Process for the preparation of 5'-nucleoside prodrugs and intermediates

Abstract

The application provides a preparation method and intermediates of 5'-nucleoside prodrugs. Specifically, the application provides a method for preparing a compound of formula VI, the method comprising the steps of: (a) reacting a compound of formula I with a compound of formula II to obtain a compound of formula III; (b) reacting the compound of formula III with a reagent M to obtain a compound of formula IV; (c) reacting the compound of formula IV in the presence of a reagent N to obtain a compound of formula V; and (d) reacting the compound of formula V with a reagent O to obtain the compound of formula VI. The preparation method has the advantages of low cost, high yield and good product purity, and can realize efficient synthesis of 5'-nucleoside prodrugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a method for preparing 5'-nucleoside prodrugs and intermediates. Background Technology

[0002] Nucleoside analogs play a crucial role in antiviral drugs. After entering cells, they are converted to nucleoside triphosphates by kinases. These triphosphates then competitively insert into the elongating DNA or RNA chains during viral replication, causing chain termination or mutation and thus inhibiting viral proliferation. However, some nucleoside compounds fail to achieve their expected efficacy due to inhibited phosphorylation or low bioavailability. Prodrug modification is a classic method to address this issue. Nucleoside 5'-hydroxyl esterification or phosphorylation is a common prodrug modification strategy. Since nucleoside structures contain other active groups besides the 5'-hydroxyl group, such as 2'-hydroxyl, 3'-hydroxyl, and amino groups, selectively modifying the 5'-hydroxyl group for prodrug application is a challenge. Currently, the commonly used synthetic method for nucleoside 5'-hydroxy prodrug modification is the functional group protection method. This involves first protecting the non-target active group, then introducing a prodrug group into the 5'-hydroxy group, and finally removing the protecting group to achieve selective prodrug modification of the nucleoside 5'-hydroxy group, such as the nucleoside prodrugs Molnupiravir and Remdesivir.

[0003] Molnupiravir (EIDD-2801 / MK4482) is an oral anti-SARS-CoV-2 candidate drug developed by Merck & Co. in collaboration with Ridgeback Biotech, and is currently in Phase II / III clinical trials. Existing literature (WO2019173602A1; Eur. J. Org. Chem. 2020, 6736–6739; Synlett 2020, 31, A–C) reports the following preparation method.

[0004]

[0005]

[0006] Remdesivir (GS-5734) is a novel carbon nucleoside aminophosphate prodrug developed by Gilead Sciences and is currently approved by the US FDA for the treatment of SARS-CoV-2. Existing literature (J.Med.Chem.2017,60,1648-61; Nature.2016,531,381-5; Bioorg.Med.Chem.Lett.2012,22,2705-7; WO2016069826) has reported the following preparation methods for Remdesivir:

[0007]

[0008] As can be seen from the above preparation methods, the two nucleoside prodrugs employ the same synthetic strategy: forming acetal condensate at the 2' and 3' positions of the nucleoside, then modifying the 5'-hydroxyl group of the nucleoside as a prodrug, followed by deprotection to obtain the nucleoside prodrug. Although this synthetic strategy is relatively common, the harsh deprotection conditions lead to many drawbacks, such as nucleoside prodrug degradation, low yield, and difficulty in product purification.

[0009] In summary, there is an urgent need in this field to develop a new method for preparing 5'-nucleoside prodrugs. In particular, when the 2', 3', and 5' positions of the nucleoside are all hydroxyl groups, there is a pressing need to find a more economical, practical, and environmentally friendly new synthetic method for selectively modifying the 5'-hydroxyl groups of the nucleoside to improve process stability, reduce costs, and improve product quality. Summary of the Invention

[0010] The purpose of this invention is to provide a method for synthesizing 5'-nucleoside prodrugs and their intermediates that is low in cost, high in yield, and produces products with good purity. Another purpose of this invention is to provide compounds that can be used as intermediates for preparing 5'-nucleoside prodrugs (as shown in Formula VI).

[0011] In one aspect of the present invention, a method for preparing a VI compound is provided, the method comprising the steps of:

[0012] (d) React compound V with reagent O to obtain compound VI;

[0013]

[0014] Wherein, reagent O is selected from the following group: hydroxylamine or its salt, organic acid, inorganic acid, hydrazine hydrate, or a combination thereof;

[0015] Among the various types,

[0016] R1, R2 and R3 are each independently selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C16 alkyl (preferably, C1-C8 alkyl; more preferably, C1-C4 alkyl), substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, azide (-N=N=N), and cyano.

[0017] R8 is

[0018]

[0019] R9 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl (preferably C1-C8 alkyl; more preferably C1-C4 alkyl);

[0020] R 10 Selected from the following group: C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aryl;

[0021] R 11 Selected from the group consisting of: substituted or unsubstituted C1-C16 alkyl (preferably C1-C8 alkyl), substituted or unsubstituted C3-C7 cycloalkyl, and arylmethylene;

[0022] Y is

[0023] or

[0024] Z is

[0025] or

[0026] Indicates a single bond or a double bond;

[0027] X1 is selected from the following group: N, CR 12 ;

[0028] X2 is selected from the following group: C (=O);

[0029] X3 is selected from the following groups: C(=O), C(N=CHNR4R5);

[0030] X4 is selected from the following group: N, NH;

[0031] X5, X6, and X7 are selected from the following groups: C and N;

[0032] X8 is selected from the following group: C(=O), C(NHR) 15 );

[0033] R 15 It is H or OH;

[0034] R4 and R5 are each independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C16 alkyl (preferably, C1-8 alkyl; more preferably, C1-4 alkyl; most preferably, C1-2 alkyl); or R4 and R5 together with the nitrogen atom attached to them to form a substituted or unsubstituted 4- to 7-membered saturated heterocyclic group (preferably, the saturated heterocyclic group contains only the N heteroatom attached to R4 and R5);

[0035] R 12 and R 13Each of the following is independently hydrogen, deuterium, substituted or unsubstituted C1-C16 alkyl (preferably C1-8 alkyl; more preferably C1-4 alkyl; most preferably C1-2 alkyl), substituted or unsubstituted C2-C16 alkenyl (preferably C2-C6 alkenyl), halogen, substituted or unsubstituted amino, or cyano.

[0036] Unless otherwise specified, the substitution refers to the substitution of one or more hydrogens (preferably 1, 2, 3 or 4) in a group by a substituent selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl; wherein the benzyl, aryl and cycloalkyl may also optionally be substituted by one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of the substituted halogen, C1-C3 alkyl, C1-C3 haloalkyl.

[0037] In another preferred embodiment, R4 and R5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl groups; preferably, both R4 and R5 are methyl.

[0038] In another preferred embodiment, the aryl group is selected from the group consisting of substituted or unsubstituted phenyl groups and substituted or unsubstituted naphthyl groups.

[0039] In another preferred example, Y is selected from the following group:

[0040]

[0041] In another preferred example, Y is selected from the following group:

[0042]

[0043] Or the cis-trans isomers of the above groups.

[0044] In another preferred embodiment, Y is

[0045] In another preferred embodiment, Y is Or the cis-trans isomers of the above groups.

[0046] In another preferred example, Z is selected from the following group:

[0047]

[0048] In another preferred embodiment, R1, R2 and R3 are each independently selected from the group consisting of: hydrogen, fluorine, azide, methyl, chloromethyl (CH2Cl), fluoromethyl (CH2F), difluoromethyl, vinyl, ethynyl, and cyano.

[0049] In another preferred embodiment, R3 is hydrogen or cyano.

[0050] In another preferred embodiment, R1 and R2 are hydrogen.

[0051] In another preferred embodiment, R 12 and R 13 It is hydrogen.

[0052] In another preferred embodiment, in each formula, R1, R2, R3, R4, R5, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 X1, X2, X3, X4, X5, X6, X7, X8, Y, and Z are each independently the corresponding group in the specific compound in the examples.

[0053] In another preferred embodiment, Y is and / or Z is

[0054] In another preferred embodiment, Y is Or the cis-trans isomer of the above groups; and / or Z is

[0055] In another preferred embodiment, in step (d), the hydroxylamine or a salt thereof includes: hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, or a combination thereof.

[0056] In another preferred embodiment, in step (d), reagent O is selected from the group consisting of hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, or combinations thereof.

[0057] In another preferred embodiment, in step (d), the organic acid in reagent O is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, or combinations thereof.

[0058] In another preferred embodiment, in step (d), the inorganic acid in reagent O is selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, or combinations thereof.

[0059] In another preferred embodiment, in step (d), reagent O is hydrazine hydrate.

[0060] In another preferred embodiment, when R8 is And Y is When reagent O is hydroxylamine or its salt, and Z is...

[0061] In another preferred embodiment, when R8 is And Y is When the above groups are in cis-trans isomer form, reagent O is hydroxylamine or a salt thereof, and Z is...

[0062] In another preferred embodiment, when R1, R2, and R3 are hydrogen, and R8 is... Y is Among them, R4, R5, R9 and R 12 As defined above,

[0063] In another preferred embodiment, when R1, R2, and R3 are hydrogen, and R8 is... Y is Or the cis-trans isomers of the above groups, wherein R4, R5, R9 and R 12 As defined above,

[0064] Reagent O is hydroxylamine or its salt, and Z is...

[0065] In another preferred embodiment, when R8 is And Y is When; reagent O is an inorganic acid, organic acid, or hydrazine hydrate; Z is

[0066] In another preferred embodiment, when R8 is And Y is Or the cis-trans isomer of the above groups; reagent O is an inorganic acid, organic acid, or hydrazine hydrate; Z is

[0067] In another preferred embodiment, when R1 and R2 are hydrogen, R3 is cyano, and R8 is... Y is Among them, R4, R5, R 10 R 11 and R 12 As defined above;

[0068] Reagent O is an inorganic acid, an organic acid, or hydrazine hydrate, and Z is...

[0069] In another preferred embodiment, when R1 and R2 are hydrogen, R3 is cyano, and R8 is... Y is Or the cis-trans isomers of the above groups, wherein R4, R5, R 10 R 11 and R 12 As defined above;

[0070] Reagent O is an inorganic acid, an organic acid, or hydrazine hydrate, and Z is...

[0071] In another preferred embodiment, in step (d), the reaction is carried out in a fourth solvent.

[0072] In another preferred embodiment, in step (d), the fourth solvent is selected from the group consisting of alcohol solvents, water, tetrahydrofuran, acetonitrile, or combinations thereof.

[0073] In another preferred embodiment, in step (d), the alcohol solvent is a C1-C6 alcohol solvent; preferably, it is selected from the group consisting of methanol, ethanol, propanol, or combinations thereof.

[0074] In another preferred embodiment, in step (d), the reaction temperature is from 0 to reflux temperature, preferably 25 to 100°C.

[0075] In another preferred embodiment, in step (d), compound V reacts with reagent O to directly obtain compound VI; or, compound V can react with reagent O to form an intermediate product, which is then converted into compound V to obtain compound V.

[0076] In another preferred embodiment, the intermediate product is a compound of formula VII.

[0077]

[0078] Y' is or

[0079] X 10 For C (NHC = NOH);

[0080] Among them, X1, X2, X4, X5, X6, X7, R1, R2, R3, R8, R 12 and R 13 As defined above.

[0081] In another preferred embodiment, step (d) includes the step of reacting compound V with reagent O in a fourth solvent at a temperature T1 to directly obtain compound VI.

[0082] In another preferred embodiment, T1 is 0 to reflux temperature; more preferably, it is 50 to 100°C.

[0083] In another preferred embodiment, step (d) includes the following steps:

[0084] (d1) In a fourth solvent, at temperature T2, compound V is reacted with reagent O to form compound VII; and

[0085] (d2) In the fourth solvent, at temperature T3, the compound of formula VII is reacted with reagent O to form the compound of formula VI;

[0086] And T3 > T2.

[0087] In another preferred embodiment, the compound of non-separable form VII is used.

[0088] In another preferred embodiment, T2 = 0–50°C.

[0089] In another preferred embodiment, T3 is 30°C to reflux temperature, more preferably, T3 is 50 to 100°C.

[0090] In another preferred embodiment, in step (d), the molar ratio of compound V to reagent O is 1:(1-50); more preferably, 1:(1-20); even more preferably, 1:(2-20).

[0091] In another preferred embodiment, the method further includes the step of preparing compound V.

[0092] In another preferred embodiment, the preparation of the compound of formula V is as described in the third aspect.

[0093] In a second aspect of the invention, a compound of formula V is provided.

[0094]

[0095] R1, R2, R3, R8 and Y are defined as in the first aspect.

[0096] In another preferred embodiment, R3 is hydrogen or cyano; Y is... And R1, R2, R4, R5, R8 and R 12 As defined above.

[0097] In another preferred embodiment, R3 is hydrogen or cyano; Y is... Or the cis-trans isomers of the above groups; and R1, R2, R4, R5, R8 and R 12 As defined above.

[0098] In another preferred embodiment, R4 and R5 are methyl groups.

[0099] In another preferred embodiment, the compound of formula V is a compound of formula VI, or a compound of formula V-II;

[0100]

[0101] In another preferred embodiment, the compound of formula V is a compound of formula Va-I or its cis-trans isomer, or a compound of formula Va-II or its cis-trans isomer.

[0102]

[0103] In a third aspect of the invention, a method for preparing compound V is provided, the method comprising the steps of:

[0104] (a) Reacting compound I with compound II to obtain compound III;

[0105]

[0106] (b) Reacting compound III with reagent M to obtain compound IV;

[0107]

[0108] Reagent M is selected from the following group: (carboxylic acid reagent) (acid anhydride reagent) (acyl chloride reagent), or (phosphoramide reagent);

[0109] (c) In the presence of reagent N, compound IV is reacted to obtain compound V;

[0110]

[0111] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof;

[0112] Among the various types,

[0113] X is

[0114] or

[0115] R6 and R7 are each independently hydrogen or C1-C16 alkyl;

[0116] X9 is C(=O) or C(NH2);

[0117] R 14 -W1-R 16 Where W1 is OS(O)2 or O; R 16 It is a hydrogen, chlorine, substituted or unsubstituted phenyl group (preferably, R). 16 (e.g., halophenyl, nitro-substituted phenyl); preferably, R 14 It is a benzenesulfonate group (-OS(O)2-Ar), or a substituted phenoxy group;

[0118] Replacement, X1, X2, X4, X5, X6, X7, R1, R2, R3, R4, R5, R8, R9, R 10 R 12 R 13 Y is as defined in the first aspect.

[0119] In another preferred example, X is selected from the following group:

[0120]

[0121] In another preferred embodiment, in step (a), the compound of formula II is N,N-dimethylformamide dimethyl acetal (i.e., R4, R5, R6 and R7 are all methyl groups).

[0122] In another preferred embodiment, the salt in reagent N comprises ammonium chloride; and / or the inorganic acid comprises hydrochloric acid.

[0123] In another preferred embodiment, in step (a), the reaction is carried out in a first inert solvent.

[0124] In another preferred embodiment, the first inert solvent is pyridine.

[0125] In another preferred embodiment, step (a) is: reacting the compound of formula I with N,N-dimethylformamide dimethyl acetal in a first inert solvent to obtain the compound of formula III; and in formula III, R4 and R5 are methyl groups.

[0126] In another preferred embodiment, in step (a), the molar ratio of compound I to compound II is 1:(2-10); more preferably, 1:(2-5).

[0127] In another preferred embodiment, in step (a), the reaction temperature is 0°C to reflux temperature; more preferably, 10°C to 50°C.

[0128] In another preferred embodiment, in step (b), R9 is selected from the group consisting of isobutyl and tert-butyl.

[0129] In another preferred embodiment, in step (b), reagent M is selected from the group consisting of: isobutyric anhydride, isobutyric acid, isobutyryl chloride, tervaline chloride, or its salt,

[0130] Among them, R 10 For substituted or unsubstituted phenyl groups, substituted or unsubstituted naphthyl groups; R 11 Selected from the following group: methyl, ethyl, isopropyl (iPr), 2-ethylbutyl, benzyl.

[0131] In another preferred embodiment, The salt of the salt thereof includes salts formed with a base; preferably, the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, NaOH, KOH, LiOH, Ca(OH)2, Mg(OH)2, or combinations thereof.

[0132] In another preferred embodiment, in step (b), the reaction is carried out in the presence of a basic reagent and / or optionally a Lewis acid.

[0133] In another preferred embodiment, the alkaline reagent is an organic base or an organometallic base.

[0134] In another preferred embodiment, the organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or combinations thereof.

[0135] In another preferred embodiment, the organometallic base is a Grignard reagent; preferably, the Grignard reagent is selected from the group consisting of: methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, or combinations thereof.

[0136] In another preferred embodiment, the Lewis acid is selected from the group consisting of: magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride, or combinations thereof.

[0137] In another preferred embodiment, in step (b), the reaction is carried out in a second inert solvent.

[0138] In another preferred embodiment, the second inert solvent includes: halocarbon solvents (such as dichloromethane), ether solvents (such as tetrahydrofuran and / or 2-methyltetrahydrofuran), pyridine, acetonitrile, or combinations thereof.

[0139] In another preferred embodiment, in step (b), when Y is The reaction is carried out in the presence of an organic base.

[0140] In another preferred embodiment, when Y is (For example, Y is) When (or the cis-trans isomer of the above-mentioned groups), step (b) is as follows:

[0141] In a second inert solvent, in the presence of an organic base, compound III reacts with reagent M to form compound IV;

[0142] Preferably, the organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or combinations thereof.

[0143] In another preferred embodiment, in step (b), when The reaction is carried out in the presence of an organic base and a Lewis acid, or in the presence of an organometallic base.

[0144] In another preferred embodiment, when Y is (For example, Y is) When the above groups are in cis-trans isomers, step (b) is as follows: in a second inert solvent, in the presence of an organometallic base or in the presence of an organic base and a Lewis acid, the compound of formula III reacts with reagent M to obtain the compound of formula IV.

[0145] Preferably, the organometallic base includes, but is not limited to, Grignard reagents, wherein the Grignard reagent is selected from the group consisting of: methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, or combinations thereof; and / or

[0146] The organic base is selected from the group consisting of: N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or combinations thereof; and / or

[0147] The Lewis acid is selected from the group consisting of: magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride, or combinations thereof.

[0148] In another preferred embodiment, in step (b), when reagent M is When used with its salts, the reaction must be carried out in the presence of a condensing agent.

[0149] In another preferred embodiment, the condensing agent is selected from 1-propylphosphonic anhydride (T3P), N,N'-carbonyldiimidazole (CDI), methanesulfonyl chloride (MsCl), 4-toluenesulfonyl chloride (TsCl), phosphorus oxychloride (POCl3), tert-valerate chloride (PivCl), oxaloyl chloride (COCl2), N,N'-disuccinimidyl carbonate (NDSC), ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), isobutyl 1,2-dihydro-2-isobutoxyquinoline-1-carboxylate (IIDQ), 1-tert-butoxy-2-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI), and cyanuric chloride (TCT). N,N'-Diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), (2-oxime-cyanoethyl acetate)-N,N-dimethyl-morpholinylurea hexafluorophosphate (COMU), 6-chlorobenzotriazol-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazol-1,1,3,3-tetramethylurea tetrafluoroborate (TCTU), 2-(1H-benzotriazol-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate (TB) TU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TOTU), 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU), O-(1,2-dihydro-2-oxo-1-pyridine)-N,N,N',N'-tetramethylthiourea tetrafluoroborate (TPTU), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBrOP), chlorotripyrrolidinyl hexafluorophosphate (PyClOP), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinyl hexafluorophosphate (PyClU), 1-(3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (EDCI) (3H-1,2,3-triazolo[4,5-B]pyridin-3-oxy)tri-1-pyrrolidinyl hexafluorophosphate (PyAOP), diethyl chlorophosphate (DEPC), bis(2-oxo'-3-oxazolyl)phosphinochloride (BOPCl), diphenylphosphinochloride (DppCl), diphenyl phosphate (DPP), diphenyl chlorophosphate (DPC), 2-chloro-1,3-dimethylimidazolium hexafluorophosphate (CIP), N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)urea tetrafluoroborate (TOBTU), pentafluorophenyl diphenyl phosphate (FDPP), 4-(4,6-Dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), tetramethylfluorourea hexafluorophosphate (TFFH), and 2-(5-norbornene-2,3-dicarboximide)-1,1,3,3-tetramethylurea tetrafluoroborate quaternary ammonium salt (TNTU).

[0150] In another preferred embodiment, the molar ratio of compound I to reagent M is 1:(1-4); more preferably, 1:(1-3); even more preferably, 1:(1-2); and most preferably, 1:(1-1.5).

[0151] In another preferred embodiment, the molar ratio of the compound of formula I to the basic reagent is 1:(1 to 10); more preferably, 1:(1 to 5); even more preferably, 1:(1 to 4).

[0152] In another preferred embodiment, the molar ratio of the basic reagent to the optional Lewis acid is 1:(1-5); more preferably, 1:(1-2).

[0153] In another preferred embodiment, in step (b), the reaction temperature is -30 to 50°C; more preferably, -10 to 30°C.

[0154] In another preferred embodiment, in step (c), the reaction is carried out in a third inert solvent.

[0155] In another preferred embodiment, the third inert solvent includes: a halocarbon solvent (such as dichloromethane), an ether solvent (such as tetrahydrofuran and / or 2-methyltetrahydrofuran), or an alcohol solvent (including methanol, ethanol, isopropanol, or combinations thereof), or combinations thereof.

[0156] In another preferred embodiment, the third inert solvent is the same as the second inert solvent.

[0157] In another preferred embodiment, in step (c), reagent N is selected from the group consisting of acetic acid, water, aqueous ammonium chloride solution, aqueous hydrochloric acid solution, methanol, ethanol, isopropanol, or combinations thereof.

[0158] In another preferred embodiment, the compounds obtained in steps (a) and / or (b) and / or (c) may be separated and then used.

[0159] In another preferred embodiment, steps (a), (b) and (c) are performed using a "one-pot method".

[0160] In another preferred embodiment, steps (b) and (c) are performed in a “one-pot” manner (i.e., the compound of formula IV obtained in step (b) is used directly without separation).

[0161] In another preferred embodiment, in each formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 X1, X2, X3, X4, X5, X6, X7, X9, W1, X, Y, and Z are each independently the corresponding groups in the specific compounds in the examples.

[0162] In a fourth aspect of the invention, a compound of formula III is provided.

[0163]

[0164] In the formula, R1, R2, R3, R4, R5 and Y are defined as in the third aspect.

[0165] In another preferred embodiment, R4 and R5 are methyl groups.

[0166] In another preferred embodiment, R1 and R2 are hydrogen; when R3 is hydrogen or cyano, Y is... R4, R5 and R 12 As defined above.

[0167] In another preferred embodiment, R1 and R2 are hydrogen; when R3 is hydrogen or cyano, Y is... Or the cis-trans isomers of the above groups; R4, R5 and R 12 As defined above.

[0168] In another preferred embodiment, the compound of formula III is a compound represented by formula III-I or a compound represented by formula III-II;

[0169]

[0170] In another preferred embodiment, the compound of formula III is a compound of formula IIIa-I or a cis-trans isomer thereof, or a compound of formula IIIa-II or a cis-trans isomer thereof;

[0171]

[0172] In a fifth aspect of the invention, a compound of formula IV is provided.

[0173]

[0174] R1, R2, R3, R4, R5, R8 and Y are defined as in the third aspect.

[0175] In another preferred embodiment, R3 is hydrogen or cyano; R8 is Y is R4, R5, R9 and R 11 As defined above.

[0176] In another preferred embodiment, R3 is hydrogen or cyano; R8 is Y is Or the cis-trans isomers of the above groups; R4, R5, R9 and R 11 As defined above.

[0177] In another preferred embodiment, the compound of formula IV is a compound represented as shown in formula IV-I or a compound represented as shown in formula IV-II.

[0178]

[0179] In another preferred embodiment, the compound of formula IV is a compound represented by formula IVa-I or its cis-trans isomer, or a compound represented by formula IVa-II or its cis-trans isomer.

[0180]

[0181] In a sixth aspect of the invention, a method for preparing a compound of formula VI-I is provided, the method comprising the steps of:

[0182] (d1) React compound VI with reagent O to obtain compound VI-I;

[0183]

[0184] Wherein, reagent O is hydroxylamine or its salt; preferably, it is hydroxylamine sulfate.

[0185] In another preferred embodiment, step (d1) is to react the compound of formula VI with hydroxylamine sulfate to obtain the compound of formula VI-I.

[0186] In another preferred embodiment, in step (d1), the molar ratio of compound of formula VI to reagent O is 1:(1-50); more preferably, 1:(1-20); even more preferably, 1:(2-10); and most preferably, 1:(2-5).

[0187] In another preferred embodiment, the method further includes the step of preparing compound of formula VI.

[0188] In another preferred embodiment, the preparation of the compound of formula VI is as described in aspect seven.

[0189] In a seventh aspect of the invention, a method for preparing a compound of formula VI is provided, the method comprising the steps of:

[0190] (a1) Reacting compound II with compound III to obtain compound III-I.

[0191]

[0192] (b1) React the compound of formula III-I with reagent M to obtain the compound of formula IV-I;

[0193]

[0194] Wherein, reagent M is isobutyric anhydride, isobutyric acid, or isobutyryl chloride;

[0195] (c1) In the presence of reagent N, the compound of formula IV-I is reacted to obtain the compound of formula VI;

[0196]

[0197] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

[0198] In each formula, R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0199] In another preferred embodiment, the compound of formula VI is a compound of formula Va-I and / or its cis-trans isomer.

[0200] In another preferred embodiment, the compound of formula III-I is a compound of formula IIIa-I and / or its cis-trans isomer.

[0201] In another preferred embodiment, the compound of formula IV-I is a compound of formula IVa-I and / or its cis-trans isomer.

[0202] In another preferred embodiment, the method includes the steps of:

[0203] (a1) Reacting compound II with compound IIIa-I to obtain compound IIIa-I or its cis-trans isomer.

[0204]

[0205] (b1) React the compound of formula IIIa-I or its cis-trans isomer with reagent M to obtain the compound of formula IVa-I or its cis-trans isomer;

[0206]

[0207] Wherein, reagent M is isobutyric anhydride, isobutyric acid, or isobutyryl chloride;

[0208] (c1) In the presence of reagent N, the compound of formula IVa-I or its cis-trans isomer is reacted to obtain the compound of formula Va-I or its cis-trans isomer;

[0209]

[0210] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

[0211] In each formula, R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0212] In another preferred embodiment, in step (a1), the compound of formula II is N,N-dimethylformamide dimethyl acetal.

[0213] In another preferred embodiment, in step (a1), the reaction is carried out in a first inert solvent (such as pyridine).

[0214] In another preferred embodiment, step (a1) is: in pyridine, the compound of formula II is reacted with N,N-dimethylformamide dimethyl acetal to obtain formula III-I.

[0215] In another preferred embodiment, in step (a1), the molar ratio of compound II to compound III is 1:(2-10); more preferably, 1:(2-5).

[0216] In another preferred embodiment, in step (a1), the reaction temperature is 0°C to reflux temperature; more preferably, 10°C to 50°C.

[0217] In another preferred embodiment, in step (b1), the reaction is carried out in the presence of an organic base.

[0218] In another preferred embodiment, in step (b1), the reaction is carried out in a second inert solvent.

[0219] In another preferred embodiment, the second inert solvent is as defined in the third aspect.

[0220] In another preferred embodiment, step (b1) is: in a second inert solvent, in the presence of an organic base, the compound of formula III-I is reacted with reagent M to obtain the compound of formula IV-I.

[0221] In another preferred embodiment, in step (b1), the organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or combinations thereof; more preferably, it is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, or combinations thereof.

[0222] In another preferred embodiment, step (b1) is: reacting compound III-I with isobutyric anhydride in a second inert solvent in the presence of triethylamine and 4-dimethylaminopyridine to obtain compound IV-I.

[0223] In another preferred embodiment, in step (b1), the molar ratio of compound II to reagent M is 1:(1-4); more preferably, 1:(1-3); even more preferably, 1:(1-2); and most preferably, 1:(1-1.5).

[0224] In another preferred embodiment, in step (b1), the molar ratio of the compound of formula III-I to the organic base is 1:(1-10); more preferably, 1:(1-5); even more preferably, 1:(1-4). In another preferred embodiment, in step (b1), the reaction temperature is 0-50°C; more preferably, 10-30°C.

[0225] In another preferred embodiment, in step (c1), the reaction is carried out in a third inert solvent.

[0226] In another preferred embodiment, the third inert solvent is as defined in the third aspect.

[0227] In another preferred embodiment, step (c1) is: reacting compound IV-I in a third inert solvent in the presence of reagent N to obtain compound VI.

[0228] In another preferred embodiment, reagent N in step (c1) is selected from the group consisting of acetic acid, water, aqueous solution of hydrochloric acid, aqueous solution of ammonium chloride, methanol, ethanol, isopropanol, or combinations thereof; preferably, it is methanol, ethanol, isopropanol, or combinations thereof.

[0229] In another preferred embodiment, step (c1) is: reacting compound IV-I in a third inert solvent in the presence of ethanol to obtain compound VI.

[0230] In another preferred embodiment, the compounds obtained in steps (a1), (b1) and (c1) may be separated and then used.

[0231] In another preferred embodiment, steps (a1), (b1), and (c1) are performed using a "one-pot method".

[0232] In another preferred embodiment, steps (b1) and (c1) are carried out in a "one-pot" manner (i.e., the formula IV-I compound obtained in step (b1) is used directly without separation).

[0233] In a seventh aspect of the invention, a method for preparing a compound of formula VI-II is provided, the method comprising the steps of:

[0234] (d2) Compound V-II reacts with reagent O to form compound VI-II;

[0235]

[0236] Reagent O is selected from the following group: organic acids, inorganic acids, hydrazine hydrate, or combinations thereof.

[0237] In another preferred embodiment, the compound of formula V-II is a compound of formula Va-II and / or its cis-trans isomer.

[0238] In another preferred embodiment, the method includes the steps of:

[0239] (d2) The Va-II compound or its cis-trans isomer reacts with reagent O to generate the VI-II compound;

[0240]

[0241] Reagent O is selected from the following group: organic acids, inorganic acids, hydrazine hydrate, or combinations thereof.

[0242] In another preferred embodiment, step (d2) is to react the compound of formula V-II with acetic acid to obtain the compound of formula VI-II.

[0243] In another preferred embodiment, step (d2) is to react compound V-II with trifluoroacetic acid to obtain compound VI-II.

[0244] In another preferred embodiment, in step (d2), the molar ratio of compound V-II to reagent O is 1:(1-50); more preferably, 1:(1-30); even more preferably, 1:(10-30); and most preferably, 1:(15-25).

[0245] In another preferred embodiment, the method further includes the step of preparing a compound of formula V-II.

[0246] In another preferred embodiment, the preparation of the compound of formula V-II is as described in aspect VIII.

[0247] In an eighth aspect of the invention, a method for preparing a compound of formula V-II is provided, the method comprising the steps of:

[0248] (a2) Compounds of formula I-II react with compounds of formula II to produce compounds of formula III-II;

[0249]

[0250] (b2) Compound III-II reacts with reagent M to form compound IV-II;

[0251]

[0252] Wherein, reagent M is R 14 The substituted phenoxy and benzenesulfonate groups are used.

[0253] (c2) Compound IV-II reacts with reagent N to form compound V-II;

[0254]

[0255] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

[0256] Among the various types,

[0257] R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0258] In another preferred embodiment, the compound of formula III-II is a compound of formula IIIa-II and / or its cis-trans isomer.

[0259] In another preferred embodiment, the compound of formula IV-II is a compound of formula IVa-II and / or its cis-trans isomer.

[0260] In another preferred embodiment, the compound of formula V-II is a compound of formula Va-II and / or its cis-trans isomer.

[0261] In another preferred embodiment, the method includes the steps of:

[0262] (a2) Compounds of formula I-II react with compounds of formula II to produce compounds of formula IIIa-II or their cis-trans isomers;

[0263]

[0264] (b2) The compound of formula IIIa-II or its cis-trans isomer reacts with reagent M to generate the compound of formula IVa-II or its cis-trans isomer;

[0265]

[0266] Wherein, reagent M is R 14 The substituted phenoxy and benzenesulfonate groups are used.

[0267] (c2) The IVa-II compound or its cis-trans isomer reacts with reagent N to produce the Va-II compound or its cis-trans isomer;

[0268]

[0269] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

[0270] Among the various types,

[0271] R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0272] In another preferred embodiment, in step (a2), the compound of formula II is N,N-dimethylformamide dimethyl acetal.

[0273] In another preferred embodiment, in step (a2), the reaction is carried out in a first inert solvent (such as pyridine).

[0274] In another preferred embodiment, step (a2) is: reacting compound I-II with N,N-dimethylformamide dimethyl acetal in pyridine to obtain compound III-II.

[0275] In another preferred embodiment, in step (a2), the molar ratio of compound I-II to compound II is 1:(2-10); more preferably, 1:(2-5).

[0276] In another preferred embodiment, in step (a2), the reaction temperature is 0 to 50 °C reflux temperature; more preferably, 10 to 50 °C.

[0277] In another preferred embodiment, in step (b2), the reaction is carried out in the presence of an organic base.

[0278] In another preferred embodiment, in step (b2), the reaction is carried out in a second inert solvent.

[0279] In another preferred embodiment, the second inert solvent is as defined in the third aspect.

[0280] In another preferred embodiment, step (b2) involves reacting compound III-II with reagent M in a second inert solvent, in the presence of an organometallic base or in the presence of an organic base and a Lewis acid, to obtain compound IV-II.

[0281] In another preferred embodiment, in step (b2), the organometallic base includes a Grignard reagent; preferably, the Grignard reagent is selected from the group consisting of: methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, or combinations thereof.

[0282] In another preferred embodiment, in step (b2), the organic base is selected from the group consisting of N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or combinations thereof.

[0283] In another preferred embodiment, in step (b2), the Lewis acid is selected from the group consisting of: magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride, or combinations thereof.

[0284] In another preferred embodiment, step (b2) is: in a second inert solvent, in the presence of methylmagnesium bromide, the compound of formula III-II and (where R) 14 for The reaction yields compound IV-II.

[0285] In another preferred embodiment, step (b2) is: in a second inert solvent, in the presence of magnesium chloride and N,N-diisopropylethylamine, the compound of formula III-II and (where R) 14 for The reaction yields compound IV-II.

[0286] In another preferred embodiment, in step (a2), the molar ratio of the compound of formula I-II to reagent M is 1:(1-4); more preferably, 1:(1-3); even more preferably, 1:(1-2); and most preferably, 1:(1-1.5).

[0287] In another preferred embodiment, in step (b2), the molar ratio of the compound of formula III-II to the basic reagent is 1:(1-10); more preferably, 1:(1-5); even more preferably, 1:(1-3). In another preferred embodiment, the molar ratio of the basic reagent to the optional Lewis acid is 1:(1-5); more preferably, 1:(1-2).

[0288] In another preferred embodiment, in step (b2), the reaction temperature is -30 to 10°C; more preferably, -10 to 0°C.

[0289] In another preferred embodiment, in step (c2), the reaction is carried out in a third inert solvent.

[0290] In another preferred embodiment, the third inert solvent is as defined in the third aspect.

[0291] In another preferred embodiment, step (c2) is: in a third inert solvent, in the presence of reagent N, the compound of formula IV-II is reacted to obtain the compound of formula V-II.

[0292] In another preferred embodiment, in step (c2), reagent N is selected from the group consisting of acetic acid, water, aqueous solution of hydrochloric acid, aqueous solution of ammonium chloride, methanol, ethanol or isopropanol, preferably methanol, ethanol, isopropanol, or a combination thereof.

[0293] In another preferred embodiment, step (c2) is: reacting compound IV-II in an inert solvent in the presence of an aqueous solution of hydrochloric acid and / or an aqueous solution of ammonium chloride to obtain compound V-II.

[0294] In another preferred embodiment, the compounds obtained in steps (a2), (b2) and (c2) may be separated and then used.

[0295] In another preferred embodiment, steps (a2), (b2) and (c2) are performed using a "one-pot method".

[0296] In another preferred embodiment, steps (b2) and (c2) are performed in a "one-pot" manner (i.e., the compound of formula IV-II (containing cis-trans isomers) obtained in step (b) is used directly without separation).

[0297] In a ninth aspect of the present invention, a method for preparing a compound of formula VI is provided, the method comprising the steps of:

[0298] (a) Reacting compound I with compound II to obtain compound III;

[0299]

[0300] (b) Reacting compound III with reagent M to obtain compound IV;

[0301]

[0302] Reagent M is selected from the following group: (carboxylic acid reagent) (acid anhydride reagent) (acyl chloride reagent), or (phosphoramide reagent);

[0303] (c) In the presence of reagent N, compound IV is reacted to obtain compound V;

[0304]

[0305] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof;

[0306] (d) React compound V with reagent O to obtain compound VI;

[0307]

[0308] Wherein, reagent O is selected from the following group: hydroxylamine or its salt, organic acid, inorganic acid, hydrazine hydrate, or a combination thereof;

[0309] In each formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 14 X, Y, and Z are as defined in the first or third aspect.

[0310] In another preferred embodiment, steps (a), (b), (c) and (d) are as defined in the first or third aspect.

[0311] In a tenth aspect of the present invention, a method for preparing compound VI-I is provided, the method comprising the steps of:

[0312] (a1) Reacting compound II with reagent II to obtain compound III-I.

[0313]

[0314] (b1) React the compound of formula III-I with reagent M to obtain the compound of formula IV-I;

[0315]

[0316] Wherein, reagent M is isobutyric anhydride, isobutyric acid, or isobutyryl chloride;

[0317] (c1) In the presence of reagent N, the compound of formula IV-I is reacted to obtain the compound of formula VI;

[0318]

[0319] Wherein, reagent N is a protic solvent; preferably, reagent N is selected from the group consisting of: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

[0320] (d1) React compound of formula VI with reagent O to generate compound of formula VI-I;

[0321]

[0322] Wherein, reagent O is hydroxylamine or its salt; preferably, it is hydroxylamine sulfate.

[0323] Among the various types,

[0324] R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0325] In another preferred embodiment, R4, R5, R6 and R7 are defined as in the sixth or seventh aspect.

[0326] In another preferred embodiment, steps (a1), (b1), (c1) and (d1) are as defined in the sixth or seventh aspect.

[0327] In the eleventh aspect of the present invention, a method for preparing compound VI-II is provided, the method comprising the steps of:

[0328] (a2) Compounds of formula I-II react with compounds of formula II to produce compounds of formula III-II;

[0329]

[0330] (b2) Compound III-II reacts with reagent M to form compound IV-II;

[0331]

[0332] Wherein, reagent M is R 14 The substituted phenoxy and benzenesulfonate groups are used.

[0333] (c2) Compound IV-II reacts with reagent N to form compound V-II;

[0334]

[0335] Wherein, reagent M is R 14 The substituted phenoxy and benzenesulfonate groups are used.

[0336] (d2) Compound V-II reacts with reagent O to form compound VI-II;

[0337]

[0338] Among the various types,

[0339] R4 and R5 are methyl; R6 and R7 are each independently hydrogen, C1-C16 alkyl (preferably C1-C8 alkyl, more preferably C1-C4 alkyl).

[0340] In another preferred embodiment, R4, R5, R6 and R7 are defined as in the eighth or ninth aspect.

[0341] In another preferred embodiment, steps (a2), (b2), (c2) and (d2) are defined as in the eighth or ninth aspect.

[0342] In a twelfth aspect of the invention, compounds as shown in formula III-I, formula IV-I, formula VI, or formula VII-I are provided.

[0343] In another preferred embodiment, the compound of formula III-I is a compound of formula IIIa-I and / or its cis-trans isomer.

[0344] In another preferred embodiment, the compound of formula IV-I is a compound of formula IVa-I and / or its cis-trans isomer.

[0345] In another preferred embodiment, the compound of formula VI is a compound of formula Va-I and / or its cis-trans isomer.

[0346] In another preferred embodiment, the compound of formula VII-I is a compound of formula VIIa-I and / or its cis-trans isomer.

[0347] In a thirteenth aspect of the invention, use of the compound as described in the twelfth aspect is provided for the preparation of Molnupiravir (EIDD-2801 / MK4482).

[0348] In a fourteenth aspect of the invention, compounds as shown in formula III-II, IV-II or V-II are provided.

[0349] In another preferred embodiment, the compound of formula III-II is a compound of formula IIIa-II and / or its cis-trans isomer.

[0350] In another preferred embodiment, the compound of formula IV-II is a compound of formula IVa-II and / or its cis-trans isomer.

[0351] In another preferred embodiment, the compound of formula V-II is a compound of formula Va-II and / or its cis-trans isomer.

[0352] In a fifteenth aspect of the invention, use of the compound as described in the fourteenth aspect is provided for the preparation of Remdesivir (GS-5734).

[0353] In a sixteenth aspect of the present invention, a compound of formula VII is provided.

[0354]

[0355] Among them, X1, X2, X4, X5, X6, X7, X 10 R1, R2, R3, R8, R 12 R 13 Y' is defined as in the first aspect.

[0356] In another preferred embodiment, the compound of formula VII is a compound as shown in formula VII-I;

[0357]

[0358] In another preferred embodiment, the compound of formula VII is a compound as shown in formula VIIa-I or a cis-trans isomer thereof;

[0359]

[0360] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0361] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have, for the first time, provided novel intermediate compounds of formulas III, IV, and V, and a method for further preparing 5'-nucleoside prodrugs such as Molnupiravir or Remdesivir. The methods of this invention utilize readily available raw materials, employ mild and safe reaction conditions, pose no harm to human health or the environment, and have low production costs. Furthermore, this invention offers advantages such as high product yield, high purity, and low impurity content, facilitating economical and convenient industrial production. The intermediates of this invention (especially compounds of formulas III, IV, and V) can be used as intermediates for further preparation of 5'-nucleoside prodrugs such as Molnupiravir and Remdesivir. This invention was completed based on these findings.

[0362] the term

[0363] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0364] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0365] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0366] As used herein, the term "room temperature" refers to a temperature of 4-40°C, preferably 25±5°C.

[0367] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0368] As used in this article, the term "halogenated" refers to the substitution of one or more hydrogen atoms in a group by a halogen.

[0369] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms (i.e., C1-6 means 1-6 carbons, preferably 1, 2, or 3 carbons). Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0370] Unless otherwise stated, the term "cycloalkyl" in this document refers to a ring with a specified number of ring atoms (e.g., C12, C23 ... 3-6A cycloalkyl group is a hydrocarbon ring that is fully saturated or has no more than one double bond between the ring apexes. The terms "heterocyclic alkyl" or "heterocyclic group" refer to a cycloalkyl group containing one, two, or three heteroatoms selected from N, O, and S (preferably, only N heteroatoms). In one specific embodiment, the heterocyclic alkyl or heterocyclic group can be a monocyclic, bicyclic, or polycyclic system, preferably a monocyclic system.

[0371] Unless otherwise stated, the term “substitution” means that one or more hydrogen atoms (1, 2, 3 or 4) in a group are substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, and benzyl.

[0372] As used in this article, " " " represents the connection site.

[0373] As used herein, the term “heteroatoms” is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si); preferably nitrogen.

[0374] In this article, “4-dimethylaminopyridine” and “4-N,N-dimethylaminopyridine” can be used interchangeably.

[0375] Any suitable inert solvent can be used in the method of this invention. Representative inert solvents include, but are not limited to, pentane, different pentanes, hexane, different hexanes, heptane, different heptanes, petroleum ether, cyclopentane, different cyclohexanes, benzene, toluene, xylene, trifluorotoluene, halogenated benzenes such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, dichloromethane, chloroform, DMF, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, pyridine or combinations thereof. In some embodiments, the solvent may be chlorobenzene, pyridine, dichloromethane, tetrahydrofuran or combinations thereof.

[0376] The reaction in the method of the present invention can be carried out at any suitable temperature. For example, the reaction temperature can be from about -78°C to the reflux temperature, such as from -78°C to about 100°C, or from about -50°C to about 100°C, or from about -25°C to about 50°C, or from about -10°C to about 25°C, or from about 0°C to about 20°C. In some embodiments, the reaction temperature can be from about -10°C to about 0°C, or from about 20°C to 40°C.

[0377] In the method of the present invention, each step can provide the target compound or a pharmaceutically acceptable salt thereof in any suitable yield. For example, the target compound (e.g., formula II, formula IV, formula V, or Remdesivir, etc.) can be prepared in yields of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least about 95%. The method of the present invention can provide the target compound or a pharmaceutically acceptable salt thereof in any purity. For example, the target compound can be prepared in puritys of at least about 90%, 95%, 96%, 97%, 98%, or at least about 99%. In some embodiments, the target compound can be prepared in puritys of at least 95%. In some embodiments, the target compound can be prepared in puritys of at least 98%. In some embodiments, the target compound can be prepared in puritys of at least 99%.

[0378] In this document, unless otherwise specified, when a reaction process is described as "directly obtained," "directly acquired," or "directly formed," it means that the specified reaction product is directly obtained or formed in the reaction system without changing the conditions or performing operations such as heating, adding other reaction reagents, or separating intermediate products. However, it should be understood that the reaction process does not exclude the possibility of stable or unstable transition forms occurring in the reaction system, which ultimately transform into the specified reaction product.

[0379] Intermediate for the preparation of 5'-nucleoside prodrugs and its preparation method

[0380] In one specific embodiment, the present invention provides a compound of formula III.

[0381]

[0382] in,

[0383] R1, R2, and R3 are each independently hydrogen, halogen, C1-C16 alkyl, C1-C16 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, azide, or cyano;

[0384] Y is

[0385]

[0386] Among them, R4 and R5 are each independently hydrogen and C1-C16 alkyl, respectively. 12 R 13 Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano;

[0387] In another preferred embodiment, Y is

[0388]

[0389] Or the cis-trans isomers of these groups.

[0390] In another preferred embodiment, when R1 and R2 are hydrogen, and R3 is hydrogen or cyano, Y is... R4 and R5 are each independently hydrogen and C1-C16 alkyl groups, respectively. 12 It can be hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano.

[0391] In another preferred embodiment, when R1 and R2 are hydrogen, and R3 is hydrogen or cyano, Y is... Or their cis-trans isomers, where R4 and R5 are each independently hydrogen, C1-C16 alkyl, and R 12 It can be hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano.

[0392] In another specific embodiment, the present invention also provides compounds (intermediates) of formula III-I and III-II.

[0393]

[0394] In one specific embodiment, the present invention provides a compound of formula IV;

[0395]

[0396] in,

[0397] R1, R2, and R3 are each independently hydrogen, halogen, C1-C16 alkyl, C1-C16 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, azide, or cyano;

[0398] R8 is Where R9 is hydrogen, C1-C16 alkyl, R 10 It is a C1-C6 alkyl, C3-C7 cyclic alkyl, or aryl group, wherein the aryl group is selected from phenyl or substituted phenyl, naphthyl or substituted naphthyl; R 11 It is a C1-C16 alkyl, a C1-C16 haloalkyl, or a C3-C7 cyclic alkyl;

[0399] Y is

[0400]

[0401] Among them, R4 and R5 are each independently hydrogen and C1-C16 alkyl, respectively. 12 R 13Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano.

[0402] In another preferred embodiment, R3 is hydrogen or cyano, and R8 is... Where R9 is hydrogen, C1-C16 alkyl, R 10 It is a C1-C6 alkyl, C3-C7 cyclic alkyl, or aryl group, wherein the aryl group is selected from phenyl or substituted phenyl, naphthyl or substituted naphthyl; R 11 It is a C1-C16 alkyl, C1-C16 haloalkyl, or C3-C7 cyclic alkyl; Y is R4 and R5 are each independently hydrogen and C1-C16 alkyl groups, respectively. 12 It can be hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano.

[0403] In another specific embodiment, the present invention provides intermediates of formula IV-I and IV-II;

[0404]

[0405] In one specific embodiment, the present invention provides a compound of formula V.

[0406]

[0407] in,

[0408] R1, R2, and R3 are each independently hydrogen, halogen, C1-C16 alkyl, C1-C16 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, azide, or cyano;

[0409] R8 is Where R9 is hydrogen, C1-C16 alkyl, R 10 It is a C1-C6 alkyl, C3-C7 cyclic alkyl, or aryl group, wherein the aryl group is selected from phenyl or substituted phenyl, naphthyl or substituted naphthyl; R 11 It is a C1-C16 alkyl, a C1-C16 haloalkyl, or a C3-C7 cyclic alkyl;

[0410] Y is

[0411]

[0412] Among them, R4 and R5 are each independently hydrogen and C1-C16 alkyl, respectively. 12 R 13 Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano;

[0413] In another preferred embodiment, R1, R2, and R3 are each independently selected from the group consisting of: hydrogen, fluorine, azide, methyl, chloromethyl, fluoromethyl, difluoromethyl, vinyl, alkynyl, and cyano.

[0414] In another specific embodiment, the present invention provides intermediates of formulas VI and V-II.

[0415]

[0416] In one specific embodiment, the present invention provides a method for preparing a compound of formula V, the method comprising the following steps:

[0417] (a) Compound I reacts with compound II to produce compound III;

[0418]

[0419] (b) Compound III reacts with reagent M to produce compound IV;

[0420]

[0421] (c) Compound IV reacts with reagent N to produce compound V;

[0422]

[0423] Among them, R1, R2, R3, R4, R5, R6, R7, R8, M, N, O, X, Y and Z are defined as above;

[0424] In step (a) above: any suitable compound of formula II can be used in the method for preparing the compound of formula III. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-diethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0425] The compound of Formula II may be present in any suitable amount. For example, the compound of Formula II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to the compound of Formula I, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). The compound of Formula II may also be present in an amount of about 2 to about 10.0 equivalents (mol / mol) relative to the compound of Formula I, such as about 2 to about 5.0 equivalents (mol / mol). In some embodiments, the compound of Formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of Formula I.

[0426] In step (b) above: any suitable reagent M can be used in the method for preparing compound of formula IV, exemplary reagents M include but are not limited to isobutyric anhydride, isobutyric acid, isobutyryl chloride, tervastatin chloride, etc.

[0427]

[0428] In some implementations, reagent M can be isobutyric anhydride, isobutyryl chloride, tervastatin chloride, etc.

[0429]

[0430] The reaction in step (b) is carried out in the presence of a basic reagent, including but not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradin, 4-dimethylaminopyridine, quinine ring, and organometallic bases; the organometallic bases include but are not limited to Grignard reagents, preferably methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; preferably, the base is N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride. The base may be present in any suitable amount. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III.

[0431] The reaction in step (b) can also be carried out in the presence of a basic reagent and a Lewis acid, wherein the basic reagent includes, but is not limited to, N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradine, 4-dimethylaminopyridine, quinine ring, and organometallic bases; the organometallic bases include, but are not limited to, Grignard reagents, preferably methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; the Lewis acid includes, but is not limited to, magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, and aluminum chloride; preferably, the basic reagent is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride, used in random combinations with magnesium chloride or lithium chloride. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the Lewis acid. Preferably, the base is present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the Lewis acid.

[0432] In step (c) above: any suitable reagent N can be used in the method for preparing compound V. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol. In another preferred embodiment, the compounds obtained in steps (a), (b), and (c) can be separated and then used, or steps (a), (b), and (c) can be performed in a "one-pot" manner.

[0433] In one specific embodiment, the present invention also provides a method for preparing a compound of formula VI, the method comprising the following steps:

[0434] (a1) Compound II of formula reacts with reagent II to produce compound III-I.

[0435]

[0436] (b1) Compound III-I reacts with reagent M to produce compound IV-I;

[0437]

[0438] (c1) Compound IV-I reacts with reagent N to produce compound VI;

[0439]

[0440] Among them, R4 and R5 are methyl groups, and R6 and R7 are each independently hydrogen or C1-C16 alkyl groups;

[0441] In step (a1) above: any suitable compound of formula II can be used in the method for preparing compound III-I. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0442] The compound of formula II may be present in any suitable amount. For example, the compound of formula II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to the compound of formula II, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). The compound of formula II may also be present in an amount of about 2.0 to about 10.0 equivalents (mol / mol) relative to the compound of formula II, such as about 2.0 to about 5.0 equivalents (mol / mol). In some embodiments, the compound of formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula II.

[0443] In step (b1) above: any suitable reagent M can be used in the method for preparing the IV-I compound. Exemplary reagents M include, but are not limited to, isobutyric anhydride, isobutyric acid, and isobutyryl chloride; in some embodiments, reagent M may be isobutyric anhydride.

[0444] The reaction in step (b1) is carried out in the presence of a basic reagent, including but not limited to one or more of N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradine, 4-dimethylaminopyridine, and quinine ring. The base may be present in any suitable amount. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III-I. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III-I.

[0445] In step (c1) above: any suitable reagent N can be used in the method for preparing compound VI. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol. In another preferred embodiment, the compounds obtained in steps (a1), (b1), and (c1) can be separated and then used, or steps (a1), (b1), and (c1) can be performed in a one-pot process.

[0446] In one specific embodiment of the present invention, the present invention also provides a method for preparing a compound of formula V-II, the method comprising the following steps:

[0447] (a2) Compounds of formula I-II react with compounds of formula II to produce compounds of formula III-II;

[0448]

[0449] (b2) Compound III-II reacts with reagent M to form compound IV-II;

[0450]

[0451] (c2) Compound IV-II reacts with reagent N to form compound V-II;

[0452]

[0453] Among them, R4 and R5 are methyl groups, and R6 and R7 are each independently hydrogen or C1-C16 alkyl groups;

[0454] In step (a2) above: any suitable compound of formula II can be used in the method for preparing compounds of formula III-II. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0455] Compound II may be present in any suitable amount. For example, compound II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to compound I-II, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). Compound II may also be present in an amount of about 2.0 to about 10.0 equivalents (mol / mol) relative to compound I-II, such as about 2.0 to about 5.0 equivalents (mol / mol). In some embodiments, compound II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to compound I-II.

[0456] In step (b2) above: any suitable reagent M can be used in the method for preparing compound IV-II.

[0457] Exemplary reagent M includes, but is not limited to, In some implementations, reagent M can be

[0458] The reaction in step (b2) is carried out in the presence of an organometallic base, which includes, but is not limited to, a Grignard reagent; preferably, the Grignard reagent is selected from one or more of methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, and ethyl magnesium chloride; more preferably, the organometallic base is methyl magnesium bromide. The organometallic base may be present in any suitable amount. Preferably, the organometallic base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III-II. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III-II.

[0459] The reaction in step (b) can also be carried out in the presence of a basic reagent and a Lewis acid, wherein the basic reagent includes an organic base or an organometallic base. In another preferred embodiment, the organic base includes, but is not limited to, one or more of N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradin, 4-dimethylaminopyridine, and quinine ring, and / or the organometallic acid includes, but is not limited to, Grignard reagents. Preferably, the organometallic base is selected from one or more of methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; and / or the Lewis acid includes, but is not limited to, one or more of magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, and aluminum chloride; preferably, the alkaline reagent is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride, and the alkaline reagent is optionally used in combination with magnesium chloride and / or lithium chloride. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the Lewis acid. Preferably, the base is present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the Lewis acid.

[0460] In step (c2) above: any suitable reagent N can be used in the method for preparing compound V-II. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol.

[0461] In another preferred embodiment, the compounds obtained in steps (a2), (b2) and (c2) can be separated and then used, or steps (a2), (b2) and (c2) can be carried out in a "one-pot" manner.

[0462] In one specific embodiment, the present invention provides a method for preparing a compound of formula VI, comprising the steps of:

[0463] (d) Compound V reacts with reagent O to produce compound VI.

[0464]

[0465] The definitions of R1, R2, R3, R8, Y, and Z are the same as those above;

[0466] In step (d) above: any suitable reagent O can be used in the method for preparing compound VI. Exemplary reagent O includes, but is not limited to, hydroxylamine or its salts, organic acids, inorganic acids, and hydrazine hydrate.

[0467] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to compound V, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 2.0 to about 30.0 (e.g., about 2.0 to about 20.0) equivalents (mol / mol) relative to compound V.

[0468] Preferably, the method for preparing compound VI of the present invention includes the following steps:

[0469] (a) Compound I reacts with compound II to produce compound III;

[0470]

[0471] (b) Compound III reacts with reagent M to produce compound IV;

[0472]

[0473] (c) Compound IV reacts with reagent N to produce compound V;

[0474]

[0475] (d) Compound V of formula V reacts with reagent O to produce compound VI;

[0476]

[0477] Among the various types,

[0478] R1, R2, and R3 are each independently hydrogen, halogen, C1-C16 alkyl, C1-C16 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, azide, or cyano;

[0479] R4, R5, R6, and R7 are each independently hydrogen or C1-C16 alkyl groups;

[0480] X is

[0481]

[0482] Among them, R 12 R 13 Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano;

[0483] Y is

[0484]

[0485] Among them, R4 and R5 are each independently hydrogen and C1-C16 alkyl, respectively. 12 R 13 Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano;

[0486] Z is

[0487]

[0488] Among them, R 12 R 13 Each of them is independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, or cyano;

[0489] Reagent M is a carboxylic acid anhydride ( ),carboxylic acid( ), acyl chloride ( ), phosphoramide reagent ( ); where R 14 Benzenesulfonate group, substituted phenoxy group;

[0490] R8 is Where R9 is hydrogen, C1-C16 alkyl, R 10 It is a C1-C6 alkyl, C3-C7 cyclic alkyl, or aryl group, wherein the aryl group is selected from phenyl or substituted phenyl, naphthyl or substituted naphthyl; R 11 It is a C1-C16 alkyl, a C1-C16 haloalkyl, or a C3-C7 cyclic alkyl;

[0491] Reagent N is a protic solvent; C1-C6 alkyl alcohols, water, and water salt solutions;

[0492] Reagent O is hydroxylamine or its salt, an organic acid, an inorganic acid, or hydrazine hydrate;

[0493] The term “substitution” refers to the substitution of one or more hydrogen atoms (2, 3 or 4) in a group by a substituent selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, and benzyl.

[0494] In step (a) above: any suitable compound of formula II can be used in the method for preparing the compound of formula III. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-diethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0495] The compound of Formula II may be present in any suitable amount. For example, the compound of Formula II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to the compound of Formula I, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). The compound of Formula II may also be present in an amount of about 2 to about 10.0 equivalents (mol / mol) relative to the compound of Formula I, such as about 2 to about 5.0 equivalents (mol / mol). In some embodiments, the compound of Formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of Formula I.

[0496] In step (b) above: any suitable reagent M can be used in the method for preparing compound of formula IV. Exemplary reagents M include, but are not limited to, isobutyric anhydride, isobutyric acid, isobutyryl chloride, tervastatin chloride, etc. In some implementations, reagent M can be isobutyric anhydride, isobutyryl chloride, tervastatin chloride, etc.

[0497] The reaction in step (b) is carried out in the presence of a basic reagent, including but not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradin, 4-dimethylaminopyridine, quinine ring, and organometallic bases; the organometallic bases include but are not limited to Grignard reagents, preferably methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; preferably, the base is N,N-diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride. The base may be present in any suitable amount. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III.

[0498] The reaction in step (b) can also be carried out in the presence of a basic reagent and a Lewis acid, wherein the basic reagent includes, but is not limited to, N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradine, 4-dimethylaminopyridine, quinine ring, and organometallic bases; wherein the organometallic bases include, but are not limited to, Grignard reagents, preferably methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; wherein the Lewis acid includes, but is not limited to, magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, and aluminum chloride; preferably, the base is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride, used in random combinations with magnesium chloride or lithium chloride. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the Lewis acid. Preferably, the base is present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the Lewis acid.

[0499] In step (c) above: any suitable reagent N can be used in the method for preparing compound V. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol.

[0500] In step (d) above: any suitable reagent O can be used in the method for preparing compound VI. Exemplary reagent O includes, but is not limited to, hydroxylamine or its salts, organic acids, inorganic acids, and hydrazine hydrate.

[0501] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to compound V, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 2.0 to about 20.0 equivalents (mol / mol) relative to compound I. In some embodiments, compound II may be present in an amount of about 2.0 to about 20.0 equivalents (mol / mol) relative to compound I.

[0502] In another preferred embodiment, the compounds obtained in steps (a), (b), and (c) may be separated and then used, or steps (a), (b), and (c) may be carried out in a "one-pot" manner.

[0503] In another preferred embodiment, steps (a), (b), (c) and (d) are performed using a "one-pot method".

[0504] In one specific embodiment, the present invention provides a method for preparing a compound of formula VI-I, comprising the steps of...

[0505] (d1) VI reacts with reagent O to form VI-I.

[0506]

[0507] In the above steps: any suitable reagent O can be used in the method for preparing compound VI-I. Exemplary reagent O includes, but is not limited to, hydroxylamine, aqueous hydroxylamine solution, hydroxylamine hydrochloride, and hydroxylamine sulfate.

[0508] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula VI, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula VI. In some embodiments, the compound of formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula II.

[0509] In one specific embodiment, the present invention provides a method for preparing VI-I, comprising the steps of:

[0510] (a1) Compound II of formula reacts with reagent II to produce compound III-I.

[0511]

[0512] (b1) Compound III-I reacts with reagent M to produce compound IV-I;

[0513]

[0514] (c1) Compound IV-I reacts with reagent N to produce compound VI;

[0515]

[0516] (d1) Compound VI reacts with reagent O to produce compound VI-I.

[0517]

[0518] Among them, R4 and R5 are methyl groups, and R6 and R7 are each independently hydrogen or C1-C16 alkyl groups;

[0519] In step (a1) above: any suitable compound of formula II can be used in the method for preparing compound III-I. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0520] The compound of formula II may be present in any suitable amount. For example, the compound of formula II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to the compound of formula II, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). The compound of formula II may also be present in an amount of about 2.0 to about 10.0 equivalents (mol / mol) relative to the compound of formula II, such as about 2.0 to about 5.0 equivalents (mol / mol). In some embodiments, the compound of formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula II.

[0521] In step (b1) above: any suitable reagent M can be used in the method for preparing the IV-I compound. Exemplary reagents M include, but are not limited to, isobutyric anhydride, isobutyric acid, and isobutyryl chloride; in some embodiments, reagent M may be isobutyric anhydride.

[0522] The reaction in step (b1) is carried out in the presence of a basic reagent, including but not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coradine, 4-dimethylaminopyridine, and quinine ring. The base may be present in any suitable amount. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III-I. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III.

[0523] In step (c1) above: any suitable reagent N can be used in the method for preparing compound VI. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol.

[0524] In step (d1) above: any suitable reagent O can be used in the method for preparing compound VI-I. Exemplary reagent O includes, but is not limited to, hydroxylamine, aqueous hydroxylamine solution, hydroxylamine hydrochloride, and hydroxylamine sulfate.

[0525] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula VI, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula VI. In some embodiments, the compound of formula II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to the compound of formula I.

[0526] In another preferred embodiment, the compounds obtained in steps (a1), (b1) and (c1) can be separated and then used, or steps (a1), (b1) and (c1) can be carried out in a "one-pot" manner.

[0527] In another preferred embodiment, steps (a1), (b1), (c1) and (d1) are performed using a "one-pot method".

[0528] In one embodiment, the present invention provides a method for preparing VI-II, comprising the steps of

[0529] (d2) V-II reacts with reagent O to form VI-II.

[0530]

[0531] In the above steps: any suitable reagent O can be used in the method for preparing compounds of formula VI-II. Exemplary reagent O includes, but is not limited to, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, hydrazine hydrate, or solutions thereof.

[0532] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula V-II, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 30.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 10.0 to about 30.0 equivalents (mol / mol) relative to the compound of formula V-II.

[0533] In one embodiment, the present invention provides a method for preparing VI-II, comprising the steps of:

[0534] (a2) Compounds of formula I-II react with compounds of formula II to produce compounds of formula III-II;

[0535]

[0536] (b2) Compound III-II reacts with reagent M to form compound IV-II;

[0537]

[0538] (c2) Compound IV-II reacts with reagent N to form compound V-II;

[0539]

[0540] (d2) Compound V-II reacts with reagent O to form compound VI-II;

[0541]

[0542] Wherein, R4 and R5 are methyl groups, and R6 and R7 are each independently hydrogen or C1-C16 alkyl groups; in step (a2) above: any suitable compound of formula II can be used in the method for preparing compounds of formula III-II. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

[0543] Compound II may be present in any suitable amount. For example, compound II may be present in an amount of at least 2.0 equivalents (mol / mol) relative to compound I-II, such as about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol / mol). Compound II may also be present in an amount of about 2.0 to about 10.0 equivalents (mol / mol) relative to compound I-II, such as about 2.0 to about 5.0 equivalents (mol / mol). In some embodiments, compound II may be present in an amount of about 2.0 to about 5.0 equivalents (mol / mol) relative to compound I-II.

[0544] In step (b2) above: any suitable reagent M can be used in the method for preparing compounds of formula IV-II. Exemplary reagent M includes, but is not limited to, those mentioned above. In some implementations, reagent M can be

[0545] The reaction in step (b2) is carried out in the presence of an organometallic base, which includes, but is not limited to, Grignard reagents, preferably methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, and ethyl magnesium chloride; preferably, the organometallic base is methyl magnesium bromide. The base may be present in any suitable amount. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula III-II. Preferably, the base is present in an amount of about 1.0 to about 4.0 equivalents (mol / mol) relative to the compound of formula III-II.

[0546] The reaction in step (b2) can also be carried out in the presence of a basic reagent and a Lewis acid, wherein the basic reagent includes, but is not limited to, N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-corridin, 4-dimethylaminopyridine, quinine ring, and organometallic bases; wherein the organometallic bases include, but are not limited to, Grignard reagents, preferably methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, and ethylmagnesium chloride; wherein the Lewis acid includes, but is not limited to, magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, and aluminum chloride; preferably, the base is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, or tert-butylmagnesium chloride, used in random combinations with magnesium chloride or lithium chloride. The base is present in an amount of at least 1.0 equivalents (mol / mol) relative to the Lewis acid. Preferably, the base is present in an amount of about 1.0 to about 5.0 equivalents (mol / mol) relative to the Lewis acid.

[0547] In step (c2) above: any suitable reagent N can be used in the method for preparing compound V-II. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride solution, methanol, ethanol, and propanol.

[0548] In step (d2) above: any suitable reagent O can be used in the method for preparing compound VI-II. Exemplary reagent O includes, but is not limited to, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, hydrazine hydrate, or solutions thereof.

[0549] Reagent O may be present in any suitable amount. For example, reagent O may be present in an amount of at least 1.0 equivalents (mol / mol) relative to the compound of formula V-II, such as about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents (mol / mol). Reagent O may also be present in an amount of about 10.0 to about 20.0 equivalents (mol / mol) relative to the compound of formula V-II. In some embodiments, reagent O may also be present in an amount of about 10.0 to about 20.0 equivalents (mol / mol) relative to the compound of formula V-II (including the cis-trans isomer).

[0550] The main advantages of this invention include

[0551] (a) High yield, mild deprotection conditions, simple purification, and compounds obtained in intermediate steps can be directly used for subsequent reactions without separation and / or purification (i.e., "one-pot" method).

[0552] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0553] Unless otherwise specified, the raw materials or reagents used in the examples are commercially available or prepared in accordance with conventional knowledge in the art.

[0554] Example 1

[0555]

[0556] Compound II (5.00 g, 20.57 mmol) and N,N-dimethylformamide dimethyl acetal (9.80 g, 82.28 mmol) were added to pyridine (50 mL) and stirred overnight at 25 °C. TLC showed that the starting materials had reacted completely. The reaction solution was concentrated and used directly for the next reaction.

[0557] Compound III-I obtained in the previous step was added to dichloromethane (50 mL). At 25 °C, isobutyric anhydride (4.88 g, 30.86 mmol), triethylamine (4.16 g, 41.40 mmol), and 4-N,N-dimethylaminopyridine (244 mg, 2.00 mmol) were added sequentially. After the addition was complete, the reaction proceeded for 2 h, and TLC showed that the starting material had reacted completely. Then, ethanol (1.89 g, 411.40 mmol) was added to the reaction solution, and the mixture was stirred for 2 h. The reaction solution was concentrated, then slurried with isopropyl acetate, and filtered to obtain compound VI, 6.06 g of an off-white solid, with a yield of 80%. 1H NMR (500MHz, DMSO) δ8.64(s,1H),7.80(d,J=7.3Hz,1H),5.97(d,J=7.2Hz,1H),5.77(d,J= 3.3Hz,1H),5.53(d,J=5.2Hz,1H),5.23(d,J=6.2Hz,1H),4.29(dd,J=12.2,3.0Hz,1H),4.2 2(dd,J=12.3,5.1Hz,1H),4.05–4.01(m,1H),4.01–3.98(m,1H),3.91(dd,J=11.6,6.3Hz,1 H),3.17(s,3H),3.04(s,3H),2.59(dt,J=14.0,7.0Hz,1H),1.10(dd,J=7.0,2.1Hz,6H).MS m / z=369.4[M+H] +

[0558] Example 2

[0559]

[0560] Compound II (5.00 g, 20.57 mmol), N,N-dimethylformamide dimethyl acetal (9.80 g, 82.28 mmol), and pyridine (16.25 g, 205.7 mmol) were added to tetrahydrofuran (50 mL) and refluxed overnight. TLC showed that the starting materials had reacted completely. The reaction solution was concentrated and used directly for the next step of the reaction.

[0561] Compound III-I obtained in the previous step was added to dichloromethane (50 mL). At 25 °C, isobutyric anhydride (4.88 g, 30.86 mmol), triethylamine (4.16 g, 41.40 mmol), and 4-N,N-dimethylaminopyridine (244 mg, 2.00 mmol) were added sequentially. After the additions were complete, the reaction proceeded for 2 h. TLC showed that the starting material had reacted completely. Then, ethanol (1.89 g, 411.40 mmol) was added to the reaction solution, and the mixture was stirred for 2 h. The reaction solution was concentrated, then slurried with isopropyl acetate, and filtered to obtain compound VI, 6.06 g of an off-white solid, with a yield of 80%.

[0562] Example 3

[0563]

[0564] Compound VI (500 mg, 1.36 mmol) was added to a mixed solution of isopropanol and water (w / w, isopropanol / water = 7:3, 7 g), followed by the addition of hydroxylamine sulfate (892 mg, 5.44 mmol). The mixture was heated to 80°C and reacted for 24 h. TLC showed that the starting material had reacted completely. The reaction mixture was cooled, filtered, concentrated, and column chromatography was performed to obtain compound VI-I, a white solid of 380 mg, with a yield of 80%. 1 H NMR (500MHz, MeOD) δ6.94(d,J=8.3Hz,1H),5.84(d,J=4.9Hz,1H),5.63(d,J=8.2Hz,1H),4.31(d,J=3.8H z,2H),4.15(t,J=5.0Hz,1H),4.12–4.08(m,2H),2.64(sept,7.0Hz,1H),1.20(dd,J=7.0,1.6Hz,6H).MS m / z=328.2[MH] -

[0565] Example 4

[0566]

[0567] Compound VI (400 mg, 1.09 mmol) was added to a mixed solution of isopropanol and water (w / w, isopropanol / water = 7:3, 7 g), followed by the addition of hydroxylamine sulfate (714 mg, 4.35 mmol). The reaction was carried out at room temperature for 24 h. TLC showed that the starting material had reacted completely. The reaction mixture was filtered, concentrated, and column chromatography was performed to obtain compound VII-I, a white solid of 323 mg, with a yield of 85%. 1 H NMR (600MHz, DMSO-d6) δ10.66(s,1H),10.06(d,J=8.8Hz,1H),7.86(d,J=7.4Hz,1H),7.73( d,J=9.5Hz,1H),6.33(d,J=7.4Hz,1H),5.75(d,J=3.3Hz,1H),5.52(d,J=5.1Hz,1H),5.22( d,J=6.2Hz,1H),4.29(dd,J=12.2,3.0Hz,1H),4.23(dd,J=12.2,5.6Hz,1H),4.05–3.98(m, 2H),3.91(dd,J=11.8,6.3Hz,1H),2.58(hept,J=7.0Hz,1H),1.10(dd,J=7.0,2.6Hz,6H)MS m / z=357.2[M+H] +

[0568] Example 5

[0569]

[0570] Compound VI (500 mg, 1.36 mmol) was added to a mixed solution of isopropanol and water (w / w, isopropanol / water = 7:3, 7 g), followed by the addition of hydroxylamine sulfate (892 mg, 5.44 mmol). The reaction was carried out at room temperature for 24 h, and TLC showed that the starting material had been completely converted to compound VII-I. The reaction was then heated to 80°C and continued for 24 h. TLC showed that the compound had reacted completely. The reaction mixture was cooled, filtered, concentrated, and column chromatography was performed to obtain compound VI-I as a white solid (380 mg), yield 80%. 1 H NMR (500MHz, MeOD) δ6.94(d,J=8.3Hz,1H),5.84(d,J=4.9Hz,1H),5.63(d,J=8.2Hz,1H),4.31(d,J=3.8H z,2H),4.15(t,J=5.0Hz,1H),4.12–4.08(m,2H),2.64(sept,7.0Hz,1H),1.20(dd,J=7.0,1.6Hz,6H).MS m / z=328.2[MH] -

[0571] Example 6

[0572]

[0573] Cytidine (5 g, 20.6 mmol), DMF-DMA (9.86 g, 82.4 mmol), and pyridine (16.3 g, 206 mmol) were added to THF (50 mL) and refluxed overnight. The next day, TLC showed that the starting material had reacted completely. The reaction solution was concentrated to obtain a crude product, which was directly used in the next step. The obtained crude product was dissolved in dichloromethane (50 mL), and then triethylamine (6.25 g, 61.8 mmol), DMAP (189 mg, 1.55 mmol), and isobutyric anhydride (4.89 g, 30.9 mmol) were added sequentially. After about 2 hours, TLC showed that the starting material had reacted completely. Ethanol (18.9 g, 412 mmol) was added to quench the reaction, and then the reaction was concentrated and carried out once with isopropanol to obtain the crude product. Hydroxylamine sulfate (13.5 g, 82.4 mmol) was dissolved in purified water (30 g) and added to isopropanol (70 g). Then, the crude product obtained in the previous step was added, and the temperature was raised to 78 degrees Celsius and reacted for 18 h. Heating was stopped and the mixture was cooled to room temperature. The reaction solution separated into two layers. The isopropanol layer was concentrated to dryness and dissolved in 2-methyltetrahydrofuran. The aqueous layer was diluted with purified water (30 g) and used to wash the 2-methyltetrahydrofuran layer. After washing, the organic layer was dried with anhydrous sodium sulfate, concentrated, and then dissolved in isopropyl acetate (50 mL) to obtain compound VI-1, a white solid (4.8 g, total yield 70%).

[0574] Example 7

[0575]

[0576] Compound I-II (500 mg, 1.72 mmol) and N,N-dimethylformamide dimethyl acetal (820 mg, 6.00 mmol) were added to pyridine (10 mL) and reacted overnight at 25 °C. TLC showed that the starting materials had reacted completely. The reaction solution was concentrated and used directly for the next reaction.

[0577] The III-II and III-3 (935 mg, 1.89 mmol) obtained in the previous step were dissolved in dry tetrahydrofuran (10 mL), cooled to -10 °C, and a 3.0 M methylmagnesium bromide solution in 2-methyltetrahydrofuran (0.86 mL, 2.58 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at 0 °C for 2 h. TLC showed that the starting material had reacted completely. The reaction solution was quenched in saturated ammonium chloride (20 mL), extracted with ethyl acetate, and the organic phase was washed successively with dilute hydrochloric acid solution, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound V-II, 847 mg of foamy solid, yield 75%. 1H NMR(500MHz,DMSO)δ8.95(s,1H),8.14(s,1H),7.36–7.32(m,2H),7.20–7.15(m,3H),6.93(d,J=4.5Hz,1H) ,6.80(d,J=4.5Hz,1H),6.34(d,J=6.2Hz,1H),6.03(dd,J=13.0,10.1Hz,1H),5.40(d,J=5.6Hz,1H),4.70– 4.66(m,1H),4.28–4.21(m,2H),4.09(dt,J=12.2,6.2Hz,1H),4.00–3.92(m,2H),3.88–3.77(m,2H),3.25( s,3H),3.18(s,3H),1.44–1.38(m,1H),1.26–1.22(m,4H),1.19(d,J=7.1Hz,3H),0.78(t,J=7.4Hz,6H).MS m / z=658.3[M+H] +

[0578] Example 8

[0579]

[0580] Compound I-II (500 mg, 1.72 mmol) and N,N-dimethylformamide dimethyl acetal (820 mg, 6.00 mmol) were added to pyridine (10 mL) and reacted overnight at 25 °C. TLC showed that the starting materials had reacted completely. The reaction solution was concentrated and used directly for the next reaction.

[0581] The III-II and III-3 (935 mg, 1.89 mmol) obtained in the previous step were dissolved in dry tetrahydrofuran (10 mL), and then anhydrous magnesium chloride (246 mg, 2.58 mmol) was added. The mixture was stirred at 25 °C for 30 minutes, and then N,N-diethylisopropylamine (444 mg, 3.44 mmol) was added dropwise. After the addition was complete, the mixture was reacted overnight at 25 °C. TLC showed that the starting material had reacted completely. The reaction solution was added to 2M hydrochloric acid solution (3 mL), and then extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound V-II, 800 mg of foamy solid, with a yield of 71%.

[0582] Example 9

[0583]

[0584] Compound V-II (500 mg, 0.76 mmol) was dissolved in ethanol (5 mL), and then acetic acid (912 mg, 15.20 mmol) was added. The reaction was carried out overnight at 45 °C. The next day, TLC showed that the starting material had reacted completely. The reaction solution was concentrated, and then ethyl acetate was added. The solution was then washed successively with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain compound VI-II, 343 mg of white solid, yield 75%. 1 H NMR(500MHz,MeOD)δ7.87(s,1H),7.33–7.28(m,2H),7.21–7.14(m,3H),6.91(d, J=4.6Hz,1H),6.88(d,J=4.6Hz,1H),4.79(d,J=5.3Hz,1H),4.42–4.35(m,2H),4. 31–4.25(m,1H),4.17(t,J=5.6Hz,1H),4.02(dd,J=10.9,5.8Hz,1H),3.95–3.85( m,2H),1.45(dt,J=12.5,6.3Hz,1H),1.35–1.26(m,7H),0.85(t,J=7.5Hz,6H).MS m / z = 603.3 [M+H] +

[0585] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing a compound of formula VI, characterized in that, The method includes the following steps: (d) React compound V with reagent O to obtain compound VI; in, Reagent O is: hydroxylamine or its salt; Among the various types, R1, R2, and R3 are each independently selected from the group consisting of: hydrogen, halogen, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, azide, and cyano; wherein, substitution means that one or more hydrogen atoms in the group are substituted by a substituent selected from the group consisting of: C1-C6 alkyl and halogen. R8 is or ; R9 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl groups; R 10 Selected from the following group: C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aryl; R 11 Selected from the following group: substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, arylmethylene; Y is or ; Z is or ; Indicates a single bond or a double bond; X1 is selected from the following group: N, CR 12 ; X2 is selected from the following group: C (=O); X3 is: C(N=CHNR4R5); X4 is selected from the following group: N, NH; X5, X6, and X7 are selected from the following groups: C and N; X8 is C(NHR) 15 ); R 15 It is OH; R4 and R5 are each independently C1-C16 alkyl groups; R 12 and R 13 Each is independently hydrogen, deuterium, or C1-C16 alkyl; Unless otherwise specified, substitution means that one or more hydrogen atoms in a group are substituted by a substituent selected from the group consisting of: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl; wherein the benzyl, aryl, and cycloalkyl groups may optionally be substituted by one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl.

2. The method as described in claim 1, characterized in that, Y is selected from the following group: , , , , and .

3. The method as described in claim 1, characterized in that, R1, R2, and R3 are each independently selected from the following group: hydrogen, fluorine, azide, methyl, chloromethyl (CH2Cl), fluoromethyl (CH2F), difluoromethyl, vinyl, ethynyl, and cyano.

4. The method as described in claim 1, characterized in that, In step (d), the hydroxylamine or its salt is hydroxylamine sulfate.

5. The method as described in claim 1, characterized in that, When R8 is And Y is When reagent O is hydroxylamine or its salt, and Z is... .

6. The method as described in claim 1, characterized in that, In step (d), compound V reacts with reagent O to directly obtain compound VI; or, compound V reacts with reagent O to form an intermediate product, which is then converted into compound V to obtain compound V; wherein the intermediate product is compound VII. Y' is or ; X 10 For C (NHC=NOH); Among them, X1, X2, X4, X5, X6, X7, R1, R2, R3, R8, R 12 and R 13 As defined in claim 1.

7. The method as described in claim 1, characterized in that, The method further includes the step of: preparing a compound of formula V; and the preparation of the compound of formula V includes the step of: (a) Reacting compound I with compound II to obtain compound III; (b) React the compound of formula III with reagent M to obtain the compound of formula IV; Reagent M is selected from the following group: , , ,or ; (c) In the presence of reagent N, the compound of formula IV is reacted to obtain the compound of formula V; Wherein, reagent N is a protic solvent; Among the various types, X is or ; R6 and R7 are each independently hydrogen or C1-C16 alkyl; X9 is C(NH2); R 14 For chlorine or -W1-R 16 Where W1 is OS(O)2 or O; R 16 It is a hydrogenated, substituted, or unsubstituted phenyl group; Replacement, X1, X2, X4, X5, X6, X7, R1, R2, R3, R4, R5, R8, R9, R 10 R 11 R 12 R 13 Y is as defined in claim 1.

8. The method as described in claim 7, characterized in that, Reagent N is selected from the following group: C1-C6 alkyl alcohols, water, aqueous solutions of salts, organic acids, aqueous solutions of organic acids, aqueous solutions of inorganic acids, or combinations thereof.

9. The method as described in claim 7, characterized in that, X is selected from the following group: 、 、 、 、 、 、 。 10. The method as described in claim 8, characterized in that, In reagent N, the salt includes ammonium chloride; and / or the inorganic acid includes hydrochloric acid.

11. The method as described in claim 7, characterized in that, In step (a), the molar ratio of compound I to compound II is 1:(2~10); and / or, the reaction temperature is 0℃ to reflux temperature.

12. The method as described in claim 7, characterized in that, In step (a), the molar ratio of compound I to compound II is 1:(2~5); and / or the reaction temperature is 10~50℃.

13. The method as described in claim 7, characterized in that, In step (b), reagent M is selected from the following group: Isobutyric anhydride, isobutyric acid, isobutyryl chloride, tervaline chloride, , , , ; Among them, R 10 For substituted or unsubstituted phenyl groups, substituted or unsubstituted naphthyl groups; R 11 Selected from the following group: methyl, ethyl, isopropyl, 2-ethylbutyl, benzyl.

14. The method as described in claim 7, characterized in that, In step (b), the reaction is carried out in the presence of a basic reagent and / or optionally a Lewis acid.

15. The method as described in claim 14, characterized in that, The alkaline reagent is an organic base; and / or the Lewis acid is selected from the group consisting of: magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride, or combinations thereof.

16. The method as described in claim 15, characterized in that, The organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-coridine, 4-dimethylaminopyridine, quinine ring, or a combination thereof, or the organic base is a Grignard reagent.

17. The method as described in claim 16, characterized in that; The Grignard reagent is selected from the group consisting of: methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, or combinations thereof.

18. The method as described in claim 7, characterized in that, In step (b), When Y is The reaction is carried out in the presence of an organic base; When Y is The reaction is carried out in the presence of an organic base and a Lewis acid, or in the presence of an organometallic base.

19. The method as described in claim 7, characterized in that, In step (b), when reagent M is The reaction needs to be carried out in the presence of a condensing agent.

20. The method as described in claim 19, characterized in that, The condensing agent is selected from the group consisting of: 1-propylphosphoric anhydride, N,N'-carbonyldiimidazole, methanesulfonyl chloride, 4-toluenesulfonyl chloride, phosphorus oxychloride, tert-valerate chloride, oxaloyl chloride, N,N'-disuccinimidyl carbonate, ethyl chloroformate, isobutyl chloroformate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, 1,2-dihydro-2-isobutoxyquinoline-1-carboxylic acid isobutyl ester, 1-tert-butoxy-2-butoxycarbonyl-1,2-dihydroisoquinoline, cyanuric chloride, N,N'-diisopropylcarbodiimide, dicyclohexylcarbodiimide, N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1- (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea tetrafluoroborate, 2-(1H-benzotriazolyl-L-1-yl)-1,1,3,3-tetramethylurea tetrafluoroborate, O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoroborate, 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate Fluoroborates, O-(1,2-dihydro-2-oxo-1-pyridine)-N,N,N',N'-tetramethylthiourea tetrafluoroboric acid, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, chlorotripyrrolidinyl hexafluorophosphate, 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinyl hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, (3H-1,2,3-triazolo[4,5-B]pyridin-3-oxy)tri-1-pyrrolidinyl hexafluorophosphate, diethyl chlorophosphate, bis(2-oxazole) Alkyl)phosphinochloride, diphenylphosphinochloride, diphenyl phosphate, diphenyl chlorophosphate, 2-chloro-1,3-dimethylimidazolium hexafluorophosphate, N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)urea tetrafluoroborate, pentafluorophenyl diphenyl phosphate, 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, tetramethylfluorourea hexafluorophosphate, 2-(5-norbornene-2,3-dicarboximide)-1,1,3,3-tetramethylurea tetrafluoroborate quaternary ammonium salt.

21. The method as described in claim 7, characterized in that, The molar ratio of compound I to reagent M is 1:(1~4).

22. The method as described in claim 7, characterized in that, The molar ratio of compound I to reagent M is 1:(1~3).

23. The method as described in claim 7, characterized in that, The molar ratio of compound I to reagent M is 1:(1~2).

24. The method as described in claim 7, characterized in that, The molar ratio of compound I to reagent M is 1:(1~1.5).

25. The method as described in claim 7, characterized in that, In step (b), the reaction temperature is -30~50℃.

26. The method as described in claim 7, characterized in that, In step (b), the reaction temperature is -10 to 30°C.

27. The method as described in claim 7, characterized in that, Steps (a), (b), and (c) are performed using the "one-pot method"; or, steps (b) and (c) are performed using the "one-pot method".

28. A method for preparing a compound of formula VI, characterized in that, The compound of formula VI is a compound of formula VI-I, and the method includes the following steps: (d1) React compound VI with reagent O to obtain compound VI-I; Wherein, reagent O is hydroxylamine or a salt thereof; and the hydroxylamine or a salt thereof is selected from the group consisting of hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, or a combination thereof.

29. The method as described in claim 28, characterized in that, The method further includes the step of: preparing a compound of formula VI; and the preparation of the compound of formula VI includes the step of: (a1) React compound II with compound III to obtain compound III-I; (b1) React the compound of formula III-I with reagent M to obtain the compound of formula IV-I; Wherein, reagent M is isobutyric anhydride, isobutyric acid, or isobutyryl chloride; (c1) In the presence of reagent N, the compound of formula IV-I is reacted to obtain the compound of formula VI; Wherein, reagent N is a protic solvent; In each formula, R4 and R5 are methyl groups; R6 and R7 are each independently hydrogen or C1-C16 alkyl groups.

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