Deuterated heterocyclic compounds, their preparation methods and applications

Abstract

This invention provides a method for preparing deuterated heterocyclic compounds. This method introduces deuteration early in the synthetic route of compound A, which helps reduce the conversion steps of expensive raw materials in later stages of the synthesis, significantly reducing the synthesis cost of compound A. Furthermore, it offers high yield, simple process, and readily available raw materials. Based on this, the inventors completed this invention.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing a class of deuterated heterocyclic compounds. Background Technology

[0002] Compound A is a nucleoside analog with excellent antiviral activity, exhibiting superior inhibitory activity against the replication of novel coronavirus, respiratory syncytial virus (RSV), human coronavirus OC43, influenza A virus, Zika virus, porcine epidemic diarrhea virus (PEDV), and dengue virus (DENV).

[0003] Reference [CN112778310] reports a method for preparing compound A, which involves selective iodination of compound B to obtain compound C, followed by ID exchange to obtain compound D, de-Bn removal to obtain compound E, and finally acylation to obtain compound A. However, the conversion from B to D involves: 1) the use of expensive B; 2) the iodination reaction requiring relatively expensive iodine; and 3) the need for expensive palladium catalysts and sodium borodeuteride, or the use of complex metal-I exchange methods with low yields. These problems contribute to the high price of nucleoside analog compound A.

[0004]

[0005] Therefore, there is an urgent need in this field for a preparation method that is simple in steps, has a high yield, uses inexpensive raw materials, and is suitable for industrial production. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing deuterated heterocyclic compounds that is simple in preparation steps, has a high yield, and uses inexpensive raw materials.

[0007] Another object of the present invention is to provide a deuterated heterocyclic compound.

[0008] Another object of the present invention is to provide an application of a deuterated heterocyclic compound in the preparation of nucleoside analogs, said nucleoside analogs for inhibiting viral replication and / or treating diseases related to viral infection.

[0009] In a first aspect of the present invention, a method for preparing deuterated heterocyclic compounds is provided, the method comprising the following steps:

[0010] (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G.

[0011]

[0012] (2) Compound G was deuterated to obtain compound K.

[0013]

[0014] Where X is a halogen, selected from the following group: chlorine, bromine, iodine.

[0015] In another preferred embodiment, in step (1), the first halogenated reagent is selected from the group consisting of N-bromosuccinimide (NBS), N-bromosuccinimide, dibromohydantoin, N-chlorosuccinimide, ICl, elemental iodine, N-iodosuccinimide (NIS), or combinations thereof.

[0016] In another preferred embodiment, step (1) includes one or more features selected from the group consisting of:

[0017] (a) The molar ratio of the first halogenated reagent to compound F is 2-5:1, preferably 2-4:1;

[0018] (b) The first halogenated reagent is added in batches at -5 to 15°C (preferably 0 to 10°C);

[0019] (c) The reaction is carried out at -5 to 50°C (preferably 0-10°C or 20-40°C);

[0020] (d) The reaction time is 6-50 h (preferably 10-40 h);

[0021] (e) The first inert solvent is selected from the group consisting of dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, tetrahydrofuran, or combinations thereof.

[0022] In another preferred embodiment, step (2) further includes amino protection and deprotection steps.

[0023] In another preferred embodiment, the amino protection refers to the substitution of hydrogen in the amino group by a protecting group or the amino group condensing to form an oxime.

[0024] In another preferred embodiment, step (2) includes the following steps:

[0025] (2.1) In a second inert solvent, compound G obtained in step (1) is mixed with the first protecting reagent to carry out an N-protection reaction, yielding compound H.

[0026]

[0027] (2.2) In a third inert solvent, compound H is mixed with the first organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with the first deuterated reagent to undergo a deuteration reaction and optionally a deprotection reaction to obtain compound J.

[0028]

[0029] (2.3) In the fourth inert solvent, compound J was mixed with the first deprotecting agent and completely deprotected to give compound K.

[0030]

[0031] Among them, R 1 From the following group: H, Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; R 2 Selected from the following group: Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; or R 1 R 2 Together with adjacent heteroatoms or carbon atoms, they form a substituted or unsubstituted carbon ring or heterocycle, wherein the heteroatoms are selected from N, O, S, and Si.

[0032] In another preferred embodiment, step (2.1) includes one or more features selected from the group consisting of:

[0033] (a) The first protective reagent is selected from the group consisting of: di-tert-butyl dicarbonate (Boc2O), TMSCl, TMSOTf, CH3OD, CD3OD, heavy water, or a combination thereof, preferably di-tert-butyl dicarbonate;

[0034] (b) The molar ratio of compound G to the first protecting reagent is 1-5:1, preferably 1-3:1;

[0035] (c) The second inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0036] In another preferred embodiment, when the first protecting agent is Boc2O, step (2.1) includes one or more features selected from the group consisting of:

[0037] (a) The reaction is carried out in the presence of a catalyst, wherein the catalyst is a Boc condensation reaction catalyst, preferably DMAP;

[0038] (b) The reaction is carried out in the presence of a base, preferably triethylamine;

[0039] (c) The reaction is carried out at 15-40°C (preferably 20-30°C);

[0040] (d) The reaction time is 18-48h, preferably 24-36h.

[0041] In another preferred embodiment, step (2.1) requires no post-processing or only simple post-processing before proceeding to the next reaction.

[0042] In another preferred embodiment, step (2.2) includes one or more features selected from the group consisting of:

[0043] (a) The first organometallic reagent is selected from the group consisting of n-butyllithium, isobutyllithium, or isopropyl magnesium chloride, or combinations thereof;

[0044] (b) The first deuterated reagent is selected from the group consisting of: deuterated water, CH3OD, CD3OD, or a combination thereof;

[0045] (c) The third inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0046] In another preferred embodiment, R 1 Selected from the following groups: H, Boc protecting group, deuterium atom; R 2 Selected from Boc protecting groups or deuterium atoms.

[0047] In another preferred embodiment, R 1 As an H or Boc protecting group, R 2 It is a Boc protecting group.

[0048] In another preferred embodiment, in step (2.2), the metal-halogen exchange reaction includes one or more features selected from the group consisting of:

[0049] (a) The equivalence ratio of the first organometallic reagent to compound H is 1-3, preferably 2-3;

[0050] (b) The reaction is carried out under a protective atmosphere;

[0051] (c) The reaction is carried out at -40 to 15°C (preferably -40 to -30°C or 5 to 20°C);

[0052] (d) The reaction time is 30-90 minutes;

[0053] (e) The reaction solution does not require treatment and can proceed directly to the next reaction step.

[0054] In another preferred embodiment, in step (2.2), the deuteration reaction includes one or more features selected from the group consisting of:

[0055] (a) The deuteration reaction includes directly adding the first deuteration reagent to the reaction solution obtained in the previous step, reacting, and obtaining compound J;

[0056] (b) The equivalence ratio of the first deuterated reagent to compound H is 2-5, preferably 3-4;

[0057] (c) The reaction time is 5-30 minutes (preferably 10-20 minutes).

[0058] In another preferred embodiment, step (2.2) further includes a pretreatment step of adding a strong base (preferably NaH), then adding a deuterated reagent (preferably deuterated water), evaporating the solvent, and pulping.

[0059] In another preferred embodiment, step (2.3) includes one or more features selected from the group consisting of:

[0060] (a) The first deprotecting agent is selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, or a combination thereof;

[0061] (b) The mass ratio of compound J to the first deprotecting agent is 0.5-2:1;

[0062] (c) The fourth inert solvent is selected from the group consisting of: dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof;

[0063] (d) The deprotection is carried out at 5-40°C (preferably 10-20°C);

[0064] (e) The deprotection time is 10-20 hours.

[0065] In another preferred embodiment, step (2) includes the following steps:

[0066] (2.4) In a fifth inert solvent, compound G obtained in step (1) is mixed with a second protecting agent to perform N-imine protection, yielding compound H'.

[0067]

[0068] (2.5) In a sixth inert solvent, compound H is mixed with a second organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a second deuterating reagent to undergo a deuteration reaction, yielding compound J'.

[0069]

[0070] (2.6) In the seventh inert solvent, compound J' was mixed with the second deprotecting agent and completely deprotected to give compound K.

[0071]

[0072] Among them, R 1 R 2 It is a phenyl group.

[0073] In another preferred embodiment, step (2.4) includes one or more features selected from the group consisting of:

[0074] (a) The second protecting agent is a ketone reagent, preferably benzophenone;

[0075] (b) The molar ratio of compound G to the second protecting agent is 1-5:1, preferably 1-1.5:1;

[0076] (c) The fifth inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof;

[0077] (d) The N-imine protection is carried out under reflux conditions;

[0078] (e) The protection time of the N-imine is 0.5-2h.

[0079] In another preferred embodiment, step (2.4) requires no post-processing or only simple post-processing before proceeding to the next reaction.

[0080] In another preferred embodiment, step (2.5) includes one or more features selected from the group consisting of:

[0081] (a) The second organometallic reagent is selected from the group consisting of n-butyllithium, isobutyllithium, or isopropyl magnesium chloride, or combinations thereof;

[0082] (b) The second deuterated reagent is selected from the group consisting of: deuterated water, CH3OD, CD3OD, or a combination thereof;

[0083] (c) The sixth inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0084] In another preferred embodiment, in step (2.5), the metal-halogen exchange reaction includes one or more features selected from the group consisting of:

[0085] (a) The equivalent ratio of the second organometallic reagent to compound H' is 1-3, preferably 2-3;

[0086] (b) The reaction is carried out under a protective atmosphere;

[0087] (c) The reaction is carried out at -40 to -15°C (preferably -40 to -30°C);

[0088] (d) The reaction time is 30-90 minutes (preferably 40-60 minutes);

[0089] (e) The reaction solution does not require treatment and can proceed directly to the next reaction step.

[0090] In another preferred embodiment, in step (2.5), the deuteration reaction includes one or more features selected from the group consisting of:

[0091] (a) The deuteration reaction includes directly adding a second deuteration reagent to the reaction solution obtained in the previous step, reacting, and obtaining compound J';

[0092] (b) The equivalence ratio of the second deuterated reagent to compound H' is 2-5, preferably 3-4;

[0093] (c) The reaction time is 5-30 minutes (preferably 10-20 minutes).

[0094] In another preferred embodiment, the reaction mixture after step (2.5) is simply separated before proceeding to the next reaction.

[0095] In another preferred embodiment, step (2.6) includes adding a second deprotecting agent to the mother liquor obtained by simple separation after the previous step reaction, and reacting to obtain compound K.

[0096] In another preferred embodiment, step (2.6) includes one or more features selected from the group consisting of:

[0097] (a) The second deprotecting agent is hydroxylamine, preferably added in the form of an aqueous solution of hydroxylamine;

[0098] (b) The molar ratio of compound J' to the first deprotecting agent is 1-3:1;

[0099] (c) The seventh inert solvent is selected from the group consisting of: dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof;

[0100] (d) The deprotection process is carried out at 30-50°C;

[0101] (e) The deprotection time is 1-2 hours.

[0102] In another preferred embodiment, step (2) includes the following steps:

[0103] (2.7) In the presence of acid or base, the compound G obtained in step (1) is mixed with an active metal and a third deuterated reagent to carry out a deuteration reduction reaction to obtain compound K.

[0104]

[0105] In another preferred embodiment, in step (2.7), the acid or base also serves as a third deuterated reagent, which is a deuterated acid or a deuterated base.

[0106] In another preferred embodiment, step (2.7) includes one or more features selected from the group consisting of:

[0107] (a) The active metal is selected from the group consisting of zinc, tin, aluminum, iron, or combinations thereof;

[0108] (b) The acid is selected from the group consisting of CD3COOD, CH3COOD, CF3COOD, DCl, or combinations thereof; the base is selected from the group consisting of NaOD, KOD, or combinations thereof.

[0109] (c) The molar ratio of the compound G to the active metal is 1:15-50;

[0110] (d) The molar ratio of the compound G to the acid is 1:10-30;

[0111] (e) The third deuterated reagent is selected from deuterated water, deuterated methanol, CD3COOD, CH3COOD, CF3COOD, DCl, NaOD, KOD, or a combination thereof.

[0112] In another preferred embodiment, step (2.7) includes one or more features selected from the group consisting of:

[0113] (a) The reaction is carried out under a protective atmosphere;

[0114] (b) The reaction is carried out at 50–100°C (preferably 80°C);

[0115] (c) The reaction time is 10-20 h.

[0116] In another preferred embodiment, step (2) includes the following steps:

[0117] (2.8) In an eighth inert solvent, in the presence of a noble metal catalyst containing Pd or Pt, compound G obtained in step (1) is mixed with a fourth deuterated reagent to carry out a deuteration reduction reaction to obtain compound K.

[0118]

[0119] In another preferred embodiment, step (2.8) includes one or more features selected from the group consisting of:

[0120] (a) The noble metal catalyst is selected from: palladium on carbon, platinum on carbon, platinum dioxide, palladium hydroxide, palladium acetate, palladium chloride, tetraphenylphosphine-based palladium, or combinations thereof;

[0121] (b) The molar ratio of the noble metal catalyst to compound G is 1:10-50;

[0122] (c) The fourth deuterated reagent is selected from: deuterium gas, sodium borodeuteride, deuterated water, deuterated methanol, or a combination thereof.

[0123] In another preferred embodiment, step (2.8) includes one or more features selected from the group consisting of:

[0124] (a) The reaction is carried out under a protective atmosphere (preferably deuterium);

[0125] (b) The reaction is carried out at 30–100°C (preferably 50°C);

[0126] (c) The reaction time is 10-20 h.

[0127] In another preferred embodiment, the method further includes the following steps:

[0128] (3) In the ninth inert solvent, the compound K obtained in step (2) is mixed with the second halogenating reagent to carry out a monohalogenation reaction to obtain compound L.

[0129]

[0130] (4) In the tenth inert solvent, compound L is mixed with the third organometallic reagent to carry out a metal-halogen exchange reaction, and then mixed with a proton-containing reagent to carry out a protonation reaction to obtain compound K1.

[0131]

[0132] (5) In the eleventh inert solvent, compound K1 was mixed with the Boc protecting reagent to carry out the Boc protection reaction, yielding compound J2.

[0133]

[0134] Wherein, Y is a halogen, selected from the following group: chlorine, bromine, iodine.

[0135] In another preferred embodiment, in step (3), the second halogenated reagent is selected from the group consisting of N-bromosuccinimide, N-bromosuccinimide, dibromohydantoin, N-chlorosuccinimide, ICl, elemental iodine, N-iodosuccinimide, or combinations thereof.

[0136] In another preferred embodiment, step (3) includes one or more of the following features:

[0137] (a) The equivalence ratio of the second halogenated reagent to compound K is 1-1.3:1, preferably 1-1.15:1;

[0138] (b) The reaction is carried out at -10 to 10°C (preferably -5 to 5°C or 0 to 10°C);

[0139] (c) The reaction time of the above reaction is 2-20 h;

[0140] (d) The ninth inert solvent is selected from the group consisting of N,N-dimethylformamide, dichloromethane, tetrahydrofuran, acetone, acetonitrile, or combinations thereof.

[0141] In another preferred embodiment, step (4) includes one or more features selected from the group consisting of:

[0142] (a) The third organometallic reagent is selected from the group consisting of n-butyllithium, isobutyllithium, or isopropyl magnesium chloride, or combinations thereof;

[0143] (b) The proton-containing reagent is selected from the group consisting of water, methanol, ethanol, or combinations thereof;

[0144] (c) The tenth inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0145] In another preferred embodiment, in step (4), the metal-halogen exchange reaction includes one or more features selected from the group consisting of:

[0146] (a) The equivalent ratio of the third organometallic reagent to compound L is 1-3;

[0147] (b) The reaction is carried out under a protective atmosphere;

[0148] (c) The reaction is carried out at -40 to -10°C (preferably -40 to -30°C);

[0149] (d) The reaction time of the above reaction is 10-60 minutes;

[0150] (e) The reaction solution does not require treatment and can proceed directly to the next reaction step.

[0151] In another preferred embodiment, in step (4), the protonation reaction includes one or more features selected from the group consisting of:

[0152] (a) The protonation reaction includes directly adding a proton-containing reagent to the reaction solution obtained in the previous step, reacting, and obtaining compound K1;

[0153] (b) The equivalence ratio of the proton-containing reagent to compound K1 is 2-5, preferably 3-4;

[0154] (c) The reaction time is 5-30 minutes (preferably 10-20 minutes).

[0155] In another preferred embodiment, step (5) includes one or more features selected from the group consisting of:

[0156] (a) The Boc protecting agent is Boc2O;

[0157] (b) The mass ratio of compound K1 to the Boc protecting agent is 3-6:1;

[0158] (c) The reaction is carried out in the presence of a catalyst, wherein the catalyst is a Boc condensation reaction catalyst, preferably DMAP;

[0159] (d) The reaction is carried out in the presence of a base, preferably triethylamine.

[0160] In another preferred embodiment, step (5) includes one or more features selected from the group consisting of:

[0161] (a) The reaction is carried out under a protective atmosphere;

[0162] (b) The reaction is carried out at 15-40°C;

[0163] (c) The reaction time is 2-6 hours, preferably 3-4 hours;

[0164] (d) The eleventh inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0165] In another preferred embodiment, step (5) further includes adding an alkali (preferably NaOH) and continuing the reaction (preferably at 50-60°C for 3-5 hours).

[0166] In a second aspect of the invention, a method for preparing compound M is provided, the method comprising the following steps:

[0167] (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G.

[0168]

[0169] (2) Compound G was deuterated to obtain compound K.

[0170]

[0171] (3) In the ninth inert solvent, the compound K obtained in step (2) is mixed with the second halogenating reagent to carry out a monohalogenation reaction to obtain compound L.

[0172]

[0173] (6) In the twelfth inert solvent, compound L was mixed with the Boc protecting reagent to carry out the Boc protection reaction, yielding compound M.

[0174]

[0175] Among them, X and Y are halogens, each independently selected from the following group: chlorine, bromine, and iodine.

[0176] In another preferred embodiment, steps (1), (2), and (3) are each independently as described in the first aspect of the invention.

[0177] In another preferred embodiment, in step (6), the Boc protecting agent is Boc2O.

[0178] In another preferred embodiment, step (6) includes one or more features selected from the group consisting of:

[0179] (a) The reaction is carried out in the presence of a catalyst, preferably DMAP / triethylamine;

[0180] (b) The molar ratio of the Boc protecting agent to compound L is 2-5:1, preferably 2.5:1;

[0181] (c) The reaction is carried out at 15-40°C;

[0182] (d) The reaction time is 1-6 hours;

[0183] (e) The reaction is carried out under a protective atmosphere;

[0184] (f) The twelfth inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0185] In another preferred embodiment, step (6) further includes a process of adding an alkali (preferably NaOH) to treat the reaction.

[0186] In a third aspect of the invention, a method for preparing compound M is provided, the method comprising the following steps:

[0187] (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G.

[0188]

[0189] (2.1a) In a second inert solvent, compound G obtained in step (1) is mixed with a Boc protecting agent to carry out a Boc protection reaction, yielding compound H”.

[0190]

[0191] (2.2a) In a third inert solvent, compound H” is mixed with a first organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a first deuterated reagent to undergo a deuteration reaction and optionally a deprotection reaction to give compound J1.

[0192]

[0193] (7) Compound J1 was mixed with the third halogenating agent in the thirteenth inert solvent and subjected to a monohalogenation reaction to obtain compound M.

[0194]

[0195] In the above formulas, X and Y are each independently a halogen, selected from chlorine, bromine, and iodine;

[0196] R1a and R2a are each independently H or Boc, where R1a and R2a are not both H at the same time.

[0197] In another preferred embodiment, step (1) is as described in the first aspect of the invention.

[0198] In another preferred embodiment, step (2.1a) includes one or more features selected from the group consisting of:

[0199] (a) The Boc protecting agent is Boc2O;

[0200] (b) The molar ratio of the Boc protecting agent to compound G is 1-2:1;

[0201] (c) The second inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0202] In another preferred embodiment, step (2.1a) includes one or more features selected from the group consisting of:

[0203] (a) The reaction is carried out in the presence of a catalyst, wherein the catalyst is a Boc condensation reaction catalyst, preferably DMAP;

[0204] (b) The reaction is carried out in the presence of a base, preferably triethylamine;

[0205] (c) The reaction is carried out at 15-40°C (preferably 20-30°C);

[0206] (d) The reaction time is 18-48h, preferably 24-36h.

[0207] In another preferred embodiment, step (2.2a) includes one or more features selected from the group consisting of:

[0208] (a) The first organometallic reagent is selected from the group consisting of n-butyllithium, isobutyllithium, or isopropyl magnesium chloride, or combinations thereof;

[0209] (b) The first deuterated reagent is selected from the group consisting of: deuterated water, CH3OD, CD3OD, or a combination thereof;

[0210] (c) The third inert solvent is selected from the group consisting of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0211] In another preferred embodiment, in step (2.2a), the metal-halogen exchange reaction includes one or more features selected from the group consisting of:

[0212] (a) The equivalence ratio of the first organometallic reagent to compound H is 1-3, preferably 2-3;

[0213] (b) The reaction is carried out under a protective atmosphere;

[0214] (c) The reaction is carried out at -40 to 15°C (preferably -40 to -30°C or 5 to 20°C);

[0215] (d) The reaction time is 30-90 minutes;

[0216] (e) The reaction solution does not require treatment and can proceed directly to the next reaction step.

[0217] In another preferred embodiment, in step (2.2a), the deuteration reaction includes one or more features selected from the group consisting of:

[0218] (a) The deuteration reaction includes directly adding the first deuteration reagent to the reaction solution obtained in the previous step, reacting, and obtaining compound J;

[0219] (b) The equivalence ratio of the first deuterated reagent to compound H is 2-5, preferably 3-4;

[0220] (c) The reaction time is 5-30 minutes (preferably 10-20 minutes).

[0221] In another preferred embodiment, step (7) includes one or more features selected from the group consisting of:

[0222] (a) The molar ratio of the third halogenated reagent to compound J1 is 1-1.3:1, preferably 1-1.15:1;

[0223] (b) The third halogenated reagent is selected from the group consisting of: N-bromosuccinimide, N-bromosuccinimide, dibromohydantoin, N-chlorosuccinimide, ICl, elemental iodine, N-iodosuccinimide, or combinations thereof;

[0224] (c) The third halogenated reagent is added in batches;

[0225] (d) The reaction is carried out at -5 to 20°C (preferably 0 to 10°C);

[0226] (e) The reaction time is 10-20 h (preferably 14 h);

[0227] (f) The thirteenth inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetone, acetonitrile, or combinations thereof.

[0228] In a fourth aspect of the invention, a nucleoside analog intermediate, or a stereoisomer thereof, is provided, the intermediate having a structure as shown in Formula I or Formula II:

[0229]

[0230] in,

[0231] Z1 is selected from D, F, Cl, Br, or I;

[0232] Z2 is selected from H, D, F, Cl, Br, or I;

[0233] R 3 R 4 Each is independently selected from H and Boc;

[0234] R 5 Selected from H, Boc;

[0235] R 6 Selected from OH and CN.

[0236] In another preferred embodiment, the intermediate includes compound K, compound K1, compound L, compound M, or compound J1.

[0237] In another preferred embodiment, the intermediate is selected from the group consisting of:

[0238]

[0239]

[0240] In a fifth aspect of the invention, the use of a nucleoside analog intermediate or a stereoisomer thereof as described in the fourth aspect of the invention is provided for the preparation of (1) compound A; or (2) an intermediate for the preparation of compound A.

[0241] In a sixth aspect of the invention, a method for preparing compound A is provided, the method being carried out using a compound of formula I or formula II as a raw material or intermediate.

[0242] In a seventh aspect of the invention, a method for preparing compound A is provided, wherein one or more of compounds K, L, M, K1, and J2 are used as intermediates or raw materials in the preparation process.

[0243] In another preferred embodiment, the method includes the steps of preparing compound K as described in the first aspect of the present invention, or the steps of preparing compound L as described in the first aspect of the present invention, or the steps of preparing compound M as described in the second aspect of the present invention, or the steps of preparing compound K1 as described in the first aspect of the present invention, or the steps of preparing compound J2 as described in the first aspect of the present invention.

[0244] In another preferred embodiment, the method includes steps (1)-(2) of preparing compound K as described in the first aspect of the present invention, or steps (1)-(4) of preparing compound K1 as described in the first aspect of the present invention, or steps (1)-(5) of preparing compound J2 as described in the first aspect of the present invention.

[0245] In another preferred embodiment, the method includes the steps for preparing compound L as described in the second aspect of the present invention, or the steps for preparing compound M as described in the second aspect of the present invention.

[0246] In another preferred embodiment, the method includes steps (1)-(3) of preparing compound L as described in the first aspect of the present invention, or steps (1)-(3) and (6) of preparing compound M as described in the second aspect of the present invention.

[0247] In another preferred embodiment, the method includes the steps for preparing compound M as described in the third aspect of the invention.

[0248] In another preferred embodiment, the method includes steps (1), (2.1a), (2.2a), and (7) for preparing compound M as described in the third aspect of the present invention.

[0249] In another preferred embodiment, the method further includes: when R 1 For H, R 2 When the compound is Boc, starting with compound J1 or compound J2, compound D or E is synthesized using a similar method reported in literature [CN202010095099], and finally compound A is obtained.

[0250]

[0251] In another preferred embodiment, the method further includes: starting from compound K or compound K1, synthesizing compound D using a similar method reported in document [CN2020109353131], and finally obtaining compound A.

[0252]

[0253] In another preferred embodiment, the method further includes: starting from compound L, synthesizing compound D using a similar method reported in the literature DOI: 10.1021 / acs.oprd.0c00370, and finally obtaining compound A.

[0254]

[0255] In another preferred embodiment, the method further includes: starting from compound M, through N1 and O1, compound D can be synthesized, ultimately yielding compound A.

[0256]

[0257] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0258] Through extensive and in-depth research, the inventors unexpectedly discovered a method for preparing deuterated heterocyclic compounds. This method introduces deuteration in the early stages of the synthetic route of compound A, which helps to reduce the conversion steps of expensive raw materials in the later stages of the synthetic route, significantly reducing the synthesis cost of compound A. Furthermore, it offers high yield, simple process, and readily available raw materials. Based on this, the inventors completed this invention.

[0259] the term

[0260] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0261] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.

[0262] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0263] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0264] As used herein, the terms “multiple” or “more than” refer to two or more species, such as 2, 3, 4, 5 or 6 species.

[0265] As used in this article, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0266] The method of the present invention

[0267] This invention provides a method for preparing nucleoside compound intermediates.

[0268] The cheaper compound F is selectively dihalogenated to obtain G, then N-protected or temporarily protected to obtain compound H, then halogen-D exchanged to obtain compound I, then deprotected to obtain compound J or K, then selectively halogenated to obtain compound L, and the compound can be further protected to obtain M.

[0269]

[0270] Specifically, reacting compound F with a brominating agent yields compound G1, wherein the brominating agent includes, but is not limited to, N-bromosuccinimide and dibromohydantoin.

[0271] Compound G1 was temporarily protected with a silane reagent, followed by metal-Br exchange with an organometallic reagent, and then a deuterated reagent was added and post-treated to obtain compound K. The silane reagent included, but was not limited to, TMSCl and TMSOTf; the organometallic reagent included, but was not limited to, isopropylmagnesium chloride and butyllithium; and the deuterated reagent included, but was not limited to, heavy water, CH3OD, and CD3OD.

[0272] Reacting compound K with an iodinated reagent yields compound L1, wherein the iodinated reagent includes, but is not limited to, elemental iodine and N-iodosuccinimide; or reacting compound K with a brominated reagent yields compound L2, wherein the brominated reagent includes, but is not limited to, N-bromosuccinimide; or reacting compound K with a chlorinated reagent yields compound L3, wherein the brominated reagent includes, but is not limited to, N-chlorosuccinimide and ICl.

[0273] Furthermore, L1, L2, or L3 can be reacted with Boc2O to obtain compounds M1, M2, or M3, respectively.

[0274]

[0275] In another approach, compound G1 can be temporarily protected with a silane reagent, followed by metal-Br exchange with an organometallic reagent, and then post-treated with a deuterating reagent to obtain compound K. The silane reagent includes, but is not limited to, TMSCl and TMSOTf; the organometallic reagent includes, but is not limited to, isopropylmagnesium chloride and butyllithium; and the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0276]

[0277] In another approach, compound G1 can be temporarily protected with a silane reagent, followed by metal-Br exchange with an organometallic reagent, and then post-treated with a deuterating reagent to obtain compound K. The organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0278]

[0279] In another approach, compound G1 can be N-Boc protected to obtain compound H4. Then, metal-Br exchange is performed using an organometallic reagent, followed by the addition of a deuterating agent to obtain compound J1, which is then deprotected to obtain compound K. The organometallic reagents include, but are not limited to, isopropyl magnesium chloride and butyllithium; the deuterating agents include, but are not limited to, heavy water, CH3OD, and CD3OD.

[0280]

[0281] In another approach, compound G1 can be N-Boc protected to obtain compound H4a. Then, metal-Br exchange is performed using an organometallic reagent, followed by the addition of a deuterating agent to obtain compound J1a. Deprotection then yields compound K or J1. The organometallic reagents include, but are not limited to, isopropyl magnesium chloride and butyllithium; the deuterating agents include, but are not limited to, heavy water, CH3OD, and CD3OD.

[0282]

[0283] In another approach, compound G1 can be protected with an N-imine by a ketone reagent. Then, a metal-Br exchange reaction is performed using an organometallic reagent, followed by the addition of a deuterating reagent to obtain compound J2, which is then hydrolyzed to give compound K. The ketone reagent includes, but is not limited to, benzophenone; the organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; and the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0284]

[0285] In another approach, compound G1 can be exchanged with a deuterating reagent to obtain H6, which is then temporarily protected with a silane reagent and subjected to metal-Br exchange with an organometallic reagent. Further deuteration and post-treatment yield compound K. The silane reagent includes, but is not limited to, TMSCl and TMSOTf; the organometallic reagent includes, but is not limited to, isopropylmagnesium chloride and butyllithium; and the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0286]

[0287] In another approach, compound G1 can be exchanged with a deuterating reagent to obtain H6, followed by direct metal-Br exchange with an organometallic reagent, then the addition of a deuterating reagent and post-treatment to obtain compound K. The organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0288]

[0289] In another approach, compound G1 can be reduced with an active metal and a deuterated reagent in the presence of an acid or a base, and then post-treated to obtain K. The active metal includes, but is not limited to, zinc, tin, aluminum, and iron; the deuterated reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD; the acid includes, but is not limited to, CD3COOD, CH3COOD, CF3COOD, and DCl; and the base includes, but is not limited to, NaOD and KOD.

[0290]

[0291] In another approach, compound G1 can be reduced with a hydrogenation catalyst and a deuterated reagent, and then post-treated to obtain K, wherein the hydrogenation catalyst includes, but is not limited to, palladium on carbon, palladium hydroxide, and platinum on carbon; and the deuterated reagent includes, but is not limited to, deuterium gas and sodium borodeuteride.

[0292] In another approach, referring to the method in reference [DOI:10.1139 / v01-156], compound G1 can be coupled with a transition metal catalyst and a deuterated reagent, and then post-treated to obtain K. The hydrogenation catalyst includes, but is not limited to, tetraphenylphosphine-based palladium, palladium chloride, palladium acetate, and platinum dioxide; the deuterated reagent includes, but is not limited to, heavy water, CH3OD, CD3OD, and sodium borodeuteride.

[0293] Similarly, reacting compound F with an iodination reagent yields compound G2, wherein the iodination reagent includes, but is not limited to, elemental iodine and N-iodosuccinimide. Reacting compound F with a chlorination reagent yields compound G3, wherein the chlorination reagent includes, but is not limited to, N-chlorosuccinimide and ICl.

[0294]

[0295] The above deuteration reaction can also be carried out similarly starting from compounds G2 or G3.

[0296] In one approach, compound G2 can be temporarily protected with a silane reagent, followed by metal-I exchange with an organometallic reagent, and then post-treated with a deuterating reagent to obtain compound K. The silane reagent includes, but is not limited to, TMSCl and TMSOTf; the organometallic reagent includes, but is not limited to, isopropylmagnesium chloride and butyllithium; and the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0297]

[0298] In another approach, compound G2 can be N-Boc protected to obtain compound H9. Then, metal-I exchange is performed using an organometallic reagent, followed by the addition of a deuterating agent to obtain compound J1, which is then deprotected to obtain compound K. The organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; the deuterating agent includes, but is not limited to, heavy water, CH3OD, and CD3OD. J1 can also react with a halogenating agent to generate structure M, where the halogenating agent includes, but is not limited to, N-halosuccinimide, ICl, and iodine; and X is Cl, Br, or I.

[0299]

[0300] In another approach, compound G2 can be N-Boc protected to obtain compound H9a. Then, metal-I exchange is performed using an organometallic reagent, followed by the addition of a deuterating agent to obtain compound J1a. Deprotection then yields compound K or J1. The organometallic reagents include, but are not limited to, isopropyl magnesium chloride and butyllithium; the deuterating agents include, but are not limited to, heavy water, CH3OD, and CD3OD.

[0301]

[0302] In another approach, compound G2 can be protected with an N-imine by a ketone reagent. Then, a metal-I exchange is performed using an organometallic reagent, followed by the addition of a deuterating agent to obtain compound J2, which is then hydrolyzed to give compound K. The ketone reagent includes, but is not limited to, benzophenone; the organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; and the deuterating agent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0303]

[0304] In another approach, compound G2 can be exchanged with a deuterating reagent to obtain H11, which is then temporarily protected with a silane reagent and subjected to metal-I exchange with an organometallic reagent. After adding a deuterating reagent and post-treatment, compound K is obtained. The silane reagent includes, but is not limited to, TMSCl and TMSOTf; the organometallic reagent includes, but is not limited to, isopropylmagnesium chloride and butyllithium; and the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0305]

[0306] In another approach, compound G2 can be exchanged with a deuterating reagent to obtain H11, followed by direct metal-Br exchange with an organometallic reagent, then the addition of a deuterating reagent and post-treatment to obtain compound K. The organometallic reagent includes, but is not limited to, isopropyl magnesium chloride and butyllithium; the deuterating reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD.

[0307]

[0308] In another approach, compound G2 can be reduced with an active metal and a deuterated reagent in the presence of an acid or a base, and then post-treated to obtain K. The active metal includes, but is not limited to, zinc, tin, aluminum, and iron; the deuterated reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD; the acid includes, but is not limited to, CD3COOD, CH3COOD, CF3COOD, and DCl; and the base includes, but is not limited to, NaOD and KOD.

[0309]

[0310] In another approach, compound G3 can be reduced with an active metal and a deuterated reagent in the presence of an acid or a base, and then post-treated to obtain K. The active metal includes, but is not limited to, zinc, tin, aluminum, and iron; the deuterated reagent includes, but is not limited to, heavy water, CH3OD, and CD3OD; the acid includes, but is not limited to, CD3COOD, CH3COOD, CF3COOD, and DCl; and the base includes, but is not limited to, NaOD and KOD.

[0311]

[0312] Furthermore, from compound J1, compounds D or E can be synthesized using a similar method reported in document [CN202010095099], ultimately yielding A.

[0313]

[0314] Starting from compound K, compound D can also be synthesized using a similar method reported in literature [CN2020109353131], ultimately yielding A.

[0315]

[0316] Starting from compound L, compound D can be synthesized using a similar method reported in the literature [DOI: 10.1021 / acs.oprd.0c00370, 10.1021 / acs.oprd.0c00310, 10.1021 / acs.oprd.1c00024, and citations thereof], ultimately yielding A.

[0317]

[0318] Starting from compound M, compound D can be synthesized via N1 and O1, ultimately yielding A.

[0319]

[0320] The present invention has the following technical advantages:

[0321] (a) The method of the present invention introduces deuterium substitution in the early stage of the synthetic route of the target compound, and puts the deuteration reaction forward, which helps to reduce the conversion steps of expensive raw materials in the later stage of the synthetic route, improve the yield in the later stage, and significantly reduce the synthesis cost of A.

[0322] (b) The method of the present invention can eliminate the potential metal residue problem caused by the use of heavy metals in the later stages of the route.

[0323] (c) The method of the present invention has a high yield, is easy to operate, and is suitable for industrial production.

[0324] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0325] The method of the present invention is shown in the following formula:

[0326]

[0327] The cheaper compound F is selectively dihalogenated to obtain G, then N-protected or temporarily protected to obtain compound H, then halogen-D exchanged to obtain compound I, then deprotected to obtain compound J or K, then selectively halogenated to obtain compound L, and the compound can be further protected to obtain M.

[0328] Example 1: Preparation of compound G from compound F

[0329] Example 1.1 Preparation of compound G1 from compound F

[0330]

[0331] F (300g) was suspended in dichloromethane (8016g). The starting material NBS (875.7g) was added in batches at approximately 0°C to 10°C. The reaction was carried out for 14 hours at approximately 0°C to 10°C. The reaction was monitored by HPLC until completion. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was then added to 1500g of Na2SO3 aqueous solution (3%), stirred for 1-2 hours, filtered, and the filter cake was added to 1500g of water. The mixture was stirred for 1-2 hours, filtered, and dried to obtain product G1 (off-white solid, 607.2g, yield 93%). 1 H NMR (400MHz, DMSO-D6) δ7.96 (s, 1H), 7.05 (s, 1H).

[0332] Example 1.2 Preparation of compound G2 from compound F

[0333]

[0334] F (50g) was suspended in N,N-dimethylformamide (80g) and acetone (400g). The starting material NIS (184.5g) was added in batches at approximately 0°C to 10°C. The reaction was carried out at approximately 20°C to 40°C for 40 hours. The reaction was monitored by HPLC until completion. The acetone was removed by concentration, and 250g of Na₂SO₃ aqueous solution (3%) was added. The mixture was stirred for 1-2 hours, filtered, and the filter cake was added to 250g of water. The mixture was stirred for 1-2 hours, filtered, and dried to obtain product G2 (off-white solid, 135.3g, yield 94%). 1 H NMR (400MHz, DMSO-D6) δ7.96 (s, 1H), 7.09 (s, 1H).

[0335] Example 1.3 Preparation of compound G3 from compound F

[0336]

[0337] F (1g) was suspended in dichloromethane (5mL). The starting material NCS (3g) was added in batches at approximately 0°C to 10°C. The reaction was carried out for 14 hours at approximately 0°C to 10°C. The reaction was monitored by HPLC until completion. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was added to 50g of Na₂SO₃ aqueous solution (3%), stirred for 1-2 hours, filtered, and then added to 5g of water. The mixture was stirred for 1-2 hours, filtered, and dried to obtain product G3 (off-white solid, 1.1g). HRMS (ESI+): C₆H₅Cl₂N₄ + , MW204.0339.

[0338] Example 2: Preparation of compound H from compound G

[0339] Example 2.1 Preparation of compound H4 from compound G1

[0340]

[0341] G1 (2.5 g) was suspended in tetrahydrofuran (30 mL), DMAP (0.2 g) and triethylamine (3 g) were added, followed by the addition of di-tert-butyl dicarbonate (3.0 g) in portions. The mixture was reacted at room temperature for 24 h, filtered, and the filter cake was washed with ethyl acetate. The product H4 (pale yellow solid, 1.6 g) was purified by column chromatography. HRMS (ESI+): C 11 H 13 Br2N4O2 + , MW390.9408.

[0342] Example 2.2 Preparation of compound H4a from compound G1

[0343]

[0344] G1 (150 g) was suspended in tetrahydrofuran (1350 g), DMAP (10.04 g) and triethylamine (156 g) were added, followed by the addition of di-tert-butyl dicarbonate (269.2 g) in batches. The mixture was heated to approximately 20-30°C and reacted for 24 h. The reaction was monitored by HPLC until completion. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to obtain product H4a (yellow solid, 195 g, 77.1%). 1 H NMR (400MHz, DMSO-D6) δ8.77(s,1H),7.59(s,1H),1.36(s,18H).

[0345] Example 2.3 Preparation of compound H9 from compound G2

[0346]

[0347] G2 (3.0 g) was suspended in tetrahydrofuran (30 mL), DMAP (0.2 g) and triethylamine (3 g) were added, followed by the addition of di-tert-butyl dicarbonate (3.0 g) in portions. The mixture was reacted at room temperature for 24 h, filtered, and the filter cake was washed with ethyl acetate. The product H4 (pale yellow solid, 2.1 g) was purified by column chromatography. HRMS (ESI+): C 11 H 13 I₂N₄O₂ + , MW486.9129.

[0348] Example 2.4 Preparation of compound H9a from compound G2

[0349]

[0350] G2 (30 g) was suspended in tetrahydrofuran (270 g), DMAP (1.52 g) and triethylamine (23.6 g) were added, followed by the addition of di-tert-butyl dicarbonate (40.72 g) in portions. The mixture was heated to approximately 20-30°C and reacted for 36 h. The reaction was monitored by HPLC until completion. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to obtain product H9a (yellow solid, 34.2 g, 75.1%). HRMS (ESI+): C 16 H 21 I2N4O4 + , MW586.9655.

[0351] Example 3: Preparation of compound J from compound H

[0352] Example 3.1 Preparation of compound J1 from compound H4

[0353]

[0354] H4 (0.2 mmol) was dissolved in tetrahydrofuran (10 mL), and 60% NaH (0.3 mmol) was added under nitrogen protection. After stirring at room temperature for 1 h, deuterated water (0.5 mL) was added, and all solvents were evaporated. The mixture was then slurried with methyl ether. The residue was redissolved in tetrahydrofuran (10 mL), and n-butyllithium (0.45 equiv.) was added at -40 to -30 °C. The mixture was reacted at -40 to -30 °C for 40–60 min. Deuterated water (4.0 equiv.) was added to the reaction mixture, and the mixture was stirred for 10–20 min. The reaction mixture was heated to room temperature, and all solvents were evaporated. The mixture was purified by column chromatography to obtain J1 (0.13 mmol). 1 H NMR (400MHz, DMSO-D6) δ8.15(s,1H),6.86(s,1H),1.52(s,9H).

[0355] Example 3.2 Preparation of compound J1 from compound H4a

[0356]

[0357] H4a (10 g) was suspended in tetrahydrofuran (90 g), purged three times with nitrogen, and under nitrogen protection, isopropyl magnesium chloride (THF solution, 2.4 equiv.) was added dropwise at 5-15°C. The reaction was carried out at 5-15°C for 60-90 minutes. Deuterium water (3.0 equiv.) was added to the reaction solution, and the mixture was stirred for 10-20 minutes. The mixture was filtered, the mother liquor was concentrated, and purified by column chromatography (PE / THF = 10 / 1) to obtain product J1 (off-white to pale yellow solid, 3.9 g). 1 H NMR (400MHz, DMSO-D6) δ8.15(s,1H),6.86(s,1H),1.52(s,9H).

[0358] Example 3.3 Preparation of compound J1 from compound H4a

[0359]

[0360] H4a (10 g) was suspended in tetrahydrofuran (90 g) under nitrogen protection. Butyllithium (2.1 equiv.) was added at -40 to -30°C, and the reaction was continued at -40 to -30°C for 40-60 minutes. Deuterium water (3.0 equiv.) was then added to the reaction solution, and the mixture was stirred for 10-20 minutes. The mixture was filtered, the mother liquor was concentrated, and purified by column chromatography (PE / THF = 10 / 1) to obtain product J1 (off-white to pale yellow solid, 3.5 g, 33%). 1 H NMR (400MHz, DMSO-D6) δ8.15(s,1H),6.86(s,1H),1.52(s,9H).

[0361] Example 3.4 Preparation of compound J1 from compound H9a

[0362]

[0363] H9a (10 g) was suspended in tetrahydrofuran (90 g), purged three times with nitrogen, and under nitrogen protection, isopropyl magnesium chloride (THF solution, 2.4 equiv.) was added dropwise at 5-15°C. The reaction was carried out at 5-15°C for 60-90 minutes. Deuterium water (3.0 equiv.) was added to the reaction solution, and the mixture was stirred for 10-20 minutes. The mixture was filtered, the mother liquor was concentrated, and purified by column chromatography (PE / THF = 10 / 1) to obtain product J1 (off-white to pale yellow solid, 1.6 g). 1 H NMR (400MHz, DMSO-D6) δ8.15(s,1H),6.86(s,1H),1.52(s,9H).

[0364] Example 4: Preparation of compound K from compound J

[0365]

[0366] J1 (13g) was dissolved in DCM (13g), and trifluoroacetic acid (18.82g) was added at 5-15°C. The reaction was carried out at 10-20°C for 14 hours. The DCM was removed by concentration, and 100g of saturated Na2CO3 aqueous solution was added. The mixture was stirred for 1-2 hours, filtered, and dried to obtain product K (off-white solid, 7.3g, 98%). HRMS (ESI+): C6H5D2N4 + , MW137.0798.

[0367] Example 5: Preparation of compound K from compound G

[0368] Example 5.1 Preparation of compound K from compound G1 via imine protection

[0369]

[0370] G1 (0.2 mmol) was dissolved in tetrahydrofuran (10 mL), benzophenone (0.25 mmol) was added, the mixture was heated under reflux for 1 h, cooled and concentrated to dryness, and the residue was slurried with methyl ether to obtain crude product H5.

[0371] H5 was suspended in tetrahydrofuran (10 mL) and added under nitrogen protection. Butyllithium (2.1 equiv.) was added at -40 to -30°C, and the reaction was continued at -40 to -30°C for 40-60 minutes. Deuterium water (3.0 equiv.) was added to the reaction solution, and the mixture was stirred for 10-20 minutes. The mixture was filtered, and hydroxylamine aqueous solution (0.5 mmol) was added to the mother liquor. The reaction was continued at 50°C for 1 hour. The solvent was then evaporated, and the residue was purified by column chromatography to obtain product K (0.11 mmol). HRMS (ESI+): C6H5D2N4 + , MW137.0798.

[0372] Example 5.2 Direct preparation of compound K from compound G1

[0373]

[0374] G1 (0.2 mmol) was dissolved in deuterated acetic acid (2 mL), zinc powder (5 mmol) was added, and the mixture was heated at 80°C for 14 h under nitrogen protection. The solvent was evaporated, and the residue was purified by column chromatography to obtain product K (0.11 mmol) HRMS (ESI+): C6H5D2N4 + , MW137.0798.

[0375] Example 5.3 Preparation of compound K from compound G1 via N-deuteration protection

[0376]

[0377] G1 (0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and diisopropylaminolithium (0.4 equiv.) was added at -40 to -30 degrees Celsius. The mixture was stirred at this temperature for 1 h, and deuterated water (0.5 mL) was added. The solvent was then evaporated to dryness. The residue was then dissolved in tetrahydrofuran (5 mL), and diisopropylaminolithium (0.4 equiv.) was added at -40 to -30 degrees Celsius. The mixture was stirred at this temperature for 1 h, and deuterated water (0.5 mL) was added. The solvent was then evaporated to dryness. The residue was then slurried with methyl tert-ethyl ether.

[0378] The residue was redissolved in tetrahydrofuran (5 mL), and n-butyllithium (0.45 equiv.) was added at -40 to -30 °C. The reaction was continued at -40 to -30 °C for 40–60 min. Deuterium water (4.0 equiv.) was added to the reaction solution, and the mixture was stirred for 10–20 min. The reaction mixture was then heated to room temperature, and all solvents were evaporated. The product K (0.11 mmol) was purified by column chromatography. HRMS (ESI+): C6H5D2N4 + , MW137.0798.

[0379] The overall yield for preparing compound K from compound F was 23.9%.

[0380] Example 5.4 Direct preparation of compound K from compound G1

[0381]

[0382] Compound G1 (0.2 mmol) was dissolved in deuterated methanol (10 mL), and anhydrous 5% Pd / C (5% w / w) was added. The mixture was heated at 50°C for 14 h under deuterium (10 bar pressure). The solvent was evaporated, and the residue was purified by column chromatography to give product K (0.11 mmol) HRMS (ESI+): C6H5D2N4 + , MW137.0798.

[0383] Example 6: Preparation of compound L from compound K

[0384] Example 6.1 Preparation of compound L1 from compound K

[0385]

[0386] K (500 mg) was dissolved in DMF (4 g), and NIS (870 mg) was added at -5 to 5 degrees Celsius. The mixture was reacted at -5 to 5 degrees Celsius for 2 hours, concentrated, and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain product L1 (off-white solid, 840 mg, 87.7%). 1 H NMR (400MHz, DMSO-D6) δ7.84(s,1H),6.85(s,1H).

[0387] Example 6.1 Preparation of compound L2 from compound K

[0388]

[0389] K (1.5 g) was suspended in dichloromethane (10 mL). Dibromohydantoin (1.1 equiv.) was added in batches at approximately 0-10°C, and the reaction was carried out at approximately 0-10°C for 14 h. After filtration, the filter cake was washed with ethyl acetate. The filter cake was added to 10 g of Na2SO3 aqueous solution (3%), stirred for 1-2 hours, filtered, and the filter cake was added to 10 g of water, stirred for 1-2 hours, filtered, and column chromatography was used to obtain product L2 (off-white solid, 1.7 g). HRMS (ESI+): C6H5DBrN4 + , MW213.9842.

[0390] The overall yield for preparing compound L from compound F was 21.0%.

[0391] Example 7: Preparation of Compound M from Compound L

[0392] Example 7.1 Preparation of compound M1 from compound L1

[0393]

[0394] L1 (0.55 g) was suspended in tetrahydrofuran (5.5 mL), DMAP (40 mg) and triethylamine (0.64 g) were added, and the mixture was purged three times with nitrogen under nitrogen protection. Boc₂O (1.10 g) was added at room temperature and the reaction was carried out for 4 hours. Then, 15% aq. NaOH (5.5 g) was added, and the mixture was heated to 50-60°C and stirred for 3-5 hours. The reaction was confirmed by HPLC. The mixture was then concentrated using a water pump and an oil pump, followed by column chromatography purification (PE:THF = 10:1) to obtain product M1 (pale yellow solid, 0.54 g, 71.7%). 1 H NMR (400MHz, DMSO-D6) δ8.26(s,1H),7.05(s,1H),1.49(s,9H).

[0395] Example 7.1 Preparation of compound M2 from compound L2

[0396]

[0397] L2 (0.89 g) was suspended in tetrahydrofuran (8.9 mL), DMAP (80 mg) and triethylamine (1.26 g) were added, and the mixture was purged three times with nitrogen under nitrogen protection. Boc2O (2.18 g) was added at room temperature and the reaction was carried out for 4 hours. Then, 15% aq. NaOH (8.9 g) was added, and the mixture was heated to 50-60°C and stirred for 3-5 hours. The reaction was confirmed by HPLC. The mixture was then concentrated using a water pump and an oil pump, followed by column chromatography purification (PE:THF = 10:1) to obtain product M2 (off-white to yellow solid, 0.98 g, 75.2%). 1 H NMR (400MHz, DMSO-D6) δ8.26(s,1H),6.98(s,1H),1.48(s,9H).

[0398] The overall yield for preparing compound M from compound F was 15.8%.

[0399] Example 8: Direct preparation of compound M from compound J

[0400]

[0401] J1 (1.2 g) was suspended in dichloromethane (10 mL). NIS (1.2 equiv.) was added in batches at approximately 0-10°C, and the reaction was carried out for 14 h at approximately 0-10°C. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was then added to 10 g of Na2SO3 aqueous solution (3%), stirred for 1-2 hours, filtered, and the filter cake was added to 10 g of water. The mixture was stirred for 1-2 hours, filtered, and column chromatography was used to obtain product M1 (a light yellow solid, 1.2 g). HRMS (ESI+): C 11 H 13 DIN4O2 + , MW362.0227.

[0402] Example 9: Preparation of monodeuterated compound K1

[0403]

[0404] L2 (1 mmol) was suspended in tetrahydrofuran (10 mL) under nitrogen protection. Butyllithium (2.1 equiv.) was added at -40 to -30°C, and the reaction was continued at -40 to -30°C for 40–60 minutes. Water (3.0 equiv.) was then added to the reaction mixture, and the mixture was stirred for 10–20 minutes. The mixture was filtered, the mother liquor was concentrated, and purified by column chromatography to obtain product K1 (0.27 mmol). HRMS (ESI+): C6H6DN4 + , MW136.0735.

[0405] Example 10: Preparation of compound J2 from monodeuterated compound K1

[0406]

[0407] K1 (0.55 g) was suspended in tetrahydrofuran (5.5 mL), DMAP (80 mg) and triethylamine (1.24 g) were added, and the mixture was purged with nitrogen three times under nitrogen protection. Boc2O (2.13 g) was added at room temperature and the reaction was carried out for 4 hours. Then, 15% aq. NaOH (5.5 g) was added, and the mixture was heated to 50-60 degrees Celsius and stirred for 3-5 hours. The reaction was detected by HPLC and the product was concentrated by water pump and oil pump, and purified by column chromatography (PE:THF = 10:1) to obtain product J2 (white to yellow solid, 0.72 g, 77.6%). 1 H NMR (400MHz, DMSO-D6) δ8.08(s,1H),7.82(d,1H),6.80(d,1H),1.45(s,9H).

[0408] Example 11 Preparation of compound D or E from compound J

[0409] From compound J1, compounds D or E can be synthesized using a similar method reported in literature [CN202010095099], ultimately yielding A.

[0410]

[0411] Example 11.1 Preparation of compound N1 from compound J1

[0412]

[0413] Dissolve J1 (1.0 mmol) in THF (7 mL), cool to -50 to -70 degrees Celsius, slowly add n-butyllithium (2.5 M hexane solution, 2.2 mmol), and stir at -60 degrees Celsius for 2 h after the addition is complete.

[0414] In a separate reaction flask, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (1.1 mmol), THF (10 mL), neodymium trichloride (1.1 mmol), and anhydrous tetrabutylammonium chloride (1.1 mmol) were added. The mixture was stirred at room temperature for 5 h. The reaction solution was pre-cooled to -60 °C, and the above-mentioned lithiumized mixture was added to this reaction solution. The mixture was stirred at -50 °C for 3 h, gradually heated to -20 °C, and the reaction was quenched by adding acetic acid (3 mmol). The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product N1 (0.66 mmol). HRMS (ESI+): C 37H 40 DN4O7 + , MW654.3039.

[0415] Example 11.2 Preparation of compound N1 from compound J2

[0416]

[0417] Dissolve J2 (1.0 mmol) in THF (7 mL), cool to -50 to -70 degrees Celsius, slowly add n-butyllithium (2.5 M hexane solution, 2.2 mmol), and stir at -60 degrees Celsius for 2 h after the addition is complete.

[0418] In a separate reaction flask, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (1.1 mmol), THF (10 mL), neodymium trichloride (1.1 mmol), and anhydrous tetrabutylammonium chloride (1.1 mmol) were added. The mixture was stirred at room temperature for 5 h. The reaction solution was pre-cooled to -60 °C, and the above-mentioned lithiumized mixture was added to this reaction solution. The mixture was stirred at -50 °C for 3 h, gradually heated to -20 °C, and the reaction was quenched by adding acetic acid (3 mmol). The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product N1 (0.67 mmol). HRMS (ESI+): C 37 H 40 DN4O7 + , MW654.3039.

[0419] Example 11.3 Preparation of compound O1 from compound N1

[0420]

[0421] The solution of compound N1 (2.2 mmol) in DCM (50 mL) was cooled to -40 °C. Trifluoroacetic acid (6 mmol) was added, followed by a mixture of TMSOTf (10 mmol) and TMSCN (10 mmol) pre-cooled to -40 °C in DCM (20 mL). This mixture was then stirred at -30 °C for 30 min, and the stirring was stopped by adding KOH aqueous solution pre-cooled to -10 °C. After separation, the organic phase was washed with saturated brine and concentrated. Finally, the concentrated organic phase was subjected to column chromatography to obtain product O1 (0.90 mmol). HRMS (ESI+): C 38 H 39 DN5O6 + , MW663.3045.

[0422] Example 11.4 Preparation of compound D from compound O1

[0423]

[0424] O1 (1.0 g) was dissolved in DCM (10 mL), and trifluoroacetic acid (2.5 equiv.) was added at 5-15°C. The reaction was carried out at 10-20°C for 14 hours. The DCM was removed by concentration, and 100 g of saturated Na2CO3 aqueous solution was added. The mixture was stirred for 1-2 hours, filtered, and the column chromatography product (D) (off-white solid, 0.45 g) was obtained. HRMS (ESI+): C 33 H 31 DN5O4 + , MW563.2518.

[0425] Example 11.5 Preparation of compound E from compound O1

[0426]

[0427] O1 (1 mmol) was dissolved in DCM (5 mL) and cooled to -60 °C. Boron trichloride (1 M DCM solution, 5.0 mmol) was added, and the mixture was stirred at -60 °C for 3 h. Then, methanol (30 mL) was added, and the mixture was concentrated below -10 °C until no solvent flowed out. Methanol (30 mL) was added again, and the mixture was concentrated until no solvent flowed out. Then, potassium carbonate aqueous solution (20%) was added, and the mixture was gradually heated to room temperature. A solid precipitated, which was filtered, washed with water, and dried to give product E (0.71 mmol). HRMS (ESI+): C 12 H 13 DN5O4 + , MW293.1110.

[0428] Example 11.6 Preparation of compound E from compound D

[0429]

[0430] Compound D (1 mmol) was dissolved in DCM (5 mL) and cooled to -20 °C. Boron trichloride (1 M DCM solution, 3.4 mmol) was added, and the mixture was stirred at -20 °C for 3 h. Then, methanol (30 mL) was added, and the mixture was concentrated below -10 °C until no solvent flowed out. Another 30 mL of methanol was added, and the mixture was concentrated until no solvent flowed out. Then, potassium carbonate aqueous solution (20%) was added, and the mixture was gradually heated to room temperature. A solid precipitated, which was filtered, washed with water, and dried to give product E in 75% yield. HRMS (ESI+): C 12 H 13 DN5O4 + , MW293.1110.

[0431] Example 11.7 Preparation of Compound A from Compound E

[0432]

[0433] Compound E (1.0 mmol) was dissolved in anhydrous DMF (10 mL), isobutyric acid (5.0 mmol) was added, followed by diisopropylcarbodiimide (5 mmol) in portions, and finally DMAP (10 mg). The mixture was stirred at room temperature for 14 h, diluted with water, and extracted with methyl ether. The organic phase was concentrated to dryness and subjected to column chromatography to obtain compound A (0.71 mmol). HRMS (ESI+): C 24 H 31 DN5O7 + , MW503.2367.

[0434] Example 12 Preparation of compound A from compound K

[0435] Starting from compound K, compound D can be synthesized using a similar method reported in literature [CN2020109353131], ultimately yielding A.

[0436]

[0437] Example 12.1 Preparation of compound P from compound K

[0438]

[0439] Compound K (1.0 mmol) was suspended in THF (5 mL), and TMSCl (1.1 mmol) was added at room temperature. The mixture was then cooled to 0 °C, and N,N-diisopropylethylamine (2.0 mmol) was added. The mixture was stirred at 0 °C for 30 min, then cooled to -60 °C, and n-butyllithium (2.2 mmol in 2.5 M hexane solution) was added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 2 h.

[0440] In a separate reaction flask, 1.1 mmol of 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone, 10 mL of THF, 1.1 mmol of neodymium trichloride, and 1.1 mmol of anhydrous tetrabutylammonium chloride were added. The mixture was stirred at room temperature for 5 h. The reaction solution was then pre-cooled to -60 °C, and the above-mentioned lithiumized mixture was added to this reaction solution. The mixture was stirred at -60 °C for another 3 h, gradually heated to -20 °C, and the reaction was quenched by adding acetic acid (3 mmol). The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product P in 75% yield. HRMS (ESI+): C 32 H 32 DN4O5 +, MW554.2515.

[0441] Example 12.2 Preparation of compound P from compound K1

[0442]

[0443] Compound K1 (1.0 mmol) was suspended in THF (5 mL), and TMSCl (1.1 mmol) was added at room temperature. The mixture was then cooled to 0 °C, and N,N-diisopropylethylamine (2.0 mmol) was added. The mixture was stirred at 0 °C for 30 min, then cooled to -60 °C, and n-butyllithium (2.2 mmol in 2.5 M hexane solution) was added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 2 h.

[0444] In a separate reaction flask, 1.1 mmol of 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone, 10 mL of THF, 1.1 mmol of neodymium trichloride, and 1.1 mmol of anhydrous tetrabutylammonium chloride were added. The mixture was stirred at room temperature for 5 h. The reaction solution was then pre-cooled to -60 °C, and the above-mentioned lithiumized mixture was added to this reaction solution. The mixture was stirred at -60 °C for 3 h, gradually heated to -20 °C, and the reaction was quenched by adding acetic acid (3 mmol). The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product P in 74% yield. HRMS (ESI+): C 32 H 32 DN4O5 + , MW554.2515.

[0445] Example 12.3 Preparation of compound D from compound P

[0446]

[0447] The solution of compound P (1 mmol) in DCM (5 mL) was cooled to -40 °C, and trifluoroacetic acid (3 mmol) was added. Then, a mixed solution of TMSOTf (6 mmol) and TMSCN (6 mmol) in DCM (5 mL) pre-cooled to -40 °C was added. This mixture was then stirred at -30 °C for 30 min, and the stirring was terminated by adding KOH aqueous solution pre-cooled to -10 °C. After separation, the organic phase was washed with saturated brine, concentrated, and subjected to column chromatography to obtain product D in 73% yield. HRMS (ESI+): C 33 H 31 DN5O4 + , MW563.2519.

[0448] Example 12.4 Preparation of Compound A from Compound D

[0449] Compound A was prepared from compound D using the methods of Examples 11.6 and 11.7.

[0450] Example 13 Preparation of Compound A from Compound L

[0451] Starting from compound L, compound D can be synthesized using a similar method reported in the literature [DOI: 10.1021 / acs.oprd.0c00370, 10.1021 / acs.oprd.0c00310, 10.1021 / acs.oprd.1c00024, and citations thereof], ultimately yielding A.

[0452]

[0453] Example 13.1 Preparation of compound P from compound L1

[0454]

[0455] Compound L1 (1.0 mmol) was suspended in THF (5 mL), and TMSCl (1.1 mmol) was added at room temperature. The mixture was then cooled to 0 °C, and N,N-diisopropylethylamine (2.0 mmol) was added. The mixture was stirred at 0 °C for 30 min, then cooled to -60 °C, and n-butyllithium (2.2 mmol in 2.5 M hexane solution) was added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 2 h.

[0456] In a separate reaction flask, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (1.1 mmol), THF (10 mL), neodymium trichloride (1.1 mmol), and anhydrous tetrabutylammonium chloride (1.1 mmol) were added. The mixture was stirred at room temperature for 5 h. This reaction solution was pre-cooled to -60 °C and added to the above lithium-ionized mixture. The mixture was stirred at -60 °C for 3 h, then gradually heated to -20 °C. Acetic acid (3 mmol) was added to quench the reaction. The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product P in 35% yield. HRMS (ESI+): C 32 H 32 DN4O5 + , MW554.2515.

[0457] Example 13.2 Preparation of compound P from compound L2

[0458]

[0459] Compound L2 (1.0 mmol) was suspended in THF (5 mL), and TMSCl (1.1 mmol) was added at room temperature. The mixture was then cooled to 0 °C, and N,N-diisopropylethylamine (2.0 mmol) was added. The mixture was stirred at 0 °C for 30 min, then cooled to -60 °C, and n-butyllithium (2.2 mmol in 2.5 M hexane solution) was added dropwise. After the addition was complete, the mixture was stirred at -60 °C for 2 h.

[0460] In a separate reaction flask, 2,3,5-tribenzyloxy-D-ribonucleo-1,4-lactone (1.1 mmol), THF (10 mL), neodymium trichloride (1.1 mmol), and anhydrous tetrabutylammonium chloride (1.1 mmol) were added. The mixture was stirred at room temperature for 5 h. This reaction solution was pre-cooled to -60 °C and added to the above lithium-ionized mixture. The mixture was stirred at -60 °C for 3 h, then gradually heated to -20 °C. Acetic acid (3 mmol) was added to quench the reaction. The reaction solution was then washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine. Finally, the obtained organic phase was concentrated and column chromatography was performed to obtain product P in 39% yield. HRMS (ESI+): C 32 H 32 DN4O5 + , MW554.2515.

[0461] Example 13.3 Preparation of Compound A from Compound P

[0462] Compound A was prepared from compound P using the methods described in Examples 12.3 and 12.4.

[0463] Example 14 Preparation of Compound A from Compound M

[0464] Starting from compound M, compound D can be synthesized via N1 and O1, ultimately yielding A.

[0465]

[0466] Example 14.1 Preparation of compound N1 from compound M2

[0467]

[0468] Under anhydrous and oxygen-free conditions, a 5 mL solution of M2 (0.64 mmol) in THF was cooled to -30°C. A 415 μL solution of diisopropylaminolithium THF (0.83 mmol, 2 M tetrahydrofuran solution) was added dropwise, maintaining the temperature at -30°C. After stirring for 50 min, the temperature was further lowered to -78°C, and n-BuLi (100 μL, 1.60 mmol, 1.6 M hexane solution) was added dropwise. After the addition was complete, the reaction was stirred for 5 min, followed by the dropwise addition of 2,3,5-tribenzyloxy- A solution of D-ribonucleoside-1,4-lactone (803 mg, 1.92 mmol) in 10 mL of THF was prepared and reacted at -78 °C for 2 hours. After the reaction was complete as detected by TLC, the reaction was quenched with 10 mL of saturated NH4Cl aqueous solution. After returning to room temperature, the mixture was extracted four times with ethyl acetate (10 mL × 4). The organic layers were combined, washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to column chromatography to give compound N1 (0.35 mmol). HRMS (ESI+): C 37 H 40 DN4O7 + , MW654.3039.

[0469] Example 14.2 Preparation of compound A from compound N1

[0470] Compound A was prepared from compound N1 using the method described in Examples 11.3-11.7.

[0471] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing deuterated heterocyclic compounds, characterized in that, The method includes the following steps: (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G. ； (2) Compound G undergoes deuteration to yield compound K. ； Wherein, X is a halogen, selected from the following group: chlorine, bromine, iodine.

2. The method as described in claim 1, characterized in that, Step (2) further includes amino protection and deprotection steps.

3. The method as described in claim 1, characterized in that, Step (2) includes the following steps: (2.1) In a second inert solvent, compound G obtained in step (1) is mixed with the first protecting reagent to carry out an N-protection reaction, yielding compound H. ； (2.2) In a third inert solvent, compound H is mixed with the first organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with the first deuterated reagent to undergo a deuteration reaction and optionally a deprotection reaction to obtain compound J. ； (2.3) In the fourth inert solvent, compound J was mixed with the first deprotecting agent and completely deprotected to give compound K. ； Alternatively, step (2) may include the following steps: (2.4) In a fifth inert solvent, compound G obtained in step (1) is mixed with a second protecting agent to perform N-imine protection, yielding compound H'. ； (2.5) In a sixth inert solvent, compound H' is mixed with a second organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a second deuterating reagent to undergo a deuteration reaction to obtain compound J'. ； (2.6) In the seventh inert solvent, compound J' was mixed with the second deprotecting agent and completely deprotected to give compound K. ； Among them, R 1 Selected from the following groups: H, Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; R 2 Selected from the following group: Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; or R 1 R 2 Together with adjacent heteroatoms or carbon atoms, they form a substituted or unsubstituted carbon ring or heterocycle, wherein the heteroatoms are selected from N, O, S, and Si; Alternatively, step (2) may include the following steps: (2.7) In the presence of acid or base, the compound G obtained in step (1) is mixed with an active metal and a third deuterated reagent to carry out a deuteration reduction reaction to obtain compound K. ； Alternatively, step (2) may include the following steps: (2.8) In an eighth inert solvent, in the presence of a noble metal catalyst containing Pd or Pt, compound G obtained in step (1) is mixed with a fourth deuterated reagent to carry out a deuteration reduction reaction to obtain compound K. 。 4. The method as described in claim 1, characterized in that, The method further includes the following steps: (3) In the ninth inert solvent, the compound K obtained in step (2) is mixed with the second halogenating reagent to carry out a monohalogenation reaction to obtain compound L. ； (4) In the tenth inert solvent, compound L is mixed with the third organometallic reagent to carry out a metal-halogen exchange reaction, and then mixed with a proton-containing reagent to carry out a protonation reaction to obtain compound K1. ； (5) In the eleventh inert solvent, compound K1 was mixed with a Boc protecting agent to perform Boc protection, yielding compound J2. ； Wherein, Y is a halogen, selected from the following group: chlorine, bromine, iodine.

5. A method for preparing compound M, characterized in that, The method includes the following steps: (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G. ； (2) Compound G undergoes deuteration to yield compound K. ； (3) In the ninth inert solvent, the compound K obtained in step (2) is mixed with the second halogenating reagent to carry out a monohalogenation reaction to obtain compound L. ； (6) In the twelfth inert solvent, compound L was mixed with the Boc protecting reagent to carry out the Boc protection reaction, yielding compound M. ； Among them, X and Y are halogens, each independently selected from the following group: chlorine, bromine, and iodine.

6. The method as described in claim 5, characterized in that, Step (2) includes the following steps: (2.1) In a second inert solvent, compound G obtained in step (1) is mixed with the first protecting reagent to carry out an N-protection reaction, yielding compound H. ； (2.2) In a third inert solvent, compound H is mixed with the first organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with the first deuterated reagent to undergo a deuteration reaction and optionally a deprotection reaction to obtain compound J. ； (2.3) In the fourth inert solvent, compound J was mixed with the first deprotecting agent and completely deprotected to give compound K. ； Alternatively, step (2) may include the following steps: (2.4) In a fifth inert solvent, compound G obtained in step (1) is mixed with a second protecting agent to perform N-imine protection, yielding compound H'. ； (2.5) In a sixth inert solvent, compound H' is mixed with a second organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a second deuterating reagent to undergo a deuteration reaction to obtain compound J'. ； (2.6) In the seventh inert solvent, compound J' was mixed with the second deprotecting agent and completely deprotected to give compound K. ； Among them, R 1 Selected from the following groups: H, Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; R 2 Selected from the following group: Boc protecting group, deuterium atom, C1-C4 alkyl, C1-C6 alkylsilyl, phenyl; or R 1 R 2 Together with adjacent heteroatoms or carbon atoms, they form a substituted or unsubstituted carbon ring or heterocycle, wherein the heteroatoms are selected from N, O, S, and Si; Alternatively, step (2) may include the following steps: (2.7) In the presence of acid or base, the compound G obtained in step (1) is mixed with an active metal and a third deuterated reagent to carry out a deuteration reduction reaction to obtain compound K. ； Alternatively, step (2) may include the following steps: (2.8) In an eighth inert solvent, in the presence of a noble metal catalyst containing Pd or Pt, compound G obtained in step (1) is mixed with a fourth deuterated reagent to carry out a deuteration reduction reaction to obtain compound K. 。 7. A method for preparing compound M, characterized in that, The method includes the following steps: (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G. ； (2.1a) In a second inert solvent, compound G obtained in step (1) is mixed with a Boc protecting agent to carry out a Boc protection reaction, yielding compound H'' ； (2.2a) In a third inert solvent, compound H'' is mixed with a first organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a first deuterated reagent to undergo a deuteration reaction and optionally a deprotection reaction to give compound J1. ； (3) In the thirteenth inert solvent, compound J1 was mixed with the third halogenating reagent and subjected to a monohalogenation reaction to obtain compound M. ； Among them, X and Y are each independently halogens, selected from chlorine, bromine, and iodine; R1a and R2a are each independently H or Boc, where R1a and R2a are not both H at the same time.

8. A method for preparing compound A, wherein the structure of compound A is shown below: ， Its features are, Compound A is prepared by using one of compounds K, M, or J2 as an intermediate in the preparation process; and the method comprises the method of any one of claims 1-7.

9. The method as described in claim 8, characterized in that, The method further includes: Starting from compound M, compound D is synthesized via N1 and O1, ultimately yielding compound A. 。 10. A method for preparing compound A, wherein the structure of compound A is shown below: ， Its features are, Compound A is prepared by using one of compounds L or K1 as an intermediate in the preparation process, and the method includes the following steps: (1) In a first inert solvent, compound F is mixed with a first halogenating reagent and undergoes a selective dihalogenation reaction to give compound G. ； (2) Compound G undergoes deuteration to yield compound K. ； Wherein, X is a halogen, selected from the following group: chlorine, bromine, iodine; (3) In the ninth inert solvent, the compound K obtained in step (2) is mixed with the second halogenating reagent to carry out a monohalogenation reaction to obtain compound L. ;and Optionally (4), in a tenth inert solvent, compound L is mixed with a third organometallic reagent to undergo a metal-halogen exchange reaction, and then mixed with a proton-containing reagent to undergo a protonation reaction, yielding compound K1. 。

Images