WO2016155473A1 - 一种mek激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法 - Google Patents

一种mek激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法 Download PDF

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WO2016155473A1
WO2016155473A1 PCT/CN2016/075853 CN2016075853W WO2016155473A1 WO 2016155473 A1 WO2016155473 A1 WO 2016155473A1 CN 2016075853 W CN2016075853 W CN 2016075853W WO 2016155473 A1 WO2016155473 A1 WO 2016155473A1
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fluoro
methyl
iodophenyl
dihydropyridine
carbonyl
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PCT/CN2016/075853
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English (en)
French (fr)
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武乖利
高晓晖
边林
贾君磊
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江苏恒瑞医药股份有限公司
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Priority to CA2978796A priority Critical patent/CA2978796A1/en
Priority to MX2017011392A priority patent/MX2017011392A/es
Priority to RU2017134709A priority patent/RU2704251C2/ru
Priority to EP16771228.0A priority patent/EP3275866B1/en
Priority to US15/559,516 priority patent/US10118911B2/en
Priority to CN201680001860.4A priority patent/CN106795116B/zh
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to AU2016239028A priority patent/AU2016239028B2/en
Priority to JP2017545735A priority patent/JP2018509407A/ja
Priority to BR112017018580-6A priority patent/BR112017018580A2/zh
Priority to KR1020177029896A priority patent/KR20170131506A/ko
Publication of WO2016155473A1 publication Critical patent/WO2016155473A1/zh
Priority to US16/125,896 priority patent/US20180370948A1/en

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

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  • the present invention relates to a p-toluenesulfonate of a MEK kinase inhibitor and a Form I crystal thereof, particularly 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-(6 p-Toluenesulfonate of -methylpyridin-3-yl)oxy)-6-carbonyl-1,6-dihydropyridine-3-carboxamide and its Form I crystal.
  • Melanoma is one of the most common malignant tumors in clinical practice, and it is also one of the fastest growing malignant tumors with an annual growth rate of 3-5%. There are 199627 cases of new cases of melanoma in the world, and 46327 cases of deaths. . Melanoma has a low incidence in China, but it has doubled in recent years. In 2000, the incidence rate was only 0.2/100,000. In 2005-2007, the incidence rate in China was about 1/100,000, and the annual incidence of new cases was about 20,000. Therefore, melanoma has become one of the diseases that seriously endanger the health of our people.
  • MEK kinase inhibitors have an excellent effect on "the king of cancer" - advanced melanoma. Therefore, MEK kinase inhibitors have become a popular anti-cancer target developed by major companies.
  • the applicant's PCT/CN2014/085976 provides a MEK kinase inhibitor of the formula: 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4 -((6-Methylpyridin-3-yl)oxy)-6-carbonyl-1,6-dihydropyridine-3-carboxamide, which has been found to have potent inhibitory activity against MEK kinase and is expected to be developed Become a new melanoma treatment and provide new treatment options for melanoma patients.
  • the present invention provides 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-carbonyl-1, 6-Dihydropyridine-3-carboxamide p-toluenesulfonate (as shown in formula (I)).
  • the compound of the formula (I) can be obtained from p-toluenesulfonic acid and 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl).
  • the reaction of oxy)-6-carbonyl-1,6-dihydropyridine-3-carboxamide is obtained.
  • a series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound represented by the formula (I) can be subjected to the specific crystallization conditions of the present invention.
  • a crystal form with good stability is obtained, which we call a type I crystal.
  • the DSC pattern of the type I crystal in the present application shows a melting endotherm peak near 237 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the present invention also provides the preparation of 2-((2-fluoro-4-iodophenyl)amino)-1-methyl-4-((6-methylpyridin-3-yl)oxy)-6-carbonyl-
  • a method of crystallizing Form I of 1,6-dihydropyridine-3-carboxamide p-toluenesulfonate comprises the following steps:
  • the organic solvent is preferably methanol, ethanol, isopropanol
  • the mixed solvent of the organic solvent and water is preferably methanol/water, ethanol/water, isopropanol/water, Acetonitrile / water, acetone / water, tetrahydrofuran / water.
  • the most preferred single solvent is isopropanol.
  • a preferred mixed solvent is acetone/water, and the ratio of the two is not particularly limited. In a preferred embodiment of the present invention, the volume ratio of the two is 9:1.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be heated and dissolved in a solvent, and then slowly cooled and crystallized. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
  • the crystals to be filtered are usually under a reduced pressure of about 30 to 100 ° C, preferably 40 °.
  • the effect of removing the recrystallization solvent can be attained by vacuum drying under heating at 60 °C.
  • the crystal form of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • the type I crystal of the compound of the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared It is used as a pharmaceutical active ingredient.
  • the type I crystal of the compound of the formula (I) prepared by the present invention has good stability under high temperature and high humidity conditions, and has good crystal form stability under conditions of grinding, pressure and heat, and can satisfy production.
  • the medicinal requirements for transport and storage, the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an X-ray powder diffraction pattern of a compound of the formula I form of the formula (I).
  • Fig. 2 is a DSC chart of the crystal of the type I compound of the formula (I).
  • 2-Fluoro-4-iodoaniline 1a (50.80 g, 214 mmol) was dissolved in 254 mL of chloroform, triethylamine (60 mL, 429 mmol) was added, and then cooled to 0 ° C, and N,N'-carbonyldiimidazole (69.50) was added. g, 429 mmol), the reaction was stirred for 15 minutes, allowed to warm to room temperature and stirred for 4 hours. The temperature was lowered to 0 ° C, 254 mL of aqueous ammonia was added, and the mixture was filtered.
  • reaction mixture was concentrated under reduced vacuolulululululululululululululu -8-Methyl-2,4,7-tricarbonyl-pyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate 1j (4.13 g, yellow solid), yield: 37.1%.
  • 6-Methyl-3-hydroxy-pyridine (26 mg, 0.24 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (12 mg, 0.30 mmol) was added, and the reaction was stirred for 2 hours, and 1-(2-fluoro-4-iodobenzene) was added.
  • 3-(4-methoxybenzyl)-8-methyl-2,4,7-tricarbonyl-pyrido[2,3-d]pyrimidin-5-yltrifluoromethanesulfonate 1j (136 mg, 0.20 mmol), the temperature was raised to 60 ° C, and the reaction was stirred for 1 hour.
  • the heating was stopped, stirring was continued for 12 to 14 hours, the reaction was stopped, and the filter cake was washed with isopropyl alcohol (100 g), and dried under reduced pressure at 40 to 45 ° C for 6 to 7 hours to obtain a solid 1.10 g, yield: 81.6%.
  • the X-ray diffraction spectrum of the crystal sample is shown in Fig. 1.
  • the crystals are at about 10.18 (8.68), 11.51 (7.68), 12.34 (7.17), 12.97 (6.82), 13.72 (6.45), 14.83 (5.97), 15.76 (5.62), 17.13 (5.17), 17.59 (5.04), 17.92.
  • Example 2 The sample of the type I crystalline product obtained in Example 2 was separately placed in an open position, and the stability of the sample under illumination, heating (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%) was examined. The sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.
  • the crystal of the compound type I represented by the formula (I) obtained by the method of the second embodiment is ground and added. Heat and tableting treatment, the results show that the crystal form is stable, detailed experimental data see Table 2 below.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

一种MEK激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法被公开。具体地，公开了2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(式(I)化合物)、其I型结晶及其制备方法。所得式(I)化合物的I型结晶具备良好的晶型稳定性和化学稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种MEK激酶抑制剂的对甲苯磺酸盐、其结晶形式及制备方法 技术领域
本发明涉及一种MEK激酶抑制剂的对甲苯磺酸盐及其I型结晶，特别是2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺的对甲苯磺酸盐及其I型结晶。
背景技术
黑色素瘤是临床上较为常见的恶性肿瘤之一，也是发病率增长最快的恶性肿瘤之一，年增长率为3-5％，全球每年黑色素瘤新发病例199627例，死亡例数为46327例。黑色素瘤在我国发病率较低，但近年来成倍增长，2000年发病率统计仅为0.2/10万，2005-2007年我国的发病率约1/10万，每年新发病例约2万人，因此，黑色素瘤已经成为严重危及我国人民健康的疾病之一。
目前我国对治疗这种疾病的药物研究尚处于初级阶段，同样作为黑色素瘤的治疗方案的药物威罗菲尼片(Vemurafenib)以及伊匹单抗(Ipilimumab，Ipilimumab是一种单克隆抗体)，这两个药物在起效的同时，也会引起其他的皮肤疾病如鳞状上皮细胞癌等，因此，寻找有效的治疗黑色素瘤的药物，具有十分重要的意义。
从临床反馈的结果看来，MEK激酶抑制剂对“癌中之王”——晚期黑色素瘤有优异的疗效。因此，MEK激酶抑制剂成为各大公司争相研发的一个热门的抗癌靶点。
本申请人的PCT/CN2014/085976提供了一种如下式所示的MEK激酶抑制剂，其化学名为2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺，已经发现该化合物对MEK激酶具有很强的抑制活性，有望开发成为新的黑色素瘤治疗药物，为黑色素瘤患者提供新的治疗选择。
Figure PCTCN2016075853-appb-000001
本领域技术人员知道，自由碱形式的化合物由于其特定的缺陷往往不能直接药用，多数药物需要提供其它形式的活性化合物来改进这些缺陷，将自由碱形式的化合物转化为其可药用盐即为一种常用的方法。另外，药用的活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。因此，改善上述产物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本发明提供了2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐(如式(I)所示)。
Figure PCTCN2016075853-appb-000002
式(I)所示化合物的可由对甲苯磺酸和2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺反应得到。
式(I)所示化合物相对于2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺来说，其溶解度和生物 利用度大大提高，更加适合药用。
式(I)所示化合物在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现式(I)所示化合物在本发明特定的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为I型结晶。本申请中的I型结晶的DSC图谱显示在237℃附近有熔融吸热峰，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在约10.18(8.68)，11.51(7.68)，12.34(7.17)，12.97(6.82)，13.72(6.45)，14.83(5.97)，15.76(5.62)，17.13(5.17)，17.59(5.04)，17.92(4.95)，18.50(4.79)，19.72(4.50)，20.03(4.43)，20.42(4.35)，21.04(4.22)，21.51(4.13)，21.88(4.06)，23.15(3.84)，24.14(3.68)，24.53(3.63)，24.77(3.59)，25.88(3.44)和26.37(3.38)附近有特征峰。
本发明还提供了制备2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐的I型结晶的方法。该方法包括如下步骤：
(1)将对甲苯磺酸和2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺，或者将任意晶型或无定型的式(I)所示化合物在有机溶剂或有机溶剂和水的混合溶剂中析晶，所述有机溶剂选自碳原子数小于等于3的醇类、酮类、腈类、醚类中的一种或几种；
(2)过滤结晶并洗涤，干燥。
在本发明优选的实施方案中，步骤(1)中，有机溶剂优选为甲醇，乙醇，异丙醇，有机溶剂和水的混合溶剂优选为甲醇/水，乙醇/水，异丙醇/水，乙腈/水，丙酮/水，四氢呋喃/水。
进一步地，最优选的单一溶剂为异丙醇。
在本发明的一个实施方案中，优选的混合溶剂为丙酮/水，二者比例没有特别限制，在本发明优选的实施方案中，二者体积比为9：1。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在溶剂中加热溶解后慢慢冷却析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。需特别说明的是，所滤取的结晶体通常在减压下，在30～100℃左右，优选40～ 60℃的加热条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X-衍射图谱测定，对得到的式(I)所示化合物结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)所示化合物I型结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
经研究表明，本发明制备的式(I)所示化合物I型结晶在高温、高湿的条件下稳定性良好，且在研磨、压力和受热等条件下，晶型稳定性良好，能够满足生产运输储存的药用要求，生产工艺稳定可重复可控，能够适应于工业化生产。
附图说明
图1是式(I)所示化合物I型结晶的X-射线粉末衍射图谱。
图2是式(I)所示化合物I型结晶的DSC谱图。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：Mettler Toledo DSC 1 Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱
仪器型号：Bruker D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40°
电压：40KV，电流：40mA
实施例1(2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺的制备)
Figure PCTCN2016075853-appb-000003
第一步
1-(2-氟-4-碘苯基)脲
将2-氟-4-碘苯胺1a(50.80g，214mmol)溶解于254mL三氯甲烷中，加入三乙胺(60mL，429mmol)，降温至0℃，加入N,N'-羰基二咪唑(69.50g，429mmol)，搅拌反应15分钟，升至室温，搅拌反应4小时。降温至0℃，加入254mL氨水，过滤，滤饼依次用水(50mL×2)，三氯甲烷(20mL×2)，乙酸乙酯洗涤(50mL×2)，烘干，得到粗品标题产物1-(2-氟-4-碘苯基)脲1b(53g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):281.0 [M+1]
第二步
2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺
将粗品1-(2-氟-4-碘苯基)脲1b(113g，404mmol)溶解于450mL N,N-二甲基甲酰胺中，加入2-氰基乙酸(41g，488mmol)，降温至0℃，加入甲磺酰氯(55.44g，484mmol)，升至室温，搅拌反应2小时。加入 780mL水和异丙醇(V:V＝1:2)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，乙酸乙酯洗涤(50mL)，烘干，得到粗品标题产物2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺1c(143g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):345.9[M-1]
第三步
6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮
将粗品2-氰基-N-((2-氟-4-碘苯基)氨基甲酰基)乙酰胺1c(156g，430mmol)溶解于628mL水中，加入2M氢氧化钠溶液(22.6mL，42mmol)，加热至85℃，搅拌反应1小时。冷却至0℃，滴加2M盐酸至反应液pH为3，加入300mL异丙醇，过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(100mL×3)，烘干，得到粗品标题产物6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮1d(128g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):348.0[M+1]
第四步
(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品6-氨基-1-(2-氟-4-碘苯基)嘧啶-2,4(1H,3H)-二酮1d(128g，368.80mmol)溶解于250mL N,N-二甲基甲酰胺中，加入N,N-二甲基甲酰胺二甲基缩醛(124mL，935mmol)，搅拌反应4.5小时。加入720mL水和异丙醇(V:V＝5:1)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(132g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):403.0[M+1]
第五步
(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒
将粗品(E)-N'-(3-(2-氟-4-碘苯基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1e(20g，50mmol)溶解于150mL N,N-二甲基甲酰 胺中，加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(22.4mL，150mmol)和4-甲氧基氯苄(14.1mL，104.30mmol)，升温至75℃，搅拌反应3小时。冷却至室温，加入675mL水和异丙醇(V:V＝2:1)的混合溶液，再搅拌1小时。过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1f(35g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):523.0[M+1]
第六步
1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮
将硼氢化钠(3.80g，100mmol)溶解于210mL乙醇和叔丁醇(V:V＝1:2)的混合溶液中，加入粗品(E)-N'-(3-(2-氟-4-碘苯基)-1-(4-甲氧基苄基)-2,6-二羰基-1,2,3,6-四氢嘧啶-4-基)-N,N-二甲基甲脒1f(35g，67mmol)，升温至65℃，搅拌反应1小时。冷却至0℃，加入175mL水，再加入140mL 10％柠檬酸，过滤，滤饼依次用水(200mL×2)，异丙醇洗涤(50mL×2)，烘干，得到粗品标题产物1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮1g(33g，白色固体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):482.0[M+1]
第七步
1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将粗品1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮1g(10.80g，22.44mmol)和丙二酸二乙酯(21.20g，157.09mmol)溶解于100mL苯醚中，升温至230℃，搅拌反应1小时。冷却至室温，反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1h(8.97g，橙黄色固体)，产率：72.9％。
MS m/z(ESI):550.0[M+1]
第八步
1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯
将1-(2-氟-4-碘苯基)-5-羟基-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1h(8.97g，16.33mmol)溶解于100mL二氯甲烷中，加入三乙胺(7.00g，65.32mmol)，冷却至0℃，再加入三氟甲基磺酸酐(9.21g，32.66mmol)，升至室温，搅拌反应3小时。反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系B纯化所得残余物，得到标题产物1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(4.13g，黄色固体)，产率：37.1％。
MS m/z(ESI):682.0[M+1]
第九步
5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮
将6-甲基-3-羟基-吡啶(26mg，0.24mmol)溶解于5mL四氢呋喃中，加入氢化钠(12mg，0.30mmol)，搅拌反应2小时，加入1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基-2,4,7-三羰基-吡啶并[2,3-d]嘧啶-5-基三氟甲磺酸酯1j(136mg，0.20mmol)，升温至60℃，搅拌反应1小时。反应液减压浓缩，得到粗品标题产物5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮31a(128mg，浅黄色液体)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):641.1[M+1]
第十步
4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品5-(6-甲基吡啶-3-基氧基)-1-(2-氟-4-碘苯基)-3-(4-甲氧基苄基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮1k128mg，0.20mmol)溶解于6mL四氢呋喃和水(V:V＝4:1)的混合溶液中，加入氢氧化锂(168mg，4mmol)，升温至40℃，搅拌反应1小时。加入50mL乙酸乙酯，有机相用1M氢氧化钠溶液洗涤(30mL×3)，无水硫酸钠干 燥，过滤，滤液减压浓缩，得到粗品标题产物4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺1l(123mg，棕色油状物)，产物不经纯化直接进行下一步反应。
MS m/z(ESI):615.0[M+1]
第十一步
4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺
将粗品4-(6-甲基吡啶-3-基氧基)-2-(2-氟-4-碘苯氨基)-N-(4-甲氧基苄基)-1-甲基-6-羰基-1,6-二氢吡啶-3-甲酰胺1l(123mg，0.20mmol)溶解于5mL苯甲醚中，加入氯化铝(133mg，1mmol)，升温至120℃，搅拌反应4小时。加入50mL乙酸乙酯和15mL水，有机相用水洗涤(25mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用制备分离法纯化所得残余物，得到标题产物2-(2-氟-4-碘苯氨基)-1-甲基-4-(6-甲基吡啶-3-基氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺1(30mg，浅棕色固体)，产率：30.3％。
MS m/z(ESI):495.0[M+1]
1H NMR(400MHz,DMSO-d6):δ9.78(s,1H),8.38-8.44(m,1H),7.57-7.75(m,4H),7.35-7.49(m,2H),6.65(t,1H),5.09(s,1H),3.15(s,3H),2.51(s,3H).
实施例2
将(1g，2.02mmol)2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺、对甲苯磺酸(0.39g，2.27mmol)和异丙醇(20.41g)加入反应瓶中，回流反应2～2.5h。停止加热，继续搅拌12～14h，停止反应，过滤，滤饼用异丙醇(100g)洗，40～45℃减压干燥6～7h，得固体1.10g，产率：81.6％。该结晶样品的X-射线衍射谱图见图1。该结晶在约10.18(8.68)，11.51(7.68)，12.34(7.17)，12.97(6.82)，13.72(6.45)，14.83(5.97)，15.76(5.62)，17.13(5.17)，17.59(5.04)，17.92(4.95)，18.50(4.79)，19.72(4.50)，20.03(4.43)，20.42(4.35)，21.04(4.22)，21.51(4.13)，21.88(4.06)，23.15(3.84)，24.14(3.68)，24.53(3.63)，24.77(3.59)，25.88(3.44) 和26.37(3.38)处有特征峰。DSC谱图见图2，在237℃附近有尖锐熔融吸热峰，我们定义为I晶型。
实施例3
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入28ml甲醇，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.30g，收率30.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例4
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到250ml单口瓶中，加入100ml乙醇，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.40g，收率40.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例5
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到25ml单口瓶中，加入6ml 95％甲醇，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.48g，收率48.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例6
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入24ml 95％乙醇，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.50g，收率50.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例7
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入18ml 90％异丙醇，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.48g，收率48.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例8
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入12ml 90％乙腈，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.46g，收率46.0％。其X-衍射 和DSC图谱经研究比对，确定产物为I晶型。
实施例9
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入28ml 95％四氢呋喃，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.70g，收率70.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例10
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入20ml 90％丙酮，加热溶解，再冷却至室温，搅拌析晶，抽滤，真空干燥，得到固体0.54g，收率54.0％。其X-衍射和DSC图谱经研究比对，确定产物为I晶型。
实施例11
取(1.0g，1.50mmol)式(I)所示化合物(按实施例2制备)加入到50ml单口瓶中，加入20ml 90％丙酮，加热回流溶清，冷却至室温，冷却过程中加入40ml丙酮，搅拌析晶。次日，抽滤，干燥得白色固体710mg，收率为71.0％。
实施例12
将实施例2所得的I型结晶产物样品分别敞口平摊放置，考察在光照，加热(40℃，60℃)，高湿(RH75％，RH90％)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度见表1。
表1.式(I)所示化合物I型结晶样品的稳定性
Figure PCTCN2016075853-appb-000004
稳定性考察结果表明，式(I)所示化合物I型结晶样品在敞口放置的条件下，经光照、高温和高湿条件下的稳定性比较发现，光照、高湿和高温对产品的质量影响不大，说明其具有较好的稳定性。
实施例13
将按实施例2方法制得的式(I)所示化合物I型结晶进行研磨、加 热及压片处理，研究结果表明晶型稳定，详细的实验数据参见下表2。
表2.式(I)所示化合物I晶型特殊稳定性研究
Figure PCTCN2016075853-appb-000005

Claims (7)

  1. 式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐，
    Figure PCTCN2016075853-appb-100001
  2. 根据权利要求1所述的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐的I型结晶，其特征在于：使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约10.18(8.68)，11.51(7.68)，12.34(7.17)，12.97(6.82)，13.72(6.45)，14.83(5.97)，15.76(5.62)，17.13(5.17)，17.59(5.04)，17.92(4.95)，18.50(4.79)，19.72(4.50)，20.03(4.43)，20.42(4.35)，21.04(4.22)，21.51(4.13)，21.88(4.06)，23.15(3.84)，24.14(3.68)，24.53(3.63)，24.77(3.59)，25.88(3.44)和26.37(3.38)附近有特征峰。
  3. 一种制备根据权利要求1所述的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐的方法，包括将对甲苯磺酸和2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺反应的步骤。
  4. 一种制备根据权利要求1所述的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲 酰胺对甲苯磺酸盐的I型结晶的方法，所述方法包括下述步骤：
    1)将对甲苯磺酸和2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺，或者将任意晶型或无定型的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐在有机溶剂或有机溶剂和水的混合溶剂中析晶，所述有机溶剂选自碳原子数小于等于3的醇类、酮类、腈类、醚类的一种或几种；
    2)过滤结晶并洗涤，干燥。
  5. 根据权利要求4所述的方法，其特征在于在步骤1)中所述的有机溶剂选自甲醇，乙醇，异丙醇的一种或几种；有机溶剂和水的混合溶剂选自甲醇/水，乙醇/水，异丙醇/水，乙腈/水，丙酮/水，四氢呋喃/水；优选单一溶剂为异丙醇，混合溶剂为丙酮/水。
  6. 一种药物组合物，其含有根据权利要求1所述的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐或其I型结晶以及药学上可接受的载体。
  7. 根据权利要求1所述的式(I)所示的2-((2-氟-4-碘苯基)氨基)-1-甲基-4-((6-甲基吡啶-3-基)氧基)-6-羰基-1,6-二氢吡啶-3-甲酰胺对甲苯磺酸盐、权利要求2所述的I型结晶或权利要求6所述的药物组合物在制备治疗与MEK激酶抑制剂有关的疾病的药物中的用途；所述疾病优选为肿瘤，更优选为黑色素瘤。
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