WO2022127920A1

WO2022127920A1 - Preparation method for and intermediate of 5'-nucleoside prodrug

Info

Publication number: WO2022127920A1
Application number: PCT/CN2021/139339
Authority: WO
Inventors: 沈敬山; 胡天文; 谢元超; 朱富强
Original assignee: 上海特化医药科技有限公司
Priority date: 2020-12-18
Filing date: 2021-12-17
Publication date: 2022-06-23
Also published as: CN114644666A

Abstract

Provided in the present invention are a preparation method for and an intermediate of a 5'-nucleoside prodrug. Specifically, provided in the present invention is a method for preparing a compound of formula VI. The method comprises the steps of: (a) reacting a compound of formula I and a compound of formula II to obtain a compound of formula III; (b) reacting the compound of formula III and reagent M to obtain a compound of formula IV; (c) reacting the compound of formula IV in the presence of reagent N to obtain a compound of formula V; and (d) reacting the compound of formula V with reagent O to obtain a compound of formula VI. The preparation method provided by the present invention has the advantages of having low costs, high yield, good product purity and the like, and is capable of achieving the efficient synthesis of 5'-nucleoside prodrugs.

Description

Preparation method and intermediate of 5'-nucleoside prodrug

technical field

The invention relates to the technical field of pharmacy, in particular to a preparation method and an intermediate of a 5'-nucleoside prodrug.

Background technique

Nucleoside drugs play an important role in antiviral drugs. After entering cells, they are converted into nucleoside triphosphates under the action of kinases, and nucleoside triphosphates compete with DNA polymerase or RNA polymerase of virus or host Insertion into the DNA strand or RNA strand that is being extended during viral replication causes chain termination or strand mutation and thus inhibits viral proliferation. However, some nucleoside compounds cannot achieve their expected efficacy due to hindered phosphorylation process or low bioavailability. Prodrug modification is a classic approach to this problem. Nucleoside 5'-hydroxyesterification or phosphorylation is a common prodrug modification strategy. In addition to the 5'-hydroxyl group, the nucleoside structure also contains some other active groups such as 2'-hydroxyl group, 3'-hydroxyl group, amino group, etc., so it is difficult to selectively modify the nucleoside 5'-hydroxyl group with prodrugs . At present, the commonly used synthetic method for the modification of nucleoside 5'-hydroxyl prodrugs is the functional group protection method, that is, the non-target active group is first protected, and then the prodrug group is introduced into the 5'-hydroxyl group and then the protective group is removed to achieve selectivity. Prodrug modification of nucleoside 5'-hydroxyl groups, such as nucleoside prodrugs Molnupiravir and Remdesivir for the treatment of new coronary pneumonia (SARS-Cov-2).

Molnupiravir (EIDD-2801/MK4482) is an oral anti-SARS-Cov-2 drug candidate developed by Merck in the United States in cooperation with Ridgeback Bio, and is currently in Phase II/III clinical research. The existing literature (WO2019173602A1; Eur.J.Org.Chem.2020, 6736-6739; Synlett 2020, 31, A-C) reported the following preparation methods.

Remdesivir (Remdesivir, GS-5734) is a novel carbon nucleoside phosphoramidate prodrug developed by Gilead and has been 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 on Remdesivir The preparation method is as follows:

It can be seen from the above preparation methods that the above two nucleoside prodrugs adopt the same synthesis strategy, that is, the 2' and 3' hydroxyl groups of the nucleosides are formed into acetal, and then the 5'-hydroxyl groups of the nucleosides are modified by the prodrug, and then deprotected to obtain Nucleoside prodrugs. Although the above synthetic strategies are relatively common, their severe deprotection conditions lead to many disadvantages such as degradation of nucleoside prodrugs, low yields, and difficulty in product purification.

In summary, there is an urgent need in the art to develop a new preparation method for 5'-nucleoside prodrugs. Especially when the 2', 3', and 5' positions of nucleosides are all hydroxyl groups, it is urgent to find a more economical, practical and environmentally friendly new synthetic method for the selective prodrug modification of the 5'-hydroxyl group of nucleosides. Improve process stability, reduce costs and improve product quality.

SUMMARY OF THE INVENTION

The purpose of this invention is to provide a kind of synthetic method of 5'-nucleoside prodrug and intermediate thereof with low cost, high yield and good product purity. Another object of the present invention is to provide compounds that can be used as intermediates in the preparation of 5'-nucleoside prodrugs (as shown in formula VI).

In one aspect of the present invention, there is provided a method for preparing a compound of formula VI, the method comprising the steps of:

(d) reacting the compound of formula V with reagent O to obtain the compound of formula VI;

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

various,

R ₁ , R ₂ and R ₃ 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, azido (-N=N=N), cyano;

_R8 is

R ₉ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl (preferably, C1-C8 alkyl; more preferably, C1-C4 alkyl);

R ₁₀ is selected from the group consisting of C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aryl;

R ₁₁ is selected from the group consisting of substituted or unsubstituted C1-C16 alkyl (preferably, C1-C8 alkyl), substituted or unsubstituted C3-C7 cycloalkyl, arylmethylene;

Y is

Z is

Indicates a single bond or a double bond;

X ₁ is selected from the group consisting of N, CR ₁₂ ;

X ₂ is selected from the group consisting of C(=O);

X ₃ is selected from the group consisting of C(=O), C(N=CHNR ₄ R ₅ );

X is selected from the group consisting of N, NH _;

X ₅ , X ₆ and X ₇ are selected from the group consisting of C, N;

X ₈ is selected from the group consisting of C(=O), C(NHR ₁₅ );

R ₁₅ is H or OH;

R ₄ and R ₅ 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 R ₄ and R ₅ and the nitrogen atom to which they are attached together form a substituted or unsubstituted 4- to 7-membered saturated heterocyclic group (preferably, the saturated heterocyclic group contains only a ₄ and R ₅ connected N heteroatom);

R ₁₂ and R ₁₃ are each 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, cyano;

Unless otherwise specified, the substitution means that one or more hydrogens (preferably, 1, 2, 3 or 4) in the group are replaced 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 can also be optionally substituted with one or more (eg, 1, 2, or 3) substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl.

In another preferred embodiment, R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl; preferably, both R ₄ and R ₅ are methyl groups.

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

In another preferred embodiment, Y is selected from the following group:

In another preferred embodiment, Y is selected from the following group:

or the cis-trans isomeric forms of the above groups.

In another preferred embodiment, Y is

In another preferred embodiment, Y is

or the cis-trans isomeric forms of the above groups.

In another preferred embodiment, Z is selected from the following group:

In another preferred embodiment, R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, fluorine, azido, methyl, chloromethyl (CH ₂ Cl), fluoromethyl (CH ₂ F ), difluoromethyl, vinyl, ethynyl, cyano.

In another preferred example, R ₃ is hydrogen or cyano.

In another preferred embodiment, R ₁ and R ₂ are hydrogen.

In another preferred example, R ₁₂ and R ₁₃ are hydrogen.

In another preferred example, in each formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₈ , Y and Z are each independently the corresponding groups in the specific compounds in the examples.

In another preferred embodiment, Y is

and/or Z is

In another preferred embodiment, Y is

or the cis-trans isomeric forms of the above groups; and/or Z is

In another preferred example, in step (d), the hydroxylamine or its salt includes: hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate, or a combination thereof.

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

In another preferred example, in step (d), in reagent O, the organic acid 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 a combination thereof.

In another preferred example, in step (d), in reagent O, the inorganic acid is selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, or a combination thereof.

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

In another preferred embodiment, when R ₈ is

and Y is

, reagent O is hydroxylamine or a salt thereof, and Z is

In another preferred embodiment, when R ₈ is

and Y is

or the cis-trans isomeric forms of the above groups, reagent O is hydroxylamine or a salt thereof, and Z is

In another preferred embodiment, when R ₁ , R ₂ and R ₃ are hydrogen, R ₈ is

Y is

wherein, when R ₄ , R ₅ , R ₉ and R ₁₂ are as defined above,

Y is

or cis-trans isomeric forms of the above groups, wherein R ₄ , R ₅ , R ₉ and R ₁₂ are as defined above,

Reagent O is hydroxylamine or its salt, Z is

In another preferred embodiment, when R ₈ is

and Y is

When; reagent O is inorganic acid, organic acid or hydrazine hydrate; Z is

In another preferred embodiment, when R ₈ is

and Y is

or the cis-trans isomeric form of the above groups; reagent O is inorganic acid, organic acid or hydrazine hydrate; Z is

In another preferred example, when R ₁ and R ₂ are hydrogen, R ₃ is cyano, and R ₈ is

Y is

wherein, R ₄ , R ₅ , R ₁₀ , R ₁₁ and R ₁₂ are as defined above;

Reagent O is inorganic acid, organic acid, hydrazine hydrate, Z is

Y is

or the cis-trans isomeric forms of the above groups, wherein R ₄ , R ₅ , R ₁₀ , R ₁₁ and R ₁₂ are as defined above;

Reagent O is inorganic acid, organic acid, hydrazine hydrate, Z is

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

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

In another preferred example, 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 a combination thereof.

In another preferred embodiment, in step (d), the reaction temperature of the reaction is 0 to reflux temperature, preferably 25-100°C.

In another preferred example, in step (d), the compound of formula V reacts with reagent O to directly obtain the compound of formula VI; or, the compound of formula V can react with reagent O to form an intermediate product, which is then converted into formula V from the intermediate product compound, thereby obtaining the compound of formula V.

In another preferred embodiment, the intermediate product is a compound of formula VII,

Y' is

X ₁₀ is C (NHC=NOH);

wherein X ₁ , X ₂ , X ₄ , X ₅ , X ₆ , X ₇ , R ₁ , R ₂ , R ₃ , R ₈ , R ₁₂ , and R ₁₃ are as defined above.

In another preferred embodiment, step (d) includes the step of: in the fourth solvent, at T1 temperature, the compound of formula V is reacted with reagent O, thereby directly obtaining the compound of formula VI.

In another preferred embodiment, T1 is 0 to reflux temperature; preferably, it is 50-100°C.

In another preferred embodiment, step (d) comprises the steps:

(d1) reacting a compound of formula V with reagent O in a fourth solvent at temperature T2 to form a compound of formula VII; and

(d2) in a fourth solvent, at T3 temperature, the compound of formula VII is reacted with reagent O to form the compound of formula VI;

And T3>T2.

In another preferred embodiment, the compound of formula VII is not isolated.

In another preferred example, T2=0∼50°C.

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

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

In another preferred embodiment, the method further comprises the step of: preparing the compound of formula V.

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

In a second aspect of the present invention, there is provided a compound of formula V,

wherein R ₁ , R ₂ , R ₃ , R ₈ and Y are as defined in the first aspect.

In another preferred example, R ₃ is hydrogen or cyano; Y is

And R ₁ , R ₂ , R ₄ , R ₅ , R ₈ and R ₁₂ are as previously defined.

In another preferred example, R ₃ is hydrogen or cyano; Y is

or cis-trans isomeric forms of the above groups; and R ₁ , R ₂ , R ₄ , R ₅ , R ₈ and R ₁₂ are as previously defined.

In another preferred embodiment, R ₄ and R ₅ are methyl groups.

In another preferred embodiment, the compound of formula V is the compound of formula V-I, or the compound of formula V-II;

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

In a third aspect of the present invention, there is provided a method for preparing a compound of formula V, 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 reagent M, thereby obtaining the compound of formula IV;

Wherein, reagent M is selected from the following group:

(Carboxylic acid reagent),

(acid anhydride reagent),

(Acyl chloride reagent), or

(phosphoramide reagent);

(c) in the presence of reagent N, the compound of formula IV is reacted to obtain the compound of formula V;

Wherein, the reagent N is a protic solvent; preferably, the reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof;

various,

X is

R ₆ and R ₇ are each independently hydrogen or C1-C16 alkyl;

X ₉ is C(=O), C(NH ₂ );

R ₁₄ is -W ₁ -R ₁₆ ; wherein, W ₁ is OS(O) ₂ or O; R ₁₆ is hydrogen, chlorine, substituted or unsubstituted phenyl (preferably, R ₁₆ is halogenated phenyl, nitro-substituted phenyl); preferably, R ₁₄ is benzenesulfonate (-OS(O) ₂ -Ar), substituted phenoxy);

Substitution, X ₁ , X ₂ , X ₄ , X ₅ , X ₆ , X ₇ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ , R ₉ , R ₁₀ , R ₁₂ , R ₁₃ and Y is as defined in the first aspect.

In another preferred embodiment, X is selected from the following group:

In another preferred example, in step (a), the compound of formula II is N,N-dimethylformamide dimethyl acetal (that is, R ₄ , R ₅ , R ₆ and R ₇ are all methyl groups).

In another preferred example, in the reagent N, the salt includes: ammonium chloride; and/or the inorganic acid includes: hydrochloric acid.

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

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

In another preferred example, step (a) is: in a first inert solvent, the compound of formula I is reacted with N,N-dimethylformamide dimethyl acetal, thereby obtaining the compound of formula III; and the compound of formula III wherein R ₄ and R ₅ are methyl groups.

In another preferred example, in step (a), the molar ratio of the compound of formula I to the compound of formula II is 1:(2-10); preferably, 1:(2-5).

In another preferred example, in step (a), the reaction temperature of the reaction is 0°C to reflux temperature; preferably, 10°C to 50°C.

In another preferred embodiment, in step (b), R ₉ is selected from the group consisting of isobutyl and tert-butyl.

In another preferred example, in step (b), the reagent M is selected from the group consisting of isobutyric anhydride, isobutyric acid, isobutyryl chloride, pivaloyl chloride,

or its salt,

Wherein, R ₁₀ is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl; R ₁₁ is selected from the following group: methyl, ethyl, isopropyl (iPr), 2-ethylbutyl, benzyl .

In another preferred embodiment,

The salts thereof include salts formed with bases; preferably, the bases are selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N- N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-colidine, 4-dimethylaminopyridine, quinuclidine, NaOH, KOH, LiOH, Ca(OH) _2. Mg(OH) ₂ , or a combination thereof.

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

In another preferred embodiment, the alkaline reagent is an organic base or an organic metal base.

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-lutidine, 2,4,6-colidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof.

In another preferred example, the organometallic base is a Grignard reagent; preferably, the Grignard reagent is selected from the following group: methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, Isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, or a combination thereof.

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, or a combination thereof.

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

In another preferred embodiment, the second inert solvent includes: halogenated hydrocarbon solvents (such as dichloromethane), ether solvents (such as tetrahydrofuran and/or 2-methyltetrahydrofuran), pyridine, acetonitrile, or a combination thereof .

In another preferred embodiment, in step (b), when Y is

, the reaction is carried out in the presence of an organic base.

In another preferred example, when Y is

(For example, Y is

or the cis-trans isomeric form of the above group), step (b) is:

In the second inert solvent, in the presence of an organic base, the compound of formula III and the reagent M react to generate the compound of formula IV;

Preferably, the organic base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2, 6-lutidine, 2,4,6-colidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof.

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.

In another preferred example, when Y is

(For example, Y is

or the cis-trans isomer form of the above-mentioned group), the step (b) is: in the second inert solvent, in the presence of an organic metal base or the co-existence of an organic base and a Lewis acid, the compound of formula III and the reagent M react, Thereby the compound of formula IV is obtained;

Preferably, organometallic bases include but are not limited to Grignard reagents, and the Grignard reagents are selected from the group consisting of methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, or a combination thereof; and/or

The organic base is selected from the following group: N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, 2,6- Lutidine, 2,4,6-colidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof; 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 a combination thereof.

In another preferred embodiment, in step (b), when the reagent M is

In the case of its salt, the reaction needs to be carried out in the presence of a condensing agent.

In another preferred embodiment, the condensing agent is selected from 1-propyl phosphoric anhydride (T3P), N,N'-carbonyldiimidazole (CDI), methylsulfonyl chloride (MsCl), 4-toluenesulfonyl chloride ( TsCl), phosphorus oxychloride (POCl3), pivaloyl chloride (PivCl), oxalyl chloride (COCl ₂ ), N,N'-disuccinimidyl carbonate (NDSC), ethyl chloroformate (ECF), Isobutyl chloroformate (IBCF), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,2-dihydro-2-isobutoxyquinoline- Isobutyl 1-carboxylate (IIDQ), 1-tert-butoxy-2-butoxycarbonyl-1,2-dihydroisoquinoline (BBDI), cyanuric chloride (TCT), N,N'-dihydroisoquinoline Isopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1- base) hexafluorophosphate urea (HATU), (2-oximo-ethyl cyanoacetate)-N,N-dimethyl-morpholinyl urea hexafluorophosphate (COMU), 6-chlorobenzotriazepine oxazole-1,1,3,3-tetramethylurea hexafluorophosphate (HCTU), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 6-Chlorobenzotriazole-1,1,3,3-tetramethylurea tetrafluoroborate (TCTU), 2-(1H-benzotriazo L-1-yl)-1,1 ,3,3-Tetramethylurea tetrafluoroborate (TBTU), O-[(ethoxycarbonyl)cyanomethylamine]-N,N,N',N'-tetramethylthiourea tetrafluoro borate (TOTU), 2-succinimidyl-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU), O-(1,2-dihydro-2-oxo- 1-pyridine)-N,N,N',N'-tetramethylthiourea tetrafluoroboric acid (TPTU), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBrOP), chlorotripyrrolidinyl hexafluorophosphate (PyClOP), 1-(chloro-1-pyrrolidinylmethylene ) pyrrolidine hexafluorophosphate (PyClU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (3H-1,2,3-triazolo[ 4,5-B]pyridin-3-oxy)tris-1-pyrrolidinyl hexafluorophosphate (PyAOP), diethyl chlorophosphate (DEPC), bis(2-oxo'-3-oxazolidine base) phosphinic acid chloride (BOPCl), diphenylphosphinic acid chloride (DppCl), diphenyl phosphate (DPP), diphenyl chlorophosphate (DPC), 2-chloro-1,3-dimethylimidazolium hexafluoro Phosphate (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-Dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (DMTMM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), tetramethylfluorourea hexafluorophosphate (TFFH), 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyl Urea tetrafluoroborate quaternary ammonium salt (TNTU).

In another preferred example, the molar ratio of the compound of formula I to the reagent M is 1:(1~4); preferably, 1:(1~3); more preferably, 1:(1~2); Preferably, 1: (1～1.5).

In another preferred example, the molar ratio of the compound of formula I to the basic reagent is 1:(1-10); preferably, 1:(1-5); more preferably, 1:(1-4).

In another preferred example, the molar ratio of the alkaline reagent to the optional Lewis acid is 1:(1-5); preferably, 1:(1-2).

In another preferred example, in step (b), the reaction temperature of the reaction is -30 to 50°C; preferably, -10 to 30°C.

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

In another preferred embodiment, the third inert solvent includes: halogenated hydrocarbon solvents (such as dichloromethane), ether solvents (such as tetrahydrofuran and/or 2-methyltetrahydrofuran), or alcohol solvents (including methanol , ethanol, isopropanol, or a combination thereof), or a combination thereof.

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

In another preferred example, in step (c), the reagent N is selected from the group consisting of acetic acid, water, aqueous ammonium chloride, aqueous hydrochloric acid, methanol, ethanol, isopropanol, or a combination thereof.

In another preferred embodiment, the compounds obtained in steps (a) and/or (b) and/or (c) can be separated and used again.

In another preferred embodiment, the steps (a), (b) and (c) are carried out in a "one-pot method".

In another preferred embodiment, steps (b) and (c) are carried out in a "one-pot method" (ie, the compound of formula IV obtained in step (b) is used directly without separation).

In another preferred embodiment, in each formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ , X ₉ , W ₁ , X, Y and Z are each independently specific compounds in the examples the corresponding group in .

In a fourth aspect of the present invention, there is provided a compound of formula III,

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and Y are as defined in the third aspect.

In another preferred embodiment, R ₄ and R ₅ are methyl groups.

In another preferred example, R ₁ and R ₂ are hydrogen; when R ₃ is hydrogen or cyano, Y is

R ₄ , R ₅ and R ₁₂ are as previously defined.

or the cis-trans isomeric forms of the above groups; R ₄ , R ₅ and R ₁₂ are as previously defined.

In another preferred embodiment, the compound of formula III is the compound of formula III-I or the compound of formula III-II;

In another preferred embodiment, the compound of formula III is the compound represented by formula IIIa-I or its cis-trans isomer or the compound represented by formula IIIa-II or its cis-trans isomer;

In a fifth aspect of the present invention, there is provided a compound of formula IV,

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₈ and Y are as defined in the third aspect.

In another preferred example, R ₃ is hydrogen or cyano; R ₈ is

Y is

R ₄ , R ₅ , R ₉ and R ₁₁ are each as defined above.

In another preferred example, R ₃ is hydrogen or cyano; R ₈ is

Y is

or cis-trans isomeric forms of the above groups; R ₄ , R ₅ , R ₉ and R ₁₁ are each as previously defined.

In another preferred example, the compound of formula IV is the compound shown in formula IV-I or the compound shown in formula IV-II,

In another preferred example, 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,

In the sixth aspect of the present invention, a preparation method of a compound of formula VI-I is provided, the method comprising the steps:

(d1) reacting the compound of formula V-I with reagent O to obtain the compound of formula VI-I;

Wherein, the reagent O is hydroxylamine or its salt; preferably, it is hydroxylamine sulfate.

In another preferred example, step (d1) is: reacting the compound of formula V-I with hydroxylamine sulfate to obtain the compound of formula VI-I.

In another preferred example, in step (d1), the molar ratio of the compound of formula V-I to reagent O is 1:(1-50); preferably, 1:(1-20); more preferably, 1:( 2-10); optimally, 1: (2-5).

In another preferred embodiment, the method further comprises the step of: preparing the compound of formula V-I.

In another preferred embodiment, the compound of formula V-I is prepared as described in the seventh aspect.

In the seventh aspect of the present invention, there is provided a preparation method of a compound of formula V-I, the method comprising the steps:

(a1) reacting a compound of formula I-I with a compound of formula II to obtain a compound of formula III-I

(b1) reacting the compound of formula III-I with reagent M, thereby obtaining 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 V-I;

Wherein, the reagent N is a protic solvent; preferably, the reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof ;

In each formula, R ₄ and R ₅ are methyl; R ₆ and R ₇ are each independently hydrogen, C1-C16 alkyl (preferably, C1-C8 alkyl, more preferably, C1-C4 alkyl) .

In another preferred embodiment, the compound of formula V-I is the compound of formula Va-I and/or its cis-trans isomer.

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

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

In another preferred embodiment, the method includes the steps:

(a1) reacting a compound of formula I-I with a compound of formula II to obtain a compound of formula IIIa-I or a cis-trans isomer thereof

(b1) reacting the compound of formula IIIa-I or its cis-trans isomer with reagent M, thereby obtaining the compound of formula IVa-I or its cis-trans isomer;

(c1) in the presence of reagent N, react the compound of formula IVa-I or its cis-trans isomer to obtain the compound of formula Va-I or its cis-trans isomer;

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

In another preferred embodiment, in step (a1), the reaction is carried out in a first inert solvent (eg, pyridine).

In another preferred example, step (a1) is: in pyridine, the compound of formula I-I is reacted with N,N-dimethylformamide dimethyl acetal, thereby obtaining formula III-I.

In another preferred example, in step (a1), the molar ratio of the compound of formula I-I to the compound of formula II is 1:(2-10); preferably, 1:(2-5).

In another preferred example, in step (a1), the reaction temperature of the reaction is 0°C to reflux temperature; preferably, 10 to 50°C.

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

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

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

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

In another preferred example, 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-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof; preferably, selected from the group : triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, or a combination thereof.

In another preferred example, step (b1) is: in the second inert solvent, in the presence of triethylamine and 4-dimethylaminopyridine, the compound of formula III-I and isobutyric anhydride are reacted to obtain formula IV -I compound.

In another preferred example, in step (b1), the molar ratio of the compound of formula I-I to the reagent M is 1:(1~4); preferably, 1:(1~3); more preferably, 1:( 1-2); optimally, 1: (1-1.5).

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

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

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

In another preferred embodiment, step (c1) is: in the presence of a reagent N in a third inert solvent, the compound of formula IV-I is reacted to obtain the compound of formula V-I.

In another preferred example, in step (c1), the reagent N is selected from the following group: acetic acid, water, an aqueous solution of hydrochloric acid, an aqueous ammonium chloride solution, methanol, ethanol, isopropanol, or a combination thereof; preferably, methanol , ethanol, isopropanol, or a combination thereof.

In another preferred embodiment, the step (c1) is: in a third inert solvent, in the presence of ethanol, the compound of formula IV-I is reacted to obtain the compound V-I.

In another preferred embodiment, the compounds obtained in steps (a1), (b1) and (c1) can be separated and used again.

In another preferred embodiment, the steps (a1), (b1) and (c1) are carried out by a "one-pot method".

In another preferred embodiment, the steps (b1) and (c1) are carried out by a "one-pot method" (ie, the compound of formula IV-I obtained in step (b1) is used directly without separation).

In the seventh aspect of the present invention, there is provided a preparation method of a compound of formula VI-II, the method comprising the steps:

(d2) the compound of formula V-II reacts with reagent O to generate the compound of formula VI-II;

Wherein, reagent O is selected from the group consisting of organic acid, inorganic acid, hydrazine hydrate, or a combination thereof.

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

In another preferred embodiment, the method includes the steps:

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

In another preferred example, step (d2) is: reacting the compound of formula V-II with acetic acid to obtain the compound of formula VI-II.

In another preferred example, step (d2) is: reacting the compound of formula V-II with trifluoroacetic acid to obtain the compound of formula VI-II.

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

In another preferred embodiment, the method further comprises the step of: preparing the compound of formula V-II.

In another preferred embodiment, the preparation of the compound of formula V-II is as described in the eighth aspect.

In the eighth aspect of the present invention, there is provided a preparation method of a compound of formula V-II, the method comprising the steps:

(a2) the compound of formula I-II reacts with the compound of formula II to generate the compound of formula III-II;

(b2) compound of formula III-II reacts with reagent M to generate compound of formula IV-II;

Among them, the reagent M is

R ₁₄ is a substituted phenoxy group, a benzenesulfonate group;

(c2) compound of formula IV-II reacts with reagent N to generate compound of formula V-II;

various,

R ₄ and R ₅ are methyl; R ₆ and R ₇ are each independently hydrogen, C1-C16 alkyl (preferably, C1-C8 alkyl, more preferably, C1-C4 alkyl).

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

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

In another preferred embodiment, the method includes the steps:

(a2) the compound of formula I-II reacts with the compound of formula II to generate the compound of formula IIIa-II or its cis-trans isomer;

(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;

Among them, the reagent M is

R ₁₄ is a substituted phenoxy group, a benzenesulfonate group;

(c2) the compound of formula IVa-II or its cis-trans isomer reacts with reagent N to generate the compound of formula Va-II or its cis-trans isomer;

various,

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

In another preferred embodiment, in step (a2), the reaction is carried out in a first inert solvent (eg, pyridine).

In another preferred example, step (a2) is: in pyridine, the compound of formula I-II is reacted with N,N-dimethylformamide dimethyl acetal, thereby obtaining the compound of formula III-II.

In another preferred example, in step (a2), the molar ratio of the compound of formula I-II to the compound of formula II is 1:(2-10); preferably, 1:(2-5).

In another preferred example, in step (a2), the reaction temperature of the reaction is 0～℃ reflux temperature; preferably, 10～50℃.

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

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

In another preferred example, in step (b2), in the second inert solvent, in the presence of an organic metal base or in the coexistence of an organic base and a Lewis acid, the compound of formula III-II and the reagent M are reacted, thereby Compounds of formula IV-II are obtained.

In another preferred example, in step (b2), the organometallic base includes a Grignard reagent; preferably, the Grignard reagent is selected from the group consisting of methylmagnesium bromide, tert-butylmagnesium chloride, tert-Butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride, or a combination thereof.

In another preferred example, in step (b2), the organic base is selected from the following group: N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N- Diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, or a combination thereof.

In another preferred example, in step (b2), the Lewis acid is selected from the following group: magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, chlorine zinc chloride, aluminum chloride, or a combination thereof.

In another preferred embodiment, step (b2) is: in the second inert solvent, in the presence of methylmagnesium bromide, make the compound of formula III-II and

(where R ₁₄ is

) reaction to obtain the compound of formula IV-II.

In another preferred example, step (b2) is: in the second inert solvent, in the presence of magnesium chloride and N,N-diisopropylethylamine, make the compound of formula III-II and

(where R ₁₄ is

) reaction to obtain the compound of formula IV-II.

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

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

In another preferred example, in step (b2), the reaction temperature of the reaction is -30-10°C; preferably, -10-0°C.

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

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

In another preferred example, in step (c2), the reagent N is selected from the following group: acetic acid, water, an aqueous solution of hydrochloric acid, an aqueous ammonium chloride solution, methanol, ethanol or isopropanol, preferably methanol, ethanol, isopropanol alcohol, or a combination thereof.

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

In another preferred embodiment, the compounds obtained in steps (a2), (b2) and (c2) can be separated and used again;

In another preferred embodiment, the steps (a2), (b2) and (c2) are carried out by a "one-pot method".

In another preferred example, wherein steps (b2) and (c2) are carried out by a "one-pot method" (that is, the compound of formula IV-II (containing cis-trans isomers) obtained in step (b) is used directly without separation) .

In a ninth aspect of the present invention, a preparation method of a compound of formula VI is provided, the method comprising the steps:

Wherein, reagent M is selected from the following group:

(Carboxylic acid reagent),

(acid anhydride reagent),

(Acyl chloride reagent), or

(phosphoramide reagent);

Wherein, reagent N is a protic solvent; Preferably, reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof;

In each formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₄ , X, Y and Z are as in the first aspect or Defined in the third aspect.

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

In the tenth aspect of the present invention, there is provided a preparation method of compound VI-I, the method comprises the steps:

(a1) reacting a compound of formula I-I with a compound of reagent II to obtain a compound of formula III-I

(d1) reacting the compound of formula V-I with reagent O to generate the compound of formula VI-I;

various,

In another preferred embodiment, R ₄ , R ₅ , R ₆ and R ₇ are as defined in the sixth or seventh aspect.

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

In the eleventh aspect of the present invention, there is provided the preparation method of compound VI-II, and described method comprises the steps:

Among them, the reagent M is

R ₁₄ is a substituted phenoxy group, a benzenesulfonate group;

Among them, the reagent M is

R ₁₄ is a substituted phenoxy group, a benzenesulfonate group;

various,

In another preferred embodiment, R ₄ , R ₅ , R ₆ and R ₇ are as defined in the eighth or ninth aspect.

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

In a twelfth aspect of the present invention, there is provided a compound of formula III-I, formula IV-I or formula V-I, or VII-I.

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

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

In a fourteenth aspect of the present invention, a compound of formula III-II, formula IV-II or formula V-II is provided.

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

In a sixteenth aspect of the present invention, there is provided a compound of formula VII,

wherein X ₁ , X ₂ , X ₄ , X ₅ , X ₆ , X ₇ , X ₁₀ , R ₁ , R ₂ , R ₃ , R ₈ , R ₁₂ , R ₁₃ , and Y' are as defined in the first aspect .

In another preferred embodiment, the compound of formula VII is the compound shown in formula VII-I;

In another preferred embodiment, the compound of formula VII is a compound represented by formula VIIa-I or its cis-trans isomer;

It should be understood that, within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other, thereby forming new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the inventors have provided novel intermediate compounds of formula III, formula IV and formula V for the first time through a large number of screening and testing, and provided further preparations such as Molnupiravir or Remdesivir before 5'-nucleoside method of medicine. The raw materials of the method of the invention are easy to obtain, the reaction conditions are mild, safe, not harmful to human health and the environment, and the production cost is low. In addition, the invention also has the advantages of high reaction product yield, high purity, less impurities and the like, which is economical and convenient. industrialized production. The intermediates of the present invention (especially the compounds of formula III, the compounds of formula IV and the compounds of formula V) can be used as intermediates to further prepare 5'-nucleoside prodrugs such as Molnupiravir and Remdesivir. The present invention has been completed on this basis.

the term

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 belongs.

As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

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

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "halo" refers to the replacement of one or more hydrogen atoms in a group with a halogen.

Unless otherwise stated, as used herein, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (ie, C1-6 represents 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, and the like.

Unless otherwise stated, as used herein, the term "cycloalkyl" refers to a compound having the specified number of ring atoms (eg, _C3-6 cycloalkyl) and either fully saturated or having no more than one double bond between the ring tips hydrocarbon ring. The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S (preferably, only N heteroatoms). In a specific embodiment, the heterocycloalkyl or heterocyclyl group may be a monocyclic, bicyclic or polycyclic ring system, preferably a monocyclic ring.

Unless otherwise stated, the term "substituted" as used herein means that one or more hydrogen atoms (1, 2, 3 or 4) in a group are replaced with 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.

As used herein,

represents the attachment site.

As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si); preferably nitrogen.

As used herein, "4-dimethylaminopyridine" and "4-N,N-dimethylaminopyridine" are used interchangeably.

Any suitable inert solvent can be used in the process of the present invention. Representative inert solvents include, but are not limited to, pentane, various pentanes, hexanes, various hexanes, heptanes, various heptanes, petroleum ether, cyclopentane, various 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 a combination thereof.

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

In the methods of the present invention, the various steps can provide the target compound or a pharmaceutically acceptable salt thereof in any suitable yield. For example, a compound of interest (eg, Formula II, Formula IV, Formula V, or Remdesivir, etc.) may be present at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or Prepared in at least about 95% yield. The methods of the present invention can provide the target compound or a pharmaceutically acceptable salt thereof in any purity. For example, a compound of interest can be prepared with a purity of at least about 90, 95, 96, 97, 98, or at least about 99%. In some embodiments, the compound of interest can be prepared with a purity of at least 95%. In some embodiments, the compound of interest can be prepared with a purity of at least 98%. In some embodiments, the compound of interest can be prepared with a purity of at least 99%.

In this paper, unless otherwise specified, when the reaction process is described as "directly obtained" or "directly obtained" or "directly formed", etc., it means that in the reaction system, without changing conditions or performing operations such as separation (such as heating, , adding additional reagents or isolating intermediate products, etc.) to directly obtain or form the specified reaction product. However, it should be understood that the reaction process does not exclude the possibility of stable or unstable transition forms in the reaction system, and the transition forms are finally converted to form the designated reaction products.

Intermediate and preparation method for preparing 5'-nucleoside prodrug

In a specific embodiment, the present invention provides compounds of formula III

in,

R ₁ , R ₂ , R ₃ are each independently hydrogen, halogen, C1-C16 alkyl, C1-C16 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, azide, cyano;

Y is

Wherein, R ₄ and R ₅ are each independently hydrogen, C1-C16 alkyl, and R ₁₂ and R ₁₃ are each independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkene base, halogen, amino, cyano;

In another preferred embodiment, Y is

or the cis-trans isomeric forms of these groups.

In another preferred example, when R ₁ and R ₂ are hydrogen, and R ₃ is hydrogen or cyano, Y is

wherein R ₄ and R ₅ are each independently hydrogen, C1-C16 alkyl, and R ₁₂ is hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, cyano base.

or their cis-trans isomeric forms, wherein R ₄ and R ₅ are each independently hydrogen, C1-C16 alkyl, and R ₁₂ is hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or Substituted alkenyl, halogen, amino, cyano.

In another specific embodiment, the present invention also provides compounds of formula III-I and III-II (intermediate)

In a specific embodiment, the present invention provides compounds of formula IV;

in,

_R8 is

Wherein R ₉ is hydrogen, C1-C16 alkyl, R ₁₀ is C1-C6 alkyl, C3-C7 cyclic alkyl or aryl, wherein, aryl is selected from phenyl or substituted phenyl, naphthyl or substituted Naphthyl; R ₁₁ is C1-C16 alkyl, C1-C16 haloalkyl or C3-C7 cyclic alkyl;

Y is

Wherein, R ₄ and R ₅ are each independently hydrogen, C1-C16 alkyl, and R ₁₂ and R ₁₃ are each independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkene base, halogen, amino, cyano.

In another preferred example, R ₃ is hydrogen or cyano, and R ₈ is

Wherein R ₉ is hydrogen, C1-C16 alkyl, R ₁₀ is C1-C6 alkyl, C3-C7 cyclic alkyl or aryl, wherein, aryl is selected from phenyl or substituted phenyl, naphthyl or substituted Naphthyl; R ₁₁ is C1-C16 alkyl, C1-C16 haloalkyl or C3-C7 cyclic alkyl; Y is

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

In a specific embodiment, the present invention provides a compound of formula V,

in,

_R8 is

Y is

In another preferred embodiment, R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, fluorine, azido, methyl, chloromethyl, fluoromethyl, difluoromethyl, vinyl , alkynyl, cyano;

In another specific embodiment, the present invention provides intermediates of formula V-I and V-II

In a specific embodiment, the present invention provides a method for the preparation of a compound of formula V, the method comprising the steps of:

(a) the compound of formula I reacts with the compound of formula II to generate the compound of formula III;

(b) compound of formula III reacts with reagent M to generate compound of formula IV;

(c) compound of formula IV reacts with reagent N to generate compound of formula V;

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R _{7 ,} R ₈ , M, N, O, X, Y and Z are as defined above;

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

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, eg, 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 I, eg, 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 I.

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

In some embodiments, reagent M can be isobutyric anhydride, isobutyryl chloride, pivaloyl chloride,

The step (b) reaction is carried out in the presence of an alkaline reagent, the alkaline reagent includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N- Diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, organometallic bases; the organometallics include but not Limited to Grignard reagent, preferably selected from methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride; preferably, the base is N,N-dichloride Isopropylethylamine, 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.

The reaction in step (b) can also be carried out in the presence of an alkaline reagent and a Lewis acid, wherein the alkaline reagent includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine , imidazole, N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, organometallic bases; all Described organometallic bases include but are not limited to Grignard reagents, preferably from methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride; the Lewis Acids include but are not limited to magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride; preferably, the alkaline reagent is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, tert-butylmagnesium chloride, used in random combination with magnesium chloride or lithium chloride. The base is present in an amount of at least 1.0 equivalent (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.

In step (c) above: any suitable reagent N can be used in the process for the preparation of compounds of formula V. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride, methanol, ethanol, propanol. In another preferred embodiment, the compounds obtained in steps (a), (b) and (c) can be separated and reused separately, or steps (a), (b) and (c) are carried out by a "one-pot method" .

In a specific embodiment, the present invention also provides a preparation method of a compound of formula V-I, the method comprising the following steps:

(a1) The compound of formula I-I reacts with the compound of reagent II to generate the compound of formula III-I

(b1) compound of formula III-I reacts with reagent M to generate compound of formula IV-I;

(c1) compound of formula IV-I reacts with reagent N to generate compound of formula V-I;

Wherein, R ₄ and R ₅ are methyl groups, and R ₆ and R ₇ are each independently hydrogen or C1-C16 alkyl;

In the above step (a1): any suitable compound of formula II can be used in the process for the preparation of compounds of formula III-I. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethylacetal, N,N-dimethylformamide diethylacetal, N,N-dimethylformamide diethylacetal isopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

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-I, eg, 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 I-I, eg, 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 I-I.

In step (b1) above: any suitable reagent M can be used in the process for the preparation of compounds of formula IV-I. Exemplary reagent M includes, but is not limited to, isobutyric anhydride, isobutyric acid, isobutyryl chloride; in some embodiments, reagent M may be isobutyric anhydride.

The reaction in step (b1) is carried out in the presence of an alkaline reagent, which includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N- One or more of diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. 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.

In step (c1) above: any suitable reagent N can be used in the process for the preparation of compounds of formula V-I. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride, methanol, ethanol, propanol. In another preferred embodiment, the compounds obtained in steps (a1), (b1) and (c1) can be separated and used separately, or steps (a1), (b1) and (c1) are carried out by a "one-pot method" .

In a specific embodiment of the present invention, the present invention also provides a preparation method of a compound of formula V-II, the method comprising the following steps:

In the above step (a2): any suitable compound of formula II can be used in the process for the preparation of compounds of formula III-II. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethylacetal, N,N-dimethylformamide diethylacetal, N,N-dimethylformamide diethylacetal isopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

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-II, eg, about 2.0, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol/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 I-II, eg, 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 I-II.

In step (b2) above: any suitable reagent M can be used in the process for the preparation of compounds of formula IV-II. Exemplary reagents M include, but are not limited to

In some embodiments, reagent M can be

The reaction in step (b2) is carried out in the presence of an organometallic base, and the organometallic base includes but is not limited to a Grignard reagent; preferably, the Grignard reagent is selected from methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl One or more of magnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride and ethylmagnesium chloride; more preferably, the organometallic base is methylmagnesium 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.

The step (b) reaction can also be carried out in the presence of a basic reagent including an organic base or an organic metal base and a Lewis acid. In another preferred example, the organic base includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N-diethylaniline, pyridine, One or more of 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, and/or the organometallic including but not Limited to Grignard reagent, 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 described Lewis acid including but not limited to magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride One or more; preferably, the alkaline reagent is N,N-diisopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, 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 equivalent (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.

In step (c2) above: any suitable reagent N can be used in the process for the preparation of compounds of formula V-II. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride, methanol, ethanol, propanol.

In another preferred embodiment, the compounds obtained in steps (a2), (b2) and (c2) can be separated and reused separately, or steps (a2), (b2) and (c2) are carried out by a "one-pot method" .

In a specific embodiment, the present invention provides the preparation method of formula VI compound, comprises the steps:

(d) compound of formula V reacts with reagent O to generate compound of formula VI,

Wherein, the definitions of R ₁ , R ₂ , R ₃ , R ₈ , Y and Z are the same as above;

In step (d) above: any suitable reagent O can be used in the process for the preparation of compounds of formula VI. Exemplary reagents O include, but are not limited to, hydroxylamine or salts thereof, organic acids, inorganic acids, hydrazine hydrate.

Reagent O can be present in any suitable amount. For example, the Reagent O compound may be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of Formula V, eg, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents (mol/mol) mol). Reagent O may also be present in an amount of about 2.0 to about 30.0 (eg, about 2.0 to about 20.0) equivalents (mol/mol) relative to the compound of formula V.

Preferably, the preparation method of the compound of formula VI of the present invention comprises the steps:

(d) compound of formula V reacts with reagent O to generate compound of formula VI;

various,

R ₄ , R ₅ , R ₆ , R ₇ are each independently hydrogen, C1-C16 alkyl;

X is

Wherein, R ₁₂ and R ₁₃ are each independently hydrogen, deuterium, C1-C16 alkyl or substituted alkyl, C1-C16 alkenyl or substituted alkenyl, halogen, amino, cyano;

Y is

Z is

Reagent M is carboxylic acid anhydride

carboxylic acid

Acid chloride

Phosphoramide reagent

Wherein, R ₁₄ benzenesulfonate group, substituted phenoxy group;

_R8 is

Reagent N is protic solvent; C1-C6 alkyl alcohol, water, salt solution of water;

Reagent O is hydroxylamine or its salt, organic acid, inorganic acid or hydrazine hydrate;

wherein "substituted" means that one or more hydrogen atoms (2, 3 or 4) in the group are substituted with a substituent selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkyne base, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl.

In step (b) above: any suitable reagent M can be used in the process for the preparation of compounds of formula IV. Exemplary reagents M include, but are not limited to, isobutyric anhydride, isobutyric acid, isobutyryl chloride, pivaloyl chloride,

The step (b) reaction can also be carried out in the presence of an alkaline reagent and a Lewis acid, the alkaline reagent includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole , N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, organometallic bases; the Organometallics include but are not limited to Grignard reagents, preferably selected from methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride; the Lewis acid includes but Not limited to magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride; preferably, the alkali is N,N-di Isopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, 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 equivalent (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.

In step (c) above: any suitable reagent N can be used in the process for the preparation of compounds of formula V. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride, methanol, ethanol, propanol.

In step (d) above: any suitable reagent O can be used in the process for the preparation of compounds of formula VI. Exemplary reagents O include, but are not limited to, hydroxylamine or its salts, organic acids, inorganic acids, hydrazine hydrate.

Reagent O can be present in any suitable amount. For example, the Reagent O compound may be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of Formula V, eg, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents (mol/mol) mol). Reagent O may also be present in an amount of about 2.0 to about 20.0 equivalents (mol/mol) relative to the compound of formula I. In some embodiments, the compound of formula II may be present in an amount of about 2.0 to about 20.0 equivalents (mol/mol) relative to the compound of formula I mol) is present.

In another preferred embodiment, the compounds obtained in steps (a), (b) and (c) can be separated and reused separately, or steps (a), (b) and (c) are carried out by a "one-pot method" .

In another preferred embodiment, steps (a), (b), (c) and (d) are carried out by a "one-pot method".

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

(d1) V-I reacts with reagent O to form VI-I

In the above steps: Any suitable reagent O can be used in the process for the preparation of compounds of formula VI-I. Exemplary reagent O includes, but is not limited to, hydroxylamine, aqueous hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate.

Reagent O can be present in any suitable amount. For example, the Reagent O compound may be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of formula V-I, eg, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol/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 V-I. 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-I mol) is present.

In a specific embodiment, the invention provides a preparation method of VI-I, comprising the steps:

(d1) The compound of formula V-I reacts with reagent O to generate the compound of formula VI-I

The reaction in step (b1) is carried out in the presence of an alkaline reagent, which includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole, N,N- Diethylaniline, pyridine, 2,6-lutidine, 2,4,6-colidine, 4-dimethylaminopyridine, quinuclidine. 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.

In step (c1) above: any suitable reagent N can be used in the process for the preparation of compounds of formula V-I. Exemplary reagent N includes, but is not limited to, water, aqueous ammonium chloride, methanol, ethanol, propanol.

In step (d1) above: any suitable reagent O can be used in the process for the preparation of compounds of formula VI-I. Exemplary reagents O include, but are not limited to, hydroxylamine, aqueous hydroxylamine, hydroxylamine hydrochloride, hydroxylamine sulfate.

Reagent O can be present in any suitable amount. For example, the Reagent O compound may be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of formula V-I, eg, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 10.0 equivalents (mol/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 V-I. 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 mol) is present.

In another preferred embodiment, the compounds obtained in steps (a1), (b1) and (c1) can be separated and used separately, or steps (a1), (b1) and (c1) are carried out by a "one-pot method" .

In another preferred embodiment, steps (a1), (b1), (c1) and (d1) are carried out in a "one-pot method".

In one embodiment, the present invention provides a preparation method of VI-II, comprising the steps of

(d2) V-II reacts with reagent O to form VI-II

In the above steps: Any suitable reagent O can be used in the process for the preparation of compounds of formula VI-II. Exemplary reagents O include, but are not limited to, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, hydrazine hydrate, or solutions thereof.

Reagent O can be present in any suitable amount. For example, the Reagent O compound may be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of Formula V-II, eg, 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.

In one embodiment, the invention provides a preparation method of VI-II, comprising the steps:

Wherein, R ₄ , R ₅ are methyl, R ₆ , R ₇ are each independently hydrogen, C1-C16 alkyl; in the above step (a2): any suitable compound of formula II can be used in the preparation of formula III-II compound method. Exemplary compounds of formula II include, but are not limited to, N,N-dimethylformamide dimethylacetal, N,N-dimethylformamide diethylacetal, N,N-dimethylformamide diethylacetal isopropyl acetal. In some embodiments, the compound of formula II may be N,N-dimethylformamide dimethyl acetal.

In some embodiments, reagent M can be

The reaction in step (b2) is carried out in the presence of an organic metal base, and the organic metal includes but is not limited to a Grignard reagent, preferably selected from methyl magnesium bromide, tert-butyl magnesium chloride, tert-butyl magnesium bromide, isopropyl magnesium chloride , methylmagnesium chloride, ethylmagnesium chloride; preferably, the organometallic base is methylmagnesium 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.

The reaction in step (b2) can also be carried out in the presence of an alkaline reagent and a Lewis acid, and the alkaline reagent includes but is not limited to N,N-diisopropylethylamine, triethylamine, diisopropylamine, imidazole , N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinuclidine, organometallic bases; the Organometallics include but are not limited to Grignard reagents, preferably selected from methylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, isopropylmagnesium chloride, methylmagnesium chloride, ethylmagnesium chloride; the Lewis acid includes but Not limited to magnesium chloride, magnesium bromide, magnesium sulfate, magnesium nitrate, lithium chloride, lithium bromide, lithium sulfate, lithium carbonate, lithium nitrate, zinc chloride, aluminum chloride; preferably, the alkali is N,N-di Isopropylethylamine, triethylamine, diisopropylamine, 4-dimethylaminopyridine, 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 equivalent (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.

In step (d2) above: any suitable reagent O can be used in the process for the preparation of compounds of formula VI-II. Exemplary reagents O include, but are not limited to, acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, hydrazine hydrate, or solutions thereof.

Reagent O can be present in any suitable amount. For example, the Reagent O compound can be present in an amount of at least 1.0 equivalents (mol/mol) relative to the compound of Formula V-II, eg, about 1.0, 2, 3, 4, 5, 6, 7, 8, 9, or about 20.0 equivalents ( mol/mol). Reagent O can also be present in an amount relative to the compound of Formula V-II (about 10.0 to about 20.0 equivalents (mol/mol) . In some embodiments, Reagent O can also be present in an amount relative to the compound of Formula V-II (cis-trans containing isomer) is present in an amount of about 10.0 to about 20.0 equivalents (mol/mol).

The main advantages of the present invention include

(a) The yield is high, the deprotection conditions are mild, and the purification is simple, and the compound prepared in the intermediate step can be directly subjected to the subsequent reaction without separation and/or purification (the "one-pot method" can be used).

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

Unless otherwise specified, the raw materials or reagents used in the examples can be obtained commercially or prepared according to conventional knowledge in the art.

Example 1

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

The compound III-I obtained in the previous step was added to dichloromethane (50 mL), and at 25° C., isobutyric anhydride (4.88 g, 30.86 mmol), triethylamine (4.16 g, 41.40 mmol) and 4-N were successively added, N-dimethylaminopyridine (244 mg, 2.00 mmol), reacted for 2 h after the addition, and TLC showed that the raw material had reacted completely. Then ethanol (1.89g, 411.40mmol) was added to the reaction solution, stirred for 2h, the reaction solution was concentrated, then slurried with isopropyl acetate, filtered to obtain compound VI, an off-white solid 6.06g, yield 80%, ¹ H 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),4.22(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,1H),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] ⁺

Example 2

Compound I-I (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 the reaction was refluxed overnight , TLC showed that the raw material had reacted completely, the reaction solution was concentrated and used directly for the next step reaction.

The compound III-I obtained in the previous step was added to dichloromethane (50 mL), and at 25° C., isobutyric anhydride (4.88 g, 30.86 mmol), triethylamine (4.16 g, 41.40 mmol) and 4-N were successively added, N-dimethylaminopyridine (244 mg, 2.00 mmol), reacted for 2 h after the addition, and TLC showed that the raw material had reacted completely. Then ethanol (1.89g, 411.40mmol) was added to the reaction solution, stirred for 2h, the reaction solution was concentrated, then slurried with isopropyl acetate, filtered to obtain compound V-I, off-white solid 6.06g, yield 80%

Example 3

Compound VI (500mg, 1.36mmol) was added to a mixed solution of isopropanol and water (w/w, isopropanol/water=7:3, 7g), then added hydroxylamine sulfate (892mg, 5.44mmol), heated to 80 After 24 hours of reaction time, TLC showed that the raw materials had reacted completely, the reaction was cooled, filtered, concentrated, and column chromatography gave compound VI-I, white solid 380 mg, yield 80%, ¹ H NMR (500 MHz, MeOD) δ 6.94 (d ,J=8.3Hz,1H),5.84(d,J=4.9Hz,1H),5.63(d,J=8.2Hz,1H),4.31(d,J=3.8Hz,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] ^-

Example 4

Compound VI (400mg, 1.09mmol) was added to a mixed solution of isopropanol and water (w/w, isopropanol/water=7:3, 7g), then hydroxylamine sulfate (714mg, 4.35mmol) was added, and the reaction was carried out at room temperature for 24h , TLC showed that the raw material had reacted completely, the reaction was filtered, concentrated, and column chromatography gave compound VII-I, white solid 323 mg, yield 85%, ¹ H NMR (600MHz, DMSO-d ₆ )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] ⁺

Example 5

Compound VI (500mg, 1.36mmol) was added to a mixed solution of isopropanol and water (w/w, isopropanol/water=7:3, 7g), then hydroxylamine sulfate (892mg, 5.44mmol) was added, and the reaction was carried out at room temperature for 24h , TLC showed that the starting material had been completely converted into compound VII-I. Then heated to 80 degrees and reacted for 24h, TLC showed that the compound had reacted completely, the reaction was cooled, filtered, concentrated, and column chromatography gave compound VI-I, white solid 380mg, 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＝3.8Hz,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] ^-

Example 6

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 the reaction was refluxed overnight. TLC the next day showed that the raw materials had reacted completely. The liquid was concentrated to obtain the 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 successively. After about 2 h, TLC The starting material was shown to have reacted completely and ethanol (18.9 g, 412 mmol) was added to quench the reaction, then the reaction was concentrated and stripped once with isopropanol to give the crude product. Hydroxylamine sulfate (13.5g, 82.4mmol) was dissolved in pure water (30g) and added to isopropanol (70g), then the crude product obtained in the previous step was heated to 78 degrees and reacted for 18h, and the heating was stopped and cooled to room temperature. For 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 washed with anhydrous sodium sulfate. Dry, concentrate, and then use isopropyl acetate (50 mL) to obtain compound VI-1 as a white solid (4.8 g, total yield 70%).

Example 7

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 the reaction was carried out at 25 °C overnight. TLC showed that the raw materials had reacted completely, The reaction solution was concentrated and used directly for the next reaction.

The III-II and III-3 obtained in the previous step (935 mg, 1.89 mmol) were dissolved in dry tetrahydrofuran (10 mL), cooled to -10°C, and a 3.0 M solution of methylmagnesium bromide in 2-methyltetrahydrofuran was slowly added dropwise. (0.86mL, 2.58mmol), after dripping, react at 0°C for 2h, TLC showed that the raw materials had reacted completely, the reaction solution was added to saturated ammonium chloride (20mL) to quench, extracted with ethyl acetate, and the organic phase was sequentially diluted with dilute hydrochloric acid The solution was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain compound V-II as a foamy solid 847 mg, 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] ⁺

Example 8

The III-II and III-3 (935 mg, 1.89 mmol) obtained in the previous step were dissolved in dry tetrahydrofuran (10 mL), then anhydrous magnesium chloride (246 mg, 2.58 mmol) was added, and the mixture was stirred at 25° C. for 30 minutes, and then N was added dropwise. N-diethylisopropylamine (444mg, 3.44mmol), after the addition, the reaction was carried out at 25°C overnight. TLC showed that the raw materials had reacted completely. The reaction solution was added to 2M hydrochloric acid solution (3mL), 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 as a foamy solid 800 mg, yield 71%.

Example 9

Compound V-II (500 mg, 0.76 mmol) was dissolved in ethanol (5 mL), then acetic acid (912 mg, 15.20 mmol) was added, and the reaction was carried out at 45° C. overnight. The next day TLC showed that the raw materials had reacted completely. The reaction solution was concentrated, and then added Ethyl acetate, then washed with saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain compound VI-II, white solid 343 mg, 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] ⁺

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

A method for preparing a compound of formula VI, characterized in that the method comprises the steps:

(d) reacting the compound of formula V with reagent O to obtain the compound of formula VI;

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

various,

R 1 , R 2 and R 3 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, azido, cyano;

R8 is

R 9 is selected from the group consisting of hydrogen, substituted or unsubstituted C1-C16 alkyl;

R 10 is selected from the group consisting of C1-C6 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aryl;

R 11 is selected from the group consisting of 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;

X 1 is selected from the group consisting of N, CR 12 ;

X 2 is selected from the group consisting of C(=O);

X 3 is selected from the group consisting of C(=O), C(N=CHNR 4 R 5 );

X is selected from the group consisting of N, NH ;

X 5 , X 6 and X 7 are selected from the group consisting of C, N;

X 8 is selected from the group consisting of C(=O), C(NHR 15 );

R 15 is H or OH;

R4 and R5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1 - C16 alkyl; or R4 and R5 and the nitrogen atom to which they are attached together form a substituted or unsubstituted 4- to 7 -membered Saturated heterocyclyl (preferably, the saturated heterocyclyl only contains N heteroatoms attached to R 4 and R 5 );

R 12 and R 13 are each independently hydrogen, deuterium, substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C2-C16 alkenyl, halogen, substituted or unsubstituted amino, cyano;

Unless otherwise specified, the substitution means that one or more hydrogens in the group are replaced by a substituent selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy group, C3-C6 cycloalkyl, halogen, C1-C3 haloalkyl, nitro, C6-C10 aryl, benzyl; wherein, the benzyl, aryl and cycloalkyl can also be optionally replaced by one or A plurality (eg 1, 2 or 3) of substituents selected from the group consisting of substituted halogen, C1-C3 alkyl, C1-C3 haloalkyl.
The method of claim 1, wherein the method further comprises the steps of: the preparation of the compound of formula V; and the preparation of the compound of the formula V comprises 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 reagent M, thereby obtaining the compound of formula IV;

Wherein, reagent M is selected from the following group:
(Carboxylic acid reagent),
(acid anhydride reagent),
(Acyl chloride reagent), or
(phosphoramide reagent);

(c) in the presence of reagent N, the compound of formula IV is reacted to obtain the compound of formula V;

Wherein, the reagent N is a protic solvent; preferably, the reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof;

various,

X is

or

R 6 and R 7 are each independently hydrogen or C1-C16 alkyl;

X 9 is C(=O), C(NH 2 );

R 14 is -W 1 -R 16 ; wherein, W 1 is OS(O) 2 or O; R 16 is hydrogen, chlorine, substituted or unsubstituted phenyl (preferably, R 16 is halogenated phenyl, nitro-substituted phenyl); preferably, R 14 is benzenesulfonate (-OS(O) 2 -Ar), substituted phenoxy);

Substitution, X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 12 , R 13 and Y is as defined in claim 1 .
A compound of formula V, characterized in that

R 1 , R 2 , R 3 , R 8 and Y are as defined in claim 1 .
The compound of formula V according to claim 3, wherein the compound of formula V is a compound shown in V-I or a compound shown in formula V-II;
a compound of formula III,

In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and Y are as defined in claim 2 .
a compound of formula IV,

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and Y are as defined in claim 2 .
A method of preparing a compound of formula VI, characterized in that,

Described formula VI compound is formula VI-I compound, and described method comprises the steps:

(d1) reacting the compound of formula V-I with reagent O to obtain the compound of formula VI-I;

Wherein, reagent O is hydroxylamine or its salt; Preferably, it is hydroxylamine sulfate;

or,

The compound of formula VI is the compound of formula VI-II, and the method comprises the steps:

(d2) the compound of formula V-II reacts with reagent O to generate the compound of formula VI-II;

Wherein, the reagent O is selected from the group consisting of organic acid, inorganic acid, hydrazine hydrate, or a combination thereof.
The method of claim 7, wherein:

The method further comprises the steps of: the preparation of the compound of formula V-I; and the preparation of the compound of the formula V-I comprises the steps:

(a1) reacting a compound of formula I-I with a compound of formula II to obtain a compound of formula III-I;

(b1) reacting 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 V-I;

Wherein, the reagent N is a protic solvent; preferably, the reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof ;

In each formula, R 4 and R 5 are methyl; R 6 and R 7 are each independently hydrogen, C1-C16 alkyl;

or,

The method further comprises the steps of: the preparation of the compound of formula V-II; and the preparation of the compound of the formula V-II comprises the steps:

(a2) the compound of formula I-II reacts with the compound of formula II to generate the compound of formula III-II;

(b2) the compound of formula III-II reacts with the reagent M to generate the compound of formula IV-II;

Among them, the reagent M is
or its salt, R 14 is OH, Cl substituted phenoxy, benzene sulfonate group;

(c2) compound of formula IV-II reacts with reagent N to generate compound of formula V-II;

Wherein, the reagent N is a protic solvent; preferably, the reagent N is selected from the following group: C1-C6 alkyl alcohol, water, aqueous solution of salt, organic acid, aqueous solution of organic acid, aqueous solution of inorganic acid, or a combination thereof ;

various,

R 4 and R 5 are methyl; R 6 and R 7 are each independently hydrogen, C1-C16 alkyl.
Use of a compound of formula III-I, compound of formula IV-I or compound of formula V-I, characterized in that it is used to prepare Molnupiravir (EIDD-2801/MK4482).
Use of a compound of formula III-II, compound of formula IV-II or compound of formula V-II, characterized in that it is used to prepare Remdesivir (GS-5734).