CN105968038A - Hydrochlorides of dipeptide compounds and preparation method thereof - Google Patents

Hydrochlorides of dipeptide compounds and preparation method thereof Download PDF

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CN105968038A
CN105968038A CN201610299415.2A CN201610299415A CN105968038A CN 105968038 A CN105968038 A CN 105968038A CN 201610299415 A CN201610299415 A CN 201610299415A CN 105968038 A CN105968038 A CN 105968038A
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compound
formula
optionally
solvent
organic solvent
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CN201610299415.2A
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王念
李涛
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湖北华世通生物医药科技有限公司
中美华世通生物医药科技(武汉)有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms

Abstract

The invention provides hydrochlorides of dipeptide compounds and a preparation method thereof. The method comprises the following steps: a first organic solvent is used for dissolving a compound shown in a formula 2; dissolving liquid of the compound shown in the formula 2 and a second organic solvent of hydrogen chloride are contacted, so that a first crude product of a compound shown in a formula 1 is obtained. The hydrochlorides of dipeptide compounds are precipitated from the solution by the method, and the product has the advantages of high purity, good properties and stability, and transport and long-time storage convenience.

Description

二肽类化合物的盐酸盐及其制备方法 Hydrochloride and a method of preparing a dipeptide compound

技术领域 FIELD

[0001] 本发明涉及化学合成领域,具体而言,本发明涉及一种二肽类化合物的盐酸盐及其制备方法。 [0001] The present invention relates to the field of chemical synthesis, in particular, the present invention relates to a process for preparing hydrochloride and dipeptide-based compound.

背景技术 Background technique

[0002] 近年来,二肽及其类似物在医药和生物行业中得到越来越多的应用,其需求量也逐年变大,然而目前所制备得到的产品纯度低,并且性状不是特别好,很容易吸潮,不稳定。 [0002] In recent years, dipeptide and the like more and more applications in the pharmaceutical and biotechnology industries, the demand increases year by year, but the low purity of the product is currently prepared, and is not particularly good traits, it is easy to absorb moisture and unstable. 为便于长时间放置和便于运输,技术人员通常选择制成盐酸盐,但大部分盐酸盐化合物表面容易吸附更多的盐酸,造成二肽或者多肽类氨基酸的等电点发生改变,从而无法从反应液中正常析出,故现有技术中并未见到固态的二肽类化合物盐酸盐产品。 To facilitate ease of transport and place a long time, the art typically selected hydrochloride formed, but most hydrochloride surface adsorb more readily hydrochloric acid, causing the isoelectric point of the dipeptide or polypeptide amino acid changes, which can not normally it precipitates from the reaction mixture, so that the prior art did not see the dipeptide hydrochloride salt of compound a solid product. 该技术问题也一直难以得到解决。 This technical problem has been difficult to solve.

[0003] 因此,目前制备二肽类化合物的盐酸盐的方法有待进一步改进。 [0003] Accordingly, current methods for preparing the hydrochloride salt of the dipeptide compound to be further improved.

发明内容 SUMMARY

[0004] 本发明旨在至少在一定程度上解决相关技术中的技术问题之一或至少提供一种有用的商业选择。 [0004] The present invention to solve at least to some extent, one of the technical issues related art or at least provide a useful commercial choice. 为此,本发明的一个目的在于提出一种式1所示二肽类化合物的盐酸盐及其制备方法,所得产品纯度高,且制备方法简单,成本低,适于工业化大生产。 To this end, an object of the present invention is to propose a method for preparing hydrochloride salts and high dipeptide of the formula 1 compounds resulting product purity, and the preparation method is simple, low cost and suitable for industrial production.

[0005] 在本发明的第一个方面,本发明提供了一种式1所示二肽类化合物盐酸盐。 [0005] In a first aspect of the present invention, the present invention provides a dipeptide hydrochloride salt of a compound of formula 1. 根据本发明的实施例,所述化合物为如下结构。 According to an embodiment of the present invention, the compound is the following structure.

Figure CN105968038AD00041

[0007] 发明人惊奇的发现,所制得的二肽类化合物盐酸盐便于从溶液中形成逼出,所得产品纯度高,性状和稳定性均很好,便于运输和长时间放置。 [0007] The inventors have surprisingly found that the resulting dipeptide compound facilitates the formation of the hydrochloride salt from the extract solution, the resulting high product purity, properties and stability are very good, easy to transport and place a long time.

[0008] 在本发明的第二方面,本发明提出了一种制备式1所示化合物的方法,所述方法包括: [0008] In a second aspect of the present invention, the present invention provides a method for preparing a compound of formula, in Figure 1, the method comprising:

[0009] (1)利用第一有机溶剂对式2所示化合物进行溶解; [0009] (1) was dissolved using an organic solvent a compound represented by formula 2 first;

[0010] (2)将式2所示化合物的溶液与氯化氢的第二有机溶剂接触,以便得到式1所示化合物的第一粗品。 [0010] (2) contacting the second organic solvent solution of hydrogen chloride with the compound represented by Formula 2, so as to obtain a first crude compound of formula 1 is shown in FIG.

Figure CN105968038AD00051

[0012] 在本文中所使用的术语"接触"应做广义理解,其可以是任何能使得至少两种反应物发生化学反应的方式,例如可以是将两种反应物在适当的条件下进行混合。 [0012] As used herein, the term "contacting" are to be broadly understood, which can be any manner such that at least two reactants of a chemical reaction, for example, two reactants may be mixed under appropriate conditions . 在本文中, "化合物N"在本文中有时也称为"式N所示化合物",在本文中N为1 一2的任意整数,例如"化合物2"在本文中也可以称为"式2所示化合物"。 As used herein, "Compound N," sometimes referred to herein as "the compound of formula N as shown in", herein N is an arbitrary integer of 2 1 a, for example "Compound 2" may also be referred to herein as "Formula 2 FIG compound. "

[0013] 在本发明的描述中,需要理解的是,术语"第一"、"第二"仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。 [0013] In the description of the present invention, it is to be understood that the terms "first", "second" are for illustrative purposes only, and not intended to indicate or imply relative importance or implicitly indicated technical features specified in quantity. 由此,限定有"第一"、"第二"的特征可以明示或者隐含地包括一个或者更多个该特征。 Thus, there is defined "first", "second" features may be explicitly or implicitly include one or more of the features. 在本发明的描述中, "多个"的含义是两个或两个以上,除非另有明确具体的限定。 In the description of the present invention, the meaning of the "plurality" is two or more, unless specifically defined otherwise specifically.

[0014] 根据本发明实施例的式1所示化合物的合成方法,还可以具有以下附加技术特征: [0014] The synthesis of compounds of the formula shown in Example 1 of the embodiment of the present invention, may also have the following additional features:

[0015] 根据本发明的实施例,步骤⑵中,在零下2摄氏度-12摄氏度下,将式2所示化合物与氯化氢的第二有机溶剂接触,优选为在5摄氏度-10摄氏度下;温度过低,反应进度很慢, 原料残留过大;温度过高,反应变杂,有杂质生成,特别是是化合物2结构式上的羟基会脱掉。 [0015] According to an embodiment of the present invention, the step ⑵, in the minus 2 degrees -12 degrees, the second organic solvent and hydrogen chloride compound represented by the formula 2 into contact, preferably under 5 -10 degrees Celsius; overtemperature low, the reaction was slow, too much residual feedstock; temperature is too high, the reaction becomes complicated, there is generation of impurities, particularly hydroxyl group on a compound of formula 2 will be off.

[0016] 根据本发明的具体实施例,步骤(2)中的接触的时间为3-4小时。 [0016] embodiment, the steps of the specific embodiment of the present invention, the contact time (2) is from 3-4 hours. 从动力学角度分析,反应进度与时间和反应底物的浓度有关系,接触时间低于3小时,原料残留过大,时间过长,影响反应的效率,通过多次试验发明人发现接触3-4小时最好。 From the kinetic point of view, with the progress of the reaction time and the concentration of the reaction substrate has a relationship, the contact time is less than three hours, starting material remained too big, too long, the influence of the reaction efficiency, the inventors have found through many experiments contacting 3- 4 hours is best.

[0017] 根据本发明的具体实施例,步骤⑵中,通过HPLC监测式2所示化合物,控制其小于2.0重量%时,停止反应。 When [0017] According to a particular embodiment of the present invention, ⑵ step, the compound represented by Formula 2 was monitored by HPLC, is less than 2.0 wt% the control, the reaction was stopped. 式2所示化合物残留过大,会导致反应收率偏低,而且反应不完的式2所示化合物在产品中属于一个已知杂质,很难除掉。 The residue compound of formula 2 is too large, the reaction will lead to low yield and incomplete reaction of the compound represented by Formula 2 in the product belongs to a known impurities difficult to remove.

[0018] 根据本发明的实施例,所述第一有机溶剂为选自二氯甲烷,二氧六环,四氢呋喃和2-甲基四氢呋喃中的至少一种,优选为二氯甲烷。 [0018] According to an embodiment of the present invention, the first organic solvent is selected from dichloromethane, dioxane, tetrahydrofuran and 2-methyltetrahydrofuran at least one, preferably methylene chloride. 第一有机溶剂主要是用作反应溶剂,且化合物2在二氯甲烷中的溶解度最好,有利于产品与氯化氢充分接触,从而有利于加快反应。 The first organic solvent is mainly used as a reaction solvent, and compound 2 is preferably a solubility in methylene chloride, facilitate full contact with the product hydrogen chloride, thereby facilitating accelerate the reaction.

[0019] 根据本发明的实施例,所述式2所示化合物与所述第一有机溶剂的重量比为1:4-1:10,优选为1:4;由此,有利于式2所示化合物原料充分溶解后,加快原料与氯化氢接触,使产品充分成盐,进而有利于得到二肽类化合物的盐酸盐产品,而不是产品的游离态。 [0019] According to an embodiment of the present invention, the compound of Formula 2 by weight of the first organic solvent ratio is 1: 4-1: 10, preferably from 1: 4; This is advantageous in Formula 2 after sufficiently dissolved starting material compound shown to accelerate the feed of hydrogen chloride into contact with the product fully salified, thereby facilitating the hydrochloride product obtained dipeptide compounds, in free form rather than a product.

[0020] 根据本发明的实施例,所述第二有机溶液为选自二氧六环溶液,乙酸乙酯溶液,甲醇溶液和异丙醇溶液中的至少一种,优选为二氧六环溶液。 [0020] According to an embodiment of the present invention, the second organic solution is selected from dioxane, ethyl acetate, methanol and isopropanol solution of at least one, preferably dioxane . 从而有利于得到纯度好收率高的产品。 Thus contributing to high yield and good purity of the product.

[0021] 根据本发明的实施例,所述式2所示化合物与所述氯化氢的第二有机溶剂的摩尔比为1:5-1:20,优选为1:6;由此,有利于式2所示化合物原料充分溶解后,加快原料与氯化氢接触,使产品充分成盐,进而有利于得到二肽类化合物的盐酸盐产品,而不是产品的游离〇 [0021] According to an embodiment of the present invention, the molar ratio of the formula compound with a second organic solvent to the hydrogen chloride is shown in FIG. 2 1: 5-1: 20, preferably from 1: 6; thus, in favor of formula 2 after sufficiently dissolved starting material compound, accelerate the feed hydrogen chloride into contact with the product fully salified, thereby facilitating the hydrochloride product obtained dipeptide compounds, rather than a free square product

[0022] 根据本发明的实施例,所述氯化氢的第二有机溶剂的浓度为2-4摩尔/升,优选为4 摩尔/升。 [0022] According to an embodiment of the present invention, the concentration of hydrogen chloride in the second organic solvent is 2 to 4 mol / l, preferably 4 moles / liter. 由此有利于式2所示化合物中Boc的脱落,因为酸浓度越大,保护基就越容易脱落, 反应就越快。 Thereby facilitating compound of the formula Boc shedding 2, since the greater the acid concentration the more easy to fall off the protective group, the faster the reaction.

[0023]根据本发明的实施例,上述实施例的制备式1所示化合物的方法进一步包括:(3) 将所述第一粗品与第三有机溶剂接触,使第一粗品以油状物的形式析出;(4)将所述油状物与第一混合溶剂接触,降温搅拌,并分离得到第二粗品。 [0023] According to an embodiment of the present invention, a process for preparing the compound of Formula 1 shown above embodiment further comprises: (3) The crude product of the first contact with the third organic solvent, so to form a first crude oil precipitation; (4) the oil was mixed with the first solvent contacting, cooling stirred, and separated to give a second crude product.

[0024]根据本发明的实施例,所述第三有机溶剂为选自甲基叔丁基醚,庚烷,己烷中的至少一种,优选为甲基叔丁基醚。 [0024] According to an embodiment of the present invention, the third organic solvent is selected from methyl tert-butyl ether, heptane, hexane, at least one, preferably methyl tert-butyl ether. 从而更容易使盐酸盐类物质从溶液中逼出。 Hydrochloride salt thus easier to extract the substance from the solution.

[0025]根据本发明的实施例,所述式2所示化合物与所述第三有机溶剂的重量比为1:15-1:25,优选为1:20。 [0025] According to an embodiment of the present invention, the compound of formula 2 and the third by weight of the organic solvent is from 1: 15-1: 25, preferably 1:20. 由此,有利于产品以油状物形式从溶液中充分析出,从而提高式1所示化合物的第二粗品的收率。 This is advantageous in the product as an oil sufficiently precipitate from the solution, thereby increasing the yield of the second crude compound of Formula 1.

[0026] 根据本发明的具体实施例,步骤(4)中,所述降温搅拌的温度为0-10摄氏度,优选为0-5摄氏度。 [0026] embodiment, the steps of the specific embodiment of the present invention (4), the cooling temperature is 0-10 ° C with stirring, preferably 0 to 5 degrees Celsius. 由于此处的粗品是油状物,温度过低,不利于油状物转化为固体;温度过高, 产品在溶剂中溶解,会降低粗品的收率。 Since crude oil is here the temperature is too low, unfavorable oil into a solid; temperature is too high, the product dissolved in a solvent, reduces the yield of crude product. 根据本发明的具体实施例,所述分离的方法为抽滤。 According to particular embodiments of the method of the present invention, the suction is isolated.

[0027] 根据本发明的实施例,所述第一混合溶剂为二氧六环和甲基叔丁基醚的混合溶剂;由此可以将油状物产品表面吸附的氯化氢充分溶解到二氧六环中,这样有利于使产品与氯化氢1:1结合,再通过甲基叔丁基醚将产品以固体形态分散在溶液中,从而有利于产品固体的形成,并且产品不容易吸潮。 [0027] According to an embodiment of the present invention, the first mixed solvent is a mixed solvent of dioxane and methyl tert-butyl ether; product whereby oil may be adsorbed on the surface of the hydrogen chloride dissolved in dioxane sufficiently , so that the beneficial product with hydrogen chloride 1: 1 binding, and then through a methyl tertiary butyl ether product in solid form dispersed in the solution, thereby facilitating the formation of a solid product, and the product is not readily absorb moisture.

[0028]根据本发明的实施例,所述式2所示化合物与所述第一混合溶剂的重量比为1:24。 [0028] According to an embodiment of the present invention, the compound of formula 2 with a mixed solvent weight ratio of the first 1:24.

[0029] 根据本发明的实施例,所述第一混合溶剂中二氧六环与甲基叔丁基醚的重量比为1:1。 [0029] According to an embodiment of the present invention, the first mixed solvent of dioxane and MTBE weight ratio of 1: 1. 甲基叔丁基醚是醚类溶剂,有利于盐酸盐类物质转化成固体,而二氧六环的作用是除掉产品表面的氯化氢,如果二氧六环比例降低,不利于除掉产品表面多余的氯化氢,相同的,如果甲基叔丁基醚过低,不利于产品以固体的形式析出。 MTBE is an ether solvent, beneficial substance into a solid hydrochloride salt, dioxane acting surface of the product is removed hydrogen chloride, dioxane proportionally reduced if not conducive to removal of the product surface excess hydrogen chloride, the same, if the MTBE is too low, unfavorable precipitation of the product as a solid.

[0030] 根据本发明的实施例,上述实施例的制备式1所示化合物的方法进一步包括:(5) 将所述第二粗品与第二混合溶剂接触,打浆搅拌,分离得到式1所示化合物的固体纯品。 [0030] The method further comprises preparing a compound of formula 1 in the embodiment of the present invention, the above-described embodiment: (5) the second crude product mixture with the second solvent contacting beating stirring was isolated Formula 1 pure solid compound.

[0031] 根据本发明的实施例,所述第二混合溶剂为四氢呋喃和庚烷的混合溶剂。 [0031] According to an embodiment of the present invention, the second mixed solvent is tetrahydrofuran and heptane mixed solvent. 由此可以有利于纯化除掉杂质,得到纯度大于99.5%的产品。 Whereby removal of impurities may facilitate purification, to obtain a product of purity greater than 99.5%.

[0032] 根据本发明的实施例,所述式2所示化合物与所述第二混合溶剂的重量比为1:16。 [0032] According to an embodiment of the present invention, the compound of formula 2 and the weight of the second mixed solvent 1:16.

[0033] 根据本发明的实施例,所述第二混合溶剂中四氢呋喃与庚烷的重量比为3:1;四氢呋喃为极性溶剂,有利于除掉极性大的杂质,而庚烷属于低极性溶剂即为反相溶剂,主要作用是让更多的产品从溶剂中析出,同样的道理,如果四氢呋喃的比例过低,可能起不到充分除掉杂质的效果,庚烷的比例过低,产品的收率会降低。 [0033] According to an embodiment of the present invention, the weight ratio of the second mixed solvent of tetrahydrofuran and heptane is 3: 1; tetrahydrofuran as a polar solvent facilitates the removal of a large polar impurities, and a low-heptane the solvent is the polar solvent inverted, the main role is to allow more product to precipitate from the solvent, the same token, if the proportion of tetrahydrofuran is too low, the effect may not achieve sufficient removal of impurities, the proportion of low heptane the yield of the product decreases.

[0034] 根据本发明的实施例,将所述第二粗品与第二混合溶剂接触方式为:将所述第二粗品中先加入四氢呋喃,搅拌30-60分钟,优选为30-40分钟,再加入庚烷,室温下打浆。 [0034] According to an embodiment of the present invention, the second solvent is mixed with a second crude contacting way: the second of tetrahydrofuran was added to the crude and stirred for 30-60 minutes, preferably 30-40 minutes, then heptane was added at room temperature beating.

[0035] 根据本发明的实施例,所述第二粗品与第二混合溶剂接触后,室温打浆,抽滤,干燥后得到式1所示化合物的固体纯品。 [0035] According to an embodiment of the present invention, after the second contacting the crude with a mixed solvent of a second, beating at room temperature, filtered off with suction, and dried to give the pure solid compound of formula 1 shown in FIG. 由此有利于得到纯度大于99.5%的产品。 Thereby facilitating to obtain a product of purity greater than 99.5%.

[0036] 根据本发明具体实施例的制备式1所示化合物的方法包括: [0036] According to a particular embodiment of the method of the present invention is the preparation of compounds of formula 1 comprises:

[0037] (1)于0~10°C下,将式2所示化合物在二氯甲烷中溶解完全后,控制温度在0~10 °(:下滴加氯化氢的二氧六环溶液,滴加完成后,开始保温反应3~4小时,HPLC监控式2所示化合物含量小于2.0%即为反应合格,待反应合格后,得到式1所示化合物的第一粗品溶液。 [0037] (1) at 0 ~ 10 ° C, the compound of formula 2 is dissolved in dichloromethane completely, controlling the temperature at 0 ~ 10 ° (: added dropwise a solution of hydrogen chloride in dioxane dropwise after the addition is complete, heat the reaction begins 3 to 4 hours, HPLC monitoring of formula 2 compound content of less than 2.0% that is shown passing the reaction, after passing of the reaction, to give a first crude solution of the compound of formula is shown in FIG.

[0038] (2)向第一粗品溶液中加入甲基叔丁基醚,产品以油状物形式从溶液中析出,倒出上层清液,加入二氧六环和甲基叔丁基醚溶剂,降温至〇~l〇°C,搅拌得到白色固体,抽滤, 得到式1所示化合物的第二粗品。 [0038] (2) methyl t-butyl ether was added to the first solution of the crude product as an oil precipitated from the solution, the supernatant was decanted, added to dioxane and methyl tert-butyl ether solvent, square cooled to ~ l〇 ° C, with stirring to give a white solid was suction filtered to give a second crude compound represented by formula 1.

[0039] (3)向所述第二粗品中加入四氢呋喃,室温下搅拌30~60分钟,然后加入庚烷溶剂,搅拌30分钟后,抽滤并干燥,以便得到式1所示化合物的固体纯品。 After [0039] (3) adding to the second crude tetrahydrofuran was stirred at room temperature for 30 to 60 minutes, then the heptane solvent was added, stirred for 30 minutes, filtered off with suction and dried, to obtain a compound of formula 1 in pure solid products.

[0040] 根据本发明的具体实施例,本发明合成式1所示化合物的方法包括以下步骤: [0040] According to a particular embodiment of the invention, the method of synthesizing Formula 1 compounds of the present invention comprises the steps of:

[0041] (1)式1粗品的合成:于0~10°C下,将化合物2溶解在溶剂中,原料溶清后,开始滴加氯化氢溶液,滴加完成后,搅拌反应3~4小时,HPLC监控原料小于2 %即为合格,反应合格后,加入甲基叔丁基醚,搅拌30分钟,将上层清液除掉,加入二氧六环和甲基叔丁基醚溶液, 搅拌,抽滤得到粗品。 [0041] Synthesis of (1) a crude product: at 0 ~ 10 ° C, the compound 2 dissolved in a solvent, raw materials after a clear solution, dropwise addition of a solution of hydrogen chloride, after completion of the dropwise addition, the reaction was stirred for 3 to 4 hours , HPLC monitoring is qualified raw materials less than 2%, after passing the reaction, methyl t-butyl ether was added, stirred for 30 minutes, the supernatant was removed, added to dioxane and methyl tert-butyl ether, stirred, filtration to obtain a crude product.

[0042]反应中原料化合物2与氯化氢溶液摩尔比为1:5-1:20,主要使产物能够充分成盐, 在反应合格后,原料化合物2与甲基叔丁基醚重量比为1:15-1:25,将产品以油状物形式从溶液中充分分离,提高粗品收率。 [0042] The reaction molar ratio of the starting compound 2 with hydrogen chloride solution is 1: 5-1: 20, mainly the product to fully salified, after passing the reaction, the starting compound with methyl t-butyl ether 2 weight ratio of 1: 15-1: 25, the product as an oil sufficiently separated from the solution, to increase the yield of crude product.

[0043]反应控制在-2~12摄氏度,温度高于12摄氏度,反应出现杂质,增加了产品后面纯化的难度,反应温度低于-2摄氏度,反应进行很缓慢,反应时间会加长,原料剩余多,不利于快速得到产品。 [0043] The reaction was controlled at -2 to 12 ° C, a temperature above 12 degrees Celsius, reactions of impurities, the purified product increases the difficulty of later, the reaction temperature is below -2 ° C, the reaction proceeds slowly, the reaction time will be longer, the remaining raw and more, is not conducive to quickly get the product.

[0044] (2)化合物1成品的纯化:在式1粗品中,于室温下加入四氢呋喃溶解澄清后,缓慢加入庚烷,搅拌30分钟,抽滤,干燥得到纯度大于99.5 %的产品。 [0044] Purification of Compound (2) the finished product 1: Formula 1 in the crude, clarified dissolved in tetrahydrofuran was added at room temperature, heptane was slowly added, stirred for 30 minutes, suction filtered, and dried to give the product purity greater than 99.5%.

[0045] 原料化合物2与四氢呋喃和庚烷的重量比为1:12:4,这样产品可以在四氢呋喃中充分溶清,加入庚烷量不能多,否则,产品析出后又会成油状物,不利于后面产品的抽滤。 [0045] The starting compound 12 in tetrahydrofuran and the weight ratio of heptane: 12: 4, so that the product can be sufficiently clear solution in tetrahydrofuran, heptane amount no more, otherwise, the precipitated product to an oil then will not conducive behind filtration products.

[0046] 发明人意外发现,利用该方法能够有效快速的合成式1所示结构的二肽类盐酸盐化合物,该方法通过对产品性状的了解,盐酸盐容易吸潮,大部分盐酸盐化合物表面容易吸附更多的盐酸,从而使二肽或者多肽类氨基酸等电点改变,从而无法从反应液中正常析出。 [0046] The inventors have unexpectedly found that, using this method can quickly dipeptide hydrochloride synthesized compound having a structure shown in Formula 1, the product of the process by understanding traits, hydrochloride easy to absorb moisture, most of the hydrochloric acid salts of the compounds more readily adsorbed hydrochloric surface, thereby changing the electrical point of amino acids of the dipeptide or polypeptide, which can not normally precipitates from the reaction mixture. 发明人通过用低极性溶剂将反应物从溶液中逼出,再用对应的氯化氢溶液的溶剂将油状物表面的氯化氢溶解,从而使氯化氢与产品1:1结合,在甲基叔丁基醚中析出得到粗品,粗品通过重结晶,纯化后得到纯度大于99.5 %的产品。 The reaction was conducted by the inventors with a low polar solvent from the extract solution, and then the solvent solution of hydrogen chloride in the hydrogen chloride corresponding to the surface of the oil was dissolved to product hydrogen chloride and 1: 1 binding, in methyl tert-butyl ether to give the crude product precipitated, the crude product by recrystallization, to give the product purity greater than 99.5%.

[0047] 本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。 Additional aspects and advantages of the [0047] present invention will be given in part in the description which follows, from the following description in part be apparent from, or learned by practice of the present invention.

附图说明 BRIEF DESCRIPTION

[0048]图1显示了根据本发明的实施例1,所得产品的HPLC色谱图; [0048] FIG. 1 shows the resulting HPLC chromatogram of the product according to one embodiment of the present invention;

[0049]图2显示了根据本发明的实施例2,所得产品的HPLC色谱图; [0049] Figure 2 shows the resulting HPLC chromatogram of the product according to embodiment 2 of the present invention;

[0050]图3显示了根据本发明的实施例3,所得产品的HPLC色谱图;以及[00511图4显示了根据本发明的实施例3,所得产品的H-NMR图。 [0050] Figure 3 shows 3, the resulting HPLC chromatogram of the product according to embodiments of the present invention; and [00511] Figure 4 shows 3, the resulting product H-NMR view of an embodiment of the present invention.

具体实施方式 Detailed ways

[0052]下面详细描述本发明的实施例。 [0052] The following detailed description of embodiments of the present invention. 下面描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。 The embodiments described below are exemplary only for explaining the present invention and should not be construed as limiting the present invention. 实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。 Technical literature or the art in accordance with the conditions described in the specific technique or conditions are not specified in the examples or in accordance with product instructions. 所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。 The reagents or equipment not specified by the manufacturer, are the conventional products available through the city.

[0053] 一般方法 [0053] General procedure

[0054] (1)化合物1粗品的合成 Synthesis of [0054] (1) 1 the crude compound

[0055]于0~10°C下,将化合物2溶解在二氯甲烷中,原料溶清后,开始滴加氯化氢二氧六环溶液,滴加完成后,搅拌反应3~4小时,HPLC监控原料小于2 %,即为合格,反应合格后,向反应液中加入甲基叔丁基醚,搅拌30分钟,将上层清液从反应瓶中倒掉,然后向反应瓶中加入二氧六环和甲基叔丁基醚溶液,搅拌,抽滤得到含有化合物1的粗品。 [0055] at 0 ~ 10 ° C, the compound 2 dissolved in methylene chloride, the raw clear solution, dropwise addition of a solution of hydrogen chloride in dioxane, after completion of the dropwise addition, the reaction was stirred for 3 to 4 hours, HPLC monitoring less than 2% starting material, is qualified, after passing the reaction, methyl t-butyl ether was added to the reaction mixture, stirred for 30 minutes, the supernatant drained from the reaction flask, then added to the reaction flask in dioxane and methyl tertiary butyl ether, stirred, filtered off with suction to give a crude product containing the compound.

[0056] (2)化合物1成品的纯化 Purification of the compounds [0056] (2) a finished product

[0057]将上述得到的化合物1粗品,加入四氢呋喃后,室温搅拌溶清,再加入缓慢加入庚烷,反应液变浑浊,搅拌30分钟,抽滤,干燥后的到纯度大于99.5 %产品。 [0057] The above crude compound obtained after addition of tetrahydrofuran, a clear solution was stirred at room temperature, then added to heptane was slowly added, the reaction solution became turbid, stirred for 30 minutes, suction filtered, and dried to a purity of greater than 99.5% product.

[0058] 化学反应方程式: [0058] The chemical reaction equation:

Figure CN105968038AD00081

[0060] 实施例1 [0060] Example 1

[00611 a、化合物1粗品溶液的合成 [00611 a, synthetic crude solution of Compound 1

[0062] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢二氧六环溶液150.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余0.07%,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g(5.7mo 1),0~5 °C搅拌30分钟,抽滤,得到粗品34.1 g,粗品纯度98.8 %,粗品收率95.7% A、式1成品的纯化 [0062] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° hydrogen chloride dioxane solution 150.0ml (0.6mol) C, dropwise addition of 4 mol / l, temperature controlled 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 0.07% starting material remaining, passing the reaction, the reaction solution was added MTBE 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes, then add methyl tert-butyl ether 504.0g (5.7mo 1), 0 ~ 5 ° C for 30 minutes, filtered off with suction, to give the crude product 34.1 g, 98.8% purity of the crude product was purified crude yield 95.7% a, formula 1 finished

[0063]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品30.3g,总收率85.1 %, HPLC纯度99.8 %,所得产品的液相色谱(HPLC)图见图1。 [0063] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 30.3 g of product, total yield 85.1%, HPLC purity 99.8%, the resulting product liquid chromatography (HPLC) shown in Figure 1.

[0064] 实施例2 [0064] Example 2

[0065] a、式1所示化合物粗品溶液的合成 Synthesis of [0065] a, a compound of formula 1 in solution of crude

[0066] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷420.0g (4.9mol ),常温搅拌溶解,待反应液溶解澄清后,降温到-2~5°C,开始滴加4摩尔/升的氯化氢二氧六环溶液125.0ml (0.5mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余1.8%,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g (5 • 7mo 1),0~5 °C搅拌30分钟,抽滤,得到粗品30 • 1 g,粗品纯度96 • 8 %,粗品收率84 • 2 %。 [0066] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 420.0g (4.9mol), stirred and dissolved at room temperature, the reaction until a clear solution after dissolution, cooled to -2 ~ 5 ° hydrogen chloride dioxane solution 125.0ml (0.5mol) C, dropwise addition of 4 mol / l, temperature controlled 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 1.8% starting material remaining, passing the reaction, the reaction solution was added MTBE 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes, then add methyl tert-butyl ether 504.0g (5 • 7mo 1), 0 ~ 5 ° C for 30 minutes, filtered off with suction to give crude product 30 • 1 g, crude product purity of 96 • 8%, crude yield 84 • 2%. [0067] b、化合物1成品的纯化 Purification of b [0067] A compound of the finished product

[0068]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品21.3g,总收率60.1 %, HPLC纯度99.5 %,所得产品的液相色谱(HPLC)图见图2。 [0068] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 21.3 g of product, total yield 60.1%, HPLC purity 99.5%, the resulting product liquid chromatography (HPLC) shown in Figure 2.

[0069] 实施例3 [0069] Example 3

[0070] a、式1所示化合物粗品溶液的合成 Synthesis of [0070] a, a compound of formula 1 in solution of crude

[0071] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加2摩尔/升氯化氢二氧六环溶液300.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余0.3%,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在5~10°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g(5.7mo 1),5~10 °C搅拌30分钟,抽滤,得到粗品32.1 g,粗品纯度98.0 %,粗品收率90.1%〇 [0071] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° C, dropwise addition of 2 mol / liter solution of hydrogen chloride in dioxane 300.0ml (0.6mol), to control the temperature of 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 0.3% starting material remaining, passing the reaction, the reaction mixture was added methyl tert-butyl ether 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) at 5 ~ 10 ° C, stirred for 10 minutes, then methyl t-butyl ether 504.0g (5.7mo 1), 5 ~ 10 ° C for 30 minutes, filtered off with suction, to give the crude product 32.1 g, crude product purity of 98.0%, 90.1% crude yield billion

[0072] b、化合物1成品的纯化 Purification of b [0072] A compound of the finished product

[0073]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol ),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品28.3g,总收率79.5%, HPLC纯度99.7 %,所得产品的液相色谱(HPLC)图见图3。 [0073] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 28.3g product, total yield 79.5%, HPLC purity 99.7%, the resulting product liquid chromatography (HPLC) shown in Figure 3.

[0074] 实施例4 [0074] Example 4

[0075] a、式1所示化合物粗品溶液的合成 Synthesis of [0075] a, a compound of formula 1 in solution of crude

[0076] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢二氧六环溶液500ml (2 . Omol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余〇.〇%,反应合格,向反应液中加入甲基叔丁基醚105(^(11.9111 〇1),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g (5 • 7mo 1),0~5 °C搅拌30分钟,抽滤,得到粗品30 • 1 g,粗品纯度98 • 3 %,粗品收率84 • 5 %。 [0077] b、化合物1成品的纯化 [0076] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° dioxane solution of hydrogen chloride in 500ml C, dropwise addition of 4 mol / l (2. Omol), controlling the temperature of 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 〇.〇% remaining starting material, passing the reaction, the reaction solution MTBE was added 105 (^ (11.9111 〇1), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes , methyl tert-butyl ether was added 504.0g (5 • 7mo 1), 0 ~ 5 ° C for 30 minutes, filtered off with suction to give crude product 30 • 1 g, crude product purity 98 • 3%, crude yield 84 • 5 %. [0077] b purified compound finished

[0078]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol ),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品27.6g,总收率77.5%, HPLC 纯度99.8%。 [0078] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 27.6 g of product, total yield 77.5%, HPLC purity 99.8%.

[0079] 实施例5 [0079] Example 5

[0080] a、式1所示化合物粗品溶液的合成 Synthesis of [0080] a, a compound of formula 1 in solution of crude

[0081 ] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢二氧六环溶液125.0ml (0.5mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余1.1 %,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g (5 • 7mol),0~5°C搅拌30分钟,抽滤,得到粗品32 • 8g,粗品纯度97 • 8%,粗品收率92 • 1 %。 [0081] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° hydrogen chloride dioxane solution 125.0ml (0.5mol) C, dropwise addition of 4 mol / l, temperature controlled 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 1.1% starting material remaining, passing the reaction, the reaction solution was added MTBE 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes, then add methyl tert-butyl ether 504.0g (5 • 7mol), 0 ~ 5 ° C for 30 minutes, filtered off with suction to give crude product 32 • 8g, crude product purity 97 • 8%, crude yield 92 • 1%. [0082] b、化合物1成品的纯化 Purification of b [0082] A compound of the finished product

[0083]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol ),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品29.3g,总收率82.3%, 册1(:纯度99.6%。 [0083] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 29.3 g of product, total yield 82.3%, Volume 1 (purity: 99.6%.

[0084] 实施例6 [0084] Example 6

[0085] a、式1所示化合物粗品溶液的合成 Synthesis of [0085] a, a compound of formula 1 in solution of crude

[0086] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢二氧六环溶液150.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余0.1 %,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g (5.7mol),0~5°C搅拌60分钟,抽滤,得到粗品33. lg,粗品纯度98.1 %,粗品收率92.9% [0087] b、化合物1成品的纯化 [0086] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° hydrogen chloride dioxane solution 150.0ml (0.6mol) C, dropwise addition of 4 mol / l, temperature controlled 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring of 0.1% remaining starting material, passing the reaction, the reaction solution was added MTBE 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes, then add methyl tert-butyl ether 504.0g (5.7mol), 0 ~ 5 ° C stirred for 60 minutes, suction filtered to give a crude product 33. lg, 98.1% purity crude, crude yield 92.9% [0087] purification B, a compound of the finished product

[0088]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品29.3g,总收率82.3%, HPLC纯度99.8% • [0088] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give the product 29.3g, overall yield of 82.3%, HPLC purity 99.8% •

[0089] 实施例7 [0089] Example 7

[0090] a、式1所示化合物粗品溶液的合成 Synthesis of [0090] a, a compound of formula 1 in solution of crude

[0091] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢乙酸乙酯溶液150.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余0.4%,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,在〇~5°C下加入二氧六环504.0g(5.7mol),搅拌10分钟,再加入甲基叔丁基醚504.0g (5 • 7mol),0~5°C搅拌30分钟,抽滤,得到粗品25 • 0g,粗品纯度92 • 3%,粗品收率70 • 2%。 [0091] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° hydrogen chloride in ethyl acetate solution 150.0ml C, dropwise addition of 4 mol / l (0.6 mol), controlling the temperature 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 0.4% starting material remaining, passing the reaction, the reaction mixture was added methyl tert-butyl ether 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, and dioxane was added 504.0g (5.7mol) square at ~ 5 ° C, stirred for 10 minutes, then methyl t-butyl ether 504.0g (5 • 7mol), 0 ~ 5 ° C for 30 minutes, filtered off with suction to give crude product 25 • 0g, crude product purity 92 • 3%, crude yield 70 • 2%. [0092] b、化合物1成品的纯化 Purification of b [0092] A compound of the finished product

[0093]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol ),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品20.3g,总收率57.0%, HPLC 纯度99.5%。 [0093] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 20.3 g of product, total yield 57.0%, HPLC purity 99.5%.

[0094] 实施例8 [0094] Example 8

[0095] a、式1所示化合物粗品溶液的合成 Synthesis of [0095] a, a compound of formula 1 in solution of crude

[0096] 向2000mL反应瓶中加入式I化合物42 • 0g(0 • lmol),二氯甲烷168 • 0g(2 • Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢甲醇溶液150.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余1.0%,反应合格,向反应液中加入甲基叔丁基醚840.0g (9.5mo 1),搅拌10分钟,将上层清液倒掉,在0~5 °C下加入二氧六环504.0〖(5.7111〇1),搅拌10分钟,再加入甲基叔丁基醚504.0〖(5.71]1〇1),0~5°〇搅拌30分钟,抽滤,得到粗品23.0g,粗品纯度93.5%,粗品收率64.6%。 [0096] 2000mL reaction flask was added to the compound of formula I 42 • 0g (0 • lmol), dichloromethane 168 • 0g (2 • Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° methanol solution of hydrogen chloride in 150.0ml C, dropwise addition of 4 mol / l (0.6 mol), controlling the temperature 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 1.0% starting material remaining, passing the reaction, the reaction solution was added to the methyl t butyl ether 840.0g (9.5mo 1), stirred for 10 minutes, the supernatant discarded, and dioxane were added 504.0 〖(5.7111〇1) at 0 ~ 5 ° C, stirred for 10 minutes, then methyl 504.0 〖t-butyl ether (5.71] 1〇1), 0 ~ 5 ° square stirred for 30 minutes suction filtration to give 23.0 g of crude product, the crude purity 93.5%, crude yield 64.6%.

[0097] b、化合物1成品的纯化 Purification of b [0097] A compound of the finished product

[0098]将上述得到的粗品,加入四氢呋喃504.0g(7. Omol ),室温搅拌溶清后,缓慢滴加庚烷168.0g(l.7mol),滴加完成后,搅拌30分钟,抽滤烘干,得到产品18.8g,总收率52.8%, HPLC 纯度99.6%。 [0098] The crude product obtained above, tetrahydrofuran 504.0g (7. Omol), After stirring at room temperature a clear solution was slowly added dropwise heptane 168.0g (l.7mol), after the completion of the dropwise addition, stirred for 30 minutes, filtered off with suction drying dryness to give 18.8 g of product, total yield 52.8%, HPLC purity 99.6%.

[0099]对比实施例1(通过其他后处理方式合成化合物1) [0099] Comparative Example 1 (post-treatment by another Synthesis of Compound 1)

[0100]化合物1产品的合成 Synthesis of Compound [0100] 1 Product

[0101] 向2000mL反应瓶中加入式2所示化合物42.0g(0. lmol),二氯甲烷168.0g (2.Omol),常温搅拌溶解,待反应液溶解澄清后,降温到5~10°C,开始滴加4摩尔/升的氯化氢二氧六环溶液150.0ml (0.6mol),控制温度5~10°C,搅拌3.0小时,HPLC监控原料剩余0.07%,反应合格,向反应液中加入甲基叔丁基醚840.0g(9.5mol),搅拌10分钟,将上层清液倒掉,得到油状物,将油状物通过减压浓缩得到白色固体吸附在瓶壁上,取样检测,纯度99.0%。 [0101] to a compound of formula 2000mL reaction flask was charged 42.0g FIG 2 (0. Lmol), dichloromethane 168.0g (2.Omol), dissolved with stirring at room temperature, the reaction until a clear solution after dissolution, cooled to 5 ~ 10 ° hydrogen chloride dioxane solution 150.0ml (0.6mol) C, dropwise addition of 4 mol / l, temperature controlled 5 ~ 10 ° C, stirred for 3.0 hours, HPLC monitoring 0.07% starting material remaining, passing the reaction, the reaction solution was added MTBE 840.0g (9.5mol), stirred for 10 minutes, the supernatant discarded, to give an oil, the oil by concentration under reduced pressure to give a white solid was adsorbed on the wall of the bottle, sample testing, purity 99.0% . 敞口放置3分钟后,瓶壁上的固体变粘稠,30分钟后,固体变成油状物。 After exposure for 3 minutes, and the solid on the sidewall becomes viscous after 30 minutes, solid to an oil. 检测纯度仅有93.5%,且产品不稳定,纯度特别容易降低。 The purity of only 93.5%, and product instability, especially the purity tends to decrease.

[0102] 对比实施例所得的固体产品是通过浓缩方式,将油状物直接除掉溶剂而得到的固体,并非从溶液中析出获得,该产品特别容易吸潮,变成油状物,不便纯化。 [0102] Comparative manner by concentrating the solvent was removed oil directly obtained in Example of solid product obtained solid was not precipitated from solution, the product is particularly easy to absorb moisture, becomes an oil, purified inconvenience. 此种方法制备得到的产品由于表面含有氯化氢,极其不稳定,只能密闭放置,十分不利于工业化大生产。 The resulting products prepared by this method due to surface containing hydrogen chloride, is extremely unstable, can only be placed in a sealed, is not conducive to industrial production.

[0103] 将对比实施例1与实施例5的产品于室温下敞口放置,检测结果如表1、表2所示。 [0103] The Comparative Example 1 and the product of Example 5 open left at room temperature, the detection results shown in Table 1, Table 2.

[0104]表1对比实施例1的终产品的稳定性考察结果 Stability results of comparison of the final product [0104] Table 1 Example 1

Figure CN105968038AD00111

[0106]表2本发明实施例5的终产品的稳定性考察结果 Results of the stability of the final product of Example 5 [0106] Table 2 of the present invention

Figure CN105968038AD00112

[0108] 通过稳定性对比数据可以看出,用本发明方法制备得到的产品稳定性明显高于不用第一混合溶剂处理的普通方法得到的产品,而且普通方法是将产品表面的有机溶剂浓缩拉干,得到白色固体,但是附在表面的氯化氢并没有离去,导致产品极容易吸潮,吸潮后的产品表面被盐酸覆盖,导致产品不稳定,而用本发明的方法不会出现这种问题,且操作简单,产品收率和纯度高,十分便于工业化生产。 [0108] As can be seen by comparison of the data stability, product stability obtained with the production method of the present invention is significantly higher than the conventional method without the first product mixture obtained solvent-treated, but common method is to concentrate the organic solvent pull the product surface dryness to give a white solid, but not attached to hydrogen and leaving the surface, resulting in the product very easy to absorb moisture, the moisture absorption product surface is covered with hydrochloric acid, resulting in product instability, but with the method of this invention does not appear simple questions, and the operation, high product yield and purity, very easy to industrial production.

[0109] 在本说明书的描述中,参考术语"一个实施例"、"一些实施例"、"示例"、"具体示例"、或"一些示例"等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。 [0109] In the description of the present specification, reference to the term "one embodiment," "some embodiments", "an example", "a specific example", or "some examples" means that a description of the exemplary embodiment or embodiments described a particular feature, structure, material, or characteristic is included in at least one embodiment of the present invention, embodiments or examples. 在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。 In the present specification, a schematic representation of the above terms must not be the same for the embodiment or exemplary embodiments. 而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。 Furthermore, the particular features, structures, materials, or characteristics described may be in any one or more embodiments or examples combined in suitable manner. 此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。 Furthermore, different embodiments or examples and embodiments or features of different exemplary embodiments without conflicting, those skilled in the art described in this specification can be combined and the combination thereof.

[0110] 尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 [0110] Although the above has been illustrated and described embodiments of the present invention, it is understood that the above embodiments are exemplary and are not to be construed as limiting the present invention, within the scope of the invention to those of ordinary skill in the art It may be variations of the above embodiments, modifications, alternatives, and modifications.

Claims (10)

1. 一种二肤类化合物的盐酸盐,其特征在于,所述化合物具有式1所示的结构, Hydrochloride A two skin-based compound, wherein the compound has the structure shown in Formula 1,
Figure CN105968038AC00021
2. -种制备式1所示化合物的方法,其特征在于,包括: (1) 利用第一有机溶剂对式2所示化合物进行溶解; (2) 将式2所示化合物的溶解液与氯化氨的第二有机溶剂接触,W便得到式1所示化合物的第一粗品 2. - Method species Formula 1 compound, comprising: (1) dissolving a compound of formula 2 using a first organic solvent; (2) the compound of formula with chlorine dissolved solution shown in Figure 2 contacting the second organic solvent is ammonia, W will give a first crude compound of formula 1
Figure CN105968038AC00022
3. 根据权利要求2所述的方法,其特征在于,进一步包括: (3) 将所述第一粗品与第Ξ有机溶剂接触,使所述第一粗品W油状物的形式析出; (4) 将所述油状物与第一混合溶剂接触,降溫揽拌,并分离得到第二粗品。 3. The method according to claim 2, characterized in that, further comprising: (3) the first crude Ξ contact with the first organic solvent, in the form of W the first oil precipitated crude product; (4) the oil was first contacted with a mixed solvent, mixed with olive cooling, and the crude product was isolated as the second.
4. 根据权利要求3所述的方法,其特征在于,进一步包括: (5) 将所述第二粗品与第二混合溶剂接触,打浆揽拌,并分离得到式1所示化合物的固体纯品。 4. The method according to claim 3, characterized in that, further comprising: (5) the second crude product mixture with the second solvent contacting, mixing olive beating, and the solid was isolated to give the compound of formula 1 pure .
5. 根据权利要求4所述的方法,其特征在于,所述第一有机溶剂为选自二氯甲烧,二氧六环,四氨巧喃和2-甲基四氨巧喃中的至少一种,优选为二氯甲烧; 任选地,所述第二有机溶剂为选自二氧六环溶液,乙酸乙醋溶液,甲醇溶液和异丙醇溶液中的至少一种,优选为二氧六环溶液. 任选地,所述第Ξ有机溶剂为选自甲基叔下基酸,庚烧,己烧中的至少一种,优选为甲基叔下基酸; 任选地,所述第一混合溶剂为二氧六环和甲基叔下基酸的混合溶剂; 任选地,所述第二混合溶剂为四氨巧喃和庚烧的混合溶剂。 5. The method as claimed in claim 4, wherein said first organic solvent is selected from methylene burning, dioxane, pyran tetraamine clever and 2-methyl-tetraamine furans least clever one, preferably methylene chloride is burned; optionally, the second organic solvent is selected from dioxane, acetic acid ethyl ester solution, methanol and isopropanol solution of at least one, preferably two oxygen was six rings optionally, the first organic solvent is selected from methyl Ξ t the acid, heptanoic burning, the burning has at least one, preferably a lower methyl t-acid; optionally, the mixing said first solvent is a mixed solvent of a tertiary acid in dioxane and methyl; optionally, the second solvent is a mixed solvent of a mixed tetraamine clever furans and heptane burning.
6. 根据权利要求2所述的方法,其特征在于,所述式2所示化合物与所述第一有机溶剂的重量比为(1:4)-( 1:10),优选为1:4; 任选地,所述式2所示化合物与所述氯化氨的第二有机溶剂的摩尔比为(1:5)-(1:20), 优选为1:6; 任选地,所述氯化氨的第二有机溶剂的浓度为2-4摩尔/升,优选为4摩尔/升。 6. The method according to claim 2, wherein the compound of Formula 2 with the weight ratio of the first organic solvent (1: 4) - (1:10), preferably from 1: 4 ; optionally, the molar ratio of the formula 2 compound and the second organic solvent is a chlorinated ammonia (1: 5) - (1:20), preferably from 1: 6; optionally, the said concentration of the second organic solvent is ammonium chloride is 2-4 mol / l, preferably 4 moles / liter.
7. 根据权利要求4所述的方法,其特征在于,所述式2所示化合物与所述第Ξ有机溶剂的重量比为(1:15)-(1:25),优选为1:20; 任选地,所述式2所示化合物与所述第一混合溶剂的重量比为1:24; 任选地,所述式2所示化合物与所述第二混合溶剂的重量比为1:16。 7. The method as claimed in claim 4, wherein the weight of the compound of Formula 2 with the first organic solvent Ξ ratio (1:15) - (1:25), preferably 1:20 ; optionally, the weight ratio of the compound of formula 2 with the first 1:24 mixed solvent; optionally, the weight ratio of the compound of formula with the second mixed solvent 2 shown in FIG. 1 : 16.
8. 根据权利要求5所述的方法,其特征在于,所述第一混合溶剂中二氧六环与甲基叔下基酸的重量比为1:1; 任选地,所述第二混合溶剂中四氨巧喃与庚烧的重量比为3:1; 任选地,将所述第二粗品与第二混合溶剂接触方式为:先向所述第二粗品中加入四氨巧喃,揽拌30-60分钟,优选为30-40分钟,再加入庚烧,室溫下打浆。 8. The method according to claim 5, wherein the weight ratio of the first mixed solvent of dioxane and methyl tert-lower acid is 1: 1; Optionally, the second mixing Qiao thiopyran tetraamine solvents and heptyl burning weight ratio of 3: 1; optionally, a second solvent is mixed with a second crude contacting way: Xianxiang said second crude product was added tetraamine clever furans, embrace mix 30-60 minutes, preferably 30-40 minutes, then add heptane burn, beating at room temperature.
9. 根据权利要求2所述的方法,其特征在于,步骤(2)中,将式2所示化合物的溶液与氯化氨的第二有机溶剂接触是在零下2摄氏度-12摄氏度下进行的,优选在5摄氏度-10摄氏度下进行; 任选地,步骤(2)中,所述接触的时间为3-4小时; 任选地,步骤(2)中,通过HPLC监测式2所示化合物,当式2所示化合物含量小于2.0重量%时,停止反应。 9. The method according to claim 2, wherein the step (2), the second contacting an organic solvent solution of the compound of formula with a chlorinating 2 ammonia is carried out at -12 ° C to minus 2 degrees , preferably carried out at 5 ° C -10 ° C; time, optionally, step (2), the contacting is 3-4 hours; optionally, step (2), the compound of formula monitored by HPLC 2 when the compounds of the formula 2 wt% content of less than 2.0, the reaction was stopped.
10. 根据权利要求3所述的方法,其特征在于,步骤(4)中,所述降溫揽拌的溫度为0-10 摄氏度,优选为0-5摄氏度; 任选地,步骤(4)中,所述分离的方式为抽滤; 任选地,步骤(5)中,将所述第二粗品与第二混合溶剂接触,室溫打浆并抽滤,干燥后得到式1所示化合物的固体纯品; 任选地,所述式1所示化合物的固体纯品的纯度大于99.5 %。 10. The method according to claim 3, wherein, in step (4), the temperature of cooling mix embrace 0-10 degrees, preferably 0-5 degrees; optionally, step (4) the separated suction way; optionally, step (5), the second contact with a second crude mixed solvent at room temperature and beating suction filtration and dried to obtain a solid compound represented by formula 1 pure; purity optionally, the solid pure compound of the formula 1 is greater than 99.5%.
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