A nirmatrelvir intermediate, and preparation method and application thereof

Abstract

The application discloses a nirmatrelvir intermediate and a preparation method and application thereof, and belongs to the technical field of drug synthesis. The nirmatrelvir intermediate and the preparation method thereof are characterized in that 3-methyl-2-butenal is used as a starting material, and a first reactant is obtained through reductive amination reaction of the 3-methyl-2-butenal and benzylamine; acylation reaction of the first reactant and bromoacetyl bromide is performed to obtain a second reactant; under the condition that tetramethylguanidine is used as an alkali, diazotization reaction of the second reactant and N,N'-bis(p-tolylsulfonyl)hydrazine is performed to obtain a diazo compound; and the diazo compound is catalyzed by a metal catalyst to obtain a chiral pure cyclopropane compound, namely the nirmatrelvir intermediate. The method for preparing the nirmatrelvir intermediate has the advantages that a metal catalyst is used for catalysis, the reaction condition is mild, and the ee value of the obtained target product can reach 92.6%.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a nematradial intermediate, its preparation method, and its application. Background Technology

[0002] Paclov is a combination antiviral drug composed of two drugs, nirmatrelvir and ritonavir. The annual demand for nirmatrelvir, the main drug component of paclov, is approximately 360 tons / year. However, the key intermediate compound 1 ((1R,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one) of nirmatrelvir is currently synthesized using racemic synthesis techniques. The product is obtained through chiral resolution, which means that 50% of the chiral isomers are discarded, resulting in poor economic efficiency and high production costs and low accessibility.

[0003] The structural formulas of nematoside and its key intermediate compound 1 are as follows:

[0004] Structural analysis reveals that nematvir is characterized by a cyclopropane-pyrrole bicyclic skeleton, and the construction of its chiral cyclopropane structural units is the key challenge in its synthesis. Currently reported synthetic methods for nematvir all suffer from varying degrees of drawbacks, such as excessively expensive starting materials, poor chiral selectivity, and low process safety. Examples are as follows:

[0005] WIPO patent WO2007075790A1 discloses a method for preparing 6,6-dimethyl-3-imino]-[3.1.0]-hexahydro compounds and their excellent salts. The disclosed synthetic method starts from expensive calonic anhydride and achieves the synthesis of the racemic mixture through multiple steps. Chiral resolution is required to obtain the final product. The reaction pathway is as follows:

[0006] This route has poor chiral selectivity, resulting in a large waste of materials and low economic efficiency.

[0007] Chinese patent CN114644587A discloses a synthetic process for bicyclic imine, an intermediate in the drug Paxlovid. The disclosed synthetic method starts with dichloroacetamide and isopentenyl chloride, which undergo a coupling reaction to form a cyclopropane compound under the action of a cobalt catalyst. This compound is then reduced to obtain the final product, which is a racemic mixture. The reaction pathway is as follows:

[0008]

[0009] This route still suffers from significant material waste and low economic efficiency.

[0010] Chinese patent CN114057627B discloses a method for preparing intermediates and salts of drugs for hepatitis C and COVID-19. The disclosed synthetic method starts from a hydroxyproline derivative, and after a hydroxyl elimination reaction, the double-bonded compound reacts with diazonium propane to obtain the final product. The reaction pathway is as follows:

[0011]

[0012] This route has two problems: 1) poor regioselectivity of hydroxyl elimination makes product separation difficult; 2) diazonium propane is a low molecular weight diazonium compound that is explosive and cannot be industrially produced. Summary of the Invention

[0013] In view of the above situation, the present invention provides a nematrib intermediate, its preparation method and application, which uses an asymmetric cyclopropanation reaction as the key reaction, and the product is optically pure, which can realize the efficient mass production of nematrib key starting material compound 1.

[0014] To solve the above-mentioned technical problems, the first aspect of the present invention provides a method for preparing a nematoside intermediate, comprising reacting a diazo compound of formula I with a material A containing a catalyst via reaction i to obtain a chiral pure cyclopropane compound of formula II, which is the nematoside intermediate.

[0015]

[0016] The catalyst is a metal catalyst composed of a metal salt and a ligand.

[0017] According to some embodiments of the present invention, in step 4), the molar ratio of the diazo compound to the catalyst is 1:0.05 to 0.2, preferably 1:0.102.

[0018] According to some embodiments of the present invention, the molar ratio of the metal salt to the ligand is 1:(1-3); preferably, the metal salt is selected from any compound formed by copper, iron, nickel, and scandium with an acid radical ion, and the acid radical ion is selected from any one of chloride ion, bromide ion, sulfate ion, and trifluoromethanesulfonate ion; preferably at least one of CuCl2, CuCl, Cu(OTf)2, FeCl3, Fe(OTf)3, NiCl2, and Sc(OTf)3; more preferably, the ligand is at least one of the structures shown in L1-L8;

[0019]

[0020] According to some embodiments of the present invention, the material A contains solvent I; preferably, solvent I is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, n-pentane, and n-hexane; more preferably, the ratio of the diazo compound to solvent I is 1.0 g: 3 mL to 10 mL, preferably 1.0 g: 5 mL.

[0021] According to some embodiments of the present invention, the conditions for reaction i include: a temperature of 20°C to 120°C, preferably 35°C, and a time of 6h to 10h, preferably 8h.

[0022] According to some embodiments of the present invention, the preparation of the diazo compound represented by Formula I includes the following steps:

[0023] 1) Material B, which contains the compound shown in Formula III and benzylamine, is reacted with reaction ii to obtain the first reactant shown in Formula IV;

[0024] R 1 CH=C(R 2 Formula III;

[0025] In Equation III, R 1 and R 2 They may be the same or different, and are each independently selected from H, alkyl groups with or without substituents, and aldehyde groups;

[0026]

[0027] 2) Material C, which contains the first reactant and bromoacetyl bromide, is reacted via reaction iii to obtain the second reactant as shown in formula V;

[0028]

[0029] 3) The second reactant was reacted with material D containing N,N'-bis(p-toluenesulfonyl)hydrazine in the presence of a base to obtain the diazo compound as shown in Formula I;

[0030]

[0031] According to some embodiments of the present invention, in Formula III, the alkyl group, with or without substituents, is selected from C1-C6 straight-chain alkyl groups or C3-C6 branched-chain alkyl groups; preferably, the substituent is a halogen, preferably bromine or chlorine; more preferably, the C1-C6 straight-chain alkyl group is selected from any one of methyl, ethyl, propyl, butyl, pentyl, and hexyl; the C3-C6 branched-chain alkyl group is isopropyl; even more preferably, the compound represented by Formula III is any one of 3-methyl-2-butenal, 1-chloro-3-methyl-2-butene, and 1-bromo-3-methyl-2-butene.

[0032] According to some embodiments of the present invention, in step 1), the molar ratio of the compound as shown in Formula III to benzylamine is 1:1 to 1.2, preferably 1:1.08;

[0033] And / or, the material B contains solvent II; preferably, solvent II is selected from at least one of methanol, ethanol, isopropanol, and tetrahydrofuran; more preferably, the ratio of the compound shown in Formula III to solvent II is 30g:120mL to 200mL, preferably 30g:150mL;

[0034] And / or, the material B contains a reducing agent selected from at least one of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride; preferably, the molar ratio of the compound as shown in Formula III to the reducing agent is 1:1 to 1.5, more preferably 1:1;

[0035] And / or, the conditions for reaction ii include: a temperature of 0℃ to 30℃ and a time of 0.5h to 2h, preferably 1h.

[0036] According to some embodiments of the present invention, in step 2), the molar ratio of the first reaction product to bromoacetyl bromide is 1:1 to 1.2, preferably 1:1.09; wherein, the bromoacetyl bromide can be replaced by chloroacetyl chloride;

[0037] And / or, the material C contains solvent III; preferably, solvent III is selected from at least one of dichloromethane, chloroform, acetonitrile, and tetrahydrofuran; more preferably, the ratio of the first reactant to solvent III is 57.5g:150mL to 400mL, preferably 57.5g:250mL;

[0038] And / or, the material C contains an acid-binding agent, which is selected from any one of N,N-diisopropylethylamine, triethylamine, and dicycloamidine (DBU); preferably, the molar ratio of the first reactant to the acid-binding agent is 1:1 to 1.5, more preferably 1:1.48;

[0039] And / or, the conditions for reaction iii include: a temperature of -10 to 10°C and a time of 0.5 to 3 hours, preferably a temperature of 0°C and a time of 1 hour.

[0040] According to some embodiments of the present invention, in step 3), the molar ratio of the second reactant to N,N'-bis(p-toluenesulfonyl)hydrazine is 1:1 to 1.8, preferably 1:1.69;

[0041] And / or, the base is at least one selected from tetramethylguanidine, N,N-diisopropylethylamine, triethylamine, potassium carbonate, and sodium carbonate; preferably, the molar ratio of the second reactant to the base is 1:2 to 3, more preferably 1:3.5;

[0042] And / or, the material D contains solvent IV; preferably, solvent IV is selected from at least one of dichloromethane, acetonitrile, toluene, tetrahydrofuran, and N,N-dimethylformamide; more preferably, the ratio of the second reactant to solvent IV is 25.0 g: 100 mL to 250 mL, preferably 25.0 g: 150 mL;

[0043] And / or, the conditions for the reaction iv include: a temperature of 0°C to 30°C and a time of 6h to 9h, preferably 8h.

[0044] In this invention, the preparation method of the nematoside intermediate is as follows:

[0045]

[0046] In this pathway, compound a (3-methyl-2-butenal) is used as the starting material and undergoes a reductive amination reaction with benzylamine (benzylamine) to obtain the first reactant (compound b); the first reactant (compound b) undergoes an acylation reaction with bromoacetyl bromide to obtain the second reactant (compound c); the second reactant (compound c) undergoes a diazotization reaction with N,N'-bis(p-toluenesulfonyl)hydrazine under the condition of tetramethylguanidine as a base to obtain a diazo compound (compound d); the diazo compound (compound d) is catalyzed by a metal catalyst (L) to obtain a chiral pure cyclopropane compound, namely the intermediate of nematevi (compound 1); the chiral pure cyclopropane compound (compound 1) can be further subjected to simple transformation (reduction, addition, esterification) to obtain compound 2 ((1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride), and then nematevi is obtained.

[0047] A second aspect of the present invention provides a nematoside intermediate prepared by the above-described preparation method, the structural formula of which is shown in Formula II:

[0048]

[0049] According to some embodiments of the present invention, the ee value of the nematradil intermediate is ≥89.0%.

[0050] A third aspect of the present invention provides a nematevir intermediate prepared by the above preparation method, or the application of the above-mentioned nematevir intermediate in the preparation of nematevir.

[0051] Beneficial effects:

[0052] The present invention provides a method for preparing nematevir intermediates, which uses a metal catalyst for catalysis and a metal catalyst combined with a chiral ligand to catalyze an asymmetric cyclopropanation reaction. The reaction conditions are mild, and the target product can achieve an ee value of up to 92.6%.

[0053] The diazo compound d used in this invention is a high molecular weight (mw = 243.14) diazo compound, which is not prone to explosion, has good stability, high safety, and is suitable for large-scale production;

[0054] Compound d of the present invention can be subjected to an asymmetric cyclopropanation reaction without purification to obtain compound 1, which facilitates industrial production. Attached Figure Description

[0055] Figure 1 The hydrogen spectrum of the first reactant in Example 1;

[0056] Figure 2 The carbon spectrum of the first reactant in Example 1;

[0057] Figure 3 The hydrogen spectrum of the second reactant in Example 1;

[0058] Figure 4 The carbon spectrum of the second reactant in Example 1;

[0059] Figure 5 The 1H NMR spectrum of the diazo compound in Example 1;

[0060] Figure 6 The proton spectrum of compound 1 in Example 1;

[0061] Figure 7 The carbon spectrum of compound 1 in Example 1;

[0062] Figure 8 This is the HPLC chromatogram of compound 1 in Example 1, used for the determination of its chiral purity. Detailed Implementation

[0063] The present invention will be further described below with reference to embodiments. However, the present invention is not limited to these embodiments.

[0064] The instrument or equipment used for TLC monitoring in this invention is a thin-layer chromatography silica gel plate (TLC, 0.2 mm, HSGF254) (Yantai Chemical (China) Co., Ltd.), and the color development method is phosphomolybdic acid color development;

[0065] The chiral purity test of the nematradil intermediate in this invention was performed using an Agilent 1260 HPLC analyzer. HPLC conditions: chiral column type: ODH0CE-SK006 column; mobile phase: Hexane:i-PrOH = 80:20, flow rate 1 mL / min, column temperature 25℃, detection wavelength 220 nm. Elution time: t isomer =16.94min,t product =19.89min;

[0066] In this invention, the ee value is used to indicate the excess of a certain optical isomer relative to its enantiomer in a compound sample, usually expressed as a percentage; the calculation formula is ee = ([A] - [B] / [A] + [B]) * 100%, where A represents the percentage of a certain optical isomer and B represents the percentage of its enantiomer.

[0067] Example 1

[0068] This embodiment provides a method for preparing a nematrib intermediate, the steps of which are as follows:

[0069] 1) 30 g (0.36 mol) of 3-methyl-2-butenal was dissolved in 150 mL of methanol, and 42.03 g (0.39 mol) of benzylamine was added at 25 °C. After stirring for 1 h, 13.5 g (0.36 mol) of sodium borohydride was added dropwise. After complete conversion of compound a by TLC monitoring, the solvent methanol was evaporated to dryness, and a saturated ammonium chloride solution was added. The mixture was extracted with ethyl acetate. The organic phases were combined, dried, and evaporated to dryness to obtain 57.5 g of the first reactant (compound b). The reaction pathway for this step is as follows:

[0070]

[0071] 2) 57.5 g (0.33 mol) of the first reactant (compound b) was dissolved in 250 mL of DCM (dichloromethane), and then 63.5 g (0.49 mol) of DIPEA (N,N-diisopropylethylamine) was added. Then, 73.3 g (0.36 mol) of bromoacetyl bromide was added dropwise at 0 °C. After reacting for 1 h at 0 °C, the reaction was quenched with 100 mL of water, extracted with dichloromethane, and the organic layer was washed with saturated brine, dried, and then vacuum-sealed to obtain 86.6 g of the second reactant (compound c). The reaction pathway for this step is as follows:

[0072]

[0073] 3) 25.0 g (0.085 mol) of the second reactant (compound c), 29.9 g (0.26 mol) of TMG (tetramethylguanidine), and 49.0 g (0.144 mol) of TsNHNHTs (N,N'-bis(p-toluenesulfonyl)hydrazine) were dissolved in 125 mL of dichloromethane. After reacting at 25 °C for 8 h, TLC monitoring confirmed that the second reactant (compound c) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, and the organic layer was washed with saturated brine. After removing the solid by filtration, the filtrate was the diazo compound (compound d). The reaction pathway for this step is as follows:

[0074]

[0075] 4) 0.10 g (0.21 mmol) of L2 ligand and 0.028 g (0.21 mmol) of CuCl2 were placed in a reaction flask, followed by the addition of 5 mL of dichloromethane. After stirring at 25 °C for 30 min, 1.00 g (4.12 mmol) of diazo compound (compound d) was added. After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, and dried to obtain 0.76 g of chiral pure cyclopropane compound, namely the nematevir intermediate (compound 1). The ee value of the nematevir intermediate was 92.6%. The reaction pathway for this step is as follows:

[0076]

[0077] The proton spectrum of the first reactant mentioned above is shown below. Figure 1 ,in:

[0078] 1 H NMR (400MHz, CDCl3) δ7.32(m,4H),7.29–7.17(m,1H),5.29(dd,J=8.3,5.5Hz,1H),3.78(s,2H),3.23(d,J=6.9Hz,2H),1.72(s,3H),1.56(s,3H);

[0079] The carbon spectrum of the first reactant is shown below. Figure 2 ,in:

[0080] 13 C NMR (101MHz, CDCl3) δ140.48,134.47,128.37,128.37,128.19,128.19,126.88,123.00,53.52,46.72,25.77,17.94;

[0081] The proton spectrum of the second reactant is shown below. Figure 3 ,in:

[0082] (Due to the effect of amide isomerization, the 1H NMR spectrum of the second reactant shows two sets of homologues, with a ratio of approximately 3:1.86. The 1H NMR spectrum reported here is that of the homologue with the larger proportion.)

[0083] 1 H NMR (400MHz, CDCl3) δ7.41–7.06(m,5H),5.11–4.95(br,1H),4.50(s,2H),3.84(br,2H),3.80(br,2H),1.66(s,3H),1.52(s,3H);

[0084] The carbon spectrum of the second reactant is shown below. Figure 4 ,in:

[0085] (Due to the effect of amide isomerization, the carbon spectra of the second reactant show two sets of homologues. The carbon spectra reported here are those of the mixture.)

[0086] 13 C NMR (101MHz, CDCl3) δ165.93,165.89,136.31,135.93,135.88,135.20,127.95,127.59,127.00,126.77, 126.43,125.37,118.33,117.52,49.82,47.37,44.73,42.49,25.64,25.42,24.71,24.68,16.89,16.83;

[0087] The proton NMR spectrum of the diazo compound is shown below. Figure 5 ,in:

[0088] 1 H NMR (400MHz, CDCl3) δ7.52–7.03(m,5H),5.11(s,1H),4.94(s,1H),4.46(s,2H),3.79(s,2H),1.71(s,3H),1.56(s,3H);

[0089] The proton NMR spectrum of compound 1 is shown below. Figure 6 ,in:

[0090] 1H NMR (400MHz, CDCl3) δ7.39–7.13(m,5H),4.50(d,J=14.5Hz,1H),4.15(d,J=14.5Hz,1H),3.37(dd,J=10.9,6.6 Hz,1H),2.99(d,J=11.0Hz,1H),1.83(dd,J=6.6,1.8Hz,1H),1.56(t,J=6.7Hz,1H),1.09(s,3H),0.94(s,3H);

[0091] The carbon spectrum of compound 1 is shown in [reference needed]. Figure 7 ,in:

[0092] 13 C NMR (101MHz, CDCl3) δ172.72,136.46,128.61,128.61,128.56,128.56,127.59,46.24,45.65,33.22,25.87,24.25,22.06,13.76;

[0093] The HPLC chromatogram for the determination of the chiral purity of compound 1 is shown in [reference needed]. Figure 8 .

[0094] Example 2

[0095] This embodiment provides a method for preparing a nematrib intermediate, the steps of which are as follows:

[0096] Steps 1), 2), and 3) are the same as in Example 1;

[0097] 4) 0.11 g (0.21 mmol) of L7 ligand and 0.076 g (0.076 mmol) of Cu(OTf)2 were placed in a reaction flask, followed by the addition of 5 mL of dichloromethane. After stirring at 25 °C for 30 min, 1.00 g (4.12 mmol) of diazo compound (compound d) was added. After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, and dried to obtain 0.84 g of chiral pure cyclopropane compound, namely the nematevir intermediate (compound 1). The ee value of the nematevir intermediate was 91.3%. The reaction pathway for this step is as follows:

[0098]

[0099] Example 3

[0100] This embodiment provides a method for preparing a nematrib intermediate, the steps of which are as follows:

[0101] Steps 1), 2), and 3) are the same as in Example 1;

[0102] 4) 0.11 g (0.21 mmol) of L7 ligand and 0.075 g (0.21 mmol) of Ni(OTf) were placed in a reaction flask, followed by the addition of 5 mL of dichloromethane. After stirring at 25 °C for 30 min, 1.00 g (4.12 mmol) of diazo compound (compound d) was added. After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, and dried to obtain 0.74 g of chiral pure cyclopropane compound, namely the nematevir intermediate (compound 1). The ee value of the nematevir intermediate was 90.2%. The reaction pathway for this step is as follows:

[0103]

[0104] Example 4

[0105] This embodiment provides a method for preparing a nematrib intermediate, the steps of which are as follows:

[0106] Steps 1), 2), and 3) are the same as in Example 1;

[0107] 4) 0.12 g (0.21 mmol) of L7 ligand and 0.11 g (0.21 mmol) of Fe(OTf)3 were placed in a reaction flask, followed by the addition of 5 mL of dichloromethane. After stirring at 25 °C for 30 min, 1.00 g (4.12 mmol) of diazo compound (compound d) was added. After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, and dried to obtain 0.76 g of chiral pure cyclopropane compound, namely the nematevir intermediate (compound 1). The ee value of the nematevir intermediate was 89.6%. The reaction pathway for this step is as follows:

[0108]

[0109] Example 5

[0110] This embodiment provides a method for preparing a nematrib intermediate, the steps of which are as follows:

[0111] Steps 1), 2), and 3) are the same as in Example 1;

[0112] 4) 0.12 g (0.21 mmol) of L7 ligand and 0.034 g (0.21 mmol) of FeCl3 were placed in a reaction flask, followed by the addition of 5 mL of dichloromethane. After stirring at 25 °C for 30 min, 1.00 g (4.12 mmol) of diazo compound (compound d) was added. After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. The reaction was quenched with water, extracted with dichloromethane, dried, and then subjected to vacuum to obtain 0.72 g of chiral pure cyclopropane compound, namely the nematevir intermediate (compound 1). The ee value of the nematevir intermediate was 90.8%. The reaction pathway for this step is as follows:

[0113]

[0114] Comparative Example 1

[0115] This comparative example provides a method for preparing a nematribetin intermediate, the steps of which are as follows:

[0116] Steps 1), 2), and 3) are the same as in Example 1;

[0117] 4) Place 0.076 g (0.076 mmol) of Cu(OTf)2 in a reaction flask, then add 5 mL of dichloromethane. Stir at 25 °C for 30 min, then add 1.00 g (4.12 mmol) of diazo compound (compound d). After reacting at 35 °C for 8 h, TLC monitoring confirmed that the diazo compound (compound d) had been completely converted. Quench the reaction with water, extract with dichloromethane, dry under vacuum, and obtain 0.84 g of chiral pure cyclopropane compound, namely the nematriberi intermediate (compound 1). The ee value of the nematriberi intermediate compound 1 is 0%, indicating that it is a racemic mixture.

[0118] Application Example 1

[0119] This application example provides a method for using the nematoside intermediate.

[0120] 2.00 g (ee = 92.6%) of the nematribetrin intermediate (compound 1) prepared in Example 1 was dissolved in 10 mL of tetrahydrofuran. 0.66 g of lithium aluminum hydride was added at 0 °C, and the mixture was stirred for 1 h. Mixture I was quenched with a saturated ammonium chloride aqueous solution, filtered through a diatomaceous earth filter, and the solvent was evaporated under reduced pressure. The resulting mixture II was diluted with a saturated potassium sodium tartrate aqueous solution and extracted three times with ethyl acetate. The combined organic extract I was then washed with brine, dried with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain 1.81 g of the residual yellow oily substance, which was an amine hemiacetal.

[0121] Then, at a temperature of 0℃, the above 1.81g of amine hemiacetal was dissolved in 10mL of methanol solution, 2.33g of pyridine p-toluenesulfonate was added, and the mixture was stirred for 15h. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The combined organic extract II was washed with brine, and the sulfate was dried with anhydrous sodium. After filtration, the mixture was evaporated under reduced pressure to obtain 1.65g of amine acetal.

[0122] Then, at a temperature of –60°C, the above-mentioned amine acetal and 2.28 g of trimethylsilyl cyanide were successively dissolved in 15 mL of dichloromethane. After stirring for 1 h, mixture III was quenched with saturated sodium bicarbonate aqueous solution, extracted three times with dichloromethane, and then the combined organic extracts were dried, anhydrousized with sodium sulfate, filtered, and evaporated under reduced pressure to obtain 2.15 g of crude nitrile product.

[0123] The crude nitrile compound was dissolved in a mixed solvent of methanol (5 ml) and water (5 ml), refluxed and stirred for 18 h, and then the solvent was dried to obtain 2.20 g of the methyl ester compound. The dr value of the methyl ester compound was measured to be 98:2 and the ee value was 92.1%.

[0124] Finally, 2.20 g of the above methyl ester compound was dissolved in 10 ml of methanol, and 0.2 g of palladium on carbon with a mass concentration of 10% was added. Hydrogenation was carried out under normal pressure to remove the benzyl group, yielding 1.42 g of compound 2. Compound 2 was then recrystallized in methanol after forming a salt with 1 M hydrochloric acid. The dr value increased to 100:0 and the ee value was 99.6%, which can be subsequently converted into nematevi.

[0125] The application pathway of the intermediate compound 1 of nematoside, as described above, is as follows:

[0126]

[0127] It should be noted that the embodiments described above are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A process for the preparation of a nirmatrelvir intermediate, characterized in that, The preparation method comprises the following steps: Formula I; Formula II; The reaction i is carried out under the action of a material A containing a catalyst, and a diazo compound shown in formula I is obtained, wherein the diazo compound is a chiral pure cyclopropane compound shown in formula II, which is a nirmatrelvir intermediate; The catalyst is a metal catalyst composed of a metal salt and a ligand; 。 2. The production method according to claim 1, characterized by, The metal salt is at least one selected from CuCl2, Cu(OTf)2, FeCl3, Fe(OTf)3 and Ni(OTf)2; and the ligand has a structure shown in L2 or L7; The molar ratio of the diazo compound and the catalyst is 1:0.05-0.2; The molar ratio of the metal salt and the ligand is 1:(1-3); The material A contains a solvent I; 3. The method of claim 2, wherein, The reaction i is carried out under the following conditions: the temperature is 20-120 DEG C, and the time is 6-10 hours. The solvent I is at least one selected from dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, n-pentane and n-hexane; 4. The production method according to claim 3, characterized by, The reaction i is carried out under the following conditions: the temperature is 35 DEG C, and the time is 8 hours.

5. The production method according to any one of claims 1 to 4, characterized by, The ratio of the diazo compound and the solvent I is 1.0 g:3-10 mL. The preparation of the diazo compound shown in formula I comprises the following steps: Formula III; Formula IV; 1) a material B containing a compound shown in formula III and benzylamine is reacted to obtain a first reactant shown in formula IV; Formula V; 2) a material C containing the first reactant and bromoacetyl bromide is reacted to obtain a second reactant shown in formula V; Formula I.

6. The production method according to claim 5, characterized by, 3) the second reactant is reacted with a material D containing N,N'-bis(p-toluenesulfonyl)hydrazine in the presence of a base to obtain the diazo compound shown in formula I; In step 1), the molar ratio of the compound shown in formula III and benzylamine is 1:1-1.2; The material B contains a solvent II; The material B contains a reducing agent selected from at least one of sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride; 7. The production method according to claim 6, wherein The reaction ii is carried out under the following conditions: the temperature is 0-30 DEG C, and the time is 0.5-2 hours. The solvent II is at least one selected from methanol, ethanol, isopropanol and tetrahydrofuran; 8. The preparation method according to claim 6, characterized in that, The molar ratio of the compound shown in formula III and the reducing agent is 1:1-1.

5.

9. The preparation method according to claim 5, characterized in that, The ratio of the compound shown in formula III and the solvent II is 30 g:120-200 mL. In step 2), the molar ratio of the first reaction product and bromoacetyl bromide is 1:1-1.2; The material C contains a solvent III; The material C contains an acid-binding agent selected from any one of N,N-diisopropylethylamine, triethylamine and dicyclamide; 10. The method of claim 9, wherein, The reaction iii is carried out under the following conditions: the temperature is -10-10 DEG C, and the time is 0.5-3 hours. The solvent III is at least one selected from dichloromethane, chloroform, acetonitrile and tetrahydrofuran; The molar ratio of the first reactant and the acid-binding agent is 1:1-1.

5.

11. The preparation method according to claim 9, characterized in that, The ratio of the first reactant to solvent III is 57.5 g: 150 mL ~ 400 mL.

12. The method of claim 5, wherein, In step 3), the molar ratio of the second reactant to N,N'-bis(p-tolylsulfonyl)hydrazine is 1:1 ~ 1.8; And / or, the base is at least one of tetramethylguanidine, N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate; And / or, the material D contains solvent IV; And / or, the conditions of the reaction iv include that the temperature is 0°C ~ 30°C, and the reaction time is 6h ~ 9h.

13. The method of claim 12, wherein, The molar ratio of the second reactant to the base is 1:2 ~ 3.5; And / or, the solvent IV is at least one of dichloromethane, acetonitrile, toluene, tetrahydrofuran, N,N-dimethylformamide; And / or, the conditions of the reaction iv include that the reaction time is 8h.

14. The method of claim 12, wherein, The ratio of the second reactant to solvent IV is 25.0 g: 100 mL ~ 250 mL.

Images