CN113004330A - Preparation method of high-purity Reidesvir - Google Patents
Preparation method of high-purity Reidesvir Download PDFInfo
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- CN113004330A CN113004330A CN202010852682.4A CN202010852682A CN113004330A CN 113004330 A CN113004330 A CN 113004330A CN 202010852682 A CN202010852682 A CN 202010852682A CN 113004330 A CN113004330 A CN 113004330A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- -1 acetonylidene protecting group Chemical group 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 229910052802 copper Inorganic materials 0.000 claims description 15
- 239000010949 copper Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- MPTQRFCYZCXJFQ-UHFFFAOYSA-L copper(II) chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Cu+2] MPTQRFCYZCXJFQ-UHFFFAOYSA-L 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012445 acidic reagent Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012071 phase Substances 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
- 238000012360 testing method Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 239000003643 water by type Substances 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- YJKXXWQTIJDTET-UHFFFAOYSA-N 2-ethylbutyl propanoate Chemical compound CCC(CC)COC(=O)CC YJKXXWQTIJDTET-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241001115402 Ebolavirus Species 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 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
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial 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
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])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
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a compound shown as a formula I, namely Reidesvir. The method has the advantages of simple operation, mild reaction conditions, few side reactions, high yield, high purity, reduced cost and operation risk, environmental protection and suitability for large-scale industrial production.
Description
Technical Field
The application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of high-purity Reidesvir.
Background
Reddeivir (Remdesivir, formula I), is an in-the-research 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 synthesis process of the Reidesciclovir mainly comprises two routes, which are as follows:
route 1: the route reported by patent W02016069826 of original Ministry of Gmelide: 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, and is not suitable for industrial production because the purification is carried out by a chiral column.
Route 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 can be scaled up to hundredths in the laboratory. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. The route is optimized for route 1, during the cyano substitution step, the isomer ratio of the obtained product is 95:5 by adding trifluoromethanesulfonic acid, the ratio of the desired beta-anomer is greatly increased by trifluoromethanesulfonic acid, and the chiral purity can be further increased by subsequent recrystallization.
In the prior art, the protecting group of the deacetone is protected by acidic reagents, such as acidic reagents of hydrochloric acid, formic acid, acetic acid and the like, as reported in patents of US20160122374, US20170071964, CN111171078 and the like. Under the condition of an acidic reagent, deprotection is carried out, a large number of byproducts are generated in the reaction, a large number of degradation impurities A and B are generated, and the product is not easy to purify, so that the final product of the Rudexiluwei is low in purity and low in route yield. In addition, the acid reagents are seriously corroded by equipment, a large amount of acid waste liquid is not easy to treat, the environment is polluted, and the environment is not friendly.
Disclosure of Invention
Aiming at the defects in the prior art, the inventor provides a novel preparation method of the Rudexiluwei through a large amount of experimental research, the method is simple and convenient to operate, the reaction condition is mild, the contents of the impurity A and the impurity B are effectively controlled, and the prepared Rudexiluwei has the advantages of good purity, high yield, low route cost and environmental friendliness, and is suitable for large-scale industrial production.
Specifically, the invention provides a preparation method for removing an acetonylidene protecting group from a compound A-1 under the action of copper halide to obtain the Reidesciclovir, which comprises the following steps:
the reaction steps are as follows:
(1) adding the compound A-1 and a reaction solvent into a reaction bottle, and stirring until the compound A-1 and the reaction solvent are dissolved;
(2) adding copper halide into a reaction bottle, heating and reacting;
(3) and after the reaction is finished, carrying out liquid separation, washing, drying and concentrating to obtain the Reidesvir.
Wherein, in the step (1), the solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane and N, N-dimethylformamide, and acetonitrile is preferred;
in the step (2), the copper halide is selected from one or more of copper chloride, copper bromide and copper iodide, and is preferably copper chloride;
the molar ratio of the compound A-1 in the step (1) to the copper halide in the step (2) is 1: 1-50, preferably 1: 2 to 20, more preferably 1: 3-12;
in the step (2), the reaction temperature is 20-100 ℃, preferably 40-80 ℃, and more preferably 55-65 ℃; the reaction time is 1 to 10 hours, preferably 3 to 4 hours.
The invention has the beneficial effects that:
firstly, the invention provides a novel preparation method of the Reidesvir, the production of impurities is effectively reduced by adopting copper halide to perform deacetony protection, and the prepared Reidesvir has high yield and good purity;
and secondly, the preparation method provided by the invention is simple and convenient to operate, mild in reaction conditions, environment-friendly, green and economical, and can effectively control the generation of waste acid and waste liquid.
It should be noted that, unless otherwise specified, the amounts of the reaction solvent and the related reagents are the conventional amounts for the reaction, and can be determined by those skilled in the art according to the prior art; the reagents used in the invention are all conventional reagents and can be purchased from the market, and the used starting materials can be prepared by the existing literature or purchased from the market.
The copper halide used in the present invention includes a hydrated form thereof, and when the hydrated form is used, the molar ratio of the compound a-1 to the copper halide described herein is the molar ratio of the compound a-1 to the copper halide hydrate. For example, copper chloride as used herein may refer to anhydrous copper chloride or copper chloride dihydrate.
The medium reaction temperature of the invention, for example, the temperature is raised to 60 +/-5 ℃, which means that the reaction can be smoothly carried out within the range of 55 ℃ to 65 ℃, and comprises 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃ and 65 ℃.
Detailed Description
The foregoing and other aspects of the present invention are achieved by the following detailed description, which should not be construed to limit the claimed subject matter in any way. All technical solutions realized based on the above contents of the present invention belong to the scope of the present invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. It is clear to those skilled in the art that, unless otherwise specified, the operation of the present invention is carried out under the ambient temperature conditions conventional in the art, and the ambient temperature has the technical meaning well known in the art, and generally means 10 to 30 ℃, preferably 15 to 25 ℃, and more preferably 20 to 25 ℃.
NMR instrument information: bruker NEO apparatus, 400MHz, determination solvent is deuterated dimethyl sulfoxide (DMSO-d)6) Internal standard is Tetramethylsilane (TMS).
HPLC detection conditions: waters e2695, Waters X-Bridge shield RP18(4.6mm 150mm, 3.5um) chromatography column; mobile phase A: 20mmol/L ammonium acetate solution, mobile phase B: methanol; gradient elution; flow rate: 0.9 ml/min; column temperature: 50 ℃; detection wavelength: 245nm/260 nm.
Example 1: preparation of (3aR,4R,6R,6aR) -4- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxacene-4-carbonitrile
(2R,3R,4S,5R) -2- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -3, 4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-carbonitrile (5.9g), 2.2-dimethoxypropane (15g), p-toluenesulfonic acid (2.5g) was added to acetone (15 ml). Reacting at 25 ℃ for 2h, after the reaction is finished, adding ethyl acetate (12ml) and 5% sodium bicarbonate (20ml), and concentrating the organic phase under reduced pressure to obtain the target product with the yield of 95.0%.
1HNMR(400MHz,DMSO-d6):δ：7.96(br,3H),6.89-6.92(m,2H),5.36-5.38(d,1H),5.01-5.04(t,1H),4.88-4.91(dd,1H),4.31-4.31(m,1H),3.49–3.55(m,2H),1.63(s,3H),1.37(s,3H).
MS(ESI)M/Z:332.1[M+H]+.
Example 2: preparation of (S) -2- (((S) - (((3aR,4R,6R,6aR) -6- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6-cyano-2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] Dioxon-4-yl) methoxy) (phenoxy) phosphoryl) amino) propanoic acid-2-ethylbutyl ester
(3aR,4R,6R,6aR) -4- (4-Aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxacene-4-carbonitrile (6.0g), N- [ (S) - (4-Nitrophenoxy) (phenoxy) phosphoryl ] -L-alanine-2-ethylbutyl ester (10.0g) and magnesium chloride (1.5g) were added to acetonitrile (120ml), diisopropylethylamine (10.0g) was added, and the reaction was carried out while maintaining the temperature at 25 ℃. After completion of the reaction, ethyl acetate (120ml) and purified water (100ml) were extracted, dried over anhydrous sodium sulfate (1g), and the organic phase was concentrated under reduced pressure and directly charged into the next step.
1HNMR(400MHz,DMSO-d6):δ：7.95(br,1H),7.29-7.34(m,2H),7.12-7.17(m,3H),6.912–6.92(m,1H),6.86-6.87(d,1H),6.02-6.08(dd,1H),5.32-5.34(d,1H),4.92-4.94(m,1H),4.51-4.52(m,1H),4.10-4.14(m,2H),3.94-3.98(m,1H),3.85-3.89(m,1H),3.77-3.79(m,1H),1.64(s,3H),1.37–1.45(m,4H),1.19-1.30(m,7H),0.79-0.83(t,6H).
MS(ESI)M/Z:643.1[M+H]+.
Example 3: preparation of Reidesciclovir
10.0g of intermediate A-1 was dissolved in 100ml of acetonitrile, and 7.96g of copper chloride (dihydrate) was added with stirring; heating to 60 +/-5 ℃, and reacting for 3.5 h; cooling to 25 +/-5 ℃; adding ethyl acetate, 10% ammonia water and saturated sodium chloride into the system, stirring and extracting, and separating liquid; extracting the aqueous phase with ethyl acetate; combining the organic phases, and washing with a mixed solution of 10% ammonia water and saturated sodium chloride; washing the organic phase with saturated sodium chloride solution; dried by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 7.96g of the Reidesciclovir with the yield of 84.9 percent, the HPLC purity of 90.43 percent, the content of the impurity A of 0.8 percent and the content of the impurity B of 2.0 percent.
1HNMR(400MHz,DMSO-d6):δ：7.94(s,1H),7.88(s,2H),7.32-7.36(m,2H),7.15-7.21(m,3H),6.84-6.91(m,2H),6.35-6.36(d,1H),6.02-6.08(m,1H),5.38-5.40(d,1H),4.64-4.67(m,1H),3.80-4.27(m,7H),1.25-1.27(m,1H),1.20-1.23(m,7H),0.76-0.80(m,6H).
MS(ESI)M/Z:603.2[M+H]+，1205.5[2M+H]+，601.2[M-H]-.
Example 4: preparation of Reidesciclovir
2kg of intermediate A-1 was dissolved in 20L of acetonitrile, and 6.4kg of copper chloride (dihydrate) was added with stirring; heating to 60 +/-5 ℃, and reacting for 3.5 h; cooling to 25 +/-5 ℃; adding ethyl acetate, 10% ammonia water and saturated sodium chloride into the system, stirring and extracting, and separating liquid; extracting the aqueous phase with ethyl acetate; combining the organic phases, and washing with a mixed solution of 10% ammonia water and saturated sodium chloride; washing the organic phase with saturated sodium chloride solution; drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 1.58kg of Reidesciclovir with yield of 84.6%, HPLC purity of 91.26%, impurity A content of 0.70%, and impurity B content of 1.93%.
Example 5: preparation of Reidesciclovir
10.0g of intermediate A-1 was dissolved in 100ml of acetonitrile, and 34.8g of copper bromide was added with stirring; heating to 60 +/-5 ℃, and reacting for 3.5 h; cooling to 25 +/-5 ℃; adding ethyl acetate, 10% ammonia water and saturated sodium chloride into the system, stirring and extracting, and separating liquid; extracting the aqueous phase with ethyl acetate; combining the organic phases, and washing with a mixed solution of 10% ammonia water and saturated sodium chloride; washing the organic phase with saturated sodium chloride solution; drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 8.02g of Reidesciclovir with yield of 85.6%, HPLC purity of 92.16%, impurity A content of 0.63%, and impurity B content of 1.88%.
Example 6: preparation of Reidesciclovir (concentrated hydrochloric acid)
10.0g of the intermediate A-1 is added into 100ml of concentrated hydrochloric acid with the mass fraction of 36% -38%, and the reaction is carried out for 12h at 25 ℃ to obtain the Reidcisvir, wherein the HPLC purity is 45.77%, and the content of the impurity A is 13.7%.
Example 7: preparation of Reidesciclovir (trifluoroacetic acid)
10.0g of the intermediate A-1 is added into 100ml of trifluoroacetic acid and 20ml of purified water, and the reaction is carried out for 18h at 0 ℃ to obtain 8.5g of the Reideciclovir, wherein the HPLC purity is 62.2%, the content of the impurity A is 6.0%, and the content of the impurity B is 17.19%.
Example 8: preparation of Reidesciclovir (formic acid)
10.0g of the intermediate A-1 is added into 100ml of formic acid and 20ml of purified water, and reacted for 12 hours at 50 ℃ to obtain the Reidexilvir, wherein the HPLC purity is 38.04%, the content of the impurity A is 17.21%, and the content of the impurity B is 29.11%.
Claims (10)
1. A preparation method of a compound Rudexilvir shown in a formula I is characterized in that,
removing the acetonylidene protecting group of the compound A-1 under the action of copper halide to obtain the Reidcisvir:
2. the method according to claim 1, characterized in that it comprises the following reaction steps:
(1) adding the compound A-1 and a reaction solvent into a reaction bottle, and stirring until the compound A-1 and the reaction solvent are dissolved;
(2) adding copper halide into a reaction bottle, heating and reacting;
(3) and after the reaction is finished, carrying out liquid separation, washing, drying and concentrating to obtain the Reidesvir.
3. The preparation method according to claim 2, wherein the solvent in step (1) is selected from one or more of acetonitrile, ethyl acetate, dichloromethane and N, N-dimethylformamide.
4. The production method according to claim 2, wherein the solvent in step (1) is selected from acetonitrile.
5. The preparation method according to claim 2, wherein the copper halide in step (2) is selected from one or more of copper chloride, copper bromide, and copper iodide.
6. The production method according to claim 2, wherein the copper halide in step (2) is selected from copper chloride.
7. The production method according to claim 2, wherein the molar ratio of the compound a-1 in the step (1) to the copper halide in the step (2) is 1: 1 to 50.
8. The production method according to claim 2, wherein the molar ratio of the compound a-1 in the step (1) to the copper halide in the step (2) is 1: 2 to 20.
9. The production method according to claim 2, wherein the molar ratio of the compound a-1 in the step (1) to the copper halide in the step (2) is 1: 3 to 12.
10. The method according to claim 2, wherein in the step (2), the reaction temperature is 20 to 100 ℃, preferably 40 to 80 ℃, more preferably 55 to 65 ℃; the reaction time is 1 to 10 hours, preferably 3 to 4 hours.
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