CN111233930A - Preparation method of Reidesciclovir - Google Patents

Preparation method of Reidesciclovir Download PDF

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Publication number
CN111233930A
CN111233930A CN202010143482.1A CN202010143482A CN111233930A CN 111233930 A CN111233930 A CN 111233930A CN 202010143482 A CN202010143482 A CN 202010143482A CN 111233930 A CN111233930 A CN 111233930A
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ridciclovir
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butyl
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CN111233930B (en
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陈本顺
江涛
朱萍
程刚
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Jiangsu Alpha Pharmaceutical Co ltd
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    • 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
    • C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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Abstract

The invention discloses a preparation method of Reidesciclovir, belonging to the field of pharmaceutical chemicals, and the invention is characterized in that a compound V and 4-trifluoromethoxyphenol react under the action of alkali to obtain a compound IV; carrying out chiral resolution on the compound IV to obtain a compound III; and carrying out acid hydrolysis reaction on the compound III and the compound II under the action of organic base with large steric hindrance to obtain the compound I. The method disclosed by the invention avoids the use of nitro substitutes with genotoxicity, reduces the risk of genotoxicity impurities, and is suitable for industrial large-scale production.

Description

Preparation method of Reidesciclovir
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of Reidesvir.
Background
At present, there is no clear specific drug available for treatment with the new coronavirus pneumonia epidemic situation. Recently some scientists at the washington state health office reported that a drug named Reidesvir (remdesivir) might be effective in treating novel coronaviruses and suggested a possible mechanism of action of this drug, inhibiting the production of the viral RdRP protein.
Reddeivir (Remdesivir) is a nucleoside analog 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. In vitro and animal models, Reidesvir (Remdesivir) has proven activity against viral pathogens of atypical pneumonia (SARS) and Middle East Respiratory Syndrome (MERS), also belongs to coronavirus, and is structurally very similar to 2019-nCoV, so Reidesvir is likely to play a therapeutic role in epidemic situations caused by similar viruses in the future. Although the Reidesciclovir is not yet on the market at present, the Reidesciclovir has a very wide market prospect and certain strategic value. The structure is shown as the following formula I:
Figure 100002_DEST_PATH_IMAGE001
in a second generation of synthesis method reported in Nature 2016 (Warren T K, Jordan R, Lo M K, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkey [ J ]. Nature 2016, 531(7594): 381-385.), a preparation method of Reidesvir is disclosed, in which compound VI is prepared by resolving p-nitrophenol as a leaving group, and then the Reidesvir is obtained by docking with compound II. The method uses nitro substituent with genotoxicity, which is explosive substance, and increases risk of genotoxicity impurity.
Therefore, the development of a substitute avoiding genotoxicity has important significance in the preparation and production of the Reidesvir.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a non-genotoxic reagent as a leaving group for preparing and producing Reidesvir.
In order to solve the technical problems, the technical scheme of the invention is as follows:
the preparation method of the Reidesciclovir comprises the following synthetic route:
Figure 381599DEST_PATH_IMAGE002
the method comprises the following steps:
1) reacting the compound V with 4-trifluoromethoxyphenol under the action of alkali to obtain a compound IV;
2) resolving the compound IV to obtain a compound III;
3) under the action of organic base with large steric hindrance, the compound III reacts with the compound II, and the compound I is obtained through acid hydrolysis.
As a preferable technical scheme, the molar ratio of the compound V to the 4-trifluoromethoxyphenol in the step 1) is 1-1.2: 1.
As a preferable technical scheme, the alkali used in the step 1) is triethylamine, the triethylamine is dropwise added at the temperature of 0-10 ℃, the reaction temperature in the step 1) is 15-20 ℃, and the reaction time is 12-24 hours. After the compound V and 4-trifluoromethoxyphenol are added, dropwise adding a dichloromethane solution containing triethylamine at a temperature of 0-10 ℃, slowly returning to room temperature (15-20 ℃) after dropwise adding, and stirring for 12-24 hours at the room temperature (15-20 ℃).
As a preferred technical scheme, the mode of adding raw materials in the step 1) is as follows: adding dichloromethane, a compound V and 4-trifluoromethoxyphenol under the protection of nitrogen, cooling to 0-5 ℃, and then slowly dropping dichloromethane solution containing triethylamine, wherein the volume ratio of the dichloromethane added for the first time to the dichloromethane containing triethylamine is 10: 3.
As a preferable technical scheme, the resolution process in the step 2) is specifically that the compound IV is dissolved in ether and alkane solvents at normal temperature, then the temperature is reduced to-50 to-20 ℃, and the mixture is stirred for 12 to 24 hours, so that the compound III is precipitated. Specifically, under the protection of nitrogen, dissolving a compound IV in an ether solvent and an alkane solvent, cooling to-50 to-20 ℃, and stirring at the temperature for 12-24 hours.
As a preferable technical scheme, in the step 2), the ether solvent is selected from one or more of methyl isopropyl ether, methyl tert-butyl ether and di (isopropyl) ether, and the hydrocarbon solvent is selected from C5-C7Is a straight or branched chain saturated or unsaturated hydrocarbon.
As a preferable technical scheme, the molar ratio of the organic base, the compound II and the compound III in the step 3) is (2.0-2.2): 1: (1.5-1.9).
As a preferable technical solution, in the step 3), the organic base with large steric hindrance is selected from one of tert-butyl magnesium chloride, tert-butyl magnesium bromide, tert-butyl sodium alkoxide, tert-butyl potassium alkoxide, tert-butyl lithium, lithium hexamethyldisilazide or sodium hexamethyldisilazide.
As a preferable technical solution, the acid in the step 3) is selected from one of hydrochloric acid and acetic acid.
Practice proves that 4-trifluoromethoxyphenol is used as a leaving group, the reactivity is good in each step of reaction, the effect is good in chiral resolution, and the overall yield of the product is improved.
The invention discloses a preparation method of Reidexilvir, which avoids the use of nitro substitutes with genotoxicity, reduces the risk of genotoxicity impurities and is suitable for industrial large-scale production.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1:
preparation of compound IV:
adding dichloromethane (100 mL), a compound V (16.48 g, 47.4 mmol) and 4-trifluoromethoxyphenol (8.01 g, 45.0 mmol) into a round-bottom flask under the protection of nitrogen, cooling to 0 ℃, then slowly dropping a dichloromethane solution (30 mL) containing triethylamine (6.28 mL), keeping the temperature of the solution in the round-bottom flask not higher than 5 ℃, after dropping, slowly raising the temperature to room temperature (15-20 ℃) and stirring at the room temperature for 24 hours; adding cold water (100 g of ice and water, and cooling the system to 0-5 ℃, wherein the ice is added firstly to cool, and the temperature is below 5 ℃ finally, but solid ice does not exist, the other embodiments are the same), stirring, layering, washing an organic layer with saturated saline water, and then using 10gMg to wash the organic layer2SO4Stirring and drying. After filtration, the organic layer was concentrated, then 100mL of toluene was added, and the mixture was evaporated to dryness under reduced pressure to obtain 21.37g of crude compound IV with a molar yield of 97% (i.e., 0.97 mol of crude compound IV per mol of 4-trifluoromethoxyphenol) which was used for the next resolution without further purification.
Preparation of compound III:
compound IV (21.37 g, 43.7 mmol) was added to 30mL of methyl tert-butyl ether under nitrogen, followed by 50mL of petroleum ether, cooled to-20 deg.C, and stirred at this temperature for 24 h. Filtering while the solution is cold, washing the solid with petroleum ether at-20 ℃ to obtain a compound III, further recrystallizing the compound III with petroleum ether to obtain a high-purity compound III, and drying to obtain 9.15g of a product with the molar yield of 42.8%.
Preparation of compound I:
compound II (314mg, 0.95mmol) and 25mL of anhydrous tetrahydrofuran were added to a reaction flask under nitrogen, cooled to 0 deg.C, and then a 1.3M solution of tert-butylmagnesium chloride (i.e., 1.5mL, 2mmol added) was slowly added dropwise. After stirring for 30min, compound III (883 mg, 1.8 mmol) was added. The mixture was stirred at room temperature for 48h, then saturated NH was used4Aqueous Cl (50 mL) was quenched. The mixture was partitioned between ethyl acetate (100 mL) and water. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue using a 0-4% methanol/dichloromethane gradient gave 298mg of a white solid in 49 mole yield (i.e., 0.49 moles of white solid per mole of compound II).
The compound (i.e., white solid) is added with 5mL of acetone, 10% hydrochloric acid is added to adjust the pH value to 3-4, the mixture is stirred for 2 hours at room temperature, the solvent is concentrated under reduced pressure, the mixture is dissolved by 10mL of ethyl acetate, the dissolved solvent is washed by 10mL of saturated sodium bicarbonate, the washed solvent is washed by 10mL of saturated saline, liquid separation is carried out, the dried product is dried by anhydrous sodium sulfate and then concentrated under reduced pressure, and the product (compound I) is obtained in 243mg of yield (the molar yield is 87% (namely, 0.87 mol of compound I is obtained per mol of white solid).
1H-NMR(400MHz，CDCl3)：δ7.81（1H），7.30-7.19（2H），7.15-7.09（3H），6.90-6.81（2H），5.32-5.20（3H），4.95(1H)，4.50（1H），4.36-4.20（2H），4.02（1H），3.90-3.80（2H），1.71-1.40（7H），1.21（1H），1.01（6H）。
Example 2:
preparation of compound IV:
under nitrogen protection, compound V (15.62 g, 4) was added to a round bottom flask5mmol) and 4-trifluoromethoxyphenol (8.01 g, 45.0 mmol) and dichloromethane (100 mL), cooling to 5 ℃, slowly adding a dichloromethane solution (30 mL) containing triethylamine (6.28 mL) to the reaction system dropwise, keeping the temperature of the solution in the round-bottom flask below 10 ℃, after dropwise addition, slowly heating to room temperature (15-20 ℃), and stirring at room temperature for 12 h; adding cold water (100 g of ice and water, cooling the system to 0-5 ℃), cooling the system to 5 ℃, stirring, layering, washing the organic layer with saturated saline water, and then washing with 10g of Mg2SO4Stirring and drying. After filtration, the organic layer was concentrated, then 100mL of toluene was added, and the mixture was evaporated to dryness under reduced pressure to give 21.1g of crude compound IV in 95.8% molar yield (i.e., 0.958 mole of crude compound IV per mole of 4-trifluoromethoxyphenol) which was used directly for the next resolution without further purification.
Preparation of compound III:
under the protection of nitrogen, compound IV (21 g, 42.9 mmol) is added into 30mL of isopropyl ether, then 50mL of n-hexane is added, the temperature is reduced to-20 ℃, and the mixture is stirred at the temperature for 12 h. Filtering while the solution is cold, washing the solid with petroleum ether at-20 ℃ to obtain a compound III, further recrystallizing the compound III with petroleum ether to obtain a high-purity compound III, and drying to obtain 9.18g of a product with the molar yield of 43.7%.
Preparation of compound I:
under nitrogen protection, compound II (3.0g, 9.06mmol) and 250mL of anhydrous tetrahydrofuran were added to a reaction flask, the temperature was lowered to 0 ℃, and then 2.23g (19.9 mmol) of potassium tert-butoxide was slowly added. After stirring for 30-40 min, compound III (7.5 g, 15.3 mmol) was added. The mixture was stirred at room temperature for 48h, then saturated NH was used4Aqueous Cl (500 mL). The mixture was partitioned between ethyl acetate (1000 mL) and water. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue using a 0-4% methanol/dichloromethane gradient gave 3.15g of a white solid in 54.1 mole yield (i.e., 0.541 moles of white solid per mole of compound II).
After 2g of the above-mentioned compound (i.e., white solid) was added to 50mL of acetone and 1g of 30% acetic acid, and stirred at room temperature for 4 hours, the solvent was concentrated under reduced pressure, and then dissolved in 100mL of ethyl acetate, washed with 70mL of saturated sodium bicarbonate, washed with 100mL of saturated saline, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.65g of the product (compound I) in 88% molar yield (i.e., 0.88 mol of compound I per mol of white solid).
Example 3:
preparation of compound IV:
adding a compound V (18.74 g, 54 mmol), 4-trifluoromethoxyphenol (8.01 g, 45.0 mmol) and dichloromethane (100 mL) into a round-bottomed flask under the protection of nitrogen, cooling to 5 ℃, then slowly dropwise adding a dichloromethane solution (30 mL) containing triethylamine (6.28 mL), keeping the temperature of the solution in the round-bottomed flask below 10 ℃, after dropwise adding, slowly raising the temperature to room temperature (15-20 ℃) and stirring at the room temperature for 16 hours; adding cold water (100 g of ice and water, cooling the system to 0-5 ℃), stirring, layering, washing the organic layer with saturated saline water, and then washing with 10g of Mg2SO4Stirring and drying. After filtration, the organic layer was concentrated, then 100mL of toluene was added, and the mixture was evaporated to dryness under reduced pressure to obtain 21.2g of crude compound IV in 96.3% molar yield (i.e., 0.963 mol of crude compound IV per mol of 4-trifluoromethoxyphenol) which was used for the next resolution without further purification.
Preparation of compound III:
under the protection of nitrogen, compound IV (21 g, 42.9 mmol), isopropyl ether 10mL and methyl tert-butyl ether 20 mL are added into a reactor, then n-hexane 50mL is added, the temperature is reduced to-20 ℃, and the mixture is stirred at the temperature for 16 h. Filtering while the solution is cold, washing the solid with petroleum ether at-20 ℃ to obtain a compound III, further recrystallizing the compound III with petroleum ether to obtain a high-purity compound III, and drying to obtain 9.20g of a product with the molar yield of 43.8%.
Preparation of compound I:
under nitrogen protection, compound II (3.0g, 9.06mmol) and 250mL of anhydrous tetrahydrofuran were added to a reaction flask, the temperature was lowered to 0 ℃, and then 3.03 g (18.1 mmol) of lithium hexamethyldisilazide was slowly added. After stirring for 30-40 min, compound III (6.65 g, 13.6 mmol) was added. The mixture was stirred at room temperature for 48h, then saturated NH was used4Aqueous Cl solution(500 mL) quench. The mixture was partitioned between ethyl acetate (500 mL) and water. The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue using a 0-4% methanol/dichloromethane gradient gave 3.1g of a white solid in 53.3 mole yield (i.e., 0.533 moles of white solid per mole of compound II).
Taking 2g of the compound (namely, white solid), adding 50mL of acetone, adding 10% hydrochloric acid to adjust the pH value to 3-4, stirring at room temperature for 3 hours, concentrating under reduced pressure to remove the solvent, dissolving with 100mL of ethyl acetate, washing with 70mL of saturated sodium bicarbonate, washing with 100mL of saturated saline solution, separating, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 1.72g of the product (compound I) with the molar yield of 91.7% (namely, 0.917 mol of compound I is obtained per mol of white solid).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (9)

1. A preparation method of Reidesciclovir is characterized in that: the method comprises the following steps:
1) reacting the compound V with 4-trifluoromethoxyphenol under the action of alkali to obtain a compound IV;
2) carrying out manual resolution on the compound IV obtained in the step 1) to obtain a compound III;
3) reacting the compound III obtained in the step 2) with a compound II under the action of organic base with large steric hindrance, and performing acid hydrolysis to obtain a compound I;
the specific reaction route is as follows:
Figure DEST_PATH_IMAGE001
。
2. a process for preparing ridciclovir according to claim 1, characterized in that: the molar ratio of the compound V to the 4-trifluoromethoxyphenol in the step 1) is 1-1.2: 1.
3. a process for preparing ridciclovir according to claim 1, characterized in that: the alkali used in the step 1) is triethylamine, the temperature is controlled at 0-10 ℃, the dropwise addition is carried out, the reaction temperature in the step 1) is 15-20 ℃, and the reaction time is 12-24 hours.
4. A process for preparing ridciclovir according to claim 3, characterized in that: the mode of adding raw materials in the step 1) is as follows: adding dichloromethane, a compound V and 4-trifluoromethoxyphenol under the protection of nitrogen, cooling to 0-5 ℃, and then slowly dropping dichloromethane solution containing triethylamine, wherein the volume ratio of the dichloromethane added for the first time to the dichloromethane containing triethylamine is 10: 3.
5. A process for preparing ridciclovir according to claim 1, characterized in that: the resolution process in the step 2) is specifically that the compound IV is dissolved in ether and alkane solvents at normal temperature, then the temperature is reduced to-50 to-20 ℃, and the mixture is stirred for 12 to 24 hours, so that the compound III is separated out.
6. A process for preparing Reidesciclovir according to claim 5, wherein: the ether solvent is selected from one or more of methyl isopropyl ether, methyl tert-butyl ether and di (isopropyl ether), and the hydrocarbon solvent is selected from C5-C7Is a straight or branched chain saturated or unsaturated hydrocarbon.
7. A process for preparing ridciclovir according to claim 1, characterized in that: the molar ratio of the organic base to the compound II to the compound III in the step 3) is (2.0-2.2): 1: (1.5-1.9).
8. A process for preparing ridciclovir according to claim 1, characterized in that: the organic base with large steric hindrance in the step 3) is selected from one of tert-butyl magnesium chloride, tert-butyl magnesium bromide, tert-butyl sodium alkoxide, tert-butyl potassium alkoxide, tert-butyl lithium, hexamethyl disilazane lithium or hexamethyl disilazane sodium.
9. A process for preparing ridciclovir according to claim 1, characterized in that: in the step 3), the acid is selected from one of hydrochloric acid and acetic acid.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111620903A (en) * 2020-06-17 2020-09-04 安徽贝克联合制药有限公司 C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir
CN113004330A (en) * 2020-08-22 2021-06-22 齐鲁制药有限公司 Preparation method of high-purity Reidesvir
WO2022029704A1 (en) 2020-08-06 2022-02-10 Richter Gedeon Nyrt. Remdesivir intermediates
CN114146091A (en) * 2020-09-08 2022-03-08 北京箭牧科技有限公司 Application of ridiflovir in preparation of medicine for preventing and treating reperfusion injury
CN114560876A (en) * 2021-01-26 2022-05-31 浙江永太科技股份有限公司 Ruidexiwei related substance and preparation method thereof
WO2022142396A1 (en) * 2020-12-28 2022-07-07 尚科生物医药（上海）有限公司 Preparation method for remdesivir intermediate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016069825A1 (en) * 2014-10-29 2016-05-06 Gilead Sciences, Inc. Methods for the preparation of ribosides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016069825A1 (en) * 2014-10-29 2016-05-06 Gilead Sciences, Inc. Methods for the preparation of ribosides

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111620903A (en) * 2020-06-17 2020-09-04 安徽贝克联合制药有限公司 C-nucleoside analogue, preparation method and application of nitrile-containing C-nucleoside compound for synthesizing Rudexilvir
WO2022029704A1 (en) 2020-08-06 2022-02-10 Richter Gedeon Nyrt. Remdesivir intermediates
CN113004330A (en) * 2020-08-22 2021-06-22 齐鲁制药有限公司 Preparation method of high-purity Reidesvir
CN114146091A (en) * 2020-09-08 2022-03-08 北京箭牧科技有限公司 Application of ridiflovir in preparation of medicine for preventing and treating reperfusion injury
WO2022142396A1 (en) * 2020-12-28 2022-07-07 尚科生物医药（上海）有限公司 Preparation method for remdesivir intermediate
CN114560876A (en) * 2021-01-26 2022-05-31 浙江永太科技股份有限公司 Ruidexiwei related substance and preparation method thereof

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