CN114149446A - Synthesis method of Reidesciclovir D-ribonolactone - Google Patents
Synthesis method of Reidesciclovir D-ribonolactone Download PDFInfo
- Publication number
- CN114149446A CN114149446A CN202111310226.8A CN202111310226A CN114149446A CN 114149446 A CN114149446 A CN 114149446A CN 202111310226 A CN202111310226 A CN 202111310226A CN 114149446 A CN114149446 A CN 114149446A
- Authority
- CN
- China
- Prior art keywords
- compound
- ribonolactone
- reaction
- ridciclovir
- molar ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CUOKHACJLGPRHD-BXXZVTAOSA-N D-ribono-1,4-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H]1O CUOKHACJLGPRHD-BXXZVTAOSA-N 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims abstract description 30
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims abstract description 20
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims abstract description 15
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims abstract 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 26
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 19
- 238000010791 quenching Methods 0.000 claims description 19
- 230000000171 quenching effect Effects 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000003223 protective agent Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 231100000614 poison Toxicity 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 238000012544 monitoring process Methods 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-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
- 239000000126 substance Substances 0.000 description 2
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 241001678559 COVID-19 virus Species 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 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
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000006198 methoxylation reaction Methods 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229940000673 orphan drug Drugs 0.000 description 1
- 239000002859 orphan drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 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 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing Ruidexilvir D-ribonolactone, which is characterized by comprising the following three synthesis steps: s1, preparing a compound RD-1; s2, preparing a compound RD-2; s3 and preparing a target product compound RD-3. The invention adopts the low-price and easily-obtained D-ribose as the starting material, and utilizes the oxidation reaction of pyridinium chlorochromate, acetyl protection, hydroxyl protection by acetonide and the like to synthesize the Ruidexiawei D-ribonolactone, so that the synthesis process route is short, the operation difficulty is effectively simplified, and no high-temperature reaction is generated, the synthesis process is safer and more reliable, the energy is effectively saved, the yield is improved, the synthesis process can be completed without using highly toxic substances, the generation of toxic and harmful waste water is effectively avoided, the environment is improved, and the industrial production can be well realized.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a synthetic method of Rudexilvir D-ribonolactone.
Background
Redevir, a nucleoside analog, CAS registry number: 1809249-37-3, structural formula II, developed by Gilidard scientific Inc., U.S. FDA Green lights on Reidesvir (Remdesivir), approved for hospitalized patients with new coronary pneumonia. Reidesciclovir is also an orphan drug for the treatment of Ebola virus infection and also the first approved drug in the United states for use in new crown patients. Can be used for treating emergency of 2019-nCoV infected patients. Has antiviral activity, has an EC50 value of 74 nM for SARS-CoV and MERS-CoV in HAE cells, has an EC50 value of 30 nM for murine hepatitis virus in delayed brain tumor cells, has good curative effect on novel coronavirus, is a potential drug for treating novel coronavirus, and reports the synthesis and preparation method of a Redeseivir key compound 2, 3, 5-tribenzyloxy-1, 4-lactone (shown in a structural formula III, CAS registration number: 55094-52-5) compound at home and abroad.
Most of the methods (the synthetic route is shown as IV) for preparing the 2, 3, 5-tribenzyloxy-1, 4-lactone at the present stage have the advantages of high reaction temperature, easy generation of impurities, low yield, use of high-toxicity substances, high environmental protection pressure and the like;
Ⅱ
Ⅲ
Ⅳ。
for example, patent documents WO2013/158746 and WO2014/78778 report that bromine is oxidized by bromine and water, but bromine is a drug which is easy to prepare, has irritation and strong corrosivity, is difficult to transport and has low operation safety coefficient, and WO2018/053706 and WO2013/084165 report that D-ribose is used as a raw material, concentrated sulfuric acid is used for methoxylation, benzylation and hydrolysis, and DMP (dess-martin periodinane) is used for oxidation, so that the yield of each step is low, and the price of the DMP raw material is high, and the like, and are not suitable for industrialization.
While the domestic patent relates to 2, 3, 5-tribenzyloxy-1, 4-lactone, the synthetic route in the prior art is as follows:
Ⅴ
the method comprises the following steps of taking D-ribose as a starting material, using oxalyl chloride and the like as catalysts in methanol to synthesize a methoxy compound 2, adding sodium hydride and benzyl chloride or benzyl bromide, carrying out high-temperature reaction to synthesize a compound 3, using dilute sulfuric acid or dilute hydrochloric acid to catalyze the compound 3, carrying out reflux stirring overnight to obtain a compound 4, dissolving the compound 4 in dichloromethane and water, adding sodium bicarbonate and tetramethylpiperidine oxynitride, oxidizing the compound with 10% sodium hypochlorite, and carrying out stirring overnight at room temperature to obtain a compound 5 Ester) to easily derived impurities, for example, in document US2016122374, in order to avoid generating impurities, after benzyl removal, ortho hydroxyl is protected by isopropylidene to avoid impurities, and then side chain docking is performed, and acetyl protection is easy to remove, thus affecting isopropylidene protection. For this reason, a new technical solution is needed to solve the above technical solution.
Disclosure of Invention
The invention aims to provide a method for synthesizing Rudexilvir D-ribonolactone, which solves the problems of various procedures, high cost, easy impurity generation, low yield and high environmental protection pressure of the existing method for synthesizing Rudexilvir D-ribonolactone in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme: a synthetic method of Reidesciclovir D-ribonolactone is characterized in that the specific synthetic route is as follows:
Ⅰ。
the method comprises the following specific steps of:
s1, preparation of Compound RD-1: stirring and dissolving D-ribose serving as an initial raw material, a stabilizer with a molar ratio of 1: 0.01-1.0 and a solvent with a mass-volume ratio of 1:5, adding an oxidant with a molar ratio of 1: 0.1-3.0 at 0-5 ℃, carrying out an oxidation reaction at 0-5 ℃, adding sodium bisulfite after the reaction is finished, quenching for 20-40 minutes at 0-5 ℃, concentrating at 45-50 ℃ under a vacuum condition to form a reaction solution, then carrying out hot filtration by using absolute ethyl alcohol, and concentrating to obtain a compound RD-1, wherein the stabilizer is diazabicyclo, the solvent is one of tetrahydrofuran and a 50% tetrahydrofuran aqueous solution, and the oxidant is pyridinium chlorochromate;
s2, preparation of Compound RD-2: stirring and dissolving the compound RD-1 obtained in S1, a reaction solvent with a mass ratio of 1:5 and 4-dimethylaminopyridine with a molar ratio of 1:0.01, adding triethylamine, cooling to 0 ℃, dropwise adding a protective agent with a molar ratio of 1: 0.1-2.0 under the protection of nitrogen, stirring for 1-2h, adding 2M hydrochloric acid, quenching at-5 ℃ for 0.5-1.5 hours, washing with saturated sodium bicarbonate, washing with water, and concentrating to obtain a compound RD-2, wherein the reaction solvent is dichloromethane, and the protective agent is acetic anhydride;
s3, preparation of Compound RD-3: stirring and dissolving the compound RD-2 obtained in S2 and a mixed protective agent with a mass ratio of 1:3, then dropwise adding an acid catalyst with a molar ratio of 1:0.01 at room temperature, then dropwise adding triethylamine with a molar ratio of 1:1.5 at 0-5 ℃ for quenching reaction, concentrating to dry, adding ethyl acetate and water for washing, concentrating, and refining with isopropyl ether to obtain the target product compound RD-3, wherein the mixed protective agent is a mixture of acetone and methanol, the molar ratio of acetone to methanol is 1:1, and the acid catalyst is one of thionyl chloride, hydrochloric acid and sulfuric acid.
Compared with the prior art, the invention has the beneficial effects that:
1. the method for synthesizing the Ruidexiwei D-ribonolactone utilizes the reaction of pyridinium chlorochromate oxidation reaction, acetyl protection, acetonide protection on hydroxyl and the like, so that the synthetic process route is short, the operation difficulty is effectively simplified, high-temperature reaction is avoided, the synthetic process is safer and more reliable, the energy is effectively saved, the yield is improved, the synthetic process can be completed without using highly toxic substances, the generation of toxic and harmful waste water is effectively avoided, the environment is improved, and the industrial production can be well realized.
2. The method for synthesizing the Ruideciclovir D-ribonolactone adopts the cheap and easily-obtained D-ribose as the starting material, so that the production cost is reduced, the synthetic process is effectively simplified, and the environmental protection pressure is effectively improved.
Drawings
FIG. 1 is a TLC chart of S1 of the present invention;
FIG. 2 is a TLC chart showing the reaction of S2 raw material according to the present invention;
FIG. 3 is a TLC chart of the product S3 of the present invention.
Detailed Description
The following examples are intended to further illustrate the invention and are not intended to limit the application of the invention.
Example 1:
s1 preparation of Compound RD-1
Weighing 100g,0.67mol of D-ribose, 25.5g,0.165mol,0.25eq of diazabicyclo, 500ml of tetrahydrofuran, 158g,0.73mol,1.1eq of pyridinium chlorochromate;
firstly, fully stirring and dissolving D-ribose, diazabicyclo and tetrahydrofuran according to the weighed amount, cooling to 0-5 ℃ under the protection of nitrogen, then, adding pyridinium chlorochromate in batches and slowly, carrying out a reaction for 2-3 hours under the monitoring of TLC (shown in figure 1), after the reaction is finished, adding 6.5g of 62.5mmol of sodium bisulfite, quenching at 0-5 ℃, stirring for 30 minutes, concentrating at 45-50 ℃ under a vacuum condition to form a reaction solution, then, carrying out hot filtration by using absolute ethyl alcohol, and concentrating to obtain 85g of compound RD-1 as a white solid, wherein the yield is 86%.
S2 preparation of Compound RD-2
Weighing 70g, 0.5mol of compound RD-1, 350g of dichloromethane, 0.6g,0.005mol,0.01eq of 4-dimethylaminopyridine, 48.5g,0.475mol,0.95eq of acetic anhydride;
the preparation method comprises the following steps of fully stirring and dissolving the compound RD-1, dichloromethane and 4-dimethylaminopyridine according to the weighed amount, adding 2mL of triethylamine, cooling to 0 ℃, dropwise adding acetic anhydride under the protection of nitrogen, stirring for 1-2 hours, carrying out heat preservation reaction for 4-6 hours under the monitoring of TLC (shown in figure 2), adding 2M hydrochloric acid, carrying out quenching for 1 hour under the condition of-5 ℃, washing with saturated sodium bicarbonate water solution, washing with water, and concentrating to obtain 77g of oily compound RD-2, wherein the yield is 80%.
S3 preparation of Compound RD-3
77g, 0.4mol of compound RD-2, 231g of acetone, 231g of methanol, 0.5g,0.004mol,0.01eq of thionyl chloride, 60.7g,0.6mol,1.5eq of triethylamine are weighed;
under the protection of nitrogen, fully stirring and dissolving the compound RD-2, acetone and methanol according to the weighed amount, slowly dropwise adding thionyl chloride at room temperature, reacting for 2-3 hours under the monitoring of TLC (shown in figure 3), dropwise adding triethylamine at 0-5 ℃ for quenching reaction, concentrating until the reaction is finished, adding ethyl acetate and water for washing, concentrating, and refining with isopropyl ether to obtain 75g of a white solid compound RD-3, namely the target product 2, 3-isopropylidene-5-acetyl-1, 4-lactone, wherein the yield is 82%.
Example 2:
s1 preparation of Compound RD-1
Weighing 100g,0.67mol of D-ribose, 20.5g,0.135mol,0.20eq of diazabicyclo, 500ml of tetrahydrofuran, 288g, 1.34mol, 2.0eq of pyridinium chlorochromate;
firstly, stirring D-ribose, diazabicyclo and tetrahydrofuran according to the weighed amount, cooling to 0-5 ℃ under the protection of nitrogen, then, adding pyridinium chlorochromate in batches and slowly, carrying out a reaction for 2-3 hours under the monitoring of TLC (shown in figure 1), after the reaction is finished, adding 6.5g of 62.5mmol of sodium bisulfite, quenching at 0-5 ℃, stirring for 30 minutes, concentrating at 45-50 ℃ under a vacuum condition to form a reaction solution, then, carrying out hot filtration by using absolute ethyl alcohol, and concentrating to obtain 66g of a white solid compound RD-1, wherein the yield is 65%.
S2 preparation of Compound RD-2
Weighing 60g, 0.40mol of compound RD-1, 330g of dichloromethane, 0.5g,0.004mol,0.01eq of 4-dimethylaminopyridine, 41.4g,0.4mol,0.95eq of acetic anhydride;
the preparation method comprises the following steps of fully stirring and dissolving the compound RD-1, dichloromethane and 4-dimethylaminopyridine according to the weighed amount, adding 1.9mL of triethylamine, cooling to 0 ℃, dropwise adding acetic anhydride under the protection of nitrogen, stirring for 1-2 hours, carrying out heat preservation reaction for 4-6 hours under the monitoring of TLC (as shown in figure 2), adding 2M hydrochloric acid, carrying out quenching for 1 hour under the condition of-5 ℃, washing with a saturated sodium bicarbonate aqueous solution, washing with water, and concentrating to obtain 66g of oily compound RD-2, wherein the yield is 80%.
S3 preparation of Compound RD-3
Weighing 60g, 0.35mol of compound RD-2, 180g of acetone, 180g of methanol, 0.13g,0.0035mol,0.01eq of hydrochloric acid, 53.6g,0.53mol and 1.5eq of triethylamine;
under the protection of nitrogen, fully stirring and dissolving the compound RD-2, acetone and methanol according to the weighed amount, slowly dropwise adding hydrochloric acid at room temperature, reacting for 2-3 hours under the monitoring of TLC (shown in figure 3), dropwise adding triethylamine at 0-5 ℃ to perform quenching reaction, concentrating until the reaction is dry, adding ethyl acetate and water for washing, concentrating, and refining with isopropyl ether to obtain 56g of a white solid compound RD-3, namely the target product 2, 3-isopropylidene-5-acetyl-1, 4-lactone, wherein the yield is 71%.
Example 3:
s1 preparation of Compound RD-1
Weighing 100g,0.67mol of D-ribose, 25.5g,0.165mol,0.25eq of diazabicyclo, 500ml of 50% tetrahydrofuran aqueous solution, 100g, 0.5mol, 0.6eq of pyridinium chlorochromate;
firstly, fully stirring and dissolving D-ribose, diazabicyclo and 50% tetrahydrofuran aqueous solution according to the weighing amount, cooling to 0-5 ℃ under the protection of nitrogen, then, slowly adding pyridinium chlorochromate in batches, carrying out a reaction for 2-3 hours under the monitoring of TLC (shown in figure 1), after the reaction is finished, adding 6.5g of 62.5mmol of sodium bisulfite, quenching at 0-5 ℃, stirring for 30 minutes, concentrating under the vacuum condition of 45-50 ℃ to form a reaction solution, then, carrying out hot filtration by using absolute ethyl alcohol, and concentrating to obtain 60g of a white solid compound RD-1, wherein the yield is 59%.
S2 preparation of Compound RD-2
Weighing 60g, 0.40mol of compound RD-1, 300g of dichloromethane, 0.5g,0.004mol,0.01eq of 4-dimethylaminopyridine, 41.4g,0.41mol,0.95eq of acetic anhydride;
the preparation method comprises the following steps of fully stirring and dissolving the compound RD-1, dichloromethane and 4-dimethylaminopyridine according to the weighed amount, adding 1.9mL of triethylamine, cooling to 0 ℃, dropwise adding acetic anhydride under the protection of nitrogen, stirring for 1-2 hours, carrying out a heat preservation reaction for 4-6 hours under the monitoring of TLC (as shown in figure 2), adding 2M hydrochloric acid, quenching for 1 hour under the condition of 0-5 ℃, washing with a saturated sodium bicarbonate aqueous solution, washing with water, and concentrating to obtain 64g of oily compound RD-2, wherein the yield is 75%.
S3 preparation of Compound RD-3
Weighing 64g, 0.35mol of compound RD-2, 180g of acetone, 180g of methanol, 0.35g,0.0035mol,0.01eq of sulfuric acid, 53.6g,0.53mol and 1.5eq of triethylamine;
under the protection of nitrogen, fully stirring and dissolving the compound RD-2, acetone and methanol according to the weighed amount, slowly dropwise adding sulfuric acid at room temperature, reacting for 2-3 hours under the monitoring of TLC (as shown in figure 3), dropwise adding triethylamine at 0-5 ℃ for quenching reaction, concentrating until the reaction is dry, adding ethyl acetate and water for washing, concentrating, and refining with isopropyl ether to obtain 52g of a white solid compound RD-3, namely the target product 2, 3-isopropylidene-5-acetyl-1, 4-lactone, wherein the yield is 64%.
Claims (10)
1. A synthetic method of Reidesciclovir D-ribonolactone is characterized in that the specific synthetic route is as follows:
Ⅰ。
2. the method for synthesizing ridciclovir D-ribonolactone according to claim 1, wherein the specific synthesis steps are as follows:
s1, preparation of Compound RD-1: taking D-ribose as a starting material, mixing a stabilizer and a solvent, stirring for dissolving, adding an oxidant at 0-5 ℃ for reaction, adding sodium bisulfite after the reaction is finished for quenching reaction, concentrating at 45-50 ℃ under a vacuum condition to form a reaction solution, then performing hot filtration by using absolute ethyl alcohol, and concentrating to obtain a compound RD-1;
s2, preparation of Compound RD-2: stirring and dissolving a mixed reaction solvent of a compound RD-1 in S1 and 4-dimethylaminopyridine, adding triethylamine, cooling to 0 ℃, dropwise adding a protective agent under the protection of nitrogen, stirring for 1-2 hours, adding 2M hydrochloric acid for quenching reaction, washing with saturated sodium bicarbonate, washing with water, and concentrating to obtain a compound RD-2;
s3, preparation of Compound RD-3: stirring and dissolving the compound RD-2 in the S2 by using a mixed protective agent, dropwise adding an acid catalyst at room temperature, stirring for 1-3 hours, dropwise adding triethylamine at 0-5 ℃ for quenching reaction, adding ethyl acetate and water for washing, concentrating, and refining by using isopropyl ether to obtain a target product compound RD-3.
3. The method for synthesizing ridciclovir D-ribonolactone according to claim 2, wherein in S1, the molar ratio of D-ribose to stabilizer is 1: 0.01-1: 1.0, the molar ratio of D-ribose to oxidant is 1: 0.1-3.0, and the mass-to-volume ratio of D-ribose to solvent is 1: 5.
4. A synthesis method of ridciclovir D-ribonolactone according to claim 2 or 3, characterized in that the stabilizer is diazabicyclo, the solvent is one of tetrahydrofuran and 50% tetrahydrofuran water solution, and the oxidant is pyridinium chlorochromate.
5. The method for synthesizing ridciclovir D-ribonolactone according to claim 2, wherein in S1, the quenching reaction temperature is 0-5 ℃, and the quenching reaction time is 20-40 minutes.
6. The method for synthesizing ridciclovir D-ribonolactone according to claim 2, wherein in S2, the mass ratio of the compound RD-1 to the reaction solvent is 1:5, the molar ratio of the compound RD-1 to the 4-dimethylaminopyridine is 1:0.01, and the molar ratio of the compound RD-1 to the protective agent is 1: 0.1-1: 2.0.
7. A synthesis method of ridciclovir D-ribonolactone according to claim 2 or 6, characterized in that the reaction solvent is dichloromethane and the protective agent is acetic anhydride.
8. The method for synthesizing ridciclovir D-ribonolactone according to claim 2, wherein in S2, the quenching reaction temperature is-5 to 5 ℃, and the quenching reaction time is 0.5 to 1.5 hours.
9. The method for synthesizing ridciclovir D-ribonolactone according to claim 2, wherein in S3, the mass ratio of compound RD-2 to the mixed protective agent is 1:3, the molar ratio of the compound RD-2 to the acid catalyst is 1:0.01, and the molar ratio of the compound RD-2 to the triethylamine is 1: 1.5.
10. A synthesis method of ridciclovir D-ribonolactone according to claim 2 or 9, characterized in that the mixed protective agent is a mixture of acetone and methanol, the molar ratio of acetone to methanol is 1:1, and the acidic catalyst is one of thionyl chloride, hydrochloric acid and sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111310226.8A CN114149446A (en) | 2021-11-08 | 2021-11-08 | Synthesis method of Reidesciclovir D-ribonolactone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111310226.8A CN114149446A (en) | 2021-11-08 | 2021-11-08 | Synthesis method of Reidesciclovir D-ribonolactone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114149446A true CN114149446A (en) | 2022-03-08 |
Family
ID=80459635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111310226.8A Pending CN114149446A (en) | 2021-11-08 | 2021-11-08 | Synthesis method of Reidesciclovir D-ribonolactone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114149446A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205327A (en) * | 2020-02-17 | 2020-05-29 | 南京法恩化学有限公司 | Preparation method of Reidesciclovir |
-
2021
- 2021-11-08 CN CN202111310226.8A patent/CN114149446A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205327A (en) * | 2020-02-17 | 2020-05-29 | 南京法恩化学有限公司 | Preparation method of Reidesciclovir |
Non-Patent Citations (4)
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS62242663A (en) | Manufacture of 1-deoxynojirimicin and n-derivative of same | |
| CN114395009B (en) | High-purity cholesterol synthesis method | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN114149446A (en) | Synthesis method of Reidesciclovir D-ribonolactone | |
| CN110437160B (en) | Preparation method of uracil | |
| CN108911954B (en) | Preparation method of trimethylhydroquinone | |
| US4982016A (en) | Conversion of diethyl phenylmalonate to 2-phenyl-1,3-propanediol | |
| CN114106063B (en) | Preparation method of anti-HIV (human immunodeficiency virus) medicine itravir | |
| CN115677483A (en) | Method for preparing o-carboxybenzaldehyde | |
| CN109824687B (en) | Novel synthetic method of xylofuranose derivative | |
| CN113717197A (en) | Preparation method and application of antituberculosis drug Pretomanid | |
| CN112010793B (en) | Synthetic method of 2-methylsulfonyl-4-trifluoromethylbenzoic acid | |
| CN108610322B (en) | Preparation method of R-glyceraldehyde acetonide | |
| CN113501771A (en) | Preparation method of N- (2-aminoethyl) glycine derivative | |
| CN105566182A (en) | Synthetic method of 2-amino-4-(ethylsulfonyl) phenol | |
| CN1201795A (en) | Preparation of 7-amino-deacetylated cefa-alkylation acid | |
| CN114560894B (en) | Preparation method of anti-new crown medicine Molnupiravir | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN108997454B (en) | Chemical synthesis method of beta-arbutin | |
| CN115925776A (en) | Method for preparing rocuronium bromide intermediate | |
| CN116284190A (en) | Pseudo-uridine intermediate, and preparation method and application thereof | |
| CN1021772C (en) | Preparation method of anti-form-cyclopentane-1,2-dicarboxylic acid | |
| CN113698292A (en) | Preparation method of 6-hydroxy-2-naphthoic acid | |
| CN114349631A (en) | Preparation method and application of 4-methoxy crotonic acid | |
| CN114292166A (en) | Preparation method of 2, 2-diethoxyethanol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |