WO2015161785A1

WO2015161785A1 - Method for preparing phosphoramidate derivative and intermediates thereof, and method for preparing intermediates

Info

Publication number: WO2015161785A1
Application number: PCT/CN2015/077088
Authority: WO
Inventors: 魏用刚; 邱关鹏; 卢泳华; 祝国智
Original assignee: 四川海思科制药有限公司
Priority date: 2014-04-21
Filing date: 2015-04-21
Publication date: 2015-10-29
Also published as: HK1217201A1; CN105531281A; CN105531281B; CN105518011B; WO2015161781A1; CN105518011A

Abstract

The present invention relates to a method for preparing a phosphoramidate derivative, as shown by general formula (I) and having an antiviral activity, and intermediates thereof, and a method for preparing the intermediates.

Description

Preparation method of phosphoramidate derivative, preparation method of intermediate and intermediate thereof

Technical field

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

Background technique

The compound represented by the formula (I) is a phosphoramidate derivative which is a prodrug of tenofovir and can inhibit the viral polymerase by directly competitively binding to the natural deoxyribose substrate. For the treatment of HIV and HBV infection.

In the compound of formula (I), R ^{3 is} selected from the natural or pharmaceutically acceptable amino acid side chain; and R ^{4 is} selected from C _1-10 alkyl.

At present, the methods disclosed in the formula (I) disclosed at home and abroad mainly include the following:

1) CN1443189A discloses the preparation of GS-7171 starting from 9-(2-(phosphonomethoxy)propyl]adenine (PMPA). The route 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, and the route is as follows:

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

In the presently disclosed synthetic method, the amino 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.

Summary of the invention

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

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

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

R ¹ and R ² are each independently selected from an amino 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:

The compound (II) is subjected to an amino deprotection reaction under an alkaline reagent, an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 100 ° C in a solvent;

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

R ^{3 is} selected from natural or pharmaceutically acceptable amino acid side chains;

R ^{4 is} selected from C _1-10 alkyl;

The solvent to be 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 not limited to an alcohol solvent, an aromatic hydrocarbon solvent, or an ether solvent. a combination of one or more of a halogenated alkane solvent, an ester solvent, a ketone solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, and water;

The acidic reagent is selected from an organic acid or a mineral acid;

The alkaline 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;

The hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon;

The amount of the alkaline agent is 1 to 10 times the molar amount of the compound (II);

The acidic reagent is used in an amount of from 1 to 30 times the molar amount of the compound (II);

The amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II).

A preferred embodiment of the invention wherein said amino protecting group is selected from a substituted or unsubstituted benzyl, alkoxycarbonyl, alkylacyl or aryl acyl group.

A preferred embodiment of the preparation of the compound (I) from the compound (II) of the present invention, wherein:

R ¹ and R ² are each independently selected from hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl, and R ¹ and R ^{2 are} not hydrogen at the same time. Preferably, R ¹ and R ^{2 are} selected from the group consisting of t-butoxycarbonyl;

R ³ is a side chain of a natural or pharmaceutically acceptable amino acid, wherein the amino acids are preferably glycine, alanine, leucine, isoleucine, tyrosine, valine, phenylalanine, methothiol Acid, tryptophan, serine, glutamine, threonine, cysteine, histidine, asparagine, tyrosine, aspartic acid, glutamic acid, naphthyl acid or arginine, Further preferred are glycine, alanine, leucine, phenylalanine, asparagine or arginine, more preferably glycine, alanine or phenylalanine, and R ^{3 is} more preferably a side chain of alanine;

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 branched isomers thereof and the like; further preferred are lower alkyl groups having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, allyl, isopropyl, n-butyl Base, 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 tert-butyl ether, dimethoxyethane, and Ethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane, 1,2-dichloroethane, chloroform, three One or a combination of two or more of ethyl chloride, acetone, methyl ethyl ketone, toluene, chlorobenzene and xylene, preferably methanol, ethanol, isopropanol, dichloromethane, 1,2-dichloroethane, Chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, diethyl ether, dioxane, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide a combination of one or more of N-methylpyrrolidone and water, more preferably one or a combination of two or more of dichloromethane, tetrahydrofuran, 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, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrofluoric acid. One or a combination of two or more of hydrochloric acid, hydrobromic acid and hydroiodic acid, preferably one or a combination of two or more of acetic acid, trifluoroacetic acid, hydrochloric acid and hydrobromic acid;

The alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogen. Calcium oxide, magnesium hydroxide, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, triethylamine, N,N-diisopropylethylamine, propylamine, methylamine, dimethylamine, tert-butylamine One or a combination of two or more of aniline and aqueous ammonia, preferably potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine and N,N- One or a combination of two or more of diisopropylethylamine, further preferably 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 palladium/carbon or palladium hydroxide/carbon;

The acidic reagent is used in an amount of 1 to 20 times, preferably 1 to 10 times the molar amount of the compound (II);

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, and more preferably 20 ° C to 50 ° C.

Another preferred embodiment of the invention for preparing compound (I) from compound (II), wherein:

R ¹ and R ² are each independently selected from hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl, preferably tert-butoxycarbonyl, and R ¹ and R ^{2 is} not hydrogen at the same time;

R ^{3 is} selected from the side chain of glycine, alanine, leucine, phenylalanine, asparagine or arginine, preferably the side chain of alanine;

R ^{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, and dioxane. One or a combination of two or more of a ring, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and water, preferably dichloromethane , one or a combination of two or more of tetrahydrofuran, 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, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrogen One or a combination of two or more of hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, preferably acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic 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 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;

The definitions of 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 one or a combination of two or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, and a nitrile solvent;

The substitution reaction can selectively add an alkaline reagent;

The compound (IV) is used in an amount of from 0.8 to 7 times the molar amount of the compound (III).

A preferred embodiment of the present invention for preparing compound (II) from compound (III) and compound (IV), wherein

The definitions of R ¹ , R ² , R ³ and R ⁴ are as defined above;

X is selected from chlorine;

The solvent used in the reaction 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;

The substitution reaction may selectively add an alkaline reagent selected from the group consisting of potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and phosphoric acid. Sodium hydrogen hydride, sodium hydrogen phosphate, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1 , one or more of 8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-methylmorpholine, morpholine, piperidine, aniline and t-butylamine a combination of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, N-methylmorpholine, morpholine, piperidine and aniline One or a combination of two or more, further preferably 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 reaction 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:

The definitions of R ¹ , R ² , R ³ and R ⁴ are as defined above;

X is selected from chlorine;

The substitution reaction can selectively add an alkaline reagent;

The solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2- One or a combination of two or more of methyltetrahydrofuran, 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 - one or a combination of two or more of dimethylaminonaphthalene, N-methylmorpholine, morpholine, piperidine and aniline, preferably triethylamine or N,N-diisopropylethylamine;

The reaction temperature is -40 ° C ~ 50 ° C;

The compound (IV) is used in an amount of from 0.8 to 7 times, preferably from 1 to 6 times the molar amount of the compound (III).

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;

The definitions of R ¹ , R ² and X are as described above;

The solvent used in the reaction is one or more selected from the group consisting of a halogenated alkane solvent, a nitrile solvent, and a sulfone solvent. The combination;

The halogenation reaction may be selectively added to the catalyst, and 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 from 1 to 15 times the molar amount of the compound (V).

The present invention provides a preferred embodiment of the compound (III) or the compound (III-1) by halogenation reaction of the compound (V) with a halogenating reagent, wherein:

The solvent used in the reaction is selected from one or a combination of two or more of dichloromethane, trichloroethane, acetonitrile and sulfolane, preferably dichloromethane or acetonitrile;

The halogenating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine chloride, dibromosulfoxide, oxalyl bromide, tribromide. Phosphorus, phosphorus pentabromide, trichlorooxo bromide, triphenylphosphine bromide or 1-chloro-N,N,2-trimethylpropenamine, preferably oxalyl chloride, oxalyl bromide, dichlorosulfoxide, Dibromosulfoxide, phosphorus pentachloride or phosphorus pentabromide; further preferably oxalyl chloride or thionyl chloride;

When preparing the compound (III), the halogenating agent is more preferably oxalyl chloride, and the solvent is more preferably dichloromethane;

When preparing the compound (III-1), the halogenating agent is more preferably thionyl chloride, and the solvent is more preferably acetonitrile;

The halogenation reaction may optionally be carried out by adding a catalyst, the catalyst being selected from the group consisting of N,N-dimethylformamide;

The halogenating agent is used in an amount of from 1 to 10 times, preferably from 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 0 ° C to 40 ° C, more preferably 0 ° C to 30 ° C; when the compound (III-1) is prepared, the reaction temperature is room temperature to 85 ° C, preferably 50. From °C to 85 °C, more preferably from 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;

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

The solvent to be 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 not limitedly selected from the group consisting of an alcohol solvent, an ether solvent, and a halogenated alkane. a solvent, an ester solvent, a ketone solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, and a combination of one or more of water;

The amount of the alkaline agent used is 1 to 15 times the molar amount of the compound (VI).

A preferred embodiment of the present invention for preparing a compound from the compound (VI):

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

The solvent used in the reaction is selected from the group consisting of ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloro Methane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran ,ether, dioxane, methyl tert-butyl ether, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone And one or a combination of two or more kinds of water, preferably dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, One or a combination of two or more of acetonitrile, propionitrile, ethyl acetate, isopropyl acetate and water, further preferably dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate or acetic acid One or a combination of two or more of propyl ester and water, more preferably acetonitrile, water or a combination thereof;

The alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogen. Calcium oxide, magnesium hydroxide, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, tert-butylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, imidazole, N-methylmorpholine, morpholine, piperidine, aniline, aqueous ammonia and hydrazine hydrate One or a combination of two or more; preferably potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, N,N-diisopropylethylamine, triethylamine And a combination of one or more of ammonia water, further preferably one or a combination of two or more of sodium hydrogencarbonate, triethylamine, and ammonia water;

The amount of the alkaline agent used 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, preferably 20 ° C to 60 ° C, and more preferably 40 ° C to 60 ° C.

Another preferred embodiment of the 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;

The alkaline agent is selected from one or a combination of two or more of sodium hydrogencarbonate, triethylamine and ammonia water;

The alkaline reagent is used in an amount of from 3 to 6 times the molar amount of the compound (VI);

The reaction temperature is from 20 ° C 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 amino protecting reagent at 0 ° C to 110 ° C in a solvent;

The definitions of R ¹ and R ² are as described 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, an amide solvent, a sulfoxide solvent, and one or more of water. combination;

The amino protecting reaction may be selectively added to the catalyst, wherein the catalyst is selected from the group consisting of triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine;

The amino 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 invention for preparing compound (VI) by reacting compound (VII) with an amino protecting reagent, wherein:

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

The solvent used in the reaction is selected from the group consisting of methanol, ethanol, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate. , one or a combination of two or more of isopropyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone and water, preferably dichloromethane, tetrahydrofuran and 1,4-dioxane One or a combination of two or more, further preferably tetrahydrofuran;

The amino protecting agent is selected from the group consisting of di-tert-butyl dicarbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride, benzyl bromide, benzyl chloride, p-methoxybenzyl. Bromo, p-methoxybenzyl chloride or trityl chloride, preferably di-tert-butyl dicarbonate, benzyl chloroformate, acetic anhydride, trifluoroacetic anhydride, acetyl chloride, benzoic anhydride or benzoyl chloride, further preferably Di-tert-butyl dicarbonate or benzyl chloroformate, particularly preferably di-tert-butyl dicarbonate;

The amino 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);

The reaction temperature is 0 ° C to 110 ° C, preferably 0 ° C to 80 ° C, more preferably room temperature to 80 ° C, and particularly preferably 50 ° C to 80 ° C.

The solvent used in the reaction is selected from the group consisting of tetrahydrofuran;

The amino protecting agent is selected from the group consisting of di-tert-butyl dicarbonate;

The amino protecting reaction may optionally be added to a catalyst selected from the group consisting of 4-dimethylaminopyridine;

The amino protecting agent is used in an amount of from 2 to 5 times the molar amount of the compound (VII);

The reaction temperature is from room temperature to 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 amino protecting group or hydrogen, provided that R ¹ and R ^{2 are} not simultaneously hydrogen; and each independently is preferably hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, Benzyloxycarbonyl, acetyl or benzoyl, and R ¹ and R ^{2 are} not simultaneously hydrogen, preferably R ¹ and R ^{2 are} selected from t-butoxycarbonyl.

The invention provides a preparation method of the compound represented by the formula (VII), which comprises the following steps:

(1) Compound (IX) is halogenated with a halogenating reagent to obtain a compound (VIII);

(2) Compound (VIII) is substituted with phenol to obtain (VII);

The definition of X is as described above.

A preferred embodiment of the invention for preparing compound (VII) from compound (IX) wherein:

The definition of X is as described above;

The halogenation reaction described in the step (1) comprises the steps of: subjecting the compound (IX) to a halogenation reaction under a action of a halogenating reagent to obtain a compound (VIII); wherein the solvent is selected One or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and toluene, preferably one or a combination of two or more of dichloromethane, acetonitrile and toluene; The reagent is selected from the group consisting of thionyl chloride or oxalyl chloride, preferably thionyl chloride; the halogenation reaction can be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide; and the halogenating agent is used in the compound (IX). The molar amount is 1 to 15 times, preferably 1 to 10 times, more preferably 2 to 6 times; the reaction temperature is room temperature to 110 ° C, preferably room temperature to 85 ° C, more preferably 40 ° C to 85 ° C;

The substitution reaction described in the step (2) comprises the step of: subjecting the compound (VIII) to a substitution reaction in the presence of a basic reagent to obtain a compound (VII); wherein the solvent is selected from the group consisting of One or a combination of two or more of methyl chloride, 1,2-dichloroethane, chloroform, trichloroethane and acetonitrile, preferably one of dichloromethane, 1,2-dichloroethane and acetonitrile Or a combination of two or more; the alkaline agent is selected from the group consisting of triethylamine, dimethylamine, N,N-diisopropylethylamine, One or a combination of two or more of 4-dimethylaminopyridine, 2,6-lutidine, pyridine, N-methylmorpholine, morpholine, piperidine, aniline and t-butylamine, preferably triethylamine or N,N-diisopropylethylamine; phenol is used in an amount of 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, more preferably 6 to 12 times, and 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; and the reaction temperature is -30 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:

The definitions of R ¹ , R ² , R ³ , R ⁴ and X are as defined above;

The method is:

a. The compound (IX) is halogenated with a halogenated reagent to form a compound (VIII) at room temperature to 85 ° C in a solvent. The solvent is selected from the group consisting of dichloromethane, acetonitrile or toluene, preferably acetonitrile or toluene, and the halogenated reagent is selected. From thionyl chloride or oxalyl chloride, The halogenation reaction may be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide, and the halogenating agent is used in an amount of 1 to 10 times that of the compound (IX);

b. At -30 ° C ~ 50 ° C and in the solvent, the compound (VIII) and phenol are substituted under alkaline conditions to form compound (VII), the solvent is selected from dichloromethane, 1,2-dichloroethane , one or a combination of two or more of chloroform and acetonitrile, the alkaline reagent is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine In one or a combination of two or more, 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 6 to 12 times the molar amount of the compound (VIII);

c. Compound (VII) is reacted with an amino protecting reagent to form compound (VI) at room temperature to 80 ° C in a solvent selected from the group consisting of methanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, acetonitrile. In combination with one or more of the two, the amino protecting agent is selected from di-tert-butyl dicarbonate or benzyl chloroformate, and the amino protecting agent is used in an amount of from 1 to 5 times the molar amount of the compound (VII);

d. The compound (VI) is hydrolyzed with an alkaline reagent at 20 ° C to 60 ° C in a solvent to form a compound (V) selected from the group consisting of dichloromethane, 1,4-dioxane, acetonitrile and water. One 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 amount of the alkaline agent is the molar amount of the compound (VI). 3 to 6 times the amount;

e. The compound (V) is halogenated with a halogenating reagent at 0 ° C to 70 ° C in a solvent to form a compound (III), the solvent is selected from dichloromethane or acetonitrile, and the halogenating agent is selected from the group consisting of oxalyl chloride, halogenated The catalyst may be optionally added to the catalyst, and the catalyst is preferably N,N-dimethylformamide. The halogenating agent is used in an amount of from 1 to 10 times the molar amount of the compound (V); or, in the solvent at room temperature to 85 ° C. The compound (V) is halogenated with a halogenating reagent to form a compound (III-1), the solvent is selected from acetonitrile, the halogenating agent is selected from the group consisting of thionyl chloride, and the halogenating agent is used in an amount of the molar amount of the compound (II). 1 to 10 times;

f. At -40 ° C ~ 50 ° C and in the solvent, the compound (III) and the compound (IV) are substituted to form the compound (II), the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, Acetonitrile or tetrahydrofuran, the reaction can be selectively added with an alkaline reagent selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine. One or a combination of two or more, the compound (IV) is used in an amount of from 1 to 6 times the molar amount of the compound (III);

g. The compound (II) undergoes amino deprotection reaction in an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 60 ° C to form a compound (I) selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and dioxane. In combination with one or more of two, the acidic reagent is selected from the group consisting of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid, and the hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel or palladium hydroxide/carbon, acid. The amount of the reagent used is 1 to 10 times the molar amount of the compound (II), 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 producing the compound (I) or the compound (III-1) from the compound (IX), wherein:

The definitions of R ¹ , R ² , R ³ , R ⁴ and X are as defined above;

a. At 75 ° C ~ 85 ° C and acetonitrile, chlorosulfin and compound (IX) chlorination reaction, the amount of thionyl chloride is 4 to 10 times the molar amount of compound (IX), reaction 3 ~ 4 hours;

b. At -30 ° C ~ 50 ° C and dichloromethane, phenol and compound (VIII) under the action of triethylamine reaction substitution reaction, the amount of phenol is 2 to 3 times the molar amount of compound (VIII), three The amount of the ethylamine is 6 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 10 to 14 hours;

c. In 60 ° C ~ 72 ° C and tetrahydrofuran, the amino protecting reagent and compound (VII) reacted under the action of 4-dimethylaminopyridine, the amino protecting reagent is selected from di-tert-butyl dicarbonate, di-tert-butyl dicarbonate The amount of the 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;

d. 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 to 4 times the molar amount of the compound (VI), and the reaction is carried out for 10 to 14 hours;

e. Chlorination reaction of oxalyl chloride with compound (V) at 0 ° C to 30 ° C and dichloromethane, the amount of oxalyl chloride is 2 to 5 times the molar amount of compound (V), and the reaction is 1-4 hours. Or, in 70 ° C ~ 85 ° C and acetonitrile, the compound (V) and chlorosulfin chlorination reaction to form (III-1), the amount of chlorine dioxide is the molar amount of the compound (V) 2 ~ 4 times, the reaction is 3 to 4 hours;

f. The compound (IV) is substituted with the compound (III) at -30 ° C to room temperature to obtain (III), and the amount of the compound (IV) is 1 to the molar amount of the compound (III). 6 times;

g. At room temperature to 30 ° C and in dichloromethane, the compound (II) and trifluoroacetic acid reacted with an amino group. The amount of trifluoroacetic acid was 8 to 12 times the molar amount of the compound (II). ~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:

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the elements, carbon, hydrogen and oxygen involved in the groups and compounds of the present invention. Sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, including ¹² C, ¹³ C and ¹⁴ C. The isotopes of hydrogen include helium (H) and helium (D, also known as heavy hydrogen). ), 氚 (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. Preference is given to alkyl groups having 1 to 10 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, allyl, isopropyl, n-butyl, isobutyl, tert-butyl, positive Amyl, n-decyl, and various branched isomers thereof; more preferred are lower alkyl groups having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, alkenyl Propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

"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. Where the group is substituted, for example an alkyl group, a benzyl group, an alkoxy group, optionally further 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 a molecular structure, and non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, n-pentanol, 3 - Pentanol, isoamyl alcohol, pentanol, 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, ethyl 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.

"Haloalkane solvent" means an alkane solvent containing a halogen (fluorine, chlorine, bromine, iodine) in its 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, B Isopropyl acrylate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate, n-butyl acetate, n-propyl acetate, n-amyl acetate, methyl acetate, sec-butyl acetate, formic acid Butyl ester, 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 isopropylidene Acetone, etc.

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

"Amide solvent" means a solvent containing an amide in a molecular structure, and non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylethyl Amide, hexamethylphosphoramide or N-methylpyrrolidone.

The "sulfoxide solvent" means a solvent containing a sulfinyl group in a molecular structure, and a non-limiting example includes dimethyl sulfoxide.

The "sulfone-based solvent" means a solvent containing a sulfuryl group in a molecular structure, and a non-limiting example includes sulfolane.

"Natural or pharmaceutically acceptable amino acids": 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, and in addition, based on these basic amino acids. The organism also synthesizes the types of amino acids derived from hydroxyproline, hydroxylysine, etc. These biosynthetic amino acids are collectively referred to as "natural amino acids"; artificially synthesized are "unnatural amino acids"; "medicinal" "Amino acid" means a pharmaceutically acceptable natural or unnatural amino acid.

"A side chain of an amino acid" means an amino acid formula

R substituents in the structure.

"Amino protecting group" refers to a group for amino protection which is useful for protecting an amino group such that the amino group does not undergo a chemical reaction, but the group is readily removed after completion of the desired chemical reaction in other portions of the molecule. 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 The chapter on the protection of amino groups in GMWuts gives a detailed description of the amino protecting group. 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, trifluoroacetyl, acetyl or benzoyl.

"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 The reaction does not have to be added to the reaction.

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

detailed description

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). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). The internal standard is tetramethylsilane (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-C18100 x 4.6 mm).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum temperature of 20 ° C to 30 ° C.

N is moles per liter.

BOC, tert-butoxycarbonyl.

Example 1: (2S)-2-[[[(1R)-2-(6-Aminofluoren-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-(diphenoxyphosphorylmethoxy)propyl]indole (1C)

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

[[(1R)-2-(6-Aminofluoren-9-yl)-1-methylethoxy]methyl]phosphoric acid (PMPA, Tenofovir) (400 g, 1.4 mol) was dissolved in acetonitrile (2.5 L) Among them, thionyl chloride (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-(dichlorophosphorylmethoxy)propyl]indole (1B).

6-Amino-9-[(2R)-2-(dichlorophosphorylmethoxy)propyl]indole (1B) was dissolved in dichloromethane (2.5 L) and phenol (289.8 g, 3.08 mol) was added. Cool to -30 ° C, add triethylamine to adjust pH > 7, and warm 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 was cooled to 0 ° C, ammonia water was added, the pH was adjusted to 7, then extracted with dichloromethane (2.0 L × 2), and the organic phase of dichloromethane was combined and washed with saturated sodium chloride solution. Dry over anhydrous sodium sulfate, filtered, and then evaporated tolulujjjjjjjjjjjjjjjjjjj (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-tert-butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester ( 1D)

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

6-Amino-9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indole (1C) (238 g, 0.54 mol) was dissolved in tetrahydrofuran (1 L), 4- 4- Methylaminopyridine (13.2 g, 0.108 mol) was added in portions to a solution of di-tert-butyl 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). Title product N-tert-Butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)propyl]indol-6-yl]carbamic acid tert-butyl ester (1D) , black oil, used directly in the next reaction.

¹ H NMR (400MHz, 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(tert-butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (1E)

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

N-tert-Butoxy-N-[9-[(2R)-2-(diphenoxyphosphorylmethoxy)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 (36.7 g) , 0.54 mol, content 25%), and the temperature was raised to 50 ° C 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]fluoren-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphoric acid (1E), dark red oil (250 g, yield 82.2%).

^{_{1 H NMR (400MHz, CDCl 3}} ) δ12.53 (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-tert-butoxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]indol-6-yl]ammonia Tert-butyl carboxylic acid (1F)

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

[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (1E) (10 g, 17.7 mmol) was dissolved in dichloromethane (100 mL), oxalyl chloride (4.49 g, 35.4 mmol) was added, and 2 drops of N,N-dimethylformamide were added dropwise and stirred for 1 hour. The reaction solution was evaporated under reduced pressure to give the title product N-t-butyloxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl] hydrazine-6- Tert-butyl carbamate (1F) was used directly in the next reaction.

The fifth step: (2S)-2-[[[2-[(1R)-6-[bis(tert-butoxycarbonyl)amino]fluoren-9-yl]-1-methyl-ethoxy]methyl -Phenoxy-phosphono]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-tert-Butoxy-N-[9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]indole-6-yl]amino group under nitrogen atmosphere The tert-butyl formate (1F) (17.7 mmol) was dissolved in dichloromethane (100 mL), cooled to 0 ° C, and a solution of L-alanine (3.56 g, 21.2 mmol) in dichloromethane (100 mL) The reaction was carried out for 1 hour at normal temperature. Saturated sodium chloride solution (50 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjj [2-[(1R)-6-[bis(tert-butoxycarbonyl)amino]fluoren-9-yl]-1-methyl-ethoxy]methyl-phenoxy-phosphono]amino]propanoic acid Isopropyl ester (1G), light yellow oil (5.6 g, yield 45.9%).

¹ H NMR (400 MHz, 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-aminofluoren-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(tert-Butoxycarbonyl)amino]]-9-yl]-1-methyl-ethoxy]methyl-phenoxy Isopropylphosphono]amino]propanoate (1G) (5.6g, 8.08mmol) was dissolved in dichloromethane (100mL), trifluoroacetic acid (9.21g, 80.8mmol) was added, and the temperature was raised to 30 ° C reaction 3 hour. The reaction solution was cooled to 0 ° C, and the aqueous solution was adjusted to pH > 7. Methylene chloride (50 mL) and saturated sodium chloride solution (50 mL) were added, and the layers were separated and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded the title product (2S)-2-[[[((())))) -Phosphate]amino]propionic acid isopropyl ester (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-Aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino Isopropyl propionate (Compound 1)

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

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

[(1R)-2-[6-[Di(tert-Butyloxycarbonyl)amino]phosphonium-9-yl]-1-methyl-ethoxy]methyl-phenoxy-monophosphate (1E) (250 g, 0.44 mol) was dissolved in acetonitrile (0.8 L), and thionyl chloride (104 g, 0.88 mol) was added, and the mixture was heated to 70 ° C for 3 hours under a nitrogen atmosphere. The reaction solution was evaporated under reduced pressure to give the title compound 6-amino-9-[(2.sup..sup..sup. In the next step.

The second step: (2S)-2-[[[(1R)-2-(6-aminofluoren-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino]amino Isopropyl propionate (Compound 1)

6-Amino-9-[(2R)-2-[[chloro(phenoxy)phosphonyl]methoxy]isopropyl]indole (2A) (40.5 g, 0.106 mol) was dissolved in a nitrogen atmosphere In a dichloromethane (200 mL), the mixture was cooled to -20 ° C, and a solution of L-alanine (69.5 g, 0.53 mol) in dichloromethane (300 mL) was added dropwise, and the mixture was warmed to room temperature overnight. 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, adjusted to pH > 7 with sodium bicarbonate, extracted with ethyl acetate (300 mL × 1), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, filtrate reduced Concentration under pressure gave the title product (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphino] Isopropyl isopropylate (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

A method for preparing a compound represented by the formula (I):

It is characterized in that the compound (II) is subjected to an amino deprotection reaction under an alkaline reagent, an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 100 ° C in a solvent;

R 1 and R 2 are each independently selected from an amino protecting group or hydrogen, provided that R 1 and R 2 are not hydrogen at the same time;

R 3 is selected from natural or pharmaceutically acceptable amino acid side chains;

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, an amide solvent, a sulfoxide solvent, and water. a combination of two or more;

The acidic reagent is selected from an organic acid or a mineral acid;

The alkaline 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;

The hydrogenolysis catalyst is selected from the group consisting of palladium/carbon, Raney nickel, platinum/carbon or palladium hydroxide/carbon;

The amount of the alkaline agent is 1 to 10 times the molar amount of the compound (II);

The acidic reagent is used in an amount of from 1 to 30 times the molar amount of the compound (II);

The amount of the hydrogenolysis catalyst is 0.01 to 1 times the molar amount of the compound (II).
The method of claim 1 wherein:

R 1 and R 2 are each independently selected from hydrogen, benzyl, p-methoxybenzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl, and R 1 and R 2 are not simultaneously hydrogen;

R 3 is selected from the side chain of glycine, alanine, leucine, phenylalanine, asparagine or arginine;

R 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, and dioxane. a combination of one or more of a ring, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, 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, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, hydrogen One or a combination of two or more of 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 acidic reagent is used in an amount of from 1 to 20 times the molar amount of the compound (II);

The reaction temperature is from 0 ° C to 60 ° C.
The method of claim 2 wherein:

R 1 and R 2 are selected from the group consisting of t-butoxycarbonyl;

R 3 is selected from the side chain of alanine;

The solvent used in the reaction is selected from one or a combination of two or more of dichloromethane, tetrahydrofuran, dioxane and water;

The acidic reagent is selected from the group consisting of acetic 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);

The reaction temperature is from 0 ° C to 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 substitution 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;

The solvent used in the reaction is selected from one or a combination of two or more of an aromatic hydrocarbon solvent, an ether solvent, a halogenated alkane solvent, an ester solvent, a ketone solvent, and a nitrile solvent;

The substitution reaction can selectively add an alkaline reagent;

The compound (IV) is used in an amount of from 0.8 to 7 times the molar amount of the compound (III).
The method of claim 4 wherein:

X is selected from chlorine;

The solvent used in the reaction is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, propionitrile, toluene. One or a combination of two or more of chlorobenzene;

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 - one or a combination of two or more of dimethylaminonaphthalene, N-methylmorpholine, morpholine, piperidine and aniline;

The reaction temperature is -40 ° C to 50 ° C.
The method of 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;

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 by:

Wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 4.
A method for preparing a compound represented by formula (III) or (III-1):

It is characterized in 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 a sulfone solvent;

The halogenation reaction may be selectively added to the catalyst, wherein 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 from 1 to 15 times the molar amount of the compound (V).
The method of claim 8 wherein:

The solvent used in the reaction is selected from one or a combination of two or more of dichloromethane, trichloroethane, acetonitrile and sulfolane;

The halogenating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, triphenylphosphine chloride, dibromosulfoxide, oxalyl bromide, tribromide. Phosphorus, phosphorus pentabromide, trichlorooxo 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 from 1 to 10 times the molar amount of the compound (V);

The temperature at which the compound (III) is prepared is from 0 ° C to 80 ° C;

The temperature at which the compound (III-1) is prepared is from room temperature to 85 °C.
The method of claim 8 wherein:

The solvent used in the reaction is selected from the group consisting of dichloromethane or acetonitrile;

Preparation of compound (III) halogenated reagent is selected from oxalyl chloride;

Preparation of compound (III-1) halogenated reagent is selected from the group consisting of thionyl chloride;

The halogenating agent is used in an amount of from 1 to 5 times the molar amount of the compound (V);

The temperature at which the compound (III) is prepared is from 0 ° C to 30 ° C;

The temperature at which the compound (III-1) is prepared is 70 ° C to 85 ° C.
A compound of the formula (III) characterized by:

Wherein R 1 , R 2 and X are as defined in claim 4.
A method for preparing a compound represented by formula (V):

It is characterized in that the compound (VI) is subjected to a hydrolysis reaction 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, an amide solvent, a sulfoxide solvent, and one or more of water. combination;

The alkaline agent is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, and alkaline earth golds. a combination of one or more of a carbonate and an organic amine;

The amount of the alkaline agent used is 1 to 15 times the molar amount of the compound (VI).
The method of 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, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, dichloro Methane, 1,2-dichloroethane, chloroform, trichloroethane, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran ,ether, dioxane, methyl tert-butyl ether, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone One or a combination of two or more in water;

The alkaline agent is selected from the group consisting of potassium carbonate, sodium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, hydrogen. Calcium oxide, magnesium hydroxide, triethylamine, propylamine, methylamine, dimethylamine, N,N-diisopropylethylamine, tert-butylamine, 1,8-bisdimethylaminonaphthalene, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, imidazole, N-methylmorpholine, morpholine, piperidine, aniline, aqueous ammonia and hydrazine hydrate One or a combination of two or more;

The alkaline reagent is used in an amount of from 1 to 10 times the molar amount of the compound (VI);

The reaction temperature is from room temperature to 80 °C.
The method of 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 ammonia water;

The alkaline reagent is used in an amount of from 3 to 6 times the molar amount of the compound (VI);

The reaction temperature is from 20 ° C to 60 ° C.
a compound of the formula (V) characterized by:

Wherein R 1 and R 2 are as defined in claim 4.
A method for preparing a compound represented by the formula (VI):

It is characterized in that the compound (VII) is reacted with an amino protecting 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, a ketone solvent, a nitrile solvent, an ester solvent, an amide solvent, a sulfoxide solvent, and one or more of water. combination;

The amino protecting reaction may be selectively added to the catalyst, wherein the catalyst is selected from the group consisting of triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine;

The amino protecting agent is used in an amount of from 1 to 15 times the molar amount of the compound (VII).
The method of 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, 1,4-dioxane, acetonitrile, propionitrile, ethyl acetate. a combination of one or more of isopropyl acetate, dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, and water;

The amino 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, trifluoroethyl Anhydride, acetyl chloride, benzoic anhydride or benzoyl chloride;

The amino protecting agent is used in an amount of from 1 to 10 times the molar amount of the compound (VII).
The method of claim 17 wherein:

The solvent used in the reaction is selected from the group consisting of tetrahydrofuran;

The amino protection reagent is selected from di-tert-butyl dicarbonate;

The catalyst is selected from the group consisting of 4-dimethylaminopyridine;

The amino protecting agent is used in an amount of from 2 to 5 times the molar amount of the compound (VII);

The reaction temperature is from room temperature to 80 °C.
A method for preparing a compound represented by the formula (VII), which comprises the following steps:

(1) Compound (IX) is halogenated with a halogenating reagent to obtain a compound (VIII);

(2) Compound (VIII) is substituted with phenol to obtain (VII);

The definition of X is as set forth in claim 4.
The method of claim 19 wherein:

The halogenation reaction described in the step (1) comprises the steps of: subjecting the compound (IX) to a halogenation reaction under a action of a halogenating reagent to obtain a compound (VIII); wherein the solvent is selected From one or a combination of two or more of dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile and toluene; the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride; the halogenation reaction is optional. Adding a catalyst, the catalyst is selected from N,N-dimethylformamide; the halogenating agent is used in an amount of from 1 to 15 times the molar amount of the compound (IX); and the reaction temperature is from room temperature to 110 ° C;

The substitution reaction described in the step (2) comprises the step of: subjecting the compound (VIII) to a substitution reaction in the presence of a basic reagent to obtain a compound (VII); wherein the solvent is selected from the group consisting of a combination of one or more of methyl chloride, 1,2-dichloroethane, chloroform, trichloroethane and acetonitrile; the alkaline agent is selected from the group consisting of triethylamine, dimethylamine, N, N One or more of diisopropylethylamine, 4-dimethylaminopyridine, 2,6-lutidine, pyridine, N-methylmorpholine, morpholine, piperidine, aniline and t-butylamine The phenol is used in an amount of from 1 to 8 times the molar amount of the compound (VIII); the basic reagent is used in an amount of from 1 to 12 times the molar amount of the compound (VIII); and the reaction temperature is from -40 ° C to 70 ° C.
The method of claim 20 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. ~85 ° 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; and the reaction temperature is -30 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 by:

a. The compound (IX) is halogenated with a halogenated reagent to form a compound (VIII) at room temperature to 85 ° C in a solvent, the solvent is selected from acetonitrile or toluene, and the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride. The halogenation reaction may be selectively added to the catalyst, the catalyst is selected from N,N-dimethylformamide, and the halogenating agent is used in an amount of 1 to 10 times that of the compound (IX);

b. At -30 ° C ~ 50 ° C and in the solvent, the compound (VIII) and phenol are substituted under alkaline conditions to form compound (VII), the solvent is selected from dichloromethane, 1,2-dichloroethane , one or a combination of two or more of chloroform and acetonitrile, the alkaline reagent is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine In one or a combination of two or more, 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 6 to 12 times the molar amount of the compound (VIII);

c. Compound (VII) is reacted with an amino protecting reagent to form compound (VI) at room temperature to 80 ° C in a solvent selected from the group consisting of methanol, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran, acetonitrile. In combination with one or more of the two, the amino protecting agent is selected from di-tert-butyl dicarbonate or benzyl chloroformate, and the amino protecting agent is used in an amount of from 1 to 5 times the molar amount of the compound (VII);

d. The compound (VI) is hydrolyzed with an alkaline reagent at 20 ° C to 60 ° C in a solvent to form a compound (V) selected from the group consisting of dichloromethane, 1,4-dioxane, acetonitrile and water. One 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 amount of the alkaline agent is changed. 3 to 6 times the molar amount of the compound (VI);

e. The compound (V) is halogenated with a halogenating reagent at 0 ° C to 70 ° C in a solvent to form a compound (III), the solvent is selected from dichloromethane or acetonitrile, and the halogenating agent is selected from the group consisting of oxalyl chloride, halogenated The catalyst may be optionally added to the catalyst, and the catalyst is preferably N,N-dimethylformamide. The halogenating agent is used in an amount of from 1 to 10 times the molar amount of the compound (V); or, in the solvent at room temperature to 85 ° C. The compound (V) is halogenated with a halogenating reagent to form a compound (III-1), the solvent is selected from acetonitrile, the halogenating agent is selected from the group consisting of thionyl chloride or oxalyl chloride, and the halogenating agent is used in the compound (II). 1 to 10 times the molar amount;

f. At -40 ° C ~ 50 ° C and in the solvent, the compound (III) and the compound (IV) are substituted to form the compound (II), the solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, Acetonitrile or tetrahydrofuran, the reaction can be selectively added with an alkaline reagent selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and 2,6-lutidine. One or a combination of two or more, the compound (IV) is used in an amount of from 1 to 6 times the molar amount of the compound (III);

g. The compound (II) undergoes amino deprotection reaction in an acidic reagent or a hydrogenolysis catalyst at 0 ° C to 60 ° C to form a compound (I) selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, and dioxane. In combination with one or more of two kinds of water, the acidic reagent is selected from the group consisting of acetic acid, trifluoroacetic acid, hydrochloric acid or hydrobromic acid, and the hydrogenolysis catalyst is preferably palladium/carbon, Raney nickel or palladium hydroxide/carbon, acidic reagent The amount used is 1 to 10 times the molar amount of the compound (II), and the amount of the hydrogenolysis catalyst is 0.01 to 10 times the molar amount of the compound (II).
The method of claim 22 wherein:

a. Chlorine reaction with the compound (IX) in the acetonitrile at 75 ° C ~ 85 ° C, the amount of the compound thionyl chloride is 4 to 10 times the molar amount of the compound (IX), the reaction 3 ~4 hours;

b. At -30 ° C ~ 50 ° C and dichloromethane, phenol and compound (VIII) under the action of triethylamine reaction substitution reaction, the amount of phenol is 2 to 3 times the molar amount of compound (VIII), three The amount of the ethylamine is 6 to 10 times the molar amount of the compound (VIII), and the reaction is carried out for 10 to 14 hours;

c. In 60 ° C ~ 72 ° C and tetrahydrofuran, the amino protecting reagent and compound (VII) reacted under the action of 4-dimethylaminopyridine, the amino protecting reagent is selected from di-tert-butyl dicarbonate, di-tert-butyl dicarbonate The amount of the 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;

d. 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 to 4 times the molar amount of the compound (VI), and the reaction is carried out for 10 to 14 hours;

e. Chlorination reaction of oxalyl chloride with compound (V) at 0 ° C ~ 30 ° C and dichloromethane, the amount of oxalyl chloride 2-4 times the molar amount of the compound (V), the reaction is 1-4 hours; or, in the acetonitrile at 70 ° C to 85 ° C, the compound (V) is reacted with the thionyl chloride to form (III- 1), the amount of the thionyl chloride is 2 to 4 times the molar amount of the compound (V), and the reaction is carried out for 3 to 4 hours;

f. At -30 ° C ~ room temperature and dichloromethane, compound (IV) and compound (III) substitution reaction, the amount of compound (IV) is 1 to 6 times the molar amount of compound (III);

g. At room temperature to 30 ° C and in dichloromethane, the compound (II) and trifluoroacetic acid reacted with an amino group. The amount of trifluoroacetic acid was 8 to 12 times the molar amount of the compound (II). ~3 hours.
a compound of the formula (VI),

R 1 and R 2 are as defined in claim 4.