CN109071551B - Preparation method of trifluoromethyl substituted pyran derivative - Google Patents
Preparation method of trifluoromethyl substituted pyran derivative Download PDFInfo
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Abstract
Provides a preparation method of trifluoromethyl substituted pyran derivative and intermediate thereof, namely a preparation method of compound shown in formula (I) and intermediate thereof, and the method has the advantages of mild reaction condition, simple operation, high reaction yield, high product purity, convenient post-treatment and suitability for industrial production
Description
Technical Field
The invention belongs to the field of chemical medicine, and relates to preparation of trifluoromethyl substituted pyran derivatives.
Background
Glucagon-like peptide-1 (GLP-1) can participate in the regulation of blood sugar homeostasis of an organism, improve the function of pancreatic islets and delay or even reverse the progression of the disease course of type 2 diabetes through multiple ways. However, endogenous GLP-1 is rapidly cleaved by dipeptidyl peptidase 4(DPP-4) and becomes inactive after secretory release into the blood. The DPP-4 inhibitor can selectively inhibit the enzymatic activity of DPP-4, prevent GLP-1 from being cracked and inactivated, improve the plasma level of active GLP-1, enhance the physiological action of the active GLP-1, and reduce HbA1, fasting blood sugar and postprandial blood sugar levels of type 2 diabetes patients.
WO2015192701 discloses a novel dipeptidyl peptidase IV (DPP-4) inhibitor shown in a formula (I), which has a good inhibition effect on the enzymatic activity of DPP-4 and has the potential of preventing and treating type II diabetes.
The compound of the formula (I) has good stability and high bioavailability, is convenient for developing preparations and has clinical value. Therefore, the research on the preparation method of the compound shown in the formula (I) in the field has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of trifluoromethyl substituted pyran derivative, namely a preparation method of a compound shown in formula (I), which has the advantages of mild reaction conditions, simple operation, high reaction yield, high product purity, convenient post-treatment and suitability for industrial production.
Specifically, in a first aspect, the present invention relates to a process for the preparation of a compound of formula (I):
reacting a compound of a formula (II) with dichloromethane or trifluoroacetic acid and water at 20-25 ℃ in an inert gas atmosphere, and carrying out post-treatment to obtain a compound of a formula (I);
wherein P in formula (II) is an amino protecting group, preferably t-butyloxycarbonyl.
In certain embodiments, p-toluenesulfonic acid monohydrate may be replaced with p-toluenesulfonic acid.
In certain embodiments, the p-toluenesulfonic acid monohydrate is an excess, preferably the molar ratio of the compound of formula (II) to the p-toluenesulfonic acid monohydrate is 1: 2.5 to 1: 3, preferably 1: 2.8.
In certain embodiments, trifluoroacetic acid is an excess, preferably the mass to volume (w/v) ratio of the compound of formula (II) to trifluoroacetic acid is from 1: 2.5 to 1: 3.5.
In certain embodiments, the mass to volume ratio (w/v) of the compound of formula (II) to the solvent dichloromethane is from 1: 8 to 1: 15, preferably 1: 10.
In certain embodiments, the ratio of trifluoroacetic acid to solvent water is from 2: 1 to 4:1 by volume.
In certain embodiments, the work-up to react p-toluenesulfonic acid monohydrate with dichloromethane comprises the steps of:
(1) sequentially adding water and methanol into the reaction solution, layering, and extracting the water layer by using a mixed solvent of dichloromethane and methanol;
(2) adjusting the solution of the organic phase obtained in the step (1) to be alkaline by alkali, washing an organic layer by using a saturated sodium carbonate solution and a saturated salt solution in sequence, drying, and concentrating under reduced pressure at the temperature of below 40 ℃;
(3) dissolving the residue obtained in the step (2) in ethyl acetate at the internal temperature of less than 40 ℃ in an inert gas atmosphere;
(4) maintaining the internal temperature to be less than 40 ℃, dripping n-heptane, and crystallizing at room temperature;
alternatively, seeding step (4) with a compound of formula (I).
In certain embodiments, the volume ratio of the water added in step (1) to the solvent dichloromethane in the reaction solution is 0.8: 1 to 1.2: 1.
In some embodiments, the water and methanol are added sequentially in step (1) at a volume ratio of 9: 1 to 12: 1, and the dichloromethane and methanol are used for extraction at a volume ratio of 9: 1 to 11: 1.
In some embodiments, the alkali used in step (2) is ammonia, and the pH value of the solution is 8-11, preferably 9-10 when the solution is adjusted to be alkaline.
In certain embodiments, the volume ratio of n-heptane added dropwise in step (4) to ethyl acetate in step (3) is from 1: 1 to 4: 1.
In certain embodiments, the work-up to carry out the reaction in the presence of trifluoroacetic acid and water comprises the steps of:
(1) adding dichloromethane into the reaction solution, dropwise adding water and ammonia water until the pH value is more than 7, and layering;
(2) extracting the aqueous layer in the step (1) by using dichloromethane, combining the organic phases obtained in the steps (1) and (2), washing the combined organic phases by using a saturated sodium carbonate solution and a saturated salt solution in sequence, drying a drying agent, and concentrating under reduced pressure to obtain a crude product;
(3) dissolving the crude product obtained in the step (2) in ethyl acetate, keeping the internal temperature at 25-35 ℃, dropwise adding n-heptane, and crystallizing at room temperature;
alternatively, seeding step (3) with a compound of formula (I).
In certain embodiments, the drying agent 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),
wherein, chloroform is used as a solvent, the mixture is heated and refluxed, and the compound of the formula (III) and the compound of the formula (IV) are reacted by Dean-Starks water separation; diluting the reaction liquid with 1, 2-dichloroethane, sequentially adding sodium triacetoxyborohydride and acetic acid under the atmosphere of inert gas, reacting at room temperature, and carrying out aftertreatment to obtain a compound of a formula (II);
wherein, in the formula (II) and the formula (III), P is an amino protecting group, preferably t-butyloxycarbonyl.
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 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 1: 1.1 to 1:2, the volume-to-mass ratio of chloroform to the compound of formula (III) is 1.5: 1 to 5: 1, and 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: 2-1: 5, preferably 1: 3-1: 4, and the molar ratio of acetic acid to the compound of the formula (III) is 1: 1-2.5: 1.
In certain embodiments, the post-treatment comprises the steps of:
(1) adding water, layering, extracting, washing with water and an alkali solution, drying, filtering and concentrating;
(2) dissolving the concentrate in the step (1) in methanol under heating, dripping water under stirring at room temperature, and filtering;
(3) dissolving the filtrate in the step (2) in dichloromethane, layering, drying an organic layer, and separating by using a silica gel column chromatography;
(4) and (4) pulping the filtrate obtained in the step (3).
In certain embodiments, the base in step (1) is aqueous ammonia.
In some embodiments, water is added dropwise in two times under stirring in step (2), wherein the volume ratio of methanol to the first dropwise added water to the second dropwise added water is preferably 4:1: 4.
In certain embodiments, the solvent used for pulping in step (4) is a mixed solvent of dichloromethane and petroleum ether, preferably the volume ratio of dichloromethane to petroleum ether is 1: 2.
In a third aspect, the present invention also relates to a process for the preparation of a compound of formula (III):
comprises the following steps:
(1) and carrying out reflux water-splitting reaction on the compound of the formula (V) and morpholine by taking toluene as a solvent, and carrying out aftertreatment to obtain a mixture of the compounds of the formula (VI-A) and the formula (VI-B):
(2) reacting N, N-dimethylacetamide, 4-dimethylaminopyridine, the mixture of the compounds of the formula (VI-A) and the formula (VI-B) obtained in the step (1) and a N, N-dimethylacetamide solution of S- (trifluoromethyl) dibenzothiophene trifluoromethylsulfonate at a temperature of-10 ℃ to room temperature under anhydrous and oxygen-free conditions;
wherein, in the formula (V), the formula (VI-A) and the formula (VI-B), P is an amino protecting group, preferably t-butyloxycarbonyl.
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 compounds of formula (VI-A) and formula (VI-B) to S- (trifluoromethyl) dibenzothiophene trifluoromethanesulfonate is from 1: 1 to 1: 1.5.
In certain embodiments, the molar ratio of the mixture of compounds 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 compounds 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 from 1: 8 to 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 compounds of formula (VI-A) and formula (VI-B) to S- (trifluoromethyl) dibenzothiophene trifluoromethanesulfonate is from 1: 1 to 1: 1.5, the molar ratio of the mixture of compounds of formula (VI-A) and formula (VI-B) to 4-dimethylaminopyridine is from 1: 0.1 to 1: 1.5, preferably 1: 1; the mass-volume ratio of the mixture of the compounds of the formula (VI-A) and the formula (VI-B) to the total N, N-dimethylacetamide in the reaction is 1: 5-1: 20, preferably 1: 8-1: 15.
In certain embodiments, the method of preparing a compound of formula (III) comprises the step of post-treating as described in step (1):
(1) pulping the hot reaction solution with n-heptane;
(2) filtering, and drying the solid to constant weight.
In certain embodiments, the process step (2) of preparing the compound of formula (III) further comprises the steps of:
(1) keeping the temperature of the system to be lower than 20 ℃, dropwise adding ice water to the reaction solution, extracting by using ethyl acetate, and combining organic phases;
(2) keeping the temperature of the system to be lower than 10 ℃, dropwise adding hydrochloric acid, and reacting at room temperature;
(3) washing, drying and concentrating;
(4) dissolving the obtained substance in the step (3) in dichloromethane, adding silica gel, concentrating under reduced pressure at the temperature of below 50 ℃ to form dry powder, and keeping the temperature until the configuration conversion end point;
(5) desorbing, and concentrating to obtain a crude product;
(6) refluxing and pulping the crude product by using normal hexane;
(7) filtering, and drying the solid to constant weight.
In certain embodiments, the molar ratio of the mixture of compounds of formula (VI-A) and formula (VI-B) in step (2) to the dropwise addition of hydrochloric acid is 1: 3 to 1: 5.
In certain embodiments, the mass ratio of the mixture of compounds 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 present invention also relates to a process for the preparation of a compound of formula (IV):
the method comprises the following steps: reacting a compound shown in a formula (VII) with a hydrochloric acid-ethyl acetate solution at-10 ℃;
wherein P in formula (VII) is an amino protecting group, preferably t-butyloxycarbonyl.
In some embodiments, the hydrochloric acid-ethyl acetate solution is ready for use, and is formed by dropping acetyl chloride into a mixed solution of ethyl acetate and ethanol, preferably a 4mol/L hydrochloric acid-ethyl acetate solution.
In some 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 process for preparing the compound of formula (IV) further comprises seeding with a compound of formula (IV).
In a fifth aspect, the present invention provides compounds of formula (III-A), formula (III-B), formula (II-A), formula (II-B) as shown below:
wherein P is an amino protecting group, preferably t-butyloxycarbonyl.
In a sixth aspect, the present invention relates to a process for the preparation of compounds of formula (III-A) and formula (III-B),
the method comprises the following steps: reacting a mixture of N, N-dimethylacetamide, 4-dimethylaminopyridine, compounds of formula (VI-A) and formula (VI-B) with an N, N-dimethylacetamide solution of S- (trifluoromethyl) dibenzothiophene trifluoromethylsulfonate at a temperature of between 10 ℃ below zero and room temperature under anhydrous and oxygen-free conditions, and separating by silica gel column chromatography to obtain compounds of formula (III-A) and formula (III-B);
wherein, in the formulae (VI-A), (VI-B), (III-A) and (III-B), P is an amino-protecting group, preferably t-butyloxycarbonyl.
In certain embodiments, the mixture of compounds of formula (VI-A) and formula (VI-B) has a molar ratio of formula (VI-A) to formula (VI-B) of from 3: 1 to 12: 1.
In certain embodiments, the molar ratio of the mixture of compounds of formula (VI-A) and formula (VI-B) to S- (trifluoromethyl) dibenzothiophene trifluoromethanesulfonate is from 1: 1 to 1: 2.
In a seventh aspect, the present invention relates to a process for the preparation of compounds of formula (II-A) and formula (II-B),
the method comprises the following steps: performing heating reflux by using chloroform as a solvent, performing Dean-Starks water separation reaction on the compound of the formula (III) and the compound of the formula (IV), and performing silica gel column chromatography separation to obtain a compound of the formula (II-A) and a compound of the formula (II-B);
wherein, in the formula (III), the formula (II-A) and the formula (II-B), P is an amino protecting group, preferably t-butyloxycarbonyl.
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 of formula (III) according to the present invention is a diastereomer comprising the following two structures:
during the preparation of the compound of formula (III), the partial conversion of configuration (III-1) into configuration (III-2) can be achieved by adsorption of the diastereoisomers on silica gel, concentration under reduced pressure below 50 ℃ to a dry powder, and maintenance of the temperature below 50 ℃.
The term "end point of configuration transition" as used herein means1H NMR (solvent DMSO-d)6) The shift () peak area ratio of H (5.2) to H (4.4) > 2: 1. Due to the fact that1The HNMR instruments are different, the experimental conditions are different to control,1h NMR shift () allows some movement.
The term "water-diversion reaction" as used herein refers to a water-diversion reaction carried out using a Dean-Starks water separator.
The separation method used in the invention is a separation method which is conventional in the chemical field, such as silica gel column chromatography, high performance liquid chromatography and thin layer chromatography.
"selectively" or "alternatively" means that the subsequently described event or circumstance can, but need not, occur, including instances where the event or circumstance occurs or does not occur.
The reaction process of the invention is carried out by HPLC,1And (4) tracking the reaction progress by HNMR or thin-layer chromatography, and judging whether the reaction is finished.
In the present invention, inert gas means a gas which does not participate in the reaction, such as nitrogen.
In the present invention, the internal temperature means the reaction system temperature.
The invention optimizes the process for generating the compound of the formula (I) from the compound of the formula (II), adopts a reaction system of trifluoroacetic acid and dichloromethane in the prior art, is not easy to control the post-treatment, has influence on the stability of the product by concentrating the trifluoroacetic acid, and increases the byproduct along with the increase of the feeding amount. The invention adopts a reaction system of p-toluenesulfonic acid monohydrate and dichloromethane or a reaction system of trifluoroacetic acid and water, and avoids the defect of significantly increased degradation products in the post-treatment. Meanwhile, the reaction system of trifluoroacetic acid and water reduces the usage amount of trifluoroacetic acid and the usage amount of organic solvent, and is more environment-friendly.
The invention optimizes the process of obtaining the compound of the formula (II) by the condensation reaction of the intermediate of the formula (III) and the intermediate of the formula (IV), uses chloroform as a solvent, adopts a reflux water separation method, avoids the unconventional operation of evaporating the solvent to dryness under the condition of toluene in the prior art, has mild reaction conditions, more thorough reaction and improved whole reaction yield. Meanwhile, the reaction conditions are suitable for amplification, and the method is in accordance with industrial production. Although column chromatography is still adopted in the purification mode, the use amount of silica gel is greatly reduced and the purification is rapid by adopting rapid silica gel column chromatography. Meanwhile, the method for evaporating the solvent toluene is adopted in the prior art, the reaction temperature is high, the concentration change is large, the product is not easy to control, and the reaction process is not convenient to monitor. And a chloroform reflux water separation mode is adopted, so that the reaction can better monitor the process.
The method for preparing the compound of the formula (III) from the compound of the formula (V) is optimized, the separation of intermediates (VI-A) and (VI-B) is omitted, the pulping method is adopted for purification, the separation by a column chromatography method is avoided, the method is more suitable for industrial production, and the yield of the compound of the formula (III) is greatly improved due to the fact that configuration conversion occurs through silica gel adsorption.
The method provided by the invention optimizes the post-treatment of each reaction step, uses conventional and simple operation steps, and is more suitable for industrial production. The reaction yield is improved, the operation process and the product are easy to control and monitor, and the method is environment-friendly.
Drawings
FIG. 1 is a drawing of Compound 21HNMR atlas.
FIG. 2 is a drawing of Compound 21H-1H NOESY map.
FIG. 3 is a drawing of Compound 21H-1H COSY map.
FIG. 4 is a drawing of Compound 6-b1H-1H NOESY map.
FIG. 5 is of Compound 7-a1H-1H NOESY map.
FIG. 6 is of Compound 7-a1H-1H COSY map.
FIG. 7 is a drawing of Compound 7-b1H-1H NOESY map.
FIG. 8 is a drawing of Compound 7-b1H-1H COSY map.
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS), two-dimensional hydrogen homonuclear shift correlation spectrum (1H-1H COSY), two-dimensional nuclear Oxyfluore enhancement spectrum (1H-1H NOESY) was used for analysis of stereoisomers. NMR shift () at 10-6The units in (ppm) are given. NMR was measured using a (Bruker Avance III 400) nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated acetone, Tetramethylsilane (TMS) as internal standard, and 85% phosphoric acid in water as external standard.
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
The room temperature is 20-30 ℃.
Boc is tert-butyloxycarbonyl.
Example 1:
tert-butyl N- [ (2R, 3S) -2- (2, 5-difluorophenyl) -5-morpholinyl-3, 4-dihydro-2H-pyran-3-yl ] carbamate (Compound 1-a) and tert-butyl N- [ (2R, 3S) -2- (2, 5-difluorophenyl) -5-morpholinyl-3, 6-dihydro-2H-pyran-3-yl ] carbamate (Compound 1-b)
Compound 1a (1.0kg, 3.06mol) was added to a 5L round bottom flask containing toluene (3L), warmed to 80 ℃ and morpholine (400g) was slowly added dropwise. After the addition, the mixture was heated to reflux and Dean-Stark was allowed to react with water for 3.5 hours. The reaction solution was pumped into a 20L round bottom flask containing n-heptane (15L) while hot, slurried for 1.5 hours, allowed to cool to room temperature, filtered, the filter cake washed once with n-heptane (5L), the solid collected and dried by forced air at 50 ℃ to constant weight to give a mixture of compound 1-a and compound 1-b (peak area ratio 90: 8(HPLC (265nm)), 1.13kg, 93% yield).
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 100L reaction kettle,under the protection of nitrogen, the mixture (1kg, 2.53mol) of the compound 1-a and the compound 1-b obtained in example 1 was added to N, N-dimethylacetamide (10L), 4-dimethylaminopyridine (296g, 2.53mmol) was added under stirring, and the temperature was reduced to-10 ℃ to obtain solution A. S- (trifluoromethyl) dibenzothiophene trifluoromethanesulfonate (1.22kg, 3.04mol) and N, N-dimethylacetamide (2L) were added to a 5L flask, stirred until clarification was obtained, and the mixture was added dropwise to the solution A while maintaining the internal temperature at a temperature slightly lower than-10 ℃ under anhydrous oxygen-nitrogen-free protection for about 30 minutes. Keeping the reaction at-10 ℃ for 5 hours, raising the temperature to 10-20 ℃ and standing for 16 hours. The temperature was reduced to 0 ℃ and ice water (36L) was added to the reaction mixture, the addition rate being controlled to maintain the temperature below 20 ℃. Extracting with ethyl acetate (20L and 10L each time), mixing organic phases, cooling to 0 deg.C, adding hydrochloric acid (10L, 1mol/L) cooled to 0 deg.C, and controlling the temperature below 10 deg.C during the addition process. After the addition, the temperature is raised to 10-20 ℃ and the reaction is stirred for 1 hour. The reaction solution was washed with water (10L. times.2) and saturated sodium chloride solution (10L) in this order, dried over anhydrous sodium sulfate (500g), and concentrated under reduced pressure at 45 ℃ to dryness to give a crude product. Dissolving the crude product with dichloromethane (10L), clarifying, adding silica gel (2kg), concentrating under reduced pressure with 20L single-neck bottle under rotary evaporation device to obtain dry powder, and rotary drying under reduced pressure under rotary evaporation device for 5 hr (water bath temperature is 50 deg.C) to configuration conversion end point. The dried solid was stirred in dichloromethane (10L) for 30 minutes, filtered through a sand-core funnel and the silica gel rinsed with dichloromethane (15L) under reduced pressure. The filtrate was concentrated to dryness under reduced pressure at 40 ℃. Adding N-hexane (20L) into the residue, heating, refluxing, pulping for 30 min, cooling to below 50 deg.C, stopping stirring, naturally cooling to 10-25 deg.C, standing for 16 hr, filtering, leaching N-hexane (10L) under reduced pressure, and drying at 40 deg.C under reduced pressure to constant weight to obtain white solid N- [ (2R, 3S) -2- (2, 5-difluorophenyl) -5-carbonyl-6- (trifluoromethyl) tetrahydropyran-3-yl]Tert-butyl carbamate (Compound 2) (609g, 61% yield by HPLC(Total purity of isomers): 95.7%, dr (diastereomer value): 82: 18 (2-2: 2-1, detection by HPLC (210 nm)).
preparation of compound 2 with deuterated acetone as solvent1The HNMR is shown in figure 1,1H-1the H NOESY map is shown in figure 2,1H-1the H COSY spectrum is shown in figure 3.
Example 3
2-methanesulfonyl-5, 6-dihydro-4H-pyrrolo [3, 4-c ] pyrazole (Compound 3)
Adding ethyl acetate (3100mL) and ethanol (985g, 21.42mol) into a 10L round-bottom flask, cooling to about-5 ℃, dropwise adding acetyl chloride (1.6kg, 20.8mol) while stirring, controlling the temperature between-10 and 0 ℃, and after the addition is finished, heating to 10-20 ℃ for reaction for 30 minutes. Cooling the reaction system to-10 ℃, adding 2- (methylsulfonyl) -4, 6-dihydropyrrolo [3, 4-c ] pyrazole-5 (2H) -tert-butyl formate (3a) (1kg, 3.48mol) under stirring, wherein a light yellow solid is generated in the process, naturally heating to react after the addition is finished, raising the temperature of the reaction system to 5-10 ℃ within 1.5 hours, and monitoring by TLC to show that the reaction is complete. The reaction was cooled to-10 ℃ and filtered under reduced pressure, and the filter cake was washed with ethyl acetate (2L). The filter cake was added to dichloromethane (5L), and a mixed solution of ammonia water (1L) and water (1L) was added with stirring, and the mixture was allowed to stand for delamination. The aqueous layer was extracted with dichloromethane (4 L.times.4), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure on a rotary evaporator to give the crude product as a yellow oil. Adding dichloromethane (1.2L) into the crude product, stirring until the crude product is completely dissolved, then adding petroleum ether (600mL) while continuing stirring, adding 2-methanesulfonyl-5, 6-dihydro-4H-pyrrolo [3, 4-c ] pyrazole seed crystals (3g), adding petroleum ether (5.4L) when a large amount of solid is separated out, stirring and crystallizing for about 2 hours, filtering under reduced pressure, washing a filter cake by using petroleum ether (2L), and drying in vacuum at 30 ℃ for 3-4 hours to obtain a yellowish white solid 2-methanesulfonyl-5, 6-dihydro-4H-pyrrolo [3, 4-c ] pyrazole (compound 3) (592g, the yield is 90.9%).
MS m/z(ESI)：188.2[M+1]；
1H NMR(400MHz，CD3OD)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)
Compound 3(142.0g, 0.7595mol) and Compound 2(200.0 g, 0.5063mol) were added successively to a reaction flask containing chloroform (400mL) with stirring, and stirred under reflux, followed by Dean-Starks reaction with water for 5 hours. After the reaction, heating was stopped, and after the reaction solution stopped boiling, the reaction solution was transferred to a 5L three-necked flask, and 1, 2-dichloroethane (1.6L) was added to dilute the reaction solution. Stirring the reaction system under the nitrogen atmosphere, cooling to 5-15 ℃, sequentially adding sodium triacetoxyborohydride (375.6g, 1.7721mol) and acetic acid (46.33mL, 0.8100mol), heating to 20-35 ℃ after the addition, and reacting for 5 hours. After the reaction was completed, water (1.2L) was slowly added, stirred for 5 minutes, allowed to stand to separate, the aqueous layer was extracted with dichloromethane (400 mL. times.2), the organic phases were combined, washed with a mixed solution of water (600mL) and aqueous ammonia (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. In a 5L three-necked flask, the residue obtained by concentration was dissolved in methanol (1.6L) under heating (not higher than 50 ℃), the temperature was lowered to room temperature under stirring, water (400mL) was added dropwise, and stirring was continued for 30 minutes after the addition was completed, during which time a solid precipitated. Water (1.6L) was again added dropwise with stirring, and stirring was continued for 30 minutes after the addition was completed, followed by filtration to give a pale yellow wet solid. Dissolving the solid in dichloromethane (2-3L), layering, drying an organic phase with anhydrous sodium sulfate, performing suction filtration on the organic phase directly through a sand core funnel containing 600g of silica gel under reduced pressure, eluting the silica gel with an organic solvent (petroleum ether/ethyl acetate (v/v) ═ 3: 2, 5-7L), and concentrating a chromatographic solution to obtain a crude product. Dissolving the crude product in dichloromethane (1.4L) under the heating condition (not higher than 45 ℃), completely dissolving, cooling to 20-30 ℃, adding petroleum ether (2.8L) within 3-8 minutes under the stirring state, separating out white solid in the process, and immediately filtering to obtain the solid after the addition is finished. At 10-35 ℃, dichloromethane (720mL) was added to the solid, stirred for 1 hour, added with petroleum ether (1.8L), and stirred at room temperature for 2 hours. Filtration gave 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 (compound 4) as a white solid (201g, yield 70%, dr > 99.95: 0.05).
1H NMR(400MHz，DMSO-d6)7.96(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 50L reaction kettle, p-toluenesulfonic acid monohydrate (752.3g, 3.958mol) is added into dichloromethane (8L), compound 4(800g, 1.413mol) is added under nitrogen atmosphere, and the mixture is stirred and reacted for 4-5 hours at the temperature of 20-25 ℃. After completion of the reaction, water (8.5L) and methanol (800mL) were added in this order, and the mixture was 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). And (3) combining organic phases, adding water (8L) and ammonia water (1.5L), stirring for 10 minutes, demixing, washing the organic phases with saturated sodium carbonate solution (8-10L) and saturated saline solution (8-10L) in sequence, drying the organic phases with anhydrous sodium sulfate, and concentrating at 35 ℃ under reduced pressure to obtain a crude product. And under the nitrogen atmosphere, controlling the internal temperature at 30-35 ℃, and dissolving the crude product in ethyl acetate (3.5L). Maintaining the internal temperature at 25-35 ℃, dropwise adding n-heptane (2.5L) with stirring, adding seed crystals of (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 (8g), continuously dropwise adding n-heptane (4.5L), stirring at room temperature for 2 hours after the addition is finished, and filtering to obtain 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 ((2R, 3S, 5R, 6S) -2- (2, 5-difluorophenyl) -5- (2- (methylsulfonyl) -4, 6-dihydropyrrolo [3, 4-c ] pyrazol- Compound 5) (508g, yield: 77.1%).
1H NMR(400MHz，DMSO-d6)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
Tert-butyl N- [ (2R, 3S, 6S) -2- (2, 5-difluorophenyl) -5-morpholinyl 6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (Compound 6-a) and tert-butyl N- [ (2R, 3S, 6R) -2- (2, 5-difluorophenyl) -5-morpholinyl 6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (Compound 6-b)
In a 250mL reaction flask, under the protection of nitrogen, a mixture (5.0g, 12.63mmol) of the compounds 1-a and 1-b obtained in example 1 was added to N, N-dimethylacetamide (25mL), 4-dimethylaminopyridine (1.85g, 15.15mmol) was added under stirring, and the temperature was reduced to-10 ℃ to obtain solution A. S- (trifluoromethyl) dibenzothiophene trifluoromethanesulfonate (6.10g, 15.15mmol) and N, N-dimethylacetamide (15mL) were added to a 25mL flask, stirred until the mixture was clear, and the mixture was added dropwise to the solution A while maintaining the internal temperature at a temperature slightly lower than-10 ℃ under anhydrous oxygen-nitrogen-free protection for about 30 minutes. Keeping the reaction at-10 ℃ for 5 hours, raising the temperature to 10-20 ℃ and standing for 16 hours. The temperature was reduced to 0 ℃ and ice water (50mL) was added to the reaction mixture, the rate of addition was controlled, and the temperature was kept below 20 ℃. Extraction was performed with ethyl acetate (100mL and 50mL each), and the organic phases were combined, washed once with saturated aqueous sodium chloride (300mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel 100g, eluent: petroleum ether/ethyl acetate (v/v) ═ 7: 1-3: 1) to give tert-butyl N- [ (2R, 3S, 6S) -2- (2, 5-difluorophenyl) -5-morpholinyl 6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (compound 6-a) (2.1g, yield 38%) and tert-butyl N- [ (2R, 3S, 6R) -2- (2, 5-difluorophenyl) -5-morpholinyl 6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (compound 6-b) (1.0g, yield 18%).
Compound 6-a:
1H NMR(400MHz，DMSO-d6)7.32-7.08(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:
1H NMR(400MHz，DMSO-d6)7.31-7.12(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)。
with DMSO-d6As solvent, of compound 6-b1H-1The H NOESY pattern is shown in figure 4.
Example 7
Tert-butyl N- [ (2R, 3S, 6S) -2- (2, 5-difluorophenyl) -5- (2-methanesulfonyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazol-5-yl) -6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (compound 7-a) and N- [ (2R, 3S, 6R) -tert-butyl 2- (2, 5-difluorophenyl) -5- (2-methanesulfonyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazol-5-yl) -6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (Compound 7-b).
Compound 2(5.0g, 12.66mmol) and compound 3(3.55g, 18.99mmol) were added successively to a reaction flask containing chloroform (10mL) with stirring, heated under reflux, and reacted with Dean-Starks of water for 5 hours. After the reaction, heating was stopped and the reaction mixture was concentrated. The residue was purified by column chromatography (silica gel 80g, eluent: petroleum ether/ethyl acetate (v/v) ═ 4: 1-3: 1) to give, respectively, white solid t-butyl N- [ (2R, 3S, 6S) -2- (2, 5-difluorophenyl) -5- (2-methanesulfonyl-4, 6-dihydropyrrolo [3, 4-c ] pyrazol-5-yl) -6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (compound 7-a) (6.0g, yield 85%) and white solid N- [ (2R, 3S, 6R) -2- (2, 5-difluorophenyl) -5- (2-methanesulfonyl-4, tert-butyl 6-dihydropyrrolo [3, 4-c ] pyrazol-5-yl) -6- (trifluoromethyl) -3, 6-dihydro-2H-pyran-3-yl) carbamate (compound 7-b) (0.4g, 5.6% yield).
Compound 7-a:
1H NMR(400MHz，DMSO-d6)8.06(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]。
with DMSO-d6As solvent, of compound 7-a1H-1The H NOESY pattern is shown in figure 5.
With DMSO-d6As solvent, of compound 7-a1H-1The H COSY spectrum is shown in figure 6.
Compound 7-b:
1H NMR(400MHz，DMSO-d6)8.08(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]。
with DMSO-d6As solvent, of compound 7-b1H-1The H NOESY pattern is shown in figure 7.
With DMSO-d6As solvent, of compound 7-b1H-1The H COSY spectrum is shown in figure 8.
Example 8
2-methanesulfonyl-5, 6-dihydro-4H-pyrrolo [3, 4-c ] pyrazole (Compound 3 seed)
Adding ethyl acetate (3100mL) and ethanol (985g, 21.42mol) into a reaction flask, cooling to about-5 ℃, dropwise adding acetyl chloride (1.6kg, 20.8mol), keeping the temperature at-10 to 0 ℃, removing, cooling, and heating to 10-20 ℃ for reaction for 30 minutes. Cooling the reaction solution to about-10 ℃, adding a compound 3a (1kg, 3.48mol), generating a light yellow solid in the process, removing a cooling device after the addition, naturally heating for reaction, and monitoring the reaction completion by TLC (thin layer chromatography) at 5-10 ℃ after 90 minutes. The reaction solution was cooled to about-10 ℃ and filtered under reduced pressure, and the filter cake was washed once with ethyl acetate (2L). The filter cake was added to dichloromethane (5L), a mixed solution of ammonia (1L) and water (1L) was added with stirring, the aqueous layer was extracted with dichloromethane (4L. times.4), the organic layers were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to dryness under reduced pressure. The concentrate was dissolved by adding methylene chloride (1.2L) and stirred, petroleum ether (6L) was added dropwise with stirring to gradually precipitate a solid, after stirring, the solid was crystallized for about 2 hours, filtered under reduced pressure, and the filter cake was washed with petroleum ether (2L) and dried under vacuum at 30 ℃ for 3 to 4 hours to obtain 2-methanesulfonyl-5, 6-dihydro-4H-pyrrolo [3, 4-c ] pyrazole (compound 3 seed crystal) as a yellowish white solid (592g, yield 90.9%).
MS m/z(ESI)：188.2[M+1]；
1H NMR(400MHz，CD3OD)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 crystals)
In a 50L reaction kettle, p-toluenesulfonic acid monohydrate (752.3g, 3.958mol) is added into dichloromethane (8L), compound 4(800g, 1.413mol) is added under nitrogen atmosphere, and the mixture is stirred and reacted for 4-5 hours at the temperature of 20-25 ℃. After completion of the reaction, water (8.5L) and methanol (800mL) were added in this order, and the mixture was 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). And (3) combining organic phases, adding water (8L) and ammonia water (1.5L), stirring for 10 minutes, demixing, washing the organic phases with saturated sodium carbonate solution (8-10L) and saturated saline solution (8-10L) in sequence, drying the organic phases with anhydrous sodium sulfate, and concentrating at 35 ℃ under reduced pressure to obtain a crude product. And (3) dissolving the crude product in ethyl acetate (3.5L) under the nitrogen atmosphere, wherein the internal temperature is controlled to be 30-35 ℃. N-heptane (7L) was added dropwise with stirring while maintaining the internal temperature at 25 to 35 ℃, after completion of the addition, stirring was continued at room temperature for 2 hours, and filtration was carried out to obtain (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 of Compound 5) (504g, yield: 76.5%) as a white solid.
HPLC purity: 99.14% (267 nm).
Example 10
(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)
Trifluoroacetic acid (442mL) was added to water (177mL) in a 5L three-necked flask and the temperature was reduced to 5-10 ℃. Under nitrogen atmosphere, adding compound 4(200g, 0.353mol) under stirring, keeping the temperature at 5-15 ℃, and supplementing trifluoroacetic acid (100 mL). Keeping the temperature at 15-25 ℃, stirring and reacting for 4-5 hours. After the reaction, methylene chloride (1.6L) was added with stirring, and water (200mL) and aqueous ammonia (730mL) were added dropwise in this order at a temperature of not higher than 25 ℃. The stirring was stopped and the layers separated and the aqueous layer was extracted with dichloromethane (300mL x 2). And (3) combining organic phases, washing the organic phases by using a saturated sodium carbonate solution (800-1000 mL) and a saturated saline solution (800-1000 mL) in sequence, drying the organic phases by using anhydrous sodium sulfate, and concentrating the dried organic phases at 35 ℃ under reduced pressure to obtain a crude product. And (3) under the nitrogen atmosphere, controlling the internal temperature at 30-35 ℃, and dissolving the crude product in ethyl acetate (900 mL). Maintaining the internal temperature at 25-35 ℃, dropwise adding n-heptane (650mL) with stirring, adding (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) (2g), further dropwise adding n-heptane (1150mL), continuing stirring at room temperature for 2 hours, and filtering to obtain 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) (140g, yield: 85.0%).
HPLC purity: 99.56% (267 nm).
1H NMR(400MHz，DMSO-d6)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 (15)
1. A process for the preparation of a compound of formula (I),
the method is characterized in that a compound of a formula (II) is reacted with dichloromethane or trifluoroacetic acid and water at the temperature of 20-25 ℃ in an inert gas atmosphere, and the compound of the formula (I) is obtained after post-treatment;
wherein, P in the formula (II) is an amino protecting group;
wherein the work-up in the presence of p-toluenesulfonic acid monohydrate and dichloromethane comprises the following steps:
(1) sequentially adding water and methanol into the reaction solution, layering, and extracting the water layer by using a mixed solvent of dichloromethane and methanol;
(2) adjusting the solution of the organic phase obtained in the step (1) to be alkaline by alkali, washing an organic layer by using a saturated sodium carbonate solution and a saturated salt solution in sequence, drying, and concentrating under reduced pressure at the temperature of below 40 ℃; adjusting the pH value of the solution to be 8-11 when the solution is alkaline;
(3) dissolving the residue obtained in the step (2) in ethyl acetate at the internal temperature of less than 40 ℃ in an inert gas atmosphere;
(4) maintaining the internal temperature to be less than 40 ℃, dripping n-heptane, and crystallizing at room temperature;
alternatively, seeding step (4) with a compound of formula (I).
2. The production process according to claim 1, wherein the post-treatment for the reaction in the presence of p-toluenesulfonic acid monohydrate and dichloromethane comprises the step (2), wherein the base is aqueous ammonia, and the pH of the solution is adjusted to be alkaline to 9 to 10.
3. The preparation method according to claim 1, wherein the post-treatment for the reaction in the presence of trifluoroacetic acid and water comprises the steps of:
(1) adding dichloromethane into the reaction solution, dropwise adding water and ammonia water until the pH value is more than 7, and layering;
(2) extracting the aqueous layer in the step (1) by using dichloromethane, combining the organic phases obtained in the steps (1) and (2), washing the combined organic phases by using a saturated sodium carbonate solution and a saturated salt solution in sequence, drying a drying agent, and concentrating under reduced pressure to obtain a crude product;
(3) dissolving the crude product obtained in the step (2) in ethyl acetate, keeping the internal temperature at 25-35 ℃, dropwise adding n-heptane, and crystallizing at room temperature;
alternatively, seeding step (3) with a compound of formula (I).
4. The production process according to claim 3, wherein the post-treatment for the reaction in the presence of trifluoroacetic acid and water comprises the step (2) wherein the drying agent is anhydrous sodium sulfate.
5. A process for the preparation of a compound of formula (II),
wherein, chloroform is used as a solvent, the mixture is heated and refluxed, and the compound of the formula (III) and the compound of the formula (IV) are reacted by Dean-Starks water separation; diluting the reaction liquid with 1, 2-dichloroethane, sequentially adding sodium triacetoxyborohydride and acetic acid under the atmosphere of inert gas, reacting at room temperature, and carrying out aftertreatment to obtain a compound of a formula (II);
wherein, in the formula (II) and the formula (III), P is an amino protecting group.
6. The method according to claim 5, characterized in that the post-processing comprises the steps of:
(1) adding water, layering, extracting, washing with water and an alkali solution, drying, filtering and concentrating;
(2) dissolving the concentrate in the step (1) in methanol under heating, dripping water under stirring at room temperature, and filtering;
(3) dissolving the filtrate in the step (2) in dichloromethane, layering, drying an organic layer, and separating by using a silica gel column chromatography;
(4) and (4) pulping the filtrate obtained in the step (3).
7. The method according to claim 6, wherein the post-treatment comprises the step (1) of treating the mixture with a base selected from the group consisting of ammonia;
and (3) dripping water twice in the step (2) of post-treatment, wherein the volume ratio of the methanol to the first dripping water to the second dripping water is 4:1: 4.
8. The method according to claim 6, wherein the pulping solvent in the step (4) is a mixed solvent of dichloromethane and petroleum ether.
9. The method of claim 8, wherein the volume ratio of dichloromethane to petroleum ether is 1: 2.
10. A process for the preparation of a compound of formula (III):
comprises the following steps:
(1) and carrying out reflux water-splitting reaction on the compound of the formula (V) and morpholine by taking toluene as a solvent, and carrying out aftertreatment to obtain a mixture of the compounds of the formula (VI-A) and the formula (VI-B):
(2) reacting N, N-dimethylacetamide, 4-dimethylaminopyridine, the mixture of the compounds of the formula (VI-A) and the formula (VI-B) obtained in the step (1) and a solution of S- (trifluoromethyl) dibenzothiophene trifluoromethylsulfonate in N, N-dimethylacetamide at a temperature of-10 ℃ to room temperature under anhydrous and oxygen-free conditions;
wherein, in formula (III), formula (V), formula (VI-A) and formula (VI-B), P is an amino protecting group; wherein the post-treatment in the step (1) comprises the following steps:
1) pulping the hot reaction solution with n-heptane;
2) filtering, and drying the solid to constant weight.
11. The method of claim 10, wherein step (2) further comprises the steps of:
1) keeping the temperature of the system to be lower than 20 ℃, dropwise adding ice water to the reaction solution, extracting by using ethyl acetate, and combining organic phases;
2) keeping the temperature of the system to be lower than 10 ℃, dropwise adding hydrochloric acid, and reacting at room temperature;
3) washing, drying and concentrating;
4) dissolving the obtained substance in the step 3) in dichloromethane, adding silica gel, concentrating under reduced pressure at the temperature of below 50 ℃ to form dry powder, and keeping the temperature until the configuration conversion end point;
5) desorbing, and concentrating to obtain a crude product;
6) refluxing and pulping the crude product by using normal hexane;
7) filtering, and drying the solid to constant weight.
12. A process for the preparation of a compound of formula (IV):
wherein, the compound shown in the formula (VII) reacts with a hydrochloric acid-ethyl acetate solution at-10 ℃;
wherein, in the formula (VII), P is an amino protecting group.
13. The method of claim 12, further comprising seeding the compound of formula (IV) with a crystallization.
14. A process for the preparation of compounds of formula (II-A) and formula (II-B),
wherein chloroform is used as a solvent, heating and refluxing are carried out, the compound of the formula (III) and the compound of the formula (IV) are subjected to Dean-Starks water separation reaction, and the compound of the formula (II-A) and the compound of the formula (II-B) are obtained by silica gel column chromatography separation;
wherein, in the formula (III), the formula (II-A) and the formula (II-B), P is an amino protecting group.
15. The process of any one of claims 1-14, wherein P is t-butyloxycarbonyl.
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| CN101410400A (en) * | 2006-03-28 | 2009-04-15 | 默克公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2014018350A1 (en) * | 2012-07-23 | 2014-01-30 | Merck Sharp & Dohme Corp. | Treating diabetes with dipeptidyl peptidase-iv inhibitors |
| WO2015192701A1 (en) * | 2014-06-17 | 2015-12-23 | 四川海思科制药有限公司 | Amino pyranoid ring derivative and composition and use thereof |
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| TW200806669A (en) * | 2006-03-28 | 2008-02-01 | Merck & Co Inc | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
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- 2017-05-25 WO PCT/CN2017/085867 patent/WO2017202357A1/en active Application Filing
- 2017-05-25 CN CN201780023946.1A patent/CN109071551B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101410400A (en) * | 2006-03-28 | 2009-04-15 | 默克公司 | Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes |
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2014018350A1 (en) * | 2012-07-23 | 2014-01-30 | Merck Sharp & Dohme Corp. | Treating diabetes with dipeptidyl peptidase-iv inhibitors |
| WO2015192701A1 (en) * | 2014-06-17 | 2015-12-23 | 四川海思科制药有限公司 | Amino pyranoid ring derivative and composition and use thereof |
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| CN109071551A (en) | 2018-12-21 |
| WO2017202357A1 (en) | 2017-11-30 |
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