WO2020125581A1 - 一种类酰胺类衍生物及其中间体的制备方法 - Google Patents

一种类酰胺类衍生物及其中间体的制备方法 Download PDF

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WO2020125581A1
WO2020125581A1 PCT/CN2019/125644 CN2019125644W WO2020125581A1 WO 2020125581 A1 WO2020125581 A1 WO 2020125581A1 CN 2019125644 W CN2019125644 W CN 2019125644W WO 2020125581 A1 WO2020125581 A1 WO 2020125581A1
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formula
compound represented
preparation
organic solvent
compound
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窦飞
靖鹏
许向阳
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江苏恩华药业股份有限公司
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Priority to CN201980083057.3A priority Critical patent/CN113195454B/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • the invention relates to a preparation method of amide-like derivatives and intermediates thereof.
  • Schizophrenia is the most serious and most harmful disease of all mental diseases, with a global incidence rate of about 1-2%.
  • the lifetime prevalence of patients with schizophrenia is 0.7 to 0.8%, and there is no obvious correlation with gender, race, or social boundaries, and the mortality rate is 2 to 3 times higher than that of the general population.
  • the latest research shows that the social burden of mental illness ranks first in China's disease, surpassing cardiovascular and cerebrovascular diseases, respiratory system and malignant tumors.
  • Patent WO2017084627A discloses a compound that acts on dopamine D 2 , 5-HT 1A and 5-HT 2A receptors and its preparation method, and has good anti-neurological activity.
  • the compound structure is as follows:
  • the preparation method disclosed in this patent has many defects such as high toxicity of reaction materials, long reaction time, high impurity content, low purity, difficulty in industrial scale production, serious environmental pollution and so on. Therefore, the present invention provides a new Synthetic ideas and routes, the entire process greatly reduces the reaction time, avoids harsh reaction conditions, and the process is strong in operability, which is beneficial to industrial production needs and reduces environmental protection pressure; in addition, due to changes in reaction conditions, it can reduce the generation of impurities and reduce the final product. Purification difficulty and cost.
  • the invention provides a method for preparing the compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V),
  • X 1 is selected from fluorine or chlorine, and n is selected from any integer between 1 and 3.
  • the present invention provides a method for preparing a compound represented by formula V, which includes the following steps: in the presence of a catalyst, a basic substance, and an organic solvent, a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • a catalyst in the presence of a catalyst, a basic substance, and an organic solvent, a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • a compound represented by formula IV reacts with a compound represented by formula (1) to obtain the formula V
  • n is selected from any integer between 1 and 3; the catalyst is selected from onium salt phase transfer catalysts; and the basic substance is selected from carbonate.
  • n 1 or 2.
  • the onium salt phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (TEBA), trioctylammonium chloride (TCMAC ) Or cetyltrimethylammonium bromide (CTMAB), preferably TEBA.
  • TBAB tetrabutylammonium bromide
  • TEBA benzyltriethylammonium chloride
  • TCMAC trioctylammonium chloride
  • CTMAB cetyltrimethylammonium bromide
  • the carbonate is selected from sodium carbonate or potassium carbonate, preferably potassium carbonate.
  • the organic solvent is selected from nitriles or ketones.
  • the nitrile is preferably acetonitrile
  • the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one, or hex-3 -Ketone, preferably acetone.
  • the molar ratio of the compound represented by formula IV to the compound represented by formula (2) may be 1:1 to 1:4, preferably 1:2 or 1:3; the molar ratio of the compound of formula IV to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the formula IV
  • the molar ratio of the compound to the catalyst is selected from 50:1 to 20:1, preferably 35:1 to 25:1. Further, the catalyst is selected from TEBA.
  • the reaction time for preparing the compound represented by formula V from the compound represented by formula IV and the compound represented by formula (1) is selected from 4 to 7 hours, It is preferably 6 hours; the reaction temperature is selected from 50 to 80°C, preferably 50 to 70°C.
  • the compound represented by formula (1) is preferably:
  • the present invention further provides a method for preparing a compound represented by formula VI, comprising the steps of: reacting a compound represented by formula V with a compound represented by formula (2) in the presence of a catalyst, a carbonate, and an organic solvent, The compound of formula VI is thus prepared;
  • X 1 is selected from fluorine or chlorine, preferably fluorine; n is 1 or 2, preferably 1, and the compound represented by formula (2) may also be selected from salts formed with acids, such as hydrochloride.
  • the catalyst is selected from elemental iodine, potassium iodide or sodium iodide, preferably sodium iodide;
  • the carbonate is selected from sodium carbonate or potassium carbonate.
  • the organic solvent is selected from nitriles or ketones.
  • the nitrile is preferably acetonitrile
  • the ketone is selected from acetone, 2-butanone, pent-2-one, pent-3-one, hex-2-one or hex- 3-ketone, preferably acetone.
  • the molar ratio of the compound represented by Formula V to the compound represented by Formula (2) may be 1:1 to 1:2, preferably 1:1; the molar ratio of the compound represented by formula V to potassium carbonate is selected from 1:1 to 1:5, preferably 1:2 or 1:3; the compound represented by formula IV and the catalyst The molar ratio is selected from 60:1 to 30:1, preferably 50:1 to 30:1. Further, the catalyst is selected from NaI or KI.
  • the compound represented by formula VI is preferably the following compound:
  • the present invention further provides a method for preparing the compound represented by formula IV, which includes the following steps: the compound represented by formula III is prepared in the presence of a Lewis acid and an organic solvent to obtain the compound represented by formula III.
  • the Lewis acid is selected from molecular Lewis acids; the molecular Lewis acid is selected from boron trifluoride, ferric chloride, aluminum trichloride, and trioxide Sulfur, dichlorocarbene or niobium pentachloride, preferably aluminum trichloride or ferric chloride.
  • the organic solvent is selected from tetrahydrofuran (THF), hexanol, methanol, toluene, N,N-dimethylformamide (DMF), preferably toluene.
  • the molar ratio of the compound represented by Formula III to Lewis acid may be 1:1 to 1:4, preferably 1:2 or 1:3.
  • the reaction time of the compound of formula IV prepared from the compound of formula III and the Lewis acid may be 3 to 6 hours, preferably 4 hours;
  • the reaction temperature is selected from 100 to 130°C, preferably 110 to 120°C.
  • the present invention further provides a method for preparing a compound represented by formula III, which includes the following steps:
  • Step 1 react in the presence of an acid-binding agent and an organic solvent to prepare a compound of formula I;
  • Step 2 react in the presence of P 2 O 5 and methanesulfonic acid to prepare the compound of formula II;
  • Step 3 react with methyl iodide in the presence of a strong base and an organic solvent to prepare the compound of formula III;
  • the acid binding agent is selected from pyridine or triethylamine, preferably triethylamine; the strong base is selected from NaH or KH, preferably NaH; the organic solvent in step 1 is selected from dichloromethane; step 3 The organic solvent in is selected from 4-dimethylaminopyridine (DMAP) or N,N-dimethylformamide (DMF).
  • DMAP 4-dimethylaminopyridine
  • DMF N,N-dimethylformamide
  • the molar ratio of the 4-methoxyphenethylamine to the acid binding agent may be 1:1 ⁇ 1:2, preferably 1:1.5; the molar ratio of the 4-methoxyphenethylamine to ethyl chloroformate is selected from 1:1 to 1:3, preferably 1:1 to 1:1.5.
  • the molar ratio of the compound represented by formula I to P 2 O 5 may be 1:1 to 2 :1, preferably 1:1 to 1.5:1.
  • the molar ratio of the compound represented by formula II to a strong base may be 1:1 to 1:2 , Preferably 1:1 to 1:1.5; the molar ratio of the compound represented by formula II to methyl iodide may be 1:1 to 1:2, preferably 1:1 to 1:1.5.
  • the present invention further provides a method for synthesizing the compound represented by formula VI, which is as follows:
  • X 1 is fluorine; n is 1 or 2, preferably 1.
  • the present invention further uses the compound represented by formula III, formula IV or formula V for preparing the compound represented by formula VI,
  • n is 1 or 2, preferably 1;
  • X 1 is fluorine or chlorine, preferably fluorine.
  • the present invention further provides the use of the compound represented by formula V in the preparation of the compound represented by formula VI, the purity of the compound represented by formula VI obtained by the preparation is above 99%,
  • n is 1 or 2, preferably 1;
  • X 1 is fluorine or chlorine, preferably fluorine.
  • the present invention further provides a method for purifying and purifying the compound represented by formula VI, which includes the following steps:
  • the organic solvent is selected from one or more of ketones and C 1-3 alcohols.
  • the ketones are selected from acetone or methyl ethyl ketone;
  • the C 1-3 alcohols are selected from methanol, ethanol, n-propanol, or isopropanol.
  • the organic solvent is selected from a mixed solvent of acetone and methanol, and the volume ratio of acetone to methanol may be 5:1 to 10:1, preferably 10:1.
  • step 1 further includes a heating process, and the heating temperature may be 60-70°C.
  • the stirring time in step 3 may be 5-10 hours, preferably 5-7 hours.
  • the drying temperature in step 4 may be 50-70°C, preferably 50-60°C.
  • the preparation method of the novel compound represented by formula VI and its key intermediates (compounds represented by formula III, formula IV and formula V) provided by the present invention can significantly improve the final preparation compared with the preparation method disclosed in the prior art
  • the purity of the product is more than 99.8% compared with the existing technology, which meets the standards of pharmaceutical grade raw materials for human use.
  • the new preparation method uses AlCl 3 demethylation to prepare the intermediate formula IV compound, labor protection requirements Low, strong operability, more suitable for industrial production.
  • Example 7 7-(3-(4-(6-fluorobenzo[d]isoxazolin-3-yl)piperidin-1-yl)propoxy)-2-methyl-3, 4-dihydroisoquinoline-1(2H)-one (compound of formula VI, purified and purified)
  • Example 8 Purity comparison of the compound (final product) represented by formula VI obtained by different preparation methods
  • Purification method Refer to the method described in Example 7 of the present invention for purification and purification.
  • Purification method Refer to the method described in Example 7 for purification and purification.
  • the comparison sample and the test sample were determined by HPLC, and the mass percentage of the compound represented by formula VI in the comparison sample and the test sample was calculated according to the area normalization method.
  • the specific test results are shown in Table 1.
  • step 4 uses AlCl 3 instead of HBr and step 5 uses 1-bromo 3-chloropropane instead of 1,3-dibromopropane
  • step 5 uses 1-bromo 3-chloropropane instead of 1,3-dibromopropane
  • the purity of the compound (final product) shown in formula VI can reach more than 99%.
  • the quality of the API is qualified and meets the grade of human API.
  • there are fewer impurities which greatly reduces the subsequent impurity identification work.
  • the LC purity of the preparation process of the comparative sample is only 92.38%, which contains many unknown impurities, and the quality of the raw material is unqualified, which is not up to the level of human raw material.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供一种如式Ⅵ所示化合物及其中间体的制备方法，利用该方法可高效、便捷、安全的制备得到式Ⅵ所示化合物，显著提高终产品式Ⅵ所示化合物的纯度。(VI)

Description

一种类酰胺类衍生物及其中间体的制备方法 技术领域
本发明涉及一种类酰胺类衍生物及其中间体的制备方法。
背景技术
精神***症是所有精神疾病中最严重，危害最大的一种疾病，全球发病率约为1～2％。精神***症患者终生患病率为0.7～0.8％，与性别，种族，或社会界限没有明显相关性，同时死亡率比一般人群高出2～3倍。最新研究显示，精神疾病的社会负担在中国疾病中排名居首，超过了心脑血管、呼吸***及恶性肿瘤等疾患。
专利WO2017084627A公开一种作用于多巴胺D 2、5-HT 1A和5-HT 2A受体的化合物及其制备方法，具有良好的抗神经类疾病活性的作用，其化合物结构如下所示：
Figure PCTCN2019125644-appb-000001
但是，该专利公开的制备方法存在反应物料毒性较大，反应时间过长，杂质含量高，纯度较低，工业化规模生产难度大，环境污染严重等诸多缺陷，为此本发明提供一种新的合成思路和路线，整个工艺大大减少了反应时长，避免苛刻反应条件，工艺可操作性强，有利于工业生产需要，降低环保压力；另外，因反应条件改变，能够减少杂质产生，减轻终产品的纯化难度和成本。
发明内容
本发明提供一种制备式Ⅵ所示化合物及其关键中间体(式Ⅲ、式Ⅳ及式Ⅴ所示化合物)的制备方法，
Figure PCTCN2019125644-appb-000002
其中X 1选自氟或氯，n选自1～3之间的任意整数。
本发明提供一种如式Ⅴ所示化合物的制备方法，其包括以下步骤：在催化剂、碱性物质和有机溶剂存在的条件下，式Ⅳ所示化合物与式(1)所示化合物反应得到式Ⅴ所示化合物，
Figure PCTCN2019125644-appb-000003
其中n选自1～3之间的任意整数；所述催化剂选自鎓盐类相转移催化剂；所述碱性物质选自碳酸盐。
在本发明的一个实施例方案中，n为1或2。
在本发明的一个实施例方案中，所述鎓盐类相转移催化剂选自四丁基溴化铵(TBAB)、苄基三乙基氯化铵(TEBA)、三辛基氯化铵(TCMAC)或十六烷基三甲基溴化铵(CTMAB)，优选为TEBA。
在本发明的一个实施例方案中，所述碳酸盐选自碳酸钠或碳酸钾，优选碳酸钾。
在本发明的一个实施例方案中，所述有机溶剂选自腈类或酮类。本发明的一个实施例方案中，所述腈类优选乙腈，所述酮类选自丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮或己-3-酮，优选丙酮。
在本发明的一个实施例方案中，为了达到充分反应的目的，且能达到较好的收率，所述式Ⅳ所示化合物与式(2)所示化合物的摩尔比可以为1:1～1:4，优选1:2或1:3；所述式Ⅳ所示化合物与碳酸钾的摩尔比选自1:1～1:5，优选1:2或1:3；所述式Ⅳ所示化合物与催化剂的摩尔比选自50:1～20:1，优选35:1～25:1，进一步的，所述催化剂选自TEBA。
在本发明的一个实施例方案中，为了使反应能够彻底进行，上述由式Ⅳ所示化合物与式(1)所示化合物制备得到式Ⅴ所示化合物的反应时间选自4～7个小时，优选6个小时；反应温度选自50～80℃，优选50～70℃。
在本发明的一个实施例方案中，所述式(1)所示化合物优选为：
Figure PCTCN2019125644-appb-000004
当本发明之式(1)所示的化合物为1-溴-3-氯丙烷时，惊奇的发现，能显著减少终产物中杂质的含量，终产物的纯度得到显著提高。
本发明进一步提供一种如式Ⅵ所示化合物的制备方法，包括以下步骤：在催化剂、碳酸盐和有机溶剂存在的条件下，使式Ⅴ所示化合物与式(2)所示化合物反应，由此制得式Ⅵ所示化合物的；
Figure PCTCN2019125644-appb-000005
其中X 1选自氟或氯，优选为氟；n为1或2，优选为1；式(2)所示化合物还可选自与酸形成的盐，如盐酸盐。
在本发明的一个实施例方案中，所述催化剂选自碘单质、碘化钾或碘化钠，优选碘化钠；所述碳酸盐选自碳酸钠或碳酸钾。
在本发明的一个实施例方案中，所述有机溶剂选自腈类或酮类。在本发明的一个实施例方案中，所述腈类优选乙腈，所述酮类选自丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮或己-3-酮，优选丙酮。
在本发明的一个实施例方案中，为了达到充分反应的目的，且能达到较好的收率，所述式Ⅴ所示化合物与式(2)所示化合物的摩尔比可以为1:1～1:2，优选1:1；所述式Ⅴ所示化合物与碳酸钾的摩尔比选自1:1～1:5，优选1:2或1:3；所述式Ⅳ所示化合物与催化 剂的摩尔比选自60:1～30:1，优选50:1～30:1，进一步的，所述催化剂选自NaI或KI。
在本发明的一个实施例方案中，所述式Ⅵ所示化合物优选为以下化合物：
Figure PCTCN2019125644-appb-000006
本发明进一步提供一种如式Ⅳ所示化合物的制备方法，包括以下步骤：式Ⅲ所示化合物在路易斯酸和有机溶剂存在条件下制备得到式Ⅲ所示化合物。
Figure PCTCN2019125644-appb-000007
在本发明的一个实施例方案中，所述路易斯酸(Lewis acid)选自分子型路易斯酸；所述分子型路易斯酸选自三氟化硼、三氯化铁、三氯化铝、三氧化硫、二氯卡宾或五氯化铌，优选三氯化铝或三氯化铁。
在本发明的一个实施例方案中，所述有机溶剂选自四氢呋喃(THF)、己醇、甲醇、甲苯、N,N-二甲基甲酰胺(DMF)，优选甲苯。
在本发明的一个实施例方案中，为了达到充分反应的目的，且能达到较好的收率，所述式Ⅲ所示化合物与路易斯酸的摩尔比可以为1:1～1:4，优选1:2或1:3。
在本发明的一个实施例方案中，为了使反应能够彻底进行，上述由式Ⅲ所示化合物与路易斯酸制备得到式Ⅳ所示化合物的反应时间可以为3～6个小时，优选4个小时；反应温度选自100～130℃，优选110～120℃。
本发明进一步提供一种如式Ⅲ所示化合物的制备方法，包括如下步骤：
Figure PCTCN2019125644-appb-000008
步骤1：在缚酸剂和有机溶剂存在条件下反应，制备得到式Ⅰ所示化合物；
步骤2：在P 2O 5和甲基磺酸存在条件下反应，制备得到式Ⅱ所示化合物；
步骤3：在强碱和有机溶剂存在条件下与碘甲烷反应，制备得到式Ⅲ所示化合物；
其中所述缚酸剂选自吡啶或三乙胺，优选三乙胺；所述强碱选自NaH或KH，优选NaH；所述步骤1中的有机溶剂选自二氯甲烷；所述步骤3中的有机溶剂选自4-二甲氨基吡啶(DMAP)或N,N-二甲基甲酰胺(DMF)。
在本发明的一个实施例方案中，步骤1为了达到充分反应的目的，且能达到较好的收率，所述4-甲氧基苯乙胺与缚酸剂的摩尔比可以为1:1～1:2，优选1:1.5；所述4-甲氧基苯乙胺与氯甲酸乙酯的的摩尔比选自1:1～1:3，优选1:1～1:1.5。
在本发明的一个实施例方案中，步骤2为了达到充分反应的目的，且能达到较好的 收率，所述式Ⅰ所示化合物与P 2O 5的摩尔比可以为1:1～2:1，优选1:1～1.5:1。
在本发明的一个实施例方案中，步骤3为了达到充分反应的目的，且能达到较好的收率，所述式Ⅱ所示化合物与强碱的摩尔比可以为1:1～1:2，优选1:1～1:1.5；式Ⅱ所示化合物与碘甲烷的摩尔比可以为1:1～1:2，优选1:1～1:1.5。
本发明进一步提供一种式Ⅵ所示化合物的合成方法，其如下所示：
Figure PCTCN2019125644-appb-000009
其中X 1为氟；n为1或2，优选1。
本发明进一步如式Ⅲ、式Ⅳ或式Ⅴ所示的化合物在制备式Ⅵ所示化合物的用途，
Figure PCTCN2019125644-appb-000010
其中n为1或2，优选1；X 1为氟或氯，优选氟。
本发明进一步提供式Ⅴ所示的化合物在制备式Ⅵ所示化合物的用途，所述制备得到的式Ⅵ所示化合物的纯度在99％以上，
Figure PCTCN2019125644-appb-000011
其中n为1或2，优选1；X 1为氟或氯，优选氟。
本发明进一步提供式Ⅵ所示的化合物的纯化精制方法，包括以下步骤：
①、将式Ⅵ所示的化合物粗品溶于有机溶液中；
②、加入活性炭搅拌，并过滤；
③、室温冷却搅拌，并抽滤得到固体；
④、有机溶剂洗涤固体，并干燥5～10小时，得到白色粉末状固体精制式Ⅴ所示的化合物。
在本发明的一个实施例方案中，所述有机溶剂选自酮类、C 1-3的醇类一种或多种。在本发明的一个实施例方案中，所述酮类选自丙酮或丁酮；所述C 1-3的醇类选自甲醇、乙醇、正丙醇或异丙醇。
在本发明的一个实施例方案中，所述有机溶剂选自丙酮与甲醇的混合溶剂，丙酮与甲醇的体积比可以为5:1～10:1，优选10:1。
在本发明的一个实施例方案中，步骤①还包括加热过程，加热温度可以为60～70℃。
在本发明的一个实施例方案中，步骤③搅拌时间可以为5～10小时，优选5～7小时。
在本发明的一个实施例方案中，步骤④的干燥温度可以为50～70℃，优选50～60℃。
发明的有益效果
本发明所提供的新的式Ⅵ所示化合物及其关键中间体(式Ⅲ、式Ⅳ及式Ⅴ所示化合物)的制备方法，与现有技术中公开的制备方法相比，能够显著提高终产品的纯度，与现有技术相比，纯度达到99.8％以上，符合人用药用级原料药标准；此外，新制备方法中采用AlCl 3脱甲基制备得到中间体式Ⅳ所示化合物，劳动防护要求低，可操作性强，更适于工业化生产。
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。
实验所用仪器的测试条件：
1、高效液相色谱法(High Performance Liquid Chromatograph,HPLC)
仪器型号：Agilent 1260(DAD)二元泵液相色谱
色谱柱：SHIMADZU VP-ODS C18柱(4.6×250mm，5μm)
流动相：
A：0.01mol/L磷酸二氢钾，0.1％三乙胺(用磷酸调pH至2.5)-甲醇(90:10)
B：0.01mol/L磷酸二氢钾，0.1％三乙胺(用磷酸调pH至2.5)-甲醇(20:80)
流速：1.0ml/min  柱温：35℃
波长：210nm      进样体积：15μL
梯度条件(体积比)：
Figure PCTCN2019125644-appb-000012
实施例1：乙基(4-甲氧基苯乙基)氨基甲酸酯(中间体Ⅰ)的制备
Figure PCTCN2019125644-appb-000013
将275.0g(2.55mol)氯甲酸乙酯(工业纯，购买自上海贝合化工有限公司)和2500mL二氯甲烷加入到5L反应瓶中，搅拌，冰盐浴冷却至0℃，缓慢滴加用1000mL二氯甲烷溶解的350g(2.32mol)4-甲氧基苯乙胺(工业纯，购自上海迈瑞尔化学技术有限公司)，控制体系温度0～5℃；滴加完毕，缓慢滴加351g(3.48mol)三乙胺，控制体系温度5～10℃；滴加完毕，在室温(25±5℃)下搅拌1小时。
反应完毕，向反应液中加入1000mL水淬灭反应，搅拌5分钟；静置分液，得到有机层，用600mL 1mol/L盐酸溶液洗有机相；有机相用600mL饱和氯化钠溶液洗涤，用150g无水硫酸钠干燥1小时，过滤；滤液浓缩干，得浅黄色油状物，置于室温中冷却1h，得浅黄色固体508g，收率98.3％，MS(ESI)m/z 223.3([M+H] +)。
实施例2：7-甲氧基-3,4-二氢异喹啉-1(2H)-酮的制备(中间体Ⅱ)
Figure PCTCN2019125644-appb-000014
将510.0g(1.80mol)五氧化二磷和2000mL甲磺酸加入至5L反应瓶中，搅拌，油浴加热125～130℃，至五氧化二磷完全溶解；置于室温中搅拌降温，至体系温度降至70℃，加入1000g(2.24mol)中间体I。油浴加热125℃，反应2小时。
反应完毕，降温，加入500g冰块淬灭反应，向体系中加入5000mL水，用二氯甲烷萃取6次(1200mL/次)，合并有机相，加入500g无水碳酸钾搅拌0.5小时，抽滤，溶液用500g无水硫酸钠干燥1小时，抽滤，滤液浓缩干得到棕色油状物，置于0℃下冷却5小时，抽滤，并用300mL乙酸乙酯洗滤饼，滤饼于50±5℃干燥8小时，得到类白色固体436.5g，收率55.1％，MS(ESI)m/z 177.1([M+H] +)。
实施例3：7-甲氧基-3,4-二氢异喹啉-1(2H)-酮的制备(中间体Ⅲ)
Figure PCTCN2019125644-appb-000015
将54.2g(1.36mol)60％氢化钠和1000ml N,N-二甲基甲酰胺加入到3L反应瓶中，搅拌，冰盐浴冷却至0～5℃，缓慢滴加用500mL N,N-二甲基甲酰胺溶解的200g(1.13mol)中间体II，控制体系温度5～10℃；滴加完毕，缓慢滴加176.5g(1.24mol)碘甲烷，控制体系温度10～15℃；滴加完毕，在室温(25±5℃)下搅拌1小时。
将500mL水滴加入反应液中淬灭反应；再加入4L水与反应液混合，加入1630g氯化钠至饱和，用乙酸乙酯萃取6次(800mL/次)，合并有机相，用饱和氯化钠溶液洗3次(500mL/次)，用300g无水硫酸钠干燥1小时；过滤，滤液浓缩干，得棕黄色油状物258g，收率超100％，MS(ESI)m/z 191.1([M+H] +)。
实施例4：7-羟基-2-甲基-3,4-二氢异喹啉-1(2H)-酮的制备(中间体Ⅳ)
Figure PCTCN2019125644-appb-000016
将257.6g(1.94mol)无水氯化铝和1500mL甲苯加入到3L反应瓶中，常温(25±5℃)搅拌，缓慢滴加用300mL甲苯溶解的185.0g(0.97mol)中间体III；滴加完毕，油浴加热至回流(约114～115℃)，氮气保护，计时反应4小时。
反应完毕，室温冷却至70℃，将甲苯溶液倒出，向瓶中倒入4mol/L盐酸溶液2000mL，加入冰块降温，室温搅动1小时，过滤，滤饼用500mL水洗至中性；用1000mL 2mol/L氢氧化钠溶液将滤饼溶解，依次用500mL甲苯和500mL二氯甲烷洗涤；用36％的盐酸溶液调节水层pH至3～4，冰浴冷却，搅拌0.5小时，过滤，滤饼用500mL水洗至中性，滤饼于50±5℃干燥12小时，得到类白色固体162.1g，收率94.7％，MS(ESI)m/z 177.2([M+H] +)。
实施例5：7-(3-氯丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(中间体Ⅴ)
Figure PCTCN2019125644-appb-000017
将156.0g(0.88mol)中间体IV、277.6g(1.76mol)式(1)所示化合物、364.9g(2.64mol)无水碳酸钾、6.0g(0.03mol)苄基三乙基氯化铵和1600mL丙酮加入到3L反应瓶中，油浴加热至回流(约60～65℃)，搅拌6小时。
反应完毕，过滤，滤液减压浓缩干溶剂，得黄色油状物；加入500mL丙酮溶解，室温搅动，加入3000mL正己烷，冰浴冷却搅动1小时，过滤，滤饼于50±5℃干燥6小时，得类白色固体213.2g，收率95.8％，MS(ESI)m/z 254.1([M+H] +)。
实施例6：7-(3-(4-(6-氟苯并[d]异恶唑呤-3-基)哌啶基-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(式Ⅵ所示化合物，粗产品)
Figure PCTCN2019125644-appb-000018
将210.0g(0.83mol)中间体V、223.6g(0.87mol)式(2)所示化合物的盐酸盐、344.3g(2.64mol)无水碳酸钾、3.7g(0.02mol)碘化钠和2100mL乙腈加入到5L反应瓶中，油浴加热至回流(约80～85℃)，搅拌24小时。
反应完毕，过滤，滤液置于冰浴中搅拌3小时，过滤，滤饼于50±5℃干燥3小时，得黄色固体264.6g，即式Ⅵ所示化合物粗品，收率82.6％。
实施例7：7-(3-(4-(6-氟苯并[d]异恶唑呤-3-基)哌啶基-1-基)丙氧基)-2-甲基-3,4-二氢异喹啉-1(2H)-酮(式Ⅵ所示化合物，纯化精制)
将260.0g式Ⅵ所示化合物粗品、800mL丙酮和80ml甲醇加入至2000mL反应瓶中， 水浴加热至回流(约60～65℃)，搅拌至全溶，加入8.0g活性炭，搅拌10分钟，趁热过滤，滤液转入2000mL反应瓶中，置于室温(25±5℃)中冷却，搅拌4小时；抽滤，用200mL丙酮洗涤，滤饼于50±5℃干燥6小时，得类白色粉末180.3g，即CY150112成品，收率79.3％。
1H-NMR(600MHz，CDCl3)δ2.02-2.19(m，8H)，2.60(t，2H，J＝12Hz)，2.96(t，2H，J＝12Hz),3.09-3.11(m,3H),3.18(s,3H),3.56(t,2H,J＝12Hz),4.11(t,2H,J＝6Hz),6.98-7.00(m,1H),7.06-7.10(m,2H),7.24-7.26(m,1H),7.64(d,1H,J＝6Hz)，7.74-7.76(m,1H)·MS(ESI)m/z 438.2([M+H] +)。
实施例8：不同制备方法得到的式Ⅵ所示化合物(终产物)纯度比较
对比样品
合成路线：
Figure PCTCN2019125644-appb-000019
制备方法：参照WO2017084627A实施例1和实施例5的方法制备。
纯化方法：参照本发明实施例7所述方法纯化精制。
供试样品
合成路线：按实施例1～6所述路线制备。
制备方法：按实施例1～6所述方法制备。
纯化方法：参照实施例7所述方法纯化精制。
对比样品和供试样品经HPLC测定，根据面积归一化法计算式Ⅵ所示化合物在对比样品和供试样品中的质量百分比，具体检测结果见表1。
表1对比样品与供试样品的HPLC纯度
样品名称 保留时间(min) 高度 面积 HPLC含量(％)
对比样品 31.820 90921937 2717110 92.38
供试样品 31.219 98195298 2934467 99.77
试验结果：在本发明所述的新的制备工艺中，尤其是当第4步采用AlCl 3替代HBr 以及第5步采用1-溴3-氯丙烷替代1,3-二溴丙烷，可显著提高式Ⅵ所示化合物(终产品)的纯度，可达到99％以上，原料药质量合格，符合人用原料药级别，同时杂质较少，大大减轻了后续杂质鉴定工作。而对比样品的制备工艺的LC纯度仅为92.38％，所含未知杂质较多，原料药质量不合格，达不到人用原料药级别。

Claims (10)

  1. 一种如式Ⅴ所示化合物的制备方法，包括以下步骤：在催化剂、碱性物质和有机溶剂存在的条件下，使式Ⅳ所示化合物与式(1)所示化合物反应，由此制得式Ⅴ所示化合物；
    Figure PCTCN2019125644-appb-100001
    其中n选自1～3之间的任意整数；所述催化剂选自鎓盐类相转移催化剂；所述碱性物质选自碳酸盐。
  2. 如权利要求1所述的制备方法，其中n为1或2；所述鎓盐类相转移催化剂选自四丁基溴化铵、苄基三乙基氯化铵、三辛基氯化铵或十六烷基三甲基溴化铵；所述碳酸盐选自碳酸钠或碳酸钾。
  3. 如权利要求1所述的制备方法，其中式Ⅵ所示化合物包括如下制得的：在催化剂、碳酸盐和有机溶剂存在的条件下，使所述式Ⅴ所示化合物与式(2)所示化合物反应；
    Figure PCTCN2019125644-appb-100002
    其中X 1选自氟或氯；n为1或2；所述催化剂选自碘单质、碘化钾或碘化钠；所述碳酸盐选自碳酸钠或碳酸钾。
  4. 如权利要求3所述的制备方法，其中所述式Ⅵ所示化合物为：
    Figure PCTCN2019125644-appb-100003
  5. 如权利要求1-4任一项所述的制备方法，其中所述有机溶剂选自腈类和酮类；所述腈类选自乙腈，所述酮类选自丙酮、2-丁酮、戊-2-酮、戊-3-酮、己-2-酮或己-3-酮。
  6. 如权利要求1所述的制备方法，其中所述式Ⅳ所示化合物通过式Ⅲ所示化合物在路易斯酸和有机溶剂存在条件下制备得到：
    Figure PCTCN2019125644-appb-100004
    其中所述路易斯酸选自三氟化硼、三氯化铁、三氯化铝、三氧化硫、二氯卡宾或五氯化铌，优选三氯化铝。
  7. 如权利要求6所述的制备方法，其中所述有机溶剂选自四氢呋喃、己醇、甲醇、甲苯、N,N-二甲基甲酰胺，优选甲苯。
  8. 如权利要求6-7任一项所述的制备方法，其中所述式Ⅲ所示化合物通过如下步骤进行制备：
    Figure PCTCN2019125644-appb-100005
    步骤1：在缚酸剂和有机溶剂存在条件下反应，制备得到式Ⅰ所示化合物；
    步骤2：在P 2O 5和甲基磺酸存在条件下反应，制备得到式Ⅱ所示化合物；
    步骤3：在强碱和有机溶剂存在条件下与碘甲烷反应，制备得到式Ⅲ所示化合物；
    其中所述缚酸剂选自吡啶或三乙胺；所述强碱选自NaH或KH；所述步骤1中的有机溶剂选自二氯甲烷；所述步骤3中的有机溶剂选自4-二甲氨基吡啶或N,N-二甲基甲酰胺。
  9. 如权利要求3-4任一项所述的制备方法，其中所述式Ⅵ所示化合物通过包括如下步骤的方法进行纯化精制：
    ①、将式Ⅵ所示的化合物粗品溶于有机溶液中；
    ②、加入活性炭搅拌，过滤；
    ③、室温冷却搅拌，抽滤得到固体；
    ④、有机溶剂洗涤固体，干燥5～10小时，得到精制的式Ⅵ所示的化合物；
    其中所述有机溶剂选自酮类、C 1-3的醇类的一种或多种；所述酮类选自丙酮或丁酮；所述C 1-3的醇类选自甲醇、乙醇、正丙醇或异丙醇。
  10. 如式Ⅴ所示的化合物在制备式Ⅵ所示化合物的用途，其中制备得到的式Ⅵ所示化合物的纯度在99％以上，
    Figure PCTCN2019125644-appb-100006
    其中n为1或2，优选1；X 1为氟或氯，优选氟。
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