CN114685558A - Preparation method of Reidesciclovir intermediate - Google Patents
Preparation method of Reidesciclovir intermediate Download PDFInfo
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- CN114685558A CN114685558A CN202011578002.0A CN202011578002A CN114685558A CN 114685558 A CN114685558 A CN 114685558A CN 202011578002 A CN202011578002 A CN 202011578002A CN 114685558 A CN114685558 A CN 114685558A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 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 11
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 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 compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- 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 group FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 claims description 5
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical group [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 group [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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 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 class 0.000 claims description 2
- 239000002585 base Substances 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
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- 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 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 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 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
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000012043 crude product 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
- 238000010438 heat treatment 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
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 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
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 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 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
- 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
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000012266 salt solution 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 class 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
- -1 (phenoxy) phosphoryl Chemical group 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
- 241001115402 Ebolavirus Species 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
Classifications
-
- 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 System
- 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 System
- 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 System
- 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
Abstract
The invention discloses a preparation method for preparing a Rudexilvir intermediate I. The method comprises the following steps: dissolving a compound II in a crystallization solvent, and then preparing a compound I under the action of a catalytic amount of mono-substituted or poly-substituted phenol alkali, wherein the chiral purity of the compound I can reach more than 99.8 percent, and the yield of the compound I can reach more than 90 percent. The method has the advantages of simple operation, mild reaction conditions and high yield, and is suitable for industrial production.
Description
The technical field is as follows:
the invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a Rudexilexir intermediate.
Background art:
remdesivir (code GS-5734) is a cyano adenosine nucleotide analogue developed and researched by Gilidard pharmacy, can inhibit the activity of multiple RNA viruses by inhibiting RNA synthetase, has poor clinical treatment effect for patients infected by Ebola viruses in early stage, and researchers find that the Remdesivir has higher anti-coronavirus activity and can inhibit multiple coronavirus.
The chemical name of the RudeSewei is as follows: 2-Ethylbutyl ((S) - (((((2R, 3S,4R,5R) -5- (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine ester. The chemical structural formula is as follows:
among them, compound I is a key intermediate for the preparation of reidesavir.
The patent WO2016069826A1 of original Producer Gilidde discloses a preparation method of compound I, which comprises the steps of taking compound II as a raw material, adding isopropyl acetate and n-heptane in sequence, adding seed crystal, then adding a second part of n-heptane, mixing and cooling, finally adding DBU, mixing and stirring for 21 hours at 0 ℃. And finally, filtering and washing the mixture by using n-heptane and the like to obtain a compound II, wherein the operation steps of the method are complicated.
The document Angew.chem.int.Ed.2020,59, 20814-20819 discloses a preparation method of a compound I, the compound II is used as a raw material, isopropyl ether is used for recrystallization to obtain the compound I, the yield of the step of recrystallization is only 39%, the yield is extremely low, and the method is not suitable for industrial production.
Therefore, it is required to develop a preparation method of intermediate I, which is simple in operation, high in yield and suitable for industrialization.
The invention content is as follows:
the invention aims to provide a preparation method of a Redexilvir intermediate I, which is simple to operate, high in yield and easy to industrialize, aiming at the defects of the prior art.
The technical scheme adopted by the invention is as follows:
dissolving the compound II in a crystallization solvent, and then preparing the compound I under the action of catalytic amount of ArOH and alkali.
Wherein Ar is defined as a mono-or poly-substituted aromatic ring selected from the group consisting of 4-nitrobenzene, 2, 4-dinitrobenzene, pentafluorobenzene.
Further, the crystallization solvent is selected from ethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, ethyl acetate, butyl acetate, n-heptane or a mixed solvent of any two or more thereof.
Still further, the crystallization solvent is selected from isopropyl ether, isopropyl acetate, n-heptane.
Still further, the crystallization solvent is selected from isopropyl ether.
Further, the catalytic amount of ArOH is selected from 4-nitrophenol, 2, 4-dinitrophenol and pentafluorophenol, and is preferably 4-nitrophenol.
Further, the base is selected from triethylamine, N-diisopropylethylamine, pyridine, N-methylmorpholine, etc., preferably triethylamine.
Furthermore, after adding a catalytic amount of mono-substituted or poly-substituted phenol and an alkali, the temperature is reduced to 0-10 ℃.
Further, after cooling, a small amount of compound I is added as a seed crystal to be crystallized and stirred.
Furthermore, after filtration, the filter cake is washed with isopropyl ether and dried in vacuum to obtain the compound I with high purity and high yield.
Further, compound I can be used for the preparation of ridciclovir, the specific route is as follows:
the compound I and the compound III are used as raw materials to prepare the Reidesciclovir.
The method has the beneficial effects that when the compound II is firstly dissolved in a crystallization solvent for recrystallization, the compound I with high yield and high chiral purity is obtained by adding the catalytic amount of the mono-substituted or poly-substituted phenol ArOH and the alkali, the operation is simple, the reaction condition is mild, the yield is high, and the method is suitable for industrial production.
Drawings
FIG. 1 HPLC picture of Compound I in example 2
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
EXAMPLE 1 preparation of Compound II (Ar is 4-Nitrobenzene)
4g of phenyl dichlorophosphate and 24mL of dichloromethane are added into a 100mL reaction bottle, and the temperature is reduced to-10 to-15 ℃. A solution of 4.22g of triethylamine, 4.17g of 4.17g L-alanine-2-ethylbutyl ester hydrochloride and 8mL of methylene chloride was added dropwise to the reaction mixture at-10 to-15 ℃. After the addition is finished, the mixture is stirred for 1 hour at the temperature of minus 10 to minus 15 ℃. Then heating to 0-10 ℃ and stirring for 1 hour. After completion of the reaction, a solution of 2.1g of triethylamine, 2.8g of 4-nitrophenol and 8mL of methylene chloride was added dropwise to the above reaction solution in this order. Stirring for 6 hours at 0-10 ℃. After the reaction is completed, inorganic salt is removed by filtration, the filtrate is concentrated to dryness at 30 ℃ under reduced pressure to obtain a crude product of the oily substance, and the crude product is purified by column chromatography to obtain 7.30g of yellow oily substance.
EXAMPLE 2 preparation of Compound I (Ar is 4-Nitrobenzene)
0.70g of the compound II obtained in example 1 and 3.5mL of isopropyl ether were charged into a 10mL reaction flask, and heated to 35 ℃ to dissolve. 22.0mg of 4-nitrophenol and 24.0mg of triethylamine were added to the reaction mixture, and then the temperature was lowered to 0 ℃. A small amount of compound I was then added as seed crystals for crystallization and stirred for 1.5 hours. Filtration and washing of the filter cake with 1mL isopropyl ether. After vacuum drying at 40 ℃ 0.64g of compound I is obtained with a chiral purity of 99.84% and a yield of 91.4%, see FIG. 1.
EXAMPLE 3 preparation of Reidesciclovir (Ar is 4-nitrobenzene)
9.6g of the compound I obtained in example 2, 6.6g of the compound III, 1.9g of magnesium chloride and 100mL of acetonitrile were mixed and stirred at room temperature for 15 minutes, 9mL of N, N-diisopropylethylamine was added, after 4 hours, the reaction was diluted with 100mL of ethyl acetate, cooled to about 0 ℃ and mixed with 100mL of an aqueous citric acid solution, and the organic phase was washed with an aqueous citric acid solution, a saturated aqueous ammonium chloride solution, an aqueous potassium carbonate solution and a saturated aqueous salt solution. And drying the organic phase by using sodium sulfate, concentrating under reduced pressure, dissolving in 100mL tetrahydrofuran, cooling to about 0 ℃, slowly adding 12mL concentrated hydrochloric acid, heating to room temperature, extracting, drying, concentrating and purifying by using a silica gel column chromatography to obtain the Reidesciclovir after the reaction is finished.
EXAMPLE 4 preparation of Compound II (Ar is 2, 4-dinitrobenzene)
4.0g of phenyl dichlorophosphate and 24mL of dichloromethane were added to a 100mL reaction flask and the temperature was reduced to-10 ℃. A solution of 4.5g of triethylamine and 4.5g of 4.5g L-alanine-2-ethylbutyl ester hydrochloride in 10mL of methylene chloride was successively added dropwise to the above reaction solution. After the addition, the mixture is stirred for 1 hour at the temperature of minus 10 ℃. Then the temperature is raised to 0 ℃ and the mixture is stirred for 1 hour. After completion of the reaction, a solution of 3g of triethylamine, 3g of 2, 4-dinitrophenol and 10mL of methylene chloride was added dropwise to the reaction mixture in this order. Stirred at 0 ℃ for 6 hours. After the reaction is completed, inorganic salt is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure at 30 ℃ to obtain a crude product of an oily substance, namely the title compound.
EXAMPLE 5 preparation of Compound I (Ar is 2, 4-dinitrobenzene)
1.0g of the compound II obtained in example 4 and 3.5mL of isopropyl acetate were charged into a 10mL reaction flask, and heated to 30 ℃ to dissolve. 30mg of 2, 4-dinitrophenol and 40mg of N, N-diisopropylethylamine were added to the reaction solution, and then the temperature was lowered to 0 ℃. A small amount of compound I was then added as seed crystals for crystallization and stirred for 2 hours. Filtration and the filter cake washed with 1mL isopropyl ether. After drying at 40 ℃ in vacuo, the title compound is obtained.
EXAMPLE 6 preparation of Reidesciclovir (Ar is 2, 4-dinitrobenzene)
10.0g of the compound I obtained in example 5, 7.0g of the compound III, 2.0g of magnesium chloride and 100mL of acetonitrile were mixed and stirred at room temperature for 15 minutes, 10mL of N, N-diisopropylethylamine was added, after 4 hours, the reaction was diluted with 100mL of ethyl acetate, cooled to about 0 ℃ and mixed with 100mL of an aqueous citric acid solution, and the organic phase was washed with an aqueous citric acid solution, a saturated aqueous ammonium chloride solution, an aqueous potassium carbonate solution and a saturated aqueous salt solution. And drying the organic phase by using sodium sulfate, concentrating under reduced pressure, dissolving in 100mL tetrahydrofuran, cooling to about 0 ℃, slowly adding 12mL concentrated hydrochloric acid, heating to room temperature, extracting, drying, concentrating and purifying by using a silica gel column chromatography to obtain the Reidesciclovir after the reaction is finished.
EXAMPLE 7 preparation of Compound II (Ar is pentafluorobenzene)
4g of phenyl dichlorophosphate and 24mL of dichloromethane are added into a 100mL reaction bottle, and the temperature is reduced to-10 ℃. A solution of 5g of triethylamine and 5g L-alanine-2-ethylbutyl ester hydrochloride in 8mL of dichloromethane was added dropwise to the above reaction solution in this order. After the addition, the mixture is stirred for 1 hour at the temperature of minus 10 ℃. Then the temperature is raised to 0 ℃ and the mixture is stirred for 1 hour. After completion of the reaction, a solution of 2.5g of triethylamine, 3.5g of pentafluorophenol and 8mL of methylene chloride was added dropwise to the above reaction solution in this order. Stirred at 0 ℃ for 6 hours. After the reaction is completed, inorganic salt is removed by filtration, and the filtrate is concentrated to dryness under reduced pressure at 30 ℃ to obtain a crude product of an oily substance, namely the title compound.
EXAMPLE 8 preparation of Compound I (Ar is pentafluorobenzene)
1.0g of the compound II obtained in example 7 and 4mL of ethyl acetate were charged into a 10mL reaction flask, and heated to 40 ℃ to dissolve. 30mg of pentafluorophenol and 30mg of triethylamine were added to the reaction solution, and then cooled to 10 ℃. A small amount of compound I was then added as seed crystals for crystallization and stirred for 2 hours. Filtration and washing of the filter cake with 1mL isopropyl ether. After drying at 40 ℃ in vacuo, the title compound is obtained.
Example 9 preparation of Reidesciclovir (Ar is pentafluorobenzene)
10.0g of Compound I, 7.0g of Compound III, 2.1g of magnesium chloride and 100mL of acetonitrile are mixed and stirred for 15 minutes at room temperature, 10mL of N, N-diisopropylethylamine are added, after 4 hours, the reaction is diluted with 100mL of ethyl acetate, cooled to about 0 ℃ and mixed with 100mL of aqueous citric acid, and the organic phase is washed with aqueous citric acid and saturated aqueous ammonium chloride, aqueous potassium carbonate and saturated aqueous brine. And drying the organic phase by using sodium sulfate, concentrating under reduced pressure, dissolving in 100mL tetrahydrofuran, cooling to about 0 ℃, slowly adding 15mL concentrated hydrochloric acid, heating to room temperature, extracting, drying, concentrating and purifying by using a silica gel column chromatography to obtain the Reidesciclovir after the reaction is finished.
Claims (4)
1. A preparation method of a Redcixvir intermediate is characterized in that a compound II is dissolved in a crystallization solvent, and then a compound I is prepared under the action of catalytic amount of ArOH and alkali.
Wherein Ar is defined as a mono-or poly-substituted aromatic ring selected from the group consisting of 4-nitrobenzene, 2, 4-dinitrobenzene, pentafluorobenzene.
2. The process for preparing a ridciclovir intermediate according to claim 1, wherein the crystallization solvent is selected from the group consisting of ethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, ethyl acetate, butyl acetate, n-heptane and a mixed solvent of any two or more thereof.
3. The preparation method of the Reidesciclovir intermediate is characterized in that the catalytic amount of ArOH is selected from 4-nitrophenol, 2, 4-dinitrophenol and pentafluorophenol.
4. A preparation method of a redciclovir intermediate is characterized in that a base is selected from triethylamine, N-diisopropylethylamine, pyridine and N-methylmorpholine.
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