CN111471070A - Synthetic method of Reidesciclovir - Google Patents
Synthetic method of Reidesciclovir Download PDFInfo
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- CN111471070A CN111471070A CN202010338730.8A CN202010338730A CN111471070A CN 111471070 A CN111471070 A CN 111471070A CN 202010338730 A CN202010338730 A CN 202010338730A CN 111471070 A CN111471070 A CN 111471070A
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- Prior art keywords
- compound
- synthesis method
- reidesciclovir
- hydroxysuccinimide
- alkali
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- Granted
Links
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims abstract description 19
- 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 19
- 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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 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 10
- 239000003513 alkali Substances 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000001308 synthesis method Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 10
- 239000002808 molecular sieve Substances 0.000 claims description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 229940102001 zinc bromide Drugs 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 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
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 19
- 239000007787 solid Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 2
- 238000001556 precipitation Methods 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
- 239000003039 volatile agent Substances 0.000 description 2
- -1 (benzyloxy) methyl Chemical group 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CJZAOLXKRSRDCO-UHFFFAOYSA-N CC(C)([O-])C.[K+].Cl Chemical compound CC(C)([O-])C.[K+].Cl CJZAOLXKRSRDCO-UHFFFAOYSA-N 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000013078 crystal Substances 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
- OZECFIJVSAYAPH-UHFFFAOYSA-N ethyl-di(propan-2-yl)azanium;chloride Chemical compound Cl.CCN(C(C)C)C(C)C OZECFIJVSAYAPH-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 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
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method of Reidesciclovir, belonging to the field of pharmaceutical chemicals, and the invention is characterized in that a compound V and N-hydroxysuccinimide react under the action of alkali to obtain a compound IV; resolving the compound IV to obtain a compound III; the compound III and the compound II generate the compound I in the presence of a base and a Lewis acid. The method disclosed by the invention adopts toxicologically harmless N-hydroxysuccinimide as a leaving group, the reaction process is safe, and the obtained target product has higher purity, can meet the market demand of products, and reduces the production cost.
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 girlidde patent WO2016069826A1 is 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, L o M K, et al, therapeutics of the small molecule GS-5734 against Ebola virus in rhesus monkey [ J ]. Nature, 2016, 531(7594): 381-385.) reports a second generation synthesis procedure that can be scaled up to hectogram with yields of 40%, 85%, 86%, 90%, 70% and 69%, respectively, optimized for route 1, with triflic acid added to give a 95: 5 ratio of product isomers during the cyano substitution step, which greatly increased the desired β -isomer ratio, and with subsequent further increase in chiral purity by recrystallization.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing the Reidesciclovir, which adopts toxicologically harmless N-hydroxysuccinimide as a leaving group and has safe reaction process.
In order to achieve the purpose, the invention provides the following technical scheme:
the synthesis method of the Reidesciclovir comprises the following specific synthetic route:
the preparation method comprises the following steps:
1) reacting the compound V with N-hydroxysuccinimide under the action of alkali to obtain a compound IV;
2) resolving the compound IV to obtain a compound III;
3) the compound III and the compound II generate the compound I in the presence of a base and a Lewis acid.
As a preferred technical scheme, the specific preparation method comprises the following steps:
1) adding the compound V into one part of aprotic organic solvent A, cooling the solution to 5 ℃ by adopting an ice bath, adding N-hydroxysuccinimide which can be partially dissolved, and then dropwise adding the other part of aprotic organic solvent A solution containing alkali for reaction; until all N-hydroxysuccinimide is dissolved, the corresponding alkali hydrochloride is observed to precipitate, and the reaction is finished to obtain a compound IV;
2) dissolving the compound IV obtained in the step 1) in methyl tert-butyl ether, adding triethylamine, stirring overnight, and splitting to obtain a compound III;
3) adding the compound III obtained in the step 2) into an aprotic organic solvent B, and adding a compound II, a base and a Lewis acid into the solution to react to generate a compound I.
As a preferable technical scheme, the mole ratio of the compound V, N-hydroxysuccinimide to the base in the step 1) is (1.2-2): 1: (1.5-2).
As a preferred technical solution, the base used in step 1) is one of triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate and potassium bicarbonate, preferably triethylamine.
As a preferred technical scheme, the aprotic organic solvent used in the step 1) is one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether, and dichloromethane is preferred.
As a preferable technical scheme, the molar ratio of the compound III, the compound II, the base and the lewis acid in the step 3) is (1.5-2.5): 1: (1-3): (0.75 to 1.5).
As a preferable technical scheme, the base used in the step 3) is one of ethyl diisopropylamine, trimethylamine, triethylamine, 1, 8-diazabicycloundece-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-methyl morpholine, 1-ethyl piperidine, potassium carbonate and potassium bicarbonate, and ethyl diisopropylamine or trimethylamine is preferable.
As a preferred technical solution, the lewis acid used in step 3) is zinc chloride, zinc bromide, zinc iodide, magnesium bromide or copper chloride, preferably zinc bromide.
As a preferred technical solution, the aprotic organic solvent used in step 3) is one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether and dimethylformamide, preferably tetrahydrofuran.
As a preferable technical scheme, the reaction in the step 3) is carried out under the condition of adding the molecular sieve, and the molecular sieve is a 4A molecular sieve.
The invention discloses a synthesis method of Reidesciclovir, which adopts toxicologically harmless N-hydroxysuccinimide as a leaving group, has safe reaction process, obtains a target product with higher purity, can meet the market demand of products, and reduces the production cost.
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 III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (34.12 g, 98.1 mmol) was dissolved in 140m L dichloromethane, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of dichloromethane (20 m L) containing triethylamine (11.91 g, 117.7 mmol) with stirring, the addition funnel was rinsed with another 5m L dichloromethane, when all the N-hydroxysuccinimide was dissolved, precipitation of triethylamine hydrochloride was observed, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃) and extracted with 90m L distilled water, the organic phase was washed with another 40m 64 distilled water, the volatiles were removed under reduced pressure to give a crude solid, compound iv, crude solid was obtained, compound iv, crude solid 160m L e (methyl tert-butyl ether) was added to 5m L triethylamine, stirred, at which time a solid was formed, the mixture i.e. solid was washed with another MTBE 3975 m 3975 until all the crude solid formed, the crude solid was dissolved in dry HP 364% crystalline (3.75 mol), and filtered to obtain an aggregate, which was obtained as a yield of crude compound III).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (8.2 g, 19.2 mmol) and 25m L tetrahydrofuran to obtain a clear solution to this solution was added compound II (2.8 g, 9.6 mmol), followed by zinc bromide (2.2 g, 9.8 mmol), 4A molecular sieve (3 g) and ethyldiisopropylamine (2.5 g, 19.3 mmol). the mixture was stirred at room temperature for 4h, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.7 g, having an HP L C purity of 99.5% and a molar yield of 81% (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):7.81(1H),7.29-7.18(2H),7.16-7.07(3H),6.91-6.82(2H),5.31-5.21(3H),4.94(1H),4.51(1H),4.36-4.21(2H),4.02(1H),3.91-3.82(2H),1.70-1.40(7H),1.21(1H),1.02(6H)。
example 2
Preparation of compound III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (40.93 g, 117.7 mmol) was dissolved in 140m L tetrahydrofuran, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of tetrahydrofuran (20 m L) containing N, N-diisopropylethylamine (12.68 g, 98.1 mmol) with stirring, the addition funnel was rinsed with another 5m L tetrahydrofuran, when all N-hydroxysuccinimide was dissolved, precipitation of N, N-diisopropylethylamine hydrochloride was observed, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃), extracted with 90m L distilled water, the organic phase was washed with another 40m L distilled water, the volatiles were removed under reduced pressure to give a crude solid, i.e. compound iv, the crude solid L m L e (methyl tert-butyl ether) was dissolved in HP (methyl L), triethylamine was added, the solid was stirred, whereupon the solid formed, i.e. compound V-t-butyl ether was filtered to form an aggregate, which was dissolved as a crude solid (dry residue) in dry, purity was measured by heating) and filtered 369.26.75 mol).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (9.4 g, 22.0 mmol) and 25m L dichloromethane to obtain a clear solution to this solution was added compound II (2.8 g, 9.6 mmol), followed by zinc chloride (1.1 g, 8.1 mmol), 4A molecular sieve (3 g) and trimethylamine (0.6 g, 10.2 mmol). the mixture was stirred at room temperature for 4h, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.6 g, having a purity of 99.2% as determined by HP L C, in 80% molar yield (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):7.81(1H),7.31-7.18(2H),7.13-7.09(3H),6.92-6.82(2H),5.30-5.21(3H),4.93(1H),4.51(1H),4.37-4.21(2H),4.02(1H),3.92-3.80(2H),1.71-1.41(7H),1.20(1H),1.02(6H)。
example 3
Preparation of compound III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (27.30 g, 78.5 mmol) was dissolved in 140m L-methyltetrahydrofuran, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of 2-methyltetrahydrofuran (20 m L) containing potassium tert-butoxide (14.68 g, 130.8 mmol) with stirring, the addition funnel was rinsed with another 5m L-methyltetrahydrofuran, when all N-hydroxysuccinimide was dissolved, potassium tert-butoxide hydrochloride was observed to precipitate, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃), extracted with 90m L distilled water, the organic phase was washed with another 40m L distilled water, the crude solid was removed under reduced pressure, i.e. compound iv, the crude solid was dissolved in 160m L e (methyl tert-butyl ether), triethylamine was added, the mixture was stirred, whereupon the crude solid formed a solid which formed as a solid which was dissolved in dry HP 6778%, the crude solid, the yield of N-hydroxysuccinimide was measured as an aggregate, after cooling to form a dry residue (20 m) of crystals, 5m 6778.75 mg).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (6.6 g, 15.5 mmol) and 25m L methyl t-butyl ether to obtain a clear solution, to this solution was added compound II (2.8 g, 9.6 mmol), followed by the addition of magnesium bromide (2.5 g, 13.6 mmol), 4A molecular sieve (3 g) and triethylamine (2.7 g, 26.7 mmol), the mixture was stirred at room temperature for 4 hours, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.5 g, having a purity of 99.3% as determined by HP L C, in 78% molar yield (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR(400MHz,CDCl3):7.82(1H),7.30-7.17(2H),7.15-7.08(3H),6.90-6.81(2H),5.32-5.20(3H),4.94(1H),4.51(1H),4.38-4.20(2H),4.03(1H),3.90-3.80(2H),1.72-1.42(7H),1.22(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 (10)
1. The synthesis method of the Reidesciclovir is characterized by comprising the following steps: the synthetic route is as follows:
the preparation method comprises the following steps:
1) reacting the compound V with N-hydroxysuccinimide under the action of alkali to obtain a compound IV;
2) resolving the compound IV obtained in the step 1) to obtain a compound III;
3) the compound III obtained in the step 2) and a compound II generate a compound I in the presence of a base and a Lewis acid.
2. A synthesis method of reed-solomon according to claim 1, wherein: the preparation method comprises the following steps:
1) adding the compound V into one part of aprotic organic solvent A, cooling the solution to 5 ℃ by adopting an ice bath, adding N-hydroxysuccinimide which can be partially dissolved, and then dropwise adding the other part of aprotic organic solvent A solution containing alkali for reaction; until all N-hydroxysuccinimide is dissolved, the corresponding alkali hydrochloride is observed to precipitate, and the reaction is finished to obtain a compound IV;
2) dissolving the compound IV obtained in the step 1) in methyl tert-butyl ether, adding triethylamine, stirring overnight, and splitting to obtain a compound III;
3) adding the compound III obtained in the step 2) into an aprotic organic solvent B, and adding a compound II, a base and a Lewis acid into the solution to react to generate a compound I.
3. A synthesis method of reed-solomon according to claim 2, wherein: the aprotic organic solvent A used in the step 1) is one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether.
4. A synthesis method of reed-solomon according to claim 2, wherein: the aprotic organic solvent B used in the step 3) is one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether and dimethylformamide.
5. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: in the step 1), the molar ratio of the compound V, N-hydroxysuccinimide to the alkali is (1.2-2): 1: (1.5-2).
6. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the alkali used in the step 1) is one of triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate and potassium bicarbonate.
7. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the molar ratio of the compound III to the compound II to the alkali to the Lewis acid in the step 3) is (1.5-2.5): 1: (1-3): (0.75 to 1.5).
8. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the base used in the step 3) is one of ethyl diisopropylamine, trimethylamine, triethylamine, 1, 8-diazabicycloundecen-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-methylmorpholine, 1-ethylpiperidine, potassium carbonate and potassium bicarbonate.
9. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the Lewis acid used in the step 3) is one of zinc chloride, zinc bromide, zinc iodide, magnesium bromide and copper chloride.
10. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the reaction in the step 3) is carried out under the condition of adding the molecular sieve, and the molecular sieve is a 4A molecular sieve.
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CN112979736B (en) * | 2021-03-04 | 2022-03-25 | 南京欧信医药技术有限公司 | Preparation method of Reidesciclovir |
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