CN111233931B - Synthesis method of Reidesciclovir - Google Patents
Synthesis method of Reidesciclovir Download PDFInfo
- Publication number
- CN111233931B CN111233931B CN202010222507.7A CN202010222507A CN111233931B CN 111233931 B CN111233931 B CN 111233931B CN 202010222507 A CN202010222507 A CN 202010222507A CN 111233931 B CN111233931 B CN 111233931B
- Authority
- CN
- China
- Prior art keywords
- compound
- synthesis
- alkali
- ridciclovir
- solvent
- 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.)
- Active
Links
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 System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a synthesis method of Reidesciclovir, belonging to the field of pharmaceutical chemicals, and the invention is characterized in that a compound V and hydroxypyridine are reacted under the action of alkali to obtain a compound IV; the compound IV and the compound III generate a compound II in the presence of a base and a Lewis acid; and resolving the compound II to obtain the compound I. The method disclosed by the invention has the advantages of mild reaction conditions, easily-controlled process and simple operation, can effectively improve the yield of the target product, reduces the production cost, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of Reidesvir.
Background
Reddeivir (Remdesivir), an in-process drug of Gilidd chemistry. Reidesciclovir is a nucleoside analogue with antiviral activity having an EC50 value of 74nM for ARS-CoV and MERS-CoV in HAE cells and an EC50 value of 30nM for murine hepatitis virus in delayed brain tumor cells.
At present, the process for synthesizing the Reidesvir at home and abroad roughly comprises two routes, which are as follows:
(1) the route adopted by the original inventor girard patent WO2016069826A1 (as follows): the preparation method comprises the steps of taking (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-alcohol as an initial raw material, and performing oxidation, addition, substitution, resolution, debenzylation, protection and substitution, and finally performing resolution to obtain the Reidesvir. The route has poor selectivity, only adopts a chiral column for purification, and is not suitable for industrial production.
(2) Nature 2016 (Warren T K, Jordan R, Lo M K, et al. Therapeutic efficacy of the small molecule GS-5734 by against Ebola virus in rhesus monkey [ J ] Nature 2016, 531(7594): 381 and 385.) reports a second generation of synthetic methods that could be scaled up to hundredths. The yield was 40%, 85%, 86%, 90%, 70% and 69% in total for 6 steps. This route (as follows) was optimized for route 1, and at the cyano substitution step, the ratio of the product isomers obtained was 95 by addition of triflic acid: 5, the triflic acid greatly increases the proportion of the desired beta-anomer, and the chiral purity can be further increased by subsequent recrystallization. However, this method uses genotoxic nitro substitutes, increasing the risk of genotoxic impurities.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing the Reidesciclovir.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthesis method of Reidesciclovir comprises the following specific synthetic route:
the preparation method comprises the following steps:
1) reacting the compound V with hydroxypyridine under the action of alkali to obtain a compound IV;
2) the compound IV and the compound III generate a compound II in the presence of a base and a Lewis acid;
3) and resolving the compound II to obtain the compound I.
As a preferred technical scheme, the specific preparation method comprises the following steps:
1) under the protection of nitrogen, adding hydroxypyridine and a solvent A, stirring, cooling to-10 ℃, slowly dropwise adding alkali, heating to-5-0 ℃ within 1-2h, then controlling the temperature to be 0 ℃, adding a mixture V, and reacting at 15-20 ℃ to obtain a compound IV;
2) under the protection of nitrogen, adding a compound III, a compound IV obtained in the step 1), a base, Lewis acid and a solvent B to generate a compound II;
3) and 2) pulping and crystallizing the compound II obtained in the step 2) by using acetone/dichloromethane, and resolving to obtain the compound I. Namely, the resolution method in the step 3) adopts pulping and crystallization of acetone/dichloromethane.
As a preferable technical scheme, the molar ratio of the compound V, the hydroxypyridines and the base in the step 1) is (1-1.5): 1: (1-1.5).
As a preferred embodiment, X is halogen, and the hydroxyl group and X may be at different substitution positions on the pyridine ring.
As a preferred technical scheme, X is Cl or Br, and is preferably Cl.
As a preferable technical solution, the base used in the step 1) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
As a preferable technical scheme, the solvent A used in the step 1) is one of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether and toluene.
As a preferable technical scheme, the molar ratio of the compound IV, the compound III, the base and the lewis acid in the step 2) is (1.2-2): 1: (1.2-2): (1.2-2).
As a preferable technical solution, the base used in the step 2) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
As a preferable technical scheme, the Lewis acid used in the step 2) is zinc chloride, zinc bromide, magnesium chloride, magnesium bromide, aluminum chloride, aluminum bromide or ferric chloride.
As a preferable technical scheme, the solvent B used in the step 2) is one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and tert-butyl methyl ether, and the reaction temperature is 50 ℃ to 80 ℃.
The invention discloses a synthesis method of Reidesciclovir, which has the advantages of mild reaction conditions, easily-controlled process and simple operation, can effectively improve the yield of a target product, reduces the production cost, and is suitable for industrial large-scale production.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1
Preparation of compound IV:
under the protection of nitrogen, adding 2-hydroxy-6-chloropyridine (1.48 g, 11.4 mmol) and 20mL tetrahydrofuran into a round-bottom flask, stirring and cooling to-10 ℃, slowly dropwise adding triethylamine (1.47 g, 14.5 mmol), and after dropwise adding, heating to-5-0 ℃ within 1-2 h. Adding the compound V (5.15 g, 14.8 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 4.95g of compound IV with a molar yield of 98.5% (based on 2-hydroxy-6-chloropyridine).
Preparation of compound I:
under nitrogen protection, compound III (2.8 g, 9.6 mmol), compound IV (6.8 g, 15.4 mmol), triethylamine (1.6 g, 15.8 mmol), zinc chloride (2.1 g, 15.4 mmol) and 40mL of tetrahydrofuran were added to a reaction flask, heated to 65 ℃ and stirred for 25 h. After the reaction was complete, 80mL of ethyl acetate was added and washed with saturated ammonium chloride (40 mL of 1, i.e., 40mL of saturated chlorideAmmonium wash once, expressed in the same manner as below with respect to the amount and number of times of this form), 0.5M hydrochloric acid wash (40 mL × 1), 0.5M Na2CO3/NaHCO3The buffer solution (mass ratio of both 1: 1.4) was washed (40 mL × 1), washed with saturated brine (40 mL × 1), and dried over anhydrous sodium sulfate. The solvent was removed by rotary drying, and the crystals were isolated by slurrying with acetone/dichloromethane (1/8, V/V) to give 2.5g of compound I in 44% molar yield (based on compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：δ7.80（1H），7.29-7.18（2H），7.15-7.07（3H），6.91-6.82（2H），5.32-5.21（3H），4.94(1H)，4.52（1H），4.36-4.21（2H），4.01（1H），3.91-3.81（2H），1.70-1.40（7H），1.21（1H），1.03（6H）。
example 2
Preparation of compound IV:
under the protection of nitrogen, 3-hydroxy-5-chloropyridine (1.48 g, 11.4 mmol) and 20mL dichloromethane are added into a round-bottom flask, the mixture is stirred and cooled to-10 ℃, N-diisopropylethylamine (2.17 g, 16.8 mmol) is slowly added dropwise, and the temperature is raised to-5-0 ℃ within 1-2h after the dropwise addition. Adding the compound V (5.84 g, 16.8 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 4.88g of compound IV in 97% molar yield (based on 3-hydroxy-5-chloropyridine).
Preparation of compound I:
compound III (2.8 g, 9.6 mmol), compound IV (8.3 g, 18.8 mmol), N-diisopropylethylamine (1.5 g, 11.6 mmol), magnesium chloride (1.1 g, 11.6 mmol) and 40mL dioxane were added to a reaction flask under nitrogen blanket, heated to 55 ℃ and stirred for 25 h. After completion of the reaction, 80mL of ethyl acetate was added, washed with saturated ammonium chloride (40 mL. times.1), 0.5M hydrochloric acid (40 mL. times.1), 0.5M Na2CO3/NaHCO3Washing (40 m) with buffer solution (mass ratio of the two is 1: 1.4)L1), washed with saturated brine (40 mL 1), and dried over anhydrous sodium sulfate. The solvent was removed by rotary drying, and the crystals were isolated by slurrying with acetone/dichloromethane (1/8, V/V) to give 2.4g of compound I in 42% molar yield (based on compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：δ7.81（1H），7.31-7.17（2H），7.13-7.08（3H），6.92-6.83（2H），5.30-5.20（3H），4.93(1H)，4.50（1H），4.37-4.21（2H），4.02（1H），3.91-3.80（2H），1.71-1.41（7H），1.20（1H），1.02（6H）。
example 3
Preparation of compound IV:
under the protection of nitrogen, adding 3-hydroxy-5-bromopyridine (1.98 g, 11.4 mmol) and 20mL methyl tert-butyl ether into a round-bottom flask, stirring and cooling to-10 ℃, slowly dropwise adding potassium carbonate (1.67 g, 12.1 mmol), and after dropwise adding, heating to-5-0 ℃ within 1-2 h. Adding the compound V (4.31 g, 12.4 mmol) into the mixed solution, controlling the temperature to be about 0 ℃, heating to room temperature (15-20 ℃) after finishing dripping, and stirring for 8 hours. After the reaction, the organic phase was washed with water 2 times, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and the solvent was removed by spin-drying to give 5.26g of compound IV with a molar yield of 95% (based on 3-hydroxy-5-bromopyridine).
Preparation of compound I:
under nitrogen protection, compound III (2.8 g, 9.6 mmol), compound IV (5.8 g, 12.0 mmol), potassium carbonate (2.5 g, 18.1 mmol), zinc bromide (4.1 g, 18.2 mmol) and 40mL of tert-butyl methyl ether were added to a reaction flask, heated to 75 deg.C, and stirred for 25 h. After completion of the reaction, 80mL of ethyl acetate was added, washed with saturated ammonium chloride (40 mL. times.1), 0.5M hydrochloric acid (40 mL. times.1), 0.5M Na2CO3/NaHCO3The buffer solution (mass ratio of both 1: 1.4) was washed (40 mL × 1), washed with saturated brine (40 mL × 1), and dried over anhydrous sodium sulfate. The solvent is removed by rotary drying, and the compound I is separated out by beating with acetone/dichloromethane (1/8, V/V) to obtain 2.3g of the compound I with the molar yield of 40.5 percent (calculated by the compound III).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：δ7.80（1H），7.30-7.19（2H），7.14-7.08（3H），6.90-6.80（2H），5.31-5.20（3H），4.95(1H)，4.51（1H），4.37-4.20（2H），4.03（1H），3.90-3.80（2H），1.72-1.40（7H），1.21（1H），1.02（6H）。
the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. A synthetic method of Reidesciclovir is characterized in that: the synthetic route is as follows:
x is halogen, hydroxy and X at different substitution positions on the pyridine ring;
the preparation method comprises the following steps:
1) reacting the compound V with hydroxypyridine under the action of alkali to obtain a compound IV;
2) generating a compound II by the compound IV and the compound III obtained in the step 1) in the presence of alkali and Lewis acid;
3) resolving the compound II obtained in the step 2) to obtain a compound I.
2. A synthesis method of reed-solomon according to claim 1, wherein: the preparation method comprises the following steps:
1) under the protection of nitrogen, adding hydroxypyridine and a solvent A, stirring, cooling to-10 ℃, slowly dropwise adding alkali, heating to-5-0 ℃ within 1-2h, then controlling the temperature to be 0 ℃, adding a mixture V, and reacting at 15-20 ℃ to obtain a compound IV;
2) under the protection of nitrogen, adding a compound III, a compound IV obtained in the step 1), a base, Lewis acid and a solvent B to generate a compound II;
3) and 2) pulping and crystallizing the compound II obtained in the step 2) by using acetone/dichloromethane, and resolving to obtain the compound I.
3. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the molar ratio of the compound V, the hydroxypyridine and the alkali in the step 1) is (1-1.5): 1: (1-1.5).
4. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: and X is Cl or Br.
5. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the base used in the step 1) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
6. A synthesis method of reed-solomon according to claim 2, wherein: the solvent A used in the step 1) is one of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether and toluene.
7. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: in the step 2), the molar ratio of the compound IV to the compound III to the alkali to the Lewis acid is (1.2-2): 1: (1.2-2): (1.2-2).
8. A process for the synthesis of ridciclovir according to claim 1 or 2, characterized in that: the base used in the step 2) is one of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0 ] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-ethylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the Lewis acid used in the step 2) is zinc chloride, zinc bromide, magnesium chloride, magnesium bromide, aluminum chloride, aluminum bromide or ferric chloride.
9. A synthesis method of reed-solomon according to claim 2, wherein: the solvent B used in the step 2) is one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane and tert-butyl methyl ether, and the reaction temperature is 50-80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010222507.7A CN111233931B (en) | 2020-03-26 | 2020-03-26 | Synthesis method of Reidesciclovir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010222507.7A CN111233931B (en) | 2020-03-26 | 2020-03-26 | Synthesis method of Reidesciclovir |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111233931A CN111233931A (en) | 2020-06-05 |
| CN111233931B true CN111233931B (en) | 2022-03-22 |
Family
ID=70869978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010222507.7A Active CN111233931B (en) | 2020-03-26 | 2020-03-26 | Synthesis method of Reidesciclovir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233931B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
| CN112979736B (en) * | 2021-03-04 | 2022-03-25 | 南京欧信医药技术有限公司 | Preparation method of Reidesciclovir |
Citations (1)
| 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 |
-
2020
- 2020-03-26 CN CN202010222507.7A patent/CN111233931B/en active Active
Patent Citations (1)
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111233931A (en) | 2020-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111233930B (en) | Preparation method of Reidesciclovir | |
| CN111233931B (en) | Synthesis method of Reidesciclovir | |
| CN111187269A (en) | Synthetic method of Reidesciclovir intermediate | |
| CN114437031B (en) | Synthesis method of 6-methyl nicotine | |
| CN114805314A (en) | Synthesis method of Ensaitevir | |
| CN111471070B (en) | Synthetic method of Reidesciclovir | |
| CN107011404A (en) | A kind of method using cholic acid as Material synthesis lithocholic acid | |
| TW201912656A (en) | Method for preparing sugammadex sodium and crystalline form thereof | |
| CN107540685B (en) | Preparation method and intermediate of Sotagliflozin | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| CN106366057A (en) | Synthetic method of sofosbuvir intermediate | |
| CN106317024A (en) | Crizotinib intermediate, preparation method and crizotinib preparation method | |
| CN115651022A (en) | Synthetic method of high-purity Reidesvir intermediate | |
| CN108239019B (en) | Synthesis method of (2S,5S or 5R) -N-tert-butyloxycarbonyl-5-hydroxy-2-ethyl piperidinecarboxylate | |
| CN112979736B (en) | Preparation method of Reidesciclovir | |
| CN108997236B (en) | Preparation method of anastrozole impurity | |
| CN115197058A (en) | Anticancer natural product Dysideanone B analogue and preparation method thereof | |
| CN110746471B (en) | Preparation method of fondaparinux sodium disaccharide intermediate | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN115611858B (en) | Method for preparing nicotine and its derivatives | |
| JP3989997B2 (en) | Method for producing radiosensitizer | |
| CN116082361B (en) | Method for preparing Marbalo Sha Wei intermediate and Marbalo Sha Wei | |
| CN113004245B (en) | Preparation method of desloratadine | |
| CN113480453B (en) | Synthesis method of NH2-PEG5-NHBoc | |
| CN114736186B (en) | Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |