WO2016095662A1 - Method for preparing (2s,3r,4r)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-d-ribose-γ-lactone and intermediate thereof - Google Patents

Abstract

The present invention relates to a method for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone and an intermediate thereof. The intermediate has a structure represented by formula II. According to the present invention, a compound represented by formula II is used as an intermediate for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone, so the stereoselectivity is good, the yield is high, the reaction condition is mild, and the raw material 2-C-methyl-D-ribonic acid-1,4-lactone for preparing the intermediate has wide sources, is simple to prepare and has low cost.

Description

Preparation method and intermediate of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone Technical field

The invention relates to the field of synthesis of ribose lactone, in particular to (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone intermediate And preparation method thereof, preparation method of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy2-methyl D-ribose-γ-lactone, and (2S, 3R, 4R A process for the preparation of 3-,5-disubstituted-2-deoxy-2-halo-2-hydroxy D-ribose-γ-lactone.

Background technique

(2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (compound of formula IV) and its derivatives are various antiviral An important intermediate for anti-tumor active ingredients, such as Sofosbuvir approved by the US FDA for the treatment of chronic HCV infection at the end of 2013. This drug is effective against various types of HCV infection, and is highly safe, and for GT2. Type, GT3 infection does not need to be combined with interferon, it is the most potential new drug in the hepatitis C market. (2R,3R,4R) obtained by the reaction of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone and a fluorinating reagent -3,5-Disubstituted-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone can be directly used for the preparation of various antiviral and antitumor drugs.

Routes for the preparation of (2R,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone and derivatives thereof have been reported. For example, US2006199783A1 reports a preparation method as shown in Route 1:

Route 1:

The method uses D-glyceraldehyde protected by acetone fork as raw material to obtain (2S,3R,4R)-3,5-dibenzoyl-2-deoxy-2-hydroxy-2-methyl D by four steps. - Ribose-gamma-lactone (Compound 1). The route yield is higher, but the Wittig and Sharpless hydroxylation reagents are expensive, and the osmium tetroxide is too toxic to be industrially suitable.

The preparation method shown in Scheme 2 is reported for the starting compound 2 of Compound 1, Tetrahedron: Asymmetry, 2008, 19, 2417-2424. It uses D-erythronolactone as raw material to obtain (2R,3R,4R)-3,5-dihydroxy-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ by three-step reaction. - lactone (compound 2). Among them, the second step uses Grignard reagent, the conditions are harsh, the third step of the Kiliani reaction of sodium cyanide has a long duration, low yield, difficult separation, and the raw material D-erythronolactone is expensive, not suitable for application. In mass production. In addition, the second step requires low temperature reaction conditions, the reaction conditions are harsh, and the requirements for equipment are relatively high.

Route 2:

(2S,3R,4R)-3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D- is reported in WO2008045419 and J. Org. Chem, 2009, 74, 6819-6824. The preparation method of ribose-γ-lactone is shown in Route 3. The asymmetric synthesis method is used to control the chirality of the C-2 position, but the route is long, the operation is cumbersome, and the yield is low. Further, in the preparation method shown in the third route, some of the intermediates are unstable, which results in the quality of the intermediate being not easily controlled, and the quality of the final product is also unstable.

Route 3:

Chinese Patent Publication No. CN 103420955A discloses a preparation method of 3,5-dibenzoyl-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone, which is to make compound 2 By benzoylation, 3,5-dibenzoyl-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (Compound 1) is obtained, and then 3,5-II Preparation of 3,5-dibenzoyl-2-deoxy-2- by benzoyl-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone and fluorination reagent sulfuryl fluoride Fluoro-2-methyl-D-ribose-γ-lactone. This method does not disclose the preparation and source of the compound 2, and the synthesis of the compound 2 is difficult and costly, and therefore, the method is not suitable for industrial production.

Summary of the invention

One of the objects of the present invention is to provide a novel preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone and An intermediate of the derivative thereof and a method for preparing the intermediate.

A further object of the present invention is to provide an improved preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone method.

A third object of the present invention is to provide an improved (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-halo-D-ribose-γ-lactone method.

In order to achieve the above object, in one aspect, the present invention provides a preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone Intermediate (II) having the structure shown in Formula II:

among them,

R ₁ and R _{2 are} independently R"C(O)-, and R" is selected from C1-C10 alkyl; C3-C8 cycloalkyl; C6-C10 aryl; five- or six-membered heterocyclic; One or more selected from the group consisting of C1-C4 alkoxy, C6-C10 aryloxy, nitro, cyano, sulfonate, sulfate, phosphonate, phosphate, phosphonate, chlorine, bromine a C1-C6 alkyl group substituted with a substituent of fluorine and iodine; substituted by one or more substituents selected from the group consisting of chlorine, bromine, fluorine, iodine, nitro, C1-C4 alkyl and C1-C4 alkoxy Aryl or heterocyclic; trityl;

R ₃ is -NO ₂ , -S(=O)nR ₄ or -C(=O)-R ₄ , wherein R ₄ is hydrogen, C 1 which is unsubstituted or substituted by one or more electron withdrawing substituents. C6 alkyl; n is 1 or 2.

According to the invention, the choice of R ₃ in the intermediate (II) for the subsequent preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ - The effect of the lactone reaction has a critical impact. Preferred R ₃ is -S(=O)nR ₄ . More preferably R ₃ is -S(=O) ₂ R ₄ .

According to the present invention, the electron withdrawing substituent in R ₄ is not particularly limited and includes, but is not limited to, one or more of those electron withdrawing groups well known in the art of organic synthesis. Specific examples of the electron withdrawing group include a nitro group, a cyano group, a fluorine group, a chlorine group, a bromine group, an iodine group, an acetaldehyde group, a hydroxyl group, a phenyl group, an olefin group and the like. According to a preferred aspect, the electron withdrawing substituent in R ₄ is selected from the group consisting of fluorine, chlorine, nitro and cyano.

Preferred R ₄ according to the invention is methyl, ethyl or a C1-C3 alkyl substituted by one or more electron withdrawing substituents. Further preferably, R ₄ is a methyl group or a C1-C3 alkyl group substituted by an electron withdrawing substituent, and the electron withdrawing substituent includes at least fluorine, preferably at least two fluorines, more preferably at least three fluorines.

According to a particular and preferred aspect of the invention, said R ₃ is -S(=O) ₂ CH ₃ or -S(=O) ₂ CF ₃ .

The present invention has no particular requirements for R ₁ and R ₂ , and is specifically determined according to the product to be actually prepared. R ₁ and R ₂ may be the same or different substituents, but from the viewpoint of easier preparation, it is preferred to make R ₁ and R ₂ the same substituent. According to a preferred aspect of the invention, R" is unsubstituted or substituted by one or more substituents selected from the group consisting of chlorine, bromine, fluorine, iodine, nitro, C1-C4 alkyl and C1-C4 alkoxy Phenyl, unsubstituted or substituted by one or more substituents selected from the group consisting of chlorine, bromine, fluorine, iodine, nitro, C1-C4 alkyl and C1-C4 alkoxy a heterocyclic group, or a C1-C4 alkyl group. In a still further preferred embodiment, R" is phenyl; a phenyl group substituted with one selected from the group consisting of fluorine, chlorine and methoxy, wherein the substitution position is adjacent Position, meta or para; furyl, tert-butyl, methyl or ethyl.

According to the present invention, typical intermediates II can be represented by the following formulas II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9. Compound:

The present invention also provides a process for the preparation of the intermediate (II) as described above, which comprises preparing the intermediate (II) by acylating the intermediate (I) with the reagent R ₃ -Y in the presence of a base via the step d). ):

Wherein Y is halogen or OR ₃ ; and R ₁ , R ₂ and R ₃ are as defined above.

According to the present invention, the above-mentioned step d) acylation reaction is not particularly limited for a specific base, and those well known in the art of organic synthesis can be selected. Among them, the base to be preferably used is an organic base, and particularly preferably one or more of pyridine, triethylamine, 4-dimethylaminopyridine and diisopropylethylamine.

According to the invention, in the reagent taken in the above step d, Y is further chlorine or bromine or OR ₃ .

Further, the acylation reaction can be carried out at a temperature of from -50 °C to 25 °C.

Further, the preparation method may further comprise reacting 2-C-methyl-D-ribosic acid-1,4-lactone in the presence of a base with the reagent R"CO-Z to carry out step e) to prepare an intermediate ( I),

Wherein Z is halogen or OCOR"; R ₁ , R ₂ and R" are as defined above.

The base to be used in the step e is not particularly limited as in the step d, but one or more of pyridine, triethylamine, 4-dimethylaminopyridine and diisopropylethylamine are preferably used. The Z is chlorine or bromine or OCOR".

According to the invention, the reaction of step e) can be carried out at a temperature of from -50 ° C to room temperature (25 ° C). It is preferably -40 ° C to 0 ° C, more preferably -10 ° C to 0 ° C.

According to the invention, step e) and step d) can be carried out stepwise or in a one-pot process. It is preferably carried out in a one-pot process.

A further technical solution adopted by the present invention is: a (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV) The preparation method comprises the above intermediate (II) as a reaction starting material, the intermediate (II) is subjected to the step a) substitution reaction or the step b) cyclization reaction and the step c) ring-opening substitution reaction. (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV),

Wherein R ₁ , R ₂ , R′′ and R _{3 have} the same meanings as defined above.

According to the invention, the reaction of step a) and step b) or step c) is preferably carried out in the presence of water, the amount of water being not required, being very small, such as moisture in air, present in an organic solvent such as DMSO Moisture in an isopolar organic solvent; it may also be a relatively large amount, such as a solvent amount.

According to a particular aspect of the invention, the substitution of step a) can be carried out by dissolving the intermediate (II) in a solvent and stirring the reaction to give the compound IV. Preferably, the step a) substitution reaction is carried out in a mixed solvent of dimethyl sulfoxide or dimethyl sulfoxide with another solvent. The other solvent may specifically be one or more selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, water, acetone, and methanol. Suitable temperatures for the substitution reaction of step a) for different reactants and products can be determined experimentally, for example at a temperature of from -20 to 100 ° C. According to a preferred aspect, the substitution of step a) is carried out under milder conditions, for example The temperature is -20 ° C to 60 ° C, more preferably -20 ° C to 30 ° C. Most preferably, it is carried out at room temperature.

According to still another specific aspect of the present invention, the substitution reaction of the step a) can also be carried out in the presence of a solvent, a phase transfer catalyst and a nitrite, wherein the solvent is a mixed solvent of an organic solvent and water.

Preferably, the organic solvent is a first organic solvent or a combination of a first organic solvent and a second organic solvent, and the first organic solvent may be selected from the group consisting of DMSO, N,N-dimethylformamide, N-A One or more of a pyrrolidone or the like; the second organic solvent may be one or more selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, water, acetone, methanol, and the like.

Preferably, the nitrite is sodium nitrite or potassium nitrite or a combination of the two. A specific embodiment is as follows: a solution of a phase transfer catalyst and a nitrite is added to a solution containing the organic solvent of the intermediate (II), and the reaction is carried out at a set temperature to form a compound IV. The phase transfer catalyst may be those conventionally used, and is not particularly limited, and may specifically be, for example, tetrabutylammonium iodide, tetrabutylammonium bromide, crown ether or the like. The set temperature is, for example, 25 to 100 °C.

According to a particular aspect of the invention, the b) reaction of step b) can be carried out by dissolving the intermediate (II) in a solvent and stirring the reaction to form the intermediate III. Wherein the solvent is N, N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and another solvent, and the other solvent may be one or more selected from the group consisting of tetrahydrofuran, acetonitrile and acetone. . According to the invention, the suitable temperature for the cyclization reaction of step b) for different reactants and products can be determined experimentally, for example at a temperature of from -40 to 100 °C. It is preferably -20 to 30 °C. According to a specific and preferred aspect, the step b) cyclization reaction is carried out at room temperature.

Preferably, the step c) ring opening substitution reaction is carried out in a solvent in the presence of a base. The base in step c) ring opening substitution reaction may be an organic base, an inorganic base or a combination of the two. Preferably, the base in the step c) ring-opening substitution reaction is selected from the group consisting of sodium alkoxide, potassium alkoxide, triethylamine, diisopropylethylamine, 1,8-diazaheterocycle [5,4,0] One or more of monoene-7, pyridine, 4-dimethylaminopyridine and metal hydride.

The reaction temperature of the step c) can also be determined according to a conventional test, for example, 0 to 100 ° C, preferably 20 to 100 ° C.

According to the invention, step b) and step c) can be carried out either stepwise or in a one-pot process. The "stepwise" means that the product is separated from the system after the completion of the previous step reaction and the next reaction is carried out. The "one-pot process" means that the separation is not carried out after the completion of the previous step reaction, and the reagents required for the next step reaction are directly added to carry out the reaction or all the raw materials are added together to the reaction vessel for reaction.

Further, the preparation method further comprises the preparation of the intermediate II by the preparation method of the above intermediate II of the present invention.

For the preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV), the reagent R ₃ -Y is preferably three Fluoromethanesulfonic anhydride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, methanesulfonic anhydride, and the like.

According to the invention, step d) and step a) are carried out stepwise or in one pot, step d) and step b) are carried out stepwise or in one pot.

In a specific embodiment of the invention, step d), step b), and step c) are carried out in three steps. In another specific embodiment, step d), step b), and step c) are carried out in one pot. Alternatively, step d), step b) may be carried out in one pot, and step c) may be carried out stepwise, or step b) and step c) may be carried out in one pot, and step d) Step by step.

The present invention still further provides a method for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-halo-2-methyl-D-ribose-γ-lactone (V) Which comprises preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV) according to the above method, and Preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV) with a halogenating reagent by halogenation in step f) (2S,3R,4R)-3,5-Disubstituted-2-deoxy-2-halo-2-methyl-D-ribose-γ-lactone (V):

Wherein R ₁ and R _{2 have} the same meanings as defined above; and X is fluorine, chlorine, bromine or iodine.

The halogenating agent is a fluorinating reagent, a chlorinating reagent, a brominating reagent or an iodinating reagent. The chlorinating agent may be one or more selected from the group consisting of thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, sulfuryl chloride and phosphorus oxychloride; the fluorinating agent may be selected from the group consisting of One or more of sulfuryl fluoride, perfluorobutylsulfonyl fluoride, dimethylaminosulfur trifluoride, diethylaminosulfur trifluoride and bis(2-methoxyethyl)amine sulfur trifluoride Kind. When X is fluorine, a fluorine-containing reagent may be further added to the reaction system, and the fluorine-containing reagent may be one selected from the group consisting of triethylamine trihydrofluoride, pyridine hydrofluoride solution, potassium fluoride and cesium fluoride. One or more; the brominating agent may be one or more selected from the group consisting of thionyl bromide and phosphorus tribromide. The halogenation reaction may be carried out in the presence of a base or in the absence of a base. When carried out in the presence of a base, the base may be selected from the group consisting of pyridine, imidazole, triethylamine, diethylamine, diisopropylamine, N,N-isopropylethylamine, aniline, N,N-dimethyl One or more of aniline, N-methylmorpholine, 2-methyl-5-ethylpyridine, 2,6-lutidine and 2,3-dimethylpyridine. The solvent for the halogenation reaction may be one or more selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, acetonitrile, carbon tetrachloride, chloroform, ethyl acetate, and N,N-dimethylformamide.

Further, the step f) the halogenation reaction is carried out stepwise or in one pot with step a) or step c).

Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

The invention adopts the intermediate (II) as an intermediate for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone, Not only the stereoselectivity is good, the yield is high, the reaction conditions are mild, and the raw material for preparing the intermediate has a wide source of 2-C-methyl-D-ribonic acid-1,4-lactone, and the preparation is simple and the cost is low.

detailed description

The invention provides a method for synthesizing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone in a single configuration. The method has the advantages of high stereoselectivity, high yield, low cost, mild reaction conditions and the like.

The present invention provides the use of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone in a single configuration, by formula The compound represented by the general formula V obtained by the halogenation reaction of the compound represented by IV can be directly used for the preparation of a plurality of antiviral and antitumor drugs.

The present invention provides a one-pot method for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone in a single configuration and 2S,3R,4R)-2,3,5-trisubstituted-2-deoxy-2-methyl-D-ribose-γ-lactone, the reaction step can be combined into one reaction vessel The separation and purification of the intermediate are not required, and the reaction liquid is finally separated and purified, the product loss in the operation step is reduced, the process flow is simplified, the production cost is reduced, and the preparation is simple and economical. method.

It is presumed that the reaction mechanism of the step a of the present invention is as follows (R ₁ = R ₂ = Bz, R ₃ = Tf):

It is speculated that the reaction mechanism of steps b and c of the present invention is as follows (R ₁ = R ₂ = Bz, R ₃ = Tf):

The present invention will be further described in detail below with reference to specific embodiments, but the invention is not limited to the following examples. Conditions not specified in the examples are conventional conditions. The reagents used in the following examples are of analytical grade, using a polar organic solvent such as DMSO moisture content ≤ 0.2% and DMF moisture content ≤ 0.1%.

The 2-C-methyl-D-ribonucleic acid-1,4-lactone used in the following examples was synthesized according to methods reported in the literature (Tetrahedron Letters 2007, 48, 517-520).

Example 1: Preparation of Intermediate I-1 (R ₁ = R ₂ = Bz in Formula I)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (3.24 g, 20 mmoL) was suspended in 60 mL of ethyl acetate. Under ice bath, benzoyl chloride (4.6 mL, 40 mmoL, 2 eq) was added dropwise. ). After the addition was completed, triethylamine (6.09 mL, 44 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was allowed to flow for at least 3 hours, and the reaction was continued overnight. After filtration, the cake was washed with EtOAc (EtOAc) (EtOAc) Filtration, evaporation of the solvent under reduced pressure, and toluene and petroleum ether was afforded to afford 6 g of white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.09 (dd, 2H, J = 8.4, 1.2 Hz), 8.03 (dd, 2H, J = 8.4, 1.2 Hz), 7.62-7.77 (m, 1H) ), 7.56-7.63 (m, 1H), 7.49 (t, 2H, J = 8.0 Hz), 7.44 (t, 2H, J = 8.0 Hz), 5.44 (d, 1H, J = 6.0 Hz), 4.95-5.01 (m, 1H), 4.75 (dd, 1H, J = 12.4, 4.0 Hz), 4.63 (dd, 1H, J = 12.4, 6.0 Hz), 2.64 (br, 1H), 1.69 (s, 3H). The product was confirmed to be the compound I-1.

Example 2: Preparation method of intermediate II-1 (in the formula II, R ₁ = R ₂ = Bz, R ₃ = Tf)

Compound I-1 (0.74 g, 2 mmol) was dissolved in 10 mL dichloromethane and pyridine (0.18 mL, 2.2. 1.1 eq), stirring at -40 ° C, then trifluoromethanesulfonic anhydride (0.37 mL, 2.2 mmoL, 1.1 eq) was slowly added. After the addition was completed, the mixture was slowly warmed to room temperature and stirring was continued for 1 hour. 15 mL of 2M dilute hydrochloric acid and 20 mL of dichloromethane were added to the reaction mixture, and the mixture was stirred for 5 minutes, then the methylene chloride layer was separated, dried and concentrated to give 1.0 g of pale yellow oil as Intermediate II-1. %.

Nuclear magnetic data of the obtained product ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.15 (dd, 2H, J = 8.4, 1.2 Hz), 8.00 (dd, 2H, J = 8.4, 1.2 Hz), 7.64 - 7.69 (m , 1H), 7.57-7.63 (m, 1H), 7.51 (t, 2H, J = 8.0 Hz), 7.44 (t, 2H, J = 8.0 Hz), 5.63 (d, 1H, J = 6.4 Hz), 5.06 -5.11 (m, 1H), 4.79 (dd, 1H, J = 12.8, 3.2 Hz), 4.67 (dd, 1H, J = 12.8, 4.4 Hz), 2.05 (s, 3H). The product was confirmed to be Compound II-1.

Example 3: Preparation method of intermediate III-1 (in the formula III, R ₂ =R"=Bz)

Compound II-1 (0.5 g, 1 mmoL) was dissolved in 4 mL of N,N-dimethylformamide, and stirred at room temperature for 30 minutes, then 50 mL of water was added to precipitate a white solid, which was filtered and dried to give 0.39 g of Intermediate III-1 The yield is 98%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.07-8.12 (m, 3H), 8.03 - 8.06 (m, 2H), 7.63 - 7.68 (m, 1H), 7.54 - 7.59 (m, 1H), 7.50 (t, 2H, J = 8.0 Hz), 7.41 (t, 2H, J = 8.0 Hz), 6.26 (d, 1H, J = 7.6 Hz), 4.77 - 4.84 (m, 2H), 4.66 - 4.72 (m) , 1H), 1.68 (s, 3H).

The product obtained was MS = 399.0.

Example 4: (2S,3R,4R)-3-substituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (in Formula IV, R ₁ =R ₂ =Bz , which is Method for preparing compound IV-1)

Intermediate III-1 (0.39 g, 0.98 mmol) was dissolved in 20 mL of acetone, and 0.5 mL of triethylamine was added and stirred at 50 °C. After the reaction was completed by TLC, acetone was evaporated, and the residue was applied to ethyl acetate (25mL, 3). The organic phases were combined, dried, concentrated and then evaporated tolululu

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.04 - 8.08 (m, 4H), 7.63 - 7.68 (m, 1H), 7.55 - 7.61 (m, 1H), 7.49 (2H, J = 8.0 Hz) , 7.44 (t, 2H, J = 8.0 Hz), 5.60 (d, 1H, J = 6.8 Hz), 4.73-4.83 (m, 2H), 4.65 (dd, 1H, J = 12, 5.2 Hz), 3.46- 3.49 (m, 1H), 1.59 (s, 3H). The product was confirmed to be compound IV-1.

Example 5: (2S,3R,4R)-3-substituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (in Formula IV, R ₁ =R ₂ =B _z , that is, Method for preparing compound IV-1)

The intermediate II-1 (1 g, 2 mmoL) was dissolved in 10 mL of dimethyl sulfoxide, and after stirring for about 10 min, 40 mL of ethyl acetate was added to the reaction mixture, and the organic layer was separated, dried and concentrated to petroleum ether. /Acetone = 3:1 column chromatography gave 0.69 g of a white solid, yield 95%, purity 99.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.04 - 8.08 (m, 4H), 7.63 - 7.68 (m, 1H), 7.55 - 7.61 (m, 1H), 7.49 (2H, J = 8.0 Hz) , 7.44 (t, 2H, J = 8.0 Hz), 5.60 (d, 1H, J = 6.8 Hz), 4.73-4.83 (m, 2H), 4.65 (dd, 1H, J = 12, 5.2 Hz), 3.46- 3.49 (m, 1H), 1.59 (s, 3H). The product was confirmed to be compound IV-1.

Example 6: (2S,3R,4R)-3-substituted-2-deoxy-2-fluoro-2-methyl-D-ribose-γ-lactone (in the formula V, R ₁ =R ₂ = B _z , X=F, That is, the preparation method of the compound V-1)

Compound IV-1 (0.74 g, 2 mmol) was dissolved in 6 mL of acetonitrile, and then triethylamine trifluoride (0.49 mL, 3mmoL, 1.5 eq) and triethylamine (1.4mL, 10mmoL, 5eq) Stirring was carried out, and sulfuryl fluoride gas was introduced at this temperature. After the reaction was completely monitored by TLC, the solvent was evaporated, and a brown-brown solid was precipitated, which was then beaten with water and methanol to obtain 0.67 g of a white solid. The yield was 90% and the purity was 98.5%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (dd, 2H, J = 8.4, 1.2 Hz) 8.01 (dd, 2H, J = 8.4, 1.2 Hz), 7.63 - 7.68 (m, 1H), 7.56-7.62 (m, 1H), 7.50 (t, 2H, J = 8.0 Hz), 7.43 (t, 2H, J = 8.0 Hz), 5.53 (dd, 1H, J = 17.6, 7.2 Hz), 4.99-5.04 (m, H), 4.77 (dd, 1H, J = 12.4, 3.6 Hz), 4.62 (dd, 1H, J = 12.4, 4.8 Hz), 1.68 (d, 3H, J = 23.6 Hz). The product was confirmed to be compound V-1.

Example 7: (2S,3R,4R)-3-substituted-2-deoxy-2-chloro-2-methyl-D-ribose-γ-lactone (in the formula V, R ₁ =R ₂ = Bz, X=Cl, That is, the preparation method of the compound V-2)

Compound IV-1 (1.8 g, 4.86 mmol) was dissolved in 10 mL of pyridine, and 3 mL of thionyl chloride was added and stirred at room temperature overnight. The pyridine was evaporated under reduced pressure, extracted with 20 ml of diluted hydrochloric acid and ethyl acetate (30mL×3), and the organic phase was combined, dried, concentrated, and then evaporated to give a white solid (yield: 55%, purity 99.4%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (dd, 2H, J = 7.2, 1.2 Hz), 8.1 (dd, 2H, J = 7.2, 1.2 Hz), 7.66 (t, 1H, J) =7.6 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.51 (t, 2H, J = 7.6 Hz), 7.42 (t, 2H, J = 7.6 Hz), 5.63 (d, 1H, J = 8.4) Hz), 4.94 - 4.99 (m, H), 4.79 (dd, 1H, J = 12.8, 3.2 Hz), 4.62 (dd, 1H, J = 12.8, 4.8 Hz), 1.93 (s, 3H). The product was confirmed to be compound V-2.

Example 8: One-pot method for the preparation of compound IV-1 from intermediate I-1

Intermediate I-1 (0.74 g, 2 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.18 mL, 2.2mmoL, 1.1 eq) was added and stirred at -40 ° C, then trifluoromethanesulfonic anhydride (0.37 mL, 2.2 mmoL, 1.1 eq), after the addition was completed, slowly warmed to room temperature and stirring was continued for 1 hour. 1.5 mL of DMSO was added to the reaction solution, stirred at room temperature, and the reaction was monitored by TLC. After that, the reaction solution was washed with 1 M hydrochloric acid, water and saturated brine. The organic layer was dried, concentrated, and then purified,jjjjjjjj

Example 9: One-pot method for the preparation of compound IV-1 from 2-C-methyl-D-ribonucleic acid-1,4-lactone

2-C-Methyl-D-ribonucleic acid-1,4-lactone (0.32 g, 2 mmoL) was suspended in 10 mL of dichloromethane, and benzoyl chloride (0.46 mL, 4 mmoL, 2 eq) was added dropwise in an ice bath. ). After the addition, triethylamine (0.61 mL, 4.4 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was allowed to flow at least for one hour, and the reaction was continued overnight. Pyridine (0.18 mL, 2.2 mmoL, 1.1 eq) was added to the reaction system, and stirred at -40 ° C, then trifluoromethanesulfonic anhydride (0.37 mL, 2.2 mmoL, 1.1 eq) was slowly added. After the addition was completed, the temperature was slowly raised to room temperature. , continue to stir for 1 hour. 1.5 mL of DMSO was added to the reaction mixture, and the mixture was stirred at room temperature. After the reaction was completed by TLC, the reaction mixture was washed with 1M hydrochloric acid, water and brine, and then dried and evaporated. 63%, purity 99.2%.

Example 10: One-pot method for the preparation of compound V-1 from intermediate I-1

Intermediate I-1 (0.74 g, 2 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.18 mL, 2.2mmoL, 1.1 eq) was added and stirred at -40 ° C, then trifluoromethanesulfonic anhydride (0.37 mL, 2.2 mmoL, 1.1 eq), after the addition was completed, slowly warmed to room temperature and stirring was continued for 1 hour. 1.5 mL of DMSO was added to the reaction solution, and the mixture was stirred at room temperature. After the reaction was completely monitored by TLC, the reaction mixture was concentrated to a small volume, and acetonitrile (15 mL) and triethylamine trihydrofluoric acid salt (0.49 mL, 3mmoL) were sequentially added to the reaction system. 1.5 eq) and triethylamine (1.40 mL, 10 mmoL, 5 eq) were stirred under ice bath, and sulfuryl fluoride gas was introduced at this temperature. After the reaction was completed by TLC, the solvent was evaporated, and a brown-brown solid was precipitated, which was then purified with water and methanol to give 0.59 g of white solid, yield 78%, purity 98.0%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (dd, 2H, J = 8.4, 1.2 Hz) 8.1 (dd, 2H, J = 8.4, 1.2 Hz), 7.63 - 7.68 (m, 1H), 7.56- 7.62 (m, 1H), 7.50 (t, 2H, J = 8.0 Hz), 7.43 (t, 2H, J = 8.0 Hz), 5.53 (dd, 1H, J = 17.6, 7.2 Hz), 4.99-5.04 (m) , H), 4.77 (dd, 1H, J = 12.4, 3.6 Hz), 4.62 (dd, 1H, J = 12.4, 4.8 Hz), 1.68 (d, 3H, J = 23.6 Hz).

Example 11: One-pot method for the preparation of compound V-1 from 2-C-methyl-D-ribose-1,4-lactone

2-C-Methyl-D-ribonucleic acid-1,4-lactone (0.32 g, 2 mmoL) was suspended in 10 mL of dichloromethane, and benzoyl chloride (0.46 mL, 4 mmoL, 2 eq) was added dropwise in an ice bath. ). After the addition, triethylamine (0.61 mL, 4.4 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was allowed to flow at least for one hour, and the reaction was continued overnight. Pyridine (0.18 mL, 2.2 mmoL, 1.1 eq) was added to the reaction system, and stirred at -40 ° C, then trifluoromethanesulfonic anhydride (0.37 mL, 2.2 mmoL, 1.1 eq) was slowly added. After the addition was completed, the temperature was slowly raised to room temperature. , continue to stir for 1 hour. 1.5 mL of DMSO was added to the reaction solution, and the mixture was stirred at room temperature. After the reaction was completed by TLC, the reaction mixture was concentrated to a small volume, and then acetonitrile (12 mL) and triethylamine trihydrofluoric acid salt (0.49 mL, 3mmoL) were sequentially added to the reaction system. 1.5 eq) and triethylamine (1.40 mL, 10 mmoL, 5 eq) were stirred under ice bath, and sulfuryl fluoride gas was introduced at this temperature. After the reaction was completely monitored by TLC, solvent was evaporated, 20 mL of water was added, and a brown-red solid was precipitated at room temperature. Filtration, drying, and pulverization with methanol afforded 0.42 g of pale white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (dd, 2H, J = 8.4, 1.2 Hz) 8.1 (dd, 2H, J = 8.4, 1.2 Hz), 7.63 - 7.68 (m, 1H), 7.56- 7.62 (m, 1H), 7.50 (t, 2H, J = 8.0 Hz), 7.43 (t, 2H, J = 8.0 Hz), 5.53 (dd, 1H, J = 17.6, 7.2 Hz), 4.99-5.04 (m) , H), 4.77 (dd, 1H, J = 12.4, 3.6 Hz), 4.62 (dd, 1H, J = 12.4, 4.8 Hz), 1.68 (d, 3H, J = 23.6 Hz).

Example 12: Preparation of intermediate I-2 (in the formula I, R ₁ = R ₂ = 4-bromo-benzoyl)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (1.62 g, 10 mmoL) was suspended in 40 mL of acetonitrile, and 4-bromo-benzoyl chloride (4.36 g, 20 mmoL, was added in an ice bath. 2 eq), triethylamine (3.0 mL, 22 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was stirred over 2 hours and stirred overnight. Filter, wash the filter cake with 10 mL acetonitrile and combine the organic phases. The solvent was evaporated, and ethyl acetate (50 mL) was evaporated. After filtration and concentration, the column was separated to give 1.89 g of white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.91 (d, 2H, J = 8.4 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.57 (d, 2H, J = 8.4 Hz), 5.36 (d, 1H, J = 5.6 Hz), 4.92-4.97 (m, 1H), 4.71 (dd, 1H, J = 12.4, 4.4 Hz), 4.60 (dd , 1H, J = 12.4, 5.6 Hz), 1.66 (s, 3H).

Example 13: Preparation of Compound IV-2 (R ₁ = R ₂ = 4-bromo-benzoyl group in Formula IV) from Intermediate I-2 by one-pot method law

Intermediate I-2 (0.52 g, 1.0 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.097 mL, 1.2 EtOAc, 1.2 eq) was added and stirred at -15 ° C, trifluoromethanesulfonic anhydride (0.19 mL, 1.1 mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After the TLC monitoring material was completely reacted, the reaction flask was placed in an ice bath, 3 mL of DMSO was added, and the mixture was stirred at room temperature for 3 hours, and then 20 mL of dichloromethane was added. The reaction mixture was washed with water, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88 (d, 2H, J = 8.4 Hz), 7.78 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz), 5.56 (d, 1H, J = 6.4 Hz), 4.77 (dd, 1H, J = 12.0, 3.6 Hz), 4.68 - 4.73 (m, 1H), 4.62 (dd , 1H, J = 12.0, 5.6 Hz), 3.29 (s, 1H), 1.57 (s, 3H). The product was confirmed to be compound IV-2.

Example 14: Preparation of intermediate I-3 (in the formula I, R ₁ = R ₂ = 4-chloro-benzoyl)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (1.62 g, 10 mmoL) was suspended in 40 mL of ethyl acetate, and 4-chloro-benzoyl chloride (3.48 g, 20 mmol, 2 eq), triethylamine (3.0 mL, 22 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was stirred over 2 hours and stirred overnight. After filtration, the cake was washed with EtOAc (EtOAc) (EtOAc) After filtration and concentration, the column was separated to give 2.45 g of white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.00 (d, 2H, J = 8.4 Hz), 7.92-7.97 (m, 2H), 7.44-7.48 (m, 2H), 7.39-7.43 (m, 2H), 5.38 (d, 1H, J = 5.6 Hz), 4.94 - 4.99 (m, 1H), 4.72 (dd, 1H, J = 12.4, 4.0 Hz), 4.61 (dd, 1H, J = 12.4, 6.0 Hz) ), 1.67 (s, 3H).

Example 15: Preparation of Compound IV-3 (R ₁ = R ₂ = 4-chloro-benzoyl group in Formula IV) from Intermediate I-3 by one-pot method law

Intermediate I-3 (0.44 g, 1.0 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.105 mL, <RTI ID=0.0>> 1.2 mmoL, 1.2 eq), after adding, warmed to room temperature and continued to stir. After the TLC monitoring material was completely reacted, the reaction flask was placed in an ice bath, 3 mL of DMSO was added, and the mixture was stirred at room temperature for 3 hours, and then 20 mL of dichloromethane was added. The reaction mixture was washed with water, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.98 (d, 2H, J = 8.8 Hz), 7.97 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 5.58 (d, 1H, J = 6.8 Hz), 4.79 (dd, 1H, J = 12.0, 3.2 Hz), 4.71-4.75 (m, 1H), 4.65 (dd , 1H, J = 12.0, 5.6 Hz), 3.34 (s, 1H), 1.59 (s, 3H). The product was confirmed to be compound IV-3.

Example 16: Preparation of Intermediate I-4 (R ₁ = R ₂ = 3-methoxy-benzoyl) in Formula I

2-C-Methyl-D-ribonucleic acid-1,4-lactone (1.62 g, 10 mmoL) was suspended in 40 mL of ethyl acetate, and 3-methoxybenzoyl chloride (3.40 g) was added in an ice bath. , 20 mmol, 2 eq), triethylamine (3.0 mL, 22 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was stirred over 2 hours and stirred overnight. After filtration, the cake was washed with EtOAc (EtOAc) (EtOAc) After filtration and concentration, the column was separated to give 1.72 g of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (d, 1H, J = 7.6 Hz), 7.61 (d, 1H, J = 7.6 Hz), 7.52-7.58 (m, 2H), 7.30-7.40 (m, 2H), 7.16 (dd, 1H, J = 8.4, 2.0 Hz), 7.12 (dd, 1H, J = 8.4, 2.0 Hz), 5.41 (d, 1H, J = 5.6 Hz), 4.95 - 4.99 ( m, 1H), 4.72 (dd, 1H, J = 12.4, 4.0 Hz), 4.61 (dd, 1H, J = 12.4, 5.6 Hz), 3.85 (s, 3H), 3.84 (s, 3H), 1.68 (s) , 3H).

Example 17: Preparation of Compound IV-4 (R ₁ = R ₂ = 3-methoxy-benzoyl group in Formula IV) from Intermediate I-4 by one-pot method Preparation method

Intermediate I-4 (0.43 g, 1.0 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.105 mL, <RTI ID=0.0>> 1.2 mmoL, 1.2 eq), after adding, warmed to room temperature and continued to stir. After the TLC monitoring material was completely reacted, the reaction flask was placed in an ice bath, 3 mL of DMSO was added, and the mixture was stirred at room temperature for 3 hours, and then 20 mL of dichloromethane was added. The reaction mixture was washed with water, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.62 - 7.66 (m, 2H), 7.54 - 7.57 (m, 2H), 7.39 (t, 1H, J = 8.0 Hz), 7.33 (t, 1H, J = 8.0 Hz), 7.18 (dd, 1H, J = 8.4, 2.0 Hz), 7.12 (dd, 1H, J = 8.4, 2.0 Hz), 5.60 (d, 1H, J = 6.4 Hz), 4.72-4.81 ( m, 2H), 4.65 (dd, 1H, J = 11.6, 4.8 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.65 (s, 1H), 1.59 (s, 3H). The product was confirmed to be compound IV-4.

Example 18: Preparation of intermediate I-5 (in the formula I, R ₁ = R ₂ = trimethylacetyl)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (2.43 g, 15 mmoL) was suspended in 40 mL of acetonitrile, and trimethylacetyl chloride (3.62 g, 30 mmoL, 2 eq) was added in an ice bath. Triethylamine (4.64 mL, 33 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was stirred over 2 hours and stirred overnight. The solvent was evaporated, and ethyl acetate (50 mL) was evaporated. After filtration and concentration, the column was separated to give 1.38 g of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.12 (d, 1H, J = 5.2 Hz), 4.48-4.52 (m, 1H), 4.01 (dd, 1H, J = 12.8, 3.2 Hz), 3.80 (dd, 1H, J = 12.8, 4.0 Hz), 1.59 (s, 3H), 1.27 (s, 9H).

Example 19: Preparation of Compound IV-5 from Compound I-5 by One-Pot Method (R ₁ = R ₂ = Trimethylacetyl in Formula IV)

Intermediate I-5 (0.33 g, 1.0 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.097 mL, <RTI ID=0.0>> 1.1 mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After the TLC was monitored for complete reaction of the material, the reaction mixture was placed in an ice bath, and 3 mL of DMSO was added thereto. After stirring at room temperature for 3 hours, 20 mL of dichloromethane was added to the reaction mixture, and the organic layer was dried, filtered and concentrated. Chromatography on petroleum ether / ethyl acetate = 4:1 to give 0.21 g ofyield:

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.12 (d, 1H, J = 4.8 Hz), 4.55 - 4.59 (m, 1H), 3.90 (dd, 1H, J = 11.6, 3.2 Hz), 3.80 (dd, 1H, J = 11.6, 4.0 Hz), 1.60 (s, 3H), 1.27 (s, 9H). The product was confirmed to be compound IV-5.

Example 20: Preparation of intermediate I-6 (in the formula I, R ₁ = R ₂ = 4-methylbenzoyl)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (1.62 g, 10 mmoL) was suspended in 40 mL of ethyl acetate, and 4-methylbenzoyl chloride (2.08 g, 20 mmoL, 2 eq), triethylamine (3.0 mL, 22 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was dropped over 2 hours and allowed to react overnight. After filtration, the cake was washed with EtOAc (EtOAc) (EtOAc) After filtration and concentration, the column was separated to give 2.43 g of white solid.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.94 (d, 2H, J = 8.1 Hz), 7.89 (d, 2H, J = 8.1 Hz), 7.19-7.27 (m, 4H), 5.38 (d) , 1H, J = 5.7 Hz), 4.90-4.96 (m, 1H), 4.69 (dd, 1H, J = 12.6, 3.9 Hz), 4.57 (dd, 1H, J = 12.6, 5.7 Hz), 2.42 (s, 3H), 2.39 (s, 3H), 1.65 (s, 3H).

Example 21: Preparation of Compound IV-6 (R ₁ = R ₂ = 4-methylbenzoyl in Formula IV) from Intermediate I-6 by one-pot method law

Intermediate I-6 (0.40 g, 1.0 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.105 mL, <RTI ID=0.0>> 1.2 mmoL, 1.2 eq), after adding, warmed to room temperature and continued to stir. After the TLC was monitored for complete reaction of the material, the reaction flask was placed in an ice bath and 3 mL of DMSO was added. After stirring at room temperature for 3 hours, 20 mL of dichloromethane was added. The reaction mixture was washed with water, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,

¹ H NMR (300MHz, CDCl ₃ ): δ 7.90-7.93 (m, 4H), δ 7.19-7.28 (m, 4H), 5.52 (d, 1H, J = 6.6 Hz), 4.70-4.79 ( m, 2H), 4.59 (dd, 1H, J = 10.8, 5.2 Hz), 3.48 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 1.54 (s, 3H). The product was confirmed to be compound IV-6.

Example 22: Preparation of intermediate I-7 (in the formula I, R ₁ = R ₂ = furyl)

2-C-Methyl-D-ribonucleic acid-1,4-lactone (1.62 g, 10 mmoL) was suspended in 40 mL of ethyl acetate, and decanoyl chloride (2.6 g, 20 mmoL, 2 eq) was added under ice bath. Triethylamine (3.0 mL, 22 mmoL, 2.2 eq) was slowly added dropwise, and the mixture was stirred over 2 hours and stirred overnight. After filtration, the cake was washed with EtOAc (EtOAc) (EtOAc) After filtration and concentration, the column was separated to give 1.89 g of oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (dd, 1H, J = 1.6, 0.8 Hz), 7.59 (dd, 1H, J = 1.6, 0.8 _Hz ), 7.33 (dd, 1H, J) = 3.6, 0.8 Hz), 7.24 (dd, 1H, J = 3.6, 0.8 Hz), 6.57 (dd, 1H, J = 3.6, 1.6 Hz), 6.53 (dd, 1H, J = 3.6, 1.6 Hz), 5.37 (d, 1H, J = 5.2 Hz), 4.89 - 4.93 (m, 1H), 4.71 (dd, 1H, J = 12.4, 3.6 Hz), 4.58 (dd, 1H, J = 12.4, 5.2 Hz), 1.71 ( s, 3H).

Example 23: Preparation of Compound IV-7 from Compound I-7 by One-Pot Method (R ₁ = R ₂ = Furyl Group in Formula IV)

Intermediate I-7 (0.28 g, 0.8 mmoL) was dissolved in 10 mL dichloromethane, pyridine (0.13 mL, 1.6mmoL, 2.0 eq) was added and stirred under ice-cooling, then trifluoromethanesulfonic acid anhydride (0.20 mL) was slowly added. , 1.2mmoL, 1.5eq). After the addition, the temperature was raised to room temperature and stirring was continued. After the TLC was monitored for complete reaction of the material, the reaction flask was placed in an ice bath and 3 mL of DMSO was added. Stir at room temperature overnight and add 20 mL of dichloromethane. The reaction mixture was washed with water, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.65 (dd, 1H, J = 1.6, 0.8 Hz), 7.59 (dd, 1H, J = 1.6, 0.8 Hz), 7.29 (dd, 1H, J = 3.6, 0.8 Hz), 7.25 (dd, 1H, J = 3.6, 0.8 Hz), 6.57 (dd, 1H, J = 3.6, 1.6 Hz), 6.52 (dd, 1H, J = 3.6, 1.6 Hz), 5.53 ( d, 1H, J = 5.6 Hz), 4.74 (dd, 1H, J = 11.6, 3.2 Hz), 4.67 - 4.72 (m, 1H), 4.61 (dd, 1H, J = 11.6, 4.8 Hz), 3.78 (br) , 3H), 1.56 (s, 3H). The product was confirmed to be compound IV-7.

Example 24: Preparation of Compound IV-1 from Intermediate I-1 by Two-Step Reaction

The first step: Intermediate I-1 (3.7g, 10mmoL) was added to 50mL of dichloromethane, added triethylamine (3.0mL, 21.3mmoL, 2.1eq), stirred under ice bath, slowly added with methanesulfonyl chloride (0.93 mL, 12 mmmoL, 1.2 eq), after completion, stirring was continued. After the reaction was completed by TLC, 20 mL of dichloromethane was added to the mixture, and washed successively with saturated sodium hydrogen carbonate, 1 M diluted hydrochloric acid and brine. After drying, the column was separated to give 3.81 g of a white solid.

¹ H NMR (300MHz, CDCl ₃ ): δ 8.16 (d, 2H, J = 7.8 Hz), 7.99 (d, 2H, J = 7.8 Hz), 7.56-7.62 (m, 2H), 7.40-7.50 (m, 4H), 5.44 (d, 1H, J = 5.7 Hz), 5.08-5.13 (m, 1H), 4.78 (dd, 1H, J = 12.6, 3.0 Hz), 4.65 (dd, 1H, J = 12.6) , 4.2 Hz), 3.19 (s, 3H), 1.90 (s, 3H). The product was confirmed to be intermediate II-8.

The second step: Intermediate II-8 (1.0 g, 2.2 mmoL) was dissolved in 4 mL of DMSO, tetrabutylammonium iodide (0.16 g, 0.2 eq) was added, stirred at 75 ° C, and slowly added dropwise KNO ₂ (0.62 g, 7.26 mmoL, 3.3 eq) of a 0.4 mL aqueous solution was added over 15 minutes and stirring was continued for 20-25 minutes. After adding 60 ml of ethyl acetate, the mixture was washed with EtOAc EtOAc EtOAc.

Example 25: Preparation of Compound IV-3 from Intermediate I-3 by Two-Step Reaction

The first step: Intermediate I-3 (0.44g, 1.0mmoL) was added to 10mL of dichloromethane, added triethylamine (0.28mL, 2.0mmoL, 2.0eq), stirred under ice bath, slowly added with methyl sulfonate The acid chloride (0.093 mL, 1.2 mmmoL, 1.2 eq) was added and the stirring was continued. After the reaction was completely monitored by TLC, 10 mL of dichloromethane was added to the mixture, and the mixture was washed successively with saturated sodium hydrogen carbonate, 1M diluted hydrochloric acid and brine. After drying, the column was separated to give 0.41 g of a white solid.

¹ H NMR (300MHz, CDCl ₃ ): δ 8.09 (d, 2H, J = 8.4 Hz), 7.92 (d, 2H, J = 8.4 Hz), 7.26-7.46 (m, 4H), 5.38 (d) , 1H, J = 5.7 Hz), 5.02-5.13 (m, 1H), 4.76 (dd, 1H, J = 12.9, 3.0 Hz), 4.65 (dd, 1H, J = 12.9, 4.2 Hz), 3.20 (s, 3H), 1.87 (s, 3H). The product was confirmed to be the intermediate H-9.

The second step: Intermediate II-9 (0.26g, 0.5mmoL) was dissolved in 1mL DMSO, tetrabutylammonium iodide (37mg, 0.2eq) was added, stirred at 75 ° C, slowly added KNO ₂ (0.15g, 1.75) A 0.1 mL aqueous solution of mmoL, 3.5 eq) was added over 15 minutes and stirring was continued until the reaction was complete. After adding 20 mL of ethyl acetate, the mixture was washed with EtOAc EtOAc EtOAc.

Comparative Example 1: Compound IV-1 could not be obtained by using Compound A

Intermediate I-1 (3.7 g, 10 mmoL) was added to 50 mL of dichloromethane, and DBU (3.0 mL, 20mmoL, 2.0 eq) was added and stirred under ice-bath, and p-toluenesulfonyl chloride (2.1 g, 11mmmoL, 1.1eq), after adding, continue to stir. After the reaction was completed by TLC, 20 mL of dichloromethane was added to the mixture, and the mixture was washed with saturated sodium hydrogen carbonate, 1 M diluted hydrochloric acid and brine. After drying, the column was separated to give 3.93 g of a white solid.

¹ H NMR (300MHz, CDCl ₃ ): δ 7.97-8.01 (m, 4H), 7.59-7.66 (m, 4H), 7.43-7.52 (m, 4H), 7.14 (d, 2H, J = 8.1 Hz), 4.89-4.96 (m, 2H), 4.59 (dd, 1H, J = 12.6, 1.8 Hz), 4.19 (dd, 1H, J = 12.6, 3.0 Hz), 2.37 (s, 3H), 1.77 (s) , 3H). The product was confirmed to be Compound A.

Compound A (0.52 g, 1.0 mmoL) was dissolved in 2 mL DMSO, tetrabutylammonium iodide (0.16 g, 0.2 eq) was added, stirred at 85 ° C, and slowly added dropwise KNO ₂ (0.62 g, 7.26 mmoL, 3.3 eq) The 0.2 mL aqueous solution was added in 15 minutes. Stirring was continued for 1 hour with almost no target product formation.

Example 26: Preparation of Compound IV-1 from Intermediate II-1

Intermediate II-1 (1 g, 2 mmol) was dissolved in 15 mL of dichloromethane and stirred at room temperature, and 2 mL of dimethyl sulfoxide was slowly added dropwise. After the addition was completed, the stirring was continued for 2 hours, 15 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with water, and the organic layer was dried, filtered, concentrated, and then purified with petroleum ether/acetone = 3:1 column to obtain 0.61 g of product IV-1. The rate is 82%.

Example 27: Preparation of Compound IV-1 from Intermediate II-1

Intermediate II-1 (0.5 g, 1 mmol) was dissolved in 15 mL of acetone, stirred at room temperature, 1 mL water was added and stirred at 40 ° C overnight. The solvent was evaporated, 20 mL of ethyl acetate was added, and the organic layer was separated and dried. Filtration, concentration and chromatography on a petroleum ether / acetone = 3:1 column yielded 0.19 g of product IV-1, yield 51%.

Example 28: Preparation of intermediate III-1 from intermediate II-1

The intermediate II-1 (0.5 g, 1 mmoL) was dissolved in 10 mL of acetone, stirred at room temperature, and 2 mL of N,N-dimethylformamide was slowly added thereto. After the addition was continued for 2 hours, the reaction solution was poured into 50 mL. Water, a white solid precipitated, which was filtered and dried to give 0.35 g of Intermediate III-1.

Comparative Example 2: Preparation of intermediate III-1 from intermediate II-1

The intermediate II-1 (0.5 g, 1 mmoL) was dissolved in 12 mL of acetone, stirred at room temperature, and added, and stirring was continued for 2 hours, and no target product was formed.

Example 30: Preparation of intermediate II-2 from intermediate I-2

Intermediate I-2 (0.105 g, 0.2 mmol) was dissolved in 4 mL of dichloromethane, pyridine (0.02 mL, 0.24 mmol, 1.2 eq) was added, and stirred at -15 ° C, trifluoromethanesulfonic anhydride (0.04 mL, 0.22 mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After the TLC was monitored for complete reaction of the starting material, the solvent was distilled off, and the column was separated to obtain 0.11 g of an oily substance, yield 87%, purity 98.8%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.96 (d, 2H, J = 8.4 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.57 (d, 2H, J = 8.4 Hz), 5.55 (d, 1H, J = 6.4 Hz), 5.02 - 5.07 (m, 1H), 4.75 (dd, 1H, J = 12.8, 3.6 Hz), 4.65 (dd , 1H, J = 12.8, 4.8 Hz), 2.00 (s, 3H). The product was confirmed to be intermediate II-2.

Example 31: Preparation of intermediate II-3 from intermediate I-3

Intermediate I-3 (88 mg, 0.2 mmol) was dissolved in 4 mL dichloromethane, pyridine (0.02 mL, 0.24 mmol, 1.2 eq) was added and stirred at -15 ° C, and trifluoromethanesulfonic anhydride (0.04 mL, 0.22) was slowly added. mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After the TLC was monitored for complete reaction of the starting material, the solvent was evaporated, and the column was separated to yield 0.10 g of an oily substance with a yield of 90% and a purity of 99.2%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.01 (d, 2H, J = 8.8 Hz), 7.97 (d, 2H, J = 8.8 Hz), 7.48-7.50 (m, 4H), 5.14-5.17 (m, 1H), 5.09 (d, 1H, J = 5.6 Hz), 4.81 (dd, 1H, J = 12.8, 3.6 Hz), 4.64 (dd, 1H, J = 12.8, 3.6 Hz), 1.86 (s, 3H). The product was confirmed to be intermediate II-3.

Example 32: Preparation of intermediate II-4 from intermediate I-4

Intermediate I-4 (0.25 g, 0.25 mmoL) was dissolved in 5 mL of dichloromethane, pyridine (0.025 mL, 0.3mmoL, 1.2 eq) was added and stirred at -15 ° C, trifluoromethanesulfonic anhydride (0.05 mL, 0.27 mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After TLC was used to monitor the complete reaction of the starting material, the solvent was evaporated, and the column was separated to yield 0.11 g of oil. The yield was 82% and the purity was 98.2%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74 (d, 1H, J = 7.6 Hz), 7.64-7.66 (m, 1H), 7.56-7.59 (m, 1H), 7.50-7.52 (m, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.34 (t, 1H, J = 8.0 Hz), 7.20 (dd, 1H, J = 8.4, 2.0 Hz), 7.14 (dd, 1H, J = 8.4) , 2.0 Hz), 5.63 (d, 1H, J = 6.8 Hz), 5.04-5.09 (m, 1H), 4.78 (dd, 1H, J = 12.8, 3.6 Hz), 4.65 (dd, 1H, J = 12.8, 4.4 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 2.04 (s, 3H). The product was confirmed to be intermediate II-4.

Example 33: Preparation of Intermediate II-5 from Intermediate I-5

Intermediate I-5 (0.20 g, 0.6 mmol) was dissolved in 8 mL dichloromethane, pyridine (0.058 mL, 0.72 mmol, 1.2 eq) was added and stirred at -15 ° C, trifluoromethanesulfonic acid anhydride (0.11 mL, 0.66 mmoL, 1.1 eq), after adding, warmed to room temperature and continued to stir. After the TLC was monitored for complete reaction of the starting material, the solvent was evaporated, and the column was separated to give 0.21 g of oil, yield 75%, purity 98%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.03 (d, 1H, J = 6.0 Hz), 3.90 (dd, 1H, J = 12.8, 4.4 Hz), 4.64 - 4.71 (m, 1H), 1.59 (s, 3H), 1.29 (s, 9H). The product was confirmed to be intermediate II-5.

Example 34: Preparation of intermediate II-6 from intermediate I-6

Intermediate I-6 (0.12 g, 0.3 mmol) was dissolved in 5 mL dichloromethane, pyridine (0.03 mL, 0.36 mmol, 1.2 eq) was added and stirred at -15 ° C, trifluoromethanesulfonic anhydride (0.06 mL, 0.33mmoL, 1.1eq), after adding, rise to room temperature, Continue to stir. After the TLC was monitored for complete reaction of the starting material, the solvent was distilled off, and the column was separated to obtain 0.13 g of an oily substance. The yield was 83%, and the purity was 98.9%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02 (d, 2H, J = 8.0 Hz), 7.78 (d, 2H, J = 8.0 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 8.0 Hz), 5.61 (d, 1H, J = 6.4 Hz), 5.04-5.09 (m, 1H), 4.77 (dd, 1H, J = 12.8, 3.6 Hz), 4.65 (dd , 1H, J = 12.8, 4.4 Hz), 2.45 (s, 3H), 2.43 (s, 3H), 2.03 (s, 3H). The product was confirmed to be intermediate II-6.

Example 35: Preparation of intermediate II-7 from intermediate I-7

Intermediate I-7 (67 mg, 0.2 mmol) was dissolved in 4 mL dichloromethane. pyridine (EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) mmoL, 1.1eq). After the addition, the temperature was raised to room temperature and stirring was continued. After the TLC was monitored for complete reaction of the starting material, the solvent was evaporated, and the column was separated to yield 0.083 g of an oily material, yield 87%, purity 98.2%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, 1H, J = 1.2 Hz), 7.59 (d, 1H, J = 1.2 Hz), 7.49 (d, 1H, J = 3.2 Hz), 7.27 (d, 1H, J = 3.2 Hz), 6.61 (dd, 1H, J = 3.6, 2.0 Hz), 6.56 (dd, 1H, J = 3.6, 2.0 Hz), 5.58 (d, 1H, J = 5.6 Hz) ), 4.97-5.01 (m, 1H), 4.79 (dd, 1H, J = 12.8, 3.2 Hz), 4.63 (dd, 1H, J = 12.8, 3.6 Hz), 2.08 (s, 3H). The product was confirmed to be intermediate II-7.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (29)

An intermediate (II) for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone, characterized in that Has the structure shown in Formula II:

among them, R ₁ and R _{2 are} independently R"C(O)-, and R" is selected from C1-C10 alkyl; C3-C8 cycloalkyl; C6-C10 aryl; five- or six-membered heterocyclic; One or more selected from the group consisting of C1-C4 alkoxy, C6-C10 aryloxy, nitro, cyano, sulfonate, sulfate, phosphonate, phosphate, phosphonate, chlorine, bromine a C1-C6 alkyl group substituted with a substituent of fluorine and iodine; substituted by one or more substituents selected from the group consisting of chlorine, bromine, fluorine, iodine, nitro, C1-C4 alkyl and C1-C4 alkoxy Aryl or heterocyclic; trityl; R ₃ is -NO ₂ , -S(=O)nR ₄ or -C(=O)-R ₄ , wherein R ₄ is hydrogen, C 1 which is unsubstituted or substituted by one or more electron withdrawing substituents. C6 alkyl; n is 1 or 2. The intermediate (II) according to claim 1, wherein the electron withdrawing substituent in R ₄ is one or more selected from the group consisting of fluorine, chlorine, nitro and cyano. The intermediate (II) according to claim 1, wherein the R ₄ is a methyl group, an ethyl group, or a C1-C3 alkyl group substituted by one or more electron withdrawing substituents. The intermediate (II) according to claim 3, wherein the R ₄ is a methyl group or a C1-C3 alkyl group substituted with an electron withdrawing substituent, and the electron withdrawing substituent includes at least fluorine. The intermediate (II) according to claim 1, wherein the R ₃ is -S(=O) ₂ CH ₃ or -S(=O) ₂ CF ₃ . The intermediate (II) according to claim 1, wherein R ₁ and R ₂ are the same substituent. The intermediate (II) according to any one of claims 1 to 6, wherein R" is unsubstituted or one or more selected from the group consisting of chlorine, bromine, fluorine, iodine, and nitro a phenyl group substituted with a substituent of a C1-C4 alkyl group and a C1-C4 alkoxy group, unsubstituted or substituted by one or more selected from the group consisting of chlorine, bromine, fluorine, iodine, nitro, C1-C4 alkyl and A five- or six-membered aromatic heterocyclic group substituted with a substituent of a C1-C4 alkoxy group, or a C1-C4 alkyl group. The intermediate (II) according to claim 7, wherein R" is a phenyl group; a phenyl group substituted with one selected from the group consisting of fluorine, chlorine and methoxy, wherein the substitution position is ortho, Meta or para; 2-furyl, tert-butyl, methyl or ethyl. The intermediate (II) according to claim 1, wherein the intermediate (II) is selected from the group consisting of the following formulas II-1, II-2, II-3, II-4, II-5, II- 6. Compounds represented by II-7, II-8, II-9:

A process for the preparation of an intermediate (II) according to any one of claims 1 to 9, wherein the preparation comprises the step of allowing the intermediate (I) and the reagent R ₃ -Y to exist in the base The intermediate (II) is prepared by the acylation reaction of step d):

Wherein Y is halogen or OR ₃ ; and R ₁ , R ₂ and R ₃ are as defined in the preceding claims. The process according to claim 10, wherein the base used in the step d) acylation is one or more of pyridine, triethylamine, 4-dimethylaminopyridine and diisopropylethylamine. The Y is chlorine or bromine or OR ₃ , and the acylation reaction is carried out at a temperature of -50 ° C to 25 ° C. The preparation method according to claim 10, wherein the preparation method further comprises subjecting 2-C-methyl-D-ribofanoate-1,4-lactone in the presence of a base to the reagent R"CO-- Z occurs in step e) to produce intermediate (I),

Wherein Z is halogen or OCOR"; R ₁ , R ₂ and R" are as defined in the preceding claims. The preparation method according to claim 12, wherein the base used in the reaction of the step e) is one or more of pyridine, triethylamine, 4-dimethylaminopyridine and diisopropylethylamine. The Z is chlorine or bromine or OCOR", and the reaction of the step e) is carried out at a temperature of -50 ° C to 25 ° C. The preparation method according to claim 12 or 13, wherein the step e) and the step d) are carried out stepwise or in one pot. Process for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV), characterized in that Using the intermediate (II) according to any one of claims 1 to 9 as a reaction starting material, the intermediate (II) is subjected to the step a) substitution reaction or the step b) cyclization reaction and Step c) ring-opening substitution reaction to give (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV),

In the above formula, R ₁ , R ₂ , R" and R ₃ are as defined in the preceding claims. The process according to claim 15, wherein the step a) substitution reaction is carried out in a mixed solvent of dimethyl sulfoxide or dimethyl sulfoxide and another solvent selected from the group consisting of two. One or more of methyl chloride, ethyl acetate, tetrahydrofuran, acetonitrile, water, acetone, and methanol. The process according to claim 15 or 16, wherein the step a) substitution reaction is carried out at -20 ° C to 30 ° C. The process according to claim 15, wherein the step b) is carried out in a mixed solvent of N,N-dimethylformamide or N,N-dimethylformamide and another solvent. The other solvent is one or more selected from the group consisting of tetrahydrofuran, acetonitrile and acetone. The process according to claim 15 or 18, wherein the step b) is carried out at a temperature of from -20 ° C to 30 ° C. The process according to claim 15, wherein the step c) ring-opening substitution reaction is carried out in a solvent in the presence of a base. The preparation method according to claim 15 or 20, wherein the base in the step c) ring-opening reaction is selected from the group consisting of sodium alkoxide, potassium alkoxide, triethylamine, diisopropylethylamine, 1,8. One or more of didiazacyclo[5,4,0]undecene-7, pyridine, 4-dimethylaminopyridine and metal hydride. The preparation method according to claim 15 or 18 or 20, wherein the step b) and the step c) are carried out stepwise or in one pot. The process according to claim 15, wherein the substitution of the step a) is carried out in the presence of a solvent, a phase transfer catalyst and a nitrite, and the solvent is a mixed solvent of an organic solvent and water. The preparation method according to claim 23, wherein in the step a), the organic solvent is a first organic solvent or a combination of a first organic solvent and a second organic solvent, and the first organic solvent is selected from the group consisting of One or more of DMSO, N,N-dimethylformamide, N-methylpyrrolidone; the second organic solvent is selected from the group consisting of dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, water, acetone, and One or more of methanol, the nitrite being sodium nitrite or potassium nitrite or a combination of the two. The process according to claim 23 or 24, wherein the substitution reaction in the step a is carried out at a temperature of from 25 ° C to 100 ° C. The production method according to claim 15, wherein the preparation method further comprises the preparation of the intermediate (II) by the preparation method of the intermediate (II) according to any one of claims 10 to 14. . The preparation method according to claim 26, wherein the step d) and the step a) are carried out stepwise or in one pot, and the step d) and the step b) are carried out stepwise or in one pot. A method for preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-halo-2-methyl-D-ribose-γ-lactone (V), characterized in that: A method of preparing (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D- according to the method of any one of claims 15 to 27. Ribose-γ-lactone (IV), and the (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-hydroxy-2-methyl-D-ribose-γ-lactone (IV) Preparation of (2S,3R,4R)-3,5-disubstituted-2-deoxy-2-halo-2-methyl-D-ribose-γ-lactone by halogenation reaction with halogenating reagent in step f) (V):

Wherein R ₁ and R ₂ are as defined in the preceding claims; X is fluorine, chlorine, bromine or iodine. The preparation method according to claim 28, wherein the step f) the halogenation reaction is carried out stepwise or in one-step process with the step a) or the step c).