CN115010639B - Intermediate compound and preparation method and application thereof - Google Patents

Intermediate compound and preparation method and application thereof Download PDF

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CN115010639B
CN115010639B CN202111565569.9A CN202111565569A CN115010639B CN 115010639 B CN115010639 B CN 115010639B CN 202111565569 A CN202111565569 A CN 202111565569A CN 115010639 B CN115010639 B CN 115010639B
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CN115010639A (en
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唐家邓
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Shanghai Aiyang Chemical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
    • Y02E60/10—Energy storage using batteries
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of organic synthesis and preparation of bulk drugs, and discloses an intermediate of PF-07321332 with a structure of formula A and a preparation method thereof for preparing an intermediate compound of PF-07321332. Compared with the prior art, the intermediate and the compound can directly obtain the target product after condensation reaction, thereby simplifying the reaction, reducing byproducts and having high product purity.

Description

Intermediate compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis and preparation of bulk drugs, and relates to an intermediate of F-07321332 and a preparation method thereof.
Background
The novel coronavirus COVID-19 is an RNA virus, and after invading cells, long polypeptide chains containing various functional proteins can be generated by utilizing a protein synthesis mechanism of the cells; and cleavage by proteases produces functional proteins. Among them, 3CL protease is a key enzyme for cleavage of long polypeptide chains by new coronaviruses. F-07321332 is an oral medicine developed by the company of the best (Pfizer) for treating a new crown, the main component PF-07321332 is a new coronavirus 3CL protease inhibitor, and the structure of the novel coronavirus 3CL protease inhibitor can block the virus replication process and is shown as a formula I.
According to reports, F-07321332 is shown in three-phase clinical results, and is claimed to be taken within 3 days after symptoms appear, so that the serious disease rate, hospitalization rate and death risk can be greatly reduced. The medicine has good therapeutic effect, controllable side effects, and also has effect on variant virus.
The structure of PF-07321332 contains a plurality of chiral structures, which makes synthesis difficult. According to the report in the literature, intermediate VI and compound FM2019PF-A5 are synthesized into compound VIII, and then the compound VIII is dehydrated to change the amido into cyano, so as to obtain the active substance of PF-07321332.
Wherein the compound VI is formed from the compound IV (CAS: 328086-60-8) by sequential amination and acidification of the deprotection agent.
Disclosure of Invention
The present invention aims to provide an intermediate compound a for preparing F-07321332.
The invention also discloses a preparation method of the intermediate A.
The third object of the invention is the use of the above intermediate and a process for preparing PF-07321332 using the intermediate.
The technical proposal is as follows: an intermediate (S) -2-amino-3- ((S) -oxopyrrol-3-yl) propionitrile for preparing PF-07321332, which has a structure shown in formula A.
The preparation method comprises the following steps:
(1) Reduction of compound IV with protecting group (CAS: 328086-60-8), N- (tert-butylcarbonyl) -3- [ 2-oxopyrrolidin-3 (S) -yl ] -L-alanine methyl ester to a compound of formula II' (CAS: 249736-45-6), i.e. (S) -2-BOC-amino-3- ((S) -2-oxopyrrolidin-3-yl) -1-propanol;
(2) Carrying out a cyanidation reaction on the compound II 'to produce a compound of a formula III'; further removing the Boc protecting group to obtain the compound of the formula A.
In step (1), the reduction is performed with a borohydride, preferably sodium borohydride.
Specifically, the molar ratio of compound IV to borohydride is 1:2-20, preferably 1:5-15; in a preferred embodiment of the present invention, the molar ratio is 1:10. the reaction conditions are as follows: placing the compound of formula IV in an organic solvent, adding borohydride in batches at the temperature of-5-0 ℃, stirring, and reacting at room temperature. The organic solvent is an alcohol, preferably methanol.
Extracting after the reaction is completed, and concentrating to obtain a compound II'. Preferably, the organic phases are combined by washing with water and an organic extraction solvent, and the organic extraction solvent is removed after drying by water removal to obtain the compound II'. The organic extraction solvent is ethyl acetate.
In the step (2), the compound II ', oxidant, oxidation catalyst and ammonium acetate are taken and placed in a solvent for stirring reaction, and the compound III' is obtained. The reaction is preferably carried out at room temperature.
Preferably, the oxidant is iodobenzene diacetate (PhI (OAc) 2 ) The oxidation catalyst is 2, 6-tetramethyl piperidine nitrogen oxide (TEMPO).
The molar ratio of the compound II', the oxidant, the oxidation catalyst and the ammonium acetate is 1:2-4:0.01-0.1:3-6; preferably 1:2-2.5:0.03-0.06:3.5-4.5. In a preferred embodiment of the present invention, the molar ratio is 1:2.2:0.05:4.
the solvent is a mixture of water and acetonitrile, wherein the volume ratio of acetonitrile to water is 8-10:1, preferably 9:1.
the method for removing the Boc protecting group comprises the following steps: and adding an organic solution containing hydrogen chloride into the solid obtained after the organic extraction solvent is removed, and stirring and reacting for 0.5-6h. The solid was taken and dried to give compound a. The molar ratio of hydrogen chloride to compound II' is 4-6:1. hydrogen chloride was dissolved in ethyl acetate.
After the reaction is completed, the solid is taken and dried to obtain the compound A.
The compounds of formula A above may be used to prepare PF-07321332.
PF-077321332 is further synthesized using a compound of formula A, and a compound of formula VII, (1R, 2S, 5S) -6,6-Dimethyl-3- [3-methyl-N- (trifluoroacetyl) -L-valyl ] -3-azabicyclo [3.1.0] -2-cyclohexanoic acid, i.e., (1R, 2S, 5S) -6,6-Dimethyl-3- [3-methyl-N- (trifluoroacetyl) -L-valyl ] -3-azabicyclo [3.1.0] hexane-2-carboxic acid.
The reaction conditions are as follows: the compound VII, the condensation reagent and the catalyst are dissolved in an organic solvent, and the compound A is added until the reaction is complete. The organic solvent is dichloromethane, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol or butanol.
The condensing reagent is 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea Hexafluorophosphate (HATU) and 1-hydroxybenzotriazole (HOBt), and the catalyst is triethylamine. The molar ratio of compound VII to compound A, HATU, HOBt and triethylamine was 1:0.9-1.2:1-1.5:1-1.3:2.5-4. In a preferred embodiment of the present invention, the molar ratio is 1:1:1.2:1.1:3, the solvent is dichloromethane.
The invention improves the preparation process and provides a novel intermediate. Firstly reducing the ester group on the conventional raw material N- (tert-butylcarbonyl) -3- [ 2-oxo-pyrrole-3 (S) -yl ] -L-alanine methyl ester into hydroxyl, introducing cyano into an intermediate structure, and reacting with a compound VII to obtain the active substance of PF-07321332. Unlike the prior art in which an ester group is aminated to an amide group to obtain an intermediate, the intermediate is condensed with VII and then subjected to cyanidation.
Therefore, compared with the prior art, the intermediate of the invention can directly obtain the target product after the condensation reaction of VII, thereby simplifying the reaction, reducing byproducts and impurities and lowering the cost. The yield of PF-07321332 can reach 59% and the product purity can reach 99% based on N- (tert-butylcarbonyl) -3- [ 2-oxo-pyrrole-3 (S) -yl ] -L-alanine methyl ester.
Detailed Description
EXAMPLE 1 preparation of Compound II
(1) At room temperature, 3.05g (10.65 mmol) of the compound of formula IV is placed in a 100mL reaction bottle, 75mL of methanol is added, and the temperature is reduced by ice water bath;
(2) Adding 4.03g (106.5 mmol) of sodium borohydride in batches, cooling and stirring for 10min in an ice-water bath after the addition, removing the ice-water bath, stirring at room temperature for continuous reaction, and paying attention to deflation;
(3) After the complete reaction of the starting materials was shown by TCL (developing solvent methylene chloride: methanol=20:1, iodine color development), the solvent was removed by rotary evaporation, 70mL of water and 70mL of ethyl acetate were added, and the solution was separated; the aqueous phase was extracted 3 times (50 mL/time) with ethyl acetate and the organic phases were combined and dried over anhydrous sodium sulfate.
(4) The salt was removed by suction filtration and the solvent was removed by rotary evaporation to give 2.41g of a white solid in 87.96% yield. Is a compound of formula II' (CAS: 249736-45-6). HPLC purity: 98.5%
1 H NMR(600MHz,CDCl3)δ6.34(s,1H),5.48(s,1H),3.73(s,2H),3.45(d,J＝34.7Hz,1H),3.35(d,J＝8.1Hz,2H),2.46(d,J＝45.2Hz,2H),1.99(d,J＝34.3,2H),1.90-1.78(m,1H),1.62(s,1H),1.44(s,9H).ESI[m+1] + :259,[m-100] + :159.
Example 2
And (3) cyaniding reaction: 12g (46.5 mmol) of the product obtained in example 1, 363mg (2.32 mmol) of 2, 6-tetramethylpiperidine nitroxide (TEMPO) and iodobenzene diacetate (PhI (OAc) 2 ) 33.9g (102 mmol) and 14.34g ammonium acetate (186 mmol), 100mL acetonitrile-water mixture (acetonitrile 90mL, water 10 mL) were placed in a single-necked flask and reacted at room temperature with stirring for 2 hours.
TLC showed the starting material had reacted (developing solvent dichloromethane: methanol=20:1, post-iodine development). And (5) rotary steaming.
TLC showed complete reaction of the starting material and rotary evaporation. After that, 300mL of water and 300mL of ethyl acetate were added, and the solid remained undissolved and filtered with suction. The filtrate was separated, the aqueous phase was extracted with ethyl acetate (500 ml x 2), and the organic phases were combined and dried over anhydrous sodium sulfate. Suction filtration and rotary evaporation of filtrate. The end of the rotary evaporation gave 18.5g of solid, which was the compound of formula III'.
Deprotection: 54mL of methylene chloride and 18mL of methanol were added thereto and dissolved with stirring. 100mL (2M) of ethyl hydrogen chloride acetate solution was added thereto, and the mixture was stirred at room temperature. The solution started clouding, a white solid precipitated and gas was generated. TLC for 3 hours showed the end of the reaction. Suction filtration is carried out, and the filter cake is put into a vacuum drying oven at 30 ℃ for drying overnight to obtain 7.12g of white solid with the yield of 82.5%. HPLC purity 99.3%.
1 H NMR(600MHz,D 2 O)δ4.79(d,J＝7.5Hz,1H),3.48-3.41(m,2H),2.86-2.80(m,1H),2.46-2.40(m,1H),2.35-2.30(m,1H),2.26-2.21(m,1H),1.96-1.92(m,1H).ESI[m+1] + :154
Example 3
The intermediate compound a obtained in example 2 was reacted with a compound of formula VII to give F-07321332 active ingredient of formula I.
23.79g of Compound VII (65.28 mmol), 29.79g (78.34 mmol) of 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 9.70g (71.81 mmol) of 1-hydroxybenzotriazole (HOBt) and 19.82g of triethylamine (195.84 mmol) were dissolved in 100ml of dichloromethane, and after stirring at room temperature for 1h, 10.0g of Compound A (65.28 mmol) was added, and after stirring at room temperature for 2h, TLC (PE: EA=1:1) showed complete reaction of the starting materials. Insoluble matters in the reaction liquid were filtered off, and then the organic phase was washed with water and evaporated to dryness. The solid obtained was recrystallized from ethyl acetate/petroleum ether (V: v=5:1) to give a white solid which was dried at 45 ℃ in vacuo to give 26.7g of the product in 81% yield. HPLC purity: 99.5%.
1 H NMR(600MHz,CDCl 3 )δ8.30(s,br,1H),8.05(s,br,1H),4.55(m,1H),4.30(d,J＝6.8Hz,1H),4.24(s,1H),3.52-3.45(m,2H),3.35-3.27(m,2H),2.10-1.95(m,6H),1.27(dd,J1＝6.8Hz,J2＝7.1Hz,1H),0.98-0.93(m,1H),0.89(s,9H),0.94(s,6H).ESI[m+1] + :500

Claims (2)

1. Application of compound shown in formula A in preparing PF-07321332
；
The structure of the PF-07321332 is shown in the formula I,
。
2. a method of making PF-07321332 comprising the steps of: under the action of condensing agent and catalyst, the compound of formula A and the compound of formula VII generate PF-07321332, and the structure of PF-07321332 is shown in formula I:
the condensation reagent is 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and 1-hydroxybenzotriazole, and the catalyst is triethylamine.
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CN112125849A (en) * 2019-06-25 2020-12-25 鲁南制药集团股份有限公司 Preparation method of (2- (1H-imidazole-4-yl) phenyl) methanol
US11124497B1 (en) * 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2021250648A1 (en) * 2020-09-03 2021-12-16 Pfizer Inc. Nitrile-containing antiviral compounds
CN116478140A (en) * 2022-01-14 2023-07-25 江西隆莱生物制药有限公司 Synthesis method of 3CL pro inhibitor antiviral drug compound

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108329332A (en) * 2018-03-16 2018-07-27 安徽华昌高科药业有限公司 A method of preparing Glecaprevir
CN112125849A (en) * 2019-06-25 2020-12-25 鲁南制药集团股份有限公司 Preparation method of (2- (1H-imidazole-4-yl) phenyl) methanol
US11124497B1 (en) * 2020-04-17 2021-09-21 Pardes Biosciences, Inc. Inhibitors of cysteine proteases and methods of use thereof
WO2021250648A1 (en) * 2020-09-03 2021-12-16 Pfizer Inc. Nitrile-containing antiviral compounds
CN116478140A (en) * 2022-01-14 2023-07-25 江西隆莱生物制药有限公司 Synthesis method of 3CL pro inhibitor antiviral drug compound

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Title
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"Novel CADD-based peptidyl vinyl ester derivatives as potential proteasome inhibitors";Ke Mou et al;ioorganic & Medicinal Chemistry Letters;第18卷(第6期);第2200页 *
"One-Pot Oxidative Conversion of Alcohols into Nitriles by Using a TEMPO/PhI(OAc)2/NH4OAc System";Jean-Michel Vatele;《Later》;第1275页，摘要 *
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Linlin zhang,et al."Alpha-ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication:tructure-Based Design, Synthesis, andActivity Assessment".《Medicinal Chemistry》.2020,第20卷第4562-4578页。. *
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