CN104844486B - Amido propylene glycol derivative, preparation method and its pharmaceutical composition and purposes - Google Patents

Abstract

Disclosed herein is a kind of amido propylene glycol derivative, preparation method and its pharmaceutical composition and purposes, in particular to a new class of such as general formula（Ⅰ）Shown in immunomodulator, preparation method, containing their pharmaceutical composition, especially as the purposes of immunoregulation medicament.It is this kind of with excellent curative effect and the low compound of toxicity, can be used for immunologic derangement, in terms of immunosupress；And it can be used for treatment and/or hypoimmunity, rejection and autoimmune disease after organ transplant.

Description

Amido propylene glycol derivative, preparation method and its pharmaceutical composition and purposes

Technical field

The present invention relates to a new class of immunomodulators.Preparation method, the pharmaceutical composition containing them and its conduct Drug belongs to medical science especially as the purposes for preventing and treating the immunoregulation medicament by the disease of T cell mediateds Field.

Background technology

The immune response of body is that antibody excludes foreign substance such as bacterium, the important defense mechanism of virus and graft etc., And prevent the important homeostasis that own cells make a variation and cause a disease.By influencing body's immunity, reach prevention and treatment The means of disease are known as immunization therapy or immunotherapy.

Immunological regulation refers to acting on the different links of immune response, plays its adjustment effect, makes at organism immune response Within the scope of required, achieve the purpose that prevention or treatment disease.Low immune function is promoted to restore normal with drug Or prevent immune function from reducing, reach prevention purpose, claims immunopotentiation therapy.With Drug inhibition and the immune proliferation in relation to cell And function, lower the therapy of organism immune response, referred to as immunosuppressive therapy.Used drug is referred to as immunopotentiator And immunosuppressor, general name immunomodulator.

Immunosuppressor is clinically mainly used for the rejection after autoimmunity disease and organ transplant.But mesh The immunosuppressor of preceding Clinical practice also has more adverse reaction.

The side effect of glucocorticoid be caput femoris necrosis, cataract, edema, hirsutism, hyperglycemia, hyperlipidemia, Hypertension, impaired wound healing, myopathy, osteoporosis, peptic ulcer, personality change and obesity；The side effect of cyclosporin For diarrhea, gingival hyperplasia, headache, hemolytic uremic syndrome, hirsutism, hyperkalemia, hyperlipidemia, hypertension, high urine Acid, nausea, renal toxicity, pancreatitis, paralysis, itch, trembles and phlebothrombosis at hypomagnesemia；The side effect of tacrolimus is heart Hypertrophy, low cholesterol, diarrhea, headache, hyperglycemia, hyperkalemia, hypertension, hypomagnesemia, renal toxicity, neurotoxicity, nausea, itch And it trembles；The side effect of imuran is cancer, hepatotoxicity wind agitation, leukopenia, nausea, pancreatitis and vomiting；Mycophenolic Acid The side effect of ester is diarrhea, edema, headache, hypertension, bone marrow suppression, nausea, renal toxicity and trembles；The side effect of Lei Pa meter stars It is integrated for canker sore, arthralgia, deep vein thrombosis, oedema, headache, hyperlipidemia, hypertension, interstitial lung disease and Fan Keni Sign（Pancytopenia）Deng.

In conclusion the immunoregulation medicament of research and development high-efficiency low-toxicity side effect is very necessary.

Nineteen ninety, Japanese Fujita et al. isolated compound ISP- from the culture medium of cordyceps sinensis stick capsule spore bacterium I has found that this molecule has higher immunosuppressive activity.Compound ISP-I was once used as antifungal agent also true from two kinds respectively It is isolated in the culture medium of bacterium Myrioccocum albomyces and Mycelia sterilia, it is referred to as Myriocin And Thermozymocidin.The lymphocyte proliferation assay that rat allogeneic lymphoid gland effect causes（MLR）With it is homologous in rat body The generation of effector cell's toxin T lymphocytes is tested（CTL）Show that the activity of ISP-I is 10-100 times higher than cyclosporin.

In the research to the structure of modification of ISP-I, Fujita et al. has found that FTY720 has more satisfactory be immunized again Inhibitory activity, the derivative for having many FTY720 at present are reported in the literature, and document is shown in Tetsuro Fujita et al., raw Object is organic with pharmaceutical chemistry bulletin（Bioorganic&Medicinal Chemisrty Letters）, 5,1857（1995）； Ryoji Hirose et al., biological organic and pharmaceutical chemistry bulletin（Bioorganic&Medicinal Chemisrty Letters）, 6,2647（1996）；Masatoshi Kiuchi et al., biological organic and pharmaceutical chemistry bulletin（Bioorganic& Medicinal Chemisrty Letters）, 8,101（1998）；Tetsuro Fujita et al., journal of Medicinal Chemistry （J.Med.Chem.）, 39,4451（1996）；Masatoshi Kiuchi et al., journal of Medicinal Chemistry（J.Med.Chem.）, 43,2946（2000）.But the FTY720 derivatives of all above-mentioned document reports are different from chemical combination involved in the present invention Object.

Invention content

The present invention is by studying for a long period of time it has been found that the new FTY720 derivatives of explained later have excellent immunological regulation Activity especially shows excellent medicinal property in terms of immunosuppressive activity.The present invention obtains on the basis of above find To complete.

One aspect of the invention provides excellent curative effect and the low immunomodulator of toxicity, such as general formula（Ⅰ）Compound and its Stereoisomer.

Another aspect of the present invention refers to pharmaceutical composition, including the general formula as active constituent（Ⅰ）Chemical combination Object and/or its stereoisomer.

Further aspect of the present invention refers to general formula（Ⅰ）Compound is being prevented and/or is being controlled containing his pharmaceutical composition Treat the purposes in terms of immunological regulation.

Further aspect of the present invention refers to the method prevented and/or treat disease of immune system comprising by general formula（Ⅰ） Compound delivers medicine to the host that need to prevent and/or treat containing its pharmaceutical composition.

Compound of the present invention is such as general formula（Ⅰ）Compound represented and its pharmaceutically acceptable salt and ester

Wherein

R is selected from hydrogen, C1-6 alkyl, C1-6 acyl groups ,-P (=O) (OR ') (OR "), and wherein OR ' and OR " is identical or different, R ' and R " is independent selected from hydrogen, C1-6 alkyl, C1-6 acyl groups；

R₁It is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyanogen selected from hydrogen, substituted or non-substituted C1-6 alkyl, and substituent group Base, amino；

R₂It is selected from halogen, carbonyl, hydroxyl, mercapto selected from hydrogen, substituted or non-substituted C1-8 alkoxy acyls, and substituent group Base, cyano, amino, phenyl；

M is selected from the integer of 1-4；

R₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkylaminos, C1-6 alkylaminos are including single alkylamino and double alkylaminos, the acyl group of C1-6, C1-6 The halogenated alkyl of acyloxy, the amide groups of C1-6, C1-61, the alkene of C2-6；

W is selected from oxygen atom, sulphur atom or nitrogen-atoms；

X is selected from oxygen atom, sulphur atom or singly-bound, indicates that phenyl and phenyl are connected directly when X is singly-bound；

When X is selected from oxygen atom, sulphur atom；Y is selected from the alkoxy of the alkyl of C0-8, C1-8, C2-8 alkene, five yuan or six The aromatic ring of member, the told heteroaromatic of heteroaromatic are five-membered ring, hexa-atomic to go back, and can contain 1,2 or 3 hetero atom, institute Can be identical or different containing hetero atom, the hetero atom told is selected from N, O, S；When Y is selected from the alkyl of C0, Y missings, i.e. Z are indicated Directly it is connected with phenyl ring；

When X is selected from singly-bound；Y be selected from five yuan or hexa-atomic aryl, the told aromatic ring of heteroaromatic be five-membered ring, hexatomic ring, and And 1,2 or 3 hetero atom can be contained, contained hetero atom can be identical or different, and the hetero atom told is selected from N, O, S；When Y is selected from the alkyl of C0, indicate that Y missings, i.e. Z are directly connected with phenyl ring；

Z be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkylthio groups, C1-6 alkylaminos including single alkylamino and double alkylaminos, C1-6 alcoxyl C1-6 alkyl, C1-6 acyl groups, C1-6 acyloxy, C1-6 amide groups, C1-6 halogenated alkyls, the alkene of C2-6.

Preferred five yuan of aromatic rings are selected from

Preferred hexa-atomic aromatic ring is selected from

It is preferred to be selected from containing the 1-4 heteroatomic quinary heterocyclic radicals selected from N, O or S：

It is preferred to be selected from containing the 1-4 heteroatomic hexa-member heterocycle bases selected from N, O or S：

Preferred heterocycle is selected from

Preferred formula（I）Compound represented and its pharmaceutically acceptable salt and ester, including but not limited to,（IA）Institute The compound shown

R is selected from hydrogen, C1-4 alkyl, C1-4 acyl groups ,-P (=O) (OR ') (OR "), and wherein OR ' and OR " is identical or different, R ' and R " is independent selected from hydrogen, C1-4 alkyl, C1-4 acyl groups；

R₁It is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyanogen selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituent group Base, amino, sulfonate group；

R₂It is selected from halogen, carbonyl, hydroxyl, mercapto selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyls, and substituent group Base, cyano, amino, phenyl；

M is selected from integer of 1 to 3；

R₃For hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkylaminos, C1-6 alkylaminos including single alkylamino and double alkylaminos, C1-61 alcoxyl C1-6 alkyl, The halogenated alkyl of the acyl group of C1-6, the acyloxy of C1-6, the amide groups of C1-6, C1-61, the alkene of C2-6；

W is selected from oxygen atom, sulphur atom or nitrogen-atoms；

X is selected from oxygen atom, sulphur atom

C rings are selected from

R₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkylaminos are including single alkylamino and double alkylaminos, the acyl group of C1-4, C1-4 The halogenated alkyl of acyloxy, the amide groups of C1-4, C1-4, the alkene of C2-4.

Preferred formula（I）Compound represented and its pharmaceutically acceptable salt and ester, including but not limited to,（IB）Institute The compound shown

R is selected from hydrogen, C1-4 alkyl, C1-4 acyl groups ,-P (=O) (OR ') (OR "), and wherein OR ' and OR " is identical or different, R ' and R " is independent selected from hydrogen, C1-4 alkyl, C1-4 acyl groups；

R₁It is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyanogen selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituent group Base, amino, sulfonate group；

R₂It is selected from halogen, carbonyl, hydroxyl, mercapto selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyls, and substituent group Base, cyano, amino, phenyl；

M is integer of 1 to 3；

W is selected from oxygen atom, sulphur atom or nitrogen-atoms；

R₃For hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkylaminos, C1-6 alkylaminos are including single alkylamino and double alkylaminos, the acyl group of C1-6, C1-6 The halogenated alkyl of acyloxy, the amide groups of C1-6, C1-61, the alkene of C2-6；

X is selected from oxygen atom, sulphur atom；

R₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkylaminos including single alkylamino and double alkylaminos, C1-4 alcoxyl C1-4 alkyl, The halogenated alkyl of the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4, benzyl, the alkene of C2-4.

Preferred formula（I）Compound represented and its pharmaceutically acceptable salt and ester, including but not limited to,（I C） Compound represented

R is selected from hydrogen, C1-4 alkyl, C1-4 acyl groups ,-P (=O) (OR ') (OR "), and wherein OR ' and OR " is identical or different, R ' and R " is independent selected from hydrogen, C1-4 alkyl, C1-4 acyl groups；

R₁It is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyanogen selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituent group Base, amino；

R₂It is selected from halogen, carbonyl, hydroxyl, mercapto selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyls, and substituent group Base, cyano, amino, phenyl；

M is integer of 1 to 3；

W is selected from oxygen atom, sulphur atom or nitrogen-atoms；

R₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkoxies, C1-6 alkylaminos, C1-6 alkylaminos are including single alkylamino and double alkylaminos, the acyl group of C1-6, C1-6 The halogenated alkyl of acyloxy, the amide groups of C1-6, C1-61, the alkene of C2-6.

D rings are selected from

R₅Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkylaminos are including single alkylamino and double alkylaminos, the acyl group of C1-4, C1-4 The halogenated alkyl of acyloxy, the amide groups of C1-4, C1-4, the alkene of C2-4.

Preferred formula（IA）Compound represented and its pharmaceutically acceptable salt and ester, it is including but not limited to, as follows Compound represented

W is selected from oxygen atom, sulphur atom or nitrogen-atoms；

X is selected from oxygen or sulphur；

R₅₁、R₅₂、R₅₃、R₅₄、R₅₅、R₅₆It is independent selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, Halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkylaminos are including single alkylamino and double The halogenated alkyl of alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4, the alkene of C2-4.

Further preferred formula（ⅠA）Compound represented and its pharmaceutically acceptable salt and ester, including but do not limit In compound as follows：

R₅₁、R₅₂、R₅₃、R₅₄、R₅₅、R₅₆It is independent selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, Fluorine, chlorine, bromine, nitro, cyano, methyl, ethyl, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, ring propoxyl group, n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, Isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, ring Propylamino, n-butylamine-based, isobutyl amine, tert-butylamine base, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive fourth Acyl group, isobutyryl, tertiary bytyry, formamido, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive fourth Amide groups, isobutyl amide, t-butyl carboxamide base, vinyl, acrylic, allyl, cyclobutenyl.

Further preferred formula（IA）Compound represented and its pharmaceutically acceptable salt and ester, including but do not limit In compound as follows：

Preferred formula（IC）Compound represented and its pharmaceutically acceptable salt and ester, it is including but not limited to, as follows Compound represented

R₅₁、R₅₂、R₅₃、R₅₄、R₅₅、R₅₆It is independent selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, Halogen, nitro, cyano, C1-4 alkyl, C1-4 alkoxies, C1-4 alkylthio groups, C1-4 alkylaminos are including single alkylamino and double The halogenated alkyl of alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4, the alkene of C2-4.

In the present invention, term " alkyl " refers to the linear or branched alkyl group containing one or more carbon atoms, such as methyl, Ethyl, propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, amyl, isopentyl, neopentyl, sec-amyl, hexyl, isohesyl, Sec-Hexyl, heptyl, octyl, nonyl, decyl etc..

In the present invention, term " alkyl " refers to being free of or the alkyl containing one or more double or triple bonds.The alkane Base is as defined above.

Most preferred compound is selected from：

Present invention simultaneously relates to general formulas（Ⅰ）The form and/or solvate of acceptable salt in compound pharmaceutics.

General formula（Ⅰ）The example of compound salt includes inorganic acid salt, such as hydrochloride, hydrobromate, sulfate and phosphate, And acylate, such as acetate, fumarate, maleate, benzoate, citrate, succinate, apple Hydrochlorate, mesylate, benzene sulfonate and tartrate.Work as general formula（Ⅰ）Compound is in a salt form in application, tend to these medicines Acceptable salt on.The present invention also includes the hydrate and solvate of 1 compound or its salt of general formula.

According to the present invention, general formula（Ⅰ）Compound can exist in the form of isomers, and the usually described present invention " change.Conjunction object " includes the isomers of the compound.

General formula（Ⅰ）Compound may exist the cis-trans isomerism of double bond, and asymmetric center has S configurations or R configurations, the present invention Mixture including all possible stereoisomer and two or more isomers.If there is cis/trans isomers, this hair The bright mixture for being related to cis form and trans forms and these forms, can be according to conventional side if necessary to individual isomer Method is detached or is prepared by Stereo-selective synthesis.

Further aspect of the present invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine Content in compositions is usually 0.1-95 weight %.

The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be divided into intestines Road or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, mucous membrane of mouth, eye, lung and respiratory tract, skin Skin, vagina, rectum etc..

Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution（Including True solution and colloidal solution）, emulsion（Including o/w types, w/o types and emulsion）, suspension, injection（Including liquid drugs injection, powder-injection And infusion）, eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet（Including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet）, capsule（Including hard capsule, soft capsule, capsulae enterosolubilis）, granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, gas（Powder）Mist agent, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..

It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.

In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including slow Release agent, binder, wetting agent, disintegrated tablet, lubricant, glidant.Diluent can be starch, dextrin, sucrose, glucose, breast Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, poly(ethylene oxide)polymers etc..

Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.

In order to which capsule is made in administration unit, active ingredient the compounds of this invention and diluent, glidant can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It also can active ingredient the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrant, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention.

For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used It makees solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjusting agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..If preparing freeze-drying Powder-injection can also be added mannitol, glucose etc. and be used as proppant.

In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.

To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any Prescription method is administered.

The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.Generally by of the present inventionization The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.1-100mg/Kg weight, more preferably 1-60mg/Kg weight, most preferably 2-30mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on doctor's clinical experience and includes the dosage regimen with other treatment means.

The bright compound of this law or pharmaceutical composition can individually be taken, or merge with other treatment drug or symptomatic drugs It uses.When the compound of the present invention and other medicines, which exist, to act synergistically, its dosage should be adjusted according to actual conditions.

The compounds of this invention can be used as a kind of immunomodulator, especially can be used as prevention and treatment by T cell mediateds Disease immunoregulation medicament purposes, especially prepare treatment immunologic derangement, hypoimmunity immunosupress, organ transplant Application in rejection and/or autoimmune disease drug afterwards.

Specific implementation mode

Embodiment 1

This is the experiment proves that 2- amino -2-（（4-（（4- benzyloxy-phenyls）Sulphur）Benzene oxygen）Methylene）- 1,3- propylene glycol salt The preparation of hydrochlorate

（1-1）4-（（4- benzyloxies）Thiophenyl）The preparation of phenol

By 4,4- diphenyl sulfide diphenol（10g, 45.8mmol, 1equiv）Put into the 250mL three-necked bottles for being put into stirrer In, spherical condensation tube is housed, constant pressure funnel puts into 100mLN, dinethylformamide into reactor on three-necked bottle （DMF）, stir to dissolving, put into potassium hydroxide into reactor successively（2.827g, 50.4mmol, 1.1equiv）, potassium iodide （380mg, 2.29mmol, 0.05equiv）, stir 5 minutes, the DMF solution of bromobenzyl be added dropwise into reactor（6.0mL bromobenzyls+ 20mL DMF）, it is added dropwise within 4 hours, the reaction was continued 8 hours, is warming up to 40 DEG C and reacts 4 hours.Reaction is finished, and reaction solution is poured into It in water, stirs 30 minutes, a large amount of solids is precipitated, place 30 minutes, filter, be dried to white solid, flash column chromatographies obtain 6.40g white solid（45.3%）.¹HNMR(300MHz,Acetone-d₆)δ(ppm):8.57(s,1H),7.46(d,J=7.2, 2H),7.41-7.32(m,3H),7.24(d,J=8.4,2H),7.24(d,J=9,2H),6.99(d,J=8.4,2H),6.84(d,J =9,2H).MS:307.0791. fusing point：105.6-106.4℃.

（1-2）2- methyl -4,4- dihydroxymethyl -4,5- dihydro-oxazoles

By 2- amino -2- methylol -1,3- propylene glycol（5.00g, 41.3mmol, 1equiv）, n,N-Dimethylformamide （50mL）, triethly orthoacetate（9.10mL）, n,N-diisopropylethylamine（7.20mL）It puts into successively in 250mL eggplant-shape bottles, It is warming up to back flow reaction 8 hours.Reaction is finished, and solvent is evaporated off, and 100mL petroleum ethers are added into residue, is stirred 2 hours, is precipitated Solid, suction filtration obtain 4.63g faint yellow solids, yield 77.3%.¹HNMR(300MHz,CD₃OD)δ(ppm):4.17(s,2H), 3.46(d,J=1.8,4H),1.89(s,3H).MS:146.0879. fusing point：79.1-80.6℃.

（1-3）2- methyl 4- methylols -4- ((4- (4- benzyloxies) thiophenyl) phenoxy group) -4,5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（187mg, 0.713mmol, 1.1equiv）, dry toluene（20mL）It throws successively Enter into 100mL eggplant-shape bottles, diethyl azodiformate is added dropwise in ice bath cooling（40% toluene solution, 324uL, 0.73mmol, 1.1equiv）, drip off within 10 minutes, stirred 1 hour under ice bath, 2- methyl -4,4- dihydroxymethyl -4,5- bis- is put into reactor Qing oxazoles（141mg, 0.972mmol, 1.5equiv）, it is stirred at room temperature 5 minutes, is warming up to back flow reaction 48 hours, reaction is finished, and is steamed Except toluene, residue is dissolved with dichloromethane, and flash column chromatographies obtain 63g white solids（22.0%）.¹HNMR(300MHz, Acetone-d₆)δ(ppm):7.47(d,J=7.2,2H),7.42-7.33(m,3H),7.29(d,J=8.7,4H),7.02-7.00 (d,J=8.4,2H),6.94(d,J=8.7,2H),5.12(s,2H),4.24(s,2H),4.07-3.95(m,2H),3.85(t, 1H),3.66-3.62(m,2H),1.89(s,3H).MS:436.1614. fusing point：89.3-90.1℃.

（1-4）2- amino -2-（（4-（（4- benzyloxy-phenyls）Sulphur）Benzene oxygen）Methylene）- 1,3- propanediol hydrochlorides

By 2- methyl 4- methylols -4- ((4- (4- benzyloxies) thiophenyl) phenoxy group) -4,5- dihydro-oxazoles（68mg）, nothing Water-ethanol（2mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb（2mL）, it is warming up to 70 DEG C are reacted 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and it is solid to obtain 60mg whites for concentrated solvent Body, yield 85.9%.¹HNMR(300MHz,CD₃OD)δ(ppm):7.35-7.18(m,9H),6.91(d,J=8.4,4H),5.01 (s,2H),4.08(s,2H),3.73(s,2H).¹³CNMR(125MHz,MeOD)δ(ppm):159.94,159.02,138.46, 134.30,133.42,130.42,129.52,128.95,128.56,128.45,117.30,116.90,116.62,116.52, 71.15,67.74,61.54,61.33,49.51,49.34,49.17,49.00,48.83,48.66,48.49.HRMS,calcm/ z:412.1577;found:412.157. fusing point：136-137℃.

Embodiment 2

This is the experiment proves that 2- amino -2-（4-（4-（4-（（4- methyl）Phenyl）Thiophenyl）Benzene Oxymethylene））-1,3- The preparation of propanediol hydrochloride

（2-1）4-（（4- hydroxyls）Thiophenyl）The preparation of trifluoromethanesulfonic acid phenyl ester

By 4,4 ,-diphenyl sulfide diphenol (2.00g）, acetone（35mL）It puts into successively in 100mL eggplant-shape bottles, ice salt bath is cold But to -15 DEG C, the dichloromethane solution of trifluoromethanesulfanhydride anhydride is added dropwise into reaction solution（1.6mL trifluoromethanesulfanhydride anhydride+2mL dichloros Methane）, it is added dropwise within 20 minutes, reacts at room temperature 3 hours.Reaction, which is finished, pours into reaction solution in ice water, dichloromethane extraction（20mL ×3）, anhydrous sodium sulfate drying, steam solvent.Flash column chromatographies obtain 1.034g pale solids, yield 32.2%.¹HNMR (400MHz,Acetone-d₆)δ(ppm):8.890(s,1H),7.44(d,J=8.4,2H),7.36(d,J=8.4,2H),7.23 (d,J=8.8,2H),6.97(d,J=8.4,2H).MS:348.9821,698.9625. fusing point：73.5-74.7℃.

（2-2）4-（4-（4-（（4- methyl）Phenyl）Thiophenyl））Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Thiophenyl）Trifluoromethanesulfonic acid phenyl ester（800mg, 2.28mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（132mg, 0.114mmol, 0.05equiv）, sodium carbonate Solution（483mg sodium carbonate+3ml）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （340mg, 2.28mmol, 1equiv）, to methylphenylboronic acid（373mg, 2.74mmol, 1.2equiv）It puts into reaction bulb, It is warming up to back flow reaction, is reacted 20 minutes 6 hours.Reaction is finished, and reaction solution is cooled to room temperature, hydroxide is put into reaction bulb Aqueous solutions of potassium（1.279g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3- 4, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent, it is cream-coloured solid to obtain 0.50g for flash column chromatographies Body, yield 75.0%.¹H NMR(300MHz,Acetone-d₆)δ(ppm):8.74(s,1H),7.55-7.49(m,4H),7.39 (d,J=8.4,2H),7.25-7.18(m,4H),6.93(d,J=8.4,2H),2.34(s,3H).MS:291.0932. fusing point： 138.2-139.1℃。

（2-3）2- methyl -4- methylols -4-（4-（4-（（4- methyl）Phenyl）Thiophenyl）Phenoxy group）- 4,5- Er Qing Evil Azoles

Under argon gas protection, by triphenylphosphine（338mg, 1.29mmol, 1.3equiv）, toluene（12mL）It puts into successively In 50mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（586μL, 1.29mmol 1.3equiv）, it is added dropwise within 30 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（288mg, 1.984mmol, 2equiv）, 4-（4-（4-（（4- methyl）Phenyl）Thiophenyl））Phenol（290mg, 0.992mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, flash column chromatographies obtain 139mg white solids, yield 33.4%.¹H NMR(300MHz,Acetone-d₆)δ(ppm): 7.59-7.52(m,4H),7.47(d,J=8.7,2H),7.28-7.24(m,4H),7.05(d,J=8.7,2H),4.27(s,2H), 4.13-4.06(m,2H),3.86(t,J=5.7,1H),3.70-3.65(m,2H),2.37(s,3H),1.91(s,3H).MS: 420.1654. fusing point：131.4-132.9℃.

（2-4）2- amino -2-（4-（4-（4-（（4- methyl）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- propylene glycol salt Hydrochlorate

By 2- methyl -4- methylols -4-（4-（4-（（4- methyl）Phenyl）Thiophenyl）Phenoxy group）- 4,5- dihydro-oxazoles （139mg）, absolute ethyl alcohol（4mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb （4mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent is taken out Filter, obtains 132mg white solids, yield 92.3%.¹H NMR(300MHz,CD₃OD)δ(ppm):7.46-7.42(m,3H), 7.39-7.36(m,3H),7.19-7.17(m,4H),7.00(d,J=8.7,2H),4.13(s,2H),3.75(s,4H),2.29 (s,3H).¹³CNMR(100MHz,CD₃OD)δ(ppm):159.70,140.60,138.63,138.43,137.79,135.80, 130.57,130.54,128.38,127.89,127.59,116.87,67.28,61.89,61.06,21.09.HRMS,calc m/z:396.1628;found:396.1616. fusing point：192-194℃.

Embodiment 3

This is the experiment proves that 2- amino -2-（4-（4-（（2- n-propyls）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）-1, The preparation of 3-propanediol hydrochloride

（3-1) 4- (acetyl bromide) bromobenzene

By bromobenzene（13.0mL, 0.127mmol, 1equiv）, dichloromethane（200mL）, bromoacetyl bromide（11.0mL, 0.127mmol, 1equiv）It puts into successively in 500mL three-necked bottles, ice bath is cooled to 0 DEG C, puts into alchlor powder in batches （34.0g, 0.254mmol, 2equiv）, add within 1 hour, react at room temperature 2 hours.Reaction finishes, and reaction solution is poured into addition ice It in the 2N hydrochloric acid of block, is stirred at room temperature 1 hour, liquid separation, dichloromethane extraction（50mL×2）, anhydrous sodium sulfate drying, steam dichloro Methane obtains 26.44g yellow solids, yield 74.9%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.86(d,J=8.1,2H), 7.65(d,J=7.8,2H),4.40(s,2H).MS:279.1562,301.1381. fusing point：103.9-104.8℃.

（3-2）2-（4- bromophenyls）- 2- oxoethyl butyrates

By 4-（Acetyl bromide）Bromobenzene（5.00g, 18.0mmol, 1equiv）, acetonitrile（100mL）, triethylamine（5.00mL 36mmol, 2equiv）, n-butyric acie（3.3mL, 36.0mmol, 2equiv）It puts into successively in 250mL eggplant-shape bottles, is warming up to 80 DEG C reaction 2 hours.Reaction finishes, and steams solvent, and residue 100mL dichloromethane dissolves, 2N salt acid elutions（100mL）Have several Layer, saturated aqueous sodium carbonate（100mL）Washing has several layers of, distillation water washing organic layer, anhydrous sodium sulfate drying to steam molten Agent, flash column chromatographies obtain 4.55g yellow solids, yield 88.7%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.78(d,J =8.4,2H),7.63(d,J=6,2H),5.29(s,2H),2.47(t,J=7.2,2H),1.76-1.71(m,2H),1.01(t,J= 7.2,3H).MS:285.0097,287.0076. fusing point：47.5-49.2℃.

（3-3）4-（4- bromophenyls）-2-（1- butyl）Oxazole

By 2-（4- bromophenyls）- 2- oxoethyl butyrates（4.36g, 15.3mmol, 1equiv）, dimethylbenzene（60mL）, Acetamide（4.52g, 76.5mmol, 5equiv）, boron trifluoride ether（0.77mL）It puts into 100mL eggplant row bottles, rises successively Temperature is reacted 30 hours to back flow reaction.Reaction finishes, and steams dimethylbenzene, and residue is dissolved with dichloromethane, distills water washing two Chloromethanes layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatographies obtain 1.15g yellow solids, yield 28.1%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.81(s,1H),7.59(dd,J1=8.4,J2=1.5,2H),7.51(d,J=8.7, 2H),2.81-2.76(m,2H),1.87-1.79(m,2H),1.04-0.99(m,3H).MS:266.01888,268.0167. molten Point：43.7-44.1℃.

（3-4）2-（1- butyl）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole

Under argon air-flow protection, by 4-（4- bromophenyls）-2-（1- butyl）Oxazole（709mg, 2.66mmol, 1equiv）, N,N-dimethylformamide（8mL）, palladium（30mg, 0.133mmol, 0.05equiv）, 4,5- bis- diphenylphosphines -9,9- bis- Methyl xanthene（154mg, 0.266mmol, 0.1equiv）It puts into 50mL eggplant-shape bottles, stirs 5 minutes, to reaction bulb successively Middle input N, N- diisopropylethylamine（742 μ L, 4.26mmol, 1.6equiv）, thiohydroquinone（604mg, 4.79mmol, 1.8equiv）, it is warming up to back flow reaction 4 hours.Reaction finishes, and steams n,N-Dimethylformamide, dichloromethane dissolving, mistake Filter, flash column chromatographies obtain 0.76g yellow solids, yield 91.8%.¹H NMR(300MHz,Acetone-d₆)δ(ppm): 8.76(s,1H),8.21(s,1H),7.71(d,J=8.7,2H),7.38(d,J=8.7,2H),7.18(d,J=8.4,2H),6.93 (d,J=8.7,2H),2.76(t,J=7.2,2H),1.84-1.76(m,2H),0.99(t,J=7.5,3H).MS:310.0888. molten Point：122.4-123.9℃.

（3-5）2- methyl -4- methylols -4-（4-（4-（2-（（1- butyl）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（960mg, 3.66mmol, 1.5equiv）, toluene（25mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.66mL, 1.29mmol 1.3equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（708mg, 4.88mmol, 2equiv）, 2-（1- butyl）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole （760mg, 2.44mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, Toluene is steamed, residue is dissolved with dichloromethane, flash column chromatographies, obtains 382mg yellow solids, yield 35.7%.¹H NMR (300MHz,Acetone-d₆)δ(ppm):8.76(s,1H),8.21(s,1H),7.71(d,J=8.7,2H),7.38(d,J= 8.7,2H),7.17(d,J=8.4,2H),6.93(d,J=8.7,2H),2.76(t,J=7.2,2H),1.84-1.76(m,2H), 1.00(t,J=7.5,3H).MS:439.1655℃。

（3-6）2- amino -2-（4-（4-（2-（1- butyl）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）- 1,3- the third two The preparation of alcohol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（2-（（1- butyl）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4,5- Dihydro-oxazole（350mg）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）It puts into successively in 50mL eggplant-shape bottles, is stirred at room temperature 3 Hour.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to neutrality pH with sodium hydroxide solution, dichloromethane extraction It takes（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance 15mL methanol is dissolved, by sodium hydroxide （35mg, 0.878mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction, obtains 217mg yellow solids, yield 60.4%。¹H NMR(400MHz,CD₃OD)δ(ppm):8.11(s,1H),7.56-7.54(d,J=8,2H),7.40-7.38(s, 2H),7.13(d,J=8.4,2H),7.02(d,J=8.8,2H),4.14(s,2H),3.75(s,4H),2.76(t,J=7.2,2H), 1.79-1.74(m,2H),0.95(t,J=7.6,3H).¹³C NMR(125MHz,CD₃OD)δ(ppm):167.527,159.972, 140.549,139.704,136.396,135.650,129.800,129.699,127.136,126.952,116.978, 67.280,61.896,61.055,30.688,21.484,13.873.HRMS,calc m/z:415.1686;found: 415.1678. fusing point：104-105℃.

Embodiment 4

This is the experiment proves that 2- amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）-1,3- The preparation of propanediol hydrochloride

（4-1）2-（4- bromophenyls）- 2- oxoethyl propionic esters

By 4-（Acetyl bromide）Bromobenzene（14.00g, 50.4mmol, 1equiv）, acetonitrile（200mL）, triethylamine （14.00mL, 100.8mmol, 2equiv）, propionic acid（7.5mL, 100.8mmol, 2equiv）500mL eggplant-shape bottles are put into successively In, it is warming up to 80 DEG C and reacts 2 hours.Reaction finishes, and steams solvent, and residue 200mL dichloromethane dissolves, 2N salt acid elutions （150mL）Organic layer, saturated aqueous sodium carbonate（150mL）Washing has several layers of, distillation water washing organic layer, anhydrous sodium sulfate dry It is dry, solvent is steamed, flash column chromatographies obtain 12.38g yellow solids, yield 90.6%.¹H NMR(300MHz,CDCl₃)δ (ppm):7.79(d,J=8.7,2H),7.64(d,J=8.1,2H),5.29(s,2H),2.53(q,J=7.8,2H),1.23(t,J= 7.5,3H).MS:270.9948,272.9926. fusing point：47.8-49.1℃.

（4-2）4-（4- bromophenyls）-2-（1- ethyls）Oxazole

By 2-（4- bromophenyls）- 2- oxoethyl propionic esters（12.38g, 45.7mmol, 1equiv）, dimethylbenzene （120mL）, acetamide（13.50g, 229mmol, 5equiv）, boron trifluoride ether（2.285mL）250mL eggplants are put into successively In row bottle, it is warming up to back flow reaction, is reacted 30 hours.Reaction finishes, and steams dimethylbenzene, and residue is dissolved with dichloromethane, steams Distilled water washs dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, flash column chromatographies obtain 3.06g yellow solids, yield 26.6%。¹H NMR(300MHz,CDCl₃)δ(ppm):7.83(s,1H),7.60(d,J=8.7,2H),7.52(d,J=8.4,2H), 2.85(q,J=7.8,2H),1.39(t,J=7.8,3H).MS:252.0009,253.9989. fusing point：44.0-45.5℃.

（4-3）2-（1- ethyls）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole

Under argon air-flow protection, by 4-（4- bromophenyls）-2-（1- ethyls）Oxazole（1.076g, 4.27mmol, 1equiv）, N,N-dimethylformamide（8mL）, palladium（48mg, 0.214mmol, 0.05equiv）, 4,5- bis- diphenylphosphines -9,9- bis- Methyl xanthene（124mg, 0.214mmol, 0.05equiv）It puts into 50ml eggplant-shape bottles, stirs 5 minutes, to reaction successively N, N- diisopropylethylamine are put into bottle（1.19mL, 6.83mmol, 1.6equiv）, thiohydroquinone（970mg, 7.69mmol 1.8equiv）, it is warming up to back flow reaction 15 hours.Reaction finishes, and steams n,N-Dimethylformamide, dichloromethane Alkane dissolves, and filtering, flash column chromatographies obtain 1.01g yellow solids, yield 79.5%.¹H NMR(300MHz,CDCl₃)δ (ppm):7.81(s,1H),7.55(d,J=8.7,2H),7.37-7.34(m,2H),7.10(d,J=8.7,2H),6.88-6.85 (m,2H),2.88(q,J=7.5,2H),1.37(t,J=7.5,3H).MS:296.0754. fusing point：130.4-131.9℃.

（4-4）2- methyl -4- methylols -4-（4-（4-（2-（（1- ethyls）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（1.338g, 5.10mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（2.3mL, 5.10mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（987g, 6.80mmol, 2equiv）, 2-（1- ethyls）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole （1.01g, 3.40mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, Toluene is steamed, residue is dissolved with dichloromethane, flash column chromatographies, obtains 601mg greenish yellow solids, yield 41.6%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.77(s,1H),7.59(d,J=8.4,2H),7.39(d,J=8.4,2H),7.20(d,J =7.8,2H),6.88(d,J=8.4,2H),4.39(d,J=8.7,1H),4.28(d,J=8.7,1H),4.08(d,J=9,1H), 3.95(d,J=9,1H),3.83(d,J=11.7,1H),3.72(d,J=11.4,1H),2.83(q,J=7.5,2H),2.06(s, 3H),1.37(t,J=7.5,3H).MS:425.1509. fusing point：126.4-127.9℃.

（4-5）2- amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）- 1,3- propylene glycol The preparation of hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（2-（（1- ethyls）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4,5- Dihydro-oxazole（350mg,0.824mmol）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）It puts into successively in 50mL eggplant-shape bottles, It is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to neutrality pH with sodium hydroxide solution, two Chloromethanes extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance 15mL methanol is dissolved, by hydrogen Sodium oxide molybdena（36mg, 0.906mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction, obtains 169mg yellow solids, Yield 48.9%.¹H NMR(400MHz,CD₃OD)δ(ppm):8.09(s,1H),7.55(d,J=8,2H),7.39(d,J=8.4, 2H),7.12(d,J=8,2H),7.01(d,J=.4,2H),4.14(s,2H),3.75(s,4H),2.80(q,J=7.6,2H), 1.30(t,J=7.6,3H).¹³C NMR(125MHz,CD₃OD)δ(ppm):168.389,159.952,140.628,139.623, 136.372,135.585,129.802,127.128,126.956,116.978,61.891,61.050,30.688,22.384, 11.424.HRMS,calc m/z:401.1530;found:401.1534. fusing point：107-108℃.

Embodiment 5

This is the experiment proves that 2- amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）-1,3- The preparation of propanediol hydrochloride

（5-1）2- (4- bromophenyls) -2- oxoe thyl acetates

By 4-（Acetyl bromide）Bromobenzene（6.00g, 21.6mmol, 1equiv）, acetonitrile（50mL）, triethylamine（6.0mL 43.2mmol 2equiv）, acetic acid（2.5mL, 43.2mmol, 2equiv）It puts into successively in 100mL eggplant-shape bottles, is warming up to 80 DEG C reaction 2 hours.Reaction finishes, and steams solvent, and residue 100mL dichloromethane dissolves, 2N salt acid elutions（100mL）It is organic Layer, saturated aqueous sodium carbonate（100mL）Washing has several layers of, distillation water washing organic layer, anhydrous sodium sulfate drying to steam molten Agent, flash column chromatographies obtain 5.01g yellow solids, yield 90.2%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.79(dd, J₁=6.6,J₂=1.8,2H),7.65(dd,J₁=6.6,J₂=2.1,2H),5.29(s,2H),2.23(s,4H).MS:256.9787, 258.9770. fusing point：71.8-73.2℃.

（5-2）4-（4- bromophenyls）-2-（1- methyl）Oxazole

By 2-（4- bromophenyls）- 2- oxoe thyl acetates（12.38g, 45.7mmol, 1equiv）, dimethylbenzene （120mL）, acetamide（13.50g, 229mmol, 5equiv）, boron trifluoride ether（2.285mL）250mL eggplants are put into successively In row bottle, it is warming up to back flow reaction, is reacted 30 hours.Reaction finishes, and steams dimethylbenzene, and residue is dissolved with dichloromethane, steams Distilled water washs dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, flash column chromatographies obtain 3.06g yellow solids, yield 26.6%。¹H NMR(300MHz,CDCl₃)δ(ppm):7.83(s,1H),7.60(d,J=8.7,2H),7.52(d,J=8.4,2H), 2.85(q,J=7.8,2H),1.39(t,J=7.8,3H).MS:252.0009,253.9989. fusing point：44.0-45.5℃.

（5-3）2-（1- methyl）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole

Under argon air-flow protection, by 4-（4- bromophenyls）-2-（1- methyl）Oxazole（1.05g, 4.41mmol, 1equiv）, N,N-dimethylformamide（8mL）, palladium（50mg, 0.221mmol, 0.05equiv）, 4,5- bis- diphenylphosphines -9,9- bis- Methyl xanthene（255mg, 0.441mmol, 0.1equiv）It puts into 50mL eggplant-shape bottles, stirs 5 minutes, to reaction bulb successively Middle input N, N- diisopropylethylamine（1.23mL, 7.06mmol, 1.6equiv）, thiohydroquinone（946mg, 7.50mmol, 1.7equiv）, it is warming up to back flow reaction 15 hours.Reaction finishes, and steams n,N-Dimethylformamide, dichloromethane dissolving, mistake Filter, flash column chromatographies obtain 0.85g white solids, yield 68.0%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.80(s, 1H),7.55(d,J=8,2H),7.36(d,J=8.4,2H),7.11(d,J=8,2H),6.86(d,J=8.4,2H),2.55(s, 3H).MS:282.0607. fusing point：156.4-157.5℃.

（5-4）2- methyl -4- methylols -4-（4-（4-（2-（（1- methyl）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（1.180g, 4.50mmol, 1.5equiv）, toluene（25mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（2.0mL, 4.50mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（871g, 6.00mmol, 2equiv）, 2-（1- methyl）-4-（4-（4- hydroxy benzenes sulfenyls）Phenyl））Oxazole （0.85g, 3.00mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, Toluene is steamed, residue is dissolved with dichloromethane, flash column chromatographies, obtains 571mg light pink solids, yield 46.4%.¹H NMR(300MHz,Acetone-d₆)δ(ppm):8.20(s,1H),7.71(d,J=8.4,2H),7.44(d,J=8.7,2H), 7.25(d,J=8.1,2H),7.03(d,J=8.7,2H),4.25(s,2H),4.12-4.00(m,2H),3.858(t,1H), 3.680-3.637(m,2H),2.438(s,2H),1.897(s,3H).MS:411.1516. fusing point：146.1-147.4℃.

（5-5）2- amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Thiophenyl）Benzene Oxymethylene）- 1,3- propylene glycol The preparation of hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（2-（（1- methyl）Oxazole -4- bases）Thiophenyl）Phenoxy group））-4,5- Dihydro-oxazole（350mg,0.828mmol）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）It puts into successively in 50mL eggplant-shape bottles, It is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to neutrality pH with sodium hydroxide solution, two Chloromethanes extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance 15mL methanol is dissolved, by hydrogen Sodium oxide molybdena（36mg, 0.906mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction, obtains 267mg yellow solids, Yield 76.2%.¹H NMR(400MHz,CD₃OD)δ(ppm):8.08(s,1H),7.54(d,J=8.4,2H),7.39(d,J=8.4, 2H),7.12(d,J=8,2H),7.02(d,J=8.4,2H),4.14(s,2H),3.75(s,4H),2.45(s,3H).¹³C NMR (125MHz,CD₃OD)δ:164.50,159.97,140.29,139.94,136.42,135.91,129.71,129.13, 127.08,126.68,117.03,67.28,61.89,61.01,13.53.HRMS,calc m/z:387.1373;found: 387.1381. fusing point：164-165℃.

Embodiment 6

This is the experiment proves that 2- amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））-1,3- The preparation of propanediol hydrochloride

（6-1）4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl））Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Thiophenyl）Trifluoromethanesulfonic acid phenyl ester（1.20g, 3.43mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（199mg, 0.172mmol, 0.05equiv）, sodium carbonate Solution（727mg sodium carbonate+4ml）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （422mg, 3.43mmol, 1equiv）, to ethyl phenyl boric acid（618mg, 4.12mmol, 1.2equiv）It puts into reaction bulb, It is warming up to back flow reaction, is reacted 8 hours.Reaction finishes, and reaction solution is cooled to room temperature, and potassium hydroxide water is put into reaction bulb Solution（1.924g potassium hydroxide+20mL water）, 60 DEG C react 1 hour, into reaction bulb put into 6N hydrochloric acid, adjust pH to 3-4, two Chloromethanes extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent, flash column chromatographies obtain 0.73g white solids, receive Rate 69.5%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.48-7.45(m,4H),7.42-7.39(m,2H),7.26-7.22 (m,4H),6.86-6.83(m,2H),2.68(q,J=7.5,2H),1.27(t,J=7.5,3H).MS:305.1017. fusing point： 144.4-145.3℃。

（6-2）2- methyl -4- methylols -4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Phenoxy group）- 4,5- Er Qing Evil Azoles

Under argon gas protection, by triphenylphosphine（936mg, 3.57mmol, 1.5equiv）, toluene（20mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.6mL, 3.57mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（691mg, 4.76mmol, 2equiv）, 4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl））Phenol（0.73g, 2.38mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 340mg white solids, yield 32.9%.¹H NMR (400MHz,Acetone-d₆)δ(ppm):7.58-7.54(m,4H),7.46(d,J=8.4,2H),7.29(d,J=7.6,2H), 7.24(d,J=8,2H),7.04(d,J=8.8,2H),4.26(s,2H),4.11(d,J=9.2,1H),4.02(d,J=9.6,2H), 3.85(t,J=5.6,1H),3.71-3.61(m,2H),2.67(q,J=7.6,2H),1.90(s,3H),1.24(t,J=7.6, 3H).MS:434.1797. fusing point：126.1-127.7℃.

（6-3）2- amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- propylene glycol salt Hydrochlorate

By SYL1402-c（200mg）, absolute ethyl alcohol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving, to anti- Answer input 6N hydrochloric acid in bottle（5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white is precipitated Solid, concentrated solvent filter, obtain 130mg white solids, yield 63.1%.¹H NMR(300MHz,CD₃OD)δ(ppm): 7.45-7.40(m,4H),7.36(d,J=8,2H),7.19-7.15(m,4H),6.98(d,J=8.7,2H),4.11(s,2H), 3.73(s,4H),2.59(q,J=7.2,2H),1.18(t,J=7.5,3H).¹³C NMR(125MHz,CD₃OD)δ:159.69, 144.89,140.60,138.87,137.79,135.78,130.56,129.36,128.39,127.85,127.68,116.88, 67.29,61.90,61.05,49.51,49.34,49.17,49.00,48.83,48.66,48.49,29.47,16.13.HRMS, calc m/z:410.1784;found:410.1794. fusing point：185-186℃.C

Embodiment 7

This is the experiment proves that 2- amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- propylene glycol salt The preparation of hydrochlorate

（7-1）4-(4-（（4- phenyl）Thiophenyl)) phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Thiophenyl）Trifluoromethanesulfonic acid phenyl ester（1.2g, 3.43mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（199mg, 0.172mmol, 0.05equiv）, sodium carbonate Solution（727mg sodium carbonate+4ml）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （422mg, 3.43mmol, 1equiv）, phenyl boric acid（502mg, 4.12mmol, 1.2equiv）It puts into reaction bulb, is warming up to Back flow reaction is reacted 8 hours.Reaction finishes, and reaction solution is cooled to room temperature, and potassium hydroxide aqueous solution is put into reaction bulb （1.924g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3-4, dichloromethane Alkane extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent, flash column chromatographies obtain 0.60g beige solids, yield 62.9%。¹H NMR(300MHz,CDCl₃)δ(ppm):7.56-7.53(m,2H),7.49-7.44(m,2H),7.42-7.40(m, 4H),7.35-7.33(m,1H),7.25-7.22(m,2H)6.87-6.84(m,2H).MS:277.0706. fusing point：141.1- 142.4℃。

（7-2）2- methyl -4- methylols -4- (4- ((4- phenyl) thiophenyl) phenoxy group) -4,5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（850mg, 3.24mmol, 1.5equiv）, toluene（20mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.47mL, 3.24mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（627mg, 4.32mmol, 2equiv）, 4-（4-（（4- phenyl）Thiophenyl））Phenol（600mg, 2.16mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams toluene, residue It is dissolved with dichloromethane, flash column chromatographies, obtains 531mg white solids, yield 60.6%.¹H NMR(300MHz,Acetone- d₆)δ(ppm):7.63(d,J=8.1,2H),7.59(d,J=8.7,2H),7.48-7.42(m,4H),7.37-9.34(m,1H), 7.25(d,J=8.4,2H),7.05(d,J=8.7,2H),7.25(d,J=8.7,2H),4.28(s,2H),4.12(d,J=9.6, 1H),4.04(d,J=9,1H),3.72-3.67(m,2H),1.92(s,3H).MS:406.1639. fusing point：116.3-117.5℃.

（7-3）2- amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））The system of -1,3- propanediol hydrochlorides It is standby

By 2- methyl -4- methylols -4- (4- ((4- phenyl) thiophenyl) phenoxy group) -4,5- dihydro-oxazoles（200mg）, nothing Water-ethanol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb（5mL）, it is warming up to 70 DEG C are reacted 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent filters, obtains 145mg White solid, yield 70.4%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.51-7.45(m,4H),7.37(m,4H),7.27 (m,1H),7.19(d,J=7.8,2H),7.00(d,J=7.2,2H),4.08(s,2H),3.71(s,4H).¹³C NMR(125MHz, CD₃OD)δ:159.95,141.57,140.54,138.45,136.03,130.34,129.90,128.59,128.46, 127.75,127.42,116.90,67.78,61.60,61.26,49.51,49.34,49.17,49.00,48.83,48.66, 48.49.HRMS,calc m/z:382.1471;found:382.1489. fusing point：160-162℃.

Embodiment 8

This is the experiment proves that 2- amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））- The preparation of 1,3- propanediol hydrochlorides

（8-1）4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl））Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Thiophenyl）Trifluoromethanesulfonic acid phenyl ester（1.00g, 2.85mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（165mg, 0.143mmol, 0.05equiv）, sodium carbonate Solution（604mg sodium carbonate+4ml）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （350mg, 2.85mmol, 1equiv）, to trifluoromethylbenzene boronic acid（650mg, 3.42mmol, 1.2equiv）Put into reaction bulb In, it is warming up to back flow reaction, is reacted 8 hours.Reaction finishes, and reaction solution is cooled to room temperature, and hydroxide is put into reaction bulb Aqueous solutions of potassium（1.599g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3- 4, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying steams solvent, and it is solid to obtain 720mg whites for flash column chromatographies Body, yield 76.9%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.68-7.62(m,4H),7.47-7.42(m,4H),7.23 (d,J=8.4,2H),6.67(d,J=8.4,2H).MS:345.0580,691.1106. fusing point：145.3-146.3℃.

（8-2）2- methyl -4- methylols -4- (4- (4- ((4- trifluoromethyls) phenyl) thiophenyl) phenoxy group) -4,5- two Qing oxazoles

Under argon gas protection, by triphenylphosphine（863mg, 3.29mmol, 1.5equiv）, toluene（20mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.50mL 3.29mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（636mg, 4.38mol, 2equiv）, 4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl））Phenol（720mg, 2.19mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 336mg white solids, yield 32.4%.¹H NMR (400MHz,Acetone-d₆)δ(ppm):7.86(d,J=8,2H),7.78(d,J=8,2H),7.66(d,J=8,2H),7.50 (d,J=8.4,2H),7.26(d,J=8.4,2H),7.07(d,J=8.4,2H),4.26(s,2H),4.13-4.03(m,2H), 3.87(t,J=5.6,3H),3.72-3.62(m,2H),1.91(s,3H).MS:474.1521. fusing point：146.4-147.1℃.

（8-3）2- amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- the third two Alcohol hydrochloride

By 2- methyl -4- methylols -4- (4- (4- ((4- trifluoromethyls) phenyl) thiophenyl) phenoxy group) -4,5- Er Qing Evil Azoles（336mg）, absolute ethyl alcohol（10mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb （5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent is taken out Filter, obtains 213mg white solids, yield 61.7%.¹HNMR(400MHz,CD₃OD)δ(ppm):7.72(d,J=8,2H),7.65 (d,J=8,2H),7.53(d,J=8,2H),7.42(d,J=8.4,2H),7.20(d,J=8.4,2H),7.03(d,J=8.4,2H), 4.15(s,2H),3.76(s,4H).¹³CNMR(125MHz,CD₃OD)δ(ppm):160.028,145.379,140.258, 138.527,135.547,129.896,128.797,128.286,126.808,126.755,117.000,67.283, 61.888,61.053.HRMS,calc m/z:450.1345;found:450.1347. fusing point：180-181℃.

Embodiment 9

This is the experiment proves that 2- amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene Oxymethylene））-1, The preparation of 3-propanediol hydrochloride

（9-1）4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl））Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Thiophenyl）Trifluoromethanesulfonic acid phenyl ester（1.08g, 2.85mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（165mg, 0.143mmol, 0.05equiv）, sodium carbonate Solution（604mg sodium carbonate+4mL）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （350mg, 2.85mmol, 1equiv）, to methoxyphenylboronic acid（520mg, 3.42mmol, 1.2equiv）Put into reaction bulb In, it is warming up to back flow reaction, is reacted 8 hours.Reaction finishes, and reaction solution is cooled to room temperature, and hydroxide is put into reaction bulb Aqueous solutions of potassium（1.599g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3- 4, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying steams solvent, and it is solid to obtain 660mg whites for flash column chromatographies Body, yield 75.1%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.48(d,J=8.8,2H),7.43(d,J=8.4,2H),7.39 (d,J=8.4,2H),7.23(d,J=8.4,2H),6.96(d,J=8.4,2H),6.84(d,J=8,2H),3.84(s,3H).MS: 307.0818,615.1610. fusing point：167.9-169.1℃.

（9-2）2- methyl -4- methylols -4-（4-（4-（（4- methoxyl group bases）Phenyl）Thiophenyl）Phenoxy group）- 4,5- two Qing oxazoles

Under argon gas protection, by triphenylphosphine（842mg, 3.21mmol, 1.5equiv）, toluene（20mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.46mL, 3.21mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（621mg, 4.28mmol, 2equiv）, 4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl））Phenol（660mg, 2.14mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 335mg white solids, yield 34.9%.¹H NMR (300MHz,CDCl₃)δ(ppm):7.49-7.41(m,6H),7.22(d,J=8.4,2H),6.96(d,J=8.7,2H),6.89 (d,J=8.7,2H),4.37(d,J=9,1H),4.26(d,J=8.4,1H),4.08(d,J=9,1H),3.93(d,J=7.5,1H), 3.84(s,3H),3.72(d,J=7.8,1H),2.05(s,3H).MS:436.164. fusing point：152.3-153.4℃.

（9-3）2- amino -2-（4-（4-（4-（（4- methoxyl group bases）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- the third two Alcohol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（4- methoxyl group bases）Phenyl）Thiophenyl）Phenoxy group）- 4,5- Er Qing Evil Azoles（335mg）, absolute ethyl alcohol（10mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb （5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent is taken out Filter, obtains 277mg white solids, yield 77.7%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.47-7.41(m,4H),7.36 (d,J=8.4,2H),7.18(d,J=8.4,2H),6.99(d,J=8.4,2H),6.92(d,J=8.4,2H),4.13(s,2H), 3.76(s,3H),3.75(s,4H).¹³C NMR(125MHz,CD₃OD)δ(ppm):160.891,159.627,140.433, 137.163,135.625,133.924,130.775,128.804,128.146,116.843,115.319,67.276, 61.888,61.055,55.755.HRMS,calc m/z:412.1577;found:412.158. fusing point：199-201℃.

Embodiment 10

This is the experiment proves that 2- amino -2-（4-（4-（2-（1- butyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）-1,3- The preparation of propanediol hydrochloride

（10-1）2-（4-（4-（（4- acetoxyl groups）Phenyl）Phenyl））- 2- oxoethyl butyrates

By 4-（（4- acetyl bromides）Phenyl）Phenoxyacetic acid ester（9.00g, 27.0mmol, 1equiv）, acetonitrile（50mL）, N-butyric acie（4.94mL, 54.0mmol, 2equiv）, triethylamine（7.53mL, 54.0mmol, 2equiv）100mL is put into successively In eggplant-shape bottle, reaction 5 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, residue is dissolved with dichloromethane, flash Column chromatography obtains 6.56g white solids, yield 71.4%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.99(d,J=8.4, 2H),7.68(d,J=7.8,2H),7.64(d,J=9,2H),7.21(d,J=8.7,2H),5.37(s,2H),2.50(t,J=7.5, 2H),2,34(s,3H),1.79-1.72(m,2H),1.03(t,J=7.5,3H).MS:341.1416,703.2574. fusing point：82- 83℃。

（10-2）2- (1- butyl) -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole

By 2-（4-（4-（（4- acetoxyl groups）Phenyl）Phenyl））- 2- oxoethyl butyrates（6.56g, 19.3mmol, 1equiv）, dimethylbenzene（50mL）, acetamide（5.70g, 96.5mmol, 5equiv）, boron trifluoride ether（0.97mL）It throws successively Enter into 100mL eggplant row bottles, be warming up to back flow reaction, reacts 30 hours.Reaction finishes, and steams dimethylbenzene, residue dichloro Methane dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, and flash column chromatographies obtain 0.93g Huangs Color solid, yield 15.0%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.99(d,J=8,2H),7.68(d,J=8,2H),7.63 (d,J=8.4,2H),7.21(d,J=8.4,2H),5.367(s,2H),2.49(t,J=7.2,2H),2.34(s,3H),1.78- 1.73(m,2H),1.02(t,J=7.6,3H).MS:322.14426. fusing point：82-83℃.

（10-3）2- (1- butyl) -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole

By 2- (1- butyl) -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole（930mg, 2.89mmol, 1equiv）, Absolute ethyl alcohol（15mL）, distilled water（2mL）, sodium hydroxide（127mg, 3.18mmol, 1.1equiv）100mL eggplants are put into successively In shape bottle, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water, dichloromethane extraction, anhydrous sulphur is added Sour sodium drying, steams solvent, obtains 751mg white solids, yield 93.0%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.33 (t,J=8,2H),7.12-7.04(d,J=7.6,1H),7.06-6.98(m,6H),2.29(s,3H).MS:280.1831. fusing point： 188-189℃。

（10-4）2- methyl -4- methylols -4-（4-（2-（（1- propyl）Oxazole -4- bases）Phenyl）Phenoxy group）- 4,5- two Qing oxazoles

Under argon gas protection, by triphenylphosphine（1.060g, 4.04mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.84mL, 4.04mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（781mg, 5.38mmol, 2equiv）, 2- (1- butyl) -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole （751mg, 2.69mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, Toluene is steamed, residue is dissolved with dichloromethane, flash column chromatographies, obtains 430mg white solids, yield 39.3%.¹H NMR (300MHz,CDCl₃)δ(ppm):7.84(s,1H),7.77(d,J=8.1,2H),7.59-7.53(m,4H),6.97(d,J= 8.7,2H),4.38(d,J=8.7,1H),4.28(d,J=9,1H),4.12(d,J=9,1H),3.97(d,J=9,1H),3.85(d, J=11.4,1H),3.75(d,J=11.1,1H),2.81(t,J=7.2,2H),2.06(s,3H),1.89-1.81(m,2H),1.03 (t,J=7.5,3H).MS:407.2021,835.3754. fusing point：167-168℃.

（10-5）2- amino -2-（4-（4-（2-（1- propyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol Hydrochloride

By 2- methyl -4- methylols -4-（4-（2-（（1- propyl）Oxazole -4- bases）Phenyl）Phenoxy group）- 4,5- Er Qing Evil Azoles（430mg,1.06mmol）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）It puts into successively in 50mL eggplant-shape bottles, room temperature is stirred It mixes 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to neutrality pH with sodium hydroxide solution, dichloromethane Extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance 15mL methanol is dissolved, by sodium hydroxide （47mg, 1.17mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction, obtains 130mg white solids, yield 29.3%。¹H NMR(300MHz,CD₃OD)δ(ppm):8.10(s,1H),7.71(d,J=8.4,2H),7.57(d,J=8.7,4H), 7.06(d,J=8.7,2H),4.17(s,2H),3.78(s,4H),2.45(s,3H).¹³C NMR(100MHz,CD₃OD)δ(ppm): 167.32,159.31,141.44,141.26,135.45,135.41,130.78,129.03,127.89,126.97,116.18, 67.24,61.96,61.00,30.79,21.60,13.91.HRMS,calc m/z:383.19653;found:383.19571. Fusing point：200-201℃.

Embodiment 11

This is the experiment proves that 2- amino -2-（4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- The preparation of 1,3- propanediol hydrochlorides

（11-1）4- phenoxy-phenoxy acetic acid esters

By 4- phenoxy phenyls（20.00g, 0.107mol, 1equiv）, dry methylene chloride（100mL）, pyridine （9.5mL, 0.118mol, 1.1equiv）It puts into successively in 500mL eggplant-shape bottles, stirs 10 minutes, second is added dropwise into reaction solution Acyl chlorides（8.3mL, 0.118mol, 1.1equiv）, it is added dropwise within 10 minutes, is stirred at room temperature 4 hours.Reaction finishes, distillation washing Wash reaction solution（150mL×3）, anhydrous sodium sulfate drying, steam solvent, obtain 22.63g colorless oils, yield 92.7%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.85(s,1H),7.76(d,J=8,2H),7.57(d,J=8,2H),7.51(d,J= 8.4,1H),6.91(d,J=8.4,1H),2.83(t,J=7.6),1.90-1.81(m,2H),1.03(t,J=7.6,3H).MS: 213.175.

（11-2）4-（4-（（4- acetyl bromides）Phenoxy group）Phenoxy group）Acetic acid esters

By 4- phenoxy-phenoxy acetic acid esters（24.63g, 0.108mol, 1equiv）, dry methylene chloride（200mL）, bromine Acetyl bromide（9.4mL, 0.108mol, 1equiv）It puts into successively in 500mL three-necked bottles, ice bath is cooled to 0 DEG C, is added in batches Alchlor（28.8g, 0.216mol, 2equiv）, 0-5 DEG C, after alchlor adds is maintained the temperature at, reaction 2 is stirred at room temperature Hour.Reaction finishes, and reaction solution is poured into the 2N hydrochloric acid that ice cube is added, and stirs 2 hours, liquid separation, and dichloromethane washs water layer （150mL×3）, be associated with it is several layers of, anhydrous slufuric acid drying, steam solvent, obtain 23.23g pink solids, yield 61.6%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.98(d,J=8.8,2H),7.15-7.07(m,4H),7.03(d,J=8.4,2H), 4.40(s,2H),2.32(s,3H).MS:349.0066,351.0047.Fusing point：76-77℃.

（11-3）2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoe thyl acetates

By 4-（4-（（4- acetyl bromides）Phenoxy group）Phenoxy group）Acetic acid esters（6.00g, 17.2mmol, 1equiv）, acetonitrile （60mL）, acetic acid（2.0mL, 34.4mmol, 2equiv）, triethylamine（4.8mL, 34.4mmol, 2equiv）It puts into successively In 100mL eggplant-shape bottles, reaction 4 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, and residue is dissolved with dichloromethane, Flash column chromatographies obtain 3.13g white solids, yield 55.4%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.90(d,J= 8.4,2H),7.13(d,J=8.8,2H),7.07(d,J=9.2,2H),7.03(d,J=8.4,2H),2.317(s,3H),2.231 (s,3H).MS:329.1043. fusing point：116-117℃.

（11-4）2- methyl -4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole

By 2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoe thyl acetates（3.13g, 9.53mmol, 1equiv）, dimethylbenzene（70mL）, acetamide（1.69g, 28.6mmol, 5equiv）, boron trifluoride ether（0.29mL）It throws successively Enter into 100mL eggplant row bottles, be warming up to back flow reaction, reacts 30 hours.Reaction finishes, and steams dimethylbenzene, residue dichloro Methane dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, and flash column chromatographies obtain 0.70g Huangs Color solid, yield 23.7%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.79(s,1H),7.71(d,J=8.4,2H),7.08- 7.02(m,6H),2.60(s,3H),2.30(s,3H).MS:310.1164.Fusing point：104-105℃.

（11-5）2- methyl -4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole

By 2- methyl -4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole（930mg, 2.89mmol, 1equiv）, nothing Water-ethanol（15mL）, distilled water（2mL）, sodium hydroxide（127mg, 3.18mmol, 1.1equiv）100mL eggplant shapes are put into successively In bottle, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water, dichloromethane extraction, anhydrous slufuric acid is added Sodium is dried, and is steamed solvent, is obtained 751mg white solids, yield 93.0%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.76(s, 1H),7.62(d,J=8.4,2H),6.92(m,4H),6.82(d,J=8.8,2H),2.54(s,3H).MS:268.0996. fusing point： 131-132℃。

（11-6）2- methyl -4- methylols -4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（441mg, 1.68mmol, 1.5equiv）, toluene（40mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（0.76mL, 1.68mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（325mg, 2.24mmol, 2equiv）, 2- methyl -4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole（300mg, 1.12mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 150mg white solids, yield 34.0%.¹H NMR (400MHz,CDCl₃)δ(ppm):7.74(s,1H),7.63(d,J=8.4,2H),6.99-6.94(d,4H),6.88(d,J= 8.8,2H),4.40(d,J=8.8,1H),4.29(d,J=8.8,1H),4.07(d,J=9.2,1H),3.93(d,J=9.2,1H), 3.85(d,J=11.2,1H),3.74(d,J=11.2,1H),2.51(s,3H),2.08(s,3H).MS:395.16031. fusing point： 138-139℃。

（11-7）2- amino -2-（4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- 1,3- third Diol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）- 4,5- two Qing oxazoles（250mg, 0.634mmol, 1equiv）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）50mL eggplant shapes are put into successively In bottle, it is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, in being adjusted to pH with sodium hydroxide solution Property, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance is molten with 15mL methanol Solution, by sodium hydroxide（28mg, 0.697mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction 12 hours.Reaction It finishes, adjusts pH to 2-3 with ethanol solution of hydrogen chloride, flash column chromatographies obtain 128mg white solids, yield 31.5%.¹H NMR(300MHz,CD₃OD)δ(ppm):7.67(s,1H),7.10(d,J=8.4,2H),6.52-6.48(m,4H),6.42(d,J= 8.4,2H),3.60(s,2H),3.25(s,4H),2.04(s,3H).¹³C NMR(100MHz,CD₃OD)δ(ppm):165.03, 160.25,156.21,152.04,139.59,135.70,128.26,124.89,122.07,118.95,117.16,67.71, 61.96,61.07,13.45.HRMS,calc m/z:371.1601;found:371.1604. fusing point：120-121℃.

Embodiment 12

This is the experiment proves that 2- amino -2-（4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- The preparation of 1,3- propanediol hydrochlorides

（12-1）2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoethyl propionic esters

By 4-（4-（（4- acetyl bromides）Phenoxy group）Phenoxy group）Acetic acid esters（6.00g, 17.2mmol, 1equiv）, acetonitrile （60mL）, propionic acid（2.57mL, 34.4mmol, 2equiv）, triethylamine（4.79mL, 34.4mmol, 2equiv）It puts into successively In 100mL eggplant-shape bottles, reaction 4 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, and residue is dissolved with dichloromethane, Flash column chromatographies obtain 2.55g white solids, yield 43.3%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.91(d,J= 8.4,2H),7.14-7.06(m,4H),7.03(d,J=9,2H),5.30(s,2H),2.53(q,J=7.5,2H),2.32(s, 3H),1.23(t,J=7.5,3H).MS:343.1200,707.2137.Fusing point：52-53℃.

（12-2）2- ethyls -4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole

By 2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoethyl propionic esters（4.33g, 12.6mmol, 1equiv）, dimethylbenzene（60mL）, acetamide（3.72g, 63.0mmol, 5equiv）, boron trifluoride ether（0.63mL）It throws successively Enter into 100mL eggplant row bottles, be warming up to back flow reaction, reacts 30 hours.Reaction finishes, and steams dimethylbenzene, residue dichloro Methane dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, flash column chromatographies obtain 0.879g White solid, yield 21.6%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.82(s,1H),7.75(d,J=8.1,2H), 7.07-7.01(m,6H),2.99(q,J=6.3,2H),2.31(s,3H),1.43(t,J=7.5,3H).MS:324.1281. molten Point：92-93℃.

（12-3）2- ethyls -4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole

By 2- ethyls -4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole（879mg, 2.72mmol, 1equiv）, nothing Water-ethanol（8mL）, distilled water（2mL）, sodium hydroxide（120mg, 2.99mmol, 1.1equiv）100mL eggplant shapes are put into successively In bottle, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water, dichloromethane extraction, anhydrous slufuric acid is added Sodium is dried, and is steamed solvent, is obtained 730mg white solids, yield 95.4%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.77(s, 1H),7.75(d,J=7.2,2H),6.96-6.92(m,4H),6.83(d,J=8.4,2H),2.89(m,2H),1.39(t,J=6, 3H).MS:282.1422. fusing point：123-124℃.

（12-4）2- methyl -4- methylols -4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（952mg, 3.63mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.65mL, 3.63mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（703mg, 4.84mmol, 2equiv）, 2- ethyls -4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole（680mg, 2.42mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 220mg white solids, yield 22.2%.¹H NMR (400MHz,CDCl₃)δ(ppm):7.74(s,1H),7.64(d,J=8.4,2H),6.99-6.94(m,4H),6.88(d,J= 8.4,2H),4.39(d,J=8.8,1H),4.28(d,J=8.8,1H),3.93(d,J=8.8,1H),3.84(d,J=11.2,1H), 3.74(d,J=11.2,1H),2.84(q,J=8,2H),2.07(s,2H),1.7(t,J=7.6,3H).MS:409.17528. molten Point：125-126℃.

（12-5）2- amino -2-（4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- 1,3- third Diol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）- 4,5- two Qing oxazoles（400mg,0.979mmol,1equiv）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）50mL eggplant shapes are put into successively In bottle, it is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, in being adjusted to pH with sodium hydroxide solution Property, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance is molten with 15mL methanol Solution, by sodium hydroxide（43mg, 1.08mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction 12 hours.It has reacted Finish, adjusts pH to 2-3 with ethanol solution of hydrogen chloride, flash column chromatographies obtain 180mg yellow solids, yield 42.8%.¹H NMR (300MHz,CD₃OD)δ(ppm):8.13(s,1H),7.59(d,J=8.4,2H),6.98(m,4H),6.89(d,J=8.4,2H), 4.08(s,2H),3.73(s,4H),2.85(q,J=7.5,2H),1.31(q,J=7.5,3H).¹³C NMR(125MHz,CD₃OD)δ (ppm):168.91,160.19,156.19,152.07,139.66,135.51,128.33,125.14,122.06,118.93, 117.16,67.71,61.95,61.08,22.32,11.11.HRMS,calc m/z:385.1758;found:385.1755. molten Point：112-113℃.

Embodiment 13

This is the experiment proves that 2- amino -2-（4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- The preparation of 1,3- propanediol hydrochlorides

（13-1）2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoethyl butyrates

By 4-（4-（（4- acetyl bromides）Phenoxy group）Phenoxy group）Acetic acid esters（6.00g, 17.2mmol, 1equiv）, acetonitrile （50mL）, n-butyric acie（3.1mL, 34.4mmol, 2equiv）, triethylamine（4.8mL, 34.4mmol, 2quiv）It puts into successively In 100mL eggplant-shape bottles, reaction 5 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, and residue is dissolved with dichloromethane, Flash column chromatographies obtain 2.50g white solids, yield 40.8%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.91(d,J= 8.7,2H),7.14-7.09(m,4H),7.03(d,J=9,2H),5.30(s,2H),2.48(t,J=7.5,2H),2.32(s, 3H),1.78-1.71(m,2H),1.02(t,J=7.5,3H).MS:357.1372. fusing point：52-53℃.

（13-2）2-（1- propyl）-4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole

By 2-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）- 2- oxoethyl butyrates（2.50g, 7.41mmol, 1equiv）, dimethylbenzene（50mL）, acetamide（2.191g, 37.1mmol, 5equiv）, boron trifluoride ether（0.37mL）Successively It puts into 100mL eggplant row bottles, is warming up to back flow reaction, react 30 hours.Reaction finishes, and steams dimethylbenzene, and residue is with two Chloromethanes dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, flash column chromatographies obtain 600mg White solid, yield 24.0%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.78(s,1H),7.70(d,J=7.8,2H), 7.05-7.00(m,6H),2.83(t,J=7.8,2H),2.30(s,3H),1.88-1.81(m,2H),1.05-1.00(t,J= 7.2,3H).MS:338.13901. fusing point：53.5-55℃.

（13-3）2-（1- propyl）-4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole

By 2-（1- propyl）-4-（4-（（4- acetoxyl groups）Phenoxy group）Phenyl）Oxazole（600mg, 1.78mmol, 1equiv）, absolute ethyl alcohol（15mL）, distilled water（2mL）, sodium hydroxide（78mg, 1.96mmol, 1.1equiv）It puts into successively In 100mL eggplant-shape bottles, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water is added, and dichloromethane extracts, Anhydrous sodium sulfate is dried, and is steamed solvent, is obtained 519mg white solids, yield 98.7%.¹H NMR(300MHz,CDCl₃)δ (ppm):7.76(s,1H),7.63(d,J=9,2H),6.92(d,J=9,4H),6.82(d,J=9.3,2H),2.83(t,J=7.5, 2H),1.87-1.80(m,2H),1.01(t,J=7.5,3H).MS:296.142. fusing point：120-121℃.

（13-4）2- methyl -4- methylols -4-（4-（4-（（2-（1- propyl）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）- 4,5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（692mg, 2.64mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.2mL, 2.64mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（511mg, 3.52mmol, 2equiv）, 2-（1- propyl）-4-（4-（（4- hydroxyls）Phenoxy group）Phenyl）Oxazole （519mg, 1.76mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, Toluene is steamed, residue is dissolved with dichloromethane, flash column chromatographies, obtains 270mg colorless oils, yield 36.3%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.75(s,1H),7.64(d,J=8.4,2H),6.99-6.94(m,4H),6.88(d,J= 8.8,2H),4.37(d,J=8.8,1H),4.26(d,J=8.8,1H),4.06(d,J=8.8,1H),3.91(d,J=9.2,1H), 3.83(d,J=11.2,1H),3.74(d,J=11.2,1H),2.78(t,J=7.6,2H),1.83(q,J=7.6,2H),1.02(t, J=7.6,3H).MS:423.1929.

（13-5）2- amino -2-（4-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenoxy group）Benzene Oxymethylene））- 1,3- third Diol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（2-（1- propyl）Oxazole -4- bases）Phenoxy group）Phenoxymethyl）-4,5- Dihydro-oxazole（380mg,0.899mmol,1equiv）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）50mL eggplants are put into successively In shape bottle, it is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to pH with sodium hydroxide solution Neutrality, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance is molten with 15mL methanol Solution, by sodium hydroxide（43mg, 0.989mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction 12 hours.Reaction It finishes, adjusts pH to 2-3 with ethanol solution of hydrogen chloride, flash column chromatographies obtain 155mg white solids, yield 39.6%.It is molten Point：171-172℃.¹H NMR(400MHz,CD₃OD)δ(ppm):8.10(s,1H),7.61(d,J=8.8,2H),7.00-6.94 (m,4H),6.88(d,J=8.4,2H),4.10(s,2H),3.75(s,4H),2.73(t,J=7.6,2H),1.76(q,J=7.6, 2H),0.95(t,J=7.6,3H).¹H NMR(125MHz,CD₃OD)δ(ppm):167.20,159.62,156.04,152.36, 141.11,134.76,128.03,126.99,121.90,118.91,117.10,67.71,61.95,61.08,30.77, 21.60,13.89.HRMS,calc m/z:399.1914;found:399.1918. fusing point：171-172℃.

Embodiment 14

This is the experiment proves that 2- amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- third The preparation of diol hydrochloride

（14-1）4- phenylphenoxy acetic acid esters

By 4- xenols（20.00g, 0.118mol, 1equiv）, dry methylene chloride（100mL）, pyridine（10.5mL, 0.130mol, 1.1equiv）It puts into successively in 500mL eggplant-shape bottles, stirs 10 minutes, chloroacetic chloride is added dropwise into reaction solution （10.1mL, 0.142mol, 1.2equiv）, it is added dropwise within 10 minutes, is stirred at room temperature 4 hours.Reaction finishes, and distillation water washing is anti- Answer liquid（150mL×3）, anhydrous sodium sulfate drying, steam solvent, obtain 24.02g, yield 95.9%.¹H NMR(400MHz, CDCl₃)δ(ppm):7.60-7.55(m,4H),7.44(t,J=7.6,2H),7.36(t,J=7.2,1H),7.16(d,J=8.4, 2H).MS:213.0912. fusing point：81-82℃.

（14-2）4-（（4- acetyl bromides）Phenyl）Phenoxyacetic acid ester

By 4- phenylphenoxy acetic acid esters（1.00g, 4.7mmol, 1equiv）, dry methylene chloride（20mL）, acetyl bromide Bromine（0.41mL, 4.7mmol, 1equiv）It puts into successively in 100mL three-necked bottles, ice bath is cooled to 0 DEG C, and trichlorine is added in batches Change aluminium（1.25g, 9.4mmol, 2equiv）, 0-5 DEG C, after alchlor adds is maintained the temperature at, reaction 2 hours is stirred at room temperature. Reaction finishes, and reaction solution is poured into the 2N hydrochloric acid that ice cube is added, and stirs 2 hours, liquid separation, and dichloromethane washs water layer（30mL ×3）, be associated with it is several layers of, anhydrous slufuric acid drying, steam solvent, obtain 0.957g white solids, yield 61.1%.¹H NMR (300MHz,CDCl₃)δ(ppm):7.99(d,J=8.1,2H),7.62(d,J=8.1,2H),7.57(d,J=8.1,2H),7.14 (d,J=7.8,2H),4.40(s,2H),2.27(s,3H).MS:333.0378,335.0334. fusing point：124.5-126℃.

（14-3）2-（4-（（4- acetoxyl groups）Phenyl）Phenyl）- 2- oxoe thyl acetates

By 4-（（4- acetyl bromides）Phenyl）Phenoxyacetic acid ester（9.00g, 27.0mmol, 1equiv）, acetonitrile（50mL）, Acetic acid（3.09mL, 54.0mmol, 2equiv）, triethylamine（7.53mL, 54.0mmol, 2equiv）100mL eggplants are put into successively In shape bottle, reaction 5 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, residue is dissolved with dichloromethane, flash columns Chromatography, obtains 5.75g faint yellow solids, yield 68.2%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.87(s,1H),7.81 (d,J=8.1,2H),7.62(d,J=7.2,4H),7.18(d,J=8.1,2H),2.58(s,3H),2.36(s,3H).MS: 313.1069. fusing point：139.5-141℃.

（14-4）2- methyl -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole

By 2-（4-（（4- acetoxyl groups）Phenyl）Phenyl）- 2- oxoe thyl acetates（5.75g, 18.4mmol, 1equiv）, dimethylbenzene（50mL）, acetamide（5.43g, 92mmol, 5equiv）, boron trifluoride ether（0.92mL）It puts into successively Into 100mL eggplant row bottles, it is warming up to back flow reaction, is reacted 30 hours.Reaction finishes, and steams dimethylbenzene, residue dichloromethane Alkane dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, it is yellowish to obtain 1.50g for flash column chromatographies Color solid, yield 27.8%.ESI-MS:294.114.Fusing point：170.5-172℃.¹H NMR(400MHz,CDCl₃)δ(ppm): 7.84(s,1H),7.75(d,J=8,2H),7.59-7.54(m,4H),6.97(d,J=8.4,2H),4.44(d,J=8.4,1H), 4.33(d,J=8.8,1H),4.12(d,J=9.2,1H),4.02(d,J=9.2,1H),3.88(d,J=11.2,1H),3.77(d,J =11.2,1H),2.53(s,3H),2.110(s,3H).MS:294.114. fusing point：170.5-172℃.

（14-5）2- methyl -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole

By 2- methyl -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole（1.33g, 4.53mmol, 1equiv）, anhydrous Ethyl alcohol（15mL）, distilled water（2mL）, sodium hydroxide（199mg, 4.98mmol, 1.1equiv）100mL eggplant-shape bottles are put into successively In, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate is added It is dry, solvent is steamed, 1.00g white solids, yield 87.9% are obtained.¹H NMR(300MHz,CDCl₃)δ(ppm):7.82(s, 1H),7.57(d,J=8.1,2H),7.37(d,J=8.1,2H),7.12(d,J=8.4,2H),6.88(d,J=7.8,2H),2.59 (s,3H).MS:252.1031. fusing point：223-224℃.

（14-6）2- methyl -4- methylols -4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（1.566mg, 5.97mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（2.71mL 5.97mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（1.155g, 7.96mmol, 2equiv）, 2- methyl -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole（1.00g 3.98mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 575mg white solids, yield 38.2%.¹H NMR (300MHz,CDCl₃)δ(ppm):7.84(s,1H),7.76(d,J=8.1,2H),7.60-7.54(m,4H),6.98(d,J= 8.7,2H),4.48(d,J=8.1,1H),4.37(d,J=8.7,1H),4.13(d,J=9,1H),4.04(d,J=9.6,1H), 3.89(d,J=11.4,1H),3.78(d,J=11.4,1H),2.54(s,3H),2.14(s,3H).MS:379.1694. fusing point： 163-164℃。

（14-7）2- amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol salt Hydrochlorate

By 2- methyl -4- methylols -4-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 4,5- two Qing oxazoles（700mg, 1.77mmol, 1equiv）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）50mL eggplant shapes are put into successively In bottle, it is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, in being adjusted to pH with sodium hydroxide solution Property, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance is molten with 15mL methanol Solution, by sodium hydroxide（78mg, 1.95mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction 12 hours.It has reacted Finish, adjusts pH to 2-3 with ethanol solution of hydrogen chloride, flash column chromatographies obtain 400mg white solids, yield 57.8%.¹H NMR (400MHz,CD₃OD)δ(ppm):8.11(s,1H),7.71(d,J=8.0,2H),7.57(d,J=8,4H),7.06(d,J=8.4, 2H),4.16(s,2H),3.78(s,4H).¹³C NMR(75MHz,CD₃OD)δ(ppm):170.85,164.06,159.30, 141.43,135.52,135.42,130.73,129.02,127.89,126.90,116.17,67.22,61.94,61.09, 13.58.HRMS,calc m/z:355.16523;found:355.16541. fusing point：233-234℃.

Embodiment 15

This is the experiment proves that 2- amino -2-（4-（4-（（2- ethyl bases）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）-1,3- The preparation of propanediol hydrochloride

（15-1）2-（4-（（4- acetoxyl groups）Phenyl）Phenyl）- 2- oxoethyl propionic esters

By 4-（（4- acetyl bromides）Phenyl）Phenoxyacetic acid ester（9.00g, 27.0mmol, 1equiv）, acetonitrile（50mL）, Propionic acid（4.03mL, 54.0mmol, 2equiv）, triethylamine（7.53mL, 54.0mmol, 2equiv）100mL eggplants are put into successively In shape bottle, reaction 5 hours is stirred at room temperature.Reaction finishes, and filters, steams solvent, residue is dissolved with dichloromethane, flash columns Chromatography, obtains 7.31g white solids, yield 83.0%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.99(d,J=8.1,2H), 7.68(d,J=8.1,2H),7.64(d,J=8.7,2H),7.21(d,J=9,2H),5.37(s,2H),2.55(q,J=7.5,2H), 2.34(s,3H),1.24(t,J=7.5,3H).MS:327.1260,675.2255. fusing point：104-105.5℃.

（15-2）2- ethyls -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole

By 2-（4-（（4- acetoxyl groups）Phenyl）Phenyl）- 2- oxoethyl propionic esters（7.31g, 22.4mmol, 1equiv）, dimethylbenzene（50mL）, acetamide（6.62g, 112mmol, 5equiv）, boron trifluoride ether（1.1mL）It puts into successively Into 100mL eggplant row bottles, it is warming up to back flow reaction, is reacted 30 hours.Reaction finishes, and steams dimethylbenzene, residue dichloromethane Alkane dissolves, and distills water washing dichloromethane layer, and anhydrous sodium sulfate drying steams solvent, flash column chromatographies obtain 1.00g yellow Solid, yield 16.8%.¹H NMR(300MHz,CDCl₃)δ(ppm):7.87(s,1H),7.81(d,J=8.1,2H),7.62- 7.61(m,4H),7.17(d,J=8.4,2H),2.91(q,J=7.5,2H),2.33(s,3H),1.41(t,J=7.2,3H).MS: 308.1338,637.2365. fusing point：176.5-178℃.

（15-3）2- ethyls -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole

By 2- ethyls -4-（4-（（4- acetoxyl groups）Phenyl）Phenyl）Oxazole（4.22g, 13.7mmol, 1equiv）, anhydrous Ethyl alcohol（15mL）, distilled water（2mL）, sodium hydroxide（604mg, 15.1mmol, 1.1equiv）100mL eggplant-shape bottles are put into successively In, back flow reaction 10 minutes.Reaction finishes, and is cooled to room temperature, and 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate is added It is dry, solvent is steamed, 3.49g white solids, yield 96.0% are obtained.¹H NMR(300MHz,CDCl₃)δ(ppm):7.84(s, 1H),7.77(d,J=7.5,2H),7.58(d,J=7.8,2H),7.52(d,J=8.7,2H),6.92(d,J=9,2H),2.87(q, J=7.8,2H),1.40(t,J=7.8,3H).MS:266.1193. fusing point：243-244℃.

（15-4）2- methyl -4- methylols -4-（4-（4-（（Ethyl-Methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 4,5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（1.485mg, 5.66mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（2.57mL, 5.66mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（1.095g, 7.54mmol, 2equiv）, 2- ethyls -4-（4-（（4- hydroxyls）Phenyl）Phenyl）Oxazole（1.00g 3.77mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 490mg white solids, yield 33.1%.¹H NMR (300MHz,CDCl₃)δ(ppm):7.85(s,1H),7.77(d,J=8.1,2H),7.59-7.54(m,4H),6.97(d,J= 8.4,2H),4.44(d,J=9,1H),4.33(d,J=8.7,1H),4.20(t,1H),4.13(d,J=9,1H),3.88(d,J= 11.4,1H),3.77(d,J=11.4,1H),2.87(q,J=7.5,2H),2.11(s,3H),1.37(t,J=2.5,3H).MS: 393.1842. fusing point：161-162℃.

（15-5）2- amino -2-（4-（4-（（2- ethyl bases）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol Hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（Ethyl-Methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）-4,5- Dihydro-oxazole（490mg,1.25mmol,1equiv）, absolute methanol（10mL）, 2N hydrochloric acid（1.5mL）50mL eggplants are put into successively In shape bottle, it is stirred at room temperature 3 hours.Reaction finishes, and 40mL distilled water is added to reaction solution, is adjusted to pH with sodium hydroxide solution Neutrality, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying, steam solvent.Obtained substance is molten with 15mL methanol Solution, by sodium hydroxide（55mg, 1.38mmol, 1.1equiv）It puts into reaction bulb, is warming up to back flow reaction 12 hours.It has reacted Finish, adjusts pH to 2-3 with ethanol solution of hydrogen chloride, flash column chromatographies obtain 260mg white solids, yield 51.4%.¹H NMR (300MHz,CD₃OD)δ(ppm):8.10(s,1H),7.71(d,J=8.1,2H),7.56(d,J=8.1,4H),7.05(d,J= 8.1,2H),4.15(s,2H),3.76(s,4H),2.80(q,J=7.5,2H),1.31(t,J=7.5,3H).¹³C NMR (125MHz,CD₃OD)δ(ppm):168.23,159.29,141.39,141.36,135.50,135.34,130.91,129.03, 127.88,126.96,116.16,67.24,61.95,61.11,22.45,11.59.HRMS,calc m/z:369.1809; found:369.1806. fusing point：213-214℃.

Embodiment 16

This is the experiment proves that 2- amino -2-（4-（（4- phenyl）Phenoxy group）Benzene Oxymethylene）- 1,3- propanediol hydrochlorides Preparation

（16-1）4-（（4- hydroxyls）Phenoxy group）The preparation of trifluoromethanesulfonic acid phenyl ester

By 4,4 ,-diphenyl ether diphenol（10.00g, 49.5mmol, 1equiv）, acetonitrile（100mL）500mL is put into successively In eggplant-shape bottle, ice bath is cooled to 0 DEG C, and trifluoromethanesulfanhydride anhydride is added dropwise into reaction solution（10.0mL, 59.4mmol, 1.2equiv）, It is added dropwise within 1.5 hours, reacts at room temperature 0.5 hour.Reaction is finished, and solvent is steamed, and dissolves residue, distillation washing with dichloromethane It washs, filters, organic layer is dried with anhydrous sodium sulfate, and Flash column chromatographies obtain 8.99g colorless oils, yield 54.3%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.22(d,J=9.2,2H),6.92(d,J=9.2,2H),6.85(d,J=8.8,2H), 6.76(d,J=8.8,2H).MS:333.0016,666.9909.%。

（16-2）4-（（4- phenyl）Phenoxy group) phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Phenoxy group）The preparation of trifluoromethanesulfonic acid phenyl ester（1.20g, 3.59mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（208mg, 0.180mmol, 0.05equiv）, sodium carbonate Solution（761mg sodium carbonate+3ml）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （441mg, 3.59mmol, 1equiv）, phenylboric acid（526mg, 4.31mmol, 1.2equiv）It puts into reaction bulb, heats up To back flow reaction, react 8 hours.Reaction is finished, and reaction solution is cooled to room temperature, potassium hydroxide aqueous solution is put into reaction bulb （2.014g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3-4, dichloromethane Alkane extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent, flash column chromatographies obtain 0.56g white solids, yield 59.5%。¹H NMR(400MHz,CDCl₃)δ(ppm):7.56-7.51(m,4H),7.44-7.40(m,2H),7.34-7.30(m, 1H),7.02-6.97(m,4H),6.84(d,J=8.8,2H).MS:291.0932. fusing point：154-155℃.

（16-3）2- methyl -4- methylols -4-（4-（（4- phenyl）Phenoxy group）Benzene Oxymethylene base）- 4,5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（748mg, 2.85mmol, 1.5equiv）, toluene（50mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.30mL 2.85mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（0.552g, 3.80mmol, 2equiv）, 4-（（4- phenyl）Phenoxy group) phenol（500mg, 1.90mmol, 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams toluene, residue It is dissolved with dichloromethane, flash column chromatographies, obtains 270mg white solids, yield 36.7%.¹H NMR(400MHz,CDCl₃)δ (ppm):7.54-7.51(m,4H),7.42(m,2H),7.33-7.32(m,1H),7.00(m,3H),6.90-6.88(m,2H), 4.37(d,J=8,1H),4.26(d,J=8,1H),4.07(d,J=8.4,1H),3.91(d,J=8.4,1H),4.07(d,J=8.4, 1H),3.91(d,J=8.4,1H),3.84(d,J=11.2,1H),3,73(d,J=10.8,2H),2.049(s,3H).MS: 390.17017. fusing point：69-70℃.

（16-4）2- amino -2-（4-（（4- phenyl）Phenoxy group）Benzene Oxymethylene）- 1,3- propanediol hydrochlorides

By 2- methyl -4- methylols -4-（4-（（4- phenyl）Phenoxy group）Benzene Oxymethylene base）- 4,5- dihydro-oxazoles （350mg）, absolute ethyl alcohol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb （5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent is taken out Filter, obtains 255mg white solids, yield 70.3%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.51(d,J=8.4,4H), 7.36-7.32(m,3H),2.25-7.23(m,1H),7.00-6.97(m,4H),6.93(d,J=8.4,2H),4.10(s,2H), 3.75(s,4H).¹³C NMR(125MHz,CD₃OD)δ(ppm):159.21,155.93,152.66,141.79,137.23, 129.85,129.33,128.05,127.71,121.73,119.14,117.07,67.73,61.95,61.09.HRMS,calc m/z:366.16998;found:366.16934. fusing point：194-195℃.

Embodiment 17

This is the experiment proves that 2- amino -2-（4-（4-（4-（（4- methyl）Phenyl）Phenoxy group base）Benzene Oxymethylene））-1, The preparation of 3-propanediol hydrochloride

（17-1）4-（4-（（4- methyl）Phenyl）Phenoxy group）Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Phenoxy group）Trifluoromethanesulfonic acid phenyl ester（1.20g, 3.59mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（208mg, 0.180mmol, 0.05equiv）, sodium carbonate Solution（761mg sodium carbonate+3mL）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （441mg, 3.59mmol, 1equiv）, p-methylphenyl boric acid（586mg, 4.31mmol, 1.2equiv）Put into reaction bulb In, it is warming up to back flow reaction, is reacted 8 hours.Reaction is finished, and reaction solution is cooled to room temperature, potassium hydroxide is put into reaction bulb Aqueous solution（2.014g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3-4, Dichloromethane extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent, flash column chromatographies obtain 0.58g white solids, Yield 58.5%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.50(d,J=8.4,2H),7.45(d,J=8,2H),7.23(d,J= 7.6,2H),7.00-6.96(m,4H),6.83(d,J=8.4,2H),2.39(s,3H).MS:277.92261. fusing point：166-167 ℃。

（17-2）2- methyl -4- methylols -4-（4-（4-（（4- methyl）Phenyl）Phenoxy group）Benzene Oxymethylene）- 4,5- two Qing oxazoles

Under argon gas protection, by triphenylphosphine（713mg, 2.72mmol, 1.5equiv）, toluene（40mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.24mL, 2.72mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（0.525g, 3.62mmol, 2equiv）, 4-（4-（（4- methyl）Phenyl）Phenoxy group）Phenol（500mg, 1.81mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 240mg white solids, yield 32.9%.¹H NMR (400MHz,CDCl₃)δ(ppm):7.50(d,J=8.4,2H),7.44(d,J=8,2H),7.23(d,J=8,2H),6.99(m, 4H),6.89(d,J=8.8,2H),4.46(d,J=8.4,1H),4.35(s,1H),4.08(d,J=8.4,1H),3.99(d,J= 8.4,1H),3.89(d,J=10.8,1H),3.76(d,J=11.2,1H),2.38(s,3H),2.13(s,3H).MS: 404.18625. fusing point：82-83℃.

（17-3）2- amino -2-（4-（4-（4-（（4- methyl）Phenyl）Phenoxy group base）Benzene Oxymethylene））- 1,3- the third two Alcohol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（4- methyl）Phenyl）Phenoxy group）Benzene Oxymethylene）- 4,5- Er Qing Evil Azoles（245mg）, absolute ethyl alcohol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N hydrochloric acid into reaction bulb （5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentrated solvent is taken out Filter, obtains 180mg white solids, yield 71.3%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.48(d,J=8.8,2H), 7.39(d,J=8,2H),7.16(d,J=8,2H),7.00-6.93(m,4H),6.91(d,J=8.4,2H),4.09(s,2H), 3.75(s,4H),2.29(s,3H).¹³C NMR(125MHz,CD₃OD)δ:158.90,155.86,152.77,138.88, 137.89,137.21,130.47,129.07,127.55,121.63,119.16,117.07,67.75,61.97,61.09, 49.51,49.34,49.17,49.00,48.83,48.66,48.49,21.07.HRMS,calc m/z:380.18563; found:380.18497. fusing point：211-212℃.

Embodiment 18

This is the experiment proves that 2- amino -2-（4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group base）Benzene Oxymethylene）-1,3- The preparation of propanediol hydrochloride

（18-1）4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group）Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Phenoxy group）Trifluoromethanesulfonic acid phenyl ester（1.20g, 3.59mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（208mg, 0.180mmol, 0.05equiv）, sodium carbonate Solution（761mg sodium carbonate+3mL）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （441mg, 3.59mmol, 1equiv）, p-methylphenyl boric acid（655mg, 4.31mmol, 1.2equiv）Put into reaction bulb In, it is warming up to back flow reaction, is reacted 8 hours.Reaction is finished, and reaction solution is cooled to room temperature, potassium hydroxide is put into reaction bulb Aqueous solution（2.014g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3-4, Dichloromethane extracts（20mL×3）, anhydrous sodium sulfate drying, steam solvent, flash column chromatographies obtain 0.56g white solids, Yield 53.4%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.49-7.46(m,4H),7.00-6.95(m,6H),6.83(d,J= 8.8,2H),3.85(s,3H).MS:291.0930,583.1751. fusing point：182-183℃.

（18-2）2- methyl -4- methylols -4-（4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group）Benzene Oxymethylene）-4,5- Dihydro-oxazole

Under argon gas protection, by triphenylphosphine（863mg, 3.29mmol, 1.5quiv）, toluene（40mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.50mL, 3.29mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（636mg, 4.38mmol, 2equiv）, 4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group）Phenol（640mg, 2.19mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 320mg white solids, yield 34.8%.¹H NMR (400MHz,CDCl₃)δ(ppm):7.48-7.46(m,4H),7.01-6.95(m,6H),6.89(d,J=8.8,2H),4.47(d, J=8.8,1H),4.35(d,J=8.4,1H),4.07(d,J=9.2,1H),3.99(d,J=9.2,1H),3.88(d,J=11.6, 1H),3.85(s,3H),3.76(d,J=11.2,1H),2.13(s,3H).MS:420.19. fusing point：108-109℃.

（18-3）2- amino -2-（4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group base）Benzene Oxymethylene）- 1,3- propylene glycol Hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（4- methoxyl groups）Phenyl）Phenoxy group）Benzene Oxymethylene）- 4,5- dihydros Oxazole（265mg）, absolute ethyl alcohol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving puts into 6N salt into reaction bulb Acid（5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, precipitation white solid, concentrated solvent, It filters, obtains 183mg white solids, yield 67.0%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.44(t,J=8.4,4H), 6.96-6.93(m,4H),6.92-6.88(m,4H),4.09(s,2H),3.75(s,3H),3.74(s,4H).¹³C NMR (75MHz,CD₃OD)δ(ppm):160.827,158.889,156.111,153.104,137.293,134.545,129.127, 129.020,121.862,119.497,117.329,115.544,68.002,62.232,61.362,50.129.HRMS,calc m/z:396.1805;found:396.1814. fusing point：190-191℃.

Embodiment 19

This is the experiment proves that 2- amino -2-（4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group base）Benzene Oxymethylene）-1, The preparation of 3-propanediol hydrochloride

（19-1）4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group）Phenol

Under protection of argon gas, by 4-（（4- hydroxyls）Phenoxy group）Trifluoromethanesulfonic acid phenyl ester（1.20g, 3.59mmol, 1equiv）, glycol dimethyl ether（20mL）, four triphenylphosphines conjunction palladium（208mg, 0.180mmol, 0.05equiv）, sodium carbonate Solution（761mg sodium carbonate+3mL）It puts into 100mL eggplant-shape bottles, is stirred at room temperature 5 minutes successively；By two water lithium bromides （441mg, 3.59mmol, 1equiv）, p-trifluoromethyl phenyl boric acid（819mg, 4.31mmol, 1.2equiv）Put into reaction In bottle, it is warming up to back flow reaction, is reacted 8 hours.Reaction is finished, and reaction solution is cooled to room temperature, hydroxide is put into reaction bulb Aqueous solutions of potassium（2.014g potassium hydroxide+20mL water）, 60 DEG C are reacted 1 hour, and 6N hydrochloric acid is put into reaction bulb, adjust pH to 3- 4, dichloromethane extraction（20mL×3）, anhydrous sodium sulfate drying steams solvent, and it is solid to obtain 0.57g whites for flash column chromatographies Body, yield 48.1%.¹H NMR(400MHz,CDCl₃)δ(ppm):7.68-7.63(m,4H),7.53(d,J=8.4,2H),7.03 (d,J=8.4,2H),6.98(d,J=8.8,2H),6.85(d,J=8.8,2H).MS:329.0729,659.1356. fusing point：138- 139℃。

（19-2）2- methyl -4- methylols -4-（4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group）Benzene Oxymethylene）-4, 5- dihydro-oxazoles

Under argon gas protection, by triphenylphosphine（740mg, 2.82mmol, 1.5equiv）, toluene（40mL）It puts into successively In 100mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and the toluene solution of diethyl azodiformate is added dropwise into reaction bulb（1.41mL, 2.82mmol 1.5equiv）, it is added dropwise within 15 minutes, is stirred 1 hour under ice bath；By 2- methyl -4,4- dihydroxymethyls -4,5- Dihydro-oxazole（546mg, 3.76mmol, 2equiv）, 4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group）Phenol（620mg, 1.88mmol 1equiv）It puts into reaction bulb successively, is warming up to back flow reaction, react 36 hours.Reaction finishes, and steams first Benzene, residue are dissolved with dichloromethane, flash column chromatographies, obtain 410mg white solids, yield 47.7%.¹H NMR (400MHz,CDCl₃)δ(ppm):7.69-7.63(m,4H),7.53(d,J=12.4,2H),7.02(d,J=8.4,4H),6.91 (d,J=8.8,2H),4.44(d,J=9.2,1H),4.33(d,J=8.8,1H),4.08(d,J=8.8,1H),3.97(d,J=9.2, 1H),3.87(d,J=11.2,1H),3.76(d,J=11.6,1H),2.36(s,3H).MS:458.1681. fusing point：97-98℃.

（19-3）2- amino -2-（4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group base）Benzene Oxymethylene）- 1,3- the third two Alcohol hydrochloride

By 2- methyl -4- methylols -4-（4-（4-（（4- trifluoromethyls）Phenyl）Phenoxy group）Benzene Oxymethylene）- 4,5- two Qing oxazoles（285mg）, absolute ethyl alcohol（5mL）, put into successively in 50mL eggplant-shape bottles, solid dissolving is put into reaction bulb 6N hydrochloric acid（5mL）, it is warming up to 70 DEG C and reacts 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and white solid is precipitated, and concentration is molten Agent filters, obtains 189mg white solids, yield 64.5%.¹H NMR(400MHz,CD₃OD)δ(ppm):7.72(d,J=8.4, 2H),7.65(d,J=8,2H),7.60(d,J=8.8,2H),7.03-6.96(m,6H),4.12(s,2H),3.76(s,4H).¹³C NMR(75MHz,CD₃OD)δ(ppm):160.201,156.157,152.234,145.580,135.263,129.677, 128.211,126.777,126.731,122.030,119.085,117.146,67.727,61.942,61.088.HRMS, calcm/z:434.15737;found:434.15665. fusing point：181-182℃.

Embodiment 20

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene oxygen Methylene））The preparation of -1,3- propylene glycol -1- phosphates

（20-1）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol

By 2- amino -2-（4-（4-（4-（（4- methyl）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- propylene glycol hydrochloric acid Salt（100mg, 0.231mmol）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions are put into successively in 50mL eggplant-shape bottles, Stirring 10 minutes；After solid dissolving, 40 μ L benzyl chloroformates are added, reaction 3 hours is stirred at room temperature；Reaction finishes, to reaction 20mL ethyl acetate is added in liquid, distillation water washing has several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 127mg colorless oils, yield 95.6%.¹H NMR(300MHz,Acetone-d₆)δ(ppm):7.57(d,J=8.1,2H), 7.52(d,J=8.1,2H),7.47-7.44(m,J=9,2H),7.35-7.23(m,8H),7.05(d,J=8.7,2H),5.05(s, 2H),4.30(s,2H),4.25-4.21(t,J=6,2H),3.97-3.87(m,4H),2.35(s,3H).MS:530.20026. molten Point：108-109℃.

（20-2）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene oxygen methylene Base））1,3-PD -1-O, O- dibenzyl phosphate

By 2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- propylene glycol（105mg, 0.198mmol, 1equiv）, 10mL dichloromethane, pyridine（32 μ L, 0.396mmol, 2equiv）, Chlorine phosphate dibenzyl ester（64 μ L, 0.277mmol, 1.4equiv）It puts into 25mL eggplant-shape bottles, reacts at room temperature 10 hours successively；Instead It should finish, 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution（15mL）, distill water washing（10mL）, Anhydrous sodium sulfate is dried, and is steamed solvent, is obtained 38mg colorless oils, yield 24.3%.CDCl3,400MHz,δ(ppm): 7.560-7.540(d,J=8,2H),7.523-7.504(d,J=7.6,2H),7.455-7.434(d,J=8.4,2H),7.378- 7.232(m,19H),7.022-7.001(d,J=8.4,2H),5.076(s,2H),5.056(s,2H),5.038(s,2H), 4.482-4.474(m,2H),4.373-4.267(m,2H),3.948-3.939(m,2H),2.352(s,3H).ESI-MS: 790.2565.

（20-3）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- methoxyl groups）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1402P-b（27mg, 0.034mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（24 μ L, 0.17mmol, 5equiv）, 0 It is stirred 1 hour at DEG C；Reaction finishes, and decompression steams solvent, and 5mL methanol is added into residue, and it is thio that 10% is added dropwise thereto Aqueous sodium persulfate solution filters until there is no solid precipitation, obtains 12mg white solids, yield 57.9%.

Embodiment 21

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene oxygen is sub- Methyl））The preparation of -1,3- propylene glycol -1- phosphates

（21-1）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol

By SYL1406（100mg, 0.231mmol）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions put into successively Into 50mL eggplant-shape bottles, stir 10 minutes；After solid dissolving, benzyl chloroformate is added（35 μ L, 0.246mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oils, yield 88.7%.CDCl3, 300MHz,δ(ppm):7.474-7.350(m,11H),7.262-7.218(m,4H),6.915-6.888((d,J=8.1,4H), 5.731(s,1H),5.097(s,2H),4.100(s,2H),3.950-3.913(d,J=11.1,2H),3.743-3.706(d,J= 11.1,2H),2.715-2.641(q,J=7.5,2H),1.288-1.237(t,7.5,3H).

（21-2）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））1,3-PD -1-O, O- dibenzyl phosphate

By SYL1406P-a（100mg, 0.184mmol, 1equiv）, 10mL dichloromethane, pyridine（30 μ L, 0.368mmol, 2equiv）, chlorine phosphate dibenzyl ester（60 μ L, 0.258mmol, 1.4equiv）25mL eggplant-shape bottles are put into successively In, it reacts at room temperature 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution （15mL）, distill water washing（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 39mg colorless oils, yield 26.4%. Acetone-d6,400MHz,δ(ppm):7.565-7.529(m,4H),7.460-7.439(d,J=8.4,2H),7.378- 7.283(m,17H),7.248-7.227(d,J=8.4,2H),7.024-7.004(d,J=8,2H),6.451(s,1H),5.075 (s,2H),5.055(s,2H),5.036(s,2H),4.40-4.472(m,2H),4.395(m,1H),4.351-4.328(d,J= 9.2,1H),4.288-4.265(d,J=9.2,1H),3.938(s,2H),2.694-2.638(q,J=7.2,2H),1.250- 1.212(t,J=7.6,3H).ESI-MS:804.2791.

（21-3）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- ethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1406P-b（39mg, 0.049mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（35 μ L, 0.245mmol, 5equiv）, It is stirred 1 hour at 0 DEG C；Reaction finishes, and decompression steams solvent, 5mL methanol is added into residue, and 10% sulphur is added dropwise thereto Sodium thiosulfate aqueous solution filters until there is no solid precipitation, obtains 12mg white solids, yield 49.1%.

Embodiment 22

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））- The preparation of 1,3- propylene glycol -1- phosphates

（22-1）2- benzyloxy-formyl base amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- third Glycol

By SYL1407（95mg, 0.227mmol）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions put into successively Into 50mL eggplant-shape bottles, stir 10 minutes；After solid dissolving, benzyl chloroformate is added（36 μ L, 0.250mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 105mg colorless oils, yield 89.7%.Acetone- d6,300MHz,δ(ppm):7.646-7.579(m,4H),7.485-7.426(m,4H),7.355-7.319(m,6H),7.272- 7.244(d,J=8.4,2H),7.069-7.040(d,J=8.7,2H),5.054(s,2H),4.308(s,2H),3.950-3.852 (m,4H).ESI-MS:516.1775.

（22-2）2- benzyloxy-formyl base amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- third Glycol -1-O, O- dibenzyl phosphate

By SYL1407P-a（116mg, 0.225mmol, 1equiv）, 10mL dichloromethane, pyridine（36 μ L, 0.45mmol, 2equiv）, chlorine phosphate dibenzyl ester（73 μ L, 0.315mmol, 1.4equiv）It puts into 25mL eggplant-shape bottles, reacts at room temperature successively 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution（15mL）, distillation washing It washs（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 39mg colorless oils, yield 26.4%.Acetone-d6, 300MHz,δ(ppm):7.637-7.612(d,J=7.5,2H),7.589-7.561(d,J=8.4,2H),7.475-7.424(m, 4H),7.378-7.240(m,18H),7.037-7.009(d,J=8.4,2H),5.083(s,2H),5.056(s,2H),5.0441 (s,2H),4.492-4.471(d,J=6.3,2H),4.333-4.300(m,3H),3.958-3937(d,J=6.3,2H).ESI- MS:776.2468.

（22-3）2- benzyloxy-formyl base amino -2-（4-（4-（（4- phenyl）Thiophenyl）Benzene Oxymethylene））- 1,3- third Glycol -1- phosphates

Under argon gas protection, by SYL1407P-b（40mg, 0.052mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（66 μ L, 0.468mmol, 9equiv）, It is stirred 1 hour at 0 DEG C；Reaction finishes, and decompression steams solvent, 5mL methanol is added into residue, and 10% sulphur is added dropwise thereto Sodium thiosulfate aqueous solution filters until there is no solid precipitation, obtains 23mg white solids, yield 74.3%.

Embodiment 23

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））The preparation of -1,3- propylene glycol -1- phosphates

（23-1）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol

By SYL1408（100mg, 0.206mmol, 1equiv）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions It puts into 50mL eggplant-shape bottles, stirs 10 minutes successively；After solid dissolving, benzyl chloroformate is added（32 μ L, 0.227mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 111mg colorless oils, yield 92.3%.CDCl3, 300MHz,δ(ppm):7.679-7.610(m,4H),7.448(m,4H),7.394(m,5H),7.252-7.217(m,2H), 6.944-6.918(d,J=7.8,2H),5.727(s,1H),5.102(s,2H),4.120(s,2H),3.962-3.924(d,J= 11.4,2H),3.751-3.712(d,J=11.7,2H).ESI-MS:584.1658.

（23-2）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））1,3-PD -1-O, O- dibenzyl phosphate

By SYL1408P-a（109mg, 0.187mmol, 1equiv）, 10mL dichloromethane, pyridine（30 μ L, 0.374mmol, 2equiv）, chlorine phosphate dibenzyl ester（61 μ L, 0.262mmol, 1.4equiv）25mL eggplant-shape bottles are put into successively In, it reacts at room temperature 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution （15mL）, distill water washing（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 34mg colorless oils, yield 21.5%. CDCl3,300MHz,δ(ppm):7.686-7.611(m,4H),7.466-7.410(m,4H),7.330-7.289(m,15H), 7.239-7.211(d,J=8.4,2H),6.871-6.843(d,J=8.4,2H),5,374(s,1H),5.056(s,2H),5.030 (s,2H),5.00(s,2H),4.304-4.277(m,1H),4.233-4.202(m,2H),4.023-3.993(d,J=9,1H), 3.850(s,2H).ESI‐MS:844.2384.

（23-3）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1408P-b（30mg, 0.035mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（26 μ L, 0.18mmol, 5equiv）, 0 It is stirred 1 hour at DEG C；Reaction finishes, and decompression steams solvent, and 5mL methanol is added into residue, and it is thio that 10% is added dropwise thereto Aqueous sodium persulfate solution filters until there is no solid precipitation, obtains 16mg white solids, yield 64.8%.

Embodiment 24

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene Oxymethylene））The preparation of -1,3- propylene glycol -1- phosphates

（23-1）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol

By SYL1409（100mg, 0.223mmol, 1equiv）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions It puts into 50mL eggplant-shape bottles, stirs 10 minutes successively；After solid dissolving, benzyl chloroformate is added（35 μ L, 0.245mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oils, yield 88.8%.CDCl3, 400MHz,δ(ppm):7.490-7.353(m,11H),7.253-7.221(m,2H),6.969-6.940(d,J=11.6,2H), 6.915-6.886(d,J=11.6,2H),5.730(s,1H),5.100(s,2H),4.102(s,2H),3.952-3.913(d,J= 15.6,2H),3.873(s,3H),3.744-3.705(d,J=15.6,2H).ESI-MS:546.1938.

（23-2）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））1,3-PD -1-O, O- dibenzyl phosphate

By SYL1409P-a（100mg, 0.183mmol, 1equiv）, 10mL dichloromethane, pyridine（29 μ L, 0.366mmol, 2equiv）, chlorine phosphate dibenzyl ester（59 μ L, 0.256mmol, 1.4equiv）25mL eggplant-shape bottles are put into successively In, it reacts at room temperature 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution （15mL）, distill water washing（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 34mg colorless oils, yield 23.1%. Acetone-d6,300MHz,δ(ppm):7.583-7.520(m,4H),7.453-7.228(m,19H),7.024-6.997(d,J =8.1,4H),5.084(s,2H),5.056(s,2H),5.043(s,2H),4.4898-4.470(d,J=5.7,2H),4.400- 4.262(m,3H),3.957-3.936(d,J=6.1H),3.837(s,3H).ESI-MS:806.2541.

（23-3）2- benzyloxy-formyl base amino -2-（4-（4-（4-（（4- trifluoromethyls）Phenyl）Thiophenyl）Benzene oxygen methylene Base））- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1409P-b（27mg, 0.034mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（24 μ L, 0.17mmol, 5equiv）, 0 It is stirred 1 hour at DEG C；Reaction finishes, and decompression steams solvent, and 5mL methanol is added into residue, and it is thio that 10% is added dropwise thereto Aqueous sodium persulfate solution filters until there is no solid precipitation, obtains 12mg white solids, yield 71.8%.

Embodiment 25

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene oxygen is sub- Methyl）The preparation of -1,3- propylene glycol -1- phosphates

（23-1）2- benzyloxy-formyl base amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol

By SYL1414（80mg, 0.205mmol, 1equiv）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions according to It is secondary to put into 50mL eggplant-shape bottles, it stirs 10 minutes；After solid dissolving, benzyl chloroformate is added（32 μ L, 0.226mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 66mg colorless oils, yield 65.9%.CDCl3, 300MHz,δ(ppm):7.861(s,1H),7.798-7.773(d,J=7.5,2H),7.603-7.573(d,J=9,2H), 7.563-7.533(d,J=9,2H),7.360(m,5H),6.988-6.971(d,J=8.1,2H),5.778(s,1H),5.06(s, 2H),4.701(s,4H),4.147(s,2H),3.966-3.927(d,J=11.7,2H),3.761-3.721(d,J=12,2H), 2.604(s,3H).ESI-MS:489.2057.

（23-2）2- benzyloxy-formyl base amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3-PD -1-O, O- dibenzyl phosphate

By SYL1414P-a（145mg, 0.194mmol, 1equiv）, 10mL dichloromethane, pyridine（31 μ L, 0.388mmol, 2equiv）, chlorine phosphate dibenzyl ester（62 μ L, 0.266mmol, 1.4equiv）25mL eggplant-shape bottles are put into successively In, it reacts at room temperature 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution （15mL）, distill water washing（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 54mg colorless oils, yield 37.2%.

（23-3）2- benzyloxy-formyl base amino -2-（4-（4-（（2- methyl）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1414P-b（35mg, 0.047mmol, 1equiv）, 10ml dichloromethane puts into successively In 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（60 μ L, 0.423mmol, 9equiv）, It is stirred 1 hour at 0 DEG C；Reaction finishes, and decompression steams solvent, 5mL methanol is added into residue, and 10% sulphur is added dropwise thereto Sodium thiosulfate aqueous solution filters until there is no solid precipitation, obtains 14mg yellow solids, yield 68.6%.

Embodiment 26

This is the experiment proves that 2- benzyloxy-formyl base amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenyl）Benzene oxygen is sub- Methyl）The preparation of -1,3- propylene glycol -1- phosphates

（23-1）2- benzyloxy-formyl base amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol

By SYL1415（100mg, 0.247mmol, 1equiv）, 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solutions It puts into 50mL eggplant-shape bottles, stirs 10 minutes successively；After solid dissolving, benzyl chloroformate is added（39 μ L, 0.272mmol, 1.1equiv）, reaction 3 hours is stirred at room temperature；Reaction finishes, and 20mL ethyl acetate is added into reaction solution, and distillation water washing has It is several layers of（20mL×3）, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oils, yield 87.0%.CDCl3, 300MHz,δ(ppm):7.907(s,1H),7.820-7.795(d,J=7.5,2H),7.613-7.588(d,J=7.5,2H), 7.563-7.536(d,J=8.1,2H),7.361(s,5H),7.006-6.977(d,J=8.7,2H),5.107(s,2H),4.147 (s,2H),3,969-3.929(d,J=12,2H),3.767-3.727(d,J=12,2H),2.952(m,2H),1.423(m,3H) .ESI-MS:503.2185.

（23-2）2- benzyloxy-formyl base amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3-PD -1-O, O- dibenzyl phosphate

By SYL1415P-a（100mg, 0.199mmol, 1equiv）, 10mL dichloromethane, pyridine（32 μ L, 0.398mmol, 2equiv）, chlorine phosphate dibenzyl ester（65 μ L, 0.279mmol, 1.4equiv）25mL eggplant-shape bottles are put into successively In, it reacts at room temperature 10 hours；Reaction finishes, and 10mL dichloromethane, the washing of 10% copper sulfate solution are added into reaction solution （15mL）, distill water washing（10mL）, anhydrous sodium sulfate drying, steam solvent, obtain 43mg colorless oils, yield 28.3%. CDCl3,300MHz,δ(ppm):7.873(s,1H),7.811-7.786(d,J=7.5,2H),7.601-7.573(d,J=8.1, 2H),7.534-7.507(d,J=8.1,2H),7.334-7.310(m,15H),6.931-6.03(d,J=8.4,2H),5.416 (s,1H),5.062(d,2H),5.031(s,2H),5.002(s,2H),4.337-4.311(m,1H),4.246-4.215(m, 2H),4.051-4.022(d,J=8.7,1H),3.884(s,2H),2.974-2.898(q,J=7.5,2H),1.442-1.391 (t,J=7.5,3H).ESI-MS:763.2829.

（23-3）2- benzyloxy-formyl base amino -2-（4-（4-（（2- ethyls）Oxazole -4- bases）Phenyl）Benzene Oxymethylene）- 1,3- propylene glycol -1- phosphates

Under argon gas protection, by SYL1415P-b（25mg, 0.0328mmol, 1equiv）, 10ml dichloromethane puts into successively Into 25mL eggplant-shape bottles, ice bath is cooled to 0 DEG C, and Iodotrimethylsilane is added dropwise into reaction solution（47 μ L, 0.328mmol, 10equiv）, stir 1 hour at 0 DEG C；Reaction finishes, and decompression steams solvent, 5mL methanol is added into residue, and thereto 10% sodium thiosulfate solution is added dropwise, until there is no solid precipitation, filters, obtains 11mg yellow solids, yield 74.8%.

Pharmacological evaluation

One, influence of the 1.1 observation S1P1 receptor stimulating agents to experimental rat vein hemolymph quantity.

1.2 experiment material

The configuration of drug：It accurately weighs the above-mentioned drugs of 10mg to be placed in mortar, measures 5 ‰ 4ml sodium carboxymethylcelluloses （CMC-Na）, homogenous suspension is developed into mortar（If not readily dissolving, 1 drop Tween-80 can be added）, dosage 10mg/Kg, Administered volume 0.4ml/100g, gavage.

Experimental animal：SD rats, male, cleaning grade, by Beijing, experimental animal Co., Ltd of dimension tonneau China provides, the quality certification Number SCXK（Capital）2006-0009；Wista rats, male, cleaning grade are bred by Institute of Experimental Animals, Chinese Academy of Medical Sciences Field provides, quality certification number：SCXK（Capital）2005-0013.The each administration group 3 of the above animal.

Instrument and equipment：The classification automatic hemacytometer of Japanese photoelectricity five, model：7222K builds vast and boundless medical skill by Beijing consonance Art development corporation, Ltd. provides paid service.Dilution, DH-640 provide service by Shanghai East Lake biomedicine Co., Ltd, Lot number：081225.

1.3 test method

Experimental animal enters after clean environment stablizes 24 hours, takes 10 μ L of blood in tail vein, is diluted in 2mL dilutions rapidly In liquid, lymphocyte quantity is counted using automatic hemacytometer.Take gavage after blood（p.o.）Give what experimental animal had configured Sample.After time point for 24 hours, animal cervical dislocation is put to death.It see the table below in detail.

Two, S1P1, S1P3 receptor-selective are tested

Influence of the table 1.S1P1 receptor stimulating agents to SD rat blood lymphocyte quantity

Note："△%"=（Lymphocyte after administration prolymphocyte-administration）/ administration prolymphocyte；

Table 2S1P1, S1P3 extracorporeal receptor Choice tests

Claims (10)

1. such as general formula IA compounds represented and its pharmaceutically acceptable salt, which is characterized in that

R is selected from hydrogen；

R₁Selected from substituted C1-4 alkyl, and substituent group is selected from hydroxyl；

R₂Selected from hydrogen；

M is selected from 1 to 4 integer；

R₃For hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 alkane Oxygroup, C1-6 alkylamino radicals, the acyl group of C1-6, the acyloxy of C1-6, the amide groups of C1-6, the halogenated alkyl of C1-6 or C2-6 Alkene, wherein the C1-6 alkylamino radicals include single alkylamino radical or double alkylamino radicals；

W is selected from oxygen atom；

X is selected from sulphur atom；

C rings are selected from

R₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, C1-4 The halogenated alkyl of amide groups, C1-4, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical or double alkylamino radicals.

2. such as general formula IC compounds represented and its pharmaceutically acceptable salt, which is characterized in that

R is selected from hydrogen；

R₁Selected from substituted C1-4 alkyl, and substituent group is selected from hydroxyl；

R₂Selected from hydrogen；

The integer that m is 1 to 4；

W is selected from oxygen atom；

R₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-6 alkyl, C1-6 Alkoxy, C1-6 alkylamino radicals, the halogenated alkyl of the amide groups of the acyloxy of the acyl group of C1-6, C1-6, C1-6, C1-6, C2-6's Alkene, wherein the C1-6 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

D rings are selected from

R₅Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated The alkene of alkyl or C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals.

3. compound according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that shown in following general formula

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₁Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated The alkene of alkyl or C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₂Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated The alkene of alkyl or C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated The alkene of alkyl or C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₅Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, C1-4 The alkene of amide groups, the halogenated alkyl of C1-4 or C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkanamines Base；

W is selected from oxygen atom；

X is selected from sulphur atom；

R₅₆Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals.

4. compound according to claim 3 and its pharmaceutically acceptable salt, which is characterized in that shown in following general formula

R₇₁Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl；

R₇₂Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl；

R₇₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl；

R₇₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl；

R₇₅Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl；

R₇₆Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, fluorine, chlorine, bromine, nitro, cyano, methyl, second Base, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tertiary butyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, It is n-butoxy, isobutoxy, tert-butoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, different Butylthio, tertiary butylthio, methylamino, ethylamino-, the third amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, tertiary fourth Amido, formoxyl, acetyl group, propiono, iso-propionyl, ring propiono, positive bytyry, isobutyryl, tertiary bytyry, formamide Base, acetamido, propionamido-, Isopropamide base, ring propionamido-, butanamide base, isobutyl amide, t-butyl carboxamide base, Vinyl, acrylic, allyl, cyclobutenyl.

5. compound according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that shown in following general formula

R₈₁Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

R₈₂Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

R₈₃Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, C1-4 The halogenated alkyl of amide groups, C1-4, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

R₈₄Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radical, C1-4 Acyl group, the acyloxy of C1-4, the amide groups of C1-4, C1-4 halogenated alkyl, the alkene of C2-4；

R₈₅Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals；

R₈₆Selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, carbamoyl, halogen, nitro, cyano, C1-4 alkyl, C1-4 Alkoxy, C1-4 alkylthio groups, C1-4 alkylamino radicals, the acyl group of C1-4, the acyloxy of C1-4, the amide groups of C1-4, C1-4 it is halogenated Alkyl, the alkene of C2-4, wherein the C1-4 alkylamino radicals include single alkylamino radical and double alkylamino radicals.

6. the compound and its pharmaceutically acceptable salt of following group, which is characterized in that

7. the preparation method of any one of claim 1-6 compounds, which is characterized in that including following method：

Method (one), wherein X select chlorine or bromine；N is the integer of 0-2,

Method (two), wherein X are singly-bound, and Y is chlorine or bromine,

Method (three), wherein X are sulphur atom, R C_0‐2Alkyl,

8. a kind of pharmaceutical composition, which is characterized in that containing described in any one of claim 1-6 compound and its in pharmacy Upper acceptable salt and pharmaceutically acceptable carrier.

9. application of the compound described in any one of claim 1-6 in preparing immunomodulator.

10. compound described in any one of claim 1-6 prepare treatment immunologic derangement, hypoimmunity immunosupress, Application after organ transplant in rejection and/or autoimmune disease drug.