CN109071551A - A kind of preparation method for the pyran derivate that trifluoromethyl replaces - Google Patents

A kind of preparation method for the pyran derivate that trifluoromethyl replaces Download PDF

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CN109071551A
CN109071551A CN201780023946.1A CN201780023946A CN109071551A CN 109071551 A CN109071551 A CN 109071551A CN 201780023946 A CN201780023946 A CN 201780023946A CN 109071551 A CN109071551 A CN 109071551A
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formula
compound
water
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preparation
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CN109071551B (en
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张晨
王健民
何平
黄龙彬
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A kind of preparation method of pyran derivate and its intermediate that trifluoromethyl replaces is provided, i.e. the preparation method of compound shown in formula (I) and its intermediate, this method reaction condition is mild, easy to operate, reaction yield is high, and product purity is high, convenient post-treatment is suitable for industrialized production

Description

A kind of preparation method for the pyran derivate that trifluoromethyl replaces Technical field
The invention belongs to chemical medicines, are related to the preparation of the pyran derivate of trifluoromethyl substitution.
Background technique
Glucagon-like peptide-1 (GLP-1) can be participated in body blood glucose steady-state adjustment by multiple approach, improve islet function, delay the progress for even reversing the diabetes B course of disease.But endogenous GLP-1 is quickly cracked by dipeptidyl peptidase 4 (DPP-4) after secretion is released into blood and is lost activity.DPP-4 inhibitor alternative inhibits the enzymatic activity of DPP-4, and GLP-1 is prevented to crack inactivation, improves the blood plasma level of activity GLP-1, enhances its physiological action, reduce HbA1, fasting blood-glucose and the level of postprandial blood sugar of type 2 diabetic patient.
WO2015192701 discloses novel DPP IV (DPP-4) inhibitor of one kind shown in formula (I), has good inhibiting effect to the enzymatic activity of DPP-4, has the potentiality for preventing, treating type-2 diabetes mellitus.
Formula (I) compound stability is good, and biological oral availability is high, convenient for the exploitation of preparation, has clinical value.Therefore, the research in this field to formula (I) compounds process for production thereof, has great importance.
Summary of the invention
The object of the present invention is to provide a kind of preparation method for the pyran derivate that trifluoromethyl replaces, i.e. the preparation method of compound shown in formula (I), this method reaction condition is mild, easy to operate, reaction yield is high, and product purity is high, convenient post-treatment is suitable for industrialized production.
Specifically, in the first aspect, the present invention relates to a kind of preparation methods of compound shown in formula (I):
Wherein, it by formula (II) compound under 20~25 DEG C, atmosphere of inert gases, is reacted with methylene chloride or in the presence of trifluoracetic acid is with water in p-methyl benzenesulfonic acid monohydrate, it is post-treated to obtain formula (I) compound；
Wherein, the P in formula (II) is amino protecting group, preferably tertbutyloxycarbonyl.
In certain embodiments, p-methyl benzenesulfonic acid monohydrate can be replaced with p-methyl benzenesulfonic acid.
In certain embodiments, p-methyl benzenesulfonic acid monohydrate is excess material, it is preferable that molar ratio 1:2.5~1:3 of formula (II) compound and p-methyl benzenesulfonic acid monohydrate, preferably 1:2.8.
In certain embodiments, trifluoracetic acid is excess material, it is preferable that formula (II) compound is 1:2.5~1:3.5 with trifluoroacetic mass volume ratio (w/v).
In certain embodiments, formula (II) chemical combination and methylene chloride mass volume ratio (w/v) are 1:8~1:15, preferably 1:10.
In certain embodiments, trifluoracetic acid and solvent water volume ratio are 2:1~4:1.
In certain embodiments, include the following steps: at p-methyl benzenesulfonic acid monohydrate with the post-processing reacted in the presence of methylene chloride
(1), water and methanol are sequentially added into reaction solution, are layered, the mixed extractant solvent of water layer methylene chloride and methanol；
(2), the alkali of organic phase obtained in (1) is adjusted into solution to alkalinity, organic layer is successively washed with saturated sodium carbonate solution and saturated common salt aqueous solution, dry, 40 DEG C or less reduced pressures；
(3), by the resulting residue of concentration in (2), temperature is dissolved in ethyl acetate less than in 40 DEG C, atmosphere of inert gases inside；
(4), temperature is added dropwise normal heptane, crystallizes at room temperature less than 40 DEG C in keeping；
Alternatively, in step (4) addition formula (I) compound crystal seed.
In certain embodiments, the methylene chloride volume ratio in water and reaction solution being added in step (1) is 0.8:1~1.2:1.
In certain embodiments, the volume ratio that water and methanol are sequentially added in step (1) is 9:1~12:1, extracts volume ratio 9:1~11:1 of the methylene chloride and methanol that use.
In certain embodiments, alkali used in step (2) is ammonium hydroxide, and the pH value for being adjusted to solution when alkalinity is 8~11, preferably 9~10.
In certain embodiments, ethyl acetate volume ratio is 1:1~4:1 in the normal heptane being added dropwise in step (4) and step (3).
In certain embodiments, it is comprised the following steps at trifluoracetic acid with the post-processing reacted in the presence of water:
(1), methylene chloride is added into reaction solution, water and ammonium hydroxide is added dropwise to pH > 7, layering；
(2), make that water layer in (1) is extracted with dichloromethane, merge organic phase obtained in (1) (2) step, combined organic phase is successively used into saturated sodium carbonate solution and saturated common salt water washing, desiccant dryness is concentrated under reduced pressure to give crude product；
(3), step (2) resulting crude product is dissolved in ethyl acetate, keeps interior 25~35 DEG C of temperature, normal heptane is added dropwise, crystallizes at room temperature；
Alternatively, in step (3) addition formula (I) compound crystal seed.
In certain embodiments, desiccant used in step (2) is anhydrous sodium sulfate.
In the second aspect, the present invention relates to the preparation methods of formula (II) compound, which is characterized in that
Wherein, solvent is made with chloroform, be heated to reflux, divide water to react by Dean-Starks formula (III) compound and formula (IV) compound；Reaction solution 1,2- dichloroethanes is diluted, under atmosphere of inert gases, sodium triacetoxy borohydride and acetic acid is sequentially added, reacts at room temperature, it is post-treated to obtain formula (II) compound；
Wherein, in formula (II) and formula (III), P is amino protecting group, preferably tertbutyloxycarbonyl.
In certain embodiments, the molar ratio of formula (III) compound and formula (IV) compound is 1:1.1~1:2.
In certain embodiments, the volume mass ratio of chloroform and formula (III) compound is 1.5:1~5:1, preferably 2:1.
In certain embodiments, reaction solution dilutes 1~20 times with 1,2- dichloroethanes, preferably dilutes 8~10 times.
In certain embodiments, formula (III) compound and sodium triacetoxy borohydride molar ratio are 1:2~1:5, preferably 1:3~1:4.
In certain embodiments, the molar ratio of acetic acid and formula (III) compound is 1:1~2.5:1.
In certain embodiments, the molar ratio of formula (III) compound and formula (IV) compound is 1:1.1~1:2, and the volume mass ratio of chloroform and formula (III) compound is 1.5:1~5:1, and reaction solution is with 1,2- dichloroethanes dilutes 1~20 times, preferably 8~10 times；Formula (III) compound and sodium triacetoxy borohydride molar ratio are 1:2~1:5, preferably 1:3~1:4, and the molar ratio of acetic acid and formula (III) compound is 1:1~2.5:1.
In certain embodiments, the post-processing includes the following steps:
(1), plus water, layering, extraction, water and aqueous slkali wash, and dry, filter concentration；
(2), the concentrate in (1) is dissolved in methanol under heating, lower dropwise addition water is stirred at room temperature, is filtered；
(3), filtrate in (2) is dissolved in methylene chloride, be layered, dry organic layer uses silica gel column layer The separation of analysis method；
(4), gained filtrate in (3) is beaten.
In certain embodiments, alkali described in step (1) is ammonium hydroxide.
In certain embodiments, water is added dropwise in two times under stirring in step (2), wherein water is added dropwise for the first time, the preferred 4:1:4 of water three volume ratio is added dropwise second for methanol.
In certain embodiments, it is methylene chloride and petroleum ether mixed solvent that step (4), which is beaten solvent for use, and preferably methylene chloride and petroleum ether volume ratio is 1:2.
In the third aspect, the invention further relates to a kind of preparation methods of formula (III) compound:
It comprises the following steps:
(1), using toluene as solvent, formula (V) compound is subjected to reflux water-dividing with morpholine and is reacted, the post-treated mixture for obtaining formula (VI-A) and formula (VI-B) compound:
(2), at -10 DEG C at room temperature, under the conditions of anhydrous and oxygen-free, by N, the n,N-dimethylacetamide solution reaction of the mixture of gained formula (VI-A) and formula (VI-B) compound and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid in N- dimethyl acetamide, 4-dimethylaminopyridine, step (1)；
Wherein, in formula (V), formula (VI-A) and formula (VI-B), P is amino protecting group, preferably tertbutyloxycarbonyl.
In certain embodiments, formula (V) compound and morpholine molar ratio are 1:1.2~1:5, preferably 1:1.5.
In certain embodiments, the mixture and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid molar ratio of formula (VI-A) and formula (VI-B) compound are 1:1~1:1.5.
In certain embodiments, the molar ratio of the mixture and 4-dimethylaminopyridine of formula (VI-A) and formula (VI-B) compound is 1:0.1~1:1.5, preferably 1:1~1:1.2.
In certain embodiments, the mixture of formula (VI-A) and formula (VI-B) compound with react in the mass volume ratio of total n,N-dimethylacetamide be 1:5~1:20, preferably 1:8~1:15.
In certain embodiments, formula (V) compound and morpholine molar ratio are 1:1.2~1:5, preferably 1:1.5, The mixture of formula (VI-A) and formula (VI-B) compound and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid molar ratio are 1:1~1:1.5, and the molar ratio of the mixture and 4-dimethylaminopyridine of formula (VI-A) and formula (VI-B) compound is the preferred 1:1 of 1:0.1~1:1.5；The mixture of formula (VI-A) and formula (VI-B) compound with react in the mass volume ratio of total n,N-dimethylacetamide be 1:5~1:20, preferably 1:8~1:15.
In certain embodiments, post-processes and include the following steps: described in the preparation method step (1) of formula (III) compound
(1), reaction solution is beaten with normal heptane while hot；
(2), it filters, solid is dry to constant weight.
In certain embodiments, the preparation method step (2) of formula (III) compound further comprises following steps:
(1), it keeps system temperature to be lower than 20 DEG C, ice water is added dropwise to reaction solution, makes to be extracted with ethyl acetate, merges organic phase；
(2), it keeps system temperature to be lower than 10 DEG C, hydrochloric acid is added dropwise, reacts at room temperature；
(3), it washs, is dry, concentration；
(4), gains in (3) are dissolved in methylene chloride, silica gel is added, 50 DEG C or less are concentrated under reduced pressure into dry powder-shaped, and temperature to configuration is kept to convert terminal；
(5), De contamination, concentration, obtains crude product；
(6), crude product is flowed back with n-hexane and is beaten；
(7), it filters, solid is dry to constant weight.
In certain embodiments, the hydrochloric acid molar ratio of the mixture and dropwise addition of step (2) Chinese style (VI-A) and formula (VI-B) compound is 1:3~1:5.
In certain embodiments, the mass ratio of the mixture and silica gel of step (4) Chinese style (VI-A) and formula (VI-B) compound is 1:1.5~1:5.
In the fourth aspect, the invention further relates to a kind of preparation methods of formula (IV) compound:
It include: at -10~10 DEG C, by formula (VII) compound and hydrochloric acid-ethyl acetate solution reaction；
Wherein, the P in formula (VII) is amino protecting group, preferably tertbutyloxycarbonyl.
In certain embodiments, hydrochloric acid-ethyl acetate solution is now to prepare current, is formed by instilling chloroacetic chloride in the mixed liquor of ethyl acetate and ethyl alcohol, preferred concentration is 4mol/L hydrochloric acid-ethyl acetate solution.
In certain embodiments, formula (VII) compound and the mass volume ratio of hydrochloric acid-ethyl acetate solution are 1:3.5~1:8.
In certain embodiments, the preparation method of formula (IV) compound further comprises addition formula (IV) compound seeded crystallization.
At the 5th aspect, the present invention provides the compound of formula (III-A) as follows, formula (III-B), formula (II-A), formula (II-B):
Wherein, P is amino protecting group, preferably tertbutyloxycarbonyl.
At the 6th aspect, the present invention relates to the method for preparation formula (III-A) and formula (III-B) compound,
It include: at -10 DEG C at room temperature, under the conditions of anhydrous and oxygen-free, by N, N- dimethyl acetamide, 4-dimethylaminopyridine, the mixture of formula (VI-A) and formula (VI-B) compound and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid N, N- dimethylacetamide solution reaction, through the isolated formula of silica gel column chromatography (III-A) and formula (III-B) compound；
Wherein, in formula (VI-A), (VI-B), (III-A) and (III-B), P is amino protecting group, It is preferred that tertbutyloxycarbonyl.
In certain embodiments, formula (VI-A) and formula (VI-B) molar ratio in the mixture of formula (VI-A) and formula (VI-B) compound are 3:1~12:1.
In certain embodiments, the mixture and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid molar ratio of formula (VI-A) and formula (VI-B) compound are 1:1~1:2.
At the 7th aspect, the present invention relates to the method for preparation formula (II-A) and formula (II-B) compound,
It include: that solvent is made with chloroform, it is heated to reflux, water is divided to react by Dean-Starks formula (III) compound and formula (IV) compound, through the isolated formula of silica gel column chromatography (II-A) and formula (II-B) compound；
Wherein, in formula (III), formula (II-A) and formula (II-B), P is amino protecting group, preferably tertbutyloxycarbonyl.
In certain embodiments, the molar ratio of formula (III) compound and formula (IV) compound is 1:1.1~1:2.
Formula (III) compound of the present invention is diastereoisomer, includes the following two kinds structure:
In formula (III) preparation of compounds, diastereoisomer is by being adsorbed on silica gel, it is concentrated under reduced pressure into dry powder-shaped at 50 DEG C or less, keeps 50 DEG C of temperature below that Partial Conversion of the configuration (III-1) to configuration (III-2) may be implemented.
" configuration conversion terminal " of the present invention refers to1H NMR (solvent DMSO-d6) (δ) is displaced in H (δ 5.2) and H (δ 4.4) peak area ratio > 2:1.Due to1HNMR instrument is different, and the control of experiment condition is different,1The movement that H NMR displacement (δ) allows to have certain.
Heretofore described " water is divided to react " refers to divides water to react with what Dean-Starks water segregator carried out.
Separation method used in the present invention is chemical this field routinely common separation method, such as silica gel column chromatography, high performance liquid chromatography, thin-layered chromatography.
" optionally " or " alternatively ", it is meant that event or environment described later can with but It need not occur, the occasion for occurring or not occurring including the event or environment.
Reaction process of the present invention by HPLC,1HNMR or thin-layered chromatography track reaction process, judge whether reaction terminates.
In the present invention, inert gas refers to the gas for being not involved in reaction, such as nitrogen.
In the present invention, the interior temperature indicates temperature of reaction system.
Present invention optimizes the techniques of formula (II) compound of formula (I) compound, in the prior art using trifluoroacetic acid and methylene chloride reaction system, post-processing should not control, and concentration trifluoroacetic acid has an impact to product stability, and by-product increases as inventory increases.The shortcomings that present invention uses p-methyl benzenesulfonic acid monohydrate and methylene chloride reaction system or the reaction system using trifluoroacetic acid and water, and catabolite significantly increases when avoiding post-processing.Meanwhile the reaction system of trifluoroacetic acid and water, reduce the usage amount of trifluoroacetic acid, the use of organic solvent is reduced, to more environment-friendly.
Condensation reaction occurs present invention optimizes formula (III) intermediate and formula (IV) intermediate and obtains the technique of formula (II) compound, make solvent using chloroform, using reflux water-dividing method, avoid the non routine operation of solvent evaporated under the conditions of toluene in the prior art, reaction condition is more mild, react more thorough, entire reaction yield improves.Simultaneous reactions condition is suitble to amplify, and meets industrialized production.Although way of purification still has column chromatography, chromatographed using Flash silica column, silica gel usage amount greatly reduces, and quickly.Meanwhile the method for using solvent evaporated toluene in the prior art, reaction temperature is high, and concentration changes greatly, it is not easy to control product, also be not easy to monitoring reaction process.And chloroform reflux water-dividing mode is used, reaction can preferably monitoring process.
Present invention optimizes the methods by formula (V) preparation of compounds of formula (III) compound, save the separation of intermediate (VI-A) and (VI-B), simultaneously using the method purifying of mashing, avoid column chromatography method separation, it is more suitable for industrialized production, configuration conversion occurs by silica gel absorption, also substantially increases the yield of formula (III).
The present invention is more suitable for industrialized production using conventional shirtsleeve operation step by optimizing the post-processing of each reaction step.Reaction yield improves, operating process and product is easily controllable and monitoring, and environmental-friendly.
Detailed description of the invention
Fig. 1 is compound 21HNMR map.
Fig. 2 is compound 21H-1H NOESY map.
Fig. 3 is compound 21H-1H COSY map.
Fig. 4 is compound 6-b1H-1H NOESY map.
Fig. 5 is compound 7-a1H-1H NOESY map.
Fig. 6 is compound 7-a1H-1H COSY map.
Fig. 7 is compound 7-b1H-1H NOESY map.
Fig. 8 is compound 7-b1H-1H COSY map.
Specific embodiment
Below by way of the beneficial effect of the specific embodiment implementation process that the present invention will be described in detail and generation, it is intended to help reader to more fully understand essence and feature of the invention, not limit the scope of the present invention.
The structure of compound be by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) come what is determined, two-dimentional hydrogen same core displacement Correlated Spectroscopy (1H-1H COSY), two-dimensional nucleus Ao Fuhaoze enhancing spectrum (1H-1H NOESY) it is used for the analysis of stereoisomer.NMR is displaced (δ) with 10-6(ppm) unit provides.The measurement of NMR is to use (Bruker Avance III 400) nuclear magnetic resonance spectrometer, and measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), deuterated acetone is inside designated as tetramethylsilane (TMS), is designated as 85% phosphate aqueous solution outside.
(Agilent 6120B (ESI) and Agilent 6120B (APCI)) is used in the measurement of MS.
The measurement of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100 × 4.6mm).
Known starting material of the invention can be used or be synthesized according to methods known in the art, or be can purchase in safe smooth science and technology, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is 20 DEG C~30 DEG C.
Boc is t-butyloxycarbonyl.
Embodiment 1:
N- [(2R, 3S) (2-2-, 5- difluorophenyl)-5- morpholinyl-3,4- dihydro-2H- pyrans-3- base] carbamate (compound 1-a) and N- [(2R, 3S) (2-2-, 5- difluorophenyl)-5- morpholinyl-3,6- dihydro-2H- pyrans-3- base] carbamate (compound 1-b)
Compound 1a (1.0kg, 3.06mol) is added in the 5L round-bottomed flask of (3L) containing toluene, is warming up to 80 DEG C, morpholine (400g) is slowly added dropwise.It is added dropwise, is heated to flowing back, Dean-Stark divides water to react 3.5 hours.Reaction solution is pumped into the 20L round-bottomed flask containing normal heptane (15L) while hot, mashing 1.5 hours, it is down to room temperature, filtering, filter cake washed once with normal heptane (5L), collect solid, 50 DEG C of forced air dryings are to constant weight, obtain compound 1-a and compound 1-b mixture (peak area ratio is 90:8 (HPLC (265nm)), 1.13kg, yield 93%).
Embodiment 2
N- [(2R, 3S) -2- (2,5- difluorophenyl) -5- carbonyl -6- (trifluoromethyl) tetrahydropyran -3-base] carbamate (compound 2)
In 100L reaction kettle; under nitrogen protection; by compound 1-a obtained in embodiment 1 and compound 1-b mixture (1kg; 2.53mol) it is added to N; in N- dimethyl acetamide (10L), 4-dimethylaminopyridine (296g, 2.53mmol) is added under stirring; it is cooled to -10 DEG C, as A liquid.By S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid (1.22kg; 3.04mol) and N; N- dimethyl acetamide (2L) is added in 5L flask; it stirs to clarify; under the conditions of anhydrous and oxygen-free nitrogen protection; slightly below -10 DEG C of temperature, are added dropwise in A liquid, are added dropwise within about 30 minutes in keeping.It is maintained at -10 DEG C and reacts 5 hours, rise to 10~20 DEG C and stand 16 hours.It is cooled to 0 DEG C, ice water (36L) is added in Xiang Shangshu reaction solution, control is added speed and temperature is kept to be lower than 20 DEG C.With ethyl acetate (20L and 10L are each primary) extraction, merges organic phase, be cooled to 0 DEG C, addition is cooled to 0 DEG C of hydrochloric acid (10L, 1mol/L), and control temperature is lower than 10 DEG C in adition process.It finishes, rises to 10-20 DEG C and be stirred to react 1 hour.Reaction solution is successively washed with water (10L × 2), saturated sodium chloride solution (10L), and anhydrous sodium sulfate (500g) is dry, is concentrated to dryness to obtain crude product at 45 DEG C.Crude product is dissolved with methylene chloride (10L), silica gel (2kg) is added after clarification, it is concentrated under reduced pressure into dry powder-shaped under rotary evaporating device with 20L single port bottle, continues to be placed in 5 hours (bath temperature is 50 DEG C) to configurations of decompression rotary drying under rotary evaporating device and converts terminal.By the solid after drying, stirring 30 minutes, sand core funnel filtering, methylene chloride (15L) decompression elute silica gel in methylene chloride (10L).Filtrate is concentrated to dryness at 40 DEG C.Residue is added in n-hexane (20L), is heated to reflux mashing 30 minutes, 50 DEG C or less stopping stirrings being cooled to, is down to 10-25 DEG C naturally, stands 16 hours, filtering, n-hexane (10L) decompression Elution, it is dried under reduced pressure at 40 DEG C to constant weight, obtain white solid N- [(2R, 3S) (2-2-, 5- difluorophenyl)-5- carbonyl-6- (trifluoromethyl) tetrahydropyran -3-base] carbamate (compound 2) (609g, yield 61%, HPLC(isomers merges total purity): 95.7%, dr (diastereoisomer value): 82:18 (2-2:2-1 is detected by HPLC (210nm))).
Compound 2 is the mixture of two kinds of stereoisomers, and the structure for including is as follows:
Using deuterated acetone as solvent, compound 21HNMR is shown in attached drawing 1,1H-1H NOESY map is shown in attached drawing 2,1H-1H COSY map is shown in attached drawing 3.
Embodiment 3
2- mesyl -5,6- dihydro -4H- pyrrolo- [3,4-c] pyrazoles (compound 3)
By ethyl acetate (3100mL) and ethyl alcohol (985g, 21.42mol) it is added in 10L round-bottomed flask, it is cooled to -5 DEG C or so, stirring is lower to instill chloroacetic chloride (1.6kg, 20.8mol) and temperature control is between -10 to 0 DEG C, it finishes, is warming up to 10~20 DEG C and reacts 30 minutes.Reaction system is cooled to -10 DEG C; it is added with stirring 2- (methyl sulphonyl) -4; 6- pyrrolin simultaneously [3; 4-c] pyrazoles -5 (2H)-t-butyl formate (3a) (1kg, 3.48mol), there is faint yellow solid generation in the process; it finishes; natural temperature reaction, 1.5 hours temperature of reaction system rise to 5~10 DEG C, TLC monitoring display fully reacting.Reaction solution is cooled to -10 DEG C, is filtered under diminished pressure, filter cake is washed with ethyl acetate (2L).Filter cake is added in methylene chloride (5L), the mixed solution of ammonium hydroxide (1L) and water (1L), stratification are added with stirring.Water layer is extracted with methylene chloride (4L × 4), merges organic layer, and anhydrous sodium sulfate is dry, and Rotary Evaporators, which are concentrated under reduced pressure, to be done, and obtains yellow oily crude product.Methylene chloride (1.2L) is added into crude product; stirring is all dissolved to crude product; it then proceedes to be added with stirring petroleum ether (600mL); 2- mesyl -5 is added; 6- dihydro -4H- pyrrolo- [3; 4-c] pyrazoles crystal seed (3g); wait which a large amount of solids are precipitated; it is added petroleum ether (5.4L), stirring and crystallizing 2 hours or so, is filtered under diminished pressure; filter cake is washed using petroleum ether (2L); 30 DEG C are dried in vacuo 3~4 hours, obtain class white-yellowish solid 2- mesyl -5,6- dihydro -4H- pyrrolo- [3,4-c] pyrazoles (compound 3) (592g, yield 90.9%).
MS m/z(ESI):188.2[M+1]；
1H NMR(400MHz,CD3OD)δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)；
HPLC purity: 99.09% (230nm).
Embodiment 4
N- [(2R; 3S; 5R; 6S) (2-2-; 5- difluorophenyl)-5- (2- methyl sulphonyl-4; 6- pyrrolin simultaneously [3,4-c] pyrazoles-5- base)-6- (trifluoromethyl) tetrahydropyran -3-base] carbamate (compound 4)
Under stirring, successively compound 3 (142.0g, 0.7595mol) and compound 2 (200.0g, 0.5063mol) are added in the reaction flask equipped with chloroform (400mL), heating stirring reflux, Dean-Starks divide water to react 5 hours.Reaction terminates to stop heating, and after reaction solution stops boiling, reaction solution is transferred in 5L there-necked flask, and 1,2- dichloroethanes (1.6L) dilute reaction solution is added.Under nitrogen atmosphere, reaction system stirring is cooled to 5~15 DEG C, sequentially adds sodium triacetoxy borohydride (375.6g, 1.7721mol) and acetic acid (46.33mL, 0.8100mol), finishes, be warming up to 20~35 DEG C, reacted 5 hours.Reaction terminates, it is slowly added to water (1.2L), stirring 5 minutes, stratification, water layer is extracted with methylene chloride (400mL x 2), is merged organic phase, is washed organic phase with the mixed solution of water (600mL) and ammonium hydroxide (100mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure.In 5L there-necked flask, resulting residue heating (not higher than 50 DEG C) will be concentrated to be dissolved in methanol (1.6L), stirring drops to room temperature, is added dropwise water (400mL), it finishes and continues stirring 30 minutes, this has solid precipitation in the process.Water (1.6L) is added dropwise under stirring again, is added dropwise and continues stirring 30 minutes, filtering obtains faint yellow wet shape solid.The solid is dissolved in methylene chloride (2~3L), layering, organic phase is dry with anhydrous sodium sulfate, organic phase is directly depressurized by the sand core funnel containing 600g silica gel and is filtered, then organic solvent eluting silica gel (petrol ether/ethyl acetate (v/v)=3:2 is used, 5-7L), chromatographic solution is concentrated to get crude product.Crude product is dissolved in methylene chloride (1.4L) under heating condition (being not higher than 45 DEG C), dissolution is complete, it is cooled to 20~30 DEG C, petroleum ether (2.8L) is added in 3~8 minutes under stirring, there is white solid precipitation in the process, it finishes, solid is obtained by filtration immediately.Under the conditions of 10~35 DEG C, methylene chloride (720mL) is added in its solid, is stirred 1 hour, is added petroleum ether (1.8L), continues stirring 2 hours at room temperature.Filtering, obtains white solid N- [(2R, 3S, 5R, 6S) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4,6- Pyrrolin simultaneously [3,4-c] pyrazoles -5- base) -6- (trifluoromethyl) tetrahydropyran -3-base] carbamate (compound 4) (201g, yield 70%, dr > 99.95:0.05).
1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.36–7.08(m,4H),4.88-4.74(m,1H),4.69(d,1H),3.95(t,2H),3.89–3.83(m,1H),3.82–3.70(m,2H),3.55-3.43(m,4H),2.33-2.18(m,1H),2.17-2.00(m,1H),1.27-1.14(m,9H)；
MS m/z(ESI):567.1[M+1]；
HPLC purity: 98.9% (265nm).
Embodiment 5
(2R, 3S, 5R; 6S) (2-2-; 5- difluorophenyl)-5- (2- (methyl sulphonyl)-4,6- pyrrolin simultaneously [3,4-c] pyrazoles-5- base)-6- (trifluoromethyl) oxinane-3- amine (compound 5)
It, will be in p-methyl benzenesulfonic acid monohydrate (752.3g, 3.958mol) adding into dichloromethane (8L) in 50L reaction kettle, under nitrogen atmosphere, it is added compound 4 (800g, 1.413mol), is stirred to react 4~5 hours at 20~25 DEG C.Reaction terminates, and sequentially adds water (8.5L), methanol (800mL), stirs 10 minutes.Layering, water layer with the mixed extractant solvent of methylene chloride (8L) and methanol (800mL) three times.Merge organic phase, water (8L) is added and ammonium hydroxide (1.5L) stirs 10 minutes, layering, organic phase is successively washed with saturated sodium carbonate solution (8~10L) and saturated salt solution (8~10L), anhydrous sodium sulfate is dry, is concentrated under reduced pressure to give crude product in 35 DEG C.Under nitrogen atmosphere, crude product is dissolved in ethyl acetate (3.5L) by interior temperature control system at 30~35 DEG C.Temperature is at 25~35 DEG C in keeping, stirring is lower to be added dropwise normal heptane (2.5L), (2R is added, 3S, 5R, 6S) (2-2-, 5- difluorophenyl) -5- (2- (methyl sulphonyl) -4, 6- pyrrolin simultaneously [3, 4-c] pyrazoles -5- base) -6- (trifluoromethyl) oxinane -3- amine crystal seed (8g), continue that normal heptane (4.5L) is added dropwise, it finishes, continue stirring 2 hours at room temperature, filtering, obtain white solid (2R, 3S, 5R, 6S) (2-2-, 5- difluorophenyl) -5- (2- (methyl sulphonyl) -4, 6- pyrrolin simultaneously [3, 4-c] pyrazoles -5- base) -6- (trifluoromethyl) oxinane -3- amine (compound 5) (508g, yield: 77.1%).
1H NMR(400MHz,DMSO-d6)δ7.96(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% (267nm).
Embodiment 6
N- [(2R, 3S, 6S) (2-2-, 5- difluorophenyl)-5- morpholinyl 6- (trifluoromethyl)-3,6- dihydro-2H- pyrans-3- base) t-butyl carbamate (compound 6-a) and N- [(2R, 3S, 6R)-2- (2,5- difluorophenyl)-5- morpholinyl 6- (trifluoromethyl)-3,6- dihydro-2H- pyrans-3- base) t-butyl carbamate (compound 6-b)
In 250mL reaction flask; under nitrogen protection; by the mixture (5.0g of compound 1-a and 1-b obtained in embodiment 1; 12.63mmol) it is added to N; in N- dimethyl acetamide (25mL), 4-dimethylaminopyridine (1.85g, 15.15mmol) is added under stirring; it is cooled to -10 DEG C, as A liquid.By S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid (6.10g; 15.15mmol) and N; N- dimethyl acetamide (15mL) is added in 25mL flask; it stirs to clarify; under the conditions of anhydrous and oxygen-free nitrogen protection; slightly below -10 DEG C of temperature, are added dropwise in A liquid, are added dropwise within about 30 minutes in keeping.It is maintained at -10 DEG C and reacts 5 hours, rise to 10~20 DEG C and stand 16 hours.It is cooled to 0 DEG C, ice water (50mL) is added in Xiang Shangshu reaction solution, speed is added in control, and temperature is kept to be lower than 20 DEG C.With ethyl acetate (100mL and 50mL are each primary) extraction, merges organic phase, washed once using saturated sodium-chloride water solution (300mL), concentration dry using anhydrous sodium sulfate.Residue uses column chromatography purifying (silica gel 100g, eluant, eluent: petrol ether/ethyl acetate (v/v)=7:1-3:1), obtain white solid N- [(2R, 3S, 6S) (2-2-, 5- difluorophenyl) -5- morpholinyl 6- (trifluoromethyl) -3, 6- dihydro -2H- pyrans -3- base) t-butyl carbamate (compound 6-a) (2.1g, yield 38%) and N- [(2R, 3S, 6R) (2-2-, 5- difluorophenyl) -5- morpholinyl 6- (trifluoromethyl) -3, 6- dihydro -2H- pyrans -3- base) t-butyl carbamate (compound 6-b) (1.0g, yield 18%).
Compound 6-a:
1H NMR(400MHz,DMSO-d6)δ7.32-7.08(m,4H),5.41-5.31(m,1H),4.95(s,1H),4.72(d,1H),4.48-4.34(m,1H),3.66–3.52(m,4H),3.10–2.97(m,2H),2.69–2.55(m,2H),1.27–1.21(m,9H)。
Compound 6-b:
1H NMR(400MHz,DMSO-d6)δ7.31–7.12(m,3H),7.08(d,1H), 5.51-5.35(m,1H),5.04(s,1H),4.51(d,1H),4.45-4.33(m,1H),3.72-3.51(m,4H),3.02-2.85(m,2H),2.65–2.53(m,2H),1.27–1.08(m,9H)。
With DMSO-d6For solvent, compound 6-b's1H-1H NOESY map is shown in attached drawing 4.
Embodiment 7
N- [(2R; 3S; 6S) (2-2-; 5- difluorophenyl)-5- (2- mesyl-4; 6- pyrrolin [3; 4-c] pyrazoles-5- base)-6- (trifluoromethyl)-3; 6- dihydro-2H- pyrans-3- base) t-butyl carbamate (compound 7-a) and N- [(2R; 3S; 6R)-2- (2,5- difluorophenyl)-5- (2- mesyl-4,6- pyrrolin [3; 4-c] pyrazoles-5- base)-6- (trifluoromethyl)-3,6- dihydro-2H- pyrans-3- base) t-butyl carbamate (compound 7-b)
Under stirring, successively compound 2 (5.0g, 12.66mmol) and compound 3 (3.55g, 18.99mmol) are added in the reaction flask equipped with chloroform (10mL), heating stirring reflux, Dean-Starks divide water to react 5 hours.Reaction terminates, and stops heating, concentration.Residue column chromatographic isolation and purification (silica gel 80g, eluant, eluent: petrol ether/ethyl acetate (v/v)=4:1-3:1), respectively obtain white solid N- [(2R, 3S, 6S) (2-2-, 5- difluorophenyl) -5- (2- mesyl -4, 6- pyrrolin [3, 4-c] pyrazoles -5- base) -6- (trifluoromethyl) -3, 6- dihydro -2H- pyrans -3- base) t-butyl carbamate (compound 7-a) (6.0g, yield 85%) and white solid N- [(2R, 3S, 6R) (2-2-, 5- difluorophenyl) -5- (2- mesyl -4, 6- pyrrolin [3, 4-c] pyrazoles -5- base) -6- (trifluoromethyl) -3, 6- dihydro -2H- pyrans -3- base) T-butyl carbamate (compound 7-b) (0.4g, yield 5.6%).
Compound 7-a:
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.37-7.08(m,4H),5.40(q,1H),5.00-4.90(m,1H),4.86(d,1H),4.53(t,1H),4.36(t,2H),4.11–3.96(m,2H),3.52(s,3H),1.33-1.07(m,9H)。
MS m/z(ESI):565.1[M+1]。
With DMSO-d6For solvent, compound 7-a's1H-1H NOESY map is shown in attached drawing 5.
With DMSO-d6For solvent, compound 7-a's1H-1H COSY map is shown in attached drawing 6.
Compound 7-b:
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.31–7.10(m,4H),5.49(q,1H),4.99-4.84(m,1H),4.52-4.36(m,2H),4.34–4.19(m,4H),3.52(s,3H),1.27–1.15(m,9H)。
MS m/z(ESI):565.1[M+1]。
With DMSO-d6For solvent, compound 7-b's1H-1H NOESY map is shown in attached drawing 7.
With DMSO-d6For solvent, compound 7-b's1H-1H COSY map is shown in attached drawing 8.
Embodiment 8
2- mesyl -5,6- dihydro -4H- pyrrolo- [3,4-c] pyrazoles (3 crystal seed of compound)
Ethyl acetate (3100mL) and ethyl alcohol (985g, 21.42mol) are added in reaction flask, are cooled to -5 DEG C or so, it instills chloroacetic chloride (1.6kg, 20.8mol), keeps temperature -10 to 0 DEG C, it adds and removes cooling, be warming up to 10-20 DEG C and react 30 minutes.Reaction solution is cooled to -10 DEG C or so, is added compound 3a (1kg, 3.48mol), is had faint yellow solid generation in the process, add and remove cooling device, natural temperature reaction, 5-10 DEG C of temperature of reaction system after 90 minutes, TLC monitoring fully reacting.Reaction solution is cooled to -10 DEG C or so, is filtered under diminished pressure, filter cake washed once with ethyl acetate (2L).Filter cake is added in methylene chloride (5L), the mixed solution of ammonium hydroxide (1L) and water (1L) is added with stirring, water layer is extracted with methylene chloride (4L × 4), organic layer merges, anhydrous sodium sulfate is dry, is filtered under diminished pressure, is concentrated to dryness.Methylene chloride (1.2L) stirring and dissolving is added in concentrate; then stirring is lower is added dropwise petroleum ether (6L); solid is gradually precipitated, adds stirring and crystallizing 2 hours or so, is filtered under diminished pressure; filter cake is washed with petroleum ether (2L); 30 DEG C vacuum drying 3-4 hours, obtain class white-yellowish solid 2- mesyl -5,6- dihydro -4H- pyrrolo- [3; 4-c] pyrazoles (3 crystal seed of compound) (592g, yield 90.9%).
MS m/z(ESI):188.2[M+1]；
1H NMR(400MHz,CD3OD)δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)；
HPLC purity: 99.09% (230nm).
Embodiment 9
(2R, 3S, 5R; 6S) (2-2-; 5- difluorophenyl)-5- (2- (methyl sulphonyl)-4,6- pyrrolin simultaneously [3,4-c] pyrazoles-5- base)-6- (trifluoromethyl) oxinane-3- amine (5 crystal seed of compound)
It, will be in p-methyl benzenesulfonic acid monohydrate (752.3g, 3.958mol) adding into dichloromethane (8L) in 50L reaction kettle, under nitrogen atmosphere, it is added compound 4 (800g, 1.413mol), is stirred to react 4~5 hours at 20~25 DEG C.Reaction terminates, and sequentially adds water (8.5L), methanol (800mL), stirs 10 minutes.Layering, water layer with the mixed extractant solvent of methylene chloride (8L) and methanol (800mL) three times.Merge organic phase, water (8L) is added and ammonium hydroxide (1.5L) stirs 10 minutes, layering, organic phase is successively washed with saturated sodium carbonate solution (8~10L) and saturated salt solution (8~10L), anhydrous sodium sulfate is dry, is concentrated under reduced pressure to give crude product in 35 DEG C.Under nitrogen atmosphere, crude product is dissolved in ethyl acetate (3.5L) by interior temperature control system at 30~35 DEG C.Temperature is added dropwise normal heptane (7L) under stirring, finishes at 25~35 DEG C in keeping; continue stirring 2 hours at room temperature; filtering, obtains white solid (2R, 3S; 5R; 6S) -2- (2,5- difluorophenyl) -5- (2- (methyl sulphonyl) -4,6- pyrrolin simultaneously [3; 4-c] pyrazoles -5- base) -6- (trifluoromethyl) oxinane -3- amine (5 crystal seed of compound) (504g, yield: 76.5%).
HPLC purity: 99.14% (267nm).
Embodiment 10
(2R, 3S, 5R; 6S) (2-2-; 5- difluorophenyl)-5- (2- (methyl sulphonyl)-4,6- pyrrolin simultaneously [3,4-c] pyrazoles-5- base)-6- (trifluoromethyl) oxinane-3- amine (compound 5)
In 5L there-necked flask, trifluoroacetic acid (442mL) is added in water (177mL), is cooled to 5~10 DEG C.Under nitrogen atmosphere, compound 4 (200g, 0.353mol) is added under stirring, maintains the temperature at 5~15 DEG C, adds trifluoroacetic acid (100mL).15~25 DEG C are maintained the temperature to be stirred to react 4~5 hours.Reaction terminates, and methylene chloride (1.6L) is added under stirring, is not higher than at a temperature of 25 DEG C, is successively added dropwise to water (200mL), ammonium hydroxide (730mL).Stop stirring and being layered, water layer is extracted with methylene chloride (300mL x 2).Merge organic phase, successively washed with saturated sodium carbonate solution (800~1000mL) and saturated salt solution (800~1000mL), anhydrous sodium sulfate is dry, is concentrated under reduced pressure to give crude product in 35 DEG C.Under nitrogen atmosphere, crude product is dissolved in ethyl acetate (900mL) by interior temperature control system at 30~35 DEG C.Temperature is added dropwise normal heptane (650mL) under stirring, (2R is added at 25~35 DEG C in keeping; 3S, 5R, 6S) -2- (2; 5- difluorophenyl) -5- (2- (methyl sulphonyl) -4,6- pyrrolin simultaneously [3,4-c] pyrrole Azoles -5- base) -6- (trifluoromethyl) oxinane -3- amine (5 crystal seed of compound) (2g); continue that normal heptane (1150mL) is added dropwise; it finishes; continue stirring 2 hours at room temperature; filtering; obtain white solid (2R; 3S; 5R; 6S) -2- (2,5- difluorophenyl) -5- (2- (methyl sulphonyl) -4,6- pyrrolin simultaneously [3; 4-c] pyrazoles -5- base) -6- (trifluoromethyl) oxinane -3- amine (compound 5) (140g, yield: 85.0%).
HPLC purity: 99.56% (267nm).
1H NMR(400MHz,DMSO-d6)δ7.96(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 kind of preparation method of formula (I) compound,
    It is characterized in that, reacted with methylene chloride or in the presence of trifluoracetic acid is with water by formula (II) compound under 20~25 DEG C, atmosphere of inert gases in p-methyl benzenesulfonic acid monohydrate, it is post-treated to obtain formula (I) compound；
    Wherein, the P in formula (II) is amino protecting group.
  2. Preparation method according to claim 1, wherein being comprised the following steps at p-methyl benzenesulfonic acid monohydrate with the post-processing reacted in the presence of methylene chloride:
    (1), water and methanol are sequentially added into reaction solution, are layered, the mixed extractant solvent of water layer methylene chloride and methanol；
    (2), the alkali of organic phase obtained in (1) is adjusted into solution to alkalinity, organic layer is successively washed with saturated sodium carbonate solution and saturated common salt aqueous solution, dry, 40 DEG C or less reduced pressures；Preferably, the alkali is ammonium hydroxide, and the pH value for being adjusted to solution when alkalinity is 8~11, preferably 9~10；
    (3), by the resulting residue of concentration in (2), temperature is dissolved in ethyl acetate less than in 40 DEG C, atmosphere of inert gases inside；
    (4), temperature is added dropwise normal heptane, crystallizes at room temperature less than 40 DEG C in keeping；
    Alternatively, in step (4) addition formula (I) compound crystal seed.
  3. According to preparation method described in claim 1, wherein including the following steps: at trifluoracetic acid with the post-processing reacted in the presence of water
    (1), methylene chloride is added into reaction solution, water and ammonium hydroxide is added dropwise to pH > 7, layering；
    (2), make that water layer in (1) is extracted with dichloromethane, merge organic phase obtained in (1) (2) step, combined organic phase is successively used into saturated sodium carbonate solution and saturated common salt water washing, desiccant dryness is concentrated under reduced pressure to give crude product；Preferably, the desiccant is anhydrous sodium sulfate；
    (3), step (2) resulting crude product is dissolved in ethyl acetate, keeps interior 25~35 DEG C of temperature, normal heptane is added dropwise, crystallizes at room temperature；
    Alternatively, in step (3) addition formula (I) compound crystal seed.
  4. A kind of preparation method of formula (II) compound, which is characterized in that
    Wherein, solvent is made with chloroform, be heated to reflux, divide water to react by Dean-Starks formula (III) compound and formula (IV) compound；Reaction solution 1,2- dichloroethanes is diluted, under atmosphere of inert gases, sodium triacetoxy borohydride and acetic acid is sequentially added, reacts at room temperature, it is post-treated to obtain formula (II) compound；
    Wherein, in formula (II) and formula (III), P is amino protecting group.
  5. According to the method described in claim 4, it is characterized in that, the post-processing includes the following steps:
    (1), plus water, layering, extraction, water and aqueous slkali wash, and dry, filter concentration；Preferably, the alkali is ammonium hydroxide；
    (2), the concentrate in (1) is dissolved in methanol under heating, lower dropwise addition water is stirred at room temperature, is filtered；Preferably, water is added dropwise in two times, wherein water is added dropwise for the first time, water three volume ratio is added dropwise for second as 4:1:4 for methanol；
    (3), filtrate in (2) is dissolved in methylene chloride, be layered, dry organic layer is separated using silica gel column chromatography；
    (4), gained filtrate in (3) is beaten.
  6. According to the method described in claim 5, it is characterized in that, step (4) mashing solvent is methylene chloride and petroleum ether mixed solvent；Preferably, methylene chloride and petroleum ether volume ratio are 1:2.
  7. A kind of preparation method of formula (III) compound:
    It comprises the following steps:
    (1), using toluene as solvent, formula (V) compound is subjected to reflux water-dividing with morpholine and is reacted, the post-treated mixture for obtaining formula (VI-A) and formula (VI-B) compound:
    (2), at -10 DEG C to room temperature, under the conditions of anhydrous and oxygen-free, by N, the n,N-dimethylacetamide solution reaction of the mixture of gained formula (VI-A) and formula (VI-B) compound and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid in N- dimethyl acetamide, 4-dimethylaminopyridine, step (1)；
    Wherein, in formula (III), formula (V), formula (VI-A) and formula (VI-B), P is amino protecting group.
  8. Preparation method according to claim 7 wherein post-processes described in step (1) and includes the following steps:
    (1), reaction solution is beaten with normal heptane while hot；
    (2), it filters, solid is dry to constant weight.
  9. Preparation method according to claim 7, wherein step (2) further comprises following steps:
    (1), it keeps system temperature to be lower than 20 DEG C, ice water is added dropwise to reaction solution, makes to be extracted with ethyl acetate, merges organic phase；
    (2), it keeps system temperature to be lower than 10 DEG C, hydrochloric acid is added dropwise, reacts at room temperature；
    (3), it washs, is dry, concentration；
    (4), gains in (3) are dissolved in methylene chloride, silica gel is added, 50 DEG C or less are concentrated under reduced pressure into dry powder-shaped, and temperature to configuration is kept to convert terminal；
    (5), De contamination, concentration, obtains crude product；
    (6), crude product is flowed back with n-hexane and is beaten；
    (7), it filters, solid is dry to constant weight.
  10. A kind of preparation method of formula (IV) compound:
    Wherein, at -10~10 DEG C, by formula (VII) compound and hydrochloric acid-ethyl acetate solution reaction；
    Wherein, in formula (VII), P is amino protecting group.
  11. Preparation method according to claim 10 further comprises addition formula (IV) compound seeded crystallization.
  12. Formula (III-A), formula (III-B), formula (II-A), formula (II-B) compound as follows:
    Wherein, P is amino protecting group；Preferably, P is tertbutyloxycarbonyl.
  13. A kind of method of preparation formula (III-A) and formula (III-B) compound,
    Wherein, at -10 DEG C at room temperature, under the conditions of anhydrous and oxygen-free, by N, N- dimethyl acetamide, 4-dimethylaminopyridine, the mixture of formula (VI-A) and formula (VI-B) compound and S- (trifluoromethyl) dibenzothiophenes trifluoromethyl sulfonic acid N, N- dimethylacetamide solution reaction, through the isolated formula of silica gel column chromatography (III-A) and formula (III-B) compound；
    Wherein, in formula (VI-A), (VI-B), (III-A) and (III-B), P is amino protecting group.
  14. A kind of method of preparation formula (II-A) and formula (II-B) compound,
    Wherein, make solvent with chloroform, it is heated to reflux, divides water to react by Dean-Starks formula (III) compound and formula (IV) compound, through the isolated formula of silica gel column chromatography (II-A) and formula (II-B) compound；
    Wherein, in formula (III), formula (II-A) and formula (II-B), P is amino protecting group.
  15. According to claim 1, the described in any item methods of -11 or 13-14, wherein P is tertbutyloxycarbonyl.
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