WO2021258979A1 - 芳香醚类化合物的制备方法 - Google Patents

芳香醚类化合物的制备方法 Download PDF

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WO2021258979A1
WO2021258979A1 PCT/CN2021/096279 CN2021096279W WO2021258979A1 WO 2021258979 A1 WO2021258979 A1 WO 2021258979A1 CN 2021096279 W CN2021096279 W CN 2021096279W WO 2021258979 A1 WO2021258979 A1 WO 2021258979A1
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compound
solvent
ring
water
preparing
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PCT/CN2021/096279
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English (en)
French (fr)
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吴亮
周琛
邓一军
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江苏亚虹医药科技股份有限公司
上海亚虹医药科技有限公司
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Priority to BR112022022032A priority Critical patent/BR112022022032A2/pt
Priority to EP21828493.3A priority patent/EP4177243A1/en
Priority to CA3178774A priority patent/CA3178774A1/en
Priority to MX2022015958A priority patent/MX2022015958A/es
Priority to AU2021297767A priority patent/AU2021297767A1/en
Priority to US18/001,018 priority patent/US20230219928A1/en
Priority to KR1020237001588A priority patent/KR20230026411A/ko
Priority to CN202180042597.4A priority patent/CN115697970A/zh
Priority to JP2022576160A priority patent/JP2023530640A/ja
Publication of WO2021258979A1 publication Critical patent/WO2021258979A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the invention relates to a preparation method of aromatic ether compounds.
  • Nitroxoline as an antibacterial drug that has been marketed, has been used for the treatment of urinary tract infections for a long time. Recent findings indicate that nitroquinoline is also very effective in inhibiting angiogenesis and inhibiting the growth and invasion of cancer cells. It is currently being developed for anti-tumor use. Human pharmacokinetic studies have shown that nitroquinoline can be quickly absorbed into the blood circulation, but due to the serious first-pass effect of the liver on the drug, its biological half-life is very short (according to the implementation of Jiangsu Yahong Pharmaceutical Technology Co., Ltd. in China A single-arm, open, multi-center clinical phase II trial showed that its half-life is 1.22-1.44 hours), and frequent dosing is required.
  • nitroquinoline drugs are generally prescribed to be taken three times a day (TID) or four times (QID), which not only brings economic losses, is not conducive to patient compliance, and more serious is to increase drug exposure. Continuous damage to the normal body. At the same time, due to the low water solubility of nitroquinoline, it is often necessary to make it into an immediate-release preparation to increase the solubility, which virtually increases the production cost.
  • a prodrug is a compound obtained by chemical modification of an active drug, which is transformed into the original drug by the action of enzymes in the body to exert its efficacy.
  • Prodrugs have a wide range of applications in drug development, and they have been successfully studied in a variety of different drugs and have obtained good application effects.
  • the prodrug strategy can solve some deficiencies of the active agent due to its own physical and chemical properties, such as: 1) Eliminate the bad smell of the drug; 2) Increase the blood drug concentration; 3) Improve the fat solubility or water solubility of the drug Sex; 4) Extend the action time of the drug; 5) Change the route of drug administration, etc.
  • the conversion rate of the first step reaction is low, which in turn makes the yield of this step lower, and ultimately makes the yield of the overall synthesis route lower.
  • the present invention provides a preparation method of aromatic ether compounds.
  • the object of the present invention is to provide a method for preparing the compound represented by formula VII, which comprises the following steps:
  • ring A is an aromatic ring or heteroaromatic ring, preferably 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring, more preferably benzene ring, naphthalene ring, pyridine ring or quinoline ring; hydroxyl and carbon on ring A connect;
  • Each R 1 is independently selected from -R 2 , -NO 2 , -NO, -SR 2 , -OR 2 and -X; wherein each R 2 is independently selected from C 1 -C 20 alkyl groups, preferably C 1 -C 6 alkyl groups, more preferably methyl, ethyl, n-propyl Or isopropyl; X is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • k is 0 to the maximum number that can be substituted on ring A; preferably k is an integer from 0 to 6; more preferably k is an integer from 0 to 4; further preferably k is 0, 1 or 2, and most preferably k is 1;
  • the solvent is a binary or more solvent system selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the compound V is m and n are each independently 0, 1, 2 or 3; preferably m and n are each independently 0, 1, 2 or 3; more preferably Even more preferred
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the compound V is The compound VII is m and n are each independently 0, 1, 2 or 3;
  • the compound V is The compound VII is m and n are each independently 0, 1, 2 or 3;
  • the compound V is The compound VII is
  • the compound V is The compound VII is
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the halogen is fluorine, chlorine, bromine or iodine.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the solvent is selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, Binary solvent system or ternary solvent system in ethyl acetate and dioxane.
  • the solvent is water/tetrahydrofuran, water/2-methyltetrahydrofuran And any one of the binary solvent system of water/ethyl acetate; or, any one of the ternary solvent system of water/2-methyltetrahydrofuran/tetrahydrofuran and water/2-methyltetrahydrofuran/dioxane
  • the solvent is preferably water/tetrahydrofuran binary solvent system or water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system; more preferably water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system.
  • the volume ratio of water to organic solvent is preferably 10:15 to 15:0.1, more preferably 0.8:1 to 1.2:1, and still more preferably 1:1.
  • the volume ratio of the three is preferably 10:15:15 to 15:5:5, more preferably 3:2:1 to 2.25:0.5:1, and still more preferably 2:1:1; wherein , "The volume ratio of the three” refers to the volume ratio of the three substances appearing in sequence in the aforementioned ternary system.
  • the catalyst is a conventional quaternary ammonium phase transfer catalyst, preferably tetrabutyl hydrogen
  • tetrabutyl hydrogen One or more of ammonium oxide, tetrabutylammonium acetate, tetrabutylammonium hydrogen sulfate, and tetrabutylammonium chloride, more preferably tetrabutylammonium hydroxide.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the base is one of sodium bicarbonate and potassium bicarbonate Or two, preferably sodium bicarbonate.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the molar ratio of the compound V to the catalyst is 1:0.01 To 1:0.3, preferably 1:0.05 to 1:0.2, more preferably 1:0.1.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the molar ratio of the compound V to the base is 1:2.5 To 1:15, for example 1:3, preferably 1:6 to 1:10, more preferably 1:6 to 1:8, still more preferably 1:7 to 1:8.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the molar ratio of the compound V to the compound 6 is 1: 1 to 1:5, preferably 1:2 to 1:3, more preferably 1:2.5 to 1:2.7.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the volume/mass ratio of the solvent to the compound V is 20 mL /g to 50mL/g, preferably 24mL/g to 45mL/g, more preferably 25mL/g to 40mL/g, still more preferably 25mL/g to 35mL/g, most preferably 30mL/g.
  • the method for preparing the compound represented by formula VII according to the present invention wherein, in step c), the reaction temperature of the reaction is 20°C to 35°C, preferably 25°C. °C to 30°C.
  • the method for preparing the compound represented by formula VII according to the present invention may further include the following steps before step c):
  • the solvent is preferably a mixed solvent of 2-methyltetrahydrofuran and water; the base is preferably lithium hydroxide.
  • step b Before step b), the following steps can be further included:
  • the solvent is preferably dichloromethane;
  • the base is preferably one or two of triethylamine and diisopropylethylamine, more preferably triethylamine.
  • the present invention further provides a method for preparing the compound represented by formula VIII, which is characterized in that it comprises the following steps:
  • ring A is an aromatic ring or heteroaromatic ring, preferably 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring, more preferably benzene ring, naphthalene ring, pyridine ring, quinoline ring; -OCH 2 Cl and ring A The carbon connection on;
  • Each R 1 is independently selected from -R 2 , -NO 2 , -NO, -SR 2 , -OR 2 and -X; wherein each R 2 is independently selected from C 1 -C 20 alkyl groups, preferably C 1 -C 6 alkyl groups, more preferably methyl, ethyl, n-propyl Or isopropyl; X is selected from halogen, preferably fluorine, chlorine, bromine or iodine;
  • k is 0 to the maximum number that can be substituted on ring A; preferably k is an integer from 0 to 6; more preferably k is an integer from 0 to 4; further preferably k is 0, 1 or 2, and most preferably k is 1;
  • the compound VII is prepared according to the preparation method of the compound represented by formula VII according to the present invention.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the solvent is one or more of DMF, NMP and ACN Species, preferably DMF.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the base is selected from potassium carbonate, cesium carbonate and sodium carbonate One or more, preferably potassium carbonate.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the molar ratio of the compound 4 to the base is 1- 1.5:1, preferably 1.2:1.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the molar ratio of the compound 4 to the compound VII is preferably 1 -1.5:1, more preferably 1.2:1.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the ratio of the volume of the solvent to the mass of the compound 4 It is 8:1 mL/g to 12:1 mL/g, preferably 10:1 mL/g.
  • the method for preparing the compound represented by formula VIII according to the present invention wherein, in step d), the reaction temperature of the reaction is 20°C to 30°C.
  • step e) of separating and purifying compound 8 can be further included after step d).
  • the step e) preferably includes the following steps: dissolving the compound VIII obtained in step d) in a positive solvent, and then mixing it with an anti-solvent to obtain crystals of the compound VIII.
  • Said step e) more preferably includes the following steps: mixing the mixed liquid obtained after the reaction in step d) is completed with water, separating the liquids to obtain an organic phase; after extracting the organic phase with ethyl acetate and removing water, subtracting After being concentrated by pressure, a crude product is obtained; the crude product is dissolved in a normal solvent and then mixed with an anti-solvent to obtain crystals of compound VIII.
  • the dewatering can be performed by using saturated brine; preferably, after the saturated brine is dewatered, it is dried over anhydrous sodium sulfate and filtered, and then the reduced pressure concentration is performed.
  • the positive solvent is preferably ethyl acetate.
  • the anti-solvent is preferably petroleum ether.
  • the compound VII is The compound VIII is
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: the preparation method of the aromatic ether compound of the present invention can greatly increase the conversion rate of the first step reaction, and further increase the yield of this step and the entire reaction route (to obtain compound VIII The total yield of the reaction route).
  • the preparation method of the aromatic ether compound of the present invention greatly simplifies the post-treatment and purification operations of preparing compound VII. It only needs to simply filter the reaction solution, wash the filter cake, and dry, to obtain compound VII with high purity. , And compound VII in the filtrate can also be extracted by simple concentration and crystallization, thereby avoiding column chromatography and other industrial purification methods that are difficult to implement. Therefore, it is suitable for industrial scale-up production.
  • TEA is triethylamine
  • DCM is dichloromethane
  • 2-Me-THF is 2-methyltetrahydrofuran
  • TBAOH is tetra-n-butylammonium hydroxide
  • THF is tetrahydrofuran
  • DMF is N,N-dimethylformamide .
  • LCMS is Agilent 1260 infinity II liquid phase + G6125B single quadrupole mass spectrometer.
  • the purity analysis method of the sample is as follows: Kinetex EVO C18 (50 ⁇ 4.6mm, 5 ⁇ m, ) Chromatographic column, with acetonitrile-water as the mobile phase for gradient elution, the flow rate is 1.5 mL/min, and the detection wavelength is 210 nm and 254 nm.
  • silica gel column chromatography uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • Dissolve compound 6 (10.9g, 65.8mmol, 2.5eq) in 20mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 98.1%.
  • Dissolve compound 6 (10.9g, 65.8mmol, 2.5eq) in 20mL of 2-Me-THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add it for about 15 minutes. After reacting at 25-30°C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 80%.
  • Dissolve compound 6 (23.4g, 142.1mmol, 2.7eq) in 50mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 77.9%.
  • Dissolve compound 6 (21.7g, 131.6mmol, 2.5eq) in 50mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 95.8%.
  • Dissolve compound 6 (21.7g, 131.6mmol, 2.5eq) in 50mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 98.7%.
  • Dissolve compound 6 (21.7g, 131.6mmol, 2.5eq) in 25mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 97.1%.
  • Dissolve compound 6 (21.7g, 131.6mmol, 2.5eq) in 15mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and add it for about 15 minutes and then at 25-30 After reacting at °C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained by the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 85.8%.
  • the temperature was maintained at 25-30°C. After dropping for about 15 minutes, the temperature was 25- After reacting at 30°C for 1.5 hours, a large amount of compound 7 was precipitated. After that, the mixed system obtained from the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 89.2%.
  • Dissolve compound 6 (65.1g, 394.4mmol, 2.5eq) in 50mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting for 1.5 hours at °C, a large amount of compound 7 was precipitated. After that, the mixed system obtained by the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 88.0%. After filtration, the filter cake was rinsed with 50 mL of water, and the filter cake was dried to obtain 22 g of product, a yellow solid, with a yield of 59% and a purity of 92%.
  • the organic phase was concentrated under reduced pressure, and the crude product obtained by concentration was dissolved in 150 mL of ethyl acetate, and then washed with 30 mL of water and 30 mL of saturated brine in turn.
  • the obtained organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 34.8 g of colorless oily L-isobutyrylproline methyl ester (3) with a yield of 96.4% and a purity of 96.5%.
  • Dissolve compound 6 (21.7g, 131.6mmol, 2.5eq) in 25mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and then add dropwise for about 15 minutes and then at 25-30 After reacting for 1.5 hours at °C, a large amount of compound 7 was precipitated. After that, the mixed system obtained by the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 93.5%. After filtration, the filter cake was rinsed with 50 mL of water, and the filter cake was dried to obtain 7 g of product, a yellow solid, with a yield of 56% and a purity of 98.1%.
  • Dissolve compound 6 (52.1g, 315.5mmol, 2eq) in 40mL of THF, slowly add dropwise to the reaction flask, keep the temperature at 25-30°C during the dropping process, and keep the temperature at 25-30°C after dropping for about 15 minutes After 1.5 hours of reaction, a large amount of compound 7 was precipitated. After that, the mixed system obtained by the reaction was analyzed by LCMS, and the result showed that the conversion rate of compound 5 was 90.4%. After filtration, the filter cake was rinsed with 50 mL of water, and the filter cake was dried to obtain 25 g of product as a yellow solid with a yield of 66.4% and a purity of 96.5%.
  • Step 2 Preparation of 1-(tert-butyl)2-(((5-nitroquinolin-8-yl)oxy)methyl)(S)-pyrrole-1,2-carbonic acid diester (9)
  • Step 4 Preparation of ((5-nitroquinolin-8-yl)oxy)methylisobutyryl-L-proline ester (8)
  • the preparation method of the aromatic ether compound of the present invention can greatly increase the conversion rate of the reaction of compound 5 and compound 6 to prepare compound 7, and further increase the yield and overall yield of this step.
  • the total yield of the reaction route (the reaction route to obtain compound 8).
  • the preparation method of the aromatic ether compound of the present invention greatly simplifies the post-processing and preparation of compound 7 In the purification operation, simply filter the reaction solution, wash the filter cake, and dry to obtain compound 7 with a purity of more than 92%. In some embodiments, compound 7 with a purity of more than 98% can be obtained, and compound 7 in the filtrate can be obtained. It can also be extracted by simple concentration and crystallization, thereby avoiding column chromatography and other purification methods that are difficult to implement in the industry. Therefore, the above-mentioned preparation method of the present invention is suitable for industrial scale-up production.
  • the inventors of the present invention also wish to explain that the chloromethyl ether fragment contained in compound 7 is sensitive to acid, alkali and heat, so preparation and purification are difficult, and there are few published literature reports, and the present invention After a lot of research, the inventor of the invention has developed a method for preparing the highly advantageous compound 7 of the present invention.

Abstract

一种芳香醚类化合物的制备方法。该制备方法包括如下步骤：c)在溶剂中，在催化剂和碱存在下，化合物V与化合物6反应，得化合物VII，即可；所述溶剂为选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元以上的溶剂体系。本发明的芳香醚类化合物的制备方法，能够极大地提高上述反应的转化率，进而会提高该步的收率及整条反应路线的总收率；极大地简化了制备化合物VII的后处理及纯化操作，只需简单地将反应液过滤，将滤饼洗涤，干燥，即可得到纯度很高的化合物VII，适于工业放大生产。

Description

芳香醚类化合物的制备方法 技术领域
本发明涉及芳香醚类化合物的制备方法。
背景技术
硝羟喹啉(Nitroxoline)作为一种已上市销售的抗菌药，长时间被用于治疗尿路感染。最近的发现表明，硝羟喹啉对抑制血管生成以及抑制癌细胞的生长和入侵也非常有效，目前正在被开发用于抗肿瘤。人体药代动力学研究表明，硝羟喹啉能够迅速被吸收进入血液循环，但由于肝脏对药物的首过效应严重，致使其生物半衰期非常短(根据江苏亚虹医药科技有限公司在中国实施的一项单臂、开放、多中心临床二期实验表明其半衰期为1.22-1.44小时)，而需要频繁给药。为了维持连续的药物暴露量，硝羟喹啉药品一般处方要求每天服用三次(TID)或四次(QID)，这不仅带来经济损失，不利于患者依从，更严重的是加大了药物对正常机体的持续损害。同时，由于硝羟喹啉水溶性很低，往往需要将其制成速释制剂，提高溶解度，无形中增加了生产成本。
前药(prodrug)是活性药物经过化学修饰后得到的化合物，其在体内通过酶的作用转化为原来的药物而发挥药效。前药在药物研发中有广泛的应用，其已经在多种不同的药物中研究成功并得到良好的应用效果。通过前药策略可以解决母药(active agent)因其自身理化性质而产生的一些缺陷，例如：1)消除药物的不良臭味；2)提高血药浓度；3)提高药物的脂溶性或者水溶性；4)延长药物的作用时间；5)改变药物的给药途径等。
((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯是硝羟喹啉的一种前药，其能够解决硝羟喹啉的上述缺陷。目前，仅有专利申请WO2020/063824A1公开了一种((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯的制备方法，该制备方法具体如下：
Figure PCTCN2021096279-appb-000001
然而，上述制备方法中，第一步反应的转化率较低，进而会使得该步骤的收率较低，且最终会使得整体合成路线的收率较低。
发明内容
为解决上述制备方法中第一步反应的转化率较低这一技术问题，本发明提供一种芳香醚类化合物的制备方法。
因此，本发明的目的是提供一种如式VII所示的化合物的制备方法，其包括如下步骤：
c)在溶剂中，在催化剂和碱存在下，化合物V与化合物6反应，得化合物VII，即可；
Figure PCTCN2021096279-appb-000002
其中，环A为芳环或杂芳环，优选6至10元芳环或5至10元杂芳环，更优选苯环、萘环、吡啶环或喹啉环；羟基与环A上的碳连接；
每个R 1各自独立地选自-R 2、
Figure PCTCN2021096279-appb-000003
Figure PCTCN2021096279-appb-000004
-NO 2、-NO、
Figure PCTCN2021096279-appb-000005
-S-R 2、-OR 2和-X；其中，每个R 2各自独立地选自C 1-C 20烷基，优选C 1-C 6烷基，更优选甲基、乙基、正丙基或异丙基；X选自卤素，优选氟、氯、溴或碘；
k为0至环A上能够被取代的最大个数；优选k为0至6的整数；更优选k为0至4的整数；进一步优选k为0、1或2，最优选k为1；
所述溶剂为选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元以上的溶剂体系。
在本发明一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述化合物V为
Figure PCTCN2021096279-appb-000006
m和n各自独立地为0、1、2或3；优选
Figure PCTCN2021096279-appb-000007
m和n各自独立地为0、1、2或3；更优选
Figure PCTCN2021096279-appb-000008
进一步更优选
Figure PCTCN2021096279-appb-000009
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述化合物V为
Figure PCTCN2021096279-appb-000010
所述化合物VII为
Figure PCTCN2021096279-appb-000011
m和n各自独立地为0、1、2或3；
优选地，所述化合物V为
Figure PCTCN2021096279-appb-000012
所述化合物VII为
Figure PCTCN2021096279-appb-000013
m和n各自独立地为0、1、2或3；
更优选地，所述化合物V为
Figure PCTCN2021096279-appb-000014
所述化合物VII为
Figure PCTCN2021096279-appb-000015
进一步更优选地，所述化合物V为
Figure PCTCN2021096279-appb-000016
所述化合物VII为
Figure PCTCN2021096279-appb-000017
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述卤素为氟、氯、溴或碘。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述溶剂选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元溶剂体系或三元溶剂体系。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述溶剂为水/四氢呋喃、水/2-甲基四氢呋喃和水/乙酸乙酯的二元溶剂体系中的任意一种；或者，水/2-甲基四氢呋喃/四氢呋喃和水/2-甲基四氢呋喃/二氧六环的三元溶剂体系中的任意一种；所述溶剂优选水/四氢呋喃二元溶剂体系或水/2-甲基四氢呋喃/四氢呋喃三元溶剂体系；更优选水/2-甲基四氢呋喃 /四氢呋喃三元溶剂体系。所述二元溶剂体系中，水与有机溶剂的体积比优选10:15至15:0.1，更优选0.8:1至1.2:1，进一步更优选1:1。所述三元溶剂体系中，三者的体积比优选10:15:15至15:5:5，更优选3:2:1至2.25:0.5:1，进一步更优选2:1:1；其中，“三者的体积比”指的是前述的三元体系中按先后顺序出现的三种物质的体积比。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述催化剂为常规的季铵相转移催化剂，优选四丁基氢氧化铵、四丁基醋酸铵、四丁基硫酸氢铵和四丁基氯化铵中的一种或多种，更优选四丁基氢氧化铵。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述碱为碳酸氢钠和碳酸氢钾中的一种或两种，优选碳酸氢钠。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述化合物V与所述催化剂的摩尔比为1:0.01至1:0.3，优选1:0.05至1:0.2，更优选1:0.1。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述化合物V与所述碱的摩尔比为1:2.5至1:15，例如1:3，优选1:6至1:10，更优选1:6至1:8，进一步更优选1:7至1:8。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述化合物V与所述化合物6的摩尔比为1:1至1:5，优选1:2至1:3，更优选1:2.5至1:2.7。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述溶剂与所述化合物V的体积/质量比为20mL/g至50mL/g，优选24mL/g至45mL/g，更优选25mL/g至40mL/g，进一步更优选25mL/g至35mL/g，最优选30mL/g。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII所示的化合物的制备方法，其中，步骤c)中，所述反应的反应温度为20℃至35℃，优选25℃至30℃。
在本发明另一个优选的实施方案中，根据本发明所述的如式VII 所示的化合物的制备方法，其中，步骤c)之前还可进一步包括以下步骤：
b)在溶剂中，在碱存在下，化合物3水解，得化合物4，
Figure PCTCN2021096279-appb-000018
步骤b)中，所述溶剂优选2-甲基四氢呋喃和水的混合溶剂；所述碱优选氢氧化锂。
步骤b)之前还可进一步包括以下步骤：
a)在溶剂中，在碱存在下，化合物1与化合物2反应，得化合物3，
Figure PCTCN2021096279-appb-000019
步骤a)中，所述溶剂优选二氯甲烷；所述碱优选三乙胺和二异丙基乙基胺中的一种或两种，更优选三乙胺。
本发明进一步提供一种如式VIII所示的化合物的制备方法，其特征在于，其包括如下步骤：
d)在溶剂中，在碱存在下，化合物4与化合物VII反应，得到化合物VIII，
Figure PCTCN2021096279-appb-000020
其中，环A为芳环或杂芳环，优选6至10元芳环或5至10元杂芳环，更优选苯环、萘环、吡啶环、喹啉环；-OCH 2Cl与环A上的碳 连接；
每个R 1各自独立地选自-R 2、
Figure PCTCN2021096279-appb-000021
Figure PCTCN2021096279-appb-000022
-NO 2、-NO、
Figure PCTCN2021096279-appb-000023
-S-R 2、-OR 2和-X；其中，每个R 2各自独立地选自C 1-C 20烷基，优选C 1-C 6烷基，更优选甲基、乙基、正丙基或异丙基；X选自卤素，优选氟、氯、溴或碘；
k为0至环A上能够被取代的最大个数；优选k为0至6的整数；更优选k为0至4的整数；进一步优选k为0、1或2，最优选k为1；
所述化合物VII根据本发明所述的如式VII所示的化合物的制备方法制得。
在本发明一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述溶剂为DMF、NMP和ACN中的一种或多种，优选DMF。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述碱为碳酸钾、碳酸铯和碳酸钠中的一种或多种，优选碳酸钾。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述化合物4与所述碱的摩尔比为1-1.5:1，优选1.2:1。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述化合物4与所述化合物VII的摩尔比优选1-1.5:1，更优选1.2:1。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述溶剂的体积与所述化合物4的质量的比值为8:1mL/g至12:1mL/g，优选10:1mL/g。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)中，所述反应的反应温度为20℃至30℃。
根据本发明所述的如式VIII所示的化合物的制备方法，其中，在步骤d)之后还可包括将化合物8分离纯化的步骤e)。所述步骤e) 优选包括如下步骤：将步骤d)得到的化合物VIII溶解于正溶剂中，然后与反溶剂混合，得到化合物VIII的晶体。所述步骤e)更优选包括如下步骤：将步骤d)中所述反应结束后所得混合液与水混合，分液，得有机相；所述有机相经乙酸乙酯萃取及除水后，减压浓缩，得粗品；所述粗品经正溶剂溶解后，再与反溶剂混合，即得化合物VIII的晶体。
其中，所述除水可采用饱和食盐水进行除水；优选地，在饱和食盐水除水之后，再经无水硫酸钠干燥，以及过滤之后，再进行所述减压浓缩。
其中，所述正溶剂优选乙酸乙酯。
其中，所述反溶剂优选石油醚。
在本发明另一个优选的实施方案中，根据本发明所述的如式VIII所示的化合物的制备方法，其中，所述化合物VII为
Figure PCTCN2021096279-appb-000024
所述化合物VIII为
Figure PCTCN2021096279-appb-000025
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的芳香醚类化合物的制备方法，能够极大地提高上述第一步反应的转化率，进而会提高该步的收率及整条反应路线(制得化合物VIII的反应路线)的总收率。本发明的芳香醚类化合物的制备方法，极大地简化了制备化合物VII的后处理及纯化操作，只需简单地将反应液过滤，将滤饼洗涤，干燥，即可得到纯度很高的化合物VII，而滤液中的化合物VII也可以经简单浓缩结晶而提取出来，从而避免了柱层析等工业上难以实施的纯化手段，因此，适于工业放大生产。
具体实施方式
以下将结合实施例更详细地阐述本发明，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。
下文中，TEA为三乙胺；DCM为二氯甲烷；2-Me-THF为2-甲基四氢呋喃；TBAOH为四正丁基氢氧化铵；THF为四氢呋喃；DMF为N,N-二甲基甲酰胺。
下文中，LCMS为Agilent 1260 infinity II液相+G6125B单四级杆质谱。
下文中，样品的纯度分析方法如下：采用Kinetex EVO C18(50×4.6mm，5μm，
Figure PCTCN2021096279-appb-000026
)色谱柱，乙腈-水为流动相进行梯度洗脱，流速为1.5mL/min，检测波长为210nm和254nm。
下文中，氢谱的型号为WNMR-I-400MHz。
下文中，硅胶柱层析色谱法使用烟台黄海硅胶200-300目硅胶为载体。
实施例的合成路线如下：
Figure PCTCN2021096279-appb-000027
表1 实施例及对比例的实验参数及实验结果
Figure PCTCN2021096279-appb-000028
Figure PCTCN2021096279-appb-000029
实施例1：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(1g，5.28mmol，1eq)置于1L的圆底烧瓶中，加入碳酸氢钠(2.64g，31.7mmol，6eq)，接着加入20mL水，室温搅拌。然后加入四丁基氢氧化铵的水溶液(0.34g，0.528mmol，0.1eq，水中40w.t.％)和20mL的THF，室温搅拌30分钟。将化合物6(1.74g，10.56mmol，2.0eq)慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为82.7％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例2：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(1g，5.28mmol，1eq)置于1L的圆底烧瓶中，加入碳酸氢钠(2.64g，31.7mmol，6eq)，接着加入20mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(0.34g，0.528mmol，0.1eq，水中40w.t.％)和20mL的2-Me-THF，室温搅拌30分钟。将化合物6(1.74g，10.56mmol，2.0eq)慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为75.2％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例3：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(1g，5.28mmol，1eq)置于1L的圆底烧瓶中，加入碳酸氢钠(2.64g，31.7mmol，6eq)，接着加入20mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(0.34g，0.528mmol，0.1eq，水中40w.t.％)和20mL的乙酸乙酯，室温搅拌30分钟。将化合物6(1.74g，10.56mmol，2.0eq)慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为73.8％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例4：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(5g，26.3mmol，1eq)置于1L的圆底烧瓶中，加入碳酸氢钠(15.5g，197.3mmol，7.5eq)，接着加入100mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(1.7g，2.63mmol，0.1eq，水中40w.t.％)和80mL的THF，室温搅拌30分钟。将化合物6(10.9g，65.8mmol，2.5eq)溶解于20mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为98.1％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例5：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(5g，26.3mmol，1eq)置于1L的圆底烧瓶中，加入碳酸氢钾(19.8g，197.3mmol，7.5eq)，接着加入100mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(1.7g，2.63mmol，0.1eq，水中40w.t.％)和80mL的2-Me-THF，室温搅拌30分钟。将化合物6(10.9g，65.8mmol，2.5eq)溶解于20mL的2-Me-THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为80％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例6：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(35.7g，426.2mmol，8.1eq)，接着加入200mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)和150mL的THF，室温搅拌30分钟。将化合物6(23.4g，142.1mmol，2.7eq)溶解于50mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为77.9％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例7：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(33.1g，394.6mmol，7.5eq)，接着加入200mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)和150mL的THF，室温搅拌30分钟。将化合物6(21.7g，131.6mmol，2.5eq)溶解于50mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5 小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为95.8％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例8：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(33.1g，394.6mmol，7.5eq)，接着加入200mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)和100mL的2-Me-THF和50mL的THF，室温搅拌30分钟。将化合物6(21.7g，131.6mmol，2.5eq)溶解于50mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为98.7％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例9：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(33.1g，394.6mmol，7.5eq)，接着加入150mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)、75mL的2-Me-THF和50mL的THF，室温搅拌30分钟。将化合物6(21.7g，131.6mmol，2.5eq)溶解于25mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为97.1％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例10：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(33.1g，394.6mmol，7.5eq)，接着加入100mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)、50mL的2-Me-THF和35mL的THF，室温搅拌30分 钟。将化合物6(21.7g，131.6mmol，2.5eq)溶解于15mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为85.8％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例11：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(30g，157.8mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(99.4g，1183.2mmol，7.5eq)，接着加入450mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(10.24g，15.8mmol，0.1eq，水中40w.t.％)、100mL的2-Me-THF和150mL的THF，室温搅拌30分钟。将化合物6(65.1g，394.4mmol，2.5eq)溶解于50mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后，再在25-30℃反应1.5小时，大量化合物7析出。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为89.2％。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例12：((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)的制备
1、5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(30g，157.8mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(99.4g，1183.2mmol，7.5eq)，接着加入450mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(10.24g，15.8mmol，0.1eq，水中40w.t.％)、300mL的2-Me-THF和100mL的THF，室温搅拌30分钟。将化合物6(65.1g，394.4mmol，2.5eq)溶解于50mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出，之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为88.0％。之后，过滤，滤饼用50mL水淋洗，滤饼干燥，得到22g产品，黄色固体，收率59％，纯度92％。
1H-NMR(400MHz,CDCl 3)δ：9.18(d,J＝8.8Hz,1H),9.06(m,1H),8.51(dd,J＝8.8Hz,1.2Hz,1H),7.76(m,1H),7.45(d,J＝1.2Hz,1H),6.25(s,2H)。
MS计算值：238.1；MS实测值：239.1[M+H] +。
2、L-异丁酰脯氨酸甲酯(3)的制备
将L-脯氨酸甲酯盐酸盐(1)(30g，181.1mmol)置于1L的三口瓶中，加入300mL二氯甲烷，冰浴冷却。氮气保护下，搅拌状态下慢慢滴入三乙胺(37.6g，371.3mmol)并搅拌20分钟。然后在0-10℃慢慢滴入异丁酰氯(2)(20.3g，190.2mmol)，搅拌1小时。然后升至20℃反应2小时，停止反应。之后，加入30mL水，静置分液后，得有机相。将有机相减压浓缩，浓缩得到的粗品用150mL的乙酸乙酯溶解，然后依次用30mL的水和30mL的饱和食盐水洗涤。将得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到无色油状的L-异丁酰脯氨酸甲酯(3)34.8g，收率96.4％，纯度96.5％。
MS计算值：199.2；MS实测值：200.2[M+H] +。
3、L-异丁酰脯氨酸(4)的制备
将L-异丁酰脯氨酸甲酯(3)(34.8g，124.5mmol)用210mL2-Me-THF溶解并加入140mL水，然后再加入LiOH·H 2O(10.4g，249.0mmol)。反应液在20℃搅拌2小时。停止反应后静置分液，得水相。再用HCl水溶液(35mL，6N)将水相pH调至4-5，然后用二氯甲烷(70mLx2)萃取。将得到的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到白色固体状的L-异丁酰脯氨酸(4)29.5g，收率91.3％，纯度99％。
1H-NMR(400MHz,DMSO-d6):δ12.47(s,1H),4.20-4.24(m,1H),3.58-3.55(m,2H),2.68-2.65(m,1H),2.19-2.14(m,1H),1.92-1.85(m,2H),1.83-1.78(m,1H),0.95(d,J＝3.6Hz,3H),0.89(d,J＝3.6Hz.3H)。
MS计算值：185.2；MS实测值：186.2[M+H] +。
4、((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)的制备
将L-异丁酰脯氨酸(4)(40g，215.6mmol，1.2eq)溶解到400mL无水DMF中，于室温搅拌下加入碳酸钾(25g，179.6mmol，1.0eq)。室温搅拌25分钟后，加入5-硝基-8-氯甲氧基喹啉(7)(42.8g，179.6mmol， 1.0eq)，室温反应1.5小时。反应停止后加入2L水稀释，之后分液，得有机相。有机相再用乙酸乙酯萃取(1Lx2)，然后用1L饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得65g粗品。将粗品用130mL乙酸乙酯室温溶解，加入390mL石油醚重结晶。将晶体过滤，得到62g((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)，纯度99.1％，收率89.2％。
1H-NMR(400MHz,DMSO-d6)δ：9.05(d,J＝4.0Hz,1H),9.00(d,J＝8.8Hz,1H),8.56(d,J＝8.8Hz,1H),7.89-7.86(dd,J＝4.0Hz,8.8Hz,1H),7.55(d,J＝8.8Hz,1H),6.24-6.11(m,2H),4.36-4.33(m,1H),3.58-3.55(m,2H),2.68-2.65(m,1H),2.19-2.14(m,1H),1.92-1.85(m,2H),1.83-1.78(m,1H),0.95(d,J＝6.8Hz.3H),0.89(d,J＝6.8Hz.3H)。
MS计算值：387.3；MS实测值：388.3[M+H] +。
实施例13：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(10g，52.6mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(33.1g，394.6mmol，7.5eq)，接着加入150mL水，室温搅拌，然后加入四丁基氢氧化铵的水溶液(3.4g，5.26mmol，0.1eq，水中40w.t.％)、75mL的2-Me-THF和50mL的THF，室温搅拌30分钟。将化合物6(21.7g，131.6mmol，2.5eq)溶解于25mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出，之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为93.5％。之后，过滤，滤饼用50mL水淋洗，滤饼干燥，得到7g产品，黄色固体，收率56％，纯度98.1％。
1H-NMR(400MHz,CDCl3)δ：9.18(d,J＝8.8Hz,1H),9.06(m,1H),8.51(dd,J＝8.8Hz,1.2Hz,1H),7.76(m,1H),7.45(d,J＝1.2Hz,1H),6.25(s,2H)。
MS计算值：238.1；MS实测值：239.1[M+H] +。
实施例14：5-硝基-8-氯甲氧基喹啉(7)的制备
将化合物5(30g，157.8mmol，1eq)置于3L的圆底烧瓶中，加入碳酸氢钠(79.5g，947mmol，6eq)，接着加入360mL水，室温搅 拌，然后加入四丁基氢氧化铵的水溶液(10.24g，15.8mmol，0.1eq，水中40w.t.％)、180mL的2-Me-THF和140mL的THF，室温搅拌30分钟。将化合物6(52.1g，315.5mmol，2eq)溶解于40mL的THF中，慢慢滴加到反应瓶中，滴加过程保持温度25-30℃，滴加大约15分钟后再在25-30℃反应1.5小时，大量化合物7析出，之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为90.4％。之后，过滤，滤饼用50mL水淋洗，滤饼干燥，得到25g产品，黄色固体，收率66.4％，纯度96.5％。
1H-NMR(400MHz,CDCl 3)δ：9.18(d,J＝8.8Hz,1H),9.06(m,1H),8.51(dd,J＝8.8Hz,1.2Hz,1H),7.76(m,1H),7.45(d,J＝1.2Hz,1H),6.25(s,2H)。
MS计算值：238.1；MS实测值：239.1[M+H] +。
对比例1：((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)的制备
Figure PCTCN2021096279-appb-000030
步骤1：5-硝基-8-氯甲氧基喹啉(7)的制备
于室温，将碳酸氢钠水溶液(150mL，0.88mol/L)、四丁基硫酸氢铵(1.78g，5.24mmol)加入到硝羟喹啉(5)(10.00g，52.59mmol)的二氯甲烷(150mL)溶液中，搅拌20分钟。向反应体系中滴加氯磺酸氯甲酯(17.44g，105.7mmol)，于室温搅拌16小时。之后，将反应所得混合体系经LCMS分析，结果显示，化合物5的转化率为30.7％。之后，将反应液过滤，之后分液，得有机相。有机相依次用饱和碳酸钾溶液(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。再将所得固体通过硅胶柱层析色谱法纯化(洗脱剂：二氯甲烷:甲醇＝20:1，该比值为体积比)，得5-硝基-8-氯甲氧基喹啉(7)2.5g，收率20％，纯度为98％。
1H-NMR(400MHz,CDCl 3)δ：9.18(d,J＝8.8Hz,1H),9.06(m,1H),8.51(dd,J＝8.8Hz,1.2Hz,1H),7.76(m,1H),7.45(d,J＝1.2Hz,1H),6.25(s,2H)。
MS计算值：238.1；MS实测值：239.1[M+H] +。
步骤2：1-(叔丁基)2-(((5-硝基喹啉-8-基)氧基)甲基)(S)-吡咯-1,2-碳酸二酯(9)的制备
于室温，将5-硝基-8-氯甲氧基喹啉(7)(1.5g，6.3mmol)和L-Boc脯氨酸(2.02g，9.4mmol)溶于15mL的DMF中，加入碳酸钾(1.73g，12.6mmol)，室温反应3小时。向反应液中加入70mL水，分液，得有机相。再将有机相用乙酸乙酯(50mL x 2)萃取，然后用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物通过硅胶柱层析色谱法纯化(洗脱剂：PE：EA＝1:1，该比值为体积比)，得黄色油状的1-(叔丁基)2-(((5-硝基喹啉-8-基)氧基)甲基)(S)-吡咯-1,2-碳酸二酯(9)2.8g，收率106％，纯度97％。
MS计算值：417.1；MS实测值：418.2[M+H] +。
步骤3：((5-硝基喹啉-8-基)氧基)甲基-L-脯氨酸酯盐酸盐(10)的制备
于0℃，将1-(叔丁基)2-(((5-硝基喹啉-8-基)氧基)甲基)(S)-吡咯-1,2-碳酸二酯(9)(2.8g，6.71mmol)置于30mL HCl的二氧六环溶液(4M)中，室温搅拌20分钟。将反应液减压浓缩，得白色固体状的((5- 硝基喹啉-8-基)氧基)甲基L-脯氨酸酯盐酸盐(10)2.3g，收率97％，纯度96％。
MS计算值：317.1；MS实测值：318.1[M+H] +。
步骤4：((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)的制备
于室温，将((5-硝基喹啉-8-基)氧基)甲基-L-脯氨酸酯盐酸盐(10)(150mg，0.43mmol)置于10mL的DCM中，冰浴冷却至0-5℃，加入异丁酰氯(0.86mmol)，然后慢慢加入TEA(170mg，1.72mmol)。加毕，室温搅拌20分钟，将反应液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：PE：EA＝1:1，该比值为体积比)，得到((5-硝基喹啉-8-基)氧基)甲基异丁酰-L-脯氨酸酯(8)41mg，收率24.6％，纯度99％。
1H-NMR(400MHz,DMSO-d6)δ：9.05(d,J＝4.0Hz,1H),9.01(d,J＝8.8Hz,1H),8.58(d,J＝8.8Hz,1H),7.80-7.86(dd,J＝4.0Hz,8.8Hz,1H),7.55(d,J＝8.8Hz,1H),6.22-6.14(m,2H),4.36-4.33(m,1H),3.55-3.55(m,2H),2.68-2.65(m,1H),2.19-2.13(m,1H),1.92-1.85(m,2H),1.86-1.78(m,1H),0.94(d,J＝6.8Hz.3H),0.89(d,J＝6.8Hz.3H)。
MS计算值：387.3；MS实测值：388.3[M+H] +。
根据表1的相关实验数据可知，本发明的芳香醚类化合物的制备方法，能够极大地提高化合物5与化合物6制备化合物7这一反应的转化率，进而会提高该步的收率及整条反应路线(制得化合物8的反应路线)的总收率。
此外，在化合物5与化合物6制备化合物7这一反应结束时，反应体系中会有大量化合物7析出，故本发明的芳香醚类化合物的制备方法，极大地简化了制备化合物7的后处理及纯化操作，只需简单地将反应液过滤，将滤饼洗涤，干燥，即可得到92％以上纯度的化合物7，有些实施例甚至可以得到98％以上纯度的化合物7，而滤液中的化合物7也可以经简单浓缩结晶而提取出来，从而避免了柱层析等工业上难以实施的纯化手段，因此，本发明的上述制备方法，适于工业放大生产。此处，本发明的发明人还希望说明的是，化合物7中所含的氯甲醚片段，对酸碱及热均敏感，故制备纯化难度大，而公开的文献报道很少，且本发明的发明人经过大量的研究，才研究出本发明的极具优势的化 合物7的制备方法。

Claims (10)

  1. 一种如式VII所示的化合物的制备方法，其特征在于，其包括如下步骤：
    c)在溶剂中，在催化剂和碱存在下，化合物V与化合物6反应，得化合物VII，即可；
    Figure PCTCN2021096279-appb-100001
    其中，环A为芳环或杂芳环，优选6至10元芳环或5至10元杂芳环，更优选苯环、萘环、吡啶环或喹啉环；羟基与环A上的碳连接；
    每个R 1各自独立地选自
    Figure PCTCN2021096279-appb-100002
    Figure PCTCN2021096279-appb-100003
    其中，每个R 2各自独立地选自C 1-C 20烷基，优选C 1-C 6烷基，更优选甲基、乙基、正丙基或异丙基；X选自卤素，优选氟、氯、溴或碘；
    k为0至环A上能够被取代的最大个数；优选k为0至6的整数；更优选k为0至4的整数；进一步优选k为0、1或2，最优选k为1；
    所述溶剂为选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元以上的溶剂体系。
  2. 根据权利要求1所述的如式VII所示的化合物的制备方法，其特征在于，步骤c)中，所述化合物V为
    Figure PCTCN2021096279-appb-100004
    m和n各自独立地为0、1、2或3；优选
    Figure PCTCN2021096279-appb-100005
    m和n各自独立地为 0、1、2或3；更优选
    Figure PCTCN2021096279-appb-100006
    进一步更优选
    Figure PCTCN2021096279-appb-100007
  3. 根据权利要求1所述的如式VII所示的化合物的制备方法，其特征在于，
    步骤c)中，所述化合物V为
    Figure PCTCN2021096279-appb-100008
    所述化合物VII为
    Figure PCTCN2021096279-appb-100009
    m和n各自独立地为0、1、2或3；
    优选地，所述化合物V为
    Figure PCTCN2021096279-appb-100010
    所述化合物VII为
    Figure PCTCN2021096279-appb-100011
    m和n各自独立地为0、1、2或3；
    更优选地，所述化合物V为
    Figure PCTCN2021096279-appb-100012
    所述化合物VII为
    Figure PCTCN2021096279-appb-100013
    进一步更优选地，所述化合物V为
    Figure PCTCN2021096279-appb-100014
    所述化合物VII为
    Figure PCTCN2021096279-appb-100015
  4. 根据权利要求1至3中任一项所述的如式VII所示的化合物的制备方法，其特征在于，步骤c)中，所述溶剂为选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元溶剂体系或三元溶剂体系。
  5. 根据权利要求1至3中任一项所述的如式VII所示的化合物的制备方法，其特征在于，步骤c)中，所述溶剂为水/四氢呋喃、水/2-甲基四氢呋喃和水/乙酸乙酯的二元溶剂体系中的任意一种；或者，水/2-甲基四氢呋喃/四氢呋喃和水/2-甲基四氢呋喃/二氧六环的三元溶剂体系中的任意一种；所述溶剂优选水/四氢呋喃二元溶剂体系或水/2-甲基四氢呋喃/四氢呋喃三元溶剂体系；更优选水/2-甲基四氢呋喃/四氢呋喃三元溶剂体系；
    所述二元溶剂体系中，水与有机溶剂的体积比优选10:15至15:0.1，更优选0.8:1至1.2:1，进一步更优选1:1；
    所述三元溶剂体系中，三者的体积比优选10:15:15至15:5:5，更优选3:2:1至2.25:0.5:1，进一步更优选2:1:1。
  6. 根据权利要求1至5中任一项所述的如式VII所示的化合物的制备方法，其特征在于，
    步骤c)中，所述催化剂为季铵相转移催化剂，优选四丁基氢氧化铵、四丁基醋酸铵、四丁基硫酸氢铵和四丁基氯化铵中的一种或多种，更优选四丁基氢氧化铵；
    优选地，步骤c)中，所述碱选自碳酸氢钠和碳酸氢钾中的一种或两种，优选碳酸氢钠；
    优选地，步骤c)中，所述化合物V与所述催化剂的摩尔比为1:0.01至1:0.3，优选1:0.05至1:0.2，更优选1:0.1；
    优选地，步骤c)中，所述化合物V与所述碱的摩尔比为1:2.5至 1:15，优选1:6至1:10，更优选1:6至1:8，进一步更优选1:7至1:8；
    优选地，步骤c)中，所述化合物V与所述化合物6的摩尔比为1:1至1:5，优选1:2至1:3，更优选1:2.5至1:2.7；
    优选地，步骤c)中，所述溶剂与所述化合物V的体积/质量比为20mL/g至50mL/g，优选24mL/g至45mL/g，更优选25mL/g至40mL/g，进一步更优选25mL/g至35mL/g，再进一步更优选30mL/g；
    优选地，步骤c)中，所述反应的反应温度为20℃至35℃，优选25℃至30℃。
  7. 根据权利要求1至6中任一项所述的如式VII所示的化合物的制备方法，其特征在于，步骤c)之前还进一步包括以下步骤：
    b)在溶剂中，在碱存在下，化合物3水解，得化合物4，
    Figure PCTCN2021096279-appb-100016
    步骤b)中，所述溶剂优选2-甲基四氢呋喃和水的混合溶剂；所述碱优选氢氧化锂；
    优选地，步骤b)之前还进一步包括以下步骤：
    a)在溶剂中，在碱存在下，化合物1与化合物2反应，得化合物3，
    Figure PCTCN2021096279-appb-100017
    步骤a)中，所述溶剂优选二氯甲烷；所述碱优选三乙胺和二异丙基乙基胺中的一种或两种，更优选三乙胺。
  8. 一种如式VIII所示的化合物的制备方法，其特征在于，其包括如下步骤：
    d)在溶剂中，在碱存在下，化合物4与化合物VII反应，得到化 合物VIII，
    Figure PCTCN2021096279-appb-100018
    其中，环A为芳环或杂芳环，优选6至10元芳环或5至10元杂芳环，更优选苯环、萘环、吡啶环或喹啉环；-OCH 2Cl与环A上的碳连接；
    每个R 1各自独立地选自
    Figure PCTCN2021096279-appb-100019
    Figure PCTCN2021096279-appb-100020
    其中，每个R 2各自独立地选自C 1-C 20烷基，优选C 1-C 6烷基，更优选甲基、乙基、正丙基或异丙基；X选自卤素，优选氟、氯、溴或碘；
    k为0至环A上能够被取代的最大个数；优选k为0至6的整数；更优选k为0至4的整数；进一步优选k为0、1或2，最优选k为1；
    所述化合物VII根据权利要求1至7中任一项所述的如式VII所示的化合物的制备方法制得；
    步骤d)中，所述溶剂优选DMF、NMP和ACN中的一种或多种，更优选DMF；
    步骤d)中，所述碱优选碳酸钾、碳酸铯和碳酸钠中的一种或多种，更优选碳酸钾；
    步骤d)中，所述化合物4与所述碱的摩尔比优选1-1.5:1，更优选1.2:1；
    步骤d)中，所述化合物4与所述化合物VII的摩尔比优选1-1.5:1，更优选1.2:1；
    步骤d)中，所述溶剂的体积与所述化合物4的质量的比值优选8:1mL/g至12:1mL/g，更优选10:1mL/g；
    步骤d)中，所述反应的反应温度优选20℃至30℃。
  9. 根据权利要求8中所述的如式VIII所示的化合物的制备方法，其特征在于，步骤d)之后还包括将化合物VIII分离纯化的步骤e)；所述步骤e)优选包括如下步骤：将步骤d)得到的化合物VIII溶解于正溶剂中，然后与反溶剂混合，得到化合物VIII的晶体；
    其中，所述正溶剂优选乙酸乙酯；所述反溶剂优选石油醚。
  10. 根据权利要求8或9中所述的如式VIII所示的化合物的制备方法，其特征在于，所述化合物VII为
    Figure PCTCN2021096279-appb-100021
    所述化合物VIII为
    Figure PCTCN2021096279-appb-100022
PCT/CN2021/096279 2020-06-22 2021-05-27 芳香醚类化合物的制备方法 WO2021258979A1 (zh)

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