CN111233931B - Synthesis method of Reidesciclovir - Google Patents
Synthesis method of Reidesciclovir Download PDFInfo
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- CN111233931B CN111233931B CN202010222507.7A CN202010222507A CN111233931B CN 111233931 B CN111233931 B CN 111233931B CN 202010222507 A CN202010222507 A CN 202010222507A CN 111233931 B CN111233931 B CN 111233931B
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- alkali
- ridciclovir
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- 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 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 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 10
- 239000002585 base Substances 0.000 claims abstract description 10
- 239000002841 Lewis acid Substances 0.000 claims abstract description 9
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 8
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 229940102001 zinc bromide Drugs 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 5
- 238000003786 synthesis reaction Methods 0.000 claims 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VNYBIBSZZDAEOK-UHFFFAOYSA-N 5-bromopyridin-3-ol Chemical compound OC1=CN=CC(Br)=C1 VNYBIBSZZDAEOK-UHFFFAOYSA-N 0.000 description 2
- TUIDQYRZDZRHPQ-UHFFFAOYSA-N 5-chloropyridin-3-ol Chemical compound OC1=CN=CC(Cl)=C1 TUIDQYRZDZRHPQ-UHFFFAOYSA-N 0.000 description 2
- CLNNBQDAAGDAHI-UHFFFAOYSA-N 6-chloro-1h-pyridin-2-one Chemical compound OC1=CC=CC(Cl)=N1 CLNNBQDAAGDAHI-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 2
- 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 2
- 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 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- -1 (benzyloxy) methyl Chemical group 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 241000711466 Murine hepatitis virus Species 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000004806 hydroxypyridines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthesis method of Reidesciclovir, belonging to the field of pharmaceutical chemicals, and the invention is characterized in that a compound V and hydroxypyridine are reacted under the action of alkali to obtain a compound IV; the compound IV and the compound III generate a compound II in the presence of a base and a Lewis acid; and resolving the compound II to obtain the compound I. The method disclosed by the invention has the advantages of mild reaction conditions, easily-controlled process and simple operation, can effectively improve the yield of the target product, reduces the production cost, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of Reidesvir.
Background
Reddeivir (Remdesivir), an in-process drug of Gilidd chemistry. Reidesciclovir is a nucleoside analogue with antiviral activity having an EC50 value of 74nM for ARS-CoV and MERS-CoV in HAE cells and an EC50 value of 30nM for murine hepatitis virus in delayed brain tumor cells.
At present, the process for synthesizing the Reidesvir at home and abroad roughly comprises two routes, which are as follows:
(1) the route adopted by the original inventor girard patent WO2016069826A1 (as follows): the preparation method comprises the steps of taking (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-alcohol as an initial raw material, and performing oxidation, addition, substitution, resolution, debenzylation, protection and substitution, and finally performing resolution to obtain the Reidesvir. The route has poor selectivity, only adopts a chiral column for purification, and is not suitable for industrial production.
(2) Nature 2016 (Warren T K, Jordan R, Lo M K, et al. Therapeutic efficacy of the small molecule GS-5734 by against Ebola virus in rhesus monkey [ J ] Nature 2016, 531(7594): 381 and 385.) reports a second generation of synthetic methods that could be scaled up to hundredths. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. This route (as follows) was optimized for route 1, and at the cyano substitution step, the ratio of the product isomers obtained was 95 by addition of triflic acid: 5, the triflic acid greatly increases the proportion of the desired beta-anomer, and the chiral purity can be further increased by subsequent recrystallization. However, this method uses genotoxic nitro substitutes, increasing the risk of genotoxic impurities.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing the Reidesciclovir.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthesis method of Reidesciclovir comprises the following specific synthetic route:
the preparation method comprises the following steps:
1) reacting the compound V with hydroxypyridine under the action of alkali to obtain a compound IV;
2) the compound IV and the compound III generate a compound II in the presence of a base and a Lewis acid;
3) and resolving the compound II to obtain the compound I.
As a preferred technical scheme, the specific preparation method comprises the following steps:
1) under the protection of nitrogen, adding hydroxypyridine and a solvent A, stirring, cooling to-10 ℃, slowly dropwise adding alkali, heating to-5-0 ℃ within 1-2h, then controlling the temperature to be 0 ℃, adding a mixture V, and reacting at 15-20 ℃ to obtain a compound IV;
2) under the protection of nitrogen, adding a compound III, a compound IV obtained in the step 1), a base, Lewis acid and a solvent B to generate a compound II;
3) and 2) pulping and crystallizing the compound II obtained in the step 2) by using acetone/dichloromethane, and resolving to obtain the compound I. Namely, the resolution method in the step 3) adopts pulping and crystallization of acetone/dichloromethane.
As a preferable technical scheme, the molar ratio of the compound V, the hydroxypyridines and the base in the step 1) is (1-1.5): 1: (1-1.5).
As a preferred embodiment, X is halogen, and the hydroxyl group and X may be at different substitution positions on the pyridine ring.
As a preferred technical scheme, X is Cl or Br, and is preferably Cl.
As a preferable technical solution, the base used in the step 1) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
As a preferable technical scheme, the solvent A used in the step 1) is one of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether and toluene.
As a preferable technical scheme, the molar ratio of the compound IV, the compound III, the base and the lewis acid in the step 2) is (1.2-2): 1: (1.2-2): (1.2-2).
As a preferable technical solution, the base used in the step 2) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
As a preferable technical scheme, the Lewis acid used in the step 2) is zinc chloride, zinc bromide, magnesium chloride, magnesium bromide, aluminum chloride, aluminum bromide or ferric chloride.
As a preferable technical scheme, the solvent B used in the step 2) is one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and tert-butyl methyl ether, and the reaction temperature is 50 ℃ to 80 ℃.
The invention discloses a synthesis method of Reidesciclovir, which has the advantages of mild reaction conditions, easily-controlled process and simple operation, can effectively improve the yield of a target product, reduces the production cost, and is suitable for industrial large-scale production.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1
Preparation of compound IV:
under the protection of nitrogen, adding 2-hydroxy-6-chloropyridine (1.48 g, 11.4 mmol) and 20mL tetrahydrofuran into a round-bottom flask, stirring and cooling to-10 ℃, slowly dropwise adding triethylamine (1.47 g, 14.5 mmol), and after dropwise adding, heating to-5-0 ℃ within 1-2 h. Adding the compound V (5.15 g, 14.8 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 4.95g of compound IV with a molar yield of 98.5% (based on 2-hydroxy-6-chloropyridine).
Preparation of compound I:
under nitrogen protection, compound III (2.8 g, 9.6 mmol), compound IV (6.8 g, 15.4 mmol), triethylamine (1.6 g, 15.8 mmol), zinc chloride (2.1 g, 15.4 mmol) and 40mL of tetrahydrofuran were added to a reaction flask, heated to 65 ℃ and stirred for 25 h. After the reaction was complete, 80mL of ethyl acetate was added and washed with saturated ammonium chloride (40 mL of 1, i.e., 40mL of saturated chlorideAmmonium wash once, expressed in the same manner as below with respect to the amount and number of times of this form), 0.5M hydrochloric acid wash (40 mL × 1), 0.5M Na2CO3/NaHCO3The buffer solution (mass ratio of both 1: 1.4) was washed (40 mL × 1), washed with saturated brine (40 mL × 1), and dried over anhydrous sodium sulfate. The solvent was removed by rotary drying, and the crystals were isolated by slurrying with acetone/dichloromethane (1/8, V/V) to give 2.5g of compound I in 44% molar yield (based on compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):δ7.80(1H),7.29-7.18(2H),7.15-7.07(3H),6.91-6.82(2H),5.32-5.21(3H),4.94(1H),4.52(1H),4.36-4.21(2H),4.01(1H),3.91-3.81(2H),1.70-1.40(7H),1.21(1H),1.03(6H)。
example 2
Preparation of compound IV:
under the protection of nitrogen, 3-hydroxy-5-chloropyridine (1.48 g, 11.4 mmol) and 20mL dichloromethane are added into a round-bottom flask, the mixture is stirred and cooled to-10 ℃, N-diisopropylethylamine (2.17 g, 16.8 mmol) is slowly added dropwise, and the temperature is raised to-5-0 ℃ within 1-2h after the dropwise addition. Adding the compound V (5.84 g, 16.8 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 4.88g of compound IV in 97% molar yield (based on 3-hydroxy-5-chloropyridine).
Preparation of compound I:
compound III (2.8 g, 9.6 mmol), compound IV (8.3 g, 18.8 mmol), N-diisopropylethylamine (1.5 g, 11.6 mmol), magnesium chloride (1.1 g, 11.6 mmol) and 40mL dioxane were added to a reaction flask under nitrogen blanket, heated to 55 ℃ and stirred for 25 h. After completion of the reaction, 80mL of ethyl acetate was added, washed with saturated ammonium chloride (40 mL. times.1), 0.5M hydrochloric acid (40 mL. times.1), 0.5M Na2CO3/NaHCO3Washing (40 m) with buffer solution (mass ratio of the two is 1: 1.4)L1), washed with saturated brine (40 mL 1), and dried over anhydrous sodium sulfate. The solvent was removed by rotary drying, and the crystals were isolated by slurrying with acetone/dichloromethane (1/8, V/V) to give 2.4g of compound I in 42% molar yield (based on compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):δ7.81(1H),7.31-7.17(2H),7.13-7.08(3H),6.92-6.83(2H),5.30-5.20(3H),4.93(1H),4.50(1H),4.37-4.21(2H),4.02(1H),3.91-3.80(2H),1.71-1.41(7H),1.20(1H),1.02(6H)。
example 3
Preparation of compound IV:
under the protection of nitrogen, adding 3-hydroxy-5-bromopyridine (1.98 g, 11.4 mmol) and 20mL methyl tert-butyl ether into a round-bottom flask, stirring and cooling to-10 ℃, slowly dropwise adding potassium carbonate (1.67 g, 12.1 mmol), and after dropwise adding, heating to-5-0 ℃ within 1-2 h. Adding the compound V (4.31 g, 12.4 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 5.26g of compound IV with a molar yield of 95% (based on 3-hydroxy-5-bromopyridine).
Preparation of compound I:
under nitrogen protection, compound III (2.8 g, 9.6 mmol), compound IV (5.8 g, 12.0 mmol), potassium carbonate (2.5 g, 18.1 mmol), zinc bromide (4.1 g, 18.2 mmol) and 40mL of tert-butyl methyl ether were added to a reaction flask, heated to 75 deg.C, and stirred for 25 h. After completion of the reaction, 80mL of ethyl acetate was added, washed with saturated ammonium chloride (40 mL. times.1), 0.5M hydrochloric acid (40 mL. times.1), 0.5M Na2CO3/NaHCO3The buffer solution (mass ratio of both 1: 1.4) was washed (40 mL × 1), washed with saturated brine (40 mL × 1), and dried over anhydrous sodium sulfate. The solvent is removed by rotary drying, and the compound I is separated out by beating with acetone/dichloromethane (1/8, V/V) to obtain 2.3g of the compound I with the molar yield of 40.5 percent (calculated by the compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):δ7.80(1H),7.30-7.19(2H),7.14-7.08(3H),6.90-6.80(2H),5.31-5.20(3H),4.95(1H),4.51(1H),4.37-4.20(2H),4.03(1H),3.90-3.80(2H),1.72-1.40(7H),1.21(1H),1.02(6H)。
the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. A synthetic method of Reidesciclovir is characterized in that: the synthetic route is as follows:
x is halogen, hydroxy and X at different substitution positions on the pyridine ring;
the preparation method comprises the following steps:
1) reacting the compound V with hydroxypyridine under the action of alkali to obtain a compound IV;
2) generating a compound II by the compound IV and the compound III obtained in the step 1) in the presence of alkali and Lewis acid;
3) resolving the compound II obtained in the step 2) to obtain a compound I.
2. A synthesis method of reed-solomon according to claim 1, wherein: the preparation method comprises the following steps:
1) under the protection of nitrogen, adding hydroxypyridine and a solvent A, stirring, cooling to-10 ℃, slowly dropwise adding alkali, heating to-5-0 ℃ within 1-2h, then controlling the temperature to be 0 ℃, adding a mixture V, and reacting at 15-20 ℃ to obtain a compound IV;
2) under the protection of nitrogen, adding a compound III, a compound IV obtained in the step 1), a base, Lewis acid and a solvent B to generate a compound II;
3) and 2) pulping and crystallizing the compound II obtained in the step 2) by using acetone/dichloromethane, and resolving to obtain the compound I.
3. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the molar ratio of the compound V, the hydroxypyridine and the alkali in the step 1) is (1-1.5): 1: (1-1.5).
4. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: and X is Cl or Br.
5. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the base used in the step 1) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
6. A synthesis method of reed-solomon according to claim 2, wherein: the solvent A used in the step 1) is one of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether and toluene.
7. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: in the step 2), the molar ratio of the compound IV to the compound III to the alkali to the Lewis acid is (1.2-2): 1: (1.2-2): (1.2-2).
8. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the base used in the step 2) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the Lewis acid used in the step 2) is zinc chloride, zinc bromide, magnesium chloride, magnesium bromide, aluminum chloride, aluminum bromide or ferric chloride.
9. A synthesis method of reed-solomon according to claim 2, wherein: the solvent B used in the step 2) is one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and tert-butyl methyl ether, and the reaction temperature is 50-80 ℃.
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