WO2019128983A1 - 一种制备噁拉戈利中间体的方法及其组合物 - Google Patents

一种制备噁拉戈利中间体的方法及其组合物 Download PDF

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WO2019128983A1
WO2019128983A1 PCT/CN2018/123468 CN2018123468W WO2019128983A1 WO 2019128983 A1 WO2019128983 A1 WO 2019128983A1 CN 2018123468 W CN2018123468 W CN 2018123468W WO 2019128983 A1 WO2019128983 A1 WO 2019128983A1
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formula
compound
group
reaction
organic layer
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PCT/CN2018/123468
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English (en)
French (fr)
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苏虎
郭效文
梁玉坤
石凯强
杨锦涛
何康
陶安平
黄鲁宁
安建国
陈茜
顾虹
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浙江华海药业股份有限公司
上海科胜药物研发有限公司
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Priority to US16/957,685 priority Critical patent/US11365178B2/en
Priority to CN201880081586.5A priority patent/CN111511722B/zh
Priority to EP18895688.2A priority patent/EP3733650A4/en
Publication of WO2019128983A1 publication Critical patent/WO2019128983A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to the field of medicinal chemistry, and in particular to a method for preparing an intermediate of fasugoli and a composition thereof.
  • Endometriosis is a common and frequently-occurring disease in gynecology. It is a benign invasive disease common to women in reproductive stages and is one of the gynecological diseases. The prevalence of middle-aged women is about 15%; the age of onset is mostly between 30-49 years old. The incidence rate of women in reproductive period accounts for 70%-80% of infertility patients, which seriously affects women's physical and mental health, work and childbirth.
  • Elagolix is an oral active non-peptide gonadotropin releasing hormone receptor (GnRH) antagonist developed by AbbVie in collaboration with Neurocrine Biosciences Inc (NBIX) for the treatment of endometriosis.
  • GnRH gonadotropin releasing hormone receptor
  • the compound of formula IV is used as a key intermediate for the preparation of moxagolide, and there are few reports in the literature.
  • the route uses toxic and explosive diketene, which has a high production safety risk and is not suitable for industrial production.
  • the yield of the synthetic route is only 62%, and the yield of the route is only 57%.
  • the yield of the process is low, resulting in a large amount of waste of materials, resulting in an increase in cost, and the post-treatment requires overnight stirring, which has a long process time and is not suitable for industrialization. produce.
  • a large amount of impurities are found in the formula IV, and the impurities are difficult to purify.
  • the invention mainly relates to a preparation method of the intermediate of the intermediate of the moxagolide sodium.
  • a first aspect of the present invention relates to a process for the preparation of a compound of the formula IV, which comprises: subjecting a compound of the formula I and a compound of the formula II to an aminolysis reaction in a mixed solvent of an organic solvent and water, followed by acid catalysis Guanhuan preparation gives the compound of formula IV;
  • R is selected from a linear or branched C1-C4 substituent or a benzyl group.
  • the linear or branched C1-C4 substituent is an alkyl group or an alkenyl group; the alkyl group is preferably a methyl group, an ethyl group, an isopropyl group or a t-butyl group; and the alkenyl group is preferably an allyl group.
  • the organic solvent is an aprotic organic solvent; preferably, the aprotic organic solvent is selected from the group consisting of toluene, chlorobenzene, xylene, N,N-dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).
  • the organic solvent is toluene;
  • the volume ratio of the organic solvent to water is 1:0.001 to 2; more preferably 1:0.1 to 1.0;
  • the mass ratio of the compound of the formula I and the compound of the formula II is 1:0.66 to 4, more preferably 1:1.5 to 2.0;
  • the ratio of the mass of the compound of formula II to the volume of the mixed solvent is from 1:8 to 1:20 (g/ml).
  • the reaction temperature of the aminolysis reaction is 80 to 150 ° C, preferably 100 to 120 ° C;
  • the reaction temperature of the acid-catalyzed shutdown ring preparation is 40-150 ° C, preferably 60-120 ° C, the reaction time is 0.5-6 h, preferably 1-3 h;
  • the acid is p-toluenesulfonic acid, methanesulfonic acid, sodium dihydrogen phosphate, more preferably p-toluenesulfonic acid;
  • the mass ratio of the compound of the formula II to the acid is 1:0.5 to 1.5.
  • the III-imp impurity formed by the reaction can be reconverted into the starting materials I and II in the presence of water ( Instead of almost always converting into the formula IV-imp), the raw material can be further fully converted into the formula III and the formula IV, the formation of the impurity of the formula IV-imp is reduced, the utilization rate of the raw material is improved, and the yield is improved, and the yield is improved. Obvious; and the reaction solvent water and the organic solvent are easy to recover, and the treatment cost of the three wastes is reduced; the reaction condition is mild, and has the advantages of simple post-treatment, high yield, and easy industrialization.
  • the reaction mechanism is as follows:
  • a second aspect of the technical solution of the present invention relates to a composition
  • a composition comprising a compound of the formula IV in an amount of not less than 99.5%, in an amount of not more than 0.5% of the compound of the formula IV-imp, wherein the content is normalized by HPLC area Method determination.
  • the composition can be used to prepare high-purity moxaol; preferably, the compound of formula IV is prepared by the aforementioned method.
  • the technical scheme of the present invention avoids further generation of the impurity of the formula IV-imp after the formation of the formula III-imp, thereby reducing the presence of IV-imp impurities in the compound of the formula IV, not only improving the yield, but also
  • the invention solves the problem that the impurities are difficult to be purified, the post-processing is troublesome, the operation is simple, and the cost is reduced.
  • reaction solvent water and the organic solvent are easily recovered, and the reaction conditions are mild, and the post-treatment is simple, and the industrialization is easy.
  • the organic layer was concentrated, and the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the organic layer was concentrated, and the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the organic layer was concentrated, and the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the organic layer was concentrated, and the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the organic layer was concentrated, and the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • the organic layer was concentrated, the organic layer was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种噁拉戈利钠中间体(式IV)的制备方法，所述方法通过下面的路线制备，该方法操作简捷安全，收率良好，同时环境污染小，有很好的经济效应，适宜工业生产，其中R代表C1-4取代或不取代的苄基、烯丙基。

Description

一种制备噁拉戈利中间体的方法及其组合物 技术领域
本发明涉及药物化学领域，具体涉及一种制备噁拉戈利中间体的方法及其组合物。
技术背景
子宫内膜异位症是妇科的常见病、多发病，为生育期妇女常见的一种良性浸润性疾病，属妇科疑难病之一。中年妇女患病率约为15％；其发病年龄多在30－49岁之间。生育期妇女的发病率，约占不孕症患者的70％—80％，严重影响妇女的身心健康、工作及生育。噁拉戈利(elagolix)是由AbbVie与Neurocrine Biosciences Inc(NBIX)合作开发的一种口服活性非肽促性腺激素释放激素受体(GnRH)拮抗剂，用于治疗子宫内膜异位症。目前该药物已向美国FDA提交上市申请。其结构式如式I所示：
Figure PCTCN2018123468-appb-000001
式IV化合物作为制备噁拉戈利关键中间体，现有文献报道不多，
CN200480019502报道的合成路线一如下：
Figure PCTCN2018123468-appb-000002
该路线使用有毒且易爆的双乙烯酮，生产安全风险较高，不适合工业化生产。
WO 2009062087A1报道的合成路线如下：
Figure PCTCN2018123468-appb-000003
该合成路线收率只有62％，我们重复该路线收率只有57％，该过程收率偏低，造成物料大量浪费，导致成本升高，而且后处理需要过夜搅拌，工序时间长，不适合工业化生产。且在式IV中发现有大量杂质存在，该杂质纯化困难。
由此可见，开发一种新的噁拉戈利中间体的制备方法具有重要意义。
发明内容
为了克服现有技术中制备噁拉戈利中间体式IV化合物工艺使用有毒试剂、收率低、后处理麻烦等缺点，提出了本发明的技术方案。本发明主要涉及一种噁拉戈利钠中间体式IV的制备方法。
本发明技术方案的第一方面涉及一种式IV化合物的制备方法，该制备方法包括：将式I化合物和式II化合物在有机溶剂和水的混合溶剂中进行氨解反应，接着在酸催化下关环制备得到式IV化合物；
Figure PCTCN2018123468-appb-000004
其中R选自直链或支链的C1-C4取代基或苄基。
所述直链或支链的C1-C4的取代基为烷基或烯基；所述烷基优选甲基、乙基、异丙基或叔丁基；所述烯基优选烯丙基。
所述有机溶剂为非质子有机溶剂；优选所述的非质子有机溶剂选自甲苯、氯苯、二甲苯、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)的一种或几种；更优选地所述的有机溶剂为甲苯；
所述式IV化合物的制备方法具体为：
(1)将式I化合物、式II化合物、有机溶剂和水混合后进行回流反应，反应后将反应体系分层，保留有机层；
(2)向有机层中加入酸继续反应，反应结束后分离纯化得到式IV化合物。
优选地，所述的有机溶剂与水的体积比为1：0.001～2；更优选为1：0.1～1.0；
优选地，所述的式I化合物、式II化合物的质量比为1:0.66～4，更优选为1:1.5～2.0；
优选地，所述式II化合物的质量与所述混合溶剂的体积之比为1:8～1:20(g/ml)。
优选地，所述氨解反应的反应温度为80～150℃，优选为100-120℃；
优选地，所述酸催化下关环制备的反应温度为40～150℃，优选60～120℃，反应时间为0.5～6h，优选1～3h；
优选地，所述的酸为对甲苯磺酸、甲磺酸、磷酸二氢钠，更优选为对甲苯磺酸；
优选地，所述的式II化合物与酸的质量比为1:0.5～1.5。
经研究发现，按照现有文献WO 2009062087 A1的方法在式III化合物合成中采用甲苯做反应溶剂时，再进行酸化反应，会有大量的式IV-imp杂质生成，且该杂质跟式IV化合物的极性比较相近，需要多次结晶才能去除，但不能完全去除，后处理麻烦，且造成物料浪费。
我们经过多次试验发现在式III化合物合成中使用有机溶剂和水的混合溶剂做反应溶剂时，可以使反应生成的式III-imp杂质在水的存在下重新转化成原料式I和式II(而不是几乎都转化成式IV-imp)，进而使原料能够进一步的充分转化成式III和式IV，减少式IV-imp杂质生成，提高了原料利用率，进而提高了收率，收率提高明显；且 反应溶剂水与有机溶剂易于回收，减少物料三废处理成本；本反应条件温和，具有后处理简单，收率高，易于工业化等优点。该反应机理如下：
Figure PCTCN2018123468-appb-000005
本发明的技术方案的第二方面涉及一种组合物，包括含量不低于99.5％的式IV化合物，含量不高于0.5％式IV-imp化合物，其中所述含量均采用HPLC面积归一化法测定。该组合物可用于制备高纯度的噁拉戈利；优选地，所述式IV化合物由前述方法制备得到
Figure PCTCN2018123468-appb-000006
本发明的技术方案的有益效果：
1.本发明的技术方案相比现有技术，避免了式III-imp生成后进一步生成式IV-imp杂质，从而减少式IV化合物中IV-imp杂质的存在，不但提高了收率，而且也解决了杂质难以纯化，后处理麻烦的问题，操作简便，降低了成本。
2.本发明的技术方案中反应溶剂水与有机溶剂易于回收，且反应条件温和，具有后处理简单，易于工业化等优点。
具体实施方式
下面将结合实施例对本发明的实施方式做详细说明。本发明的实施方式包括但不局限于下述实施例，其不应当被视为对本发明保护范围的限制。
原料式II化合物的合成可参考现有技术CN100424078C，其全部内容通过引用并入本文。
检测式IV化合物和式IV-imp化合物含量的HPLC分析方法：
色谱柱：Waters Xbridge-phenyl 4.6*150mm 3.5μm
洗脱剂A：1.0mL全氟丁酸加入1L水中(％V/V)
洗脱剂B：MEOH:ACN＝1:1(％V/V)
梯度：
时间(min) 洗脱剂A 洗脱剂B
0.00 60 40
17 30 70
20 30 70
20.1 60 40
30 60 40
流速：1.0mL/min
运行时间：30min
样品体积：10μL
检测器：265nm
柱温：30℃
实施例1：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000007
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(100g)、乙酰乙酸叔丁酯(194.2g)、甲苯(1000ml)、纯化水(100ml)加入2L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(104g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(300ml)搅拌分层，保留上层有机层，浓缩有机层，异丙醇结晶，即得产物IV化合物104.9g，收率82％，有关物质见表一。 1H NMR(400MHz,CDCl 3)δ2.15(s,3H),5.37(s,2H),5.60(s,2H),7.23～7.56(m,3H),9.02(s,1H).MS(ESI)m/z 303.0([M+H] +)。
实施例2：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(30g)、乙酰乙酸叔丁酯(58.3g)、甲苯(300ml)、纯化水(50ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(31.2g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(90ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物31.1g，收率81％，MS(ESI)m/z303.0([M+H] +)。有关物质见表一。
实施例3：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸叔丁酯(94.1g)、甲苯(500ml)、纯化水(500ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层， 保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物60.9g，收率81％，MS(ESI)m/z303.0([M+H] +)。有关物质见表一。
实施例4：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸叔丁酯(94.1g)、氯苯(500ml)、纯化水(100ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物49.9g，收率78％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例5：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(25g)、乙酰乙酸叔丁酯(47g)、二甲苯(250ml)、纯化水(200ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(27g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(75ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物24.6g，收率77％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例6：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(30g)、乙酰乙酸叔丁酯(58.3g)、N,N-二甲基甲酰胺(300ml)，纯化水(300ml)加入1L烧瓶中搅拌120℃反应4h。体 系降温浓缩，向浓缩物中加入甲苯(300ml)、对甲苯磺酸一水合物(31g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(75ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物29.1g，收率76％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例7：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(30g)、乙酰乙酸叔丁酯(58.3g)、二甲基亚砜(300ml)、纯化水(150ml)加入1L烧瓶中搅拌120℃反应4h。体系降温加入对甲苯磺酸一水合物(31g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)，乙酸乙酯萃取，有机层盐水洗涤，无水硫酸钠干燥，过滤有机层，浓缩滤液，得到的产物用异丙醇结晶，即得产物IV化合物29.6g，收率77％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例8：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(25g)、乙酰乙酸叔丁酯(47g)、甲苯(250ml)、纯化水(150ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(27g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(75ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇重结晶，即得产物IV化合物31.1g，收率81％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例9：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000008
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸乙酯(63.9g)、甲苯(500ml)、纯化水(200ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物48.5g，收率77％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例10：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000009
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸甲酯(71.3g)、甲苯(500ml)、纯化水(150ml)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物49.0g，收率78％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例11：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000010
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸异丙酯(88.5g)、甲苯(500ml)、纯化水(4.5g)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物IV化合物49.2g，收率77％，MS(ESI)m/z303.0([M+H]+)。有关物质见表一。
实施例12：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000011
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(30g)、乙酰乙酸烯丙酯(52.4g)、甲苯(300ml)、纯化水(150ml)加入1L烧瓶中搅拌120℃反应4h。体系降温加入对甲苯磺酸一水合物(31g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)， 乙酸乙酯萃取，有机层盐水洗涤，无水硫酸钠干燥，过滤有机层，浓缩滤液，得到的产物用异丙醇结晶，即得产物IV化合物29.1g，收率76％，MS(ESI)m/z 303.0([M+H]+)。有关物质见表一。
实施例13：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
Figure PCTCN2018123468-appb-000012
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(50g)、乙酰乙酸苄酯(118g)、甲苯(500ml)、纯化水(4.5g)加入1L烧瓶中搅拌回流反应6h。将反应体系分层，保留上层有机层，向有机层中加入对甲苯磺酸一水合物(52g)搅拌，60℃反应2h，降至室温搅拌，加入纯化水(150ml)搅拌分层，保留上层有机层，浓缩有机层，得到的产物用异丙醇结晶，即得产物48.5g，收率76％，MS(ESI)m/z 303.0([M+H]+)。有关物质见表一。
上述实施例2-13中所制得的式IV化合物的 1H NMR数据与实施例1相同。
对比实施例1：
1-[2-氟-6-(三氟甲基)苄基]-6-甲基嘧啶-2,4(1H,3H)-二酮(式IV)的合成
将式II化合物1-[2-氟-6-(三氟甲基)]苄基尿素(2.568g)、甲苯(125ml)加入1L烧瓶中搅拌回流，加入乙酰乙酸叔丁酯(5.0g)回流反应4h。将对甲苯磺酸一水合物(2.82g)加入回流体系中继续反应1h，用异丙醇置换甲苯至体系30ml室温搅拌过夜， 过滤，滤饼用异丙醇洗涤，得产品式IV 1.81g，收率57％.MS(ESI)m/z 303.0([M+H]+)。有关物质见表一。
表一：实施例不同批次结果对比
Figure PCTCN2018123468-appb-000013
本发明提出的一种噁拉戈利中间体的制备方法已通过实施例进行了描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所述的噁拉戈利中间体的制备方法进行改动或适当变更与组合，来实现本发明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明的精神、范围和内容中。

Claims (13)

  1. 一种式IV化合物噁拉戈利中间体的制备方法，其特征在于，该制备方法包括：将式I化合物和式II化合物在有机溶剂和水的混合溶剂中进行氨解反应，接着在酸催化下关环制备得到式IV化合物
    Figure PCTCN2018123468-appb-100001
    其中R选自直链或支链的C1-C4取代基或苄基。
  2. 根据权利要求1所述的制备方法，其特征在于，所述直链或支链的C1-C4的取代基为烷基或烯基；所述烷基优选甲基、乙基、异丙基或叔丁基；所述烯基优选烯丙基。
  3. 根据权利要求1或2所述的制备方法，其特征在于所述的有机溶剂为非质子有机溶剂；优选自甲苯、氯苯、二甲苯、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)的一种或几种。
  4. 根据权利要求1-3中任意一项所述的制备方法，其特征在于，所述的有机溶剂为甲苯。
  5. 根据权利要求1-4中任意一项所述的制备方法，其特征在于，所述的有机溶剂与水的体积比为1：0.001～2，优选为1：0.1～1.0。
  6. 根据权利要求1-5中任意一项所述的制备方法，其特征在于，所述的式I化合物、式II化合物的质量为1:0.66～4，优选为1:1.5～2.0。
  7. 根据权利要求1-6中任意一项所述的制备方法，其特征在于，所述式II化合物的质量与所述混合溶剂的体积比为1:8～1:20，单位为g/ml。
  8. 根据权利要求1-7中任意一项所述的制备方法，其特征在于，所述氨解反应的反应温度为80～150℃，优选为100-120℃。
  9. 根据权利要求1-8中任意一项所述的制备方法，其特征在于，所述酸催化下关环制备式IV化合物的反应温度40～150℃，优选60～120℃。
  10. 根据权利要求1-9中任意一项所述的制备方法，其特征在于，所述的酸选自对甲苯磺酸、甲磺酸、磷酸氢二钠，优选为对甲苯磺酸。
  11. 根据权利要求1-10中任意一项所述的制备方法，其特征在于：所述的式II化合物与酸的质量比为1:0.5～1.5。
  12. 一种组合物，包括质量百分含量不低于99.5％的式IV化合物，及质量百分含量不高于0.5％的式IV-imp化合物
    Figure PCTCN2018123468-appb-100002
  13. 根据权利要求12所述的组合物，其特征在于，所述质量百分含量均采用HPLC面积归一化法测定。
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