CN111471070A - Synthetic method of Reidesciclovir - Google Patents

Synthetic method of Reidesciclovir Download PDF

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Publication number
CN111471070A
CN111471070A CN202010338730.8A CN202010338730A CN111471070A CN 111471070 A CN111471070 A CN 111471070A CN 202010338730 A CN202010338730 A CN 202010338730A CN 111471070 A CN111471070 A CN 111471070A
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compound
synthesis method
reidesciclovir
hydroxysuccinimide
alkali
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CN111471070B (en
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陈本顺
叶金星
李大伟
石利平
徐春涛
程毅
张维冰
马骧
张凌怡
江涛
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Jiangsu Alpha Pharmaceutical Co ltd
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    • 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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Abstract

The invention relates to a synthetic method of Reidesciclovir, belonging to the field of pharmaceutical chemicals, and the invention is characterized in that a compound V and N-hydroxysuccinimide react under the action of alkali to obtain a compound IV; resolving the compound IV to obtain a compound III; the compound III and the compound II generate the compound I in the presence of a base and a Lewis acid. The method disclosed by the invention adopts toxicologically harmless N-hydroxysuccinimide as a leaving group, the reaction process is safe, and the obtained target product has higher purity, can meet the market demand of products, and reduces the production cost.

Description

Synthetic method of Reidesciclovir
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of Reidesvir.
Background
Reddeivir (Remdesivir), an in-process drug of Gilidd chemistry. Reidesciclovir is a nucleoside analogue with antiviral activity having an EC50 value of 74nM for ARS-CoV and MERS-CoV in HAE cells and an EC50 value of 30nM for murine hepatitis virus in delayed brain tumor cells.
At present, the process for synthesizing the Reidesvir at home and abroad roughly comprises two routes, which are as follows:
(1) the route adopted by the original inventor girlidde patent WO2016069826A1 is as follows: the preparation method comprises the steps of taking (3R,4R,5R) -3, 4-bis (benzyloxy) -5- ((benzyloxy) methyl) tetrahydrofuran-2-alcohol as an initial raw material, and performing oxidation, addition, substitution, resolution, debenzylation, protection and substitution, and finally performing resolution to obtain the Reidesvir. The route has poor selectivity, only adopts a chiral column for purification, and is not suitable for industrial production.
Figure 100002_DEST_PATH_IMAGE002
。
(2) Nature 2016 (Warren T K, Jordan R, L o M K, et al, therapeutics of the small molecule GS-5734 against Ebola virus in rhesus monkey [ J ]. Nature, 2016, 531(7594): 381-385.) reports a second generation synthesis procedure that can be scaled up to hectogram with yields of 40%, 85%, 86%, 90%, 70% and 69%, respectively, optimized for route 1, with triflic acid added to give a 95: 5 ratio of product isomers during the cyano substitution step, which greatly increased the desired β -isomer ratio, and with subsequent further increase in chiral purity by recrystallization.
Figure DEST_PATH_IMAGE004
。
Disclosure of Invention
The invention aims to provide a novel method for synthesizing the Reidesciclovir, which adopts toxicologically harmless N-hydroxysuccinimide as a leaving group and has safe reaction process.
In order to achieve the purpose, the invention provides the following technical scheme:
the synthesis method of the Reidesciclovir comprises the following specific synthetic route:
Figure DEST_PATH_IMAGE006
；
the preparation method comprises the following steps:
1) reacting the compound V with N-hydroxysuccinimide under the action of alkali to obtain a compound IV;
2) resolving the compound IV to obtain a compound III;
3) the compound III and the compound II generate the compound I in the presence of a base and a Lewis acid.
As a preferred technical scheme, the specific preparation method comprises the following steps:
1) adding the compound V into one part of aprotic organic solvent A, cooling the solution to 5 ℃ by adopting an ice bath, adding N-hydroxysuccinimide which can be partially dissolved, and then dropwise adding the other part of aprotic organic solvent A solution containing alkali for reaction; until all N-hydroxysuccinimide is dissolved, the corresponding alkali hydrochloride is observed to precipitate, and the reaction is finished to obtain a compound IV;
2) dissolving the compound IV obtained in the step 1) in methyl tert-butyl ether, adding triethylamine, stirring overnight, and splitting to obtain a compound III;
3) adding the compound III obtained in the step 2) into an aprotic organic solvent B, and adding a compound II, a base and a Lewis acid into the solution to react to generate a compound I.
As a preferable technical scheme, the mole ratio of the compound V, N-hydroxysuccinimide to the base in the step 1) is (1.2-2): 1: (1.5-2).
As a preferred technical solution, the base used in step 1) is one of triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate and potassium bicarbonate, preferably triethylamine.
As a preferred technical scheme, the aprotic organic solvent used in the step 1) is one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether, and dichloromethane is preferred.
As a preferable technical scheme, the molar ratio of the compound III, the compound II, the base and the lewis acid in the step 3) is (1.5-2.5): 1: (1-3): (0.75 to 1.5).
As a preferable technical scheme, the base used in the step 3) is one of ethyl diisopropylamine, trimethylamine, triethylamine, 1, 8-diazabicycloundece-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-methyl morpholine, 1-ethyl piperidine, potassium carbonate and potassium bicarbonate, and ethyl diisopropylamine or trimethylamine is preferable.
As a preferred technical solution, the lewis acid used in step 3) is zinc chloride, zinc bromide, zinc iodide, magnesium bromide or copper chloride, preferably zinc bromide.
As a preferred technical solution, the aprotic organic solvent used in step 3) is one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether and dimethylformamide, preferably tetrahydrofuran.
As a preferable technical scheme, the reaction in the step 3) is carried out under the condition of adding the molecular sieve, and the molecular sieve is a 4A molecular sieve.
The invention discloses a synthesis method of Reidesciclovir, which adopts toxicologically harmless N-hydroxysuccinimide as a leaving group, has safe reaction process, obtains a target product with higher purity, can meet the market demand of products, and reduces the production cost.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1
Preparation of compound III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (34.12 g, 98.1 mmol) was dissolved in 140m L dichloromethane, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of dichloromethane (20 m L) containing triethylamine (11.91 g, 117.7 mmol) with stirring, the addition funnel was rinsed with another 5m L dichloromethane, when all the N-hydroxysuccinimide was dissolved, precipitation of triethylamine hydrochloride was observed, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃) and extracted with 90m L distilled water, the organic phase was washed with another 40m 64 distilled water, the volatiles were removed under reduced pressure to give a crude solid, compound iv, crude solid was obtained, compound iv, crude solid 160m L e (methyl tert-butyl ether) was added to 5m L triethylamine, stirred, at which time a solid was formed, the mixture i.e. solid was washed with another MTBE 3975 m 3975 until all the crude solid formed, the crude solid was dissolved in dry HP 364% crystalline (3.75 mol), and filtered to obtain an aggregate, which was obtained as a yield of crude compound III).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (8.2 g, 19.2 mmol) and 25m L tetrahydrofuran to obtain a clear solution to this solution was added compound II (2.8 g, 9.6 mmol), followed by zinc bromide (2.2 g, 9.8 mmol), 4A molecular sieve (3 g) and ethyldiisopropylamine (2.5 g, 19.3 mmol). the mixture was stirred at room temperature for 4h, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.7 g, having an HP L C purity of 99.5% and a molar yield of 81% (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：7.81（1H），7.29-7.18（2H），7.16-7.07（3H），6.91-6.82（2H），5.31-5.21（3H），4.94(1H)，4.51（1H），4.36-4.21（2H），4.02（1H），3.91-3.82（2H），1.70-1.40（7H），1.21（1H），1.02（6H）。
example 2
Preparation of compound III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (40.93 g, 117.7 mmol) was dissolved in 140m L tetrahydrofuran, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of tetrahydrofuran (20 m L) containing N, N-diisopropylethylamine (12.68 g, 98.1 mmol) with stirring, the addition funnel was rinsed with another 5m L tetrahydrofuran, when all N-hydroxysuccinimide was dissolved, precipitation of N, N-diisopropylethylamine hydrochloride was observed, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃), extracted with 90m L distilled water, the organic phase was washed with another 40m L distilled water, the volatiles were removed under reduced pressure to give a crude solid, i.e. compound iv, the crude solid L m L e (methyl tert-butyl ether) was dissolved in HP (methyl L), triethylamine was added, the solid was stirred, whereupon the solid formed, i.e. compound V-t-butyl ether was filtered to form an aggregate, which was dissolved as a crude solid (dry residue) in dry, purity was measured by heating) and filtered 369.26.75 mol).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (9.4 g, 22.0 mmol) and 25m L dichloromethane to obtain a clear solution to this solution was added compound II (2.8 g, 9.6 mmol), followed by zinc chloride (1.1 g, 8.1 mmol), 4A molecular sieve (3 g) and trimethylamine (0.6 g, 10.2 mmol). the mixture was stirred at room temperature for 4h, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.6 g, having a purity of 99.2% as determined by HP L C, in 80% molar yield (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：7.81（1H），7.31-7.18（2H），7.13-7.09（3H），6.92-6.82（2H），5.30-5.21（3H），4.93(1H)，4.51（1H），4.37-4.21（2H），4.02（1H），3.92-3.80（2H），1.71-1.41（7H），1.20（1H），1.02（6H）。
example 3
Preparation of compound III:
in a dry two-necked round-bottom flask equipped with an addition funnel, compound V (27.30 g, 78.5 mmol) was dissolved in 140m L-methyltetrahydrofuran, the solution was cooled to about 5 ℃ with an ice bath, N-hydroxysuccinimide (7.53 g, 65.4 mmol) (only partially dissolved) was added, to the suspension was added dropwise a solution of 2-methyltetrahydrofuran (20 m L) containing potassium tert-butoxide (14.68 g, 130.8 mmol) with stirring, the addition funnel was rinsed with another 5m L-methyltetrahydrofuran, when all N-hydroxysuccinimide was dissolved, potassium tert-butoxide hydrochloride was observed to precipitate, the ice bath was removed, the reaction mixture was warmed to room temperature (15-20 ℃), extracted with 90m L distilled water, the organic phase was washed with another 40m L distilled water, the crude solid was removed under reduced pressure, i.e. compound iv, the crude solid was dissolved in 160m L e (methyl tert-butyl ether), triethylamine was added, the mixture was stirred, whereupon the crude solid formed a solid which formed as a solid which was dissolved in dry HP 6778%, the crude solid, the yield of N-hydroxysuccinimide was measured as an aggregate, after cooling to form a dry residue (20 m) of crystals, 5m 6778.75 mg).
Preparation of compound I:
to a two-necked round-bottomed flask equipped with a reflux condenser and purged with nitrogen gas were added compound III (6.6 g, 15.5 mmol) and 25m L methyl t-butyl ether to obtain a clear solution, to this solution was added compound II (2.8 g, 9.6 mmol), followed by the addition of magnesium bromide (2.5 g, 13.6 mmol), 4A molecular sieve (3 g) and triethylamine (2.7 g, 26.7 mmol), the mixture was stirred at room temperature for 4 hours, after completion of the reaction, the solvent was concentrated under reduced pressure, dissolved with ethyl acetate 40m L, washed with saturated sodium bicarbonate 50m L, washed with 50m L saturated brine, separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound I4.5 g, having a purity of 99.3% as determined by HP L C, in 78% molar yield (based on compound II).
The hydrogen spectrum of compound I obtained is as follows:
1H-NMR（400MHz，CDCl3）：7.82（1H），7.30-7.17（2H），7.15-7.08（3H），6.90-6.81（2H），5.32-5.20（3H），4.94(1H)，4.51（1H），4.38-4.20（2H），4.03（1H），3.90-3.80（2H），1.72-1.42（7H），1.22（1H），1.02（6H）。
the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (10)

1. The synthesis method of the Reidesciclovir is characterized by comprising the following steps: the synthetic route is as follows:
Figure DEST_PATH_IMAGE002
；
the preparation method comprises the following steps:
1) reacting the compound V with N-hydroxysuccinimide under the action of alkali to obtain a compound IV;
2) resolving the compound IV obtained in the step 1) to obtain a compound III;
3) the compound III obtained in the step 2) and a compound II generate a compound I in the presence of a base and a Lewis acid.
2. A synthesis method of reed-solomon according to claim 1, wherein: the preparation method comprises the following steps:
1) adding the compound V into one part of aprotic organic solvent A, cooling the solution to 5 ℃ by adopting an ice bath, adding N-hydroxysuccinimide which can be partially dissolved, and then dropwise adding the other part of aprotic organic solvent A solution containing alkali for reaction; until all N-hydroxysuccinimide is dissolved, the corresponding alkali hydrochloride is observed to precipitate, and the reaction is finished to obtain a compound IV;
2) dissolving the compound IV obtained in the step 1) in methyl tert-butyl ether, adding triethylamine, stirring overnight, and splitting to obtain a compound III;
3) adding the compound III obtained in the step 2) into an aprotic organic solvent B, and adding a compound II, a base and a Lewis acid into the solution to react to generate a compound I.
3. A synthesis method of reed-solomon according to claim 2, wherein: the aprotic organic solvent A used in the step 1) is one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether.
4. A synthesis method of reed-solomon according to claim 2, wherein: the aprotic organic solvent B used in the step 3) is one of dichloromethane, chloroform, tetrahydrofuran, toluene, dimethyl sulfoxide, methyl tert-butyl ether, cyclopentyl methyl ether and dimethylformamide.
5. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: in the step 1), the molar ratio of the compound V, N-hydroxysuccinimide to the alkali is (1.2-2): 1: (1.5-2).
6. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the alkali used in the step 1) is one of triethylamine, N-diisopropylethylamine, potassium tert-butoxide, potassium carbonate and potassium bicarbonate.
7. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the molar ratio of the compound III to the compound II to the alkali to the Lewis acid in the step 3) is (1.5-2.5): 1: (1-3): (0.75 to 1.5).
8. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the base used in the step 3) is one of ethyl diisopropylamine, trimethylamine, triethylamine, 1, 8-diazabicycloundecen-7-ene, 1, 4-diazabicyclo [2.2.2] octane, 1-methylmorpholine, 1-ethylpiperidine, potassium carbonate and potassium bicarbonate.
9. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the Lewis acid used in the step 3) is one of zinc chloride, zinc bromide, zinc iodide, magnesium bromide and copper chloride.
10. A synthesis method of Reidesciclovir according to any of claims 1-4, characterized in that: the reaction in the step 3) is carried out under the condition of adding the molecular sieve, and the molecular sieve is a 4A molecular sieve.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112979736A (en) * 2021-03-04 2021-06-18 南京欧信医药技术有限公司 Preparation method of Reidesciclovir
WO2022029704A1 (en) 2020-08-06 2022-02-10 Richter Gedeon Nyrt. Remdesivir intermediates

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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022029704A1 (en) 2020-08-06 2022-02-10 Richter Gedeon Nyrt. Remdesivir intermediates
CN112979736A (en) * 2021-03-04 2021-06-18 南京欧信医药技术有限公司 Preparation method of Reidesciclovir
CN112979736B (en) * 2021-03-04 2022-03-25 南京欧信医药技术有限公司 Preparation method of Reidesciclovir

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