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WO2017008684A1 - 化合物A的晶型α及其制备方法和含有该晶型的药物组合物 - Google Patents

化合物A的晶型α及其制备方法和含有该晶型的药物组合物 Download PDF

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WO2017008684A1
WO2017008684A1 PCT/CN2016/089239 CN2016089239W WO2017008684A1 WO 2017008684 A1 WO2017008684 A1 WO 2017008684A1 CN 2016089239 W CN2016089239 W CN 2016089239W WO 2017008684 A1 WO2017008684 A1 WO 2017008684A1
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compound
crystal form
water
stirring
ray diffraction
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谭颂德
张昌中
黄群辉
邓运
华怀杰
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Shenzhen Salubris Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of chemical drug preparation, and particularly relates to a crystal form ⁇ of a dipeptidyl peptidase-IV inhibitor compound A, a preparation method thereof, and a pharmaceutical composition containing the same.
  • Dipeptidyl peptidase IV is a serine protease that specifically hydrolyzes the Xaa-Pro or Xaa-Ala dipeptide of the N-terminus of a polypeptide or protein.
  • DPP-IV is an atypical serine protease with a Ser-Asp-His catalytic triad at the C-terminal region that differs from a typical serine protease in a reverse order.
  • DPP-IV has a variety of physiologically relevant substrates, such as inflammatory chemokines, regulated on activation normal T-cell expressed and secreted (RANTES), eosinophilic chemokines and macrophages.
  • RANTES normal T-cell expressed and secreted
  • eosinophilic chemokines and macrophages.
  • Cell-derived chemokines neuropeptides such as neuropeptide Y (NPY) and P5 substances, vasoactive peptides, incretins such as glucagon-like peptide-l (GLP-1) And glucose-dependent insulinotropic polypeptide (GIP).
  • GLP-1 glucagon-like peptide-l
  • GIP glucose-dependent insulinotropic polypeptide
  • DPP-IV inhibitors may be effective against diseases associated with DPP-IV activity, such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (IGT), and impaired fasting plasma Glucose (IFG). ), metabolic acidosis, ketosis, appetite regulation and obesity.
  • diseases associated with DPP-IV activity such as type 2 diabetes, diabetic dyslipidemia, impaired glucose tolerance (IGT), and impaired fasting plasma Glucose (IFG).
  • IGT impaired glucose tolerance
  • IGF impaired fasting plasma Glucose
  • DPP-IV inhibitor Alogliptin has a clinically good therapeutic effect on type 2 diabetes and is approved for marketing in the United States. Therefore, DPP-IV inhibitors are currently considered to be the new treatment route for the treatment of type 2 diabetes.
  • PCT/CN2010/080370 describes a series of DPP-IV inhibitors of new mother core structures.
  • compound A its chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-tri Pyrazin-4(5H)-yl)methyl)-4-fluorobenzonitrile (the product obtained by this prior art process is a yellow oil), molecular formula: C 17 H 19 FN 6 O, molecular weight: 342, chemical structural formula The following formula (I):
  • One of the objects of the present invention is to provide a stable crystalline form of a stable dipeptidyl peptidase-IV (DPP-IV) reversible competitive inhibitor Compound A.
  • DPP-IV dipeptidyl peptidase-IV
  • the crystal form ⁇ of the above-mentioned dipeptidyl peptidase-IV inhibitor compound A has a characteristic peak at 9.41° in an X-ray diffraction diagram at an angle of 2 ⁇ with an error of ⁇ 0.2°. Further, there are characteristic peaks at 15.66°, 16.33° and 22.68° with an error of ⁇ 0.2°.
  • the characteristic peak of the displacement is the strongest characteristic peak of the crystal X-ray, which can fully represent the crystal form.
  • Compound A is represented by an angle of 2 ⁇ in the X-ray diffraction diagram at 8.87°, 9.41°, 13.91°, 15.66°, 16.33°, 18.37°, 22.68°, 23.55°, 24.00°, 24.41°, and There is a characteristic peak at 24.92° with an error of ⁇ 0.2°. It should be noted that different samples of a particular crystal form have the same major XRPD peak, but small peaks in the powder pattern may vary.
  • the error of each 2 ⁇ angle is usually within ⁇ 0.2° (the meaning of each 2 ⁇ angle error is usually within ⁇ 0.2° refers to most characteristic peaks. If more than 80% of the characteristic peak errors are within this range, and occasionally there are a few minor characteristic peaks whose error exceeds the range, they should all be considered to belong to the same crystal form of the XRPD spectrum); moreover, the characteristics of the displacements
  • the peaks are medium intensity absorption peaks, while other weak absorption peaks may vary significantly due to experimental operational errors. Other absorption peaks are those that are not necessary for characterizing the crystal form.
  • the X-ray diffraction pattern of the crystal form ⁇ of the compound A is shown in Table 1 or Table 2, and the error is ⁇ 0.2°.
  • Fig. 1 the X-ray diffraction pattern of the crystal form ⁇ of the compound A is shown in Fig. 1 or Fig. 2 .
  • X-ray diffraction using Empyean X-ray diffractometer Cu target K ⁇ ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow
  • the slit is 7.5 mm, the step length is 0.02°, and the 2 ⁇ range is determined under the condition of 40s per step: 3°-50°.
  • the stability of the crystal form ⁇ of the compound A is high, and it has better stability with respect to the yellow oil obtained by PCT/CN2010/080370, and is more advantageous for the clinical application of the compound A, and sufficiently ensures the safety and effectiveness of the drug.
  • Another object of the present invention is to provide a process for preparing the crystal form ⁇ of the above compound A, which is simple in process and can be realized under normal temperature conditions.
  • the compound A can be prepared according to the method disclosed in PCT/CN2010/080370, and the specific synthesis route and main reaction conditions are as follows:
  • the preparation method of the crystal form ⁇ of the compound A includes the following steps:
  • step (2) taking the product of step (1), adding dichloromethane, stirring and dissolving, adding ice water, adjusting pH 9.0 to 10.0 with sodium carbonate/water solution, stirring, phase separation, collecting the lower dichloromethane layer, and dichlorochloric acid in the water layer.
  • the methane was extracted, and the methylene chloride layer was combined, washed with water, and then evaporated.
  • the crystallization step (3) is optimized, the oil is obtained in the step (2), methanol is added, stirred and dissolved, and the mixture is stirred, water is added dropwise, stirred until a large amount of solids are precipitated, water is continuously added dropwise, stirred, filtered, washed with water, and dried at room temperature under vacuum.
  • the crystallization step (3) takes 5 g of the oil of the step (2), 2.5 ml of methanol is added, and the mixture is stirred and dissolved. Under stirring, 5 ml of water is added dropwise, and the mixture is stirred until a large amount of solid is precipitated. Continue to drip 10-15 ml of water, stir for 3 hours, filter, wash 3 times with water, and dry at room temperature under vacuum to obtain about 4.1 to 4.3 g.
  • the yellow oil product of the prior art PCT/CN2010/080370 although having a good purity, is always difficult to obtain the crystal form of the compound A by various crystallization methods, and it is not easy to further prepare for use due to its physical form.
  • the invention adopts a large number of experiments, and obtains a yellow oil-like benzoate by synthesis, and a weak alkali to convert a new alkali oil, and optimizes the crystallization process to obtain the novel crystal form of the compound A for the first time, which is excellent. Purity and quality stability.
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned Compound A Form A or a crystalline form of the Compound A to be converted into a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the carrier comprises various medicinal excipients, packaging materials, delivery tools, etc., and is selected according to the needs of the preparation, for example, the auxiliary materials include a filler, a disintegrating agent, a binder, a lubricant, etc., and can be applied to oral, inhalation, non-gastrointestinal. Dosing or topical use; dosage forms include, but are not limited to, injections, solution preparations, tablets, capsules, granules and the like.
  • the pharmaceutical composition can be used for the preparation of a medicament for causing DPP-IV to cause a related disease, particularly type 2 diabetes.
  • the present invention has the following outstanding advantages and beneficial effects:
  • the crystal form ⁇ of the compound A of the present invention has a high purity and is a solid form having a stable quality, and is easier to arrange and use the pharmaceutical composition.
  • the crystal form ⁇ of the compound A of the present invention is obviously more stable than the yellow oil obtained by PCT/CN2010/080370, and is more favorable for ensuring the clinical efficacy and safe use of the compound A.
  • the method for preparing the crystal form ⁇ of the compound A of the invention is simple, rapid, and can be prepared under normal temperature conditions, and is more easily industrialized.
  • Example 1 is an X-ray diffraction pattern of the crystal form ⁇ of the compound A obtained in Example 2 of the present invention.
  • Example 2 is an X-ray diffraction pattern of the crystal form ⁇ of the compound A obtained in Example 3 of the present invention.
  • Compound A was prepared by the following synthetic route according to the procedures of Examples 2 and 3 of PCT/CN2010/080370:
  • Step D 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-thio-3,4-dihydro-1,2,4-triazin-5(2H)-one (5)
  • Step E 4-(2-Bromo-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (6)
  • the X-ray diffraction pattern of the crystal form ⁇ of the obtained Compound A is shown in Fig. 1 .
  • the specific characteristic absorption peaks are shown in Table 1 below, and the error is ⁇ 0.2°.
  • X-ray diffraction using Empyean X-ray diffractometer Cu target K ⁇ ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow
  • the slit is 7.5 mm, the step length is 0.02°, and the 2 ⁇ range is determined under the condition of 40s per step: 3°-50°.
  • the X-ray diffraction pattern of the crystal form ⁇ of the obtained Compound A is shown in Fig. 2 .
  • the specific characteristic absorption peaks are shown in Table 2 below, with an error of ⁇ 0.2°.
  • X-ray diffraction using Empyean X-ray diffractometer Cu target K ⁇ ray, voltage: 40.0kV, current: 40.0mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scattering narrow
  • the slit is 7.5 mm, the step length is 0.02°, and the 2 ⁇ range is determined under the condition of 40s per step: 3°-50°.
  • the crystal form has characteristic peaks at 15.66°, 16.33° and 22.68° with an error of ⁇ 0.2° and a relative absorption intensity of more than 20%, which can fully represent the crystal form.
  • Compound A is represented by an angle of 2 ⁇ in the X-ray diffraction diagram at 8.87°, 9.41°, 13.91°, 15.66°, 16.33°, 18.37°, 22.68°, 23.55°, 24.00°, 24.41°, and 24.92° has characteristic peaks with an error of ⁇ 0.2° and a relative absorption intensity greater than 10%, which can distinguish other material generations in more detail. Table crystal form.
  • the above materials were uniformly mixed according to a conventional method, and then divided into 1000 equal portions and filled into ordinary gelatin capsules to obtain 1000 capsules.

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Abstract

本发明属于化学药物制备领域，具体涉及一种二肽基肽酶-IV抑制剂化合物A的晶型α及其制备方法，以及含有该晶型的药物组合物。

Description

化合物A的晶型α及其制备方法和含有该晶型的药物组合物 技术领域
本发明属于化学药物制备领域，具体涉及一种二肽基肽酶-IV抑制剂化合物A的晶型α及其制备方法，以及含有该晶型的药物组合物。
背景技术
二肽基肽酶IV(Dipeptidyl peptidase IV，DPP-IV)是丝氨酸蛋白酶，能特异性水解多肽或蛋白质N末端的Xaa-Pro或Xaa-Ala二肽。DPP-IV是非典型丝氨酸蛋白酶，其C末端区域的Ser-Asp-His催化三联体与典型丝氨酸蛋白酶不同，为逆序排列。
DPP-IV有多种生理学相关底物，如炎症趋化因子类、正常T细胞表达和分泌因子(regulated on activation normal T-cell expressed and secreted，RANTES)、嗜酸细胞活化趋化因子和巨噬细胞衍生趋化因子、神经肽类如神经肽Y(neuropeptide Y，NPY)和P5物质、血管活性肽、肠降血糖素如胰高糖素样肽(glucagon-like peptide-l，GLP-1)和葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic polypeptide，GIP)。
抑制体内DPP-IV可使内源性GLP-1(7-36)水平上升，减少其拮抗物GLP-1(9-36)的生成。因此，DPP-IV抑制剂可能对与DPP-IV活性相关的疾病有效，例如2型糖尿病，糖尿病血脂异常，糖耐量降低(Impaired Glucose Tolerance,IGT)，空腹血糖受损(Impaired Fasting Plasma Glucose,IFG)，代谢性酸中毒，酮病，食欲调节和肥胖。
DPP-IV抑制剂阿格列汀(Alogliptin)在临床上对于2型糖尿病表现为良好的治疗效果，在美国获批上市。因此，DPP-IV抑制剂目前被认为是新的治疗2型糖尿病的治疗途径。
PCT/CN2010/080370描述了一系列的新母核结构的DPP-IV抑制剂。其中，包括化合物A，其化学名称为：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苄腈(采用该现有技术工艺获得产物为黄色油状物)，分子式：C17H19FN6O，分子量：342，化学结构式为下式(I)：
Figure PCTCN2016089239-appb-000001
为了改善该化合物的药用性质，对具有有利的稳定性性质研究可以有效地用于药物组合物中通过抑制DPP-IV而治疗病态的患者。
发明内容
本发明的目的之一在于提供一种稳定的二肽基肽酶-IV(Dipeptidyl peptidase-IV，DPP-IV)可逆的竞争性抑制剂化合物A的稳定晶型。
化合物A的化学名称为：(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苄腈，分子式：C17H19FN6O，分子量：342，化合物A的化学结构式为下式(I)，
Figure PCTCN2016089239-appb-000002
上述二肽基肽酶-IV抑制剂化合物A的晶型α在X射线衍射图中以2θ角表示在9.41°处有特征峰，误差为±0.2°。进一步在15.66°、16.33°和22.68°处有特征峰，误差为±0.2°。该位移的特征峰为该晶型X射线最强的特征峰，可以充分代表本晶型。
具体的更为详细的，化合物A在X射线衍射图中以2θ角表示在8.87°、9.41°、13.91°、15.66°、16.33°、18.37°、22.68°、23.55°、24.00°、24.41°和24.92°处有特征峰，误差为±0.2°。应注意：特定的晶型的不同样品具有同样的主要XRPD峰，但是在粉末图中的小峰可能有变化。此外，当由本领域普通技术人员，采 用相应方法得到的同晶型样品采用相同的仪器和检测方法进行检测时，各2θ角误差通常在±0.2°以内(各2θ角误差通常在±0.2°以内的含义指的是大部分特征峰，如超过80％以上的特征峰误差在此范围内，而偶然有个别少数的特征峰的误差超出该范围，均应认为属于相同晶型的XRPD谱图)；而且，所述各位移的特征峰为中等强度吸收峰，而其他弱吸收峰可能由于实验操作误差发生明显变化，对于本领域技术人员来说其他吸收峰均是表征本晶型时不必要的吸收峰。
具体地，所述化合物A的晶型α的X射线衍射图如表1或表2所示，误差为±0.2°。
更为具体地，所述化合物A的晶型α的X射线衍射图如附图1或附图2所示。
X射线衍射检测条件：
X射线衍射采用锐影(Empyrean)X射线衍射仪，在Cu靶Kα射线，电压：40.0kV，电流：40.0mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，步长0.02°，每步停留时间40s条件下测定2θ范围：3°-50°。
所述化合物A的晶型α的稳定性高，相对于PCT/CN2010/080370所获得黄色油状物具有更好的稳定性，更利于化合物A的临床应用，充分保证用药的安全性和有效性。
本发明的另一目的在于提供一种上述化合物A的晶型α的制备方法，该方法工艺简单，常温条件下即可实现。
其中，化合物A可根据PCT/CN2010/080370公开的方法制备，具体合成路线及主要的反应条件如下：
Figure PCTCN2016089239-appb-000003
化合物A的晶型α的制备方法包括以下步骤：
(1)、以甲醇或者甲醇和水的混合溶液作为溶剂，分别溶解苯甲酸和上述工艺获得化合物A，往化合物A的溶液中在特定温度下滴加等摩尔的苯甲酸溶液，滴加完毕后，在15～25℃搅拌10小时以上，然后再在0～10℃放置数小时，过滤，得固体产物；
(2)取步骤(1)产物加入二氯甲烷，搅拌溶解，加入冰水，用碳酸钠/水溶液调pH9.0～10.0，搅拌，分相，收集下层二氯甲烷层，水层用二氯甲烷提取，合并二氯甲烷层，用水洗涤，分相，收集二氯甲烷层，减压浓缩至干，得油状物。
进一步包括优化结晶步骤(3)，取步骤(2)油状物，加入甲醇，搅拌溶解，搅拌下，滴加水，搅拌至大量固体析出，继续滴加水，搅拌，过滤，用水洗涤，常温真空干燥。
具体地，优选结晶步骤(3)取步骤(2)油状物5g，加入甲醇2.5ml，搅拌溶解，搅拌下，滴加水5ml，搅拌至大量固体析出。继续滴加水10—15ml，搅拌3小时，过滤，用水洗涤3次，转常温真空干燥，得约4.1～4.3g。
现有技术PCT/CN2010/080370的黄色油状物产物，虽具有较好纯度，但始终难以通过多种结晶方法获得化合物A的晶型，由于其物理形态，不易于进一步制剂使用。本发明通过大量的实验，通过优化工艺先将合成获得黄色油状物转苯甲酸盐，弱碱下转新的碱油状物，再次优化结晶工艺才首次获得化合物A的新颖晶型，其具有优异的纯度和质量稳定性。
本发明的再一目的在于提供一种含有上述的化合物A晶型α的药物组合物或者使用所述化合物A的晶型α转为其药用盐，和一种以上药学上可接受的载体。
所述载体包括各种药用辅料，包材，传递工具等，根据制剂需要进行选择，例如辅料包括填充剂、崩解剂、粘合剂、润滑剂等，可以适用于口服、吸入、非肠胃给药或表面使用；剂型包括但不限于注射剂、溶液制剂、片剂、胶囊剂、颗粒剂等。
所述药物组合物可以用于制备DPP-IV引起相关疾病、特别是2型糖尿病的药物的应用。
本发明与现有技术相比具有如下突出的优点及有益效果：
1、本发明的化合物A的晶型α的纯度高，为质量稳定的固体形态，更易于药物组合物的配置和使用。
2、本发明的化合物A的晶型α相对于PCT/CN2010/080370所获得黄色油状物明显具有更好的稳定性，更利于保证化合物A的临床疗效和安全用药。
3、本发明制备化合物A的晶型α的方法简单、快捷、在常温条件下即可制备，更易于产业化生产。
附图说明
图1是本发明实施例2所得化合物A的晶型α的X射线衍射图谱
图2是本发明实施例3所得化合物A的晶型α的X射线衍射图谱
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但发明的实施方式不限于此。
实施例1 化合物A的制备
按照PCT/CN2010/080370说明书实施例2和3的方法，采用以下技术合成路线制备化合物A：
所得化合物A，1H-NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H).MS:m/z,343(100％,M+1)。
Figure PCTCN2016089239-appb-000004
具体制备步骤如下：
步骤A.1-溴-4-氟-2-(异硫氰酸甲基)苯(2)
向1-溴-2-(溴甲基)-4-氟苯(1,5.36g,20.0mmol)的DMF溶液(20mL)中，加入碘化钠(1.20g,8.00mmol)和硫氰酸钾(3.88g,40.0mmol)。该混合物在氮气氛围下加热到80℃反应12h后，冷却到室温，向其中加入100mL水，并用乙酸乙酯萃取(50mL×2)，合并有机层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得粗品，残余物用硅胶柱色谱纯化(洗脱剂：石油醚)得1-溴-4-氟-2-(异硫氰酸甲基)苯(2)。
步骤B.N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)
将水合肼(80％,2.22g,35.5mmol)的1,4-二氧六环溶液(20mL)冷却到0℃，向其中加入1-溴-4-氟-2-(异硫氰酸甲基)苯(2,3.16g,12.8mmol)的1,4-二氧六环溶液(5mL)。该混合物在室温搅拌2h，向其中加入100mL冰水，有固体析出，抽滤，水洗，五氧化二磷干燥过夜，得N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3)。MS:m/z,278(100％,M+1),280(100％),300(10％,M+23),302(10％)。
步骤C.甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)
向丙酮酸(352mg,4.00mmol)的甲醇溶液(15mL)中先后加入N-(2-溴-5-氟苯甲基)肼基硫代甲酰胺(3,1.112g,4.00mmol)，以及浓硫酸5滴，将该混合物加热到 回流7h，蒸除大部分溶剂，残余物用乙酸乙酯萃取(150mL)，有机层先后分别用水，饱和碳酸氢钠溶液，饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4)。MS:m/z,362(100％,M+1),364(100％),384(60％,M+23),386(60％)。
步骤D.4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5)
将由钠(273mg,11.88mmol)和干燥甲醇(30mL)新鲜制备的甲醇钠(0.4M)溶于甲醇30mL，向其中加入甲基2-(2-(2-溴-5-氟苯甲氨基硫代甲酰胺)肼基)丙酸酯(4,1.434g,3.96mmol)，将该混合物加热回流22h，蒸除大部分溶剂，残余物用水100mL稀释，用2N浓盐酸调节pH为1～2，乙酸乙酯萃取(50mL×2)，合并萃取层用饱和食盐水洗涤，无水硫酸钠干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20％～30％)，得4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5)，MS:m/z,330(65％,M+1),332(60％,M+23)。
步骤E.4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6)
将4-(2-溴-5-氟苯甲基)-6-甲基-3-硫代-3,4-二氢-1,2,4-三嗪-5(2H)-酮(5,914mg,2.77mmol)悬浮于乙醇15mL中，先后加入氢氧化钠(111mg,2.77mmol)和碘甲烷(787mg,5.54mmol)。将该混合物于室温搅拌10分钟得澄清黄色溶液，反应用水100mL稀释，乙酸乙酯萃取(30mL×2)，合并萃取层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩，残余物用硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20～25％)得4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6).1H NMR(400MHz,DMSO,ppm):δ7.73(m,1H),7.16(br,1H),7.05(d,1H),5.09(s,2H),2.56(s,3H),2.32(s,3H).MS:m/z,344(100％,M+1),346(100％)。
步骤F.(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三 嗪-3-基)哌啶-3-氨基甲酸酯(8)
将4-(2-溴-5-氟苯甲基)-6-甲基-3-(甲硫基)-1,2,4-三嗪-5(4H)-酮(6,180mg,0.523mmol)与(R)-叔丁基哌啶-3-氨基甲酸酯(7,208mg,1.04mmol)研磨5分钟，在氮气氛围下加热到135℃反应13h，反应混合物用硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝10～50％)得(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(8).MS:m/z,496(100％,M+1),498(100％)。
步骤G.(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三 嗪-3-基)哌啶-3-氨基甲酸酯(9)
向碳酸钠(53mg,0.50mmol)、醋酸钯(3mg,0.013mmol)和N-甲基吡咯烷酮0.5mL的混合物中加入异丙醇3滴和水2滴，该混合物室温搅拌5分钟，向其中加入(R)-叔丁基1-(4-(2-溴-5-氟苯甲基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(8,246mg,0.496mmol)的NMP溶液(1.0mL)，并加热到140℃，再加入K4[Fe(CN)6].3H2O(209mg,0.496mmol)，在140℃加热12h，冷却到室温，加入水10mL，乙酸乙酯萃取(20mL×2)，合并有机层用饱和食盐水洗涤，无水硫酸镁干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：乙酸乙酯/石油醚＝20～35％)得(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(9).MS:m/z,418(20％),443(100％,M+1),465(95％,M+23)。
步骤H.(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲 基)-4-氟苄腈(10，化合物A)
向(R)-叔丁基1-(4-(2-氰基-5-氟苄基)-6-甲基-5-氧代-4,5-二氢-1,2,4-三嗪-3-基)哌啶-3-氨基甲酸酯(9,37mg)的二氯甲烷溶液1mL，加入三氟醋酸0.5mL，室温搅拌1h，用饱和碳酸氢钠溶液中和，二氯甲烷萃取(10mL×3)，合并有机层用无水硫酸钠干燥，抽滤浓缩得粗品，经硅胶柱色谱纯化(洗脱剂：二氯甲烷/甲醇/氨水＝92:6:2)得(R)-2-((3-(3-氨基哌啶-1-基)-6-甲基-5-氧代-1,2,4-三嗪-4(5H)-基)甲基)-4-氟苄腈(10，黄色油状物)。
1H NMR(400MHz,DMSO,ppm):δ7.96(m,1H),7.36(br,1H),7.29(d,1H),5.23(s,2H),3.15(m,3H),2.72(m,2H),2.23(s,3H),1.78(d,1H),1.64(d,1H),1.47(m,1H),1.12(m,1H).MS:m/z,343(100％,M+1)。
实施例2 化合物A的晶型α的制备
(1)配置95％甲醇溶液：200mL烧杯中加入91.2mL甲醇，加入4.8mL水，搅拌均匀，备用。取2.14g苯甲酸，室温下加入10mL95％甲醇搅拌溶解，备用(苯甲酸的甲醇溶液)；向50mL反应瓶中加入前述方法获得的化合物A60g，用95％甲醇32mL搅拌溶解；使内温保持在15～25℃下滴加苯甲酸的甲 醇溶液，0.5～1h滴完；滴加完毕后，15～25℃左右搅拌16h，再在0～10℃左右放置6h，过滤，得固体产物。
(2)取步骤(1)产物30g，加入二氯甲烷150ml，搅拌溶解，加入冰水100ml，用碳酸钠/水溶液150ml，调pH9.0～10.0，搅拌5分钟，分相。收集下层二氯甲烷层，水层用50ml二氯甲烷提取，合并二氯甲烷层，用水100ml，洗涤，分相，收集二氯甲烷层。于30℃以下，减压浓缩至干，得油状物约22g。
(3)取油状物5g，加入甲醇2.5ml，搅拌溶解，搅拌下，滴加水5ml，搅拌至大量固体析出。继续滴加水10ml，搅拌3小时，过滤，用水洗涤3次，转常温真空干燥，得约4.1～4.3g化合物A晶型α。
所得化合物A的晶型α的X射线衍射图谱如图1所示。具体的特征吸收峰如下表1，误差为±0.2°。
表1化合物A的晶型α的X射线衍射吸收峰数据
Figure PCTCN2016089239-appb-000005
其中，No.＝序号，Rel.Int.＝Relative Intensity，Pos.[。2Th.]＝Position[。2Theta]，误差为±0.2°。Rel.Int.＝Relative Intensity只是表示特征峰强度的大致强度情况，不应作为具体晶型的限定。
X射线衍射检测条件：
X射线衍射采用锐影(Empyrean)X射线衍射仪，在Cu靶Kα射线，电压：40.0kV，电流：40.0mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，步长0.02°，每步停留时间40s条件下测定2θ范围：3°-50°。
实施例3 化合物A的晶型α的制备
(1)配置95％甲醇溶液：200mL烧杯中加入91.2mL甲醇，加入4.8mL水，搅拌均匀，备用。取2.14g苯甲酸，室温下加入10mL95％甲醇搅拌溶解，备用(苯甲酸的甲醇溶液)；向50mL反应瓶中加入前述方法获得的化合物A60g，用95％甲醇32mL搅拌溶解；使内温保持在15～25℃下滴加苯甲酸的甲醇溶液，0.5～1h滴完；滴加完毕后，15～25℃左右搅拌16h，再在0～10℃左右放置6h，过滤，得固体产物。
(2)取步骤(1)产物30g，加入二氯甲烷150ml，搅拌溶解，加入冰水100ml，用碳酸钠/水溶液150ml，调pH9.0～10.0，搅拌5分钟，分相。收集下层二氯甲烷层，水层用50ml二氯甲烷提取，合并二氯甲烷层，用水100ml，洗涤，分相，收集二氯甲烷层。于30℃以下，减压浓缩至干，得油状物约22g。
(3)取油状物5g，加入甲醇2.5ml，搅拌溶解，搅拌下，滴加水5ml，搅拌至大量固体析出。继续滴加水15ml，搅拌3小时，过滤，用水洗涤3次，转常温真空干燥，得约4.1～4.3g化合物A晶型α。
所得化合物A的晶型α的X射线衍射图谱如图2所示。具体的特征吸收峰如下表2，误差为±0.2°。
表2化合物A的晶型α的X射线衍射吸收峰数据
Figure PCTCN2016089239-appb-000006
Figure PCTCN2016089239-appb-000007
其中，No.＝序号，Rel.Int.＝Relative Intensity，Pos.[。2Th.]＝Position[。2Theta]，误差为±0.2°。Rel.Int.＝Relative Intensity只是表示特征峰强度的大致强度情况，不应作为具体晶型的限定。
X射线衍射检测条件：
X射线衍射采用锐影(Empyrean)X射线衍射仪，在Cu靶Kα射线，电压：40.0kV，电流：40.0mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，步长0.02°，每步停留时间40s条件下测定2θ范围：3°-50°。
总结：根据图1和2的XRD谱图和特征峰数据，以2θ角表示在9.41°±0.2°处有最强的特征吸收峰，误差为±0.2°，可以明显代表本晶型。
进一步所述晶型还在15.66°、16.33°和22.68°处有特征峰，误差为±0.2°，相对吸收强度大于20％，可以充分代表本晶型。
具体的更为详细的，化合物A在X射线衍射图中以2θ角表示在8.87°、9.41°、13.91°、15.66°、16.33°、18.37°、22.68°、23.55°、24.00°、24.41°和24.92°有特征峰，误差为±0.2°，相对吸收强度大于10％，可以更为详细的区分其他物质代 表本晶型。
而其他弱吸收峰可能由于实验操作误差发生明显变化，对于本领域技术人员来说其他吸收峰均是表征本晶型时可以认为不必要的吸收峰。
实施例4 稳定性对比实验
根据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》的指导，以实施例2和3得到的化合物A的晶型α和PCT/CN2010/080370公开方法制备得到的黄色油状物在同等条件下进行影响因素高湿实验，保存数日后，实验方法和结果如下：
高湿实验
依据《中国药典》2010版第二部附录XIXC《原料药于药物制剂的稳定性试验指导原则》，精密称取实施例1的化合物A(黄色油状物)、实施例2和3得到的化合物A的晶型α各5份，每份100mg，置于容器中，裸露在相对湿度为92.5％，温度为25±2℃的环境中。分别于0、1、2、13天后取样测定，结果见表3。
表3高湿实验结果(25℃±2℃，RH92.5％)
样品相对含量(％) 0天 1天 2天 13天
化合物A(黄色油状物) 100.00％ 96.776％ 96.712％ 96.707％
实施例2化合物A(晶型α) 100.00％ 98.554％ 98.308％ 98.160％
实施例3化合物A(晶型α) 100.00％ 98.552％ 98.306％ 98.159％
通过上述结果可以看出：实施例2和3所得化合物A的晶型α在25℃±2℃，RH92.5％条件下放置1、2和13天后其相对含量相对于现有技术获得化合物A黄色油状物具有明显更好的稳定性。
纯度检测方法参照《中国药典》2010版第二部附录VD的高效液相色谱法，仪器：Agilent高效液相色谱仪，C18色谱柱，5μm，流速：1mL/min，检测波长：229nm，流动相：0.1％的磷酸-乙腈：水＝3：7。
实施例5 药物组合物的制备
化合物A(晶型α)     6.78g
糊精                84.00g
按常规方法，将上述物质混合均匀后，分1000等份分别装入普通明胶胶囊，得到1000颗胶囊。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种化合物A的晶型α，所述化合物A化学结构式为下式(I)，
    Figure PCTCN2016089239-appb-100001
  2. 如权利要求1所述的化合物A的晶型α，其特征在于：所述化合物A的晶型α在X射线衍射图中以2θ角表示在9.41°处有特征峰，误差为±0.2°。
  3. 如权利要求1所述的化合物A的晶型α，其特征在于：所述化合物A的晶型α在X射线衍射图中以2θ角表示在9.41°、15.66°、16.33°和22.68°处有特征峰，误差为±0.2°。
  4. 如权利要求1所述的化合物A的晶型α，其特征在于：所述化合物A的晶型α在X射线衍射图中以2θ角表示在8.87°、9.41°、13.91°、15.66°、16.33°、18.37°、22.68°、23.55°、24.00°、24.41°和24.92°处有特征峰，误差为±0.2°。
  5. 如权利要求1所述的化合物A的晶型α，其特征在于：所述化合物A的晶型α的X射线衍射图如表1或表2所示，误差为±0.2°。
  6. 如权利要求1所述的化合物A的晶型α，其特征在于：所述化合物A的晶型α的X射线衍射图如附图1或图2所示。
  7. 一种如权利要求1～6任意一项所述的化合物A的晶型α的制备方法，其特征在于，包括如下步骤：
    (1)、以甲醇或者甲醇和水的混合溶液作为溶剂，分别溶解苯甲酸和上述工艺获得化合物A，往化合物A的溶液中在特定温度下滴加等摩尔的苯甲酸溶液，滴加完毕后，在15～25℃搅拌10小时以上，然后再在0～10℃放置数小时，过滤，得固体产物；
    (2)取步骤(1)产物加入二氯甲烷，搅拌溶解，加入冰水，用碳酸钠/水溶液调pH9.0～10.0，搅拌，分相，收集下层二氯甲烷层，水层用二氯甲烷提取，合并二氯甲烷层，用水洗涤，分相，收集二氯甲烷层，减压浓缩至干，得油状物。
    进一步包括优化结晶步骤(3)：取步骤(2)油状物，加入甲醇，搅拌溶 解，搅拌下，滴加水，搅拌至大量固体析出，继续滴加水，搅拌，过滤，用水洗涤，常温真空干燥。
  8. 一种如权利要求7所述的化合物A的晶型α的制备方法，其特征在于，所述结晶步骤(3)包括，取步骤(2)油状物5g，加入甲醇2.5ml，搅拌溶解，搅拌下，滴加水5ml，搅拌至大量固体析出。继续滴加水10—15ml，搅拌3小时，过滤，用水洗涤3次，转常温真空干燥。
  9. 一种药物组合物，其特征在于：所述药物组合物中含有如权利要求1～8任意一项所述的化合物A的晶型α或者使用所述化合物A的晶型α转为其药用盐，和一种以上药学可接受的载体。
  10. 一种药物用途，其特征在于：权利要求9所述的一种药物组合物在制备用于预防或治疗糖尿病药物的应用。
PCT/CN2016/089239 2015-07-15 2016-07-07 化合物A的晶型α及其制备方法和含有该晶型的药物组合物 Ceased WO2017008684A1 (zh)

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