CN114409727A - Preparation method of anti-coronavirus 3CLPRO inhibitor - Google Patents

Preparation method of anti-coronavirus 3CLPRO inhibitor Download PDF

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CN114409727A
CN114409727A CN202111625864.9A CN202111625864A CN114409727A CN 114409727 A CN114409727 A CN 114409727A CN 202111625864 A CN202111625864 A CN 202111625864A CN 114409727 A CN114409727 A CN 114409727A
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庄晓晓
陈勇
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Suzhou Kangchun Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/503—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses
    • C12N9/506—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses derived from RNA viruses

Abstract

A preparation method of 3CLPRO inhibitor for resisting coronavirus comprises the following steps: (a) carrying out substitution reaction on the compound 1 and ethyl trifluoroacetate under the action of an organic solvent and alkali to obtain a compound 2; (b) carrying out hydrolysis reaction on the compound 3 under the action of an organic solvent and alkali to obtain a compound 4; (c) carrying out condensation reaction on the compound 4 and the compound 2 under the conditions of an organic solvent and a condensing agent to obtain a compound 5; (d) carrying out condensation reaction on the compound 5 and the compound 6 under the conditions of an organic solvent and a condensing agent to obtain a compound 7; (e) and (3) carrying out dehydration reaction on the compound 7 under the conditions of an organic solvent, alkali and a dehydrating agent to obtain the 3CLPRO inhibitor. The preparation method of the anti-coronavirus 3CLPRO inhibitor has the advantages of short synthetic route, easy separation and purification of an intermediate, no need of column chromatography, high purity of the obtained product, safe and simple operation, high reaction yield, suitability for industrial production and wide application prospect.

Description

Preparation method of anti-coronavirus 3CLPRO inhibitor
Technical Field
The invention belongs to the technical field of medicinal chemistry, relates to a preparation method of a coronavirus-resistant 3CLPRO inhibitor, and particularly relates to a preparation method of a SARS-CoV-2-3CL protease inhibitor PF-07321332.
Background
PF-07321332 is an oral 3CL protease inhibitor developed by Perey, USA, which plays an important role in the life cycle of many coronaviruses, with the potential advantage of acting on all new coronaviruses variants at present. The single PF-07321332 drug has the inhibitory activity IC50 of 19nM to the new coronavirus at the molecular level, and the single PF-07321332 drug has the inhibitory activity EC50 of 62 nM, 99 nM and 56nM to the virus in human airway epithelial cells, HeLa and A549 cells which can express ACE2 protein, show good antiviral activity, and enter phase III clinical tests in the United states aiming at the new coronavirus infection at present. The united states pfeiy corporation has signed an agreement with the global health organization to sell alternative new crown oral drugs developed by the corporation in 95 countries worldwide without paying royalties. PF-07321332 has the following structural formula:
Figure RE-GDA0003571213290000011
the synthetic route of PF-07321332 in the prior art is shown as follows:
Figure RE-GDA0003571213290000021
from the above, the main problems of the synthetic route of PF-07321332 in the prior art are that the reaction steps are long, the synthetic route involves complicated deprotection and protection reactions, and the utilization rate of chemical atoms is low. In addition, an expensive condensing agent is used in the reaction process, a column chromatography method is used for multiple times in the intermediate purification process, the post-treatment is complicated, the total yield of the reaction is low, and the large-scale production application is greatly limited.
Therefore, the preparation method of the anti-coronavirus 3CLPRO inhibitor PF-07321332 is urgently needed to be developed, the synthetic route has the advantages of higher yield, simpler operation, higher atom utilization rate and safer reaction, and the preparation method is suitable for industrial production, provides convenience for large-scale production of the drugs and has greater social and economic benefits.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects, the invention aims to provide a preparation method of an anti-coronavirus 3CLPRO inhibitor, which is used for preparing a SARS-CoV-2-3CL protease inhibitor PF-07321332, and has the advantages of reasonable design of preparation steps, short synthetic route, easy separation and purification of an intermediate, no need of column chromatography, high purity of an obtained product, safe and simple operation, high reaction yield, suitability for industrial production and wide application prospect.
The purpose of the invention is realized by the following technical scheme:
a preparation method of 3CLPRO inhibitor for resisting coronavirus comprises the following steps:
(a) carrying out substitution reaction on the compound 1 and ethyl trifluoroacetate under the action of an organic solvent and alkali to obtain a compound 2, which has the following formula;
Figure RE-GDA0003571213290000031
(b) the compound 3 is subjected to hydrolysis reaction under the action of an organic solvent and alkali to obtain a compound 4, which has the following formula;
Figure RE-GDA0003571213290000032
(c) carrying out condensation reaction on the compound 4 and the compound 2 under the conditions of an organic solvent and a condensing agent to obtain a compound 5, which has the following formula;
Figure RE-GDA0003571213290000033
(d) carrying out condensation reaction on the compound 5 and the compound 6 under the conditions of an organic solvent and a condensing agent to obtain a compound 7, which has the following formula;
Figure RE-GDA0003571213290000041
(e) the compound 7 is subjected to dehydration reaction under the conditions of an organic solvent, alkali and a dehydrating agent to obtain the 3CLPRO inhibitor PF-07321332.
Figure RE-GDA0003571213290000042
The synthetic route is as follows:
Figure RE-GDA0003571213290000051
the preparation method of the anti-coronavirus 3CLPRO inhibitor takes a compound 1 as an initial raw material, and obtains a compound PF07321332 through a substitution reaction, a hydrolysis reaction and a condensation reaction. The reactions in the steps are conventional, the reaction conditions are relatively mild, the operation is simple and convenient, the raw materials are easy to obtain, the purification is convenient, and high yield can be obtained.
Wherein, the compound PF-07321332 is prepared by the above reaction, the reaction time of each step can be monitored by conventional detection means, such as TLC, and whether to continue the reaction or finish the reaction is selected, and whether to purify or directly perform the next step of reaction according to the requirement after the reaction is finished.
Further, the conditions for carrying out the reactions of the above-mentioned steps may be conventional ones, but when the following preferable embodiment is adopted, the reaction yield can be improved, the reaction rate can be improved, and the reaction cost can be reduced.
Preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (a), the organic solvent is one or more of methanol, ethanol and isopropanol, and the base is one or more of sodium ethoxide, sodium methoxide, diisopropylethylamine and triethylamine; the molar ratio of the compound 1 to the ethyl trifluoroacetate to the base is 1: 1.1-2: 1.1-3, the reaction temperature is 50-100 ℃, and the reaction time is 2-8 h.
More preferably, in the above method for preparing the anti-coronavirus 3CLPRO inhibitor, in step (a), the organic solvent is one of methanol and ethanol, and the base is one of sodium ethoxide and diisopropylethylamine; the molar ratio of the compound 1 to the ethyl trifluoroacetate to the base is 1: 1.5: 1.1, the reaction temperature is 60 ℃, and the reaction time is 2-4 h.
Preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (b), the organic solvent is one or more of tetrahydrofuran, dioxane, dichloromethane and acetonitrile, and the base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate; the molar ratio of the compound 3 to the base is 1: 1-1.5, the reaction temperature is 40-80 ℃, and the reaction time is 2-12 h.
More preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (b), the organic solvent is one of tetrahydrofuran and dioxane, more preferably tetrahydrofuran, and the base is one of sodium hydroxide and potassium hydroxide, more preferably sodium hydroxide; the molar ratio of the compound 3 to the base is 1: 1.1, the reaction temperature is 50-70 ℃, and the reaction time is 2-3 h.
Preferably, in the above method for preparing a 3CLPRO inhibitor against coronavirus, in step (c), the organic solvent is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, and N, N-dimethylacetamide, and the condensing agent is one or more of methyl chloroformate, isobutyl chloroformate, ethyl chloroformate, and p-toluenesulfonyl chloride; the molar ratio of the compound 4 to the compound 2 to the condensing agent is 1: 1-2: 1-1.5, the reaction temperature is 0-20 ℃, and the reaction time is 1-5 h.
More preferably, in the above method for preparing a 3CLPRO inhibitor against coronavirus, in step (c), the organic solvent is one of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran, more preferably tetrahydrofuran, and the condensing agent is one of isobutyl chloroformate and ethyl chloroformate; the molar ratio of the compound 4 to the compound 2 to the condensing agent is 1: 1.1: 1.2, the reaction temperature is 0-5 ℃, and the reaction time is 2-3 h.
Preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in the step (d), the organic solvent is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide and N, N-dimethylacetamide, the condensing agent is one or more of methanesulfonyl chloride, p-toluenesulfonyl chloride and dichloromethylenechloride, and the base is one or more of triethylamine, diisopropylethylamine and N-methylmorpholine; the molar ratio of the compound 5 to the compound 6 to the base is 1: 1-2: 1-5 ℃, the reaction temperature is 0-10 ℃, and the reaction time is 2-8 h.
More preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (d), the organic solvent is one of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran, more preferably tetrahydrofuran, the condensing agent is one of p-toluenesulfonyl chloride and methanesulfonyl chloride, and the base is one of triethylamine and diisopropylethylamine, more preferably triethylamine; the molar ratio of the compound 5 to the compound 6 to the base is 1: 1.1: 2.5, the reaction temperature is 0 ℃, and the reaction time is 2-3 h.
Preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (e), the organic solvent is one or more of ethyl acetate, isopropyl acetate, dichloromethane, acetonitrile, N-dimethylformamide and dimethyl sulfoxide, the base is one or two of triethylamine and diisopropylethylamine, and the dehydrating agent is one or two of methanesulfonic anhydride and thionyl chloride; the molar ratio of the compound 7 to the base to the dehydrating agent is 1: 2: 1, the reaction temperature is-10-0 ℃, and the reaction time is 2-5 h.
More preferably, in the above preparation method of the anti-coronavirus 3CLPRO inhibitor, in step (e), the organic solvent is one of ethyl acetate and dichloromethane, the base is one of triethylamine and diisopropylethylamine, and the dehydrating agent is one of methanesulfonic anhydride and thionyl chloride; the molar ratio of the compound 7 to the base to the dehydrating agent is 1: 2: 1, the reaction temperature is 0 ℃, and the reaction time is 2 hours.
Compared with the prior art, the invention has the following beneficial effects:
(1) the preparation method of the anti-coronavirus 3CLPRO inhibitor has reasonable design of preparation steps, and provides a method which has lower cost and simpler and more convenient operation and is suitable for industrial production of the 3CLPRO inhibitor PF-07321332;
(2) the preparation method of the anti-coronavirus 3CLPRO inhibitor has the advantages that the synthetic route is short, the intermediate is easy to separate and purify, column chromatography is not needed, and the purity of the obtained product is high;
(3) the preparation method of the anti-coronavirus 3CLPRO inhibitor is safe and simple to operate, high in reaction yield, safe and simple in reaction, capable of realizing industrial large-scale production and wide in application prospect.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to specific experimental data, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples do not show the specific conditions, and the apparatus and reagents used are commercially available according to the conventional conditions or the conditions recommended by the manufacturer.
The following examples 1 and 2 provide a method for preparing an anti-coronavirus 3CLPRO inhibitor.
Example 1
A method for preparing anti-coronavirus 3CLPRO inhibitor, namely a method for preparing SARS-CoV-2-3CL protease inhibitor (PF-07321332), comprises the following steps:
(a) preparation of compound 2 from compound 1: adding 100g of the compound 1 into a 1000ml reaction bottle, adding 500ml of absolute ethyl alcohol, adding 52.0g of sodium ethoxide in batches at room temperature, continuing to add 162g of trifluoroacetic acid ethyl ester after finishing adding, heating to 60 ℃, reacting for 3-4 hours, concentrating to remove the ethyl alcohol, adding 1500ml of 20% citric acid aqueous solution, adding 500ml of ethyl acetate, extracting twice, drying with anhydrous sodium sulfate, and concentrating to obtain 170g of white solid with the yield of 98.2%.
1HNMR(400MHz,DMSO-d6),13.02(s,1H),9.44-9.45(d,J＝7.2Hz,1H), 4.20-4.22(d,J＝7.2Hz,1H),1.0(s,9H)ppm.
ESI-MS(m/z):(M+H):228.08.
(b) Preparation of compound 4 from compound 3: adding 50g of the compound 3 into a 1000ml reaction bottle, adding 500ml of tetrahydrofuran, adding 200ml of water, adding 11.7g of sodium hydroxide at room temperature, heating to 50 ℃ for reaction overnight, cooling to room temperature, concentrating to remove tetrahydrofuran, adding concentrated hydrochloric acid to adjust the pH value to 5-6, and concentrating to obtain a white solid which is directly used for the next reaction with the yield of 100%.
1HNMR(400MHz,DMSO-d6),3.12-3.15(t,J1＝5.6Hz,J2＝9.6Hz,1H), 3.01(s,1H),2.66-2.69(d,J＝8.8Hz,1H),1.49-1.51(d,J＝8.0Hz,1H), 1.09-1.12(m,1H),1.07(s,3H),0.98(s,3H)ppm.
ESI-MS(m/z):(M+H):156.09.
(c) Preparation of compound 5 from compound 4: 2100 g of compound is added into a 1000ml reaction bottle, 500m of tetrahydrofuran is added, the temperature is reduced to 0 ℃, 74g of isobutyl chloroformate is added, the temperature is kept at 0 ℃ for reaction for 2 to 3 hours, 478 g of compound is added, the temperature is kept at 0 ℃ for reaction for 2 hours, 200ml of water is added for quenching reaction, 500ml of ethyl acetate is extracted twice, 500ml of saturated saline is washed, anhydrous sodium sulfate is used for drying, suction filtration is carried out, white solid is obtained by concentration, 200ml of methyl tert-butyl ether is used for washing, suction filtration is carried out, 135g of pure product is obtained, and the yield is 91.2%.
1HNMR(400MHz,DMSO-d6),13.02(s,1H),9.42-9.45(d,J＝12Hz,1H), 4.46-4.48(d,J＝8Hz,1H),4.18(s,1H),3.86-3.90(m,1H),3.74-3.77 (d,J＝12Hz,3H),1.54-1.58(m,1H),1.45-1.47(m,1H),1.0-1.04(m, 12H),0.98(s,3H).ppm.
ESI-MS(m/z):(M+H)365.06
(d) Preparation of compound 7 from compound 5: adding 100g of compound 5 into a 1000ml reaction bottle, adding 500ml of tetrahydrofuran, adding 68.6g of triethylamine, cooling to 0 ℃, adding 62.6g of p-toluenesulfonyl chloride in batches, keeping the temperature at 0 ℃, stirring for 2-3 hours, adding 60.7g of compound 6, and stirring back to room temperature overnight; adding 300ml of water for quenching reaction, adding 500ml of ethyl acetate for extraction twice, combining organic phases, washing by 500ml of saturated saline solution, drying and concentrating to obtain the product which is directly used for the next step with the yield of 100%.
1HNMR(400MHz,DMSO-d6),9.40-9.43(d,J＝12Hz,1H),8.29-8.31 (d,J＝8Hz,1H),7.56(s,1H),7.32(s,1H),7.05(s,1H),4.45-4.47(m,1H) 4.29-4.35(m,2H),3.90-3.94(m,1H),3.69-3.71(m,1H),3.14-3.18 (m,1H),3.06-3.09(m,1H),2.41-2.44(m,1H),2.15-2.18(m,1H),1.93-1. 96(m,2H),1.66-1.67(m,1H),1.64-1.65(m,2H),1.0(m,12H),0.87(s,3H) ppm.
ESI-MS(m/z):(M+H)503.21
(e) Preparation of compound PF-07321332 from compound 7: adding the product obtained in the previous step into a 1000ml reaction bottle, adding 500ml of ethyl acetate, adding 88g of diisopropylethylamine, cooling to 0 ℃, adding 48.6g of thionyl chloride, stirring for 2 hours, adding 200ml of water to quench after the reaction is finished, separating an organic phase, washing once by 500ml of saturated saline solution, drying, and concentrating to remove ethyl acetate; adding 500ml of methyl tert-butyl ether into the residue, separating out a large amount of white solid, cooling to room temperature, stirring for 2-3 hours, and performing suction filtration to obtain white solid powder; transferring the white solid powder to another dry 1000ml reaction bottle, adding 200ml of ethyl acetate and 800ml of n-heptane, heating to 70 ℃, stirring for 2-3 hours, cooling to room temperature, performing suction filtration, and drying to obtain 110g of a pure product with the yield of 80%.
1HNMR(400MHz,DMSO-d6),9.42-9.44(d,J＝8Hz,1H),9.03-9.05 (d,J＝8Hz,1H),7.69(s,1H),4.96-5.03(m,1H)，4.43-4.45(d,J＝8Hz，1H),4.18(s,1H),3.92-3.96(m,1H),3.70-3.73(m,1H)，3.10-3.19 (m,1H),3.03-3.07(m,1H),2.41-2.44(m,1H),2.10-2.14(m,2H),1.70-1. 77(m,2H),1.56-1.59(m,1H),1.42-1.44(m,1H),1.02(m,12H),0.88(s,3 H)ppm.
ESI-MS(m/z):(M+H)500.20
Example 2
A method for preparing anti-coronavirus 3CLPRO inhibitor, namely a method for preparing SARS-CoV-2-3CL protease inhibitor (PF-07321332), comprises the following steps:
(a) preparation of compound 2 from compound 1: adding 150g of the compound 1 into a 2000ml reaction bottle, adding 1000ml of anhydrous methanol, dropwise adding 161.0g of diisopropylethylamine at room temperature, continuously adding 195g of trifluoroacetic acid ethyl ester after dropwise adding, heating to 70 ℃ to react for 2-3 hours after dropwise adding, concentrating to remove the methanol, adding 2500ml of 20% citric acid aqueous solution, adding 500ml of ethyl acetate to extract twice, drying with anhydrous sodium sulfate, concentrating to obtain 257g of white solid, wherein the yield is 99%.
1HNMR(400MHz,DMSO-d6),13.02(s,1H),9.44-9.45(d,J＝7.2Hz， 1H),4.20-4.22(d,J＝7.2Hz,1H),1.0(s,9H)ppm.
ESI-MS(m/z):(M+H):228.08.
(b) Preparation of compound 4 from compound 3: adding 80g of the compound 3 into a 2000ml reaction bottle, adding 800ml of tetrahydrofuran, adding 400ml of water, adding 10.7g of sodium hydroxide at room temperature, heating to 70 ℃ for reaction for 2-3h, cooling to room temperature, concentrating to remove tetrahydrofuran, adding concentrated hydrochloric acid to adjust the pH value to 5-6, and concentrating to obtain a white solid which is directly used for the next reaction with the yield of 100%.
1HNMR(400MHz,DMSO-d6),3.12-3.15(t,J1＝5.6Hz,J2＝9.6Hz,1H), 3.01(s,1H),2.66-2.69(d,J＝8.8Hz,1H),1.49-1.51(d,J＝8.0Hz,1H), 1.09-1.12(m,1H),1.07(s,3H),0.98(s,3H)ppm.
ESI-MS(m/z):(M+H):156.09.
(c) Preparation of compound 5 from compound 4: adding 150g of compound 2 into a 2000ml reaction bottle, adding 900ml of tetrahydrofuran, cooling to 0 ℃, adding 115g of ethyl chloroformate, keeping the temperature at 0 ℃ for reaction for 2-3 hours, then adding 117g of compound 4, keeping the temperature at 0 ℃ for reaction for 2 hours, adding 400ml of water for quenching reaction, extracting twice with 1000ml of ethyl acetate, washing with 1000ml of saturated saline solution, drying with anhydrous sodium sulfate, carrying out suction filtration, concentrating to obtain a white solid, washing with 300ml of methyl tert-butyl ether, and carrying out suction filtration to obtain 274g of a pure product with the yield of 96%.1HNMR(400MHz,DMSO-d6),13.02(s,1H),9.42-9.45(d,J＝12Hz,1H), 4.46-4.48(d,J＝8Hz,1H),4.18(s,1H),3.86-3.90(m,1H),3.74-3.77 (d,J＝12Hz,3H),1.54-1.58(m,1H),1.45-1.47(m,1H),1.0-1.04(m, 12H),0.98(s,3H).ppm.
ESI-MS(m/z):(M+H)365.06.
(d) Preparation of compound 7 from compound 5: adding 130g of compound 5 into a 1000ml reaction bottle, adding 500ml of tetrahydrofuran, adding 89.2g of triethylamine, cooling to 0 ℃, dropwise adding 45.2g of methanesulfonyl chloride, keeping the temperature at 0 ℃, stirring for 2-3 hours, adding 78.9g of compound 6, and stirring back to room temperature overnight; adding 300ml of water for quenching reaction, adding 500ml of ethyl acetate for extraction twice, combining organic phases, washing by 500ml of saturated saline solution, drying and concentrating to obtain the product which is directly used for the next step with the yield of 100%.
1HNMR(400MHz,DMSO-d6),9.40-9.43(d,J＝12Hz,1H),8.29-8.31 (d,J＝8Hz,1H),7.56(s,1H),7.32(s,1H),7.05(s,1H),4.45-4.47 (m,1H),4.29-4.35(m,2H),3.90-3.94(m,1H),3.69-3.71(m,1H),3.14 -3.18(m,1H),3.06-3.09(m,1H),2.41-2.44(m,1H),2.15-2.18(m,1H),1. 93-1.96(m,2H),1.66-1.67(m,1H),1.64-1.65(m,2H),1.0(m,12H),0.87( s,3H)ppm.
ESI-MS(m/z):(M+H)503.21.
(e) Preparation of compound PF-0732133 from compound 7: adding the product obtained in the previous step into a 2000ml reaction bottle, adding 1000ml of dichloromethane, adding 144.2g of triethylamine, cooling to 0 ℃, adding 93.2g of methanesulfonic anhydride, stirring for 2 hours, adding 400ml of water to quench after the reaction is finished, separating an organic phase, washing once by 500ml of saturated saline solution, drying, and concentrating to remove ethyl acetate; adding 800ml of methyl tert-butyl ether into the residue, separating out a large amount of white solid, cooling to room temperature, stirring for 2-3 hours, and performing suction filtration to obtain white solid powder; transferring the white solid powder to another dry 1000ml reaction bottle, adding 300ml of ethyl acetate and 1000ml of n-heptane, heating to 70 ℃, stirring for 2-3 hours, cooling to room temperature, performing suction filtration, and drying to obtain 160g of a pure product with the yield of 90%.
1HNMR(400MHz,DMSO-d6),9.42-9.44(d,J＝8Hz,1H),9.03-9.05 (d,J＝8Hz,1H),7.69(s,1H),4.96-5.03(m,1H),4.43-4.45(d,J＝8Hz, 1H),4.18(s,1H),3.92-3.96(m,1H),3.70-3.73(m,1H),3.10-3.19 (m,1H),3.03-3.07(m,1H),2.41-2.44(m,1H),2.10-2.14(m,2H),1.70-1. 77(m,2H),1.56-1.59(m,1H),1.42-1.44(m,1H),1.02(m,12H),0.88(s,3 H)ppm.
ESI-MS(m/z):(M+H)500.20.
As can be seen from the above examples 1 and 2, the method provided by the application has the advantages of lower cost, simpler operation, suitability for industrial production of the 3CLPRO inhibitor PF-07321332, shorter synthetic route, easy separation and purification of the intermediate, no need of column chromatography, high purity of the obtained product, safe and simple operation, high reaction yield, safe and simple reaction, suitability for industrial scale-up production, and wide application prospect.
The invention has many applications, and the above description is only a preferred embodiment of the invention. It should be noted that the above examples are only for illustrating the present invention, and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various modifications can be made without departing from the principles of the invention and these modifications are to be considered within the scope of the invention.

Claims (10)

1. A preparation method of an anti-coronavirus 3CLPRO inhibitor is characterized by comprising the following steps:
(a) carrying out substitution reaction on the compound 1 and ethyl trifluoroacetate under the action of an organic solvent and alkali to obtain a compound 2, which has the following formula;
Figure FDA0003440003860000011
(b) the compound 3 is subjected to hydrolysis reaction under the action of an organic solvent and alkali to obtain a compound 4, which has the following formula;
Figure FDA0003440003860000012
(c) carrying out condensation reaction on the compound 4 and the compound 2 under the conditions of an organic solvent and a condensing agent to obtain a compound 5, which has the following formula;
Figure FDA0003440003860000013
(d) carrying out condensation reaction on the compound 5 and the compound 6 under the conditions of an organic solvent and a condensing agent to obtain a compound 7, which has the following formula;
Figure FDA0003440003860000021
(e) the compound 7 is subjected to dehydration reaction under the conditions of an organic solvent, alkali and a dehydrating agent to obtain the 3CLPRO inhibitor PF-07321332.
Figure FDA0003440003860000022
2. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 1, wherein the organic solvent is one or more of methanol, ethanol and isopropanol, and the base is one or more of sodium ethoxide, sodium methoxide, diisopropylethylamine and triethylamine in step (a); the molar ratio of the compound 1 to the ethyl trifluoroacetate to the base is 1: 1.1-2: 1.1-3, the reaction temperature is 50-100 ℃, and the reaction time is 2-8 h.
3. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 2, wherein in the step (a), the organic solvent is one of methanol and ethanol, and the base is one of sodium ethoxide and diisopropylethylamine; the molar ratio of the compound 1 to the ethyl trifluoroacetate to the base is 1: 1.5: 1.1, the reaction temperature is 60 ℃, and the reaction time is 2-4 h.
4. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 1, wherein in the step (b), the organic solvent is one or more of tetrahydrofuran, dioxane, dichloromethane and acetonitrile, and the base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate; the molar ratio of the compound 3 to the base is 1: 1-1.5, the reaction temperature is 40-80 ℃, and the reaction time is 2-12 h.
5. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 4, wherein in the step (b), the organic solvent is one of tetrahydrofuran and dioxane, and the base is one of sodium hydroxide and potassium hydroxide; the molar ratio of the compound 3 to the base is 1: 1.1, the reaction temperature is 50-70 ℃, and the reaction time is 2-3 h.
6. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 1, wherein the organic solvent in step (c) is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, and N, N-dimethylacetamide, and the condensing agent is one or more of methyl chloroformate, isobutyl chloroformate, ethyl chloroformate, and p-toluenesulfonyl chloride; the molar ratio of the compound 4 to the compound 2 to the condensing agent is 1: 1-2: 1-1.5, the reaction temperature is 0-20 ℃, and the reaction time is 1-5 h.
7. The method of claim 6, wherein in the step (c), the organic solvent is one of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran, and the condensing agent is one of isobutyl chloroformate and ethyl chloroformate; the molar ratio of the compound 4 to the compound 2 to the condensing agent is 1: 1.1: 1.2, the reaction temperature is 0-5 ℃, and the reaction time is 2-3 h.
8. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 1, wherein in the step (d), the organic solvent is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, N-dimethylformamide, and N, N-dimethylacetamide, the condensing agent is one or more of methanesulfonyl chloride, p-toluenesulfonyl chloride, and dichloromethylenechloride, and the base is one or more of triethylamine, diisopropylethylamine, and N-methylmorpholine; the molar ratio of the compound 5 to the compound 6 to the base is 1: 1-2: 1-5 ℃, the reaction temperature is 0-10 ℃, and the reaction time is 2-8 h.
9. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 8, wherein in the step (d), the organic solvent is one of dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran, the condensing agent is one of p-toluenesulfonyl chloride and methanesulfonyl chloride, and the base is one of triethylamine and diisopropylethylamine; the molar ratio of the compound 5 to the compound 6 to the base is 1: 1.1: 2.5, the reaction temperature is 0 ℃, and the reaction time is 2-3 h.
10. The method for preparing 3CLPRO inhibitor against coronavirus according to claim 1, wherein in the step (e), the organic solvent is one or more of ethyl acetate, isopropyl acetate, dichloromethane, acetonitrile, N-dimethylformamide, and dimethyl sulfoxide, the base is one or both of triethylamine and diisopropylethylamine, and the dehydrating agent is one or both of methanesulfonic anhydride and thionyl chloride; the molar ratio of the compound 7 to the base to the dehydrating agent is 1: 2: 1, the reaction temperature is-10-0 ℃, and the reaction time is 2-5 h.
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