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CN114560894B - Preparation method of anti-new crown medicine Molnupiravir - Google Patents

Preparation method of anti-new crown medicine Molnupiravir Download PDF

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CN114560894B
CN114560894B CN202210238256.0A CN202210238256A CN114560894B CN 114560894 B CN114560894 B CN 114560894B CN 202210238256 A CN202210238256 A CN 202210238256A CN 114560894 B CN114560894 B CN 114560894B
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preparation
molar ratio
trifluoromethane sulfonate
molnupiravir
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CN114560894A (en
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陈洪斌
林义
王志华
陈敏华
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Zhejiang Lepu Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention disclosesA preparation method of an anti-new crown drug Monumpiravir (compound I). The preparation method takes uridine (compound II) which is cheap and easy to obtain as a starting material, and the Molnupiravir can be obtained through a plurality of steps of reactions. The invention has the advantages of simple and reliable process, low comprehensive cost, easy commercial production and the like.

Description

Preparation method of anti-new crown medicine Molnupiravir
Technical Field
The invention belongs to the field of pharmaceutical synthetic chemistry, and particularly relates to a preparation method of an anti-new crown drug Monnpiravir.
Background
Monnupiravir (also known as MK4482 or EIDD 2801) is a ribonucleoside analogue with broad spectrum anti-RNA viral activity developed by Emerri university and is effective in inhibiting replication of influenza virus, hepatitis C virus, ebola virus, respiratory syncytial virus, coronaviruses such as SARS-CoV-1 and MERS virus, etc. EIDD2801 was licensed by the university of emery to moesadong and ridge back, which together developed into an oral anti-novel coronavirus drug candidate. Clinical trial results show that Molnupiravir can reduce the risk of hospitalization or death of new patients by 30%. The FDA grants Molnupiravir Emergency Use Authority (EUA) on day 12 and 23 of 2021 for the treatment of adult patients who are positive for detection of the novel coronavirus (SARS-CoV-2) and who are at high risk of developing severe mild or moderate new coronapneumonia (COVID-19).
The chemical name of Monnpiravir is uridine 5' -methylpropionate-4-oxime, and the chemical structure is shown as follows:
Figure BDA0003543208620000011
patent WO2019113462 first discloses a synthetic route to Molnupiravir. The method adopts uridine as a raw material, firstly protects cis-ortho-dihydroxyl, and then reacts with isopropyl anhydride to generate isobutyrate. Reacting the intermediate isobutyrate with 1,2, 4-triazole under the action of phosphorus oxychloride to produce a triazole intermediate; and reacting the triazole intermediate with hydroxylamine, and finally removing the protecting group to obtain the Molnupiravir with the total yield of 17%.
Figure BDA0003543208620000021
Synlett (2021,32,326-328) reports a route for synthesizing Monnpiravir starting from cytidine. Firstly, protecting cis-ortho-dihydroxyl of cytidine by using acetone, and then reacting with isobutyric anhydride to generate an isobutyrate intermediate; the isobutyrate intermediate reacts with hydroxylamine sulfate and is then deprotected to give Monnpiravir with a total yield of 44%.
Figure BDA0003543208620000022
The enzymatic synthetic route of Monupiravir is reported by chem.Commun. (2020,56,13363-13364). In the route, cytidine is also used as a starting material, and cytidine is selectively esterified under the action of Novelin lipase 435 to generate an isobutyrate intermediate; the intermediate is reacted with hydroxylamine sulfate to obtain Monnpiravir, and the total yield of the two steps is 75%.
Figure BDA0003543208620000031
Although chemical or enzymatic synthesis of Molnupiravir has made great progress, the current chemical synthesis method has longer steps and lower yield; although the enzyme method has shorter steps and high yield, the enzyme method has large enzyme consumption, high price and high comprehensive cost. Therefore, developing a synthetic route of Monnpiravir which is simple and reliable in route, simple and reliable in process, low in comprehensive cost and suitable for industrial production is particularly important at present.
Disclosure of Invention
The invention aims to provide a preparation method of Monumpiravir (compound I) with simple and reliable process, low comprehensive cost and easy commercial production.
The synthetic route of the invention is as follows:
Figure BDA0003543208620000041
the invention comprises the following steps:
1) And (3) performing acylation reaction on uridine (compound II) and isobutyric anhydride (compound III) under the action of Lewis acid to obtain a compound IV.
2) The compound IV reacts with hydroxylamine hydrochloride or hydroxylamine sulfate in the presence of a silicon reagent to obtain the compound I.
In the step 1), the Lewis acid is one or more of copper trifluoromethane sulfonate, zinc trifluoromethane sulfonate, nickel trifluoromethane sulfonate and lanthanum trifluoromethane sulfonate.
Further, the molar ratio of the Lewis acid to the compound II in the step 1) is 1:20 to 1:1000.
Further, in the step 1), the molar ratio of the compound II to the compound III is 1:1-1:2.
Further, the temperature of the acylation reaction in step 1) is-10 to 50 ℃.
The silicon reagent in the step 2) is one or more of hexamethyldisilazane/trimethyl silyl triflate and hexamethyldisilazane/trimethyl chlorosilane.
Further, in the step 2), the molar ratio of hexamethyldisilazane in the silicon reagent to the compound IV is 2:1 to 10:1; the molar ratio of the trifluoromethane sulfonate or the trimethylchlorosilane to the compound IV is 0.01:1-0.2:1.
Further, in the step 2), the molar ratio of the compound IV to hydroxylamine hydrochloride or hydroxylamine sulfate is 1:1-1:2.
Compared with the prior art/literature, the invention has the following remarkable advantages:
1) The invention adopts Lewis acid catalyst to catalyze uridine for selective acylation, and has less byproducts.
2) The method has the advantages of short steps, greatly reduced three wastes and more environment-friendly whole preparation process;
3) The invention has simple and reliable process and low comprehensive production cost, thus having good market competitiveness.
Detailed Description
The following examples are presented to those of ordinary skill in the art to make and evaluate the invention and are merely exemplary of the disclosure and are not intended to limit the scope. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), some errors and deviations should be accounted for. Unless otherwise indicated, temperature is in units of degrees celsius or at ambient temperature and pressure is at or near atmospheric pressure.
The methods described in this example for preparing the disclosed compounds described herein are one of many, and many others are possible for preparing the disclosed compounds of this application, and this application is not intended to be limiting. Accordingly, one of ordinary skill in the art to which the present disclosure pertains may readily modify the methods recited or utilize different methods to prepare one or more of the disclosed compounds. The following methods are merely exemplary, temperature, catalyst, concentration, reactant composition, and other process conditions may vary, and for the desired compounds, one of ordinary skill in the art can readily select appropriate reactants and conditions for preparation.
Example 1
Preparation of Compound IV
244.2g of compound II and 3.62g of copper triflate were dissolved in 2L of butanone, 166g of isobutyric anhydride were added dropwise at room temperature and stirred until the reaction was complete. Butanone was removed under reduced pressure, 1L of ethyl acetate and 500mL of water were added to the residue, and the fractions were extracted. The aqueous phase was again extracted with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/n-heptane to give 286g of compound IV in 91% yield and 99.3% purity by HPLC.
1 H NMR(DMSO-d6,400MHz)δ11.38(s,1H),7.62(d,J＝8.0Hz,1H),5.75(d,J＝ 4.1Hz,1H),5.66(d,J＝7.8Hz,1H),5.52(br s,1H),5.32(br s,1H),4.28-4.14(m, 2H),4.10-4.04(m,1H),4.02-3.92(m,2H),2.62-2.52(m,1H),1.09(d,J＝6.8Hz, 6H)；
13 C NMR(DMSO-d6,101MHz)δ176.4,163.5,151.0,141.1,102.4,89.1,81.5,73.2, 70.1,64.1,33.6,19.2；
HRMS(ESI):m/z calcd for C 13 H 18 N 2 O 7 [M+H] + 315.1187,found:315.1182.
Example 2
Preparation of Compound IV
244.2g of compound II and 3.64g of zinc triflate are dissolved in 2L of butanone, 166g of isobutyric anhydride are added dropwise at room temperature and stirred until the reaction is complete. Butanone was removed under reduced pressure, 1L of ethyl acetate and 500mL of water were added to the residue, and the fractions were extracted. The aqueous phase was again extracted with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/n-heptane to give 274g of compound IV in 87% yield and 99.2% purity by HPLC.
Example 3
Preparation of Compound IV
244.2g of compound II and 3.57g of nickel triflate are dissolved in 2L of butanone, 166g of isobutyric anhydride are added dropwise at room temperature and stirred until the reaction is complete. Butanone was removed under reduced pressure, 1L of ethyl acetate and 500mL of water were added to the residue, and the fractions were extracted. The aqueous phase was again extracted with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was recrystallized from ethyl acetate/n-heptane to give 226g of compound IV in 72% yield and 99.0% purity by HPLC.
Example 4
Preparation of Compound IV
244.2g of compound II and 5.86g of lanthanum triflate are dissolved in 2L of butanone, 166g of isobutyric anhydride are added dropwise at room temperature and stirred until the reaction is complete. Butanone was removed under reduced pressure, 1L of ethyl acetate and 500mL of water were added to the residue, and the fractions were extracted. The aqueous phase was again extracted with 1L of ethyl acetate. The combined organic phases were washed with 10% sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was recrystallized from ethyl acetate/n-heptane to give 289g of compound IV in 92% yield with HPLC purity of 99.1%.
Example 5
Preparation of Compound I
5.5g of trimethylsilyl triflate are added to 157g of compound IV and 323g of hexamethyldisilazane suspension under nitrogen, heated (80 ℃) and stirred for 3 hours. Then adding 100g of hydroxylamine sulfate, keeping the temperature, stirring until the reaction is complete, cooling, and concentrating under reduced pressure. The residue was taken up in 1L of ethyl acetate and 500mL of water, and the fractions were extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, then washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to give 147g of compound I in 89% yield and 99.8% purity by HPLC.
1 H NMR(DMSO-d6,400MHz)δ10.02(s,1H),9.67(s,1H),6.82(d,J＝8.2Hz, 1H),5.71(d,J＝5.5Hz,1H),5.59(d,J＝8.2Hz,1H),5.38(d,J＝5.5Hz,1H),5.23 (d,J＝4.5Hz,1H),4.2(dd,J＝12.0,3.1Hz,1H),4.13(dd,J＝12.0,4.9Hz,1H), 4.00(q,J＝5.3Hz,1H),3.92(h,J＝4.6Hz,2H),2.57(p,J＝7.0Hz,1H),1.09(d,J ＝7.0Hz,6H)；
13 C NMR(DMSO-d6,101MHz)δ176.4,149.9,143.7,130.3,99.2,88.1,81.1,72.4, 70.4,64.3,33.6,19.2(4),19.2(2)；
HRMS(ESI):m/z calcd for C 13 H 19 N 3 O 7 [M+H] + 330.1296,found:330.1294.
Example 6
Preparation of Compound I
To 157g of compound IV and 400g of hexamethyldisilazane suspension under nitrogen atmosphere, 10g of trimethylchlorosilane are added, heated (80 ℃ C.) and stirred for 3 hours. Then adding 100g of hydroxylamine sulfate, keeping the temperature, stirring until the reaction is complete, cooling, and concentrating under reduced pressure. The residue was taken up in 1L of ethyl acetate and 500mL of water, and the fractions were extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, then washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to give 134g of compound I in 81% yield and 99.7% purity by HPLC.
Example 7
Preparation of Compound I
To 157g of compound IV and 500g of hexamethyldisilazane suspension, 10g of trimethylsilicone triflate was added under nitrogen atmosphere, heated (80 ℃ C.) and stirred for 3 hours. Then adding 42g hydroxylamine hydrochloride, keeping the temperature, stirring until the reaction is complete, cooling, and concentrating under reduced pressure. The residue was taken up in 2L of ethyl acetate and 500mL of water, and the fractions were extracted. The organic phase was added with 10mL of glacial acetic acid, stirred at room temperature for 2 hours, then washed with 10% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained is recrystallized from ethyl acetate/methyl tert-ether to give 152g of compound I in 92% yield and 99.7% purity by HPLC.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention.

Claims (1)

1. The preparation method of the anti-new crown medicine Monnpiravir (compound I) is characterized by comprising the following steps:
1) Carrying out acylation reaction on uridine (compound II) and isobutyric anhydride (compound III) under the action of Lewis acid to obtain a compound IV; the Lewis acid agent is one or more of copper trifluoromethane sulfonate, zinc trifluoromethane sulfonate, nickel trifluoromethane sulfonate and lanthanum trifluoromethane sulfonate; the molar ratio of the Lewis acid to the compound II is 1:20-1:1000; the molar ratio of the compound II to the compound III is 1:1-1:2; the temperature of the acylation reaction is-10 ℃ to 50 ℃;
Figure FDA0004177981810000011
2) Reacting the compound IV with hydroxylamine hydrochloride or hydroxylamine sulfate in the presence of a silicon reagent to obtain a compound I: the silicon reagent is one or more of hexamethyldisilazane/trifluoromethanesulfonic acid trimethyl silicon ester, hexamethyldisilazane/trimethylchlorosilane; the molar ratio of hexamethyldisilazane in the silicon reagent to the compound IV is 2:1-10:1; the molar ratio of the trifluoromethane sulfonate or the trimethylchlorosilane to the compound IV is 0.01:1-0.2:1; the molar ratio of the compound IV to hydroxylamine hydrochloride or hydroxylamine sulfate is 1:1-1:2; the reaction temperature is 20-120 ℃;
Figure FDA0004177981810000012
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