TWI620754B - Method for preparing amino phosphate derivative and preparation method thereof - Google Patents

Abstract

The present invention relates to a process for preparing an amino phosphate derivative having an antiviral activity represented by the general formula (I), and a process for preparing the intermediate and the intermediate.

Description

Method for preparing amino phosphate derivative and preparation method thereof

The invention relates to a preparation method of a kind of amino phosphate derivative having antiviral activity, a preparation method thereof and an intermediate and an intermediate.

The compound of formula (I) is an amino phosphate derivative which is a prodrug of tenofovir and inhibits viral polymerization by directly competing with natural deoxyribose receptors. Enzyme for the treatment of HIV and HBV infection.

In the compound of the formula (I), R ^{3 is} selected from a natural or pharmaceutically acceptable amino acid side chain; and R ^{4 is} selected from a C _{1 -10} alkyl group.

At present, the methods disclosed in the formula (I) disclosed at home and abroad mainly include the following: 1) CN1443189A discloses 9-(2-(phosphonomethoxy)propyl]adenine (PMPA) as Starting material, prepare GS-7171. The path is as follows:

At the same time CN1443189A discloses another method for synthesizing monophenyl PMPA(II):

2) CN101089004A discloses a compound represented by (I) in the preparation route, the path is as follows:

WO2013052094 discloses a compound shown in 15 in the preparation route, the path is as follows:

In the presently disclosed synthetic method, the amine group of the adenine group is exposed, and the intermediate and the target product have high polarity and good water solubility, which is disadvantageous for separation and purification.

An object of the present invention is to provide a novel process for producing an aminophosphate derivative represented by the formula (I), and a process for synthesizing an intermediate for the synthesis of an aminophosphate derivative and an intermediate.

The invention provides a preparation method of the compound represented by the formula (I):

Wherein compound (II) undergoes an amine group deprotection reaction on an anthracene ring under certain conditions;

R ¹ and R ² are each independently selected from an amine protecting group or hydrogen, provided that R ¹ and R ^{2 are} not hydrogen at the same time.

A preferred embodiment of the present invention for preparing compound compound (II) from compound (I), wherein compound (II) is used as an alkaline reagent, an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 100 ° C in a solvent. The amine-based deprotection reaction is carried out; R ¹ and R ² are each independently selected from an amine protecting group or hydrogen, provided that R ¹ and R ^{2 are} not hydrogen at the same time; and R ^{3 is} selected from the side of the amino acid which is natural or pharmaceutically acceptable. R ^{4 is} selected from C _{1 -10} alkyl; the solvent used in the reaction is not particularly limited, and a solvent which can dissolve the starting material to some extent and does not inhibit the reaction can be used; wherein the solvent is not limited One or a combination of two or more selected from the group consisting of an alcohol solvent, an aromatic solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, a guanamine solvent, an anthraquinone solvent, and water The acidic reagent is selected from the group consisting of an organic acid or an inorganic acid; and the alkaline agent is selected from one of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, and an organic amine. Two or more combinations; the hydrogenolysis catalyst From palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon; the amount of alkaline reagent is 1 to 10 times the molar amount of compound (II); the amount of acidic reagent is compound (II) The molar amount is 1 to 30 times; the amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II).

In a preferred embodiment of the invention, the amine protecting group is selected from a substituted or unsubstituted benzyl, alkoxycarbonyl, alkyl fluorenyl or aryl fluorenyl group.

A preferred embodiment of the present invention for preparing compound (I) from compound (II), wherein: R ¹ and R ² are each independently selected from the group consisting of hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, and R ¹ and R ^{2 are} not simultaneously hydrogen, preferably R ¹ and R ^{2 are} selected from a third butoxycarbonyl group; R ³ is a natural or pharmaceutically acceptable Using a side chain of an amino acid, wherein the amino acid is preferably: glycine, alanine, leucine, isoleucine, leucine, valine, phenylalanine, methionine, Tryptophan, serine, glutamine, sulphate, cysteine, histidine, aspartame, lysine, aspartic acid, glutamic acid, naphthyl acid or spermine The acid is further preferably glycine, alanine, leucine, phenylalanine, aspartame or arginine, more preferably glycine, alanine or phenylalanine, and R ^{3 is} more preferably alanine. a side chain; R ^{4 is} selected from C _{1 -10} alkyl, preferably: methyl, ethyl, n-propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl, N-pentyl or n-decyl, and various a chain isomer or the like; further preferably: a lower alkyl group having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, allyl, isopropyl, n-butyl, Isobutyl or tert-butyl, etc.; the solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dioxane, Methyl third butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, two One or a combination of two or more of methyl chloride, 1,2-dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, toluene, chlorobenzene and xylene, preferably methanol or ethanol. Isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate One or a combination of two or more of ester, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water, further preferably dichloromethane or tetrahydrogen One or a combination of two or more of furan, dioxane and water; the acidic reagent is selected from the group consisting of: formic acid, acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, methanesulfonic acid, ethyl sulfonate One or a combination of two or more of acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid, preferably acetic acid, trifluoroacetic acid, One or a combination of two or more of hydrochloric acid and hydrobromic acid; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate , sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, triethylamine, N, N - a combination of one or more of diisopropylethylamine, propylamine, methylamine, dimethylamine, tert-butylamine, aniline and aqueous ammonia, preferably potassium carbonate, sodium carbonate, sodium hydrogencarbonate, hydrogencarbonate One or a combination of two or more of potassium, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, and N,N-diisopropylethylamine Further preferred is: triethylamine, N,N-diisopropylethylamine or a combination thereof; the hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon, Preferably, it is palladium/carbon or palladium hydroxide/carbon; the amount of the alkaline reagent is 1 to 10 times the molar amount of the compound (II); and the amount of the acidic reagent is 1 to 20 times the molar amount of the compound (II). Preferably, it is 1 to 10 times; the amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II); the reaction temperature is 0 ° C to 60 ° C, preferably 0 ° C to 50 ° C, further preferably 20 °C~50°C.

Another preferred embodiment of the present invention for preparing compound (I) from compound (II) wherein: R ¹ and R ² are each independently selected from the group consisting of hydrogen, benzyl, p-methoxybenzyl, and tert-butoxycarbonyl a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, preferably a third butoxycarbonyl group, and R ¹ and R ^{2 are} not simultaneously hydrogen; and R ^{3 is} selected from the group consisting of glycine, alanine, and leucine a side chain of phenylalanine, aspartame or arginine, preferably a side chain of alanine; R ^{4 is} selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or a third butyl group; the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, One or a combination of two or more of diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water Preferably, it is a combination of one or more of dichloromethane, tetrahydrofuran, dioxane and water; the acidic reagent is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, and B. One or two of acid, succinic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid More preferably, the combination is acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like. One or a combination of two or more of ethylamine and N,N-diisopropylethylamine; the acidic reagent is used in an amount of from 1 to 20 times, preferably from 1 to 10 times, the mole of the compound (II); The temperature is from 0 ° C to 60 ° C, preferably from 0 ° C to 50 ° C, further preferably from 20 ° C to 50 ° C.

The invention provides a preparation method of the compound represented by the formula (II):

Wherein the compound (III) and the compound (IV) are subjected to a substitution reaction at -78 ° C to 50 ° C in a solvent;

R ¹ , R ² , R ³ and R ⁴ are as defined above; X is selected from fluorine, chlorine, bromine or iodine; the solvent used in the reaction is selected from the group consisting of aromatic hydrocarbon solvents, ether solvents, halogenated alkane solvents, esters. One or a combination of two or more of a solvent-like solvent, a ketone solvent, and a nitrile solvent; the substitution reaction may optionally be carried out by adding an alkaline agent; and the compound (IV) is used in an amount of 0.8 based on the molar amount of the compound (III). ~7 times.

A preferred embodiment of the present invention for preparing compound (II) from compound (III) and compound (IV) wherein R ¹ , R ² , R ³ and R ⁴ are as defined above; X is selected from chlorine; The solvent used is selected from the group consisting of: dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, toluene And one or a combination of two or more of chlorobenzene; preferably dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran or acetonitrile, further preferably dichloromethane; said substitution reaction can be selected An alkaline reagent is selected, which is selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, Triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diaza a combination of one or more of dicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-methylmorpholine, morpholine, piperidine, aniline and tert-butylamine, Triethylamine One or more of N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, N-methylmorpholine, morpholine, piperidine and aniline Further, it is preferably a triethylamine or N,N-diisopropylethylamine; the compound (IV) is used in an amount of 0.8 to 7 times, preferably 1 to 6 times the molar amount of the compound (III); The temperature is -40 ° C to 50 ° C, preferably -30 ° C to 40 ° C, and more preferably -30 ° C to 30 ° C.

Another preferred embodiment of the present invention for preparing compound (II) by reacting compound (III) with compound (IV) wherein: R ¹ , R ² , R ³ and R ⁴ are as defined above; Chlorine; the substitution reaction may optionally be added with an alkaline reagent; the solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran. One or a combination of two or more of 1,4-dioxane, acetonitrile, propionitrile, toluene and chlorobenzene, preferably dichloromethane; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, Potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, triethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine , 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N- a combination of one or more of methylmorpholine, morpholine, piperidine and aniline, preferably triethylamine or N,N-diisopropylethylamine; reaction temperature is -40 ° C to 50 ° C; The amount of the compound (IV) is the compound (III) The molar amount is 0.8 to 7 times, preferably 1 to 6 times.

The present invention provides a compound of the formula (II):

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above.

The invention provides a preparation method of a compound represented by formula (III) or (III-1):

Wherein, the compound (V) is halogenated with a halogenating reagent to form a compound (III) or a compound (III-1) at 0 ° C to 110 ° C in a solvent;

R ¹ , R ² and X are as defined above; the solvent used in the reaction is selected from one or a combination of two or more of a halogenated alkane solvent, a nitrile solvent and an anthraquinone solvent; The catalyst is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylaniline, triethylamine or pyridine; the halogenating agent is used in an amount of 1 to 15 times the molar amount of the compound (V). .

A preferred embodiment of the present invention for preparing a compound (III) or a compound (III-1) by halogenation of a compound (V) with a halogenating reagent, wherein the solvent used in the reaction is selected from the group consisting of dichloromethane and trichloroethane. And one or a combination of two or more of acetonitrile and cyclobutyl hydrazine, preferably dichloromethane or acetonitrile; The halogenating agent is selected from the group consisting of dichlorohydrazine, grass chloroform, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine chloride, dibromoarylene, grass bromo, and tribromide. Phosphorus, phosphorus pentabromide, trichlorooxo bromide, triphenylphosphine bromide or 1-chloro-N,N,2-trimethylpropenamine, preferably grass chloro, grass mash, dichloro Azulene, dibromoarylene, phosphorus pentachloride or phosphorus pentabromide; further preferably grassy chlorine or dichlorohydrazine; when compound (III) is prepared, the halogenating agent is more preferably grassy chlorine, and the solvent is better. For the preparation of the compound (III-1), the halogenating agent is more preferably dichlorohydrazine, and the solvent is more preferably acetonitrile; the halogenation reaction may be selectively added to the catalyst, and the catalyst is selected from N, N-dimethylformamide; the halogenating agent is used in an amount of 1 to 10 times, preferably 1 to 5 times the molar amount of the compound (V); when the compound (III) is prepared, the reaction temperature is 0 ° C to 80 ° C. Preferably, it is 0 ° C ~ 40 ° C, further preferably 0 ° C ~ 30 ° C; when the compound (III-1) is prepared, the reaction temperature is room temperature ~ 85 ° C, preferably 50 ° C ~ 85 ° C, more preferably Further preferably, it is 70 ° C to 85 ° C.

The present invention provides a compound of the formula (III):

Wherein R ¹ , R ² and X are as defined above.

The present invention provides a method for preparing a compound represented by the formula (V):

Wherein the compound (VI) is hydrolyzed with an alkaline reagent at 0 ° C to 110 ° C in a solvent;

R ¹ and R ² are as defined above; the solvent used in the reaction is not particularly limited, and a solvent which can dissolve the starting material to a certain extent and does not inhibit the reaction can be used; wherein the solvent is selected without limitation a combination of one or more of an alcohol solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, a guanamine solvent, an anthraquinone solvent, and water; The agent is selected from the group consisting of one or a combination of two or more of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, and an organic amine; and the amount of the alkaline agent is a mole of the compound (VI). The amount is 1~15 times.

A preferred embodiment of the present invention for preparing a compound from the compound (VI): R ¹ and R ² are as defined above; the solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, and isopropyl alcohol. Alcohol, n-butanol, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane 1,2-Dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dioxane, methyl tert-butyl ether, acetonitrile, propionitrile, One or a combination of two or more of ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water, preferably dichloromethane, 1 , 2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate and one of water or Further, two or more combinations are further preferably one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, isopropyl acetate and water. More preferably, it is acetonitrile, water or a combination thereof; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, Potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, third butylamine, 4 - dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, imidazole, N- One or a combination of two or more of methylmorpholine, morpholine, piperidine, aniline, aqueous ammonia and hydrazine hydrate; preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or potassium hydroxide One or a combination of two or more of sodium hydroxide, N,N-diisopropylethylamine, triethylamine and aqueous ammonia, further preferably one or two of sodium hydrogencarbonate, triethylamine and aqueous ammonia The above combination; the amount of the alkaline reagent is 1 to 10 times, preferably 3 to 10 times, more preferably 3 to 6 times the molar amount of the compound (VI); the reaction temperature is room temperature to 80 ° C, Good for 20 ° C~ 60 ° C, further preferably 40 ° C ~ 60 ° C.

Another preferred embodiment of the present invention for preparing compound (V) from compound (VI), wherein: the solvent used in the reaction is selected from the group consisting of acetonitrile, water or a combination thereof; and the alkaline agent is selected from the group consisting of sodium hydrogencarbonate, three One or a combination of two or more of ethylamine and ammonia; the amount of the alkaline reagent is 3 to 6 times the molar amount of the compound (VI); and the reaction temperature is 20 to 60 °C.

The present invention provides a compound of the formula (V):

Wherein R ¹ and R ² are as defined above.

The invention provides a preparation method of the compound represented by the formula (VI):

Wherein the compound (VII) is reacted with an amine protecting agent at 0 ° C to 110 ° C in a solvent;

R ¹ and R ² are as defined above; the solvent used in the reaction is selected from the group consisting of an alcohol solvent, an ether solvent, a halogenated alkane solvent, a ketone solvent, a nitrile solvent, an ester solvent, a guanamine solvent, and a sub-solvent. a combination of an hydrazine-based solvent and one or more of the two; the amine-based protecting reaction may be optionally added to the catalyst, wherein the catalyst is selected from the group consisting of triethylamine, N,N-diisopropylethylamine or 4 - dimethylaminopyridine; the amine protecting agent is used in an amount of from 1 to 15 times the molar amount of the compound (VII).

A preferred embodiment of the present invention for preparing compound (VI) by reacting compound (VII) with an amine protecting agent, wherein: R ¹ and R ² are as defined above; the solvent used in the reaction is selected from the group consisting of methanol and ethanol. , dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, dimethyl One or a combination of two or more of guanamine, dimethyl hydrazine, acetone, methyl ethyl ketone and water, preferably one or a combination of two or more of dichloromethane, tetrahydrofuran and 1,4-dioxane Further preferred is tetrahydrofuran; the amine protecting agent is selected from the group consisting of ditributin dicarbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride, ethyl hydrazine chloride, benzoic anhydride, benzamidine chloride, benzyl bromide. , benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride or trityl chloride, preferably dibutyl butyl carbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride And acetonitrile, benzoic anhydride or benzamidine chloride, further preferably dibutyl butyl carbonate or benzyl chloroformate, particularly preferably dicarbonic acid The third butyl ester; the amine protecting agent is used in an amount of 1 to 10 times, preferably 1 to 5 times, more preferably 2 to 5 times the molar amount of the compound (VII); and the reaction temperature is 0 ° C to 110 ° C It is preferably 0 ° C to 80 ° C, further preferably room temperature to 80 ° C, and particularly preferably 50 ° C to 80 ° C.

A preferred embodiment of the present invention for preparing compound (VI) by reacting compound (VII) with an amine protecting agent, wherein: the solvent used in the reaction is selected from tetrahydrofuran; and the amine protecting agent is selected from dibutyl butyl dicarbonate. The amine-protecting reaction may optionally be carried out by adding a catalyst selected from the group consisting of 4-dimethylaminopyridine; the amine protecting agent is used in an amount of 2 to 5 times the molar amount of the compound (VII); It is room temperature ~80 °C.

The present invention provides a compound represented by (VI), which has the structure as follows:

Wherein R ¹ and R ² are each independently selected from an amine protecting group or hydrogen, provided that R ¹ and R ^{2 are} not hydrogen at the same time; each independently preferably hydrogen, benzyl, p-methoxybenzyl, third butyl An oxycarbonyl group, a benzyloxycarbonyl group, an ethyl fluorenyl group or a benzhydryl group, and R ¹ and R ^{2 are} not simultaneously hydrogen, and preferably R ¹ and R ^{2 are} selected from the group consisting of a third butoxycarbonyl group.

The present invention provides a process for the preparation of a compound of the formula (VII), which comprises the steps of: (1) halogenation of a compound (IX) with a halogenating reagent to obtain a compound (VIII); (2) compound (VIII) and phenol Substituting the reaction to obtain (VII);

The definition of X is as described above.

A preferred embodiment of the present invention for preparing compound (VII) from compound (IX) wherein: X is as defined above; the halogenation reaction described in step (1) comprises the following steps: in a solvent, in a halogenating reagent The compound (VIII) is obtained by subjecting the compound (IX) to a halogenation reaction, wherein the solvent is selected from one of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and toluene or A combination of two or more kinds, preferably one or a combination of two or more of dichloromethane, acetonitrile and toluene; the halogenating agent is selected from the group consisting of dichlorohydrazine or chlorinated chlorine, preferably dichlorohydrazine; Optionally, the catalyst is selected from the group consisting of N,N-dimethylformamide; the halogenating agent is used in an amount of from 1 to 15 times, preferably from 1 to 10 times, more preferably from 1 to 10 times the molar amount of the compound (IX). 2 to 6 times; the reaction temperature is room temperature to 110 ° C, preferably room temperature to 85 ° C, further preferably 40 ° C to 85 ° C; the substitution reaction described in the step (2) comprises the following steps: in a solvent a compound (VIII) is subjected to a substitution reaction under the action of an alkaline reagent to obtain a compound (VII); wherein Agent is selected from dichloromethane, 1,2-dichloroethane A chloroform, acetonitrile trichloroethane, and combinations of two or more, preferably dichloromethane, 1,2-dichloroethane And one or a combination of two or more of acetonitrile; the alkaline agent is selected from the group consisting of triethylamine, dimethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6 - one or a combination of two or more of lutidine, pyridine, N-methylmorpholine, morpholine, piperidine, aniline and tert-butylamine, preferably triethylamine or N,N-diiso The amount of the phenol is 1 to 8 times, preferably 2 to 6 times, more preferably 2 to 3 times the molar amount of the compound (VIII); and the amount of the alkaline agent is the compound (VIII). The molar amount is 1 to 12 times, preferably 4 to 12 times, further preferably 6 to 12 times; the reaction temperature is -40 to 70 ° C, preferably -30 to 50 ° C.

Another preferred embodiment of the invention for preparing compound (VII) from compound (IX) wherein: The solvent in the step (1) is selected from one or a combination of two or more of dichloromethane, acetonitrile and toluene; the halogenating agent is used in an amount of from 1 to 10 times the molar amount of the compound (IX); and the reaction temperature is room temperature. 80 ° C; The solvent described in the step (2) is selected from the group consisting of dichloromethane; the alkaline agent is selected from the group consisting of triethylamine; the amount of the phenol is 2 to 3 times the molar amount of the compound (VIII); and the amount of the alkaline agent is The molar amount of the compound (VIII) is 6 to 12 times; the reaction temperature is -30 ° C to 50 ° C.

The present invention provides a method for producing a compound represented by the formula (I) or a compound represented by the formula (III-1), and the synthetic route of the method is as follows:

R ¹ , R ² , R ³ , R ⁴ and X are as defined above; the method is: a. halogenation of compound (IX) with a halogenating reagent to form a compound at room temperature to 85 ° C in a solvent ( VIII), the solvent is selected from the group consisting of dichloromethane, acetonitrile or toluene, preferably acetonitrile or toluene, the halogenating agent is selected from the group consisting of dichlorohydrazine or chloroform, the halogenation reaction can be selectively added to the catalyst, and the catalyst is selected from N, N- Dimethylformamide, the halogenating agent is used in an amount of 1 to 10 times that of the compound (IX); b. The compound (VIII) and the phenol are substituted under an alkaline reagent at -30 ° C to 50 ° C in a solvent. The reaction produces the compound (VII), the solvent is selected from one or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform and acetonitrile, and the alkaline agent is selected from the group consisting of triethylamine, N, N-di One or a combination of two or more of isopropylethylamine, 4-dimethylaminopyridine, and 2,6-lutidine, and the amount of the phenol is 2 to 3 times the molar amount of the compound (VIII), and the base is used. The amount of the reagent is 6 to 12 times the molar amount of the compound (VIII); c. The compound (VII) is reacted with an amine protecting agent to form a compound (VI) at room temperature to 80 ° C in a solvent. The solvent is selected from the group consisting of one or a combination of two or more of methanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, acetonitrile and water, and the amine-based protecting agent is selected from dibutyl butyl carbonate or The benzyl chloroformate and the amine protecting agent are used in an amount of 1 to 5 times the molar amount of the compound (VII); d. The compound (VI) is hydrolyzed with the alkaline reagent at 20 ° C to 60 ° C in a solvent. Compound (V), the solvent is selected from one or a combination of two or more of dichloromethane, 1,4-dioxane, acetonitrile and water, and the alkaline agent is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine and One or a combination of two or more kinds in the aqueous ammonia, the amount of the alkaline agent is 3 to 6 times the molar amount of the compound (VI); e. the compound (V) and the halogenating agent at 0 ° C to 70 ° C and in a solvent The halogenation reaction occurs to form the compound (III), the solvent is selected from dichloromethane or acetonitrile, the halogenating agent is selected from the group consisting of grass chloroform, the halogenation reaction is selectively added to the catalyst, and the catalyst is preferably N,N-dimethylformamide. The amount of the halogenating agent is 1 to 10 times the molar amount of the compound (V); or, at room temperature to 85 ° C and in the solvent, the compound (V) Halogenation reaction with a halogenating reagent to form compound (III-1), the solvent is selected from acetonitrile, the halogenating agent is selected from the group consisting of dichlorohydrazine, and the halogenating agent is used in an amount of 1 to 10 times the molar amount of the compound (II); f. The compound (III) is substituted with the compound (IV) at -40 ° C to 50 ° C to form the compound (II). The solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile or tetrahydrofuran. The reaction may optionally be carried out by adding an alkaline reagent selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine. Or a combination of two or more kinds, the amount of the compound (IV) is 1 to 6 times the molar amount of the compound (III); g. the compound (II) in an acidic reagent or hydrogenolysis at 0 ° C to 60 ° C and in a solvent The catalyst undergoes amine-based deprotection reaction to form compound (I). The solvent is selected from one or a combination of two or more of dichloromethane, acetonitrile, tetrahydrofuran, dioxane and water. The acidic reagent is selected from the group consisting of acetic acid, trifluoroacetic acid and hydrogen. Chloric acid or hydrobromic acid, the hydrogenolysis catalyst is selected from palladium/carbon, Raney nickel or palladium hydroxide/carbon, and the amount of the acidic reagent is compound (I) The molar amount of I) is 1 to 10 times, and the amount of the hydrogenolysis catalyst is 0.01 to 10 times the molar amount of the compound (II).

A preferred embodiment of the present invention for preparing compound (I) or compound (III-1) from compound (IX) wherein: R ¹ , R ² , R ³ , R ⁴ and X are as defined above; Chlorine reaction of dichlorohydrazine with compound (IX) at 75 ° C ~ 85 ° C and acetonitrile, the amount of dibromide is 4 to 10 times the molar amount of compound (IX), reaction 3 ~ 4 b. Between -30 ° C ~ 50 ° C and dichloromethane, phenol and compound (VIII) in the reaction of triethylamine reaction substitution, the amount of phenol is 2 to 3 times the molar amount of compound (VIII) , the amount of triethylamine used is 6 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 10 to 14 hours; c. at 60 ° C to 72 ° C and in tetrahydrofuran, the amine protecting agent and the compound (VII) are in 4 - The reaction occurs under the action of dimethylaminopyridine, the amine protecting agent is selected from dibutyl butyl dicarbonate, and the dibutyl butyl dicarbonate is used in an amount of 2 to 4 times the molar amount of the compound (VII), 4 - dimethylaminopyridine is used in an amount of 0.2 to 0.5 times the molar amount of the compound (VII), and the reaction is carried out for 2 to 4 hours; d. in a mixed solvent of acetonitrile-water at 50 ° C to 60 ° C, the compound (VI) In the action of triethylamine and ammonia The hydrolysis reaction occurs, the amount of triethylamine is 2 to 5 times the molar amount of the compound (VI), the amount of the ammonia water is 1 to 4 times the molar amount of the compound (VI), and the reaction is 10 to 14 hours; e. Chlorine reacts with compound (V) at 0 °C ~ 30 °C and dichloromethane. The amount of grass chloroform is 2~5 times of the molar amount of compound (V), and the reaction takes 1~4 hours. Or, at 70 ° C ~ 85 ° C and acetonitrile, the compound (V) and chlorinated chlorination reaction to produce (III-1), the amount of dibromide is the molar amount of the compound (V) 2 ~4 times, the reaction is 3~4 hours; f. The compound (IV) is substituted with the compound (III) at -30 ° C ~ room temperature and dichloromethane to prepare (III), the amount of the compound (IV) 1 to 6 times the molar amount of the compound (III); g. The amine group deprotection reaction of the compound (II) with trifluoroacetic acid at room temperature ~ 30 ° C and dichloromethane, the amount of trifluoroacetic acid It is 8 to 12 times the molar amount of the compound (II), and the reaction is carried out for 2 to 3 hours.

The present invention provides a compound represented by the formula (VI),

The definitions of R ¹ and R ² are as described above.

DETAILED DESCRIPTION OF THE INVENTION: Unless otherwise stated, the terms used in the specification and claims are intended to have the following meaning.

The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention include their isotopic states, and the elements of the groups and compounds of the present invention: carbon, hydrogen, Any of oxygen, sulfur or nitrogen is further replaced by 1 to 5 of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include helium (H) and helium (D, also known as heavy Hydrogen), strontium (T, also known as super-heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

The term "alkyl" refers to a saturated or unsaturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preferred are alkyl groups having from 1 to 10 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl a group, a n-pentyl group, a n-decyl group, and various branched isomers thereof; more preferably a lower alkyl group having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, and propyl groups. Base, allyl, isopropyl, n-butyl, isobutyl or tert-butyl, and the like.

"Substituted or unsubstituted" refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.

"Substitution" refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom. In the case where the group is substituted, for example, an alkyl group, a benzyl group or an alkoxy group is further selected from 0 to 4 selected from H, F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl or C. Substituted by a substituent of _1-4 alkoxy, the group formed includes, but is not limited to, chloromethyl, trichloromethyl, hydroxymethyl, -CH ₂ OCH ₃ , CH ₂ CH ₂ CN, -OCH ₂ Cl, -OCH ₂ OCH ₂ CH ₃ , 4-methoxybenzyl or 2,4-dimethoxybenzyl.

"Alcohol solvent" means a solvent having a hydroxyl group in its molecular structure, and non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, and secondary Pentanol, 3-pentanol, isoamyl alcohol, pivalanol, n-hexanol or cyclohexanol.

The "ether solvent" means a solvent of an ether bond in a molecular structure, and non-limiting examples include tetrahydrofuran, diethyl ether, dioxane, methyl tert-butyl ether, dimethoxyethane, diisopropyl ether, and B. Butyl butyl ether, dibutyl ether, dipentyl ether, diethylene glycol dimethyl ether and triethylene glycol dimethyl ether.

The "aromatic solvent" means a solvent having an aromatic ring in its molecular structure, and non-limiting examples include benzene, toluene, xylene or chlorobenzene.

The "halogenated alkane solvent" means an alkane solvent containing a halogen (fluorine, chlorine, bromine, or iodine) in a molecular structure, and non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, tetrachlorination. Carbon, pentachlorohexane, 1-chlorobutane and tribromomethane.

"Ester solvent" means a solvent containing a carboxylic acid ester in a molecular structure, and non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetate, isoamyl acetate, and acetic acid. Propyl ester, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, second butyl acetate, butyl formate, propyl formate, n-amyl formate or diethyl carbonate.

"Ketone solvent" means a solvent containing a ketone carbonyl group in a molecular structure, and non-limiting examples include acetone, methyl ethyl ketone, acetophenone, methyl isobutyl ketone, Phorone, isophorone or Isopropyl ketone and the like.

The "nitrile solvent" means a solvent containing a cyano group in its molecular structure, and non-limiting examples include acetonitrile, butyronitrile or phenylacetonitrile.

"Amidoxime solvent" means a solvent containing a guanamine in a molecular structure, and non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-di Ethyl acetamide, hexamethylphosphonium or N-methylpyrrolidone.

"Alkene-based solvent" means a solvent containing a sulfinyl group in a molecular structure, without limitation Examples include dimethyl hydrazine.

"Hydrazine type solvent" means a solvent containing a thiol group in the molecular structure, and a non-limiting example includes cyclobutyl hydrazine.

"Amino acid for natural or pharmaceutical use": The basic skeleton of a protein molecule is an amino acid sequence, and there are 20 basic amino acids constituting a protein. These 20 basic amino acids are the basis for biological late modification of proteins. On the basis of these basic amino acids, the organism also synthesizes the types of amino acids derived from hydroxyproline, hydroxylysine, etc., which are collectively referred to as "natural amino acids" by biosynthesized amino acids; Artificially synthesized is "unnatural amino acid"; "pharmaceutical amino acid" means pharmaceutically acceptable natural or Non-natural amino acid.

"A side chain of an amino acid" means an amino acid formula R substituents in the structure.

"Amino protecting group" means a group for the protection of an amine group which is suitable for protecting an amine group such that the amine group does not undergo a chemical reaction, but the group is easy after completion of the desired chemical reaction in other parts of the molecule. Remove. In "Protective Bases in Organic Synthesis" (Translated by the Department of Organic Chemistry, East China University of Science and Technology, Rong Guobin School, East China University of Science and Technology Press, 2004; the original book is Protective Groups In Organic Synthesis (third edition), Theodora W. Green and Peter GM The protection of the amine group is described in detail in the chapter on the protection of the amine group in Wuts. This specification refers to pages 494-653 of the "Protective Groups in Organic Synthesis" as part of the book.

"Amino protecting group" includes, but is not limited to, the following groups: benzyl, p-methoxybenzyl, trityl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2 , 2,2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, trifluoroethenyl, ethenyl or benzhydryl.

"Optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "halogenation reaction can be selectively added to the catalyst" means that the catalyst can be added to the reaction without necessarily adding to the reaction.

"Room temperature" means that the reaction temperature is from 20 ° C to 30 ° C.

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethyl decane (TMS), and the external standard is 85% phosphoric acid aqueous solution.

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet. The specification of the tannin sheet used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4. Mm~0.5mm.

Column chromatography generally uses Yantai Huanghai Silicone 200-300 mesh silicone as a carrier.

Known starting materials of the invention may be employed or according to methods known in the art. Synthetic, or can be purchased from Titan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology.

In the examples, unless otherwise specified, the reaction was carried out under a nitrogen atmosphere.

In the examples, unless otherwise stated, the solution means an aqueous solution.

In the examples, unless otherwise specified, the temperature of the reaction was room temperature.

The room temperature is the optimum temperature, which is 20 ° C ~ 30 ° C.

N is moles per liter.

BOC, a third butoxycarbonyl group.

Example 1: (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)

Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

First step: 6-amino-9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indole (1C)

9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-amine

[[(1R)-2-(6-Aminopurine-9-yl)-1-methylethoxy]methyl]phosphoric acid (PMPA, Tenofovir) (400 g, 1.4 mol) was dissolved in acetonitrile (2.5 L) Among them, dichlorohydrazine (666 g, 5.6 mol) was added dropwise at normal temperature, and the mixture was heated to reflux for 3 hours. The reaction solution was cooled to room temperature and concentrated to give the compound 6-amino-9-[(2R)-2-(dichlorophosphonylmethoxy)propyl] hydrazide (1B).

6-Amino-9-[(2R)-2-(dichlorophosphoniomethoxy)propyl]indole (1B) was dissolved in dichloromethane (2.5 L), and phenol (289.8 g, 3.08) was added. Mol), cooled to -30 ° C, added triethylamine to adjust pH > 7, and warmed to room temperature overnight. Water (2.0 L) was added to the reaction mixture, and the mixture was separated and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 0.5L×2) extraction, the aqueous phase is cooled to 0 ° C, ammonia water is added, the pH is adjusted to 7, then extracted with dichloromethane (2.0 L×2), and the organic phase of dichloromethane is combined, washed with saturated sodium chloride solution, anhydrous Drying over sodium sulfate, filtration, and EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (238 g, yield 38.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.87 (s, 1H), 7.34 - 7.26 (m, 4H), 7.21 - 7.13 (m, 4H), 7.10 - 7.05 (m, 2H) , 5.86 (s, 2H), 4.35 (dd, 1H), 4.19-4.10 (m, 2H), 4.08-3.98 (m, 1H), 3.90 (dd, 1H), 1.25 (d, 3H).

Second step: N-t-butyloxy-N-[9-[(2R)-2-(diphenoxyphosphonium methoxy) Phenyl) hydrazino-6-yl] butyl methacrylate (1D)

Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]purin-6-yl]carbamate

6-Amino-9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indole (1C) (238 g, 0.54 mol) was dissolved in tetrahydrofuran (1 L), 4 -Dimethylaminopyridine (13.2 g, 0.108 mol) was added in portions to a solution of dibutyltributate dicarbonate (354 g, 1.62 mol) in tetrahydrofuran (0.5 L), and the mixture was warmed to reflux for 2 hours. The reaction solution was cooled to room temperature, and a 1N aqueous solution of hydrochloric acid (0.5 L) was added, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (0.3 L×2). Product N-tert-butoxy-N-[9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester (1D), a black oil, used directly in the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.83 (s, 1H), 8.17 (s, 1H), 7.37-7.28 (m, 4H), 7.25-7.13 (m, 6H), 4.48-4.39 (m, 1H) , 4.28 (dd, 1H), 4.15 (dd, 1H), 4.09-4.00 (m, 1H), 4.01-3.91 (m, 1H), 1.51-1.39 (m, 18H), 1.22 (d, 3H).

HPLC purity: Rt = 22.04 min, 97.2%.

Third step: [(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]indol-9-yl]-1-methyl-ethoxy]methyl-phenoxy- Monophosphate (1E)

[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphinic acid

N-tert-butyloxy-N-[9-[(2R)-2-(diphenoxyphosphonylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester (1D) (345 g, 0.54 mol) dissolved in acetonitrile (0.8 L) and water (0.2 L, acetonitrile: water (v/v) = 4:1), triethylamine (273 g, 2.7 mol), and aqueous ammonia solution (36.7 g, 0.54 mol, content 25%) The temperature was raised to 50 ° C and allowed to react overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, a saturated sodium hydrogen carbonate solution (2.0 L), stirred, and extracted with ethyl acetate (0.5 L×2), and the aqueous phase was adjusted to pH <7, and then dichloromethane. (0.7L × 2), extracted, combined with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and then evaporated to give the title product [(1R)-2-[6-[ Alkyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphoric acid (1E), dark red oil (250 g, yield 82.2%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 12.53 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 7.29-7.19 (m, 4H), 7.02 (m, 1H), 4.43 (d , 1H), 4.23 (dd, 1H), 3.91 (m, 2H), 3.66-3.61 (m, 1H), 1.42 (s, 18H), 1.09 (d, 3H).

HPLC purity: Rt = 12.33 min, 93.95%.

³¹ P NMR (162 MHz, CDCl ₃ ) δ 15.05.

Fourth step: N-t-butoxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl]indole-6-yl] Tert-butyl carbazate (1F)

Tert-butyl N-tert-butoxycarbonyl-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-yl]carbamate

[(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate ( 1E) (10 g, 17.7 mmol) was dissolved in dichloromethane (100 mL), dichloromethane (4.49 g, 35.4 mmol) was added, and 2 N of N,N-dimethylformamide was added dropwise, and the mixture was stirred for 1 hour. The reaction liquid was distilled under reduced pressure to give the titled product N-t-butyloxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl] hydrazine- 6-yl]tributyl carbamic acid (1F) was used directly in the next reaction.

The fifth step: (2S)-2-[[[2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy] Methyl-phenoxy-phosphonium]amino]propionic acid isopropyl ester (1G)

(2S)-2-[[[2-[(1R)-6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

N-Tertioxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]propyl]pyridin-6-yl under nitrogen atmosphere The third butyl carbazate (1F) (17.7 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 ° C, and then dropwiselylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylyly The solution was heated to normal temperature for 1 hour. Saturated sodium chloride solution (50 mL) was added to the reaction mixture, and the mixture was separated and evaporated, evaporated, evaporated, evaporated. 2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphonyl]amino group Isopropyl propionate (1G), light yellow oil (5.6 g, yield 45.9%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.84 (d, 1H), 8.28 (d, 1H), 7.33-7.25 (m, 2H), 7.17-7.12 (m, 3H), 5.08-4.92 (m, 1H) , 4.47 (ddd, 1H), 4.32-4.22 (m, 1H), 4.08-3.90 (m, 3H), 3.79-3.71 (m, 1H), 3.65-3.49 (m, 1H), 1.44 (d, 18H) , 1.30-1.18 (m, 12H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.38, 22.13.

The sixth step: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)

Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

(2S)-2-[[[2-[(1R)-6-[bis(t-butoxycarbonyl)amino]]-9-yl]-1-yl Isopropyl-ethoxy]methyl-phenoxy-phosphonium]amino]propionic acid isopropyl ester (1G) (5.6 g, 8.08 mmol) was dissolved in dichloromethane (100 mL). 9.21 g, 80.8 mmol), and the mixture was heated to 30 ° C for 3 hours. The reaction solution was cooled to 0 ° C, and the aqueous solution was adjusted to pH &lt;7&gt;, then dichloromethane (50 mL) and saturated sodium chloride (50 mL). (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propyl Isopropyl acrylate (Compound 1), yellow oil (2.5 g, 64.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, 1H), 8.02 (d, 1H), 7.34-7.20 (m, 2H), 7.18-7.08 (m, 2H), 7.03-6.98 (m, 1H) , 5.91 (s, 2H), 4.96 (m, 1H), 4.40 (m, 1H), 4.22-4.11 (m, 1H), 4.11-3.87 (m, 3H), 3.76-3.44 (m, 2H), 1.34 -1.16 (m, 12H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.70, 22.35.

Example 2: (2S)-2-[[[(1R)-2-(6-Aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)

Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

First step: 6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphino)]methoxy]isopropyl]anthracene (2A)

9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6 -amine

[(1R)-2-[6-[bis(t-butyloxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate ( 1E) (250 g, 0.44 mol) was dissolved in acetonitrile (0.8 L), and then dichlorothylene (104 g, 0.88 mol) was added, and the mixture was heated to 70 ° C for 3 hours under a nitrogen atmosphere. The reaction mixture was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup..sup..sup..sup. Used directly in the next step.

The second step: (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Amino] isopropyl propionate (Compound 1)

Isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate

6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonium]methoxy]isopropyl]anthracene (2A) (40.5 g, 0.106 mol) The solution was dissolved in dichloromethane (200 mL), cooled to -20 ° C, and a solution of L-alanine (69.5 g, 0.53 mol) in dichloromethane (300 mL) was added dropwise. Water (500 mL) was added to the mixture and the mixture was evaporated. The residue was added to a 1N aqueous solution of hydrochloric acid (500 mL). The aqueous layer was cooled to 0 ° C, EtOAc (EtOAc) (EtOAc) )-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino]propanoate Propyl ester (Compound 1), light brown solid (20 g, yield 40.0%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, 1H), 8.02 (d, 1H), 7.31 (t, 1H), 7.23 (t, 1H), 7.16-7.09 (m, 2H), 7.02-6.99 (m, 1H), 5.91 (s, 2H), 5.04-4.89 (m, 1H), 4.47-4.33 (m, 1H), 4.22-4.11 (m, 1H), 4.11-3.87 (m, 3H), 3.76 -3.44 (m, 2H), 1.31-1.17 (m, 12H).

HPLC purity: Rt = 14.85 min, 95.36%.

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.70, 22.35.

MS M/Z (ESI): 476.9 (M + 1).

Claims (26)

A method for preparing a compound represented by the formula (I): It is characterized in that the compound (II) is subjected to an amine group deprotection reaction under an alkaline reagent, an acidic reagent or a hydrogenohydrolysis catalyst at 0 ° C to 100 ° C in a solvent; R ¹ and R ² are each independently selected from an amine protecting group or hydrogen, provided that R ¹ and R ^{2 are} not simultaneously hydrogen; R ^{3 is} selected from natural or pharmaceutically acceptable amino acid side chains; and R ^{4 is} selected from C ₁ - ₁₀ alkyl; the solvent used in the reaction is selected from the group consisting of an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, a guanamine solvent, an anthraquinone a combination of one or more of a solvent and water; the acidic agent is selected from the group consisting of an organic acid or a mineral acid; and the alkaline agent is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metals a combination of one or more of a carbonate and an organic amine; the hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon; and the amount of the alkaline agent is a compound ( II) is 1 to 10 times the molar amount; the acidic reagent is used in an amount of 1 to 30 times the molar amount of the compound (II); and the hydrogenolysis catalyst is used in an amount of 0.01 to 1 in the molar amount of the compound (II). Times. The method according to claim 1, wherein R ¹ and R ² are each independently selected from the group consisting of hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, and B. Mercapto or benzhydryl, and R ¹ and R ^{2 are} not simultaneously hydrogen; R ^{3 is} selected from the group consisting of glycine, alanine, leucine, phenylalanine, aspartame or arginine; ^{4 is} selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; the solvent used in the reaction is selected from the group consisting of methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethyl a combination of one or more of carbamide, dimethyl hydrazine, N-methylpyrrolidone and water; the acidic reagent is selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzene a group of one or more of formic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid The alkaline agent is selected from one or a combination of two or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine, and N,N-diisopropylethylamine. The amount of the acidic reagent is 1 to 20 times the molar amount of the compound (II); and the reaction temperature is 0 ° C to 60 ° C. The method according to claim 2, wherein R ¹ and R ^{2 are} selected from the group consisting of a third butoxycarbonyl group; R ^{3 is} selected from the side chain of alanine; and the solvent used in the reaction is selected from the group consisting of a combination of one or more of methyl chloride, tetrahydrofuran, dioxane and water; the acidic reagent is selected from the group consisting of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid; and the acidic reagent is used in a compound ( II) The molar amount is 1~10 times; the reaction temperature is 0 °C~50 °C. A method for preparing a compound represented by formula (II): It is characterized in that a compound (III) and a compound (IV) are subjected to a monosubstituted reaction at -78 ° C to 50 ° C in a solvent; R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1; X is selected from fluorine, chlorine, bromine or iodine; and the solvent used in the reaction is selected from the group consisting of aromatic hydrocarbon solvents and ether solvents. And a combination of one or more of a halogenated alkane solvent, an ester solvent, a ketone solvent, and a nitrile solvent; the substitution reaction may optionally be added with an alkaline reagent; and the compound (IV) is used as a compound ( The molar amount of III) is 0.8 to 7 times. The method according to claim 4, wherein X is selected from chlorine; and the solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, One or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, toluene and chlorobenzene; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, and carbonic acid Potassium hydrogen, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, triethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-A One or a combination of two or more of morpholine, morpholine, piperidine and aniline; the reaction temperature is -40 ° C to 50 ° C. The method according to claim 5, wherein the solvent used in the reaction is selected from the group consisting of dichloromethane; The alkaline agent is selected from the group consisting of triethylamine or N,N-diisopropylethylamine; and the compound (IV) is used in an amount of from 1 to 6 times the molar amount of the compound (III). A compound of the formula (II), characterized in that: Wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 4 of the scope of the patent application. A method for preparing a compound represented by formula (III) or (III-1): Characterizing that the compound (V) is halogenated with a halogenating reagent to form a compound (III) or a compound (III-1) at 0 ° C to 110 ° C in a solvent; R ¹ , R ² and X are as defined in claim 4; the solvent used in the reaction is selected from one or a combination of two or more of a halogenated alkane solvent, a nitrile solvent and an anthraquinone solvent; The halogenation reaction may optionally be added to a catalyst, wherein the catalyst is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylaniline, triethylamine or pyridine; the amount of the halogenating agent is The molar amount of the compound (V) is 1 to 15 times. The method according to Item 8 of the patent application, characterized in that the solvent used in the reaction is selected from one or a combination of two or more of dichloromethane, trichloroethane, acetonitrile and cyclobutyl hydrazine; The halogenating agent is selected from the group consisting of dichlorohydrazine, grass chloroform, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine chloride, dibromoarylene, grass ruthenium bromide, phosphorus tribromide , phosphorus pentabromide, trichlorooxyl bromide, triphenylphosphine bromide or 1-chloro-N,N,2-trimethylpropenamine; the catalyst is selected from the group consisting of N,N-dimethylformamide The halogenating agent is used in an amount of 1 to 10 times the molar amount of the compound (V); the temperature at which the compound (III) is prepared is 0 ° C to 80 ° C; and the temperature at which the compound (III-1) is prepared is room temperature. 85 ° C. The method according to claim 8, wherein the solvent used in the reaction is selected from the group consisting of dichloromethane or acetonitrile; the halogenating agent for preparing the compound (III) is selected from the group consisting of grass chlorochloride; and the compound (III-) is prepared. 1) the halogenating agent is selected from the group consisting of dichlorohydrazine; the halogenating agent is used in an amount of 1 to 5 times the molar amount of the compound (V); the temperature at which the compound (III) is prepared is 0 ° C to 30 ° C; III-1) The temperature of the reaction is from 70 ° C to 85 ° C. A compound of the formula (III), characterized in that: Wherein R ¹ , R ² and X are as defined in item 4 of the scope of the patent application. A method for preparing a compound represented by formula (V): It is characterized in that the compound (VI) is hydrolyzed with an alkaline reagent at 0 ° C to 110 ° C in a solvent; R ¹ and R ² are as defined in claim 4; the solvent used in the reaction is selected from the group consisting of an alcohol solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent. a combination of one or more of a guanamine solvent, an anthraquinone solvent, and water; the alkaline agent is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, and One or a combination of two or more of the organic amines; the alkaline agent is used in an amount of from 1 to 15 times the molar amount of the compound (VI). The method according to claim 12, wherein the solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, and dimethoxyethane. , diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane, 1,2-dichloroethane, chloroform , trichloroethane, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dioxane, methyl tert-butyl ether, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, N, a combination of one or more of N-dimethylformamide, dimethylhydrazine, N-methylpyrrolidone and water; the alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate , potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, tert-butylamine, 1,8-bisdimethylaminonaphthalene, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8- Diaza One or a combination of two or more of undecyl-7-ene, imidazole, N-methylmorpholine, morpholine, piperidine, aniline, aqueous ammonia and hydrazine hydrate; the amount of the basic reagent is compound (VI) The molar amount is 1 to 10 times; the reaction temperature is room temperature to 80 °C. The method according to claim 12, wherein the solvent used in the reaction is selected from the group consisting of acetonitrile, water or a combination thereof; The alkaline agent is selected from one or a combination of two or more of sodium hydrogencarbonate, triethylamine and aqueous ammonia; the alkaline agent is used in an amount of from 3 to 6 times the molar amount of the compound (VI); It is 20 ° C ~ 60 ° C. A compound of the formula (V) characterized by: Wherein R ¹ and R ² are as defined in item 4 of the scope of the patent application. A method for preparing a compound represented by the formula (VI): It is characterized in that the compound (VII) is reacted with an amine-based protecting agent at 0 ° C to 110 ° C in a solvent; (VII) R ¹ and R ² are as defined in claim 4; the solvent used in the reaction is selected from the group consisting of an alcohol solvent, an ether solvent, a halogenated alkane solvent, a ketone solvent, a nitrile solvent, a combination of one or a combination of an ester solvent, a guanamine solvent, an anthraquinone solvent, and water; the amine protecting reaction may optionally be added to a catalyst, wherein the catalyst is selected from the group consisting of triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine; the amine protecting agent is used in an amount of from 1 to 15 times the molar amount of the compound (VII). The method according to claim 16, wherein the solvent used in the reaction is selected from the group consisting of methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran. , one or more of 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, dimethylformamide, dimethyl hydrazine, acetone, methyl ethyl ketone and water Combination; the amine-based protecting agent is selected from the group consisting of di-tert-butyl dicarbonate, benzyl chloroformate, p-methoxybenzyl bromide, benzyl bromide, p-methoxybenzyl chloride, benzyl chloride, acetic anhydride, Trifluoroacetic anhydride, acetamidine chloride, benzoic anhydride or benzamidine chloride; the amine protecting agent is used in an amount of from 1 to 10 times the molar amount of the compound (VII). The method according to claim 17, wherein the solvent used in the reaction is selected from the group consisting of tetrahydrofuran; the amine protecting agent is selected from dibutyl butyl dicarbonate; and the catalyst is selected from the group consisting of 4- Dimethylaminopyridine; The amine protecting agent is used in an amount of 2 to 5 times the molar amount of the compound (VII); and the reaction temperature is from room temperature to 80 °C. A process for the preparation of a compound of the formula (VII), which comprises the steps of: (1) halogenating a compound (IX) with a halogenating reagent to obtain a compound (VIII); (2) substituting a compound (VIII) with a phenol The reaction is prepared (VII); The definition of X is as described in item 4 of the patent application. The method according to claim 19, wherein the halogenation reaction in the step (1) comprises the step of halogenating the compound (IX) by a halogenating agent in a solvent. a compound (VIII) wherein the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and toluene, or a combination of two or more; the halogenating agent is selected from the group consisting of Chloride or grass chlorochloride; halogenation reaction may optionally be added to a catalyst selected from N,N-dimethylformamide; the halogenating agent is used in an amount of 1 molar amount of compound (IX) ~15 times; the reaction temperature is room temperature ~ 110 ° C; the substitution reaction described in the step (2) comprises the following steps: in a solvent, under the action of an alkaline reagent, the compound (VIII) is subjected to a substitution reaction, Producing the compound (VII); wherein the solvent is selected from one or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, and acetonitrile; Selected from triethylamine, dimethyl Amine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, N-methylmorpholine, morpholine, piperidine, aniline and third One or a combination of two or more of the amines; the amount of the phenol used is 1 to 8 times the molar amount of the compound (VIII); and the amount of the alkaline agent is 1 to 12 times the molar amount of the compound (VIII); The temperature is -40 ° C ~ 70 ° C. The method according to claim 20, wherein in the step (1), the solvent is selected from one or a combination of two or more of dichloromethane, acetonitrile and toluene; and the amount of the halogenating agent is used. 1 to 10 times the molar amount of the compound (IX); the reaction temperature is room temperature to 85 ° C; the solvent in the step (2) is selected from the group consisting of dichloromethane; the alkaline agent is selected from the group consisting of triethylamine; phenol The amount used is 2 to 3 times the molar amount of the compound (VIII); the amount of the alkaline agent is 6 to 12 times the molar amount of the compound (VIII); and the reaction temperature is -30 ° C to 50 ° C. A method for preparing a compound represented by the formula (I) or a compound represented by the formula (III-1), and the synthetic route of the method is as follows: R ¹ , R ² , R ³ , R ⁴ and X are as defined in claim 4; the method is characterized in that: a. at room temperature to 85 ° C and in a solvent, compound (IX) and The halogenation reagent is halogenated to form a compound (VIII) selected from the group consisting of acetonitrile or toluene, the halogenating agent is selected from the group consisting of dichlorohydrazine or chloroform, and the halogenation reaction can be selectively added to a catalyst. From N,N-dimethylformamide, the halogenating agent is used in an amount of from 1 to 10 times that of the compound (IX); b. at a temperature of from -30 ° C to 50 ° C in a solvent, the compound (VIII) and phenol The substitution reaction occurs under an alkaline reagent to give a compound (VII) selected from one or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform and acetonitrile, the base The reagent is selected from one or a combination of two or more of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine, and the amount of the phenol is a compound. (VIII) is 2 to 3 times the molar amount, and the alkaline reagent is used in an amount of 6 to 12 times the molar amount of the compound (VIII); c. at room temperature to 80 ° C in a solvent. (VII) reacting with an amine-based protecting agent to form compound (VI) selected from one or more of methanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, acetonitrile and water. In combination, the amine protecting agent is selected from dibutyl butyl carbonate or benzyl chloroformate, and the amine protecting agent is used in an amount of 1 to 5 times the molar amount of the compound (VII); d. at 20 ° C Compound (VI) is hydrolyzed with an alkaline reagent to form compound (V) at -60 ° C in a solvent selected from the group consisting of dichloromethane, 1,4-dioxane, acetonitrile and water. Or a combination of two or more, the alkaline agent is selected from one or a combination of two or more of sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, and aqueous ammonia, and the alkaline agent is used in an amount of the compound (VI). 3 to 6 times the molar amount; e. halogenation reaction of the compound (V) with a halogenating reagent in a solvent at 0 ° C to 70 ° C to form a compound (III) selected from dichloromethane or acetonitrile. The halogenating agent is selected from the group consisting of grasshopper chlorine, and a halogenation reaction may optionally be added to a catalyst, and the amount of the halogenating agent is the compound (V). 1 to 10 times the molar amount; or, at room temperature to 85 ° C and a solvent, the compound (V) is halogenated with a halogenating reagent to form a compound (III-1), which is selected from acetonitrile, monohalogenated The reagent is selected from the group consisting of dichlorohydrazine or chlorophyll chloride, and the amount of the monohalogenating reagent is 1 to 10 times the molar amount of the compound (II); f. at -40 ° C to 50 ° C and a solvent, the compound (III) And a compound (IV) is substituted to form a compound (II) selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile or tetrahydrofuran, and optionally an alkaline reagent is added to the reaction. The alkaline agent is selected from one or a combination of two or more of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine, and the compound (IV) The amount of the compound (III) is 1 to 6 times the molar amount; g. at 0 ° C to 60 ° C in a solvent, the compound (II) undergoes an amine deprotection reaction on an acidic reagent or a hydrogenolysis catalyst. Forming compound (I) selected from the group consisting of one or a combination of two or more of dichloromethane, acetonitrile, tetrahydrofuran, dioxane and water, the acidic reagent being selected from the group consisting of Acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid, the acidic reagent is used in an amount of from 1 to 10 times the molar amount of the compound (II), and the hydrogenolysis catalyst is used in an amount of the molar amount of the compound (II). 0.01~10 times. The method according to claim 22, wherein the catalyst is N,N-dimethylformamide. The method according to claim 22, characterized in that the hydrogenolysis The catalyst is palladium on carbon, lightning nickel or palladium hydroxide on carbon. The method according to claim 22, characterized in that: a. chlorination reaction of dichlorohydrazine with compound (IX) at 75 ° C to 85 ° C and acetonitrile, the amount of dichloroantimonium compound 4 to 10 times the molar amount of the compound (IX), the reaction is 3 to 4 hours; b. at -30 ° C to 50 ° C and in dichloromethane, the reaction of the phenol with the compound (VIII) under the action of triethylamine In the reaction, the amount of phenol is 2 to 3 times the molar amount of the compound (VIII), the amount of the triethylamine is 6 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 10 to 14 hours; c. at 60 ° C. At 72 ° C and in tetrahydrofuran, an amine-based protecting agent is reacted with compound (VII) under the action of 4-dimethylaminopyridine, which is selected from di-tert-butyl dicarbonate, diethylene carbonate The amount of the tributyl ester is 2 to 4 times the molar amount of the compound (VII), and the amount of the 4-dimethylaminopyridine is 0.2 to 0.5 times the molar amount of the compound (VII), and the reaction is carried out for 2 to 4 hours; In a mixed solvent of acetonitrile-water at 50 ° C to 60 ° C, the compound (VI) is hydrolyzed by triethylamine and aqueous ammonia, and the amount of triethylamine is 2, the molar amount of the compound (VI). ~5 times, the amount of ammonia water is 1~4 times of the molar amount of compound (VI), and the reaction is 10~14 hours; e. at 0 °C~30 °C and dichloromethane, grasshopper chlorine and compound (V) The chlorination reaction occurs. The amount of chlorine in the grass is 2 to 5 times the molar amount of the compound (V), and the reaction is carried out for 1 to 4 hours; or, in the case of 70 ° C to 85 ° C and in the acetonitrile, the compound (V) and the second The chlorination reaction of chlorinated hydrazine is formed (III-1), and the amount of dichloroarene is 2~4 of the molar amount of compound (V). The reaction is carried out for 3 to 4 hours; f. The compound (IV) is substituted with the compound (III) at -30 ° C to room temperature, and the amount of the compound (IV) is the mole of the compound (III). 1 to 6 times the amount; g. at room temperature ~ 30 ° C and dichloromethane, the compound (II) and trifluoroacetic acid amine deprotection reaction, the amount of trifluoroacetic acid is the mole of compound (II) The amount is 8~12 times and the reaction is 2~3 hours. a compound of the formula (VI), The definitions of R ¹ and R ² are as described in item 4 of the scope of the patent application.