WO2017202357A1

WO2017202357A1 - Method for preparing trifluoromethyl-substituted pyran derivative

Info

Publication number: WO2017202357A1
Application number: PCT/CN2017/085867
Authority: WO
Inventors: 张晨; 王健民; 何平; 黄龙彬
Original assignee: 四川海思科制药有限公司
Priority date: 2016-05-25
Filing date: 2017-05-25
Publication date: 2017-11-30
Also published as: CN109071551A; CN109071551B

Abstract

Provided is a method for preparing a trifluoromethyl-substituted pyran derivative, that is, a method for preparing the compound shown in formula (I) and an intermediate thereof. The method has the advantages of having mild reaction conditions, simple operations, high reaction yield, high product purity and convenient post-treatment, rendering the method suitable for industrial production.

Description

Preparation method of trifluoromethyl substituted pyran derivative

Technical field

The invention belongs to the field of chemical medicine and relates to the preparation of trifluoromethyl substituted pyran derivatives.

Background technique

Glucagon-like peptide 1 (GLP-1) can participate in the regulation of blood glucose homeostasis, improve islet function, delay or even reverse the progression of type 2 diabetes through multiple pathways. However, endogenous GLP-1 is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) after secretion into the blood and loses its activity. DPP-4 inhibitor can selectively inhibit the enzymatic activity of DPP-4, prevent the inactivation of GLP-1 cleavage, increase the plasma level of active GLP-1, enhance its physiological effects, and reduce HbA1, fasting blood glucose and meals in patients with type 2 diabetes. After blood sugar levels.

WO2015192701 discloses a novel dipeptidyl peptidase IV (DPP-4) inhibitor represented by formula (I), which has a good inhibitory effect on the enzymatic activity of DPP-4 and has the potential to prevent and treat type II diabetes. .

The compound of the formula (I) has good stability and high bio-use degree, and is convenient for the development of the preparation and has clinical value. Therefore, the research on the preparation method of the compound of the formula (I) in the art has important significance.

Summary of the invention

The object of the present invention is to provide a preparation method of a trifluoromethyl-substituted pyran derivative, which is a preparation method of the compound represented by the formula (I), which has mild reaction conditions, simple operation, high reaction yield and product purity. High, easy to handle, suitable for industrial production.

In particular, in a first aspect, the invention relates to a process for the preparation of a compound of formula (I):

Wherein, the compound of the formula (II) is reacted in p-toluenesulfonic acid monohydrate with methylene chloride or trifluoroacetic acid in the presence of water at 20 to 25 ° C under an inert gas atmosphere, and is post-treated. (I) a compound;

Wherein P in the formula (II) is an amino-protecting group, preferably a tert-butoxycarbonyl group.

In certain embodiments, p-toluenesulfonic acid monohydrate can be replaced with p-toluenesulfonic acid.

In certain embodiments, p-toluenesulfonic acid monohydrate is in excess, preferably, the molar ratio of the compound of formula (II) to p-toluenesulfonic acid monohydrate is from 1:2.5 to 1:3, preferably. 1:2.8.

In certain embodiments, trifluoroacetic acid is an excess, preferably, the mass to volume ratio (w/v) of the compound of formula (II) to trifluoroacetic acid is from 1:2.5 to 1:3.5.

In certain embodiments, the mass ratio of the formula (II) to the solvent dichloromethane (w/v) is from 1:8 to 1:15, preferably 1:10.

In certain embodiments, the volume ratio of trifluoroacetic acid to solvent water is from 2:1 to 4:1.

In certain embodiments, the post-treatment of the reaction in the presence of p-toluenesulfonic acid monohydrate in the presence of methylene chloride comprises the steps of:

(1) Water and methanol are sequentially added to the reaction liquid, and the layers are separated, and the aqueous layer is extracted with a mixed solvent of dichloromethane and methanol;

(2), the organic phase obtained in (1) is adjusted to alkaline with a base, the organic layer is washed successively with a saturated sodium carbonate solution and a saturated aqueous salt solution, dried, and concentrated under reduced pressure at 40 ° C or less;

(3) The residue obtained by concentration in (2) is dissolved in ethyl acetate at an internal temperature of less than 40 ° C in an inert gas atmosphere;

(4), keep the internal temperature less than 40 ° C, add n-heptane dropwise, crystallize at room temperature;

Alternatively, a seed crystal of the compound of formula (I) is added to step (4).

In certain embodiments, the volume ratio of water added in step (1) to solvent dichloromethane in the reaction mixture is from 0.8:1 to 1.2:1.

In certain embodiments, the volume ratio of water to methanol is sequentially added in step (1) from 9:1 to 12:1, and the volume ratio of dichloromethane to methanol used for extraction is from 9:1 to 11:1.

In certain embodiments, the base used in step (2) is aqueous ammonia, and the pH of the solution when adjusted to basic is from 8 to 11, preferably from 9 to 10.

In certain embodiments, the volume ratio of n-heptane added in step (4) to ethyl acetate in step (3) is from 1:1 to 4:1.

In certain embodiments, the post-treatment of the reaction in the presence of trifluoroacetic acid in the presence of water comprises the steps of:

(1), adding dichloromethane to the reaction solution, adding water and ammonia water to pH>7, layering;

(2) extracting (1) the aqueous layer with dichloromethane, combining the organic phases obtained in the step (1) (2), and washing the combined organic phases sequentially with saturated sodium carbonate solution and saturated brine, drying with a drying agent Concentrated under reduced pressure to give a crude product;

(3), the crude product obtained in the step (2) is dissolved in ethyl acetate, the internal temperature is maintained at 25 to 35 ° C, n-heptane is added dropwise, and crystallized at room temperature;

Alternatively, a seed crystal of the compound of formula (I) is added to step (3).

In certain embodiments, the desiccant used in step (2) is anhydrous sodium sulfate.

In a second aspect, the present invention relates to a process for the preparation of a compound of formula (II), characterized in that

Wherein, the compound of the formula (III) and the compound of the formula (IV) are reacted by Dean-Starks in water by using chloroform as a solvent, and the reaction solution is diluted with 1,2-dichloroethane under an inert gas atmosphere. Adding sodium triacetoxyborohydride and acetic acid, reacting at room temperature, and post-treatment to obtain a compound of formula (II);

Wherein, in the formula (II) and the formula (III), P is an amino-protecting group, preferably a tert-butoxycarbonyl group.

In certain embodiments, the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1.1 to 1:2.

In certain embodiments, the volume to mass ratio of chloroform to the compound of formula (III) is from 1.5:1 to 5:1, preferably 2:1.

In certain embodiments, the reaction solution is diluted 1 to 20 times, preferably 8 to 10 times, with 1,2-dichloroethane.

In certain embodiments, the molar ratio of the compound of formula (III) to sodium triacetoxyborohydride is from 1:2 to 1:5, preferably from 1:3 to 1:4.

In certain embodiments, the molar ratio of acetic acid to the compound of formula (III) is from 1:1 to 2.5:1.

In certain embodiments, the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1.1 to 1:2, and the volume-to-mass ratio of chloroform to compound of formula (III) is from 1.5:1 to 5:1. The reaction solution is diluted 1 to 20 times, preferably 8 to 10 times with 1,2-dichloroethane; the molar ratio of the compound of the formula (III) to sodium triacetoxyborohydride is 1:2 to 1:5, preferably 1: 3 to 1:4, the molar ratio of acetic acid to the compound of the formula (III) is 1:1 to 2.5:1.

In certain embodiments, the post-processing includes the following steps:

(1), adding water, layering, extraction, washing with water and alkali solution, drying, filtering and concentrating;

(2), the concentrate in (1) is dissolved in methanol under heating, and water is added dropwise with stirring at room temperature, and filtered;

(3) Dissolving the filtrate in (2) in dichloromethane, layering, drying the organic layer, using a silica gel column Analytical separation;

(4) The pulp obtained in (3) is beaten.

In certain embodiments, the base described in step (1) is aqueous ammonia.

In some embodiments, the water is added dropwise in two steps in the step (2), wherein the volume ratio of methanol, the first drop of water, and the second drop of water is preferably 4:1:4.

In some embodiments, the solvent used in the step (4) is a mixed solvent of dichloromethane and petroleum ether, preferably a volume ratio of dichloromethane to petroleum ether of 1:2.

In a third aspect, the invention also relates to a process for the preparation of a compound of formula (III):

Contains the following steps:

(1) using a toluene as a solvent, and reacting the compound of the formula (V) with morpholine in a water-repellent reaction, and post-treating to obtain a mixture of the compound of the formula (VI-A) and the formula (VI-B):

(2) N,N-dimethylacetamide, 4-dimethylaminopyridine, and the formula (VI-A) obtained in the step (1) under anhydrous and anaerobic conditions at -10 ° C to room temperature a mixture of compounds of formula (VI-B) is reacted with a solution of S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate in N,N-dimethylacetamide;

Wherein, in the formula (V), the formula (VI-A) and the formula (VI-B), P is an amino-protecting group, preferably a tert-butoxycarbonyl group.

In certain embodiments, the molar ratio of the compound of formula (V) to morpholine is from 1:1.2 to 1:5, preferably 1:1.5.

In certain embodiments, the molar ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) to S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate is 1:1 to 1 :1.5.

In certain embodiments, the molar ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) to 4-dimethylaminopyridine is from 1:0.1 to 1:1.5, preferably from 1:1 to 1:1.2.

In certain embodiments, the mass to volume ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) to the total N,N-dimethylacetamide in the reaction is from 1:5 to 1:20, preferably. 1:8 ~ 1:15.

In certain embodiments, the molar ratio of the compound of formula (V) to morpholine is from 1:1.2 to 1:5, preferably 1:1.5. The molar ratio of the mixture of the compound of the formula (VI-A) and the formula (VI-B) to the S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate is 1:1 to 1:1.5, and the formula (VI) The molar ratio of the mixture of -A) and the compound of the formula (VI-B) to 4-dimethylaminopyridine is 1:0.1 to 1:1.5, preferably 1:1; the compound of the formula (VI-A) and the formula (VI-B) The mass to volume ratio of the mixture to the total N,N-dimethylacetamide in the reaction is from 1:5 to 1:20, preferably from 1:8 to 1:15.

In certain embodiments, the post-treatment described in step (1) of the preparation of the compound of formula (III) comprises the steps of:

(1), the reaction liquid is hot and beaten with n-heptane;

(2), filtration, solid drying to constant weight.

In certain embodiments, step (2) of the method for preparing a compound of formula (III) further comprises the steps of:

(1), keeping the temperature of the system below 20 ° C, adding ice water to the reaction solution, extracting with ethyl acetate, and combining the organic phase;

(2), keeping the temperature of the system below 10 ° C, adding hydrochloric acid dropwise, and reacting at room temperature;

(3) washing, drying, and concentration;

(4), the obtained product in (3) is dissolved in dichloromethane, added to silica gel, concentrated under reduced pressure at 50 ° C or less to dry powder, maintaining the temperature to the end of the configuration transition;

(5), desorption, concentration, to obtain crude products;

(6), the crude product is beaten with n-hexane reflux;

(7), filtered, and the solid is dried to constant weight.

In certain embodiments, the molar ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) in step (2) to the added hydrochloric acid is from 1:3 to 1:5.

In certain embodiments, the mass ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) to silica gel in step (4) is from 1:1.5 to 1:5.

In a fourth aspect, the invention also relates to a process for the preparation of a compound of formula (IV):

Including: reacting a compound of the formula (VII) with a hydrochloric acid-ethyl acetate solution at -10 to 10 ° C;

Wherein P in the formula (VII) is an amino-protecting group, preferably a tert-butoxycarbonyl group.

In certain embodiments, the hydrochloric acid-ethyl acetate solution is ready for use and is formed by dropwise addition of acetyl chloride to a mixture of ethyl acetate and ethanol, preferably at a concentration of 4 mol/L hydrochloric acid-ethyl acetate solution.

In certain embodiments, the mass to volume ratio of the compound of formula (VII) to the hydrochloric acid-ethyl acetate solution is 1:3.5 to 1:8.

In certain embodiments, the method of preparing a compound of formula (IV) further comprises seeding crystals of a compound of formula (IV).

In a fifth aspect, the present invention provides a compound of the following formula (III-A), formula (III-B), formula (II-A), formula (II-B):

Wherein P is an amino protecting group, preferably a tert-butoxycarbonyl group.

In a sixth aspect, the present invention relates to a process for the preparation of a compound of formula (III-A) and formula (III-B),

The method comprises the following steps: using N,N-dimethylacetamide, 4-dimethylaminopyridine, the formula (VI-A) and the compound of the formula (VI-B) under anhydrous and anaerobic conditions at -10 ° C to room temperature. The mixture is reacted with a solution of S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate in N,N-dimethylacetamide, and separated by silica gel column chromatography to obtain formula (III-A) and formula ( III-B) a compound;

Wherein, in the formulae (VI-A), (VI-B), (III-A) and (III-B), P is an amino-protecting group, Preference is given to tert-butoxycarbonyl.

In certain embodiments, the molar ratio of formula (VI-A) to formula (VI-B) in the mixture of compounds of formula (VI-A) and formula (VI-B) is from 3:1 to 12:1.

In certain embodiments, the molar ratio of the mixture of the compound of formula (VI-A) and formula (VI-B) to S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate is 1:1 to 1 :2.

In a seventh aspect, the present invention relates to a process for the preparation of a compound of formula (II-A) and formula (II-B),

The method comprises the following steps: using chloroform as a solvent, heating and refluxing, and reacting the compound of the formula (III) and the compound of the formula (IV) by Dean-Starks, and separating by the silica gel column chromatography to obtain the formula (II-A) and the formula (II-B). Compound

Wherein, in the formula (III), the formula (II-A) and the formula (II-B), P is an amino-protecting group, preferably a tert-butoxycarbonyl group.

The compound of the formula (III) according to the invention is a diastereomer comprising the following two structures:

During the preparation of the compound of formula (III), the diastereomer is adsorbed on silica gel and concentrated under reduced pressure to dry powder at 50 ° C or lower, and the structure (III-1) conformation can be achieved by maintaining the temperature below 50 ° C. Partial conversion of type (III-2).

The "configuration transition end point" as used in the present invention means that ¹ H NMR (solvent is DMSO-d ₆ ) displacement (δ) at a peak area ratio of H (δ 5.2) to H (δ 4.4) > 2:1. The ¹ H NMR shift (δ) allows for some movement due to the different control of the experimental conditions due to the different ¹ H NMR instruments.

The "water separation reaction" described in the present invention refers to a water separation reaction carried out using a Dean-Starks trap.

The separation method used in the present invention is a conventional separation method conventionally used in the art, such as silica gel column chromatography, high performance liquid chromatography, and thin layer chromatography.

"Optional" or "as an option" means that the subsequently described event or environment may but It does not have to happen, including where the event or environment occurs or does not occur.

The reaction process of the present invention tracks the progress of the reaction by HPLC, ¹ H NMR or thin layer chromatography to determine whether the reaction is over.

In the present invention, the inert gas means a gas which does not participate in the reaction, such as nitrogen.

In the present invention, the internal temperature means the temperature of the reaction system.

The invention optimizes the process for the compound of formula (II) to form the compound of formula (I). In the prior art, the reaction system of trifluoroacetic acid and dichloromethane is adopted, the post-treatment is not suitable for control, and the concentration of trifluoroacetic acid has an influence on the stability of the product. The product increases as the amount of feed increases. The invention adopts a reaction system of p-toluenesulfonic acid monohydrate and dichloromethane or a reaction system of trifluoroacetic acid and water, thereby avoiding the disadvantage that the degradation product is significantly increased in the post-treatment. At the same time, the reaction system of trifluoroacetic acid and water reduces the use of trifluoroacetic acid, reduces the use of organic solvents, and is more environmentally friendly.

The invention optimizes the process of the condensation reaction of the intermediate of the formula (III) with the intermediate of the formula (IV) to obtain the compound of the formula (II), using chloroform as a solvent and adopting a reflux water separation method to avoid the prior art under toluene conditions. The unconventional operation of evaporating the solvent, the reaction conditions are milder, the reaction is more thorough, and the overall reaction yield is improved. At the same time, the reaction conditions are suitable for amplification, which is in line with industrial production. Although the purification method still has column chromatography, the use of silica gel column chromatography, the amount of silica gel is greatly reduced, and rapid. At the same time, in the prior art, the method of evaporating the solvent toluene is adopted, the reaction temperature is high, the concentration changes greatly, the product is not easily controlled, and the progress of the reaction is not easy to monitor. With chloroform reflux, the reaction can better monitor the process.

The invention optimizes the preparation of the compound of the formula (III) from the compound of the formula (V), and eliminates the separation of the intermediate (VI-A) and (VI-B), and simultaneously purifies by the beating method, thereby avoiding the column chromatography method. Separation, more suitable for industrial production, configuration conversion by silica gel adsorption, and greatly improve the yield of formula (III).

The present invention is more suitable for industrial production by optimizing the post-treatment of each reaction step, using conventional simple operation steps. The reaction yield is increased, the process and product are easy to control and monitor, and are environmentally friendly.

DRAWINGS

Figure 1 is a ¹ H NMR spectrum of Compound 2.

Figure 2 is a ¹ H- ¹ H NOESY map of Compound 2.

Figure 3 is a ¹ H- ¹ H COSY spectrum of Compound 2.

Figure 4 is a ¹ H- ¹ H NOESY map of compound 6-b.

Figure 5 is a ¹ H- ¹ H NOESY map of compound 7-a.

Figure 6 is a ¹ H- ¹ H COSY spectrum of compound 7-a.

Figure 7 is a ¹ H- ¹ H NOESY map of compound 7-b.

Figure 8 is a ¹ H- ¹ H COSY pattern of compound 7-b.

detailed description

The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS), two-dimensional hydrogen homonuclear displacement correlation spectrum ( ¹ H- ¹ H COSY), two-dimensional nuclear Overhofer enhancement spectrum ( ¹ analysis of stereoisomers H- ¹ H NOESY) is used. The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Avance III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), deuterated Acetone, internal standard is tetramethylsilane (TMS), 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).

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 solution means an aqueous solution.

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

The room temperature is 20 ° C ~ 30 ° C.

Boc is a tert-butyloxycarbonyl group.

Example 1:

N-[(2R,3S)-2-(2,5-Difluorophenyl)-5-morpholinyl-3,4-dihydro-2H-pyran-3-yl]carbamic acid tert-butyl ester (Compound 1-a) and N-[(2R,3S)-2-(2,5-difluorophenyl)-5-morpholinyl-3,6-dihydro-2H-pyran-3-yl Tert-butyl carbamate (compound 1-b)

Compound 1a (1.0 kg, 3.06 mol) was placed in a 5 L round bottom flask containing toluene (3 L), and the mixture was warmed to 80 ° C, and morpholine (400 g) was slowly added dropwise. After the dropwise addition was completed, the mixture was heated to reflux, and Dean-Stark was reacted in water for 3.5 hours. The reaction solution was pumped into a 20 L round bottom flask containing n-heptane (15 L), beaten for 1.5 hours, cooled to room temperature, filtered, and the filter cake was washed once with n-heptane (5 L) to collect solids and blast at 50 °C. Drying to constant weight gave a mixture of compound 1-a and compound 1-b (peak area ratio: 90:8 (HPLC (265 nm)), 1.13 kg, yield 93%).

Example 2

N-[(2R,3S)-2-(2,5-Difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamic acid tert-butyl ester ( Compound 2)

In a 100 L reactor, a mixture of the compound 1-a and the compound 1-b obtained in Example 1 (1 kg, 2.53 mol) was added to N,N-dimethylacetamide (10 L) under a nitrogen atmosphere. 4-Dimethylaminopyridine (296 g, 2.53 mmol) was added under stirring, and the temperature was lowered to -10 ° C to obtain a liquid A. Add S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (1.22 kg, 3.04 mol) and N,N-dimethylacetamide (2 L) to a 5 L flask and stir until clear. Under the condition of anhydrous oxygen-free nitrogen protection, keep the internal temperature slightly lower than -10 °C, and add dropwise to the solution A, and the addition is completed in about 30 minutes. The reaction was kept at -10 ° C for 5 hours, and allowed to stand at 10 to 20 ° C for 16 hours. The temperature was lowered to 0 ° C, and ice water (36 L) was added to the above reaction liquid, and the addition rate was controlled to keep the temperature below 20 °C. Extract with ethyl acetate (20 L and 10 L each time), combine the organic phases, cool to 0 ° C, add hydrochloric acid (10 L, 1 mol / L) cooled to 0 ° C, and control the temperature below 10 ° C during the addition. After the addition, the reaction was stirred at 10-20 ° C for 1 hour. The reaction mixture was washed with water (10 L×2), EtOAc (EtOAc) The crude product was dissolved in dichloromethane (10 L), and after clarification, silica gel (2 kg) was added, and concentrated to a dry powder under a reduced pressure using a 20 L single-mouth flask under a rotary evaporator, and then placed under a rotary evaporator under reduced pressure for 5 hours (water bath). Temperature is 50 ° C) to the end of the configuration transition. The dried solid was stirred in dichloromethane (10 L) for 30 min. The filtrate was concentrated to dryness under reduced pressure at 40 °C. Add n-hexane (20L) to the residue, heat and reflux for 30 minutes, cool down to below 50 °C, stop stirring, naturally reduce to 10-25 ° C, let stand for 16 hours, filter, hexane (10L) decompression rinse, 40 Drying under reduced pressure to constant weight at ° C to give N-[(2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydropyran as a white solid. tert-Butyl 3-yl]carbamate (Compound 2) (609 g, yield 61%, HPLC _{(isomer combined total purity)} : 95.7%, dr (diastereomer value): 82:18 (2-2: 2-1, detected by HPLC (210 nm))).

Compound 2 is a mixture of two stereoisomers and contains the following structure:

The deuterated acetone was used as the solvent, the ¹ H NMR of the compound 2 is shown in Fig. 1, the ¹ H- ¹ H NOESY spectrum is shown in Fig. 2, and the ¹ H- ¹ H COSY spectrum is shown in Fig. 3.

Example 3

2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (compound 3)

Ethyl acetate (3100 mL) and ethanol (985 g, 21.42 mol) were added to a 10 L round bottom flask, cooled to about -5 ° C, and acetyl chloride (1.6 kg, 20.8 mol) was added dropwise with stirring and the temperature was controlled at -10 to 0. After the addition of °C, the temperature was raised to 10 to 20 ° C for 30 minutes. The reaction system was cooled to -10 ° C, and 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylic acid tert-butyl ester (3a) was added with stirring. (1kg, 3.48mol), the formation of light yellow solids in the process, after the addition, the natural temperature rise reaction, 1.5 hours reaction system temperature rose to 5 ~ 10 ° C, TLC monitoring showed complete reaction. The reaction solution was cooled to -10.degree. C., filtered and evaporated. The filter cake was added to dichloromethane (5 L), and a mixed solution of aqueous ammonia (1 L) and water (1 L) was added thereto with stirring, and the layers were allowed to stand. The aqueous layer was extracted with methylene chloride (4 mL). Dichloromethane (1.2 L) was added to the crude product, stirred until all the crude was dissolved, then petroleum ether (600 mL) was added with stirring, and 2-methylsulfonyl-5,6-dihydro-4H-pyrrole[3] was added. , 4-c] pyrazole seed crystals (3g), a large amount of solids to be precipitated, petroleum ether (5.4L) was added, stirred and crystallized for about 2 hours, filtered under reduced pressure, and the filter cake was washed with petroleum ether (2 L), vacuum at 30 ° C Dry for 3 to 4 hours to obtain a yellow-white solid 2-methanesulfonyl-5,6-dihydro-4H-pyrrole [3,4-c]pyrazole (Compound 3) (592 g, yield 90.9%).

MS m/z (ESI): 188.2 [M + 1];

¹ H NMR (400 MHz, CD ₃ OD) δ 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H);

HPLC purity: 99.09% (230 nm).

Example 4

N-[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c Pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamic acid tert-butyl ester (Compound 4)

Under stirring, compound 3 (142.0 g, 0.7595 mol) and compound 2 (200.0 g, 0.5063 mol) were sequentially added to a reaction flask containing chloroform (400 mL), stirred under reflux with heating, and Dean-Starks was reacted for 5 hours. . After the reaction was terminated, the heating was stopped. After the reaction solution was stopped from boiling, the reaction solution was transferred to a 5 L three-necked flask, and the reaction mixture was diluted with 1,2-dichloroethane (1.6 L). The reaction system was stirred under a nitrogen atmosphere to a temperature of 5 to 15 ° C, and sodium triacetoxyborohydride (375.6 g, 1.771 mol) and acetic acid (46.33 mL, 0.8100 mol) were added in that order, and the temperature was raised to 20 to 35. °C, reaction for 5 hours. At the end of the reaction, water (1.2 L) was slowly added, stirred for 5 minutes, and the layers were allowed to stand. The aqueous layer was extracted with dichloromethane (400 mL×2), and the organic phase was combined and washed with a mixed solution of water (600 mL) and aqueous ammonia (100 mL) The organic phase was dried over anhydrous sodium sulfate and evaporated. In a 5 L three-necked flask, the residue obtained by concentration was heated (not higher than 50 ° C) in methanol (1.6 L), stirred to room temperature, and water (400 mL) was added dropwise, and stirring was continued for 30 minutes. There is solid precipitation in the middle. Water (1.6 L) was added dropwise while stirring, and stirring was continued for 30 minutes, and filtration was carried out to obtain a pale yellow wet solid. The solid was dissolved in dichloromethane (2 to 3 L), and the organic layer was dried over anhydrous sodium sulfate. Silica gel (petroleum ether/ethyl acetate (v/v) = 3:2, 5-7 L). The crude product was dissolved in dichloromethane (1.4 L) under heating conditions (not higher than 45 ° C), dissolved completely, cooled to 20-30 ° C, and petroleum ether (2.8 L) was added within 3-8 minutes under stirring. A white solid precipitated during the process, and after completion, it was filtered to obtain a solid. Dichloromethane (720 mL) was added to the solid at 10 to 35 ° C, stirred for 1 hour, petroleum ether (1.8 L) was added, and stirring was continued at room temperature for 2 hours. Filtration gave N-[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6- Dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamic acid tert-butyl ester (Compound 4) (201 g, The rate is 70%, dr>99.95:0.05).

^{1 H NMR (400MHz, DMSO-} d 6) δ7.96 (s, 1H), 7.36-7.08 (m, 4H), 4.88-4.74 (m, 1H), 4.69 (d, 1H), 3.95 (t, 2H ), 3.89–3.83 (m, 1H), 3.82–3.70 (m, 2H), 3.55-3.43 (m, 4H), 2.33-2.18 (m, 1H), 2.17-2.00 (m, 1H), 1.27-1.14 (m, 9H);

MS m/z (ESI): 567.1 [M+1];

HPLC purity: 98.9% (265 nm).

Example 5

(2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c] Pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (Compound 5)

In a 50 L reactor, p-toluenesulfonic acid monohydrate (752.3 g, 3.958 mol) was added to dichloromethane (8 L). Under a nitrogen atmosphere, compound 4 (800 g, 1.413 mol) was added, 20~ The reaction was stirred at 25 ° C for 4 to 5 hours. After completion of the reaction, water (8.5 L) and methanol (800 mL) were added in that order and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted three times with a mixed solvent of dichloromethane (8L) and methanol (800 mL). The organic phase was combined, and water (8 L) and aqueous ammonia (1.5 L) were added for 10 minutes, and the layers were separated. The organic phase was washed successively with saturated sodium carbonate solution (8-10 L) and saturated brine (8-10 L). Dry and concentrate under reduced pressure at 35 ° C to give a crude material. The internal temperature was controlled at 30 to 35 ° C under a nitrogen atmosphere, and the crude product was dissolved in ethyl acetate (3.5 L). Keep the internal temperature at 25-35 ° C, add n-heptane (2.5 L) with stirring, and add (2R, 3S, 5R, 6S)-2-(2,5-difluorophenyl)-5-(2- (Methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine seed crystal (8g Then, n-heptane (4.5 L) was added dropwise, and the mixture was further stirred at room temperature for 2 hours and filtered to give a white solid (2R,3S,5R,6S)-2-(2,5-difluorophenyl) 5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3 -Amine (Compound 5) (508 g, yield: 77.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.35 - 7.04 (m, 3H), 4.86 - 4.63 (qd, 1H), 4.50 (d, 1H), 3.95 (dd, 2H) ), 3.78 (dd, 2H), 3.49 (s, 3H), 3.45 (m, 1H), 3.00 (ddd, 1H), 2.33 (m, 1H), 1.82 (m, 1H), 1.48 (br., 2H) );

MS m/z (ESI): 467.1 [M + 1];

HPLC purity: 99.1% (267 nm).

Example 6

N-[(2R,3S,6S)-2-(2,5-Difluorophenyl)-5-morpholinyl 6-(trifluoromethyl)-3,6-dihydro-2H-pyran- Tert-butyl 3-carbamate (compound 6-a) and N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-morpholinyl 6-(trifluoro Tert-butyl methyl-3,6-dihydro-2H-pyran-3-yl)carbamate (compound 6-b)

A mixture of the compound 1-a and 1-b obtained in Example 1 (5.0 g, 12.63 mmol) was added to N,N-dimethylacetamide (25 mL) in a 250 mL reaction flask under nitrogen. 4-Dimethylaminopyridine (1.85 g, 15.15 mmol) was added under stirring, and the temperature was lowered to -10 ° C to obtain a liquid A. Add S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (6.10 g, 15.15 mmol) and N,N-dimethylacetamide (15 mL) to a 25 mL flask and stir until clear. Under the condition of anhydrous oxygen-free nitrogen protection, keep the internal temperature slightly lower than -10 °C, and add dropwise to the solution A, and the addition is completed in about 30 minutes. The reaction was kept at -10 ° C for 5 hours, and allowed to stand at 10 to 20 ° C for 16 hours. The temperature was lowered to 0 ° C, and ice water (50 mL) was added to the above reaction mixture, and the rate of addition was controlled to keep the temperature below 20 °C. The organic layer was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) The residue was purified by column chromatography (EtOAc EtOAcjjjjjjjjjjj tert-Butyl -2-(2,5-difluorophenyl)-5-morpholinyl 6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl)carbamate Compound 6-a) (2.1 g, yield 38%) and N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-morpholinyl 6-(trifluoromethyl) tert-butyl-3,6-dihydro-2H-pyran-3-yl)carbamate (Compound 6-b) (1.0 g, yield 18%).

Compound 6-a:

^{1 H NMR (400MHz, DMSO-} d 6) δ7.32-7.08 (m, 4H), 5.41-5.31 (m, 1H), 4.95 (s, 1H), 4.72 (d, 1H), 4.48-4.34 (m , 1H), 3.66–3.52 (m, 4H), 3.10–2.97 (m, 2H), 2.69–2.55 (m, 2H), 1.27–1.21 (m, 9H).

Compound 6-b:

^{1 H NMR (400MHz, DMSO-} d 6) δ7.31-7.12 (m, 3H), 7.08 (d, 1H), 5.51-5.35 (m, 1H), 5.04 (s, 1H), 4.51 (d, 1H ), 4.45-4.33 (m, 1H), 3.72-3.51 (m, 4H), 3.02-2.85 (m, 2H), 2.65 - 2.53 (m, 2H), 1.27 - 1.08 (m, 9H).

The ¹ H- ¹ H NOESY spectrum of compound 6-b is shown in Figure 4 using DMSO-d ₆ as the solvent.

Example 7

N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2-methanesulfonyl-4,6-dihydropyrrole[3,4-c]pyrazole- 5-Bisyl-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl)carbamic acid tert-butyl ester (Compound 7-a) and N-[(2R,3S, 6R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonyl-4,6-dihydropyrrole[3,4-c]pyrazole-5-yl)-6-( tert-Butyl trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl)carbamate (Compound 7-b)

Under stirring, compound 2 (5.0 g, 12.66 mmol) and compound 3 (3.55 g, 18.99 mmol) were sequentially added to a reaction flask containing chloroform (10 mL), stirred under reflux with heating, and Dean-Starks was reacted for 5 hours. . After the reaction was completed, the heating was stopped and concentrated. Separation and purification by column chromatography (silica gel 80 g, eluent: petroleum ether / ethyl acetate (v/v) = 4: 1-3:1) to give white solid N-[(2R,3S,6S) 2-(2,5-difluorophenyl)-5-(2-methanesulfonyl-4,6-dihydropyrrole[3,4-c]pyrazole-5-yl)-6-(trifluoro Tert-butyl methyl-3,6-dihydro-2H-pyran-3-yl)carbamate (compound 7-a) (6.0 g, yield 85%) and white solid N-[(2R,3S ,6R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonyl-4,6-dihydropyrrole[3,4-c]pyrazole-5-yl)-6- tert-Butyl (trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl)carbamate (Compound 7-b) (0.4 g, yield 5.6%).

Compound 7-a:

^{1 H NMR (400MHz, DMSO-} d 6) δ8.06 (s, 1H), 7.37-7.08 (m, 4H), 5.40 (q, 1H), 5.00-4.90 (m, 1H), 4.86 (d, 1H ), 4.53 (t, 1H), 4.36 (t, 2H), 4.11 - 3.96 (m, 2H), 3.52 (s, 3H), 1.33-1.07 (m, 9H).

MS m/z (ESI): 565.1 [M+1].

The ¹ H- ¹ H NOESY spectrum of compound 7-a is shown in Figure 5 using DMSO-d ₆ as the solvent.

The ¹ H- ¹ H COSY spectrum of compound 7-a is shown in Figure 6 using DMSO-d ₆ as the solvent.

Compound 7-b:

^{1 H NMR (400MHz, DMSO-} d 6) δ8.08 (s, 1H), 7.31-7.10 (m, 4H), 5.49 (q, 1H), 4.99-4.84 (m, 1H), 4.52-4.36 (m , 2H), 4.34 - 4.19 (m, 4H), 3.52 (s, 3H), 1.27 - 1.15 (m, 9H).

MS m/z (ESI): 565.1 [M+1].

The ¹ H- ¹ H NOESY spectrum of compound 7-b is shown in Figure 7 using DMSO-d ₆ as the solvent.

The ¹ H- ¹ H COSY spectrum of compound 7-b is shown in Figure 8 using DMSO-d ₆ as the solvent.

Example 8

2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (compound 3)

Ethyl acetate (3100 mL) and ethanol (985 g, 21.42 mol) were added to the reaction flask, cooled to about -5 ° C, and acetyl chloride (1.6 kg, 20.8 mol) was added dropwise, maintaining the temperature at -10 to 0 ° C, and the addition was completed. After cooling, the temperature was raised to 10-20 ° C for 30 minutes. The reaction solution was cooled to about -10 ° C, and compound 3a (1 kg, 3.48 mol) was added. During the process, a pale yellow solid formed, and the cooling device was removed, and the reaction was naturally heated. After 90 minutes, the temperature of the reaction system was 5-10 ° C. The TLC monitors the reaction completely. The reaction solution was cooled to about -10 ° C, filtered under reduced pressure, and the filter cake was washed once with ethyl acetate (2L). The filter cake was added to dichloromethane (5 L), and a mixed solution of aqueous ammonia (1 L) and water (1 L) was added thereto, and the aqueous layer was extracted with dichloromethane (4L×4). Filter under reduced pressure and concentrate to dryness under reduced pressure. The concentrate was added to dichloromethane (1.2 L) and stirred to dissolve. Then, petroleum ether (6 L) was added dropwise with stirring, and the solid was gradually precipitated. After stirring, the mixture was crystallized for about 2 hours, and filtered under reduced pressure. The filter cake was petroleum ether (2L). Washing, drying at 30 ° C for 3-4 hours under vacuum to obtain a yellowish white solid 2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (compound 3) (592 g) , yield 90.9%).

MS m/z (ESI): 188.2 [M + 1];

¹ H NMR (400 MHz, CD ₃ OD) δ 7.85 (s, 1H), 4.01-3.94 (m, 4H), 3.36 (s, 3H);

HPLC purity: 99.09% (230 nm).

Example 9

(2R,3S,5R,6S)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c] Pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (Compound 5 seed crystal)

In a 50 L reactor, p-toluenesulfonic acid monohydrate (752.3 g, 3.958 mol) was added to dichloromethane (8 L), and compound 4 (800 g, 1.413 mol) was added under a nitrogen atmosphere, 20~ The reaction was stirred at 25 ° C for 4 to 5 hours. After completion of the reaction, water (8.5 L) and methanol (800 mL) were added in that order and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted three times with a mixed solvent of dichloromethane (8L) and methanol (800 mL). The organic phase was combined, and water (8 L) and aqueous ammonia (1.5 L) were added for 10 minutes, and the layers were separated. The organic phase was washed successively with saturated sodium carbonate solution (8-10 L) and saturated brine (8-10 L). Dry and concentrate under reduced pressure at 35 ° C to give a crude material. The internal temperature was controlled at 30 to 35 ° C under a nitrogen atmosphere, and the crude product was dissolved in ethyl acetate (3.5 L). The internal temperature was maintained at 25 to 35 ° C, and n-heptane (7 L) was added dropwise with stirring. After the addition was completed, stirring was continued for 2 hours at room temperature, and filtered to give a white solid (2R, 3S, 5R, 6S)-2-(2, 5-difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl Tetrahydropyran-3-amine (Compound 5 seed crystal) (504 g, yield: 76.5%).

HPLC purity: 99.14% (267 nm).

Example 10

Trifluoroacetic acid (442 mL) was added to water (177 mL) in a 5 L three-necked flask and cooled to 5 to 10 °C. Under a nitrogen atmosphere, Compound 4 (200 g, 0.353 mol) was added under stirring, maintaining the temperature at 5 to 15 ° C, and trifluoroacetic acid (100 mL) was added. The reaction was stirred at 15 to 25 ° C for 4 to 5 hours while maintaining the temperature. After completion of the reaction, dichloromethane (1.6 L) was added under stirring, and water (200 mL) and aqueous ammonia (730 mL) were added dropwise at a temperature not higher than 25 °C. Stirring was stopped and the layers were separated and the aqueous layer was extracted with dichloromethane (300 mL×2). The organic phase was combined, washed with a saturated sodium carbonate solution (800-1000 mL) and brine (800-1000 mL), dried over anhydrous sodium sulfate The internal temperature was controlled at 30 to 35 ° C under a nitrogen atmosphere, and the crude product was dissolved in ethyl acetate (900 mL). Keep the internal temperature at 25-35 ° C, add n-heptane (650 mL) with stirring, and add (2R, 3S, 5R, 6S)-2-(2,5-difluorophenyl)-5-(2-( Methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyridyl Zyrom-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (Compound 5 seed crystal) (2g), continue to add n-heptane (1150 mL) dropwise, add, continue stirring at room temperature After 2 hours, filtration gave a white solid (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-4,6-dihydropyrrole And [3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (Compound 5) (140 g, yield: 85.0%).

HPLC purity: 99.56% (267 nm).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.35 - 7.04 (m, 3H), 4.86 - 4.63 (qd, 1H), 4.50 (d, 1H), 3.95 (dd, 2H) ), 3.78 (dd, 2H), 3.49 (s, 3H), 3.45 (m, 1H), 3.00 (ddd, 1H), 2.33 (m, 1H), 1.82 (m, 1H), 1.48 (br., 2H) ).

Claims

a method for preparing a compound of formula (I),

It is characterized in that the compound of the formula (II) is reacted in p-toluenesulfonic acid monohydrate with dichloromethane or in the presence of trifluoroacetic acid and water at 20 to 25 ° C under an inert gas atmosphere, and is post-treated. Obtaining a compound of formula (I);

Wherein P in the formula (II) is an amino-protecting group.
The process according to claim 1, wherein the post-treatment of the reaction in the presence of p-toluenesulfonic acid monohydrate and methylene chloride comprises the following steps:

(1) Water and methanol are sequentially added to the reaction liquid, and the layers are separated, and the aqueous layer is extracted with a mixed solvent of dichloromethane and methanol;

(2) The organic phase obtained in (1) is adjusted to alkali with a base, and the organic layer is washed successively with a saturated sodium carbonate solution and a saturated aqueous salt solution, dried, and concentrated under reduced pressure at 40 ° C or lower; preferably, the base Is ammonia water, the pH of the solution when adjusted to alkaline is 8 to 11, preferably 9 to 10;

(3) The residue obtained by concentration in (2) is dissolved in ethyl acetate at an internal temperature of less than 40 ° C in an inert gas atmosphere;

(4), keep the internal temperature less than 40 ° C, add n-heptane dropwise, crystallize at room temperature;

Alternatively, a seed crystal of the compound of formula (I) is added to step (4).
The process according to claim 1, wherein the post-treatment of the reaction in the presence of trifluoroacetic acid and water comprises the following steps:

(1), adding dichloromethane to the reaction solution, adding water and ammonia water to pH>7, layering;

(2) extracting (1) the aqueous layer with dichloromethane, combining the organic phases obtained in the step (1) (2), and washing the combined organic phases sequentially with saturated sodium carbonate solution and saturated brine, drying with a drying agent And concentrated under reduced pressure to obtain a crude product; preferably, the desiccant is anhydrous sodium sulfate;

(3), the crude product obtained in the step (2) is dissolved in ethyl acetate, the internal temperature is maintained at 25 to 35 ° C, n-heptane is added dropwise, and crystallized at room temperature;

Alternatively, a seed crystal of the compound of formula (I) is added to step (3).
A method for preparing a compound of formula (II), characterized in that

Wherein, the compound of the formula (III) and the compound of the formula (IV) are reacted by Dean-Starks in water by using chloroform as a solvent, and the reaction solution is diluted with 1,2-dichloroethane under an inert gas atmosphere. Adding sodium triacetoxyborohydride and acetic acid, reacting at room temperature, and post-treatment to obtain a compound of formula (II);

Wherein, in the formula (II) and the formula (III), P is an amino-protecting group.
The method of claim 4 wherein said post processing comprises the steps of:

(1), adding water, layering, extracting, washing with water and alkali solution, drying, filtering and concentrating; preferably, the alkali is ammonia water;

(2), the concentrate in (1) is dissolved in methanol under heating, and water is added dropwise with stirring at room temperature, and filtered; preferably, water is added dropwise in two portions, wherein methanol, the first drop of water, the second drop The volume ratio of the three water additions is 4:1:4;

(3), the filtrate in (2) is dissolved in dichloromethane, layered, and the organic layer is dried and separated by silica gel column chromatography;

(4) The pulp obtained in (3) is beaten.
The method according to claim 5, wherein the step (4) beating solvent is a mixed solvent of dichloromethane and petroleum ether; preferably, the volume ratio of dichloromethane to petroleum ether is 1:2.
A method for preparing a compound of formula (III):

Contains the following steps:

(1) using a toluene as a solvent, and reacting the compound of the formula (V) with morpholine in a water-repellent reaction, and post-treating to obtain a mixture of the compound of the formula (VI-A) and the formula (VI-B):

(2) N,N-dimethylacetamide, 4-dimethylaminopyridine, and the formula (VI-A) and formula obtained in the step (1) at -10 ° C to room temperature under anhydrous and anaerobic conditions a mixture of (VI-B) compounds is reacted with a solution of S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate in N,N-dimethylacetamide;

Wherein, in the formula (III), the formula (V), the formula (VI-A) and the formula (VI-B), P is an amino-protecting group.
The preparation method according to claim 7, wherein the post-processing in the step (1) comprises the following steps:

(1), the reaction liquid is hot and beaten with n-heptane;

(2), filtration, solid drying to constant weight.
The preparation method according to claim 7, wherein the step (2) further comprises the following steps:

(1), keeping the temperature of the system below 20 ° C, adding ice water to the reaction solution, extracting with ethyl acetate, and combining the organic phase;

(2), keeping the temperature of the system below 10 ° C, adding hydrochloric acid dropwise, and reacting at room temperature;

(3) washing, drying, and concentration;

(4), the obtained product in (3) is dissolved in dichloromethane, added to silica gel, concentrated under reduced pressure at 50 ° C or less to dry powder, maintaining the temperature to the end of the configuration transition;

(5), desorption, concentration, to obtain crude products;

(6), the crude product is beaten with n-hexane reflux;

(7), filtered, and the solid is dried to constant weight.
A method for preparing a compound of formula (IV):

Wherein, the compound of the formula (VII) is reacted with a hydrochloric acid-ethyl acetate solution at -10 to 10 ° C;

Wherein, in the formula (VII), P is an amino-protecting group.
The production method according to claim 10, further comprising adding a seed crystal of the compound of the formula (IV).
The compounds of formula (III-A), formula (III-B), formula (II-A), and formula (II-B) are as follows:

Wherein P is an amino protecting group; preferably, P is a tert-butoxycarbonyl group.
A method of preparing a compound of formula (III-A) and formula (III-B),

Wherein, at -10 ° C to room temperature, anhydrous, anaerobic conditions, N, N-dimethylacetamide, 4-dimethylaminopyridine, the formula (VI-A) and the compound of the formula (VI-B) The mixture is reacted with a solution of S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate in N,N-dimethylacetamide, and separated by silica gel column chromatography to obtain formula (III-A) and formula ( III-B) a compound;

Wherein, in the formulae (VI-A), (VI-B), (III-A) and (III-B), P is an amino-protecting group.
A method of preparing a compound of formula (II-A) and formula (II-B),

Wherein, the compound of the formula (III) and the compound of the formula (IV) are reacted by Dean-Starks in water by using chloroform as a solvent, and are separated by silica gel column chromatography to obtain the formula (II-A) and the formula (II-B). Compound

Wherein, in the formula (III), the formula (II-A) and the formula (II-B), P is an amino-protecting group.
A process according to any one of claims 1-11 or 13-14 wherein P is tert-butoxycarbonyl.