的。  The invention is further illustrated by the following examples, which are merely used to illustrate the preferred embodiments of the invention, and are not intended to limit the invention. The technical solutions of the present invention described above are all technical solutions for achieving the object of the present invention. That is, the temperatures and reagents used in the following examples can be replaced with the corresponding temperatures and reagents described above to achieve the objects of the present invention.
试验中所用溶剂或者试剂， 除非特别表明， 均由国药集团化学试剂有 限公司生产； 核磁共振氢谱在 Var ian Mercury 300仪器上完成， 所有波谱 均与推测的结构相一致， 用常规缩写表示特征峰： s，单峰； d,双重峰； t , 三重峰； q, 四重峰； m，多重峰。  The solvents or reagents used in the tests were produced by Sinopharm Chemical Reagent Co., Ltd. unless otherwise indicated; the NMR spectra were performed on a Varian Mercury 300 instrument, and all spectra were consistent with the predicted structure, and the characteristic peaks were represented by conventional abbreviations. : s, single peak; d, doublet; t, triplet; q, quartet; m, multiplet.
室温是指 20 - 25 °C。  Room temperature means 20 - 25 °C.
实施例 1 :  Example 1
R为甲基式（3)所示化合物 (甲基氨甲酸- 3- [1- (二甲胺基）乙基]苯酯 ) 的制备  Preparation of a compound of the formula (3) (methyl 3-benzoic acid 3-[1-(dimethylamino)ethyl]phenyl ester)
方法 1 : 结构式 （4)所示化合物 16.5g (0.10 mol)溶于 O mL二氯甲烷， 加 入三乙胺 11. lg (0.11 mol), 将形成的溶液冷却到 5°C以下， 将用 50mL二 氯甲烷稀释的 R为甲基式（6)所示化合物（N -甲基氨甲酰氯） 9.77g (0.105 fflol)慢慢滴加到上述溶液当中， 滴加完毕， 恢复至室温搅拌 2 小时， 加入 蒸馏水 100 mL, 分液， 有机相用 150mL饱和氯化铵洗涤三次， 无水硫酸钠 干燥， 蒸发溶剂， 产物用二氯甲垸 /石油醚重结晶， 得到 R为甲基式（3)所 示化合物 19.5g, 产率 88%。 1醒 R (300MHz, CDC13), δ: 1.39 (3Η, d)， 2.23 (6H, s)， 2.92 (3H， d) , 3.30 (1H, q) , 5.16 (1H, s)， 7.04 (1H, d) 3 7.12 (1H， s), 7.16 (1H, d), 7.32 (1H， t)。 method 1 : 16.5g (0.10 mol) of the compound of the formula (4) is dissolved in dichloromethane (OmL), 11.5% (0.11 mol) of triethylamine is added, and the resulting solution is cooled to below 5 ° C, and 50 mL of dichloromethane is used. The diluted R is a compound of the formula (6) (N-methylcarbamoyl chloride) 9.77 g (0.105 fflol) is slowly added dropwise to the above solution, the addition is completed, and the mixture is returned to room temperature and stirred for 2 hours, and distilled water is added. 100 mL, liquid separation, the organic phase was washed three times with 150 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate and evaporated. The product was recrystallized from methylene chloride / petroleum ether to give compound of formula (3). 19.5 g, yield 88%. 1 wake up R (300MHz, CDC1 3 ), δ: 1.39 (3Η, d), 2.23 (6H, s), 2.92 (3H, d), 3.30 (1H, q) , 5.16 (1H, s), 7.04 (1H , d) 3 7.12 (1H, s), 7.16 (1H, d), 7.32 (1H, t).
方法 2:  Method 2:
结构式 （4)化合物 16.5g (0, 10 mol)溶于 350 mL三氯甲垸中, 加入 三乙胺 ll. lg (0.11 mol), 将形成的溶液冷却到 5°C以下， 将用 50mL三氯 甲烷稀释的 R为甲基式（6)所示化合物（N-甲基氨甲酰氯 ） 9.77g (0.105 fflol)慢慢滴加到上述溶液当中， 滴加完毕， 恢复至室温搅拌 2小时， 加入 蒸馏水 100 mL, 分液， 有机相用 150mL饱和氯化铵洗涤三次, 无水硫酸钠 干燥， 蒸发溶剂， 产物用二氯甲垸 /石油醚重结晶， 得到 R为甲基式（3)所 示化合物 18.0g。  16.5g (0, 10 mol) of the compound of the formula (4) is dissolved in 350 mL of trichloromethane, and triethylamine ll. lg (0.11 mol) is added, and the resulting solution is cooled to below 5 ° C, and 50 mL of three is used. Methyl chloride diluted R is a compound of the formula (6) (N-methylcarbamoyl chloride) 9.77 g (0.105 fflol) was slowly added dropwise to the above solution, and the addition was completed, and the mixture was returned to room temperature and stirred for 2 hours. 100 mL of distilled water was added, and the organic phase was washed three times with 150 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was recrystallized from methylene chloride / petroleum ether to give R as methyl (3) The compound was shown to be 18.0 g.
方法 3:  Method 3:
结构式（4)化合物 16.5g (0.10 mol)溶于 350 mL四氢呋喃中， 加入 R 为甲基式 （5)所示化合物 （异氰酸甲酯 ） 6.27g (0. llfflol), 30°C -120 条件下反应完全（60°C加热 5小时）， 减压蒸除溶剂， 加入 300mL二氯甲 烷和 50niL蒸馏水， 分液， 有机相用 150mL饱和氯化铵洗涤三次， 无水硫酸 钠干燥， 蒸发溶剂， 产物用二氯甲烷 /石油醚重结晶， 得到 R为甲基式（3) 所示化合物 17.6g, 产率 79.2%。  16.5 g (0.10 mol) of the compound of the formula (4) is dissolved in 350 mL of tetrahydrofuran, and R is a compound of the formula (5) (methyl isocyanate) 6.27 g (0. llfflol), 30 ° C -120 The reaction was completed (heating at 60 ° C for 5 hours), the solvent was evaporated under reduced pressure, and dichloromethane (dichloromethane) and 50 liters of distilled water were added, and the organic phase was washed three times with 150 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate and evaporated. The product was recrystallized from methylene chloride / petroleum ether to afford 17.6 g of the compound of formula (3), yield 79.2%.
方法 4: 结构式 ( 4 )化合物 16.5g (0.10 mol)溶于 350 mL DMF中， 加入 R为 甲基式 （5)所示化合物 （异氰酸甲酯 ） 6.27g (0. llraol), 30°C - 120°C 条件下反应完全（具体可用 10(TC加热 1小时），减压蒸除溶剂， 加入 300mL 二氯甲烷和 50mL蒸馏水， 分液， 有机相用 150raL饱和氯化铵洗涤三次, 无 水硫酸钠干燥， 蒸发溶剂， 产物用二氯甲烷 /石油醚重结晶得到标题物 14.3g。 Method 4: Compound (4) 16.5 g (0.10 mol) is dissolved in 350 mL of DMF, and R is a compound of the formula (5) (methyl isocyanate) 6.27 g (0. llraol), 30 ° C - 120 The reaction was complete under the conditions of °C (specifically, 10 (TC heating for 1 hour), the solvent was evaporated under reduced pressure, 300 mL of dichloromethane and 50 mL of distilled water were added, and the organic phase was washed three times with 150 raL of saturated ammonium chloride, anhydrous sodium sulfate After drying, the solvent was evaporated.
实施例 2:  Example 2:
R为甲基的式（2)所示化合物（ (S) -N-甲基氨甲酸- 3- [ (1 - (二甲胺基）乙 基]苯酯） 的制备  Preparation of Compound (2)-N-Methylcarbamate-3-([1-(Dimethylamino)ethyl)phenyl)
方法 1:  method 1:
取实施例 1 制备化合物 11. lg (0.05mol), 溶于 llOmL 甲醇中， 加入 D(+)- 10-樟脑磺酸 12. lg (0.053mol), 60°C加热 2小时， 恢复至室温， 加 入乙酸乙酯 50mL,析出固体，抽滤所得固体，用甲醇 /乙酸乙酯重结晶三次， 50°C下干燥 2小时， 称重得产物 7.3g, 将产物溶于 20mL水中， 加入氢氧化 钠 0.64g(0.016mol),室温下搅拌 30分钟， 加入 lOOmL二氯甲烷, 分液， 二 氯甲烷相用 60mL蒸馏水洗涤三次， 减压蒸除溶剂， 得到 R为甲基的式（2) 所示化合物 3.4g, 旋光 [a] D 20 =-34.9° (c=l，乙醇）。 Example 1 Preparation of compound 11. lg (0.05 mol), dissolved in llOmL methanol, added D (+) 10- 10-camphorsulfonic acid 12. lg (0.053 mol), heated at 60 ° C for 2 hours, returned to room temperature, Ethyl acetate (50 mL) was added to precipitate a solid, and the obtained solid was filtered, and then recrystallized three times with methanol/ethyl acetate, and dried at 50 ° C for 2 hours, weighing 7.3 g of product, dissolved in 20 mL of water, sodium hydroxide 0.64 g (0.016 mol), stirring at room temperature for 30 minutes, adding 100 mL of dichloromethane, separating the liquid, and washing the dichloromethane phase three times with 60 mL of distilled water, and evaporating the solvent under reduced pressure to obtain the formula (2) wherein R is a methyl group. Compound 3.4 g, optical rotation [a] D 20 = -34.9 (c = l, ethanol).
方法 2:  Method 2:
结构式（7)所示化合物 4.13g (0.025 raol)溶于 80 mL二氯甲烷中， 加 入三乙胺 2.78g (0.028 mol), 将形成的溶液冷却到 5°C以下， 将用 10mL 二氯甲烷稀释的 R 为甲基式 （6)所示化合物 （N -甲基氨甲酰氯） 2.46g (0.026 mol)慢慢滴加到上述溶液当中， 滴加完毕， 恢复至室温搅拌 2小时， 加入蒸馏水 20 mL, 分液， 有机相用 60mL饱和氯化铵洗涤三次， 无水硫酸 钠干燥， 蒸发溶剂，产物用二氯甲烷 /石油醚重结晶， 得到 R为甲基的式（2) 所示化合物 4.66g,产率 84%, 旋光 [a] D 20 =- 35.1° (c=l, 乙醇）。 方法 3: 4.13g (0.025 raol) of the compound of the formula (7) is dissolved in 80 mL of dichloromethane, 2.78 g (0.028 mol) of triethylamine is added, and the resulting solution is cooled to below 5 ° C, and 10 mL of dichloromethane is used. The diluted R is a compound of the formula (6) (N-methylcarbamoyl chloride) 2.46g (0.026 mol) is slowly added dropwise to the above solution, the addition is completed, and the mixture is returned to room temperature and stirred for 2 hours, and distilled water is added. After 20 mL, the organic phase was washed three times with 60 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate and evaporated, and the product was crystallized from methylene chloride / petroleum ether to give compound of formula (2) 4.66 g, yield 84%, optical rotation [a] D 20 = - 35.1 ° (c = l, ethanol). Method 3:
结构式 （7)化合物 16.5g (0.10 mol)溶于 350 mL THF中， 加入 R为 甲基式 (5)所示化合物 (异氰酸甲酯 ） 6.27g (O. llmol) , 80°C加热 1 小时， 减压蒸除溶剂， 加入 300mL二氯甲烷和 50mL蒸馏水， 分液， 有机相 用 150raL饱和氯化铵洗涤三次， 无水硫酸钠干燥， 蒸发溶剂， 产物用二氯 甲烷 /石油醚重结晶得到标题物 10.6g，旋光 [a] D 2U = - 34.6。 （c=l， 乙醇）。 16.5 g (0.10 mol) of the compound of the formula (7) is dissolved in 350 mL of THF, and R is a compound of the formula (5) (methyl isocyanate) 6.27 g (0.1 mol), heated at 80 ° C The solvent was evaporated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The title material was 10.6 g, and the optical rotation [a] D 2U = - 34.6. (c=l, ethanol).
实施例 3:  Example 3:
式（1)所示化合物（（S) - N-乙基- N -甲基 -3-[1-（二甲氨基）乙基]氨基甲 酸苯酯） 的制备  Preparation of the compound of the formula (1) ((S) - N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid phenyl ester)
方法 1:  method 1:
取实施例 2制备的化合物 lg(4.5mmol), 溶于 lOniL DMF中， 加入钠氢 0.12g (5. Ommol), 慢慢滴加溴乙烷 0.54g (5. (kmol) , 加热 5(TC反应 2小 时， 恢复室温， 减压蒸除大部分 DMF, 加入 30niL 二氯甲垸提取产物， 5mL 蒸馏水洗涤， 有机相用无水硫酸钠干燥， 蒸除溶剂得式（1)所示化合物 0.89g, 产率 84%, 旋光 [a] D 20 =-31.8° (c=l, 乙醇）。 1讓 R (300MHz， CDCI3), δ: 1.39 (3Η, d), 1.44 (3H, t) , 2.24 (6H， s) , 3.24 (1H, q) , 3.40 (3H, s), 4.07 (2H, q) , 6.81 (1H, d) , 6.88 (1H, s) , 6.92 (1H, d), 7.25 (1H, t)。 The compound lg (4.5 mmol) prepared in Example 2 was dissolved in lOniL DMF, 0.12 g (5.0 mmol) of sodium hydrogen was added, and 0.54 g of ethyl bromide (5. (kmol) was added dropwise, heating 5 (TC) After reacting for 2 hours, the temperature was returned to room temperature, and most of the DMF was evaporated under reduced pressure. The product was extracted with 30niL of dichloromethane, and washed with 5 mL of distilled water. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the compound of formula (1). , yield 84%, optical rotation [a] D 20 = -31.8° (c = l, ethanol). 1 Let R (300MHz, CDCI3), δ: 1.39 (3Η, d), 1.44 (3H, t) , 2.24 (6H, s), 3.24 (1H, q), 3.40 (3H, s), 4.07 (2H, q), 6.81 (1H, d), 6.88 (1H, s), 6.92 (1H, d), 7.25 ( 1H, t).
方法 2:  Method 2:
取实施例 2化合物 lg (4.5mmol) , 溶于 10mL THF中，加入碳酸钾 0.35g (5.0腿 ol), 慢慢滴加溴乙垸 0.54g(5.0腿 ol), 加热 80°C反应 1.5小时， 恢复室温， 减压蒸除大部分 THF, 加入 30mL二氯甲烷提取产物， 5mL蒸馏 水洗涤， 有机相用无水硫酸钠干燥， 蒸除溶剂得式（1)所示化合物 0.78g。  The compound of Example 2, lg (4.5 mmol), was dissolved in 10 mL of THF, and potassium carbonate (0.35 g (5.0 lb ol) was added thereto, and 0.54 g (5.0 leg ol) of bromoacetone was slowly added dropwise thereto, and the mixture was heated at 80 ° C for 1.5 hours. After returning to room temperature, most of the THF was evaporated under reduced pressure. The product was obtained by adding 30 mL of dichloromethane, and washed with 5 mL of distilled water. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the compound of formula (1).
实施例 4:  Example 4:
R为乙基式（3)所示化合物 （乙基氨甲酸 - 3- [1- (二甲胺基）乙基]苯酯） 的制备 R is a compound of the formula (3) (ethyl carbamate 3- [1-(dimethylamino)ethyl]phenyl ester) Preparation
方法 1:  method 1:
式 （4)所示化合物 16.5g (0.10 mol)溶于 350 raL二氯甲烷中， 加入 三乙胺 ll. lg (0.11 mol), 将形成的溶液冷却到 5°C以下， 将用 50mL二氯 甲烷稀释的 R为乙基式（6)所示化合物（N -乙基氨甲酰氯） 11. ¾ (0.105 mol)慢慢滴加到上述溶液当中， 滴加完毕， 恢复至室温搅拌 2小时， 加入 蒸馏水 lGQ mL， 分液， 有机相用 OmL饱和氯化铵洗涤三次， 无水硫酸钠 干燥， 蒸除溶剂， 产物用二氯甲垸 /石油醚重结晶， 得到 R为乙基式（3)所 示化合物 20.7g, 产率 88%。 1醒 R (300MHz, CDC13), δ: 1.23 (3Η, t) , 1.86 (3H, d), 2.50 (6H, s) , 3.31 (2H, m)， 4.21 (1H, q) , 5.14 (1H， s), 7.22 (1H, d), 7.28 (1H， s) , 7.37 (1H, d) , 7.46 (1H， t)。 16.5g (0.10 mol) of the compound of the formula (4) is dissolved in 350 raL of dichloromethane, and triethylamine ll. lg (0.11 mol) is added, and the resulting solution is cooled to below 5 ° C, and 50 mL of The methyl chloride diluted R is the compound of the formula (6) (N-ethylcarbamoyl chloride) 11. 3⁄4 (0.105 mol) is slowly added dropwise to the above solution, the addition is completed, and the mixture is returned to room temperature and stirred for 2 hours. Add distilled water lGQ mL, separate the liquid, wash the organic phase three times with OmL saturated ammonium chloride, dry over anhydrous sodium sulfate, distill off the solvent, and recrystallize the product with methylene chloride / petroleum ether to give R as ethyl (3) The compound shown was 20.7 g, yield 88%. 1 wake up R (300MHz, CDC1 3 ), δ: 1.23 (3Η, t), 1.86 (3H, d), 2.50 (6H, s), 3.31 (2H, m), 4.21 (1H, q) , 5.14 (1H , s), 7.22 (1H, d), 7.28 (1H, s), 7.37 (1H, d), 7.46 (1H, t).
方法 2:  Method 2:
结构式（4)化合物 16.5g (0.10 mol)溶于 350 raL二氯甲烷中， 加入 R 为乙基式 （5)所示化合物 （异氰酸乙酯） 7.81g (O. llmol), 60°C加热 5 小时， 加入蒸馏水 50mL, 分液， 有机相用 150mL饱和氯化铵洗涤三次， 无 水硫酸钠干燥， 蒸发溶剂， 产物用二氯甲烷、 石油醚重结晶， 得到 R为乙 基式（3)所示化合物 18.9g, 产率 80%。  16.5 g (0.10 mol) of the compound of the formula (4) is dissolved in 350 raL of dichloromethane, and R is an ethyl group (5) compound (ethyl isocyanate) 7.81 g (0.1 mol), 60 ° C After heating for 5 hours, 50 mL of distilled water was added, and the organic phase was washed three times with 150 mL of saturated ammonium chloride, dried over anhydrous sodium sulfate and evaporated. The product was recrystallized from dichloromethane and petroleum ether to give R as ethyl (3) The compound shown was 18.9 g, and the yield was 80%.
实施例 5:  Example 5
R为乙基的式（2)所示化合物 ( (S)-N-乙基氨甲酸- 3-[1-（二甲胺基）乙 基]苯酯） 的制备  Preparation of a compound of formula (2) wherein R is ethyl ((S)-N-ethylcarbamate 3-[1-(dimethylamino)ethyl]phenyl ester)
方法 1:  method 1:
实施例 4 制备的化合物 11.8g (0.05mol)溶于 110mL 甲醇中， 加入 D(+)- 10-樟脑磺酸 12.2g(0.053mol), 60°C2小时， 恢复至室温， 加入乙酸 乙酯 50mL, 抽滤析的出固体， 用甲醇 /乙酸乙酯重结晶三次， 然后 5(TC下 干燥 2 小时， 称重得产物 7. lg, 将产物溶于 7(kL 水中， 加入氢氧化钠 0.6(0.015mol),室温下搅拌 30分钟， 加入 lOOmL二氯甲垸， 分液， 二氯甲 烷相用 30mL蒸馏水洗涤三次， 减压蒸除溶剂， 得到 R为乙基的式（2)所示 化合物 3.52g, 旋光 [a] D 20=-32.9° (c=l,乙醇）。 Compound 11.8g (0.05mol) prepared in Example 4 was dissolved in 110mL of methanol and D (+) - 10- camphorsulfonic acid 12. 2 g (0.053mol), 60 ° C2 hours, cooled to room temperature, ethyl acetate was added 50 mL of ester, the solid which was filtered off with suction, recrystallized three times with methanol / ethyl acetate, then 5 (dry for 2 hours at TC, weighed to give the product 7. lg, dissolved in 7 (kL water, sodium hydroxide) 0.6 (0.015 mol), stirring at room temperature for 30 minutes, adding 100 mL of dichloromethane, separating the liquid, and washing the dichloromethane phase three times with 30 mL of distilled water, and evaporating the solvent under reduced pressure to obtain the formula (2) wherein R is ethyl. Compound 3.52 g, optical rotation [a] D 20 = -32.9 ° (c = l, ethanol).
方法 2:  Method 2:
结构式（7)化合物 4.13g (0.025 mol)溶于 80 mL二氯甲烷中， 加入三 乙胺 2.78g (0.028 raol) , 将形成的溶液冷却到 5°C以下， 将用 10mL二氯 甲烷稀释的 R为乙基式（6)所示化合物（N-乙基氨甲酰氯） 2.81g (0.026 mol)慢慢滴加到上述溶液当中， 滴加完毕， 恢复至室温搅拌 2 小时， 加入 蒸馏水 20 mL, 分液， 有机相用 6QmL饱和氯化铵洗涤三次， 无水硫酸钠干 燥， 蒸发溶剂， 产物用二氯甲烷 /石油醚重结晶， 得到 R为乙基的式（2)所 示化合物 4.84g,产率 82%, 旋光 [a] D 20=-33.4° (c=l,乙醇）。 Compound (7) 4.13 g (0.025 mol) was dissolved in 80 mL of dichloromethane, and 2.78 g (0.028 raol) of triethylamine was added. The resulting solution was cooled to below 5 ° C and diluted with 10 mL of dichloromethane. R is a compound of the formula (6) (N-ethylcarbamoyl chloride) 2.81g (0.026 mol) is slowly added dropwise to the above solution, the addition is completed, the mixture is returned to room temperature and stirred for 2 hours, and distilled water is added to 20 mL. The organic phase was washed three times with 6Q mL of saturated ammonium chloride, dried over anhydrous sodium sulfate, and evaporated, and the product was recrystallized from methylene chloride / petroleum ether to give the compound of formula (2) of R. , yield 82%, optical rotation [a] D 20 = -33.4 ° (c = l, ethanol).
实施例 6:  Example 6:
式（1)化合物（ (S) - N-乙基- N-甲基 -3- [1- (二甲氨基）乙基]氨基甲酸苯 取 R为乙基的式（2)所示化合物 1.0g(4.2mmol)， 溶于 5raL DMF中， 加 入碳酸钾 0.4g (2.9mmol), 滴加碘甲烷 0.66g (4.7瞧 ol) , 50°C加热反应 2 小时， 恢复至室温， 减压蒸除大部分 DMF, 加入 20raL二氯甲垸提取产物， 5mL蒸馏水洗涤， 有机相用无水硫酸钠干燥， 蒸除溶剂， 得式（1)所示化合 物 0.76g, 产率 72%, 旋光 [a] D 20=-32.4° (c=l,乙醇）。 1匪 R (300MHz, CDC13), δ: 1.39 (3Η, d), 1.44 (3H, t), 2.24 (6H, s) , 3.24 (1H, q) , 3.40 (3H, s)， 4.07 (2H， q) , 6.81 (1H, d) , 6.88 (1H， s) , 6.92 (1H, d), 7.25 (1H, t)。 The compound of the formula (1) ((S) - N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]carbamic acid benzene is a compound represented by the formula (2) wherein R is an ethyl group. g (4.2 mmol), dissolved in 5 raL DMF, added potassium carbonate 0.4 g (2.9 mmol), added dropwise iodomethane 0.66 g (4.7 瞧ol), heated at 50 ° C for 2 hours, returned to room temperature, distilled off under reduced pressure For most DMF, 20raL of dichloromethane extract product was added, 5mL of distilled water was washed, and the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated to give the compound of formula (1): 0.76 g, yield 72%, optical rotation [a] D 20 = -32.4° (c = l, ethanol). 1匪R (300MHz, CDC1 3 ), δ: 1.39 (3Η, d), 1.44 (3H, t), 2.24 (6H, s) , 3.24 (1H , q), 3.40 (3H, s), 4.07 (2H, q), 6.81 (1H, d), 6.88 (1H, s), 6.92 (1H, d), 7.25 (1H, t).

Claims

杈 利 要 求 Patent claim
1. 式（1)所示化合物的制备方法, 其特征在于, 所述方法为， 式（2) 所示化合物与 CH3X或 CH3CH2X在碱存在条件下反应 , A process for producing a compound of the formula (1), which is characterized in that a compound represented by the formula (2) is reacted with CH 3 X or CH 3 CH 2 X in the presence of a base,
Figure imgf000013_0001
Figure imgf000013_0001
其中：  among them:
X为合适的离去基团；  X is a suitable leaving group;
R为甲基或乙基；  R is a methyl group or an ethyl group;
R为甲基时， 与 CH3CH2X反应； When R is a methyl group, it reacts with CH 3 CH 2 X;
R为乙基时, 与 CH3X反应。 When R is an ethyl group, it reacts with CH 3 X.
2. 根据杈利要求 1所述的方法， 其特征在于， 所述 X为卤素。  2. The method according to claim 1, wherein the X is a halogen.
3. 根据杈利要求 2所述的方法， 其特征在于， 所述 X为 Cl、 Br或工。 3. The method according to claim 2, wherein the X is Cl, Br or work.
4. 根据权利要求 1 - 3任意一项所述的方法， 其特征在于， 所述碱为 醇或胺的金属盐、 金属氢化物、 氢氧化物、 金属氧化物、 碳酸盐、 碳酸氢 盐。 The method according to any one of claims 1 to 3, wherein the base is a metal salt of an alcohol or an amine, a metal hydride, a hydroxide, a metal oxide, a carbonate, and a hydrogencarbonate. .
5. 根据权利要求 4所述的方法，其特征在于，所述碱为钠氢或碳酸钾。 5. A method according to claim 4 wherein the base is sodium hydrogen or potassium carbonate.
6. 根据杈利要求 1 - 5 任意一项所述的方法， 其特征在于， 所述反应 在有机溶剂中进行。 6. The method according to any one of claims 1 to 5, wherein the reaction is carried out in an organic solvent.
7. 根据权利要求 6所述的方法， 其特征在于， 所述有机溶剂为苯、 甲 苯、 二甲苯、 ***、 二氯甲垸、 氯仿、 1, 2 -二氯乙烷、 四氢呋喃、 N，N -二 甲基甲酰胺、 1, 4 -二氧六环、 1, 2 -二氯乙烷中的一种或其任意比混合物。  The method according to claim 6, wherein the organic solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, N, N. - one of dimethylformamide, 1,4-dioxacyclohexane, 1,2-dichloroethane or a mixture thereof in any ratio.
8. 根据杈利要求 1 - 7任意一项所述的方法， 其特征在于， 所述式（2 ) 所示化合物由式（3)所示化合物拆分制得， 或由的式（7)所示化合物制得，
Figure imgf000014_0001
8. The method according to any one of claims 1 to 7, wherein the compound represented by the formula (2) is obtained by resolution of the compound represented by the formula (3), or the formula (7) Made of the compound shown,
Figure imgf000014_0001
R为甲基或乙基。 R is a methyl group or an ethyl group.
9. 根据杈利要求 8 所述的方法， 其特征在于， 由式（3)所示化合物拆 分制得式（2)所示化合物的反应过程中， 拆分剂为 S- (+)-樟脑磺酸或（+ ) 9. The method according to claim 8, wherein the resolving agent is S-(+)- during the reaction of the compound represented by the formula (3) to obtain a compound represented by the formula (2). Camphor sulfonic acid or (+)
- o，( -二对甲苯甲酰 -Φ) -酒石酸; 溶剂为甲醇、 乙醇、 乙酸乙酯、 丙酮、 四氢呋喃、 水中的一种或其混合物。 - o, (-di-p-toluoyl- Φ) - tartaric acid; the solvent is methanol, ethanol, ethyl acetate, acetone, tetrahydrofuran, one of water or a mixture thereof.
10. 根据权利要求 8所述的方法， 其特征在于， 由式（7)所示化合物制 得式 （2)所示化合物的方法是， 式（7)所示化合物与式（5) 所示化合物或 式（6)所示化合物反应制得，  The method according to claim 8, wherein the compound of the formula (2) is obtained from the compound represented by the formula (7), and the compound represented by the formula (7) is represented by the formula (5). a compound or a compound represented by the formula (6) is obtained by reacting,
RR
Figure imgf000014_0002
Figure imgf000014_0002
R为甲基或乙基。  R is a methyl group or an ethyl group.
11. 根据杈利要求 10所述的方法， 其特征在于， 式（7)所示化合物与 式 （5)所示化合物反应过程， 反应温度为 3(TC - 120°C, 反应溶剂为苯、 甲苯， 二氯甲烷或三氯甲烷。  11. The method according to claim 10, characterized in that the compound of the formula (7) is reacted with the compound of the formula (5), the reaction temperature is 3 (TC - 120 ° C, the reaction solvent is benzene, Toluene, dichloromethane or chloroform.
12. 根据权利要求 11 所述的方法， 其特征在于， 式（7)所示化合物与 式 （5)所示化合物反应过程， 反应温度 5(TC - 10(TC。  The method according to claim 11, wherein a compound of the formula (7) is reacted with a compound of the formula (5) at a reaction temperature of 5 (TC - 10 (TC).
13. 根据权利要求 10所述的方法， 其特征在于， 式（7)所示化合物与 式 (6)所示化合物反应过程， 在碱存在的惰性溶剂中进行，  The method according to claim 10, wherein the reaction of the compound of the formula (7) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base.
所述惰性溶剂为苯、 甲苯、 二甲苯、 ***、 二氯甲烷、 氯仿、 1，2 -二 氯乙烷、 四氢呋喃、 1,4 -二氧六环、 1,2-二氯乙垸中的一种或其任意比混 合物； 所述碱为金属氢化物、 氢氧化物、 碳酸盐、 碳酸氢盐、 有机碱或其 组合。 The inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, 1,2-dichloroethane. a mixture or any ratio thereof; the base is a metal hydride, hydroxide, carbonate, hydrogencarbonate, organic base or a combination thereof.
14. 根据杈利要求 13所述的方法， 其特征在于， 所述有机碱为有机胺 类、 胺的金属盐或其组合。 14. The method according to claim 13, wherein the organic base is an organic amine, a metal salt of an amine or a combination thereof.
15. 根据权利要求 8所述的方法， 其特征在于， 所述式（3)所示化合物 由式（4)所示化合物反应制得：  The method according to claim 8, wherein the compound represented by the formula (3) is obtained by reacting a compound represented by the formula (4):
Figure imgf000015_0001
Figure imgf000015_0001
16. 根据权利要求 15所述的方法， 其特征在于， 式（4)所示化合物可 采用如下方法制得式（3)所示化合物：  The method according to claim 15, wherein the compound of the formula (4) can be obtained by the following method:
式（4)所示化合物与式 ( 5 )所示化合物反应制得, 或式（4)所示化合物 与式 （6 )所示化合物反应制得。  The compound represented by the formula (4) is obtained by reacting a compound represented by the formula (5), or a compound represented by the formula (4) with a compound represented by the formula (6).
17. 根据权利要求 16所述的方法， 其特征在于， 式（4)所示化合物与 式 （5 )所示化合物反应过程， 反应温度为 30Ό - 12 (TC , 反应溶剂为四氢 呋喃、 miF、 苯、 甲苯、 二氯甲烷、 三氯甲烷。  The method according to claim 16, wherein the compound of the formula (4) is reacted with the compound of the formula (5) at a reaction temperature of 30 Ό - 12 (TC, and the reaction solvent is tetrahydrofuran, miF, benzene. , toluene, dichloromethane, chloroform.
18. 根据杈利要求 17所述的方法, 其特征在于， 式（4)所示化合物与 式 （5 )所示化合物反应过程， 反应温度 6(TC - 1 Q0°C。  18. The method according to claim 17, wherein the compound of the formula (4) is reacted with the compound of the formula (5) at a reaction temperature of 6 (TC - 1 Q0 ° C).
19. 根据权利要求 16所述的方法， 其特征在于， 式（4)所示化合物与 式 ( 6 )所示化合物反应过程, 在碱存在的惰性溶剂中进行,  The method according to claim 16, wherein the reaction of the compound of the formula (4) with the compound of the formula (6) is carried out in an inert solvent in the presence of a base.
所述惰性溶剂为苯、 甲苯、 二甲苯、 ***、 二氯甲烷、 三氯甲烷、 1，2- 二氯乙烷、 四氢呋喃、 1, 4-二氧六环、 1，2-二氯乙烷中的一种或其任意比 混合物； 所述碱为金属氢化物、 氢氧化物、 碳酸盐、 碳酸氢盐、 有机碱或 其组合。  The inert solvent is benzene, toluene, xylene, diethyl ether, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, 1,2-dichloroethane. One of or a mixture of any ratio; the base is a metal hydride, hydroxide, carbonate, bicarbonate, organic base or a combination thereof.
20. 根据权利要求 19所述的方法， 其特征在于， 所述有机碱为有机胺 类、 胺的金属盐或其组合。  20. The method according to claim 19, wherein the organic base is an organic amine, a metal salt of an amine, or a combination thereof.
21. 式（2)所示化合物：
Figure imgf000016_0001
21. A compound of the formula (2):
Figure imgf000016_0001
R为乙基。 R is an ethyl group.
22. 式 (3)所示化合物:
Figure imgf000016_0002
22. Compounds of formula (3):
Figure imgf000016_0002
R为乙基。 R is an ethyl group.
PCT/CN2007/001248 2007-04-16 2007-04-16 Preparation method of rivastigmine and its intermediates WO2008124969A1 (en)

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