CN111440176B - Metal complex promoted synthesis method of Reidesciclovir intermediate - Google Patents
Metal complex promoted synthesis method of Reidesciclovir intermediate Download PDFInfo
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- CN111440176B CN111440176B CN202010347457.5A CN202010347457A CN111440176B CN 111440176 B CN111440176 B CN 111440176B CN 202010347457 A CN202010347457 A CN 202010347457A CN 111440176 B CN111440176 B CN 111440176B
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- 150000004696 coordination complex Chemical class 0.000 title claims abstract description 15
- 238000001308 synthesis method Methods 0.000 title description 2
- 229940125782 compound 2 Drugs 0.000 claims abstract description 16
- 229940126214 compound 3 Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- ADLVDYMTBOSDFE-UHFFFAOYSA-N 5-chloro-6-nitroisoindole-1,3-dione Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1C(=O)NC2=O ADLVDYMTBOSDFE-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 229910017052 cobalt Inorganic materials 0.000 claims description 4
- 239000010941 cobalt Substances 0.000 claims description 4
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 4
- 239000013110 organic ligand Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- FOBPTJZYDGNHLR-UHFFFAOYSA-N diphosphorus Chemical compound P#P FOBPTJZYDGNHLR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 150000000845 D-ribose derivatives Chemical class 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000012847 fine chemical Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 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 4
- 241000711573 Coronaviridae Species 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
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 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 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- 241001115402 Ebolavirus Species 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- ZEBGLCLVPCOXIV-UHFFFAOYSA-N 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound NC1=NC=NN2C(I)=CC=C12 ZEBGLCLVPCOXIV-UHFFFAOYSA-N 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940052810 complex b Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
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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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
- B01J2531/0241—Rigid ligands, e.g. extended sp2-carbon frameworks or geminal di- or trisubstitution
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/60—Complexes comprising metals of Group VI (VIA or VIB) as the central metal
- B01J2531/62—Chromium
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- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/845—Cobalt
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Abstract
The invention belongs to the fields of medicines, organic synthesis and fine chemicals, and particularly relates to a novel method for synthesizing a ridciclovir intermediate compound 3. The present invention proposes the use of unoxidized D-ribose derivatives, directly coupled to Compound 2. Taking a compound 8 and a compound 2 as raw materials, and placing the raw materials in a solvent to react in the presence of inorganic base and a metal complex to generate an intermediate compound 3; the method is simple and convenient to operate, does not need column chromatography, is cheap and easy to obtain reagents, is green and safe, efficient and environment-friendly, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the fields of medicines, organic synthesis and fine chemicals, and particularly relates to a novel method for synthesizing a Reidesvir intermediate.
Background
Reddeivir (CAS number 1809249-37-3) is a drug in the research of Gilidd science, a nucleoside analogue with antiviral activity, and is currently undergoing phase III clinical trials against Ebola virus (NCT 03719586). However, as the research progresses, it has been found that the antiviral effect of Remdesivir is not limited to filoviruses such as Ebola virus, but is also effective in inhibiting various viruses such as coronavirus. After 31 months at 1.2020 NEJM (New England journal of medicine) published an article of 2019-nCoV infected persons during the course of U.S. healing, clinical studies of Remdesivir in the treatment of new coronavirus (2019-nCoV) pneumonia have rapidly been developed with regard to the ability of Remdesivir to resist 2019-nCoV. According to the related report of 4 months and 17 days, in the phase 3 drug test carried out at Chicago university Hospital, 113 of 125 Xinguan patients were severe, fever and respiratory symptoms of the patients were rapidly recovered after receiving the Reidesvir treatment, most of the patients were discharged after 6 days of hospitalization, and the discharge time of only few patients required 10 days. Only 2 out of 125 patients in total died, meaning a severe mortality of only 1.6% after drug administration. Therefore, redexivir is likely to be the first approved drug for the treatment of new coronaviruses.
According to the existing RudeSewei synthesis route, 6 steps of reactions are carried out, the yield is respectively 40%, 85%, 86%, 90%, 70% and 69%, and the total yield is 12.7%. The reaction yield of the synthetic intermediate compound 3 is only about 40%, and the intermediate compound needs to be purified by column chromatography. The defect of column chromatography purification is that the productivity is very low, and for the purification of the reaction in the step in the prior art, a set of column chromatography equipment can only produce a few kilograms of intermediate compound 3 without stopping working for 24 hours, and cannot meet the market demand. Therefore, the existing production process of the Reidesvir is low in efficiency, and needs to be improved.
Disclosure of Invention
In the existing process route, an intermediate compound 3 is formed by oxidizing and protecting D-ribose and then coupling with a compound 2, namely 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine, wherein a Grignard reagent is used in the coupling reaction. On the one hand, the grignard reagent involves the use of elemental magnesium as a reducing agent, meaning that the synthesis intermediate compound 3 actually undergoes a process of oxidation before reduction, with the net result that the oxidation state of the compound is not changed, but the oxidizing agent and the reducing agent are consumed, increasing the production cost; on the other hand, the coupling reaction has low yield and more byproducts, and column chromatography is needed.
In view of the above pain points, the present invention proposes the use of unoxidized D-ribose derivatives, directly coupled to Compound 2. The method eliminates the step of oxidizing D-ribose, shortens the synthetic route; meanwhile, the method has high selectivity and few reaction byproducts, and column chromatography is not needed in the separation and purification process, so that the production process is expected to be greatly simplified, and the labor cost is saved.
The invention aims to provide a method for synthesizing a Rudexilvir intermediate compound 3 with high efficiency and low cost. The method takes the compound 8 and the compound 2 as raw materials, the raw materials are placed in a solvent to react in the presence of inorganic base and metal complexes to generate the intermediate compound 3, column chromatography is not needed for post-reaction treatment, and the cost is greatly saved.
The reaction formula is as follows:
in the structure of the compound 8, Pg refers to a protective group and is selected from one of benzyl, acetyl, trimethylsilyl and tert-butyldimethylsilyl.
The metal complex used in the reaction is a complex formed by palladium, copper, nickel, cobalt, chromium or iron and an organic ligand, wherein the organic ligand is a monophosphorus ligand, a diphosphorus ligand, a P, O-ligand, a P, N-ligand or an N-heterocyclic carbene ligand;
further, the metal complex is preferably selected from a complex of cobalt and an N-heterocyclic carbene or a complex of chromium and an N-heterocyclic carbene.
The amount ratio of the metal complex to the compound 2 is 0.01 to 0.05: 1.
the inorganic base is selected from potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate and potassium tert-butoxide, and the amount ratio of the inorganic base to the compound 2 is 1-2: 1.
the solvent used in the reaction is one or more of toluene, tetrahydrofuran, diethyl ether, acetonitrile, acetone, 1, 4-dioxane, dimethyl sulfoxide or N, N-dimethylformamide.
The mass ratio of the compound 8 to the compound 2 is 1.05-1.2: 1.
the reaction temperature is 20-110 ℃, and the reaction time is 24-48 h.
The invention has the beneficial effects that:
the invention provides a method for synthesizing a Rudexilvir intermediate compound 3 with high efficiency and low cost. The method is simple and convenient to operate, does not need column chromatography, is cheap and easy to obtain reagents, is green and safe, efficient and environment-friendly, and is suitable for industrial production.
Drawings
FIG. 1 is a synthetic route of an intermediate compound 3 in the prior art;
fig. 2 shows a synthetic route of intermediate compound 3 designed by this patent.
Detailed Description
The first embodiment is as follows:
to a 500mL reaction flask were added Dimethylformamide (DMF)150mL, 50 g (0.12mol) of Compound 8, 26 g (0.1mol) of Compound 2, 23 g of potassium phosphate, and 0.7 g of Metal Complex A in this order, and after reaction at 100 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the aqueous layer, and the organic layer was dried over anhydrous sodium sulfate. 100mL of system concentrate is added into 200mL of tert-butyl methyl ether by a rotary evaporator for pulping, and 44.1 g of Ruidexiwei intermediate compound 3 is obtained by filtration with the yield of 80%.
The synthesized intermediate compound 3 is completely matched with a standard substance control and TLC.
Example two:
after acetonitrile 150mL, 59 g (0.12mol) of Compound 8a, 26 g (0.1mol) of Compound 2, 15 g of potassium carbonate, and 1.4 g of Metal Complex B were added in this order to a 500mL reaction flask, and reacted at 80 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate. 100mL of system concentrate is added into 200mL of tert-butyl methyl ether by a rotary evaporator for pulping, and 51.2 g of Ruidexiwei intermediate compound 3a is obtained by filtration with the yield of 82%.
The synthesized intermediate compound 3a is completely matched with a standard control, TLC.
Example three:
a500 mL reaction flask was charged with 150mL of 1, 4-dioxane, 33 g (0.12mol) of Compound 8b, 26 g (0.1mol) of Compound 2, 13 g of potassium tert-butoxide, and 1.7 g of Metal Complex C in that order, reacted at 100 ℃ for 36 hours, and then extracted three times with water and ethyl acetate to remove the aqueous layer, and the organic layer was dried over anhydrous sodium sulfate. 100mL of system concentrate is added into 200mL of tert-butyl methyl ether by a rotary evaporator for pulping, and the mixture is filtered to obtain 35.3 g of Ruidexiwei intermediate compound 3b with the yield of 87%.
The synthesized intermediate compound 3b was completely matched with the standard control, TLC.
Example four:
to a 500mL reaction flask were added in the order DMSO 150mL, 50 g (0.12mol) of Compound 8, 26 g (0.1mol) of Compound 2, 35 g of cesium carbonate, and 0.8 g of Metal Complex D, and after reacting at 100 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate. 100mL of system concentrate is added into 200mL of tert-butyl methyl ether by a rotary evaporator for pulping, and 49.8 g of Rudexilvir intermediate compound 3 is obtained by filtration with the yield of 90%.
The synthesized intermediate compound 3 is completely matched with a standard substance control and TLC.
Claims (3)
1. The method for synthesizing the Rudexilvir intermediate promoted by the metal complex is characterized in that a compound 8 and a compound 2 are used as raw materials, and the raw materials are placed in a solvent to react for 24-48h at the temperature of 20-110 ℃ in the presence of inorganic base and the metal complex to generate an intermediate compound 3;
the reaction formula is as follows:
in the structure of the compound 8, Pg refers to a protective group selected from one of benzyl, acetyl, trimethylsilyl and tert-butyl dimethylsilyl;
the metal complex used in the reaction refers to a complex formed by palladium, copper, nickel, cobalt, chromium or iron and an organic ligand,
the organic ligand is a monophosphorus ligand, a diphosphorus ligand, a P, O-ligand, a P, N-ligand or an N-heterocyclic carbene ligand;
the amount ratio of the metal complex to the compound 2 is 0.01 to 0.05: 1;
the inorganic base is selected from potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate and potassium tert-butoxide, and the amount ratio of the inorganic base to the compound 2 is 1-2: 1;
the mass ratio of the compound 8 to the compound 2 is 1.05-1.2: 1.
2. the method of synthesis of claim 1, wherein: the metal complex is a complex of cobalt and N-heterocyclic carbene or a complex of chromium and N-heterocyclic carbene.
3. The method of synthesis of claim 1, wherein: the solvent used in the reaction is one or more of toluene, tetrahydrofuran, diethyl ether, acetonitrile, acetone, 1, 4-dioxane, dimethyl sulfoxide or N, N-dimethylformamide.
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