WO2017202365A1 - Preparation method for trifluoromethyl-substituted pyran derivative - Google Patents

Abstract

Provided are a preparation method for a trifluoromethyl-substituted pyran derivative and an intermediate thereof, namely, a preparation method for a compound as shown in formula (I) and an intermediate thereof. The method is characterized by 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 present invention relates to a process for the preparation of a trifluoromethyl substituted pyran derivative.

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.

Summary of the invention

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

The present invention is compared with the preparation method of the compound represented by the formula (I) disclosed in WO2015192701A1: 1) The method for preparing the formula (III) from the formula (V) is optimized, and the intermediates (VI-A) and (VI-B) are omitted. The separation is simultaneously purified by recrystallization or/and beating, which avoids separation by column chromatography, is more suitable for industrial production, and greatly improves the yield of formula (III).

2) Optimizing the process of reacting the intermediate of formula (III) with the intermediate of formula (IV) to obtain the compound of formula (II), using a polar aprotic solvent to avoid the very high evaporation of the solvent under toluene conditions in the prior art. 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. 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. The optimized reaction of the present invention can better monitor the progress. The yield of formula (II) is increased.

3) Optimizing the process for the compound of formula (II) to form the compound of formula (I). In the prior art, a reaction system of trifluoroacetic acid and dichloromethane is used, and the post-treatment is not suitable for control. The concentration of trifluoroacetic acid has an effect 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 and dichloromethane or an acidic reagent with pKa≤5 and water, which significantly reduces degradation. The content of products and other impurities. At the same time, the reaction system of trifluoroacetic acid and water reduces the use of trifluoroacetic acid, reduces the use of organic solvents, simplifies the post-treatment operation, and is more environmentally friendly.

4) Optimize the post-treatment of each reaction step, avoid the separation and purification using silica gel column chromatography, and use the simple and simple operation steps, which is more suitable for industrial production.

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

The compound of the formula (II) is reacted in the presence of p-toluenesulfonic acid with a dichloromethane system or a system of an acidic reagent having a pKa ≤ 5 and water to obtain a compound of the formula (I);

Alternatively, an organic solvent may be further added to the reaction;

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

In certain embodiments, p-toluenesulfonic acid can be p-toluenesulfonic acid containing water of crystallization, such as p-toluenesulfonic acid monohydrate or p-toluenesulfonic acid tetrahydrate.

In certain embodiments, p-toluenesulfonic acid or p-toluenesulfonic acid containing water of crystallization is an excess, preferably a compound of formula (II) and p-toluenesulfonic acid or p-toluenesulfonic acid containing water of crystallization. The molar ratio is 1:2.5 to 1:3, preferably 1:2.8.

In certain embodiments, trifluoroacetic acid is an excess, preferably, the mass ratio (w/w) of the compound of formula (II) to trifluoroacetic acid is from 1:3 to 1:6.

In certain embodiments, the acidic agent is selected from one or a mixture of two or more of hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid, and the organic solvent is selected from the group consisting of methanol, isopropanol, or ethanol.

In certain embodiments, the temperature of the reaction is from -20 to 30 °C.

Compounds of formula (II) are reacted by conventional post-treatment to give compounds of formula (I).

In certain embodiments, the post-treatment of the reaction of p-toluenesulfonic acid with a dichloromethane system comprises the steps of:

(1) adding water and an organic solvent to the reaction liquid, layering, and extracting;

(2), the organic phase obtained in (1) is adjusted to basic with a base, and the organic phase is concentrated to obtain a crude product;

(3) Recrystallizing or beating the crude product in (2);

Alternatively, seed crystals are added to step (3).

In certain embodiments, the base used in the step (2) of the post-treatment of the reaction of p-toluenesulfonic acid with a dichloromethane system is aqueous ammonia, and the pH of the solution is adjusted to a pH of 8 to 11, preferably 9 ~10.

Post-treatment of the reaction of an acidic reagent having a pKa < 5 with an aqueous system in certain embodiments comprises

Adding an organic solvent to the reaction solution, adding water and/or an alkaline solution, layering, extracting, collecting the organic phase, and concentrating under reduced pressure to obtain a crude product. According to the situation, the number of extractions of the aqueous phase after stratification can be increased, the organic phase can be collected, the organic phase can be post-treated by conventional washing or/and drying methods in the art, and then the organic phase is concentrated to obtain a crude product; the alkaline solution is pH. a solution of >7, including, but not limited to, an aqueous ammonia solution, an aqueous solution of sodium carbonate, an aqueous solution of methylamine, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of potassium hydrogencarbonate, an aqueous solution of lithium hydroxide, an aqueous solution of sodium hydroxide, and an aqueous solution of potassium hydroxide. One or two or more mixed solutions;

Alternatively, the crude product obtained above may be recrystallized or/and beaten; recrystallization or/and beating may be carried out in any suitable solvent system including, but not limited to, water, ester solvents, alcohol solvents, a mixed solvent of one or more of a nitrile solvent, an ether solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent; further preferably water, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile , methanol, ethanol, isopropanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, n-heptane, cyclohexane, hexane One or a mixture of two or more of an alkane and petroleum ether.

Alternatively, when the crude product is subjected to recrystallization or/and beating, a seed crystal of the compound of the formula (I) may be further added.

In certain embodiments, the crude product obtained by post-treatment of p-toluenesulfonic acid with a dichloromethane system or a system of an acidic reagent having a pKa < 5 and water is recrystallized or/and beaten in a solvent, recrystallized or / The temperature of the beating is preferably -10 ° C - system reflux. In certain embodiments, when the recrystallized or/and beaten solvent is selected from the group consisting of water, methanol, methyl acetate, ethyl acetate, isopropyl acetate, n-heptane, cyclohexane, n-hexane, and petroleum ether. When one type or two or more types of mixed solvents are used, the temperature is preferably -10 ° C to reflux.

The present invention relates to a process for the preparation of a compound of formula (II), wherein

In a polar aprotic solvent, a compound of the formula (III) and a compound of the formula (IV) are reacted in the presence of an organic acid to give an intermediate compound of the formula (II-M); an organic acid and an organic boron reducing agent are added, -10 to 25 ° C The reaction is carried out to obtain a compound of the formula (II);

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

In certain embodiments, the polar aprotic solvent is non-limiting selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane. a mixture of one or more of a ring, methyl tert-butyl ether, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide, preferably dichloromethane, Acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl One or a mixture of two or more of sulfones.

In certain embodiments, the organic acid has a pKa > -1.9, in which the pKa refers to a dissociation constant in water at 25 ° C, including but not limited to formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonate Acid or p-toluenesulfonic acid.

In certain embodiments, the organoboron reducing agent is selected from the group consisting of sodium tris(acetoxy)borohydride, sodium borohydride, sodium cyanoborohydride or decane borane.

In certain embodiments, the molar ratio of the compound of formula (III) to the organoboron reducing agent is from 1:2 to 1:8, preferably from 1:3 to 1:6, further preferably from 1:3 to 1:5.

In certain embodiments, the molar ratio of the compound of formula (III) to the organic acid is from 1:2 to 1:8, preferably from 1:3 to 1:6, further preferably from 1:3 to 1:5.

In certain embodiments, the molar ratio of the compound of formula (III) to the compound of formula (IV) is from 1:1 to 1:2, preferably from 1.1 to 1.5.

In certain embodiments, the mass ratio of polar aprotic solvent to the compound of formula (III) is from 1:1 to 10:1, preferably from 5:1 to 10:1.

In certain embodiments, depending on the reaction solvent, the compound of formula (III) and the compound of formula (IV) will give a different reaction temperature for the intermediate compound of formula (II-M), preferably from -30 ° C to solvent reflux. Temperature; when the solvent for the reaction is N,N-dimethylacetamide, the reaction temperature is preferably -10 to 80 ° C, more preferably -10 to 60 ° C, still more preferably -10 to 40 ° C.

In certain embodiments, the compound of formula (III) and the compound of formula (IV) are in the presence of a molecular sieve, a dehydrating agent or a water-removing vessel to give an intermediate (II-M) compound, preferably at a temperature of from -20 to 25 °C.

In certain embodiments, the compound of formula (III) and the compound of formula (IV) are in the presence of a molecular sieve to give an intermediate (II-M) compound, preferably the weight ratio of the compound of formula (III) to the molecular sieve is 1:1. 1:5, preferably 1:1 to 1:3.

In certain embodiments, the compound of formula (II) is obtained by conventional post-treatment after reduction of the intermediate (II-M) compound. Post-processing includes but is not limited to the following two options:

The first option includes the following steps:

(1), adding an alkaline aqueous solution and an organic solvent, layering, and extracting to obtain a first organic phase; the alkaline aqueous solution is preferably an aqueous ammonia solution, an aqueous solution of methylamine, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, or a potassium hydrogencarbonate. One or a mixture of two or more of an aqueous solution, an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous potassium hydroxide solution is more preferably an aqueous lithium hydroxide solution.

(2) The first organic phase in (1) is filtered through silica gel to obtain a filtrate, and the filtrate is concentrated to obtain a crude product;

(3) recrystallizing the crude product in (2) to obtain a compound of the formula (II);

Alternatively, the aqueous phase after extraction in step (1) is further extracted with an organic solvent, and the organic phase is combined and washed with water and/or an aqueous solution of sodium chloride to obtain a first organic phase;

Alternatively, the first organic phase in step (2) is filtered through silica gel, the filter cake is washed with an organic solvent, the filtrate is combined, and the filtrate is concentrated to give a crude product.

The second option includes the following steps:

(1), adding water, layering, extraction, direct concentration of the organic phase or optionally further washing with water and / or alkali solution, drying, filtering, concentration to obtain a concentrate;

(2) Dissolving the concentrate in (1) in methanol, adding water under stirring at room temperature, separating the solid, and filtering to obtain a filtrate;

(3), the filtrate in (2) is dissolved in an organic solvent, layered, the organic layer is dried, separated by silica gel column chromatography, and concentrated to give a crude product;

(4) Recrystallizing or/and beating the crude product obtained in (3).

In some embodiments, the base in the step (1) of the second embodiment is selected from the group consisting of an aqueous ammonia solution, an aqueous solution of methylamine, an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of potassium hydrogencarbonate, an aqueous solution of lithium hydroxide, One or a mixture of two or more of an aqueous sodium hydroxide solution and an aqueous potassium hydroxide solution is preferably an aqueous ammonia solution. In some embodiments, in step (2) of the second embodiment, water is added in two portions with stirring, and the volume ratio of methanol, first water addition, and second water addition is preferably 4:1:4. The recrystallization or/and beating of step (3) of the first and second modes can be carried out in any suitable solvent system, and suitable solvents are preferably water, ester solvents, alcohol solvents, nitriles solvents, ethers. a mixed solvent of one or more of a solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent; more preferably water, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, diethyl ether One or two of isopropyl ether, methyl tert-butyl ether, dichloromethane, methyl acetate, ethyl acetate, isopropyl acetate, toluene, petroleum ether, n-hexane, cyclohexane and n-heptane The above mixture is more preferably one or a mixture of two or more of dichloromethane, toluene, petroleum ether, n-hexane, cyclohexane and n-heptane, and further preferably a mixed solvent of dichloromethane and petroleum ether, preferably both. The mixing weight ratio is from 0.8:1 to 1:5, more preferably from 0.8:1 to 1:2.

The invention also relates to a process for the preparation of a compound of formula (III):

Contains the following steps:

(1), the compound of the formula (V) is dissolved in toluene, and morpholine is added dropwise at 50 to 100 ° C, and then refluxed to obtain a compound of the formula (VI-A);

(2), -10 ~ 25 ° C, a polar aprotic solvent, in the presence of the alkaline reagent 4-dimethylaminopyridine, the compound of formula (VI-A) and S-(trifluoromethyl)dibenzothiophene Reaction of trifluoromethanesulfonate or S-(trifluoromethyl)dibenzothiophene trifluoromethyltetrafluoroborate, after post-treatment to obtain intermediate state (VI-AM);

(3), the intermediate state (VI-A-M) in water or a mixed solvent of an organic solvent and water, in the presence of an acidic reagent to obtain a compound of formula (III);

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

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

(1), the compound of the formula (V) is dissolved in toluene, and morpholine is added dropwise at 50 to 100 ° C, and then refluxed to obtain a compound of the formula (VI-A);

(2), -10 ~ 25 ° C, in a polar aprotic solvent, in the presence of the alkaline reagent 4-dimethylaminopyridine, the compound of formula (VI-A) and S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or S-(trifluoromethyl)dibenzothiophene trifluoromethyltetrafluoroborate;

(3) reacting in water or a mixed solvent of an organic solvent and water in the presence of an acidic reagent to obtain a compound of the formula (III);

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

In the step (1) of preparing the compound of the formula (III), it is a significant advantage to directly add morpholine to the reaction solution in the prior art. In the prior art, in the process of adding morpholine, the reaction system is severely agglomerated and affected. The agitation of the reaction is not conducive to amplification. In the present embodiment, by adding morpholine dropwise under heating (50 to 100 ° C), agglomeration can be avoided, the yield of the reaction can be improved, and industrial production can be facilitated.

In certain embodiments, the reaction of step (1) of preparing a compound of formula (III) is further carried out under molecular sieves, dehydrating agents or water-dispensing vessel conditions.

In certain embodiments, the polar aprotic solvent for the reaction of step (2) to prepare a compound of formula (III) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, One or a mixture of two or more of N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.

In certain embodiments, the acidic reagent of step (3) for preparing a compound of formula (III) is selected from the group consisting of hydrochloric acid, formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

In certain embodiments, the molar ratio of the compound of formula (V) to morpholine is from 1:1 to 1:3, preferably 1:1.5.

In certain embodiments, the compound of formula (VI-A) is S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonate or S-(trifluoromethyl)dibenzothiophene trifluoromethyl The molar ratio of tetrafluoroborate is 1:1 to 1:3, preferably 1:1 to 1:5, more preferably 1:1.2.

In certain embodiments, the molar ratio of the compound of formula (VI-A) to 4-dimethylaminopyridine is from 1:0.1 to 1:1.5, preferably from 1:1 to 1:5, more preferably 1:1.1.

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 solution is beaten; preferably the reaction solution is added to the stirred beating solvent; the beating solvent can be completed in any suitable solvent system, suitable solvents are preferably toluene, n-heptane, n-hexane, cyclohexane and petroleum One or two or more solvents in the ether;

(2), filtration, filter cake drying.

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 solution is added to the stirred solvent; the solvent can be completed in any suitable solvent system, suitable solvent is preferably one or two of toluene, n-heptane, n-hexane, cyclohexane and petroleum ether The above solvent;

(2), filtration, filter cake drying.

In certain embodiments, step (2) of the preparation of the compound of formula (III) further comprises the following post-treatment step: adding an organic solvent and water, layering, extracting, obtaining an organic phase, and concentrating the organic phase.

In certain embodiments, step (3) of the method of preparing a compound of formula (III) further comprises the following post-processing steps:

(1) adding water and/or organic solvent to the reaction solution, layering, extracting, and collecting the organic phase; the organic phase is treated in the following manner: The organic phase is filtered through silica gel to give a filtrate which is concentrated to give a crude product; or the organic phase is further washed and / or dried and / or concentrated to give a crude product;

(2) Recrystallizing or/and beating the crude product in (1).

In certain embodiments, the step (3) of the preparation of the compound of the formula (III) further comprises adding water and/or an organic solvent to the reaction liquid, layering, extracting, and collecting the organic phase; and the organic phase is optionally treated in the following manner: The organic phase is passed through silica gel and the resulting liquid is further concentrated to give a crude product; or the organic phase is further washed and/or dried and/or concentrated to give a crude product;

Alternatively, the crude product is recrystallized or/and beaten.

In certain embodiments, the method of preparing the compound of formula (III) step (3) The recrystallization or/and the beating solvent in step (2) may be carried out in any suitable solvent system, preferably a solvent, preferably water or ester. a solvent, an alcohol solvent, a nitrile solvent, an ether solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent, or a mixed solvent of one or more; more preferably water, acetonitrile, tetrahydrofuran, 2-methyl One of tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dichloromethane, methyl acetate, ethyl acetate, isopropyl acetate, toluene, petroleum ether, n-hexane, cyclohexane and n-heptane Kind or more than two solvents.

The invention also relates to a process for the preparation of a compound of formula (IV):

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

Wherein P 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 from 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).

The present invention also relates to a compound of the formula (III-A), the formula (III-B), the formula (II-A), and the formula (II-B) shown below:

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

The invention also relates to a process for the preparation of a compound of formula (III-A) and formula (III-B),

-10 ° C to room temperature, N,N-dimethylacetamide, 4-dimethylaminopyridine, a compound of formula (VI-A) and S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonic acid The salt is reacted with a solution of N,N-dimethylacetamide to obtain a compound of the formula (III-A) and the formula (III-B);

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

The invention also relates to a process for the preparation of compounds of formula (II-A) and formula (II-B),

Chloroform as a solvent, heating under reflux, the compound of the formula (III) and the compound of the formula (IV) are reacted through a Dean-Starks trap to obtain a compound of the formula (II-A) and the formula (II-B);

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

In certain embodiments, the compounds of formula (II-A) and formula (II-B) are isolated by silica gel column chromatography.

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.

The compound P of the present invention is preferably a tert-butoxycarbonyl group.

The compound of the formula (III) according to the invention is a compound of the formula (III-1), a compound of the formula (III-2) or a mixture of the two:

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

The method of extracting used in the post-treatment of the reaction in the present invention is a conventional method in the art, and the solvent to be extracted can be selected according to the solubility of the product and the solubility of the organic solvent in water, and common extraction solvents include, but are not limited to, dichloromethane, chloroform, Acetic acid One or a mixture of two or more of ethyl ester, methyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methanol and ethanol. The number of extractions may be appropriately increased or decreased depending on the amount of product remaining in the aqueous phase. The organic phase after extraction is optionally further subjected to washing or/and drying treatment conventional in the art.

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.

"Optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur.

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.

"Closed reactor" means a reaction vessel in which the reaction system is in a closed state, such as a reaction vessel, and a closed tube.

The "configuration transition end point" as used in the present invention means that the 1H NMR (solvent is DMSO-d6) shift (δ) has a peak area ratio of H (δ5.2) to H (δ4.4) of >2:1. The 1H NMR shift (δ) allows for some movement due to the different control of the experimental conditions due to the different 1H NMR instruments.

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-C18 100 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)

Tert-butyl N-[(2R,3S)-2-(2,5-difluorophenyl)-5-morpholino-3,4-dihydro-2H-pyran-3-yl]carbamateand tert-butyl

Method 1: Compound 1a (1.0 kg, 3.06 mol) was placed in a 5 L round bottom flask containing toluene (3 L), 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 gave Compound 1 (1.13 kg, yield 93%, HPLC (265nm): 90.0%).

Method 2: 6.51Kg of toluene and 2.50Kg of compound 1a are added to the reaction kettle; stirring, heating to 70-80 ° C, 1.00 Kg of morpholine is added dropwise; after the addition is completed, the temperature is further increased to reflux, and the reaction mixture is refluxed for 5 hours; It was added to 25.10 Kg of n-heptane; it was cooled to room temperature and stirred for 1 hour; the filter cake was collected by filtration and dried at 50 ° C to obtain 2.89 Kg of Compound 1; yield 95.38%, HPLC (265 nm): 92.2%.

Example 2

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

Tert-butyl N-[(2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate

Method 1: In a 100 L reactor, the compound 1 obtained in Example 1 (prepared in the method of Example 1) (1 kg, 2.53 mol) was added to N,N-dimethylacetamide (10 L) under a nitrogen atmosphere. In the mixture, 4-dimethylaminopyridine (296 g, 2.53 mmol) was added under stirring, and the temperature was lowered to -10 ° C, which was the 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) Dichloromethane (10L) was dissolved in the crude product. After clarification, silica gel (2 kg) was added, and concentrated to a dry powder under a reduced pressure using a 20 L single-mouth bottle under a rotary evaporator, and then continuously dried under a rotary evaporator for 5 hours under reduced pressure (water bath temperature). It 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 at ° Cmielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel Tert-butyl carbamate (Compound 2) (609 g, yield 61%, HPLC _{(isomer combined total purity)} : 95.7%, dr (diastereo ratio, ratio of diastereomers): 82: 18 (2-2: 2-1, detected by HPLC (210 nm))).

Small test - after hydrolysis with hydrochloric acid solution, the crude product is mixed with silica gel and treated:

Under the protection of nitrogen, the compound 1 obtained in Example 1 (prepared in the first method of Example 1) (10 g) was added to N,N-dimethylacetamide (100 mL), and 4-dimethylamino group was added under stirring. Pyridine (3.3 g), cooled to -10 ° C, which is liquid A. S-(Trifluoromethyl)dibenzothiophene trifluoromethanesulfonate (12.2 g) in N,N-dimethylacetamide (20 mL) was added dropwise to solution A. After the addition, the reaction was kept at -10 ° C for 5 hours, and allowed to stand at room temperature for 16 hours. Ethyl acetate (100 mL) and a hydrochloric acid solution (100 mL, 1 mol/L) were added to the above reaction mixture, and the temperature was controlled to be lower than 10 ° C during the addition. After the addition was completed, the reaction was stirred for 1 hour. The reaction solution was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness It was detected by HPLC (210 nm). N-hexane (200 mL) and crude product were heated and refluxed for 30 minutes, cooled to stand for 16 hours, and dried by filtration to give a pale yellow solid compound 2 (4.3 g, yield 43%, HPLC: 75.6 %, dr: 54:32 (2-2: 2-1, detected by HPLC (210 nm)).

Method 2: 27.43 Kg of N,N-dimethylacetamide and 2.88 Kg of Compound 1 (prepared by Method 2 of Example 1) were added to the reaction vessel; stirred, cooled to -10 to 0 ° C; and added to 0.93 Kg 4- Methylaminopyridine; control temperature -10 ~ 0 ° C, add 3.52Kg S-(trifluoromethyl) dibenzothiophene trifluoromethanesulfonate; add the reaction for 5 hours; then heat to 5 ~ 15 ° C, The reaction was carried out for 15.5 hours; ethyl acetate and deionized water were added to the reaction mixture, and the organic layer was concentrated under reduced pressure to give a residue. The residue was evaporated, and the residue obtained from concentration and 38.50 Kg of dichloromethane was added to the reaction vessel, and 5.45 Kg was added with stirring. Acetic acid and 1.45Kg deionized water; heated to reflux reaction for 5 hours; after the reaction solution is cooled, add deionized water and stir and wash 5 times; dry and filter, collect filtrate; Filtration on silica gel, filter residue was washed with dichloromethane; filtrate was concentrated to dryness under reduced pressure to give crude compound 2; nitrogen-protected, crude compound 2 and n-hexane were added to the reaction vessel; stirred at 60 ° C; filtered and filtered. The filter cake was collected and dried under vacuum at 40 ° C; 1.76 Kg of Compound 2 was obtained; the yield was 61.32%, HPLC (210 nm): 96.3%, dr: 85:11 (2-2: 2-1, detected by HPLC (210 nm)) .

Compound 2 (2.5 g) was further dissolved in dichloromethane (15 mL), then added with anti-solvent n-hexane (30 mL), and stirred at room temperature, as needed, to obtain compound 2-2 of higher diastereomer purity. Filtration gave Compound 2-2 (1.0 g), HPLC (210nm):j::::::::::::

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

The deuterated acetone was used as the solvent. The ¹ HNMR 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)

2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole

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, petroleum ether (600 mL) was added with stirring, and 2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole seed crystals were added ( 3g), a large amount of solids are to be precipitated, petroleum ether (5.4L) is added, stirred and crystallized for about 2 hours, filtered under reduced pressure, filter cake petroleum ether (2L) washed, vacuum dried at 30 ° C for 3-4 hours to obtain yellow-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: 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)

Tert-butyl 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]carbamate

Method 1: 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) under stirring, and the mixture was stirred under reflux with heating, and Dean-Starks was separated. Reaction 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. The organic phase was washed with water (600 mL) and aqueous ammonia (100 mL). Dry over anhydrous sodium sulfate and concentrate under reduced pressure. 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. Water (1.6 L) was added dropwise with stirring, stirring was continued for 30 minutes, and filtration was carried out to give a pale yellow solid. The solid was dissolved in dichloromethane (2~3 L), and the organic layer was dried over anhydrous sodium sulfate. The organic phase was poured directly onto a silica gel column with dry silica gel (600 g silica gel, petroleum ether / Ethyl acetate (v/v) = 3:2). 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, yield 70%, dr >99.95:0.05).

^{1 H NMR (400MHz, DMSO-} d 6) δ7.95 (s, 1H), 7.26-7.15 (m, 4H), 4.84-4.75 (m, 1H), 4.68 (d, J = 10.5Hz, 1H), 3.94(t, 2H), 3.87–3.83 (m, 1H), 3.80–3.72 (m, 2H), 3.54-3.42 (m, 4H), 2.25-2.22 (m, 1H), 2.12-2.03 (m, 1H) ), 1.20-1.12 (m, 9H);

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

HPLC: 98.9% (265 nm).

According to the reaction mechanism, it is presumed that the compound 2 reacts with the compound 3 to form an intermediate enamine, and the enamine is subjected to reductive amination to obtain the compound 4.

The invention further optimizes the conditions for the reaction of the compound 2 with the compound 3 to form an intermediate enamine. The specific optimization is shown in Table 1.

Table 1: Conditional screening of the reaction of compound 2 with compound 3 into an intermediate enamine

In Table 1: DMA = N, N-dimethylacetamide, MTBE = methyl tert-butyl ether, eq1 is the weight ratio of 4A molecular sieve to compound 2, eq2 is the molar ratio of acetic acid to compound 2, and the remainder of compound 2 The peak area by HPLC.

The better condition 5 in Table 1 was slightly changed, and the process was enlarged.

Method 2: nitrogen protection, 13.27Kg N,N-dimethylacetamide, 1.75Kg compound 2, 1.25Kg compound 3 and 3.58Kg 4A molecular sieves were added to the reaction vessel, cooled to 0 to 5 ° C, and 0.67 Kg of acetic acid was added; After the addition is completed, the temperature is raised to 5 to 15 ° C for 29 hours; the temperature is cooled to 0 to 10 ° C, 0.53 Kg of acetic acid is added; 4.25 Kg of NaBH(OAc) _{3 is} added in portions; after the addition is completed, the reaction is carried out at 5 to 15 ° C for 16.5 hours; Methyl chloride, 5% aqueous lithium hydroxide solution and deionized water, stirred and layered; the aqueous layer was further extracted twice with dichloromethane, and the organic layer was combined, washed with deionized water and then with sodium chloride solution; Filtration on silica gel, the residue was washed with ethyl acetate- petroleum ether mixture (yield: W _{petroleum ether} : _{ethyl acetate} = 1.1: 1.0). The filtrate was concentrated to dryness under reduced pressure to afford crude compound 4; Kg dichloromethane and petroleum ether were crystallized and beaten at 15 to 25 ° C to obtain compound 4 (HPLC (265 nm): 97.9%, chiral HPLC (210 nm): 100%), in order to obtain higher purity of compound 4 as needed, Compound 4 was further treated with 18.20 Kg of petroleum ether and 9.63 Kg of dichloromethane. 15 ~ 25 ℃ crystallization; 2.09Kg compound 4 obtained; yield 82.94%, HPLC (265nm): 99.2%, chiral HPLC (210nm) 100%.

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)

(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

Method 1: p-toluenesulfonic acid monohydrate (752.3 g, 3.958 mol) was added to dichloromethane (8 L) in a 50 L reactor, and compound 4 (800 g, 1.413 mol) was added under a nitrogen atmosphere. The reaction was stirred at 20 to 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: 99.1% (267 nm).

Method 2: Trifluoroacetic acid (442 mL) was added to water (177 mL) in a 5 L three-necked flask, and the temperature was lowered 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]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine (Compound 5 Seeds) (2g), continue to add n-heptane (1150mL) dropwise, add, continue stirring at room temperature for 2 hours, and filter to give a white solid (2R,3S,5R,6S)-2-(2,5-difluorobenzene 5-(2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)tetrahydropyran 3-Amine (Compound 5) (140 g, Yield: 85.0%).

HPLC: 99.56% (267 nm).

The crude product obtained in the second method can also be purified by the following method: nitrogen protection, 3.52 kg of crude product (consistent with the reaction conditions of the method 2) is dissolved in 27.80 kg of methanol, 35.20 kg of deionized water is added under stirring, and the crystallization is stirred for 1 to 2 hours. Filter, collect the filter cake; filter cake was dried at 45-55 ° C for 10 hours; 2.80 kg of compound 5 was obtained (yield 79.55%, HPLC: 99.4% (267 nm)).

Method 3: nitrogen protection, 4mol / L hydrochloric acid solution (200ml) and ethanol (40ml) were added to the reaction flask, the temperature was lowered to 0 ~ 10 ° C, compound 4 (20g) was added; 20 ° C reaction for 1-2 hours. Dichloromethane (300ml) was added to the reaction solution, and 5% aqueous ammonia was added dropwise to adjust the pH to 8-9; the organic layer was separated, washed, and dried and filtered; n-heptane (750 ml) was added to the filtrate, and the precipitate was precipitated, filtered, and collected. The filter cake was dried 10.5 g, yield 63.8%; HPLC: 99.2% (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)

Tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-morpholino-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate( 6-a) and tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl)-5-morpholino-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3 -yl]carbamate(6-b)

Compound 1 (5.0 g, 12.63 mmol) obtained in the first method of Example 1 was added to N,N-dimethylacetamide (25 mL) in a 250 mL reaction flask under nitrogen atmosphere, and 4- Dimethylaminopyridine (1.85 g, 15.15 mmol) was cooled to -10 ° C, which was 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. It was extracted with ethyl acetate (100 mL and 50 mL each). The residue was purified by column chromatography (silica gel 100 g, eluent: petroleum ether / ethyl acetate (v/v)=7:1-3:1), obtained as a white solid N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-morpholinyl 6-( tert-Butyl 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)-3,6-dihydro-2H-pyran-3-yl)carbamic acid Butyl ester (Compound 6-b) (1.0 g, yield 18%).

Compound 6-a:

^{1 H NMR (400MHz, DMSO-} d 6) δ7.27-7.12 (m, 4H), 5.37-5.33 (m, 1H), 4.95 (s, 1H), 4.72 (d, J = 9.5Hz, 1H), 4.44-4.40 (m, 1H), 3.63–3.57 (m, 4H), 3.04–3.01 (m, 2H), 2.62–2.59 (m, 2H), 1.23–1.13 (m, 9H).

Compound 6-b:

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.24 - 7.07 (m, 4H), 5.43-5.42 (m, 1H), 5.04 (s, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.41-4.39 (m, 1H), 3.62-3.58 (m, 4H), 2.96-2.92 (m, 2H), 2.60–2.57 (m, 2H), 1.23–1.20 (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)

Tert-butyl N-[(2R,3S,6S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)- 6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(7-a) and tert-butyl N-[(2R,3S,6R)-2-(2,5-difluorophenyl) -5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)-6-(trifluoromethyl)-3,6-dihydro-2H-pyran-3-yl]carbamate(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), 7.28-7.06 (m, 4H), 5.43-5.38 (m, 1H), 4.93 (s, 1H), 4.86 (d, J = 9.7 Hz, 1H), 4.56-4.51 (m, 1H), 4.39-4.32 (m, 2H), 4.08 - 4.04 (m, 2H), 3.52 (s, 3H), 1.25-1.23 (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 with 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), 7.25-7.08 (m, 4H), 5.49-5.46 (m, 1H), 4.90 (s, 1H), 4.47 (d, J = 9.2 Hz, 1H), 4.42-4.37 (m, 1H), 4.31 - 4.21 (m, 4H), 3.52 (s, 3H), 1.23 - 1.18 (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)

2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole

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), 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, filtered under reduced pressure, and the filter cake was washed with petroleum ether (2 L). Drying under vacuum for 3-4 hours to give a yellow-white solid 2-methanesulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole (compound 3 crystals) (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: 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)

(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

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: 99.14% (267 nm).

Claims (20)

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

   

   Characterized in that the compound of the formula (II) is reacted in the presence of p-toluenesulfonic acid with a dichloromethane system or a system of an acidic reagent having a pKa ≤ 5 and water to obtain a compound of the formula (I);

   Alternatively, an organic solvent may be further added to the reaction;

   Wherein P is an amino protecting group.
2. The preparation method according to claim 1, wherein the acidic reagent is selected from the group consisting of one or a mixture of two or more of hydrochloric acid, trifluoroacetic acid and methanesulfonic acid, and the organic solvent is selected from the group consisting of methanol, ethanol or isopropyl alcohol. alcohol.
3. The process according to claim 1, wherein the reaction temperature is -20 to 30 °C.
4. The process according to any one of claims 1 to 3, wherein the compound of the formula (II) is further post-treated by reacting an acidic reagent having a pKa ≤ 5 with water to obtain a compound of the formula (I), the post-treatment comprising

   Adding an organic solvent to the reaction solution, adding water and/or an alkaline solution, layering, extracting, collecting the organic phase, and concentrating under reduced pressure to obtain a crude product;

   Alternatively, the crude product is recrystallized or/and beaten;

   Alternatively, seed crystals of the compound of formula (I) may be added during recrystallization or/and beating.
5. The preparation method according to claim 4, wherein the alkaline solution is selected from the group consisting of an aqueous ammonia solution, an aqueous solution of sodium carbonate, an aqueous solution of methylamine, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate, an aqueous solution of potassium hydrogencarbonate, an aqueous solution of lithium hydroxide, and a hydroxide. a mixed solution of one or more of an aqueous sodium solution and an aqueous potassium hydroxide solution;

   The solvent used for the recrystallization or/and beating is selected from the group consisting of water, an ester solvent, an alcohol solvent, a nitrile solvent, an ether solvent, an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated alkane solvent. The above mixed solvent.
6. A method for preparing a compound of formula (II), characterized in that

   

   In a polar aprotic solvent, a compound of formula (III) and a compound of formula (IV) are reacted in the presence of an organic acid to give an intermediate form (II-M) a compound; adding an organic acid and an organic boron reducing agent, and reacting at -10 to 25 ° C to obtain a compound of the formula (II);

   P is an amino protecting group.
7. The method of claim 6 wherein:

   The polar aprotic solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether a mixture of one or more of N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide;

   The organic acid is selected from formic acid, trifluoroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid;

   The organoboron reducing agent is selected from sodium tris(acetoxy)borohydride, sodium borohydride or sodium borane.
8. A process according to any one of claims 6 to 7, wherein the reaction is carried out in the presence of a molecular sieve, a dehydrating agent or a water-removing vessel.
9. A method for preparing a compound of formula (III):

   

   Contains the following steps:

   (1), the compound of the formula (V) is dissolved in toluene, and morpholine is added dropwise at 50 to 100 ° C, and then refluxed to obtain a compound of the formula (VI-A);

   (2), -10 ~ 25 ° C, a polar aprotic solvent, in the presence of the alkaline reagent 4-dimethylaminopyridine, the compound of formula (VI-A) and S-(trifluoromethyl)dibenzothiophene Reaction of trifluoromethanesulfonate or S-(trifluoromethyl)dibenzothiophene trifluoromethyltetrafluoroborate, after post-treatment to obtain intermediate state (VI-AM);

   (3), the intermediate state (VI-A-M) in water or a mixed solvent of an organic solvent and water, in the presence of an acidic reagent to obtain a compound of formula (III);

   Wherein P is selected from an amino protecting group;

   Alternatively, post processing of the intermediate state (VI-A-M) between steps (2) and (3) may be omitted.
10. The process according to claim 9, wherein the reaction in the step (1) is further carried out under the conditions of a molecular sieve, a dehydrating agent or a water-removing vessel.
11. The process according to claim 9, wherein the polar aprotic solvent in the step (2) is selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, N. One or a mixture of two or more of N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide.
12. The preparation method according to claim 9, wherein the acidic reagent in the step (3) is selected from the group consisting of hydrochloric acid, trifluoroacetic acid and formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid, and the organic solvent is selected from the group consisting of Dichloromethane.
13. The preparation method according to any one of claims 9 to 12, wherein the post-processing in the step (1) comprises the following steps:

    (1) adding one or two or more solvents of n-heptane, n-hexane, cyclohexane and petroleum ether to the reaction liquid;

    (2), filtration, filter cake drying.
14. The preparation method according to any one of claims 9 to 12, wherein the post-treatment in the step (2) is: adding an organic solvent and water, layering, and extracting to obtain an organic phase, and the organic phase is concentrated.
15. The preparation method according to any one of claims 9 to 12, wherein the post-treatment in the step (3) comprises adding water and/or an organic solvent to the reaction liquid, layering, extracting, collecting the organic phase, and selecting the organic phase. Treated in the following manner: the organic phase is passed through silica gel, and the obtained liquid is further concentrated to obtain a crude product; or the organic phase is further washed and/or dried and/or concentrated to obtain a crude product;

    Alternatively, the crude product is recrystallized or/and beaten.
16. The process according to claim 15, wherein the solvent used for recrystallization or/and beating of the crude product is selected from the group consisting of water, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, One or a mixture of two or more of dichloromethane, methyl acetate, ethyl acetate, isopropyl acetate, toluene, n-hexane, cyclohexane, petroleum ether and n-heptane.
17. 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.
18. A method of preparing a compound of formula (III-A) and formula (III-B),

    

    -10 ° C to room temperature, N,N-dimethylacetamide, 4-dimethylaminopyridine, a compound of formula (VI-A) and S-(trifluoromethyl)dibenzothiophene trifluoromethanesulfonic acid The salt is reacted with a solution of N,N-dimethylacetamide to obtain a compound of the formula (III-A) and the formula (III-B);

    Wherein P is an amino protecting group.
19. A method of preparing a compound of formula (II-A) and formula (II-B),

    

    Chloroform as a solvent, heating under reflux, the compound of formula (III) and the compound of formula (IV) are reacted by Dean-Starks water separation, and the compound of formula (II-A) and formula (II-B) is isolated;

    Wherein P is an amino protecting group.
20. The method according to any one of claims 1 to 16 or 18 to 19, wherein P is a tert-butoxycarbonyl group.

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