WO2022142396A1 - 一种瑞德西韦中间体的制备方法 - Google Patents
一种瑞德西韦中间体的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- LDHBSABBBAUMCZ-UBFVSLLYSA-N (3r,4r,5r)-3,4-bis(phenylmethoxy)-5-(phenylmethoxymethyl)oxolan-2-one Chemical compound C([C@H]1OC([C@@H]([C@@H]1OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)=O)OCC1=CC=CC=C1 LDHBSABBBAUMCZ-UBFVSLLYSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 claims description 5
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 claims description 5
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 5
- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 5
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims description 4
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 150000002989 phenols Chemical class 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 13
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DEAGOVGXNPHPIJ-FJXQXJEOSA-N 2-ethylbutyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CCC(CC)COC(=O)[C@H](C)N DEAGOVGXNPHPIJ-FJXQXJEOSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940126656 GS-4224 Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- APKYEXNSWQWOKS-IOSLPCCCSA-N (2r,3r,4s,5r)-2-(6-aminopurin-9-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbonitrile Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@]1(C#N)O[C@H](CO)[C@@H](O)[C@H]1O APKYEXNSWQWOKS-IOSLPCCCSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 240000007839 Kleinhovia hospita Species 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- -1 mixing After cooling Chemical compound 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
- C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the present disclosure belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a remdesivir intermediate.
- Remdesivir (codenamed GS-5734) is a cyanoadenosine-containing nucleotide analog developed by Gilead Pharmaceuticals, which can inhibit the activity of various RNA viruses by inhibiting RNA synthase.
- the clinical treatment effect of patients with bola virus infection is not good, but researchers have found that remdesivir has high anti-coronavirus activity and can inhibit a variety of coronaviruses.
- compound I is the key intermediate for the preparation of Remdesivir.
- the patent WO2016069826A1 of the original manufacturer Gilead discloses the preparation method of compound I, using compound II as raw material, adding isopropyl acetate and n-heptane successively, adding seed crystals, and then adding a second portion of n-heptane, mixing After cooling, DBU was finally added, and the mixture was mixed and stirred at 0°C for 21 hours. Finally, the compound II is obtained by filtering and washing with n-heptane, etc., and the operation steps of this method are complicated.
- Angew.Chem.Int.Ed.2020,59,20814-20819 discloses the preparation method of compound I.
- Compound II is used as raw material and recrystallized with isopropyl ether to obtain compound I.
- the yield of this step of recrystallization is only It is 39%, the yield is extremely low, and it is not suitable for industrial production.
- the purpose of the present disclosure is to provide a preparation method of Remdesivir intermediate I with simple operation, high yield and easy industrialization in view of the deficiencies of the prior art.
- Ar is defined as a monosubstituted or polysubstituted aromatic ring selected from 4-nitrobenzene, 2,4-dinitrobenzene and pentafluorobenzene.
- the crystallization solvent is selected from diethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, ethyl acetate, butyl acetate, n-heptane or a mixed solvent of any two or more thereof.
- the crystallization solvent is selected from isopropyl ether, isopropyl acetate, n-heptane.
- the crystallization solvent is selected from isopropyl ether.
- the catalytic amount of ArOH is selected from 4-nitrophenol, 2,4-dinitrophenol, pentafluorophenol, such as 4-nitrophenol.
- the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, and the like, such as triethylamine.
- the temperature is lowered to 0-10°C.
- a small amount of compound I needs to be added as a seed crystal for crystallization and stirring.
- the filter cake is washed with isopropyl ether and dried under vacuum to obtain Compound I in high purity and yield.
- Compound I can be used to prepare Remdesivir, and the specific route is as follows: Compound I and Compound III are used as raw materials to prepare Remdesivir.
- the beneficial effect of the present disclosure is that when compound II is first dissolved in a crystallization solvent for recrystallization, a catalytic amount of mono- or poly-substituted phenol ArOH and a base are added to obtain compound I with high yield and high chiral purity, the operation is simple, and the reaction conditions Mild, high yield, suitable for industrial production.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本公开提供了一种制备瑞德西韦中间体I的制备方法。本公开的方法为：将化合物II溶于结晶溶剂中，然后在催化量的单取代或多取代苯酚碱作用下，制备化合物I，其手性纯度可达99.8％以上，收率达到90％以上。本公开操作简单，反应条件温和，收率高，适合工业化生产。
Description
相关申请的交叉引用
本公开要求于2020年12月28日提交中国专利局的申请号为202011578002.0、名称为“一种瑞德西韦中间体的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本公开中。
本公开属于药物化学技术领域，具体涉及一种瑞德西韦中间体的制备方法。
瑞德西韦(Remdesivir，代号GS-5734)是由吉利德制药开发研制的一种含氰基腺苷核苷酸类似物，可通过抑制RNA合成酶抑制多种RNA病毒活性，早期用于埃博拉病毒感染患者的临床治疗效果不佳，研究人员却发现瑞德西韦具有较高抗冠状病毒活性，可抑制多种冠状病毒。
瑞德西韦化学名为：2-乙基丁基((S)-(((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)-L-丙氨酸酯。化学结构式如下：
其中，化合物I是制备瑞德西韦的关键中间体。
原研厂家吉利德的专利WO2016069826A1中公开了化合物I的制备方法，以化合物II为原料，向其中先后加入乙酸异丙基酯，正庚烷，加入晶种后再加入第二份正庚烷，混合冷却，最后再加入DBU，0℃混合搅拌21小时。最后用正庚烷等过滤洗涤得到化合物II，该方法操作步骤繁琐。
文献Angew.Chem.Int.Ed.2020,59,20814–20819中公开了化合物I的制备方法，以化合物II为原料，利用异丙醚重结晶，得到化合物I，重结晶这一步的收率仅为39％，收率极低，不适合工业化生产。
因此，我们需要开发一种操作简单、收率高以及适于产业化的中间体I的制备方法。
发明内容
本公开的目的在于针对现有技术的不足，提供一种操作简单、收率高、易于产业化的瑞德西韦中间体I的制备方法。
本公开采用的技术方案如下：
将化合物II溶于结晶溶剂中，然后在催化量的ArOH及碱作用下，制备化合物I；
其中Ar定义为单取代或多取代的芳环，选自4-硝基苯、2,4-二硝基苯、五氟苯。
在一些实施方式中，所述结晶溶剂选自乙醚、异丙醚、石油醚、乙酸异丙基酯、乙酸乙酯、乙酸丁酯、正庚烷或其中任意两种或以上的混合溶剂。
在一些实施方式中，所述结晶溶剂选自异丙醚、乙酸异丙基酯、正庚烷。
在一些实施方式中，所述结晶溶剂选自异丙醚。
在一些实施方式中，所述催化量的ArOH选自4-硝基苯酚、2,4-二硝基苯酚、五氟苯酚，例如4-硝基苯酚。
在一些实施方式中，所述碱选自三乙胺、N,N-二异丙基乙胺、吡啶、N-甲基吗啡啉等，例如三乙胺。
在一些实施方式中，加入催化量的单取代或多取代苯酚及碱后，将温度降至0～10℃。
在一些实施方式中，降温后，需要加入少量化合物I作为晶种析晶并搅拌。
在一些实施方式中，过滤后滤饼用异丙醚洗涤，真空干燥得到高纯度和高收率的化合物I。
在一些实施方式中，化合物I可以用于制备瑞德西韦，具体路线如下所示：以化合物I和化合物III为原料，制得瑞德西韦。
本公开的有益效果在于，化合物II先溶于结晶溶剂中重结晶时，通过加入催化量的单取代或多取代苯酚ArOH及碱得到高收率和高手性纯度的化合物I，操作简单、反应条件温和、收率高，适于工业化生产。
图1实施例2中化合物I的HPLC图
下面结合实施例对本公开的技术内容作进一步的阐述，为了更好的理解本公开的内容，但本公开的保护范围不限于此。
实施例1化合物II的制备(Ar为4-硝基苯)
将4g二氯磷酸苯酯和24mL二氯甲烷加入到100mL反应瓶中，降温至-10～-15℃。-10～-15℃下，将4.22g三乙胺和4.17g L-丙氨酸-2-乙基丁基酯盐酸盐和8mL二氯甲烷的溶液依次滴加到上述反应液中。加完后在-10～-15℃保温搅拌1小时。再升温至0～10℃搅拌1小时。反应完全后再依次将2.1g三乙胺和2.8g 4-硝基苯酚和8mL二氯甲烷的溶液依次滴加到上述反应液中。0～10℃搅拌6小时。反应完全后过滤除去无机盐，30℃减压浓缩滤液至干，得到油状物的粗品，粗品用柱层析纯化后得到7.30g黄色油状物。
实施例2化合物I的制备(Ar为4-硝基苯)
将0.70g实施例1中得到的化合物II和3.5mL异丙醚加入到10mL反应瓶中，加热至35℃溶清。将22.0mg 4-硝基苯酚和24.0mg三乙胺加入到上述反应液中后再降温至0℃。然后加入少量化合物I作为晶种析晶，并搅拌1.5小时。过滤，滤饼用1mL异丙醚洗涤。40℃真空干燥后得到0.64g化合物I，手性纯度99.84％，收率91.4％，参见图1。
实施例3瑞德西韦的制备(Ar为4-硝基苯)
室温下，将9.6g实施例2中得到的化合物I、6.6g化合物III、1.9g氯化镁、100mL乙腈混合搅拌15分钟，加入9mL N,N-二异丙基乙胺，4小时后，用100mL乙酸乙酯稀释反应物，冷却至约0℃，并与100mL柠檬酸水溶液混合，有机相用柠檬酸水溶液和饱和氯化铵水溶液、碳酸钾水溶液和饱和盐水溶液洗涤。有机相用硫酸钠干燥，减压浓缩，再溶于100mL四氢呋喃中，冷却至约0℃， 缓慢加入12mL浓盐酸，升至室温，反应结束后，萃取、干燥、浓缩，硅胶柱层析纯化得到瑞德西韦。
实施例4化合物II的制备(Ar为2,4-二硝基苯)
将4.0g二氯磷酸苯酯和24mL二氯甲烷加入到100mL反应瓶中，降温至-10℃。将4.5g三乙胺和4.5g L-丙氨酸-2-乙基丁基酯盐酸盐和10mL二氯甲烷的溶液依次滴加到上述反应液中。加完后在-10℃保温搅拌1小时。再升温至0℃搅拌1小时。反应完全后再依次将3g三乙胺和3g 2,4-二硝基苯酚和10mL二氯甲烷的溶液依次滴加到上述反应液中。0℃搅拌6小时。反应完全后过滤除去无机盐，30℃减压浓缩滤液至干，得到油状物的粗品，即为标题化合物。
实施例5化合物I的制备(Ar为2,4-二硝基苯)
将1.0g实施例4中得到的化合物II和3.5mL乙酸异丙基酯加入到10mL反应瓶中，加热至30℃溶清。将30mg 2,4-二硝基苯酚和40mg N,N-二异丙基乙胺加入到上述反应液中后再降温至0℃。然后加入少量化合物I作为晶种析晶，并搅拌2小时。过滤，滤饼用1mL异丙醚洗涤。40℃真空干燥后得到标题化合物。
实施例6瑞德西韦的制备(Ar为2,4-二硝基苯)
室温下，将10.0g实施例5中得到的化合物I、7.0g化合物III、2.0g氯化镁、100mL乙腈混合搅拌15分钟，加入10mL N,N-二异丙基乙胺，4小时后，用100mL乙酸乙酯稀释反应物，冷却至约0℃，并与100mL柠檬酸水溶液混 合，有机相用柠檬酸水溶液和饱和氯化铵水溶液、碳酸钾水溶液和饱和盐水溶液洗涤。有机相用硫酸钠干燥，减压浓缩，再溶于100mL四氢呋喃中，冷却至约0℃，缓慢加入12mL浓盐酸，升至室温，反应结束后，萃取、干燥、浓缩，硅胶柱层析纯化得到瑞德西韦。
实施例7化合物II的制备(Ar为五氟苯)
将4g二氯磷酸苯酯和24mL二氯甲烷加入到100mL反应瓶中，降温至-10℃。再将5g三乙胺和5g L-丙氨酸-2-乙基丁基酯盐酸盐和8mL二氯甲烷的溶液依次滴加到上述反应液中。加完后在-10℃保温搅拌1小时。再升温至0℃搅拌1小时。反应完全后再依次将2.5g三乙胺和3.5g五氟苯酚和8mL二氯甲烷的溶液依次滴加到上述反应液中。0℃搅拌6小时。反应完全后过滤除去无机盐，30℃减压浓缩滤液至干，得到油状物的粗品，即为标题化合物。
实施例8化合物I的制备(Ar为五氟苯)
将1.0g实施例7中得到的化合物II和4mL乙酸乙酯加入到10mL反应瓶中，加热至40℃溶清。将30mg五氟苯酚和30mg三乙胺加入到上述反应液中后再降温至10℃。然后加入少量化合物I作为晶种析晶，并搅拌2小时。过滤，滤饼用1mL异丙醚洗涤。40℃真空干燥后得到标题化合物。
实施例9瑞德西韦的制备(Ar为五氟苯)
室温下，将10.0g化合物I、7.0g化合物III、2.1g氯化镁、100mL乙腈混合搅拌15分钟，加入10mL N,N-二异丙基乙胺，4小时后，用100mL乙酸乙酯稀释反应物，冷却至约0℃，并与100mL柠檬酸水溶液混合，有机相用柠檬酸水溶液和饱和氯化铵水溶液、碳酸钾水溶液和饱和盐水溶液洗涤。有机相用硫酸钠干燥，减压浓缩，再溶于100mL四氢呋喃中，冷却至约0℃，缓慢加入15mL浓盐酸，升至室温，反应结束后，萃取、干燥、浓缩，硅胶柱层析纯化得到瑞德西韦。
Claims (4)
- 一种瑞德西韦中间体的制备方法，其特征在于，将化合物II溶于结晶溶剂中，然后在催化量的ArOH及碱作用下，制备化合物I；
其中Ar定义为单取代或多取代的芳环，选自4-硝基苯、2,4-二硝基苯、五氟苯。 - 如权利要求1所述的瑞德西韦中间体的制备方法，其特征在于，所述结晶溶剂选自乙醚、异丙醚、石油醚、乙酸异丙基酯、乙酸乙酯、乙酸丁酯、正庚烷或其中任意两种或以上的混合溶剂。
- 一种瑞德西韦中间体的制备方法，其特征在于，所述催化量的ArOH选自4-硝基苯酚、2,4-二硝基苯酚、五氟苯酚。
- 一种瑞德西韦中间体的制备方法，其特征在于，碱选自三乙胺、N,N-二异丙基乙胺、吡啶、N-甲基吗啡啉。
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