CN101565397B - N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof - Google Patents

N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof Download PDF

Info

Publication number
CN101565397B
CN101565397B CN 200910097326 CN200910097326A CN101565397B CN 101565397 B CN101565397 B CN 101565397B CN 200910097326 CN200910097326 CN 200910097326 CN 200910097326 A CN200910097326 A CN 200910097326A CN 101565397 B CN101565397 B CN 101565397B
Authority
CN
China
Prior art keywords
boc
piperidine
solution
aminopiperidine
reaction
Prior art date
Application number
CN 200910097326
Other languages
Chinese (zh)
Other versions
CN101565397A (en
Inventor
刘正俊
张伯引
沈大冬
Original Assignee
浙江医药股份有限公司新昌制药厂
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江医药股份有限公司新昌制药厂 filed Critical 浙江医药股份有限公司新昌制药厂
Priority to CN 200910097326 priority Critical patent/CN101565397B/en
Publication of CN101565397A publication Critical patent/CN101565397A/en
Application granted granted Critical
Publication of CN101565397B publication Critical patent/CN101565397B/en

Links

Abstract

The invention discloses an intermediate N-Boc-3-aminopiperidine and a synthesizing method of optical isomer thereof. The prior synthesizing route has the disadvantages of high requirements on reactionconditions, high possibility of racemization, a great number of byproducts, as well as difficult post-treatment and difficult industrialization. The synthesizing method comprises the following steps:taking halogenated hydrocarbon as a solvent and organic alkali as an acid-binding agent, 3-piperidine ethyl formate is added with di-tert-butyl dicarbonate by dripping at temperature of 0-10 DEG C toobtain N-Boc-3-piperidine ethyl formate; 1,4-dioxane is used as a solvent, the N-Boc-3-piperidine ethyl formate undergoes ammonolysis reaction to obtain N-Boc-3-piperidine formamide; and the N-Boc-3-piperidine formamide is added by dripping in a solution with sodium hypochlorite and sodium hydroxide to obtain N-Boc-3-aminopiperidine. The invention has the advantages of no racemization during thereaction, high optical purity of the product, relatively moderate reaction conditions, simple operation, low total production cost, and easy large-scale industrial production.

Description

N-Boc-3-氨基脈啶及其光学异构体的合成方法 The method of synthesizing N-Boc-3- piperidine semicarbazide and optical isomers

技术领域 FIELD

[0001] 本发明涉及有机化学领域,具体地说是一种中间体N-Boc-3-氨基哌啶及其光学异构体的合成方法。 [0001] The present invention relates to the field of organic chemistry, in particular to a method for the synthesis of Intermediate N-Boc-3- aminopiperidine and its optical isomers.

背景技术 Background technique

[0002] N-Boc-3-氨基哌啶及其光学异构体是是一种重要中间体,主要用作医药中间体、 有机合成中间体、有机溶剂,也可用于染料生产、农药生产及香料等方面。 [0002] N-Boc-3- aminopiperidine and its optical isomers is an important intermediate, is mainly used as pharmaceutical intermediates, organic synthetic intermediate, organic solvent, can also be used in the production of dyes, pesticides and production spices and so on.

[0003] 现有的合成方法如下: [0003] The conventional synthesis is as follows:

[0004] U Brian R. de Costa等报道的以3_羟基哌啶为原料,经上保护、甲磺酸酯化、 叠氮化、还原反应制得N-Boc-3-氨基哌啶(Journal of Medicinal Chemistry, 35 (23): 4334-4343,1992 ;PCT Int. Appl. ,2005000305,06 Jan 2005)。 [0004] U Brian R. de Costa et al reported in 3_ hydroxypiperidine as raw material, the protective, mesylated, azide, reduction reaction of N-Boc-3- aminopiperidine (Journal of Medicinal Chemistry, 35 (23):. 4334-4343,1992; PCT Int Appl, 2005000305,06 Jan 2005).. 该路线步骤长,收率低(总收率58 % ),原料3-羟基哌啶价格较高;叠氮化反应所用的试剂叠氮化钠比较危险,容易爆炸,难以工业化。 The route step length, low yield (total yield 58%), 3-hydroxypiperidine higher raw material prices; sodium azide reagent azide used in the reaction nitride dangerous, explosive, industrialization is difficult.

[0005] [0005]

Figure CN101565397BD00031

[0006] (a) (Boc) 20,aq NaHCO3, rt ; (b) MeSO3Cl, THF, Et3N ; (c) NaN3, DMF, 70°C ; (d) H2,10 % Pd/C, Me0H/Ac0H(l : 1)。 [0006] (a) (Boc) 20, aq NaHCO3, rt; (b) MeSO3Cl, THF, Et3N; (c) NaN3, DMF, 70 ° C; (d) H2,10% Pd / C, Me0H / Ac0H (l: 1).

[0007] 2、以2,5_二氨基戊酸为原料,与甲醇酯化、成环、还原、上保护得N-Boc-3-氨基哌啶(PCT Int. Appl.,2007075630,05 Jul 2007 ;Bioorganic&MedicinalChemistry,14(7), 2131-2150,2006 ;PCT Int. Appl.,2003055858,10 Jul 2003 ;Eur. Pat. Appl. ,342675,23 Nov 1989)。 [0007] 2 to 2,5_ diamino acid as raw materials, esterification with methanol, to form a ring, reduction, to give the protected N-Boc-3- aminopiperidine (PCT Int. Appl., 2007075630,05 Jul 2007; Bioorganic & MedicinalChemistry, 14 (7), 2131-2150,2006;. PCT Int Appl, 2003055858,10 Jul 2003;... Eur Pat Appl, 342675,23 Nov 1989).. 该路线在原料中导入手性源,但是在成环过程中容易发生消旋化,影响最终产物的ee值;最后一步上保护基,有两个氨基,需要严格控制溶液的PH值和反应温度,否则3 位氨基也被Boc保护。 The route in the feedstock introduced into the chiral source, but prone to racemization in the course of a ring, the influence of the ee value of the final product; the final step the protective group, there are two amino groups, it is necessary to strictly control the PH value and the temperature of the reaction solution otherwise, also 3-amino-Boc-protected.

[0008] [0008]

Figure CN101565397BD00032

[0009] (a) SOCl2, MeOH ; (b)AcCl, MeOH, t_BuOMe,2h,15 〜25°C ; (C)LiAlH4, THF,2h,0 〜 30°C ; (d) (Boc)2O, aq NaOH, 10_15°C,pH :11. 8-12. 2。 [0009] (a) SOCl2, MeOH; (b) AcCl, MeOH, t_BuOMe, 2h, 15 ~25 ° C; (C) LiAlH4, THF, 2h, 0 ~ 30 ° C; (d) (Boc) 2O, aq NaOH, 10_15 ° C, pH:.. 11 8-12 2.

[0010] 3、以3-氨基吡啶为原料,经催化加氢,上保护得N-Boc-3-氨基哌啶(Ger. Offen., 102004054054,11 May 2006 ;Heterocycles, 36 (10), 2383-96 ; 1993) „ 该合成路线中,还原 [0010] 3, 3-aminopyridine was synthesized by catalytic hydrogenation, to give the protected N-Boc-3- aminopiperidine (Ger Offen, 102004054054,11 May 2006;.. Heterocycles, 36 (10), 2383 -96; 1993) "the synthetic route, the reduction

反应所需要的压力较高,且氢化不易完全,副产物较多,后处理困难,不易工业化。 Higher pressure required for the reaction, and is difficult to completely hydrogenated, more by-products, difficult workup, easy industrialization.

[0011] [0011]

Figure CN101565397BD00041

[0012] (a) AcOH, H2, Pd, 50°C, IOObar ; (b) (Boc)2O, aq NaOH,10_15°C,pH :11. 8—12. 2。 [0012] (a) AcOH, H2, Pd, 50 ° C, IOObar; (b) (Boc) 2O, aq NaOH, 10_15 ° C, pH: 11 8-12 2...

发明内容 SUMMARY

[0013] 本发明所要解决的技术问题是要克服上述现有技术存在的缺陷,提供了一种以容易得到的3-哌啶甲酸乙酯或手性3-哌啶甲酸乙酯为原料经三步反应得到N-Boc-3-氨基哌啶及其光学异构体的合成方法,实现工业化生产。 [0013] The present invention solves the technical problem is to overcome the above defects of the prior art, provides ethyl 3-piperidin-chiral or a kind easily available 3-piperidinecarboxylate as a raw material by the three amino piperidine was obtained from N-Boc-3- optical isomers and synthetic methods of industrial production.

[0014] 为此,本发明采用如下的技术方案:N-Boc-3-氨基哌啶的合成方法,其步骤如下: 1) 3-哌啶甲酸乙酯以卤代烃为溶剂、有机碱为缚酸剂,在0-10°C之间,滴加二碳酸二叔丁酯,反应完毕后,依次用碱溶液、酸溶液、饱和盐水洗涤,所得的有机相干燥、回收溶剂得N-Boc-3-哌啶甲酸乙酯; [0014] To this end, the present invention adopts the following technical solution: N-Boc-3- aminopiperidine synthesis method, the following steps: 1) 3-piperidin-carboxylate in a halogenated hydrocarbon solvent, an organic base is acid-binding agent, at between 0-10 ° C, added dropwise di-tert-butyl after completion of the reaction, successively phase was dried with an alkaline solution, an acid solution, the organic was washed with saturated brine, the resulting recovered solvent gave N-Boc -3-piperidine carboxylic acid ethyl ester;

[0015] 2)以1,4_ 二氧六环为溶剂,N-Boc-3-哌啶甲酸乙酯进行氨解反应,之后蒸干、重结晶得N-Boc-3-哌啶甲酰氨; [0015] 2) In 1,4_ dioxane as solvent, N-Boc-3- piperidine-carboxylic acid ethyl ester aminolysis reaction was then evaporated to dryness, and recrystallized to give N-Boc-3- piperidine-formylamino ;

[0016] 3)在0°C以下,N-Boc-3-哌啶甲酰氨滴加到次氯酸钠和氢氧化钠的溶液中,反应完成后,进行萃取、洗涤、干燥、蒸干得N-Boc-3-氨基哌啶。 [0016] 3) at below 0 ° C, N-Boc-3- piperidine-formamide was added dropwise to a solution of sodium hypochlorite and sodium hydroxide. After completion of the reaction, extracted, washed, dried, and evaporated to dryness to give N- boc-3- aminopiperidine.

[0017] 以(S)或(R)-3-哌啶甲酸乙酯N-Boc-3-氨基哌啶为原料时,经上述三步反应能得到N-Boc-3-氨基哌啶光学异构体,S卩(S)或(R)-N-Boc-3-氨基哌啶。 [0017] when in (S) or (R) -3- piperidinecarboxylate N-Boc-3- aminopiperidine as a starting material, the reaction can be obtained by the above-described three-step N-Boc-3- aminopiperidine optical anisotropy isomers, S Jie (S) or (R) -N-Boc-3- aminopiperidine.

[0018] 本发明的合成路线如下: [0018] The synthetic routes of the present invention are as follows:

[0019] [0019]

Figure CN101565397BD00042

(2) (3) (4) (1) (2) (3) (4) (1)

[0020] 其中,(2)3-哌啶甲酸乙酯,(¾) (S)-3-哌啶甲酸乙酯,(2b) (R)-3-哌啶甲酸乙 [0020] wherein, (2) 3-piperidine carboxylic acid ethyl ester, (¾) (S) -3- piperidine carboxylic acid ethyl ester, (2b) (R) -3- piperidinecarboxylic acid ethyl

[0021] (3)N-Boc-3-哌啶甲酸乙酯,(3a) (S)-N-Boc-3-哌啶甲酸乙酯,(3b) (R)-N-Boc-3-哌啶甲酸乙酯; [0021] (3) N-Boc-3- piperidine-carboxylic acid ethyl ester, (3a) (S) -N-Boc-3- piperidine-carboxylic acid ethyl ester, (3b) (R) -N-Boc-3- piperidine carboxylic acid ethyl ester;

[0022] (4) N-Boc-3-哌啶甲酰胺,Ga) (S) -N-Boc-3-哌啶甲酰胺,0b) (R) -N-Boc-3-哌啶甲酰胺。 [0022] (4) N-Boc-3- piperidine-carboxamide, Ga) (S) -N-Boc-3- piperidine-carboxamide, 0b) (R) -N-Boc-3- piperidine-carboxamide .

4[0023] (5) N-Boc-3-氨基哌啶,(5a) (S) -N-Boc-3-氨基哌啶,(5b) (R) -N-Boc-3-氨基哌啶。 4 [0023] (5) N-Boc-3- aminopiperidine, (5a) (S) -N-Boc-3- aminopiperidine, (5b) (R) -N-Boc-3- aminopiperidine .

[0024] 作为本发明的进一步技术方案,所述的卤代烃为二氯甲烷或氯仿,使得反应缓慢进行,控制反应放热。 [0024] As a further aspect of the present invention, the halogenated hydrocarbon is dichloromethane or chloroform, so that the reaction proceeds slowly, controlling the reaction exotherm.

[0025] 作为本发明的进一步技术方案,所述的有机碱为三乙胺、4-二甲氨基吡啶、三甲胺、二异丙胺或吡啶,作缚酸剂。 [0025] As a further aspect of the present invention, the organic base is triethylamine, 4-dimethylaminopyridine, trimethylamine, diisopropylamine or pyridine as acid binding agent.

[0026] 作为本发明的进一步技术方案,所述的碱溶液为饱和碳酸钠、饱和碳酸氢钠或饱和碳酸氢钾溶液,优选饱和碳酸钾溶液。 [0026] As a further aspect of the present invention, the base is saturated sodium carbonate solution, saturated sodium bicarbonate or potassium bicarbonate saturated solution, preferably a saturated potassium carbonate solution.

[0027] 作为本发明的进一步技术方案,所述的酸溶液为3〜5% (质量浓度)的盐酸溶液,用于中和反应液。 [0027] As a further aspect of the present invention, the acid solution is 3 to 5% (mass concentration) of hydrochloric acid solution used to neutralize the reaction solution.

[0028] 作为本发明的进一步技术方案,所述的氨为氨气、氨水或甲胺水溶液。 [0028] As a further aspect of the present invention, the ammonia is ammonia gas, aqueous ammonia or methylamine.

[0029] 本发明的原料3-哌啶甲酸乙酯及其手性原料(S)或(R)-3_哌啶甲酸乙酯国内市场有售,价格便宜;反应过程无消旋化发生,产物光学纯度高;反应条件比较温和,操作简单,且总生产成本低,容易工业化规模生产。 [0029] The starting material of the present invention and ethyl 3-piperidin-chiral starting materials (S) or (R) -3_ domestic isonipecotate are commercially available, cheap; no racemization occurs during the reaction, high optical purity; relatively mild reaction conditions, simple operation, and low total cost, easy to industrial scale production.

[0030] 下面通过具体实施方式对本发明作进一步说明。 [0030] By following specific embodiments of the present invention will be further described.

具体实施方式 Detailed ways

[0031] 实施例1 :N-Boc-3-哌啶甲酸乙酯(3)的合成 Synthesis of N-Boc-3- piperidine-carboxylic acid ethyl ester (3): [0031] Example 1

[0032] 将3-哌啶甲酸乙酯(2) (31.4g,0. 2mol)、三乙胺(55. 8mL,0. 4mol)溶于二氯甲烷(150mL),冷却至0°C以下,滴加二碳酸二叔丁酯(52.4g,0. 24mol)的二氯甲烷(IOOmL)溶液,控温在0〜10°C之间。 [0032] piperidine-3- carboxylic acid ethyl ester (2) (31.4g, 0. 2mol), triethylamine (55. 8mL, 0. 4mol) was dissolved in dichloromethane (150mL), cooled to below 0 ° C was added dropwise tert-butyl dicarbonate (52.4g, 0. 24mol) in dichloromethane (IOOmL) solution temperature between 0~10 ° C. 滴加完毕,依次用饱和碳酸钾溶液(3X50mL)、5%HCl(3X50mL) 和饱和盐水(3 X 50mL)洗涤,有机相无水硫酸钠干燥他,抽虑,减压蒸干溶剂得N-Boc-3-哌啶甲酸乙酯(3),49. 3g,95%0 Upon completion, washed successively with saturated potassium carbonate solution (3X50mL), 5% HCl (3X50mL) and saturated brine (3 X 50mL), dried over anhydrous sodium sulfate organic phase him, suction filtration, the solvent was evaporated to dryness under reduced pressure to give N- boc-3- piperidine-carboxylic acid ethyl ester (3), 49. 3g, 95% 0

[0033] 实施例2 :N-Boc-3-哌啶甲酰胺⑷的合成 Synthesis of N-Boc-3- piperidinecarboxamide ⑷: 2 [0033] Example

[0034] N-Boc-3-哌啶甲酸乙酯(3) (41. lg,0. 16mol)、28 % 氨水溶于1,4_ 二氧六环(300mL)中,密封,设定外温为85〜90°C,保温反应1. 5h,反应完毕,减压蒸干溶剂,石油醚(340mL)重结晶,烘干得N-Boc-3-哌啶甲酰胺(4),35g, 96%。 [0034] N-Boc-3- piperidine-carboxylic acid ethyl ester (3) (41. lg, 0. 16mol), 28% aqueous ammonia 1,4_ was dissolved in dioxane (300 mL), the seal, the outside temperature set is 85~90 ° C, the reaction incubated 1. 5h, completion of the reaction, solvent was evaporated under reduced pressure, petroleum ether (340 mL) and recrystallized dried to obtain N-Boc-3- piperidine-carboxamide (4), 35g, 96 %.

[0035] 实施例3 :N-Boc-3-氨基哌啶(1)的合成 Synthesis of N-Boc-3- aminopiperidine (1): [0035] Example 3

[0036]将 Na0H(18g,0.45mol)和10%次氯酸钠溶液(30mL,0. 3mol)冷却至0°C 以下,一次性加入N-Boc-3-哌啶甲酰胺(4) (34. 2g,0. 15mol),搅拌30min后撤去冰浴。 [0036] The Na0H (18g, 0.45mol) and 10% sodium hypochlorite solution (30mL, 0. 3mol) was cooled to below 0 ° C, was added in one N-Boc-3- piperidine-carboxamide (4) (34. 2g , 0. 15mol), stirred for 30min ice bath was removed. 加热升温至700C,保温反应45min。 Heating to 700C, the reaction incubated 45min. 冷却至室温,乙醚萃取(3X50mL),合并有机相,饱和盐水(3X50mL) 洗涤,无水硫酸钠干燥乩。 Cooled to room temperature, extracted with ether (3 X 50 mL), combined organic phases were washed with saturated brine (3 X 50 mL), dried over anhydrous sodium sulfate mediums. 减压蒸干溶剂得N-Boc-3-氨基哌啶(1),26. 7g,89%。 The solvent was evaporated under reduced pressure to give N-Boc-3- aminopiperidine (1), 26. 7g, 89%.

[0037] 实施例4 :⑶-N-Boc-3-哌啶甲酸乙酯(3a)的合成 ⑶-N-Boc-3- piperidin carboxylate (3a) of: 4 [0037] Example

[0038]将(S) -3-哌啶甲酸乙酯(2a) (31. 4g,0. 2mol)、三乙胺(55. 8mL,0. 4mol)溶于二氯甲烷(150mL),冷却至0°C以下,滴加二碳酸二叔丁酯(52.4g,0. 24mol)的二氯甲烷(IOOmL)溶液,控温在0〜10°C之间。 [0038] The (S) -3- piperidine carboxylic acid ethyl ester (2a) (31. 4g, 0. 2mol), triethylamine (55. 8mL, 0. 4mol) was dissolved in dichloromethane (150mL), cooled to below 0 ° C, was added dropwise di- tert -butyl dicarbonate (52.4g, 0. 24mol) in dichloromethane (IOOmL) solution temperature between 0~10 ° C. 滴加完毕,依次用饱和碳酸钾溶液(3X50mL)、5% HCl(3X50mL)和饱和盐水(3X50mL)洗涤,有机相无水硫酸钠干燥他,抽虑,减压蒸干溶剂得(S)-N-Boc-3-哌啶甲酸乙酯(3a),49. 3g,95%0 Upon completion, washed successively with saturated potassium carbonate solution (3X50mL), 5% HCl (3X50mL) and saturated brine (3 X 50 mL), dried over anhydrous sodium sulfate organic phase him, suction filtration, solvent was evaporated under reduced pressure to give (S) - N-Boc-3- piperidine-carboxylic acid ethyl ester (3a), 49. 3g, 95% 0

[0039] 实施例5 :(S)-N-Boc-3-哌啶甲酰胺(4a)的合成[0040] (S)-N-Boc_3-哌啶甲酸乙酯(3a) (41. Ig, 0. 16mol)、28%氨水溶于1,4_ 二氧六环(300mL)中,密封,设定外温为85〜90°C,保温反应1. 5h,反应完毕,减压蒸干溶剂,石油醚(340mL)重结晶,烘干得(S)-N-Boc-3-哌啶甲酰胺(4a), 35g, 96% 0 [0039] Example 5: Synthesis of (S) -N-Boc-3- piperidine-carboxamide (4a) of [0040] (S) -N-Boc_3- piperidine carboxylic acid ethyl ester (3a) (41. Ig, 0. 16mol), 28% aqueous ammonia 1,4_ was dissolved in dioxane (300 mL), the seal, the outside temperature is set to 85~90 ° C, the reaction incubated 1. 5h, completion of the reaction, the solvent was evaporated under reduced pressure, petroleum ether (340 mL) and recrystallized dried to give (S) -N-Boc-3- piperidine-carboxamide (4a), 35g, 96% 0

[0041] 实施例6 :⑶-N-Boc-3-氨基哌啶(Ia)的合成 Synthesis ⑶-N-Boc-3- aminopiperidine (Ia) is: 6 [0041] Example

[0042]将 Na0H(18g,0.45mol)和10%次氯酸钠溶液(30mL,0. 3mol)冷却至0°C 以下,一次性加入(S)-N-Boc-3-哌啶甲酰胺Ga) (34. 2g,0. 15mol),搅拌30min后撤去冰浴。 [0042] The Na0H (18g, 0.45mol) and 10% sodium hypochlorite solution (30mL, 0. 3mol) was cooled to below 0 ° C, added in one portion (S) -N-Boc-3- piperidine-carboxamide Ga) ( 34. 2g, 0. 15mol), stirred for 30min ice bath was removed. 加热升温至70°C,保温反应45min。 Heating to 70 ° C, the reaction incubated 45min. 冷却至室温,乙醚萃取(3X 50mL),合并有机相,饱和盐水(3X50mL)洗涤,无水硫酸钠干燥Mi。 Cooled to room temperature, extracted with ether (3X 50mL), combined organic phases were washed with saturated brine (3 X 50 mL), dried over anhydrous sodium sulfate Mi. 减压蒸干溶剂得(S)-N-Boc-3-氨基哌啶(la),26. Ig, 89%。 Reduced pressure -N-Boc-3- aminopiperidine (La) solvent was evaporated to give (S), 26. Ig, 89%.

[0043] 实施例7 : (R) -N-Boc-3-哌啶甲酸乙酯(3b)的合成 [0043] Example 7: (R) -N-Boc-3- piperidine-carboxylic acid ethyl ester (3b) Synthesis of

[0044]将(R) -3-哌啶甲酸乙酯(2a) (31. 4g,0. 2mol)、三乙胺(55. 8mL,0. 4mol)溶于二氯甲烷(150mL),冷却至0°C以下,滴加二碳酸二叔丁酯(52.4g,0. 24mol)的二氯甲烷(IOOmL)溶液,控温在0〜10°C之间。 [0044] The (R) -3- piperidine carboxylic acid ethyl ester (2a) (31. 4g, 0. 2mol), triethylamine (55. 8mL, 0. 4mol) was dissolved in dichloromethane (150mL), cooled to below 0 ° C, was added dropwise di- tert -butyl dicarbonate (52.4g, 0. 24mol) in dichloromethane (IOOmL) solution temperature between 0~10 ° C. 滴加完毕,依次用饱和碳酸钾溶液(3X50mL)、5% HCl(3X50mL)和饱和盐水(3X50mL)洗涤,有机相无水硫酸钠干燥他,抽虑,减压蒸干溶剂得(R)-N-Boc-3-哌啶甲酸乙酯(3b),49. 3g,95%0 Upon completion, washed successively with saturated potassium carbonate solution (3X50mL), 5% HCl (3X50mL) and saturated brine (3 X 50 mL), dried over anhydrous sodium sulfate organic phase him, suction filtration, solvent was evaporated under reduced pressure to give (R) - N-Boc-3- piperidine-carboxylic acid ethyl ester (3b), 49. 3g, 95% 0

[0045] 实施例8 : (R) -N-Boc-3-哌啶甲酰胺Gb)的合成 Synthesis of (R) -N-Boc-3- piperidine-carboxamide Gb) is: [0045] Example 8

[0046] (R)-N-Boc-3-哌啶甲酸乙酯(3b) (41. Ig, 0. 16mol)、28%氨水溶于1,4_ 二氧六环(300mL)中,密封,设定外温为85〜90°C,保温反应1. 5h,反应完毕,减压蒸干溶剂,石油醚(340mL)重结晶,烘干得(R) -N-Boc-3-哌啶甲酰胺(4b),35g,96 %。 [0046] (R) -N-Boc-3- piperidine-carboxylic acid ethyl ester (3b) (41. Ig, 0. 16mol), 28% aqueous ammonia 1,4_ was dissolved in dioxane (300 mL) in a sealed, the outside temperature is set to 85~90 ° C, the reaction incubated 1. 5h, the reaction is completed, the solvent was evaporated under reduced pressure, petroleum ether (340 mL) and recrystallized dried to give (R) -N-Boc-3- piperidinecarboxamide amide (4b), 35g, 96%.

[0047] 实施例9 : (R) -N-Boc-3-氨基哌啶(Ib)的合成 [0047] Example 9: Synthesis of (R) -N-Boc-3- aminopiperidine (Ib) is

[0048]将 Na0H(18g,0.45mol)和10%次氯酸钠溶液(30mL,0. 3mol)冷却至0°C 以下,一次性加入(R)-N-Boc-3-哌啶甲酰胺Gb) (34. 2g,0. 15mol),搅拌30min后撤去冰浴。 [0048] The Na0H (18g, 0.45mol) and 10% sodium hypochlorite solution (30mL, 0. 3mol) was cooled to below 0 ° C, was added in one (R) -N-Boc-3- piperidinecarboxamide the Gb) ( 34. 2g, 0. 15mol), stirred for 30min ice bath was removed. 加热升温至70°C,保温反应45min。 Heating to 70 ° C, the reaction incubated 45min. 冷却至室温,乙醚萃取(3X 50mL),合并有机相,饱和盐水(3X50mL)洗涤,无水硫酸钠干燥Mi。 Cooled to room temperature, extracted with ether (3X 50mL), combined organic phases were washed with saturated brine (3 X 50 mL), dried over anhydrous sodium sulfate Mi. 减压蒸干溶剂得(R)-N-Boc-3-氨基哌啶(Ib),26. Ig, 89%。 The solvent was evaporated under reduced pressure to give (R) -N-Boc-3- aminopiperidine (Ib), 26. Ig, 89%.

[0049] 以上所述,仅是本发明的较佳实施例而已,并非对本发明的技术方案作任何形式上的限制。 [0049] As described above, only the preferred embodiment of the present invention, but not form any limitation to the aspect of the present invention. 凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均落入本发明的保护范围内。 Any embodiment based on any simple modification made to the technical spirit of the present invention to the above embodiments, modifications and equivalent, are within the scope of the present invention.

Claims (8)

1.N-Boc-3-氨基哌啶的合成方法,其步骤如下:1)3-哌啶甲酸乙酯以卤代烃为溶剂、 有机碱为缚酸剂,在0-10°C之间,滴加二碳酸二叔丁酯,反应完毕后,依次用碱溶液、酸溶液、饱和盐水洗涤,所得的有机相干燥、回收溶剂得N-Boc-3-哌啶甲酸乙酯;2)以1,4_ 二氧六环为溶剂,N-Boc-3-哌啶甲酸乙酯进行氨解反应,之后蒸干、重结晶得N-Boc-3-哌啶甲酰氨;3)在0°C以下,N-Boc-3-哌啶甲酰氨滴加到次氯酸钠和氢氧化钠的溶液中,反应完成后,进行萃取、洗涤、干燥、蒸干得N-Boc-3-氨基哌啶。 Synthesis 1.N-Boc-3- aminopiperidine, comprises the following steps: 1) 3-piperidin-carboxylate in a halogenated hydrocarbon solvent, an organic base as acid-binding agent, at between 0-10 ° C added dropwise di-tert-butyl after completion of the reaction, successively phase was dried with an alkaline solution, an acid solution, the organic was washed with saturated brine, the resulting recovered solvent to give N-Boc-3- piperidine-carboxylic acid ethyl ester; 2) 1,4_ dioxane as solvent, N-Boc-3- piperidine-carboxylic acid ethyl ester aminolysis reaction was then evaporated to dryness, and recrystallized to give N-Boc-3- piperidine-formylamino; 3) at 0 ° the following C, N-Boc-3- piperidine-formamide was added dropwise to a solution of sodium hypochlorite and sodium hydroxide. after completion of the reaction, extracted, washed, dried, and evaporated to dryness to give N-Boc-3- aminopiperidine.
2. N-Boc-3-氨基哌啶光学异构体的合成方法,其步骤如下:1)⑶或(R)-3-哌啶甲酸乙酯以卤代烃为溶剂、有机碱为缚酸剂,在0-10°C之间,滴加二碳酸二叔丁酯,反应完毕后,依次用碱溶液、酸溶液、饱和盐水洗涤,所得的有机相干燥、回收溶剂得(S)或(R)-N-Boc-3-哌啶甲酸乙酯;2)以1,4_ 二氧六环为溶剂,(S)或(R)-N-Boc-3-哌啶甲酸乙酯进行氨解反应,之后蒸干、重结晶得(S)或(R)-N-Boc-3-哌啶甲酰氨;3)在0°C以下,(S)或(R)-N-Boc-3-哌啶甲酰氨滴加到次氯酸钠和氢氧化钠的溶液中, 反应完成后,进行萃取、洗涤、干燥、蒸干得(¾或(R)-N-Boc-3-氨基哌啶。 2. N-Boc-3- aminopiperidine synthesis of optical isomers, comprises the following steps: 1) ⑶ ​​or (R) -3- piperidinecarboxylate in a halogenated hydrocarbon solvent, an organic base as an acid binding agent, between 0-10 ° C, added dropwise di-tert-butyl after completion of the reaction, successively phase was dried with an alkaline solution, an acid solution, the organic was washed with saturated brine, the resulting, recovered solvent to give (S) or ( R) -N-Boc-3- piperidine-carboxylic acid ethyl ester; 2) 1,4_ dioxane as a solvent, (S) or (R) -N-Boc-3- piperidine-carboxylic acid ethyl ester aminolysis the reaction, then evaporated to dryness, and recrystallized to give (S) or (R) -N-Boc-3- piperidine-formylamino; 3) at below 0 ° C, (S) or (R) -N-Boc-3 - piperidine formamide was added dropwise to a solution of sodium hypochlorite and sodium hydroxide. after completion of the reaction, extracted, washed, dried, and evaporated to dryness to give (¾ or (R) -N-Boc-3- aminopiperidine.
3.根据权利要求1或2所述的合成方法,其特征在于所述的卤代烃为二氯甲烷或氯仿。 The synthesis method of claim 1 or claim 2, wherein said halogenated hydrocarbon is dichloromethane or chloroform.
4.根据权利要求1或2所述的合成方法,其特征在于所述的缚酸剂为三乙胺、4- 二甲氨基吡啶、三甲胺、二异丙胺或吡啶。 The synthesis method of claim 1 or claim 2, wherein said acid binding agent is triethylamine, 4-dimethylaminopyridine, trimethylamine, diisopropylamine or pyridine.
5.根据权利要求1或2所述的合成方法,其特征在于所述的碱溶液为饱和碳酸钠、饱和碳酸氢钠或饱和碳酸氢钾溶液。 The synthesis method of claim 1 or claim 2, wherein said base is saturated sodium carbonate solution, saturated sodium bicarbonate or potassium bicarbonate saturated solution.
6.根据权利要求1或2所述的合成方法,其特征在于所述的碱溶液为饱和碳酸钾溶液。 The synthesis method of claim 1 or claim 2, wherein said alkaline solution is a saturated solution of potassium carbonate.
7.根据权利要求1或2所述的合成方法,其特征在于所述的酸溶液为3〜5%的盐酸溶液。 The synthesis method of claim 1 or claim 2, wherein said acid solution is a hydrochloric acid solution 3 to 5%.
8.根据权利要求1或2所述的合成方法,其特征在于氨解反应中所用的氨为氨气或氨水。 The synthesis method according to claim 1, characterized in that the ammonolysis with ammonia as ammonia gas or aqueous ammonia.
CN 200910097326 2009-04-07 2009-04-07 N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof CN101565397B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200910097326 CN101565397B (en) 2009-04-07 2009-04-07 N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200910097326 CN101565397B (en) 2009-04-07 2009-04-07 N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof

Publications (2)

Publication Number Publication Date
CN101565397A CN101565397A (en) 2009-10-28
CN101565397B true CN101565397B (en) 2011-08-10

Family

ID=41281790

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200910097326 CN101565397B (en) 2009-04-07 2009-04-07 N-Boc-3-aminopiperidine and synthesizing method of optical isomer thereof

Country Status (1)

Country Link
CN (1) CN101565397B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2958894A1 (en) * 2013-02-20 2015-12-30 Reuter Chemische Apparatebau KG Process for the preparation of enantiomerically enriched 3-aminopiperidine
CN103435538B (en) * 2013-08-08 2015-10-28 爱斯特(成都)医药技术有限公司 (R) -3- preparation aminopiperidine hydrochloride
CN105130879B (en) * 2015-07-24 2018-03-02 沧州那瑞化学科技有限公司 Preparing (R) -3-Boc- aminopiperidine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005000305A1 (en) 2003-06-20 2005-01-06 Eli Lilly And Company 3-aminopiperidines and 3-aminoquinuclidines as inhibitors of monoamine uptake
CN1726192A (en) 2002-11-21 2006-01-25 辉瑞产品公司 3-amino-piperadine derivatives and methods of manufacture
WO2008055959A1 (en) 2006-11-09 2008-05-15 Galapagos N.V. Novel compounds useful for the treatment of degenerative & inflammatory diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1726192A (en) 2002-11-21 2006-01-25 辉瑞产品公司 3-amino-piperadine derivatives and methods of manufacture
WO2005000305A1 (en) 2003-06-20 2005-01-06 Eli Lilly And Company 3-aminopiperidines and 3-aminoquinuclidines as inhibitors of monoamine uptake
WO2008055959A1 (en) 2006-11-09 2008-05-15 Galapagos N.V. Novel compounds useful for the treatment of degenerative & inflammatory diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Brain R. de Costa, et al.Synthesis and Biological Evaluation of Conformationally Restricted 2-(l -Pyrrolidinyl)-N-[2-(3 ,4-dichlorophenyl)ethyl]-N-mehtylethylenediamines as σ Receptor Ligands. 1. Pyrrolidine, Piperidine, Homopiperidine, and Tetrahydroisoquinoline Classes.《J. Med. Chem.》.1992,第35卷(第23期),4334-4343.
Minoru Ishikawa, et al.Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part III: Synthesis of potent antagonists with αvβ3/αIIbβ3 dual activity and improved water solubility.《Bioorganic & Medicinal Chemistry》.2006,第14卷2131-2150.

Also Published As

Publication number Publication date
CN101565397A (en) 2009-10-28

Similar Documents

Publication Publication Date Title
CN102633713A (en) Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
CN104876888B (en) A method for the preparation of pharmaceutical agent and intermediates
CN1821217B (en) Process for producing trans-4-amino-1-cyclohexanecarboxylic acid derivative
JP2006188470A (en) Indoline derivative and method for producing the same
JP3411284B2 (en) N- methyl-3- (1-methyl-4-piperidinyl)-1h-preparation of the indole-5-ethanesulfonamide
CN103360348A (en) Carfilzomib intermediate and preparation method thereof, and preparation method of Carfilzomib
CN101774978B (en) Preparation method of linezolid and intermediate thereof
CN102639486A (en) Process for manufacture of N-acylbphenyl alanine
CN104130261A (en) Idelalisib synthetic method
WO2011035725A1 (en) Sitagliptin intermediates, preparation methods and uses thereof
CN104829599B (en) Preparation Leidipawei and derivatives thereof and intermediates for the preparation of compounds of Leidipawei
CN102344415B (en) Preparation of Intermediate Archie Chastain
US8030491B2 (en) Process and intermediate for preparation of donepezil
CN101410374A (en) Synthesis and preparations of intermediates and polymorphs thereof useful for the preparation of donepezil hydrochloride
CN102766139A (en) Azilsartan polymorphic substance and preparation method thereof
US20130060038A1 (en) Preparation of dihydropyrrol derivatives as intermediates
WO2004082685A1 (en) Process for the preparation of donepezil and derivatives thereof
CN101967118B (en) Preparation method of alvimopan
CA2735560A1 (en) Process for preparing cycloalkyl-substituted piperazine compounds
CN1271057C (en) Method for preparing 1-methyl-3-ethyl-3-(3-hydroxy phenyl)-hexa hydrogen-1 H azepin hydrochloride
CN102295594B (en) 4-n- substituted 1- (3-methoxypropyl) -4-piperidinyl amine compound and preparation and application
US20130116441A1 (en) Intermediates and process for preparing a thrombin specific inhibitor
CN103304511A (en) Novel synthesis method of mirabegron
US9951012B2 (en) Process for the preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine
KR101372389B1 (en) New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

Legal Events

Date Code Title Description
C06 Publication
C10 Request of examination as to substance
C14 Granted