技术领域technical field
本发明涉及一种4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物及其在合成琥珀酸普卡必利中的应用。The invention relates to a 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound and its application in the synthesis of prucalopride succinate.
背景技术Background technique
琥珀酸普卡必利化学名为：N-[1-(3-甲氧丙基)-4-哌啶基]-4-氨基-5-氯-2，3-二氢苯并呋喃-7-甲酰胺琥珀酸盐，由比利时Janssen公司研制开发，为高选择性、特异性5-HT4受体激动剂，于2010年在英国上市，用于治疗泻药无效的女性便秘患者，结构式如下：Prucalopride succinate chemical name: N-[1-(3-methoxypropyl)-4-piperidinyl]-4-amino-5-chloro-2,3-dihydrobenzofuran-7 -Formamide succinate, developed by Janssen Company in Belgium, is a highly selective and specific 5-HT4 receptor agonist. It was launched in the UK in 2010 and is used to treat female constipation patients who are ineffective in laxatives. The structural formula is as follows:
随着经济的快速发展、生态环境的极度恶化及人们生活节奏的加快，便秘已成为社会上普遍存在的问题，患病率呈逐年上升趋势。它严重影响患者的生活质量，患者可伴有头昏、头胀、恶心、纳差、心情烦躁、多梦、少寐、腹痛、腹胀、会阴坠胀、排便不全等不适症状，可诱发或加重其它疾病，如痔疮、肠癌、前列腺肥大及心脑血管疾病，甚至可危及生命。琥珀酸普卡必利为最近上市的该类药物，与同类药物相比，具有5-HT4受体选择性高、亲和力强；起效快；不良反应少，耐受性好，患者满意度高；对老年人同样适用的特点。因此，琥珀酸普卡必利在便秘治疗领域有广阔的临床应用前景。With the rapid economic development, the extreme deterioration of the ecological environment and the acceleration of people's life rhythm, constipation has become a common problem in the society, and the prevalence rate is increasing year by year. It seriously affects the quality of life of patients. Patients may be accompanied by dizziness, dizziness, nausea, anorexia, irritability, dreaminess, insomnia, abdominal pain, abdominal distension, perineal bulge, incomplete defecation and other discomfort symptoms, which can induce or aggravate Other diseases, such as hemorrhoids, colon cancer, enlarged prostate and cardiovascular and cerebrovascular diseases, can even be life-threatening. Prucalopride succinate is a recently listed drug of this type. Compared with similar drugs, it has high 5-HT4 receptor selectivity and strong affinity; rapid onset; few adverse reactions, good tolerance, and patient satisfaction. High; a feature that is also applicable to the elderly. Therefore, prucalopride succinate has broad clinical application prospects in the field of constipation treatment.
目前，仅化合物专利CN1071332C报道了琥珀酸普卡必利的两条合成路线，具体如下：At present, only the compound patent CN1071332C has reported two synthetic routes of prucalopride succinate, specifically as follows:
路线一以4-氨基-5-氯-2，3-二氢苯并呋喃-7-甲酸(7)与1-(3-甲氧基丙基)-4-哌啶氨(4)缩合、成盐得琥珀酸普卡必利。Route 1 uses 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (7) to condense with 1-(3-methoxypropyl)-4-piperidine ammonia (4), Salt prucalopride succinate.
路线二以化合物9与1-氯-3-甲氧基丙烷缩合得普卡必利。Route 2 condenses compound 9 with 1-chloro-3-methoxypropane to obtain prucalopride.
路线一较之路线二，反应后残余原料化合物7易通过碱水洗涤去除，产物纯度较高。此外，化合物7的合成有文献报道，而化合物9的合成未见文献报道，且较之化合物7合成难度较高。相比较，路线一具有较好的优势，有利于工业化生产。但是，目前化合物4的合成未见文献报道，因此，寻找一种化合物4的合成方法，将具有重要的意义。Compared with route 2, route 1 is easy to remove the residual raw material compound 7 after the reaction by washing with alkaline water, and the product has higher purity. In addition, the synthesis of compound 7 has been reported in the literature, but the synthesis of compound 9 has not been reported in the literature, and the synthesis of compound 7 is more difficult. In comparison, route one has better advantages and is conducive to industrialized production. However, the synthesis of compound 4 has not been reported in the literature at present, therefore, it will be of great significance to find a synthesis method of compound 4.
化合物4的结构如下：The structure of compound 4 is as follows:
发明内容Contents of the invention
本发明目的在于提供一种4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物，以制备1-(3-甲氧基丙基)-4-哌啶胺(4)，用于琥珀酸普卡必利的合成，以满足有关产业部门的需要。The object of the present invention is to provide a kind of 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound, to prepare 1-(3-methoxypropyl)-4-piperidine Acidylamine (4) is used in the synthesis of prucalopride succinate to meet the needs of relevant industrial sectors.
所述的4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物，为具有式(1)所示的化合物的游离碱或其盐：The 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound is a free base or a salt thereof of a compound represented by formula (1):
其中，in,
R代表N保护基团苄氧羰基(Cbz)、叔丁氧羰基(Boc)或C1-6直链烷基酰基，优选苄氧羰基(Cbz)、叔丁氧羰基(Boc)、乙酰基或丙酰基；R represents N protecting group benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) or C1-6 straight chain alkylacyl, preferably benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), acetyl or Propionyl;
所述盐为无机酸盐，包括：盐酸盐、溴氢酸盐或硫酸盐等，也可为有机酸盐，如：乙酸盐、三氟乙酸盐、甲磺酸盐或对甲苯磺酸盐等，优选盐酸盐或氢溴酸盐；The salt is an inorganic acid salt, including: hydrochloride, hydrobromide or sulfate, etc., and can also be an organic acid salt, such as: acetate, trifluoroacetate, methanesulfonate or p-toluenesulfonate acid salt, etc., preferably hydrochloride or hydrobromide;
优选的，所述4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物为：Preferably, the 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound is:
4-N-叔丁氧羰基-1-(3-甲氧丙基)-4-哌啶胺(1-1)、4-N-tert-butoxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (1-1),
4-N-苄氧羰基-1-(3-甲氧丙基)-4-哌啶胺(1-2)、4-N-Benzyloxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (1-2),
4-N-乙酰基-1-(3-甲氧丙基)-4-哌啶胺(1-3)4-N-acetyl-1-(3-methoxypropyl)-4-piperidinamine (1-3)
所述4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物的制备方法，包括如下步骤：The preparation method of the 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound comprises the following steps:
将化合物2与化合物3在溶剂中，碱性物质作用下缩合，即可获得所述4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物，路线如下：The 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound can be obtained by condensing compound 2 and compound 3 in a solvent under the action of an alkaline substance, and the route is as follows :
其中，R如前文所定义，X代表Cl、Br、I、甲磺酰基、对甲苯磺酰基等易离去基团，优选Cl、Br、I；Wherein, R is as defined above, and X represents easy leaving groups such as Cl, Br, I, methanesulfonyl, p-toluenesulfonyl, preferably Cl, Br, I;
所使用的碱选自无机碱或有机碱，优选的为碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钠、三乙胺或二乙胺等；The base used is selected from inorganic bases or organic bases, preferably sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, triethylamine or diethylamine, etc.;
反应溶剂可为乙腈、丙酮、丁酮、DMF或二氯甲烷等；The reaction solvent can be acetonitrile, acetone, butanone, DMF or dichloromethane, etc.;
化合物2与化合物3的投料摩尔比为0.8-5，优选1-2；The molar ratio of compound 2 to compound 3 is 0.8-5, preferably 1-2;
碱与化合物2的投料摩尔比为1～5，优选1-2；The molar ratio of base to compound 2 is 1-5, preferably 1-2;
缩合反应温度为室温至回流，反应时间为1-12h；The condensation reaction temperature is from room temperature to reflux, and the reaction time is 1-12h;
化合物2、3可直接商购。Compounds 2 and 3 are directly commercially available.
化合物1可用于制备琥珀酸普卡必利关键中间体4，4再与4-氨基-5氯-2，3-二氢苯并呋喃-7-甲酸(5)的缩合，成盐后可制得琥珀酸普卡必利，路线如下：Compound 1 can be used to prepare the key intermediate 4 of prucalopride succinate, and the condensation of 4 and 4-amino-5 chloro-2,3-dihydrobenzofuran-7-carboxylic acid (5) can be prepared after salt formation To obtain prucalopride succinate, the route is as follows:
根据R结构的不同，化合物1脱保护条件亦有不同，如叔丁氧羰基(Boc)的脱保护条件一般为酸解，常用酸为盐酸、硫酸、醋酸或三氟乙酸等；Depending on the structure of R, the deprotection conditions of compound 1 are also different. For example, the deprotection condition of tert-butoxycarbonyl (Boc) is generally acidolysis, and commonly used acids are hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid, etc.;
苄氧羰基(Cbz)的脱保护条件一般为氢解或酸解裂解(HBt或TMSI)；乙酰基、丙酰基通常以碱解或酸解脱除。The deprotection conditions of benzyloxycarbonyl (Cbz) are generally hydrogenolysis or acidolysis cleavage (HBt or TMSI); acetyl and propionyl groups are usually removed by alkaline or acidolysis.
化合物4与化合物5缩合、成盐制备琥珀酸普卡必利按照文献CN1071332C操作。Compound 4 and compound 5 are condensed and salt-formed to prepare prucalopride succinate according to the document CN1071332C.
采用本发明的4-N-取代-1-(3-甲氧基丙基)-4-哌啶胺类化合物，可方便地制备化合物4，从而可以方便地制备琥珀酸普卡必利，能够满足医药工业的需要。Adopt 4-N-substituted-1-(3-methoxypropyl)-4-piperidinamine compound of the present invention, can prepare compound 4 conveniently, thereby can prepare prucalopride succinate conveniently, can Meet the needs of the pharmaceutical industry.
具体实施方式detailed description
实施例1Example 1
4-N-叔丁氧羰基-1-(3-甲氧丙基)-4-哌啶胺(1-1)的制备Preparation of 4-N-tert-butoxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (1-1)
在1000ml反应瓶内加入4-Boc-氨基哌啶(30.04g，0.15mol)、1-溴-3-甲氧基丙烷(22.95g，0.15mol)、碳酸钾(20.73g，0.15mol)和乙腈(500ml)，回流反应5h，减压浓缩，加入水(200ml)搅拌，过滤，用水(100ml)洗涤滤饼，干燥后得类白色固体4-N-叔丁氧羰基-1-(3-甲氧丙基)-4-哌啶胺(39.11g，收率95.85％)，熔点72.5-73.5℃。Add 4-Boc-aminopiperidine (30.04g, 0.15mol), 1-bromo-3-methoxypropane (22.95g, 0.15mol), potassium carbonate (20.73g, 0.15mol) and acetonitrile in a 1000ml reaction flask (500ml), reflux for 5h, concentrate under reduced pressure, add water (200ml) and stir, filter, wash the filter cake with water (100ml), and dry to obtain off-white solid 4-N-tert-butoxycarbonyl-1-(3-methyl Oxypropyl)-4-piperidinamine (39.11 g, yield 95.85%), melting point 72.5-73.5°C.
MS(m/z)：273.22([M+H]+)MS (m/z): 273.22 ([M+H]+ )
1H-NMR(400MHz，DCCl3)δ：1.41(9H，s)，1.59(2H，m)，1.60-1.86(4H，m)，2.43-2.53(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)。1 H-NMR (400MHz, DCCl3 ) δ: 1.41 (9H, s), 1.59 (2H, m), 1.60-1.86 (4H, m), 2.43-2.53 (6H, m), 3.36 (3H, s) , 3.42(2H,t), 3.63(1H,m).
实施例2Example 2
1-(3-甲氧丙基)-4-哌啶胺(4)的制备Preparation of 1-(3-methoxypropyl)-4-piperidinamine (4)
4-N-叔丁氧羰基-1-(3-甲氧丙基)-4-哌啶胺(39.11g，0.144mol)、浓盐酸(250ml)和乙醇(500ml)加入至反应瓶内，室温反应3h，减压浓缩后加入NaOH(20g)的乙醇(200ml)溶液，浓缩后用加入二氯甲烷(200ml)，过滤，滤液浓缩得浅黄色油状物4(21.75g，收率87.9％)。4-N-tert-butoxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (39.11g, 0.144mol), concentrated hydrochloric acid (250ml) and ethanol (500ml) were added to the reaction flask, room temperature After reacting for 3h, NaOH (20g) in ethanol (200ml) was added after concentration under reduced pressure. After concentration, dichloromethane (200ml) was added, filtered, and the filtrate was concentrated to give light yellow oil 4 (21.75g, yield 87.9%).
MS(m/z)：173.18([M+H]+)MS (m/z): 173.18 ([M+H]+)
实施例3Example 3
4-N-苄氧羰基-1-(3-甲氧丙基)-4-哌啶胺(1-2)的制备Preparation of 4-N-benzyloxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (1-2)
4-Cbz-氨基哌啶(23.43g，0.1mol)、1-溴-3-甲氧基丙烷(15.30g，0.1mol)、碳酸钾(8.30g，0.1mol)和丙酮(250ml)加入至500ml反应瓶内，回流反应5h。减压浓缩后加入水搅拌，过滤，干燥得白色固体4-N-苄氧羰基-1-(3-甲氧丙基)-4-哌啶胺(24.97g，81.49％)。4-Cbz-aminopiperidine (23.43g, 0.1mol), 1-bromo-3-methoxypropane (15.30g, 0.1mol), potassium carbonate (8.30g, 0.1mol) and acetone (250ml) were added to 500ml In the reaction flask, reflux for 5h. Concentrate under reduced pressure, add water, stir, filter, and dry to give white solid 4-N-benzyloxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (24.97 g, 81.49%).
MS(m/z)：307.21([M+H]+)MS (m/z): 307.21 ([M+H]+)
1H-NMR(400MHz，DCCl3)δ：1.59(2H，m)，1.62-1.85(4H，m)，2.43-2.53(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)，5.16(2H，s)，7.30-7.51(5H，m)。1H-NMR (400MHz, DCCl3) δ: 1.59 (2H, m), 1.62-1.85 (4H, m), 2.43-2.53 (6H, m), 3.36 (3H, s), 3.42 (2H, t), 3.63 (1H, m), 5.16 (2H, s), 7.30-7.51 (5H, m).
实施例4Example 4
1-(3-甲氧丙基)-4-哌啶胺(4)的制备Preparation of 1-(3-methoxypropyl)-4-piperidinamine (4)
4-N-苄氧羰基-1-(3-甲氧丙基)-4-哌啶胺(24.97g，0.081mol)、40％HBr(120ml)和乙醇(300ml)加入至反应瓶内，回流反应7h，减压浓缩后加入NaOH(20g)的乙醇(200ml)溶液，浓缩后用加入二氯甲烷(100ml)，过滤，滤液浓缩得浅黄色油状物1-(3-甲氧丙基)-4-哌啶胺(8.82g，收率63.44％)。4-N-benzyloxycarbonyl-1-(3-methoxypropyl)-4-piperidinamine (24.97g, 0.081mol), 40% HBr (120ml) and ethanol (300ml) were added to the reaction flask, reflux Reacted for 7h, concentrated under reduced pressure, added NaOH (20g) in ethanol (200ml) solution, concentrated and added dichloromethane (100ml), filtered, and the filtrate was concentrated to give light yellow oil 1-(3-methoxypropyl)- 4-Piperidinamine (8.82 g, yield 63.44%).
MS(m/z)：173.18([M+H]+)MS (m/z): 173.18 ([M+H]+)
实施例5Example 5
4-N-乙酰基-1-(3-甲氧丙基)-4-哌啶胺(1-3)的制备Preparation of 4-N-acetyl-1-(3-methoxypropyl)-4-piperidinamine (1-3)
4-乙酰基氨基哌啶(2.13g，0.015mol)、1-溴-3-甲氧基丙烷(2.30g，0.015mol)、碳酸钠(1.25g，0.015mol)和乙腈(40ml)加入至100ml反应瓶内，回流反应6h。减压浓缩后加入水搅拌，过滤，干燥得白色固体4-N-乙酰基-1-(3-甲氧丙基)-4-哌啶胺(2.53g，78.82％)。4-acetylaminopiperidine (2.13g, 0.015mol), 1-bromo-3-methoxypropane (2.30g, 0.015mol), sodium carbonate (1.25g, 0.015mol) and acetonitrile (40ml) were added to 100ml In the reaction bottle, reflux for 6h. Concentrate under reduced pressure, add water, stir, filter, and dry to give white solid 4-N-acetyl-1-(3-methoxypropyl)-4-piperidinamine (2.53 g, 78.82%).
MS(m/z)：215.25([M+H]+)MS (m/z): 215.25 ([M+H]+)
1H-NMR(400MHz，DCCl3)δ：1.59(2H，m)，1.60-1.86(7H，m)，2.41-2.55(6H，m)，3.36(3H，s)，3.42(2H，t)，3.63(1H，m)。1H-NMR (400MHz, DCCl3) δ: 1.59 (2H, m), 1.60-1.86 (7H, m), 2.41-2.55 (6H, m), 3.36 (3H, s), 3.42 (2H, t), 3.63 (1H, m).
实施例6Example 6
1-(3-甲氧丙基)-4-哌啶胺(4)的制备Preparation of 1-(3-methoxypropyl)-4-piperidinamine (4)
4-N-乙酰基-1-(3-甲氧丙基)-4-哌啶胺(2.53g，0.018mol)、15％KOH(15g)和乙醇(15ml)加入至反应瓶内，回流反应3h。减压浓缩后加入二氯甲烷(30ml)，过滤，滤液浓缩得浅黄色油状物1-(3-甲氧丙基)-4-哌啶胺(1.73g，收率67.05％)。4-N-acetyl-1-(3-methoxypropyl)-4-piperidinamine (2.53g, 0.018mol), 15% KOH (15g) and ethanol (15ml) were added to the reaction flask, and the reaction 3h. After concentration under reduced pressure, dichloromethane (30ml) was added, filtered, and the filtrate was concentrated to give light yellow oil 1-(3-methoxypropyl)-4-piperidinamine (1.73g, yield 67.05%).
MS(m/z)：173.18([M+H]+)MS (m/z): 173.18 ([M+H]+)
实施例7Example 7
琥珀酸普卡必利的制备Preparation of prucalopride succinate
4-氨基-5氯-2，3-二氢苯并呋喃-7-甲酸(13.11g，0.061mol)和THF(125ml)加入至250ml反应瓶内，冰浴冷却下加入CDI(9.95g，0.061mol)，撤去冰浴室温反应1.25h后，将4(3.44g，0.002mol)加入至反应体系室温搅拌24h。补加CDI(0.69g，0.00426mol)搅拌1.25h后再补加4(0.74g，0.00430mol)，室温搅拌3h后回流反应3h，冷却后过滤，滤液浓缩，加入水(50ml)，过滤，干燥得类白色固体普卡必利11.11g。以乙醇(55ml)溶解普卡必利(11.11g)，加入琥珀酸(3.56g，0.03mol)的乙醇水(10/3.5，V/V)溶液(30ml)，搅拌过夜，过滤，干燥得白色固体琥珀酸普卡必利24.90g(收率83.55％)，熔点：195.6-196.5℃。4-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid (13.11g, 0.061mol) and THF (125ml) were added to a 250ml reaction flask, and CDI (9.95g, 0.061 mol), after removing the ice bath and reacting at room temperature for 1.25h, 4 (3.44g, 0.002mol) was added to the reaction system and stirred at room temperature for 24h. Add CDI (0.69g, 0.00426mol) and stir for 1.25h, then add 4 (0.74g, 0.00430mol), stir at room temperature for 3h, then reflux for 3h, filter after cooling, concentrate the filtrate, add water (50ml), filter and dry 11.11 g of off-white solid prucalopride was obtained. Dissolve prucalopride (11.11g) in ethanol (55ml), add succinic acid (3.56g, 0.03mol) in ethanol water (10/3.5, V/V) solution (30ml), stir overnight, filter, and dry to obtain white Solid prucalopride succinate 24.90 g (yield 83.55%), melting point: 195.6-196.5°C.
MS(m/z)：368.18([M+H-118]+)MS (m/z): 368.18 ([M+H-118]+)
1H-NMR(400MHz，DMSO-d6)δ：7.47(s，1H，Ar-H)，7.26(d，1H，NH)，5.78(s，2H，NH2)，4.73(t，2H，CH2)，3.75(m，1H，CH)，3.34(t，2H，CH2)，3.22(s，3H，CH3)，3.04(t，2H，CH2)，2.70(m，2H，CH2)，2.31(t，2H，CH2)，2.07(t，2H，CH2)，1.83(m，2H，CH2)，1.64(m，2H，CH2)，1.40～1.49(m，2H，CH2)。1H-NMR (400MHz, DMSO-d6) δ: 7.47 (s, 1H, Ar-H), 7.26 (d, 1H, NH), 5.78 (s, 2H, NH2), 4.73 (t, 2H, CH2), 3.75(m, 1H, CH), 3.34(t, 2H, CH2), 3.22(s, 3H, CH3), 3.04(t, 2H, CH2), 2.70(m, 2H, CH2), 2.31(t, 2H , CH2), 2.07 (t, 2H, CH2), 1.83 (m, 2H, CH2), 1.64 (m, 2H, CH2), 1.40~1.49 (m, 2H, CH2).
| Application Number | Priority Date | Filing Date | Title |
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| CN201110194953.2ACN102295594B (en) | 2011-07-12 | 2011-07-12 | 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications |
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| CN201110194953.2ACN102295594B (en) | 2011-07-12 | 2011-07-12 | 4-N-replaces-1-(3-methoxy-propyl)-4-piperidinamines compound and Synthesis and applications |
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