CN104844486A - Amino propanediol derivatives, preparation method, drug compositions and uses thereof - Google Patents

Amino propanediol derivatives, preparation method, drug compositions and uses thereof Download PDF

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CN104844486A
CN104844486A CN201410053128.4A CN201410053128A CN104844486A CN 104844486 A CN104844486 A CN 104844486A CN 201410053128 A CN201410053128 A CN 201410053128A CN 104844486 A CN104844486 A CN 104844486A
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amino
alkylamino
base
ring
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CN104844486B (en
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齐建国
汪小涧
金晶
田育林
周琬琪
陈晓光
尹大力
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Institute of Materia Medica of CAMS
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Abstract

The invention discloses a class of amino propanediol derivatives, a preparation method, drug compositions and uses thereof, and particularly relates to a class of new immunoloregulation agents represented by a general formula (I), a preparation method, drug compositions containing the immunoloregulation agents, and especially uses of the immunoloregulation agents as immunoloregulation drugs. The compound with characteristics of excellent treatment effect and low toxicity can be used in the fields of immunologic derangement and immunosuppression, and can further be used for treatment of hypoimmunity, organ transplant rejection and autoimmune diseases. The formula I is defined in the instruction.

Description

Amido propylene glycol derivative, its preparation method and its pharmaceutical composition and purposes
Technical field
The present invention relates to the immunomodulator that a class is new.Its preparation method, containing their pharmaceutical composition, and as medicine, especially as the purposes of prevention and therapy by the immunoregulation druge of the disease of T cell mediated, belongs to medical art.
Background technology
The immune response of body is that antibody gets rid of foreign matter as bacterium, the important defense mechanism of virus and graft etc., is also the important homeostasis preventing own cells from making a variation and cause a disease.By affecting body's immunity, the means reaching prevention and therapy disease are called immunotherapy or immunotherapy.
Immunomodulatory refers to and acts on immunoreactive different link, plays its regulating effect, and organism immune response is within required scope, reaches the object of prevention or disease therapy.Promote that low immunologic function is recovered normal or prevents immunologic function from reducing with medicine, reach and prevent and treat object, claim immunopotentiation therapy.With the proliferation and function of Drug inhibition and immune cells involved, lower the therapy of organism immune response, be called immunosuppressant therapy.The medicine used is called immunostimulant and immunosuppressor, general name immunomodulator.
Immunosuppressor is mainly used in the rejection after autoimmune disease and organ transplantation clinically.But the immunosuppressor of current Clinical practice also has more untoward reaction.
The side effect of glucocorticosteroid is necrosis of femoral head, cataract, edema, hirsutism, hyperglycemia, hyperlipidemia, hypertension, impaired wound healing, myopathy, osteoporosis, peptide ulceration, personality change and obesity; The side effect of S-Neoral is diarrhoea, gingival hyperplasia, headache, hemolytic uremic syndrome, hirsutism, hyperkalemia, hyperlipidemia, hypertension, high lithemia, hypomagnesemia, feel sick, renal toxicity, pancreatitis, paralysis, itch, to tremble and phlebothrombosis; The side effect of tacrolimus is cardiac hypertrophy, low-cholesterol, diarrhoea, headache, hyperglycemia, hyperkalemia, hypertension, hypomagnesemia, renal toxicity, neurotoxicity, feel sick, itch and trembling; The side effect of azathioprine is cancer, liver toxicity, leukopenia, feel sick, pancreatitis and vomiting; The side effect of Mycophenolate Mofetil is diarrhoea, edema, headache, hypertension, bone marrow depression, feel sick, renal toxicity and trembling; The side effect of Lei Pa meter star is stomatocace, arthrodynia, deep venous thrombosis, oedema, headache, hyperlipidemia, hypertension, interstitial lung disease and Fanconi syndrome (pancytopenia) etc.
In sum, the immunoregulation druge researching and developing high-efficiency low-toxicity side effect is very necessary.
Nineteen ninety, the people such as the Fujita of Japan are separated and obtain Compound I SP-I from the substratum of Cordyceps sinensis rod capsule spore bacterium, find that this molecule has higher immunosuppressive activity.Compound I SP-I was once also separated respectively as anti-mycotic agent and obtained from two kinds of fungi Myrioccocum albomyces and the substratum of Mycelia sterilia, was called Myriocin and Thermozymocidin.In the lymphocyte proliferation assay (MLR) that rat allogeneic lymphoid gland effect causes and rat body, lymphocytic generations of homology effector cell toxin T is tested (CTL) and is shown, specific activity S-Neoral height 10-100 times of ISP-I.
In the research of the structure of modification to ISP-I, the people such as Fujita find that again FTY720 has more satisfactory immunosuppressive activity, the derivative of existing a lot of FTY720 is in the news in the literature at present, the people such as TetsuroFujita are shown in by document, biological organic with pharmaceutical chemistry bulletin (Bioorganic & Medicinal ChemisrtyLetters), 5,1857(1995); The people such as Ryoji Hirose, biological organic and pharmaceutical chemistry bulletin (Bioorganic & Medicinal Chemisrty Letters), 6,2647(1996); The people such as Masatoshi Kiuchi, biological organic and pharmaceutical chemistry bulletin (Bioorganic & Medicinal Chemisrty Letters), 8,101(1998); The people such as Tetsuro Fujita, pharmaceutical chemistry magazine (J.Med.Chem.), 39,4451(1996); The people such as MasatoshiKiuchi, pharmaceutical chemistry magazine (J.Med.Chem.), 43,2946(2000).But the FTY720 derivative of all above-mentioned bibliographical informations is all different from compound involved in the present invention.
Summary of the invention
Through studying for a long period of time, the present invention finds that the new FTY720 derivative of explained later has excellent immunoregulatory activity, in immunosuppressive activity, particularly show excellent medicinal character.The present invention is accomplished on the above basis found.
One aspect of the invention provides excellent curative effect and the low immunomodulator of toxicity, as logical formula I compound and steric isomer thereof.
What another aspect of the present invention related to is pharmaceutical composition, comprising as the logical formula I compound of activeconstituents and/or its steric isomer.
What further aspect of the present invention related to is that logical formula I compound or the pharmaceutical composition containing him are preventing and/or treating the purposes in immunomodulatory.
What further aspect of the present invention related to is the method preventing and/or treating disease of immune system, and it comprises and delivers medicine to the host that need prevent and/or treat by logical formula I compound or containing its pharmaceutical composition.
The compound that the present invention relates to is compound as shown in logical formula I and pharmacy acceptable salt thereof and ester
Wherein
R is selected from hydrogen, C1-6 alkyl, C1-6 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-6 alkyl, C1-6 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-6 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino;
R 2be selected from hydrogen, substituted or non-substituted C1-8 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is selected from the integer of 1-4;
R 3be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from Sauerstoffatom, sulphur atom or singly-bound, represents that phenyl is directly connected with phenyl when X is singly-bound;
When X is selected from Sauerstoffatom, sulphur atom; Y is selected from the alkyl of C0-8, the alkoxyl group of C1-8, and it is five-ring that C2-8 alkene, five yuan or hexa-atomic aromatic ring, fragrant heterocycle tell fragrant heterocycle, hexa-atomic also, and can containing 1,2 or 3 heteroatomss, contained heteroatoms can be identical or different, the heteroatoms told is selected from N, O, S; When Y is selected from the alkyl of C0, represent Y disappearance, namely Z is directly connected with phenyl ring;
When X is selected from singly-bound; Y is selected from five yuan or hexa-atomic aryl, aromatic ring that fragrant heterocycle is told is five-ring, six-ring, and can containing 1,2 or 3 heteroatomss, and contained heteroatoms can be identical or different, and the heteroatoms told is selected from N, O, S; When Y is selected from the alkyl of C0, represent Y disappearance, namely Z is directly connected with phenyl ring;
Z is selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylthio; C1-6 alkylamino is comprising single alkylamino and two alkylamino, C1-6 alcoxyl C1-6 alkyl, C1-6 acyl group; C1-6 acyloxy; C1-6 amide group; C1-6 haloalkyl, the alkene of C2-6.
Preferred five yuan of aromatic rings are selected from
Preferred hexa-atomic aromatic ring is selected from
Preferably be selected from N containing 1-4, the heteroatomic quinary heterocyclic radical of O or S is selected from:
Preferably be selected from N containing 1-4, the heteroatomic hexa-member heterocycle base of O or S is selected from:
Preferred heterocycle is selected from
Compound shown in preferred formula (I) and pharmacy acceptable salt thereof and ester, including but not limited to, the compound shown in (IA)
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl, C1-4 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, sulfonate group;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is selected from the integer of 1 to 3;
R 3for hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, C1-61 alcoxyl C1-6 alkyl, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from Sauerstoffatom, sulphur atom
C ring is selected from
R 4be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
Compound shown in preferred formula (I) and pharmacy acceptable salt thereof and ester, including but not limited to, the compound shown in (IB)
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl, C1-4 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, sulfonate group;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is the integer of 1 to 3;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
R 3for hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6;
X is selected from Sauerstoffatom, sulphur atom;
R 4be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino is comprising single alkylamino and two alkylamino, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4; benzyl, the alkene of C2-4.
Compound shown in preferred formula (I) and pharmacy acceptable salt thereof and ester, including but not limited to, the compound shown in (I C)
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl, C1-4 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is the integer of 1 to 3;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
R 3be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino; C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6.
D ring is selected from
R 5be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
Compound shown in preferred formula (IA) and pharmacy acceptable salt thereof and ester, including but not limited to, compound as follows
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 51, R 52, R 53, R 54, R 55, R 56independently be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
Further preferred compound shown in formula (I A) and pharmacy acceptable salt thereof and ester, including but not limited to, compound as follows:
R 51, R 52, R 53, R 54, R 55, R 56independently be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl.
Further preferred compound shown in formula (IA) and pharmacy acceptable salt thereof and ester, including but not limited to, compound as follows:
Compound shown in preferred formula (IC) and pharmacy acceptable salt thereof and ester, including but not limited to, compound as follows
R 51, R 52, R 53, R 54, R 55, R 56independently be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
In the present invention, term " alkyl " refers to the straight or branched alkyl containing one or more carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, amyl group, isopentyl, neo-pentyl, sec.-amyl sec-pentyl secondary amyl, hexyl, isohexyl, Sec-Hexyl, heptyl, octyl group, nonyl, decyl etc.
In the present invention, term " alkyl " refers to the alkyl not containing or contain one or more double bond or triple bond.Described alkyl is as defined above.
Most preferred compound is selected from:
The present invention relates to the form of acceptable salt in logical formula I compound pharmacopedics simultaneously, and/or solvate.
The example of logical formula I compound salt comprises inorganic acid salt, such as hydrochloride, hydrobromate, vitriol and phosphoric acid salt, and organic acid salt, such as acetate, fumarate, maleate, benzoate, citrate, succinate, malate, mesylate, benzene sulfonate and tartrate.When logical formula I compound is applied in a salt form, tend to these pharmacy acceptable salts.The present invention also comprises hydrate and the solvate of general formula 1 compound or its salt.
According to the present invention, logical formula I compound can exist with the form of isomer, and usually described the present invention " changes.Compound " comprise the isomer of this compound.
Can be there is the cis-trans isomerism of double bond in logical formula I compound, asymmetric center has S configuration or R configuration, the present invention includes the mixture of all possible steric isomer and two or more isomer.If there is cis/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms, if need individual isomer to be separated according to conventional methods or to be prepared by Stereo-selective synthesis.
Further aspect of the present invention also relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be divided into enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise sustained release dosage, tamanori, wetting agent, disintegrating tablet, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tamanori can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, poly(ethylene oxide)polymers etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, solvent can be made with water, ethanol, Virahol, propylene glycol or their mixture and add appropriate this area conventional solubilizing agent, solubility promoter, pH adjusting agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjusting agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.If prepare lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. can also be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.Generally incite somebody to action, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, is more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on doctor's clinical experience and comprises the dosage regimen using other treatment means.
The compound that this law is bright or pharmaceutical composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
The compounds of this invention can be used as a kind of immunomodulator, especially can be used as the purposes of prevention and therapy by the immunoregulation druge of the disease of T cell mediated, particularly preparation treatment immunologic derangement, hypoimmunity immunosuppression, application after organ transplantation in rejection and/or autoimmune disease medicine.
Embodiment
Embodiment 1
This experiment demonstrates 2-amino-2-((4-((4-benzyloxy-phenyl) sulphur) benzene oxygen) methylene radical) preparation of-1,3-PD hydrochloride
(1-1) 4-((4-benzyloxy) thiophenyl) preparation of phenol
By 4, 4-diphenyl sulfide diphenol (10g, 45.8mmol, 1equiv) put into the 250mL three-necked bottle putting into stirrer, three-necked bottle is equipped with spherical condensation tube, constant pressure funnel, 100mLN is dropped in reactor, dinethylformamide (DMF), be stirred to dissolving, potassium hydroxide (2.827g is dropped into successively in reactor, 50.4mmol, 1.1equiv), potassiumiodide (380mg, 2.29mmol, 0.05equiv), stir 5 minutes, the DMF solution (6.0mL bromobenzyl+20mL DMF) of bromobenzyl is dripped in reactor, within 4 hours, dropwise, continue reaction 8 hours, be warming up to 40 DEG C of reactions 4 hours.Reaction is finished, and be poured into water by reaction solution, stir 30 minutes, separate out a large amount of solid, place 30 minutes, suction filtration, is dried to white solid, flash column chromatography, obtains 6.40g white solid (45.3%). 1hNMR (300MHz, Acetone-d 6) 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 DEG C.
(1-2) 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole
By TRIS (5.00g, 41.3mmol, 1equiv), DMF (50mL), triethly orthoacetate (9.10mL), DIPEA (7.20mL) is put in 250mL eggplant-shape bottle successively, is warming up to back flow reaction 8 hours.Reaction is finished, and steaming desolventizes, and adds 100mL sherwood oil in resistates, stirs 2 hours, and separate out solid, suction filtration obtains 4.63g faint yellow solid, yield 77.3%. 1hNMR (300MHz, CD 3oD) 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 DEG C.
(1-3) 2-methyl 4-methylol-4-((4-(4-benzyloxy) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (187mg, 0.713mmol, 1.1equiv), dry toluene (20mL) is put in 100mL eggplant-shape bottle successively, ice bath cools, drip diethyl azodiformate (40% toluene solution, 324uL, 0.73mmol, 1.1equiv), within 10 minutes, drip off, stir 1 hour under ice bath, 2-methyl-4 is dropped in reactor, 4-dihydroxymethyl-4, 5-dihydro-oxazole (141mg, 0.972mmol, 1.5equiv), stirring at room temperature 5 minutes, be warming up to back flow reaction 48 hours, reaction is finished, steam except toluene, residue from dichloromethane dissolves, flash column chromatography, obtain 63g white solid (22.0%). 1hNMR (300MHz, Acetone-d 6) 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 DEG C.
(1-4) 2-amino-2-((4-((4-benzyloxy-phenyl) sulphur) benzene oxygen) methylene radical)-1,3-PD hydrochloride
By 2-methyl 4-methylol-4-((4-(4-benzyloxy) thiophenyl) phenoxy group)-4,5-dihydro-oxazole (68mg), dehydrated alcohol (2mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (2mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, obtains 60mg white solid, yield 85.9%. 1hNMR (300MHz, CD 3oD) 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 DEG C.
Embodiment 2
This experiment demonstrates 2-amino-2-(4-(4-(4-((4-methyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(2-1) 4-((4-hydroxyl) thiophenyl) preparation of trifluoromethanesulfonic acid phenyl ester
By 4,4,-diphenyl sulfide diphenol (2.00g), acetone (35mL) is put in 100mL eggplant-shape bottle successively, cryosel bath is cooled to-15 DEG C, in reaction solution, drip the dichloromethane solution (1.6mL trifluoromethanesulfanhydride anhydride+2mL methylene dichloride) of trifluoromethanesulfanhydride anhydride, within 20 minutes, dropwise, room temperature reaction 3 hours.Reaction is complete pours in frozen water by reaction solution, and dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.Flash column chromatography, obtains 1.034g pale solid, yield 32.2%. 1hNMR (400MHz, Acetone-d 6) 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 DEG C.
(2-2) 4-(4-(4-((4-methyl) phenyl) thiophenyl)) phenol
Under argon shield, by 4-((4-hydroxyl) thiophenyl) trifluoromethanesulfonic acid phenyl ester (800mg, 2.28mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (132mg, 0.114mmol, 0.05equiv), aqueous sodium carbonate (483mg sodium carbonate+3ml) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (340mg, 2.28mmol, 1equiv), put in reaction flask to methylphenylboronic acid (373mg, 2.74mmol, 1.2equiv), be warming up to back flow reaction, react 6 hours 20 minutes.Reaction is finished, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (1.279g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.50g beige solid, yield 75.0%. 1h NMR (300MHz, Acetone-d 6) 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 DEG C.
(2-3) 2-methyl-4-methylol-4-(4-(4-((4-methyl) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (338mg, 1.29mmol, 1.3equiv), toluene (12mL) is put in 50mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (586 μ L, 1.29mmol, 1.3equiv) of diethyl azodiformate is dripped in reaction flask, within 30 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (288mg, 1.984mmol, 2equiv), 4-(4-(4-((4-methyl) phenyl) thiophenyl)) phenol (290mg, 0.992mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, flash column chromatography, obtain 139mg white solid, yield 33.4%. 1h NMR (300MHz, Acetone-d 6) 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 DEG C.
(2-4) 2-amino-2-(4-(4-(4-((4-methyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-methyl) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazole (139mg), dehydrated alcohol (4mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (4mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 132mg white solid, yield 92.3%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 3
This experiment demonstrates 2-amino-2-(4-(4-((2-n-propyl) oxazole-4-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(3-1) 4-(acetyl bromide) bromobenzene
By bromobenzene (13.0mL, 0.127mmol, 1equiv), methylene dichloride (200mL), bromoacetyl bromide (11.0mL, 0.127mmol, 1equiv) is put in 500mL three-necked bottle successively, ice bath is cooled to 0 DEG C, drop into aluminum chloride powder (34.0g, 0.254mmol, 2equiv) in batches, within 1 hour, add, room temperature reaction 2 hours.React complete, poured into by reaction solution and add in the 2N hydrochloric acid of ice cube, stirring at room temperature 1 hour, separatory, dichloromethane extraction (50mL × 2), anhydrous sodium sulfate drying, steams methylene dichloride, obtains 26.44g yellow solid, yield 74.9%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(3-2) 2-(4-bromophenyl)-2-oxoethyl butyric ester
By 4-(acetyl bromide) bromobenzene (5.00g, 18.0mmol, 1equiv), acetonitrile (100mL); triethylamine (5.00mL, 36mmol, 2equiv), butanic acid (3.3mL; 36.0mmol, 2equiv) put into successively in 250mL eggplant-shape bottle, be warming up to 80 DEG C of reactions 2 hours.React complete, steam solvent, resistates 100mL methylene dichloride dissolves, and which floor 2N salt acid elution (100mL) has, and which floor saturated aqueous sodium carbonate (100mL) washing has, distilled water wash organic layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtain 4.55g yellow solid, yield 88.7%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(3-3) 4-(4-bromophenyl)-2-(1-butyl) oxazole
By 2-(4-bromophenyl)-2-oxoethyl butyric ester (4.36g, 15.3mmol, 1equiv), dimethylbenzene (60mL), ethanamide (4.52g, 76.5mmol, 5equiv), boron trifluoride diethyl etherate (0.77mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 1.15g yellow solid, yield 28.1%. 1h NMR (300MHz, CDCl 3) 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. fusing point: 43.7-44.1 DEG C.
(3-4) 2-(1-butyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole
Under argon gas stream protection, by 4-(4-bromophenyl)-2-(1-butyl) oxazole (709mg, 2.66mmol, 1equiv), N, dinethylformamide (8mL), palladium (30mg, 0.133mmol, 0.05equiv), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (154mg, 0.266mmol, 0.1equiv) put into successively in 50mL eggplant-shape bottle, stir 5 minutes, N is dropped in reaction flask, N-diisopropylethylamine (742 μ L, 4.26mmol, 1.6equiv), thiohydroquinone (604mg, 4.79mmol, 1.8equiv), be warming up to back flow reaction 4 hours.React complete, steam DMF, methylene dichloride dissolves, and filter, flash column chromatography, obtains 0.76g yellow solid, yield 91.8%. 1h NMR (300MHz, Acetone-d 6) 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. fusing point: 122.4-123.9 DEG C.
(3-5) 2-methyl-4-methylol-4-(4-(4-(2-((1-butyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (960mg, 3.66mmol, 1.5equiv), toluene (25mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.66mL, 1.29mmol, 1.3equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (708mg, 4.88mmol, 2equiv), 2-(1-butyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole (760mg, 2.44mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 382mg yellow solid, yield 35.7%. 1H NMR(300MHz,Acetone-d 6)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-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-(2-((1-butyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazole (350mg), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (35mg, 0.878mmol, 1.1equiv) is dropped in reaction flask, is warming up to back flow reaction, obtain 217mg yellow solid, yield 60.4%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 4
This experiment demonstrates 2-amino-2-(4-(4-((2-ethyl) oxazole-4-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(4-1) 2-(4-bromophenyl)-2-oxoethyl propionic ester
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) put into successively in 500mL eggplant-shape bottle, be warming up to 80 DEG C of reactions 2 hours.React complete, steam solvent, resistates 200mL methylene dichloride dissolves, 2N salt acid elution (150mL) organic layer, and which floor saturated aqueous sodium carbonate (150mL) washing has, distilled water wash organic layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtain 12.38g yellow solid, yield 90.6%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(4-2) 4-(4-bromophenyl)-2-(1-ethyl) oxazole
By 2-(4-bromophenyl)-2-oxoethyl propionic ester (12.38g, 45.7mmol, 1equiv), dimethylbenzene (120mL), ethanamide (13.50g, 229mmol, 5equiv), boron trifluoride diethyl etherate (2.285mL) is put in 250mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 3.06g yellow solid, yield 26.6%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(4-3) 2-(1-ethyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole
Under argon gas stream protection, by 4-(4-bromophenyl)-2-(1-ethyl) oxazole (1.076g, 4.27mmol, 1equiv), N, dinethylformamide (8mL), palladium (48mg, 0.214mmol, 0.05equiv), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (124mg, 0.214mmol, 0.05equiv) put into successively in 50ml eggplant-shape bottle, stir 5 minutes, N is dropped in reaction flask, N-diisopropylethylamine (1.19mL, 6.83mmol, 1.6equiv), thiohydroquinone (970mg, 7.69mmol, 1.8equiv), be warming up to back flow reaction 15 hours.React complete, steam DMF, methylene dichloride dissolves, and filter, flash column chromatography, obtains 1.01g yellow solid, yield 79.5%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(4-4) 2-methyl-4-methylol-4-(4-(4-(2-((1-ethyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (1.338g, 5.10mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (2.3mL, 5.10mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (987g, 6.80mmol, 2equiv), 2-(1-ethyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole (1.01g, 3.40mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 601mg greenish yellow solid, yield 41.6%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(4-5) 2-amino-2-(4-(4-((2-ethyl) oxazole-4-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-(2-((1-ethyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazole (350mg, 0.824mmol), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (36mg, 0.906mmol, 1.1equiv) is dropped in reaction flask, is warming up to back flow reaction, obtain 169mg yellow solid, yield 48.9%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 5
This experiment demonstrates 2-amino-2-(4-(4-((2-methyl) oxazole-4-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(5-1) 2-(4-bromophenyl)-2-oxoe thyl acetate
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) put into successively in 100mL eggplant-shape bottle, be warming up to 80 DEG C of reactions 2 hours.React complete, steam solvent, resistates 100mL methylene dichloride dissolves, 2N salt acid elution (100mL) organic layer, and which floor saturated aqueous sodium carbonate (100mL) washing has, distilled water wash organic layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtain 5.01g yellow solid, yield 90.2%. 1h NMR (300MHz, CDCl 3) δ (ppm): 7.79 (dd, J 1=6.6, J 2=1.8,2H), 7.65 (dd, J 1=6.6, J 2=2.1,2H), 5.29 (s, 2H), 2.23 (s, 4H) .MS:256.9787,258.9770. fusing point: 71.8-73.2 DEG C.
(5-2) 4-(4-bromophenyl)-2-(1-methyl) oxazole
By 2-(4-bromophenyl)-2-oxoe thyl acetate (12.38g, 45.7mmol, 1equiv), dimethylbenzene (120mL), ethanamide (13.50g, 229mmol, 5equiv), boron trifluoride diethyl etherate (2.285mL) is put in 250mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 3.06g yellow solid, yield 26.6%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(5-3) 2-(1-methyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole
Under argon gas stream protection, by 4-(4-bromophenyl)-2-(1-methyl) oxazole (1.05g, 4.41mmol, 1equiv), N, dinethylformamide (8mL), palladium (50mg, 0.221mmol, 0.05equiv), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (255mg, 0.441mmol, 0.1equiv) put into successively in 50mL eggplant-shape bottle, stir 5 minutes, N is dropped in reaction flask, N-diisopropylethylamine (1.23mL, 7.06mmol, 1.6equiv), thiohydroquinone (946mg, 7.50mmol, 1.7equiv), be warming up to back flow reaction 15 hours.React complete, steam DMF, methylene dichloride dissolves, and filter, flash column chromatography, obtains 0.85g white solid, yield 68.0%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(5-4) 2-methyl-4-methylol-4-(4-(4-(2-((1-methyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (1.180g, 4.50mmol, 1.5equiv), toluene (25mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (2.0mL, 4.50mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (871g, 6.00mmol, 2equiv), 2-(1-methyl)-4-(4-(4-hydroxybenzene sulfenyl) phenyl)) oxazole (0.85g, 3.00mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 571mg light pink solid, yield 46.4%. 1h NMR (300MHz, Acetone-d 6) 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 DEG C.
(5-5) 2-amino-2-(4-(4-((2-methyl) oxazole-4-base) thiophenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-(2-((1-methyl) oxazole-4-base) thiophenyl) phenoxy group))-4,5-dihydro-oxazole (350mg, 0.828mmol), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (36mg, 0.906mmol, 1.1equiv) is dropped in reaction flask, is warming up to back flow reaction, obtain 267mg yellow solid, yield 76.2%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 6
This experiment demonstrates 2-amino-2-(4-(4-(4-((4-ethyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(6-1) 4-(4-(4-((4-ethyl) phenyl) thiophenyl)) phenol
Under argon shield, by 4-((4-hydroxyl) thiophenyl) trifluoromethanesulfonic acid phenyl ester (1.20g, 3.43mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (199mg, 0.172mmol, 0.05equiv), aqueous sodium carbonate (727mg sodium carbonate+4ml) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (422mg, 3.43mmol, 1equiv), put in reaction flask to ethylbenzene boric acid (618mg, 4.12mmol, 1.2equiv), be warming up to back flow reaction, react 8 hours.React complete, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (1.924g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.73g white solid, yield 69.5%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(6-2) 2-methyl-4-methylol-4-(4-(4-((4-ethyl) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (936mg, 3.57mmol, 1.5equiv), toluene (20mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.6mL, 3.57mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (691mg, 4.76mmol, 2equiv), 4-(4-(4-((4-ethyl) phenyl) thiophenyl)) phenol (0.73g, 2.38mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 340mg white solid, yield 32.9%. 1h NMR (400MHz, Acetone-d 6) 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 DEG C.
(6-3) 2-amino-2-(4-(4-(4-((4-ethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD hydrochloride
By SYL1402-c(200mg), dehydrated alcohol (5mL), puts in 50mL eggplant-shape bottle, dissolution of solid successively, drops into 6N hydrochloric acid (5mL) in reaction flask, is warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 130mg white solid, yield 63.1%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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 DEG C.C
Embodiment 7
This experiment demonstrates 2-amino-2-(4-(4-((4-phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(7-1) 4-(4-((4-phenyl) thiophenyl)) phenol
Under argon shield, by 4-((4-hydroxyl) thiophenyl) trifluoromethanesulfonic acid phenyl ester (1.2g, 3.43mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (199mg, 0.172mmol, 0.05equiv), aqueous sodium carbonate (727mg sodium carbonate+4ml) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (422mg, 3.43mmol, 1equiv), phenylo boric acid (502mg, 4.12mmol, 1.2equiv) is put in reaction flask, is warming up to back flow reaction, reacts 8 hours.React complete, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (1.924g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.60g beige solid, yield 62.9%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(7-2) 2-methyl-4-methylol-4-(4-((4-phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (850mg, 3.24mmol, 1.5equiv), toluene (20mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.47mL, 3.24mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (627mg, 4.32mmol, 2equiv), 4-(4-((4-phenyl) thiophenyl)) phenol (600mg, 2.16mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 531mg white solid, yield 60.6%. 1h NMR (300MHz, Acetone-d 6) 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 DEG C.
(7-3) 2-amino-2-(4-(4-((4-phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-((4-phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazole (200mg), dehydrated alcohol (5mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 145mg white solid, yield 70.4%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 8
This experiment demonstrates 2-amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(8-1) 4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl)) phenol
Under argon shield, by 4-((4-hydroxyl) thiophenyl) trifluoromethanesulfonic acid phenyl ester (1.00g, 2.85mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (165mg, 0.143mmol, 0.05equiv), aqueous sodium carbonate (604mg sodium carbonate+4ml) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (350mg, 2.85mmol, 1equiv), put in reaction flask to trifluoromethylbenzene boronic acid (650mg, 3.42mmol, 1.2equiv), be warming up to back flow reaction, react 8 hours.React complete, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (1.599g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 720mg white solid, yield 76.9%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(8-2) 2-methyl-4-methylol-4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (863mg, 3.29mmol, 1.5equiv), toluene (20mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.50mL, 3.29mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (636mg, 4.38mol, 2equiv), 4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl)) phenol (720mg, 2.19mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 336mg white solid, yield 32.4%. 1h NMR (400MHz, Acetone-d 6) 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 DEG C.
(8-3) 2-amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazole (336mg), dehydrated alcohol (10mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 213mg white solid, yield 61.7%. 1hNMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 9
This experiment demonstrates 2-amino-2-(4-(4-(4-((4-methoxyl group) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(9-1) 4-(4-(4-((4-methoxyl group) phenyl) thiophenyl)) phenol
Under argon shield, by 4-((4-hydroxyl) thiophenyl) trifluoromethanesulfonic acid phenyl ester (1.08g, 2.85mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (165mg, 0.143mmol, 0.05equiv), aqueous sodium carbonate (604mg sodium carbonate+4mL) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (350mg, 2.85mmol, 1equiv), put in reaction flask to methoxyphenylboronic acid (520mg, 3.42mmol, 1.2equiv), be warming up to back flow reaction, react 8 hours.React complete, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (1.599g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 660mg white solid, yield 75.1%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(9-2) 2-methyl-4-methylol-4-(4-(4-((4-methoxyl group base) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (842mg, 3.21mmol, 1.5equiv), toluene (20mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.46mL, 3.21mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (621mg, 4.28mmol, 2equiv), 4-(4-(4-((4-methoxyl group) phenyl) thiophenyl)) phenol (660mg, 2.14mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 335mg white solid, yield 34.9%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(9-3) 2-amino-2-(4-(4-(4-((4-methoxyl group base) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-methoxyl group base) phenyl) thiophenyl) phenoxy group)-4,5-dihydro-oxazole (335mg), dehydrated alcohol (10mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 277mg white solid, yield 77.7%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 10
This experiment demonstrates 2-amino-2-(4-(4-(2-(1-butyl) oxazole-4-base) phenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(10-1) 2-(4-(4-((4-acetoxyl group) phenyl) phenyl))-2-oxoethyl butyric ester
By 4-((4-acetyl bromide) phenyl) phenylium ester (9.00g; 27.0mmol; 1equiv), acetonitrile (50mL), butanic acid (4.94mL; 54.0mmol; 2equiv), triethylamine (7.53mL, 54.0mmol; 2equiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 5 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 6.56g white solid, yield 71.4%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(10-2) 2-(1-butyl)-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole
By 2-(4-(4-((4-acetoxyl group) phenyl) phenyl))-2-oxoethyl butyric ester (6.56g, 19.3mmol, 1equiv), dimethylbenzene (50mL), ethanamide (5.70g, 96.5mmol, 5equiv), boron trifluoride diethyl etherate (0.97mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 0.93g yellow solid, yield 15.0%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(10-3) 2-(1-butyl)-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole
By 2-(1-butyl)-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole (930mg, 2.89mmol, 1equiv), dehydrated alcohol (15mL), distilled water (2mL), sodium hydroxide (127mg, 3.18mmol, 1.1equiv) put into successively in 100mL eggplant-shape bottle, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 751mg white solid, yield 93.0%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(10-4) 2-methyl-4-methylol-4-(4-(2-((1-propyl group) oxazole-4-base) phenyl) phenoxy group)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (1.060g, 4.04mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.84mL, 4.04mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (781mg, 5.38mmol, 2equiv), 2-(1-butyl)-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole (751mg, 2.69mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 430mg white solid, yield 39.3%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(10-5) 2-amino-2-(4-(4-(2-(1-propyl group) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(2-((1-propyl group) oxazole-4-base) phenyl) phenoxy group)-4,5-dihydro-oxazole (430mg, 1.06mmol), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (47mg, 1.17mmol, 1.1equiv) is dropped in reaction flask, is warming up to back flow reaction, obtain 130mg white solid, yield 29.3%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 11
This experiment demonstrates 2-amino-2-(4-(4-(4-((2-methyl) oxazole-4-base) phenoxy group) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(11-1) 4-phenoxy-phenoxy acetic ester
By 4-phenoxy phenyl (20.00g, 0.107mol, 1equiv), dry methylene chloride (100mL), pyridine (9.5mL, 0.118mol, 1.1equiv) is put in 500mL eggplant-shape bottle successively, stir 10 minutes, Acetyl Chloride 98Min. (8.3mL, 0.118mol, 1.1equiv) is dripped in reaction solution, within 10 minutes, dropwise, stirring at room temperature 4 hours.React complete, distilled water wash reaction solution (150mL × 3), anhydrous sodium sulfate drying, steams solvent, obtains 22.63g colorless oil, yield 92.7%. 1H NMR(400MHz,CDCl 3)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 bromide) phenoxy group) phenoxy group) acetic ester
By 4-phenoxy-phenoxy acetic ester (24.63g, 0.108mol, 1equiv), dry methylene chloride (200mL), bromoacetyl bromide (9.4mL, 0.108mol, 1equiv) put into successively in 500mL three-necked bottle, ice bath is cooled to 0 DEG C, adds aluminum chloride (28.8g, 0.216mol in batches, 2equiv), maintain the temperature at 0-5 DEG C, after aluminum chloride adds, stirring at room temperature reacts 2 hours.React complete, poured into by reaction solution and add in the 2N hydrochloric acid of ice cube, stir 2 hours, separatory, which floor washed with dichloromethane water layer (150mL × 3), is associated with, and anhydrous slufuric acid is dry, steams solvent, obtains 23.23g pink solid, yield 61.6%. 1H NMR(400MHz,CDCl 3)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 DEG C.
(11-3) 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoe thyl acetate
By 4-(4-((4-acetyl bromide) phenoxy group) phenoxy group) acetic ester (6.00g; 17.2mmol; 1equiv), acetonitrile (60mL), acetic acid (2.0mL; 34.4mmol; 2equiv), triethylamine (4.8mL, 34.4mmol; 2equiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 4 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 3.13g white solid, yield 55.4%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(11-4) 2-methyl-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole
By 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoe thyl acetate (3.13g, 9.53mmol, 1equiv), dimethylbenzene (70mL), ethanamide (1.69g, 28.6mmol, 5equiv), boron trifluoride diethyl etherate (0.29mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 0.70g yellow solid, yield 23.7%. 1H NMR(400MHz,CDCl 3)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 DEG C.
(11-5) 2-methyl-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole
By 2-methyl-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole (930mg, 2.89mmol, 1equiv), dehydrated alcohol (15mL), distilled water (2mL), sodium hydroxide (127mg, 3.18mmol, 1.1equiv) put into successively in 100mL eggplant-shape bottle, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 751mg white solid, yield 93.0%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(11-6) 2-methyl-4-methylol-4-(4-(4-((2-methyl) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (441mg, 1.68mmol, 1.5equiv), toluene (40mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (0.76mL, 1.68mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (325mg, 2.24mmol, 2equiv), 2-methyl-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole (300mg, 1.12mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 150mg white solid, yield 34.0%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(11-7) 2-amino-2-(4-(4-(4-((2-methyl) oxazole-4-base) phenoxy group) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((2-methyl) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazole (250mg, 0.634mmol, 1equiv), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (28mg, 0.697mmol, 1.1equiv) is dropped in reaction flask, be warming up to back flow reaction 12 hours.React complete, regulate pH to 2-3, flash column chromatography with ethanol solution of hydrogen chloride, obtain 128mg white solid, yield 31.5%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 12
This experiment demonstrates 2-amino-2-(4-(4-(4-((2-ethyl) oxazole-4-base) phenoxy group) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(12-1) 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoethyl propionic ester
By 4-(4-((4-acetyl bromide) phenoxy group) phenoxy group) acetic ester (6.00g; 17.2mmol; 1equiv), acetonitrile (60mL), propionic acid (2.57mL; 34.4mmol; 2equiv), triethylamine (4.79mL, 34.4mmol; 2equiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 4 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 2.55g white solid, yield 43.3%. 1H NMR(300MHz,CDCl 3)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 DEG C.
(12-2) 2-ethyl-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole
By 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoethyl propionic ester (4.33g, 12.6mmol, 1equiv), dimethylbenzene (60mL), ethanamide (3.72g, 63.0mmol, 5equiv), boron trifluoride diethyl etherate (0.63mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 0.879g white solid, yield 21.6%. 1h NMR (300MHz, CDCl 3) 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. fusing point: 92-93 DEG C.
(12-3) 2-ethyl-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole
By 2-ethyl-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole (879mg, 2.72mmol, 1equiv), dehydrated alcohol (8mL), distilled water (2mL), sodium hydroxide (120mg, 2.99mmol, 1.1equiv) put into successively in 100mL eggplant-shape bottle, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 730mg white solid, yield 95.4%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(12-4) 2-methyl-4-methylol-4-(4-(4-((2-ethyl) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (952mg, 3.63mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.65mL, 3.63mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (703mg, 4.84mmol, 2equiv), 2-ethyl-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole (680mg, 2.42mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 220mg white solid, yield 22.2%. 1h NMR (400MHz, CDCl 3) 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. fusing point: 125-126 DEG C.
(12-5) 2-amino-2-(4-(4-(4-((2-ethyl) oxazole-4-base) phenoxy group) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((2-ethyl) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazole (400mg, 0.979mmol, 1equiv), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (43mg, 1.08mmol, 1.1equiv) is dropped in reaction flask, be warming up to back flow reaction 12 hours.React complete, regulate pH to 2-3, flash column chromatography with ethanol solution of hydrogen chloride, obtain 180mg yellow solid, yield 42.8%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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. fusing point: 112-113 DEG C.
Embodiment 13
This experiment demonstrates 2-amino-2-(4-(4-(4-((2-ethyl) oxazole-4-base) phenoxy group) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(13-1) 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoethyl butyric ester
By 4-(4-((4-acetyl bromide) phenoxy group) phenoxy group) acetic ester (6.00g; 17.2mmol; 1equiv), acetonitrile (50mL), butanic acid (3.1mL; 34.4mmol; 2equiv), triethylamine (4.8mL, 34.4mmol; 2quiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 5 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 2.50g white solid, yield 40.8%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(13-2) 2-(1-propyl group)-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole
By 2-(4-((4-acetoxyl group) phenoxy group) phenyl)-2-oxoethyl butyric ester (2.50g, 7.41mmol, 1equiv), dimethylbenzene (50mL), ethanamide (2.191g, 37.1mmol, 5equiv), boron trifluoride diethyl etherate (0.37mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 600mg white solid, yield 24.0%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(13-3) 2-(1-propyl group)-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole
By 2-(1-propyl group)-4-(4-((4-acetoxyl group) phenoxy group) phenyl) oxazole (600mg, 1.78mmol, 1equiv), dehydrated alcohol (15mL), distilled water (2mL), sodium hydroxide (78mg, 1.96mmol, 1.1equiv) put into successively in 100mL eggplant-shape bottle, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 519mg white solid, yield 98.7%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(13-4) 2-methyl-4-methylol-4-(4-(4-((2-(1-propyl group) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (692mg, 2.64mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.2mL, 2.64mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (511mg, 3.52mmol, 2equiv), 2-(1-propyl group)-4-(4-((4-hydroxyl) phenoxy group) phenyl) oxazole (519mg, 1.76mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 270mg colorless oil, yield 36.3%. 1H NMR(400MHz,CDCl 3)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-ethyl) oxazole-4-base) phenoxy group) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((2-(1-propyl group) oxazole-4-base) phenoxy group) Phenoxymethyl)-4,5-dihydro-oxazole (380mg, 0.899mmol, 1equiv), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (43mg, 0.989mmol, 1.1equiv) is dropped in reaction flask, be warming up to back flow reaction 12 hours.React complete, regulate pH to 2-3, flash column chromatography with ethanol solution of hydrogen chloride, obtain 155mg white solid, yield 39.6%.Fusing point: 171-172 DEG C. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 14
This experiment demonstrates 2-amino-2-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(14-1) 4-phenylphenoxy acetic ester
By 4-xenol (20.00g, 0.118mol, 1equiv), dry methylene chloride (100mL), pyridine (10.5mL, 0.130mol, 1.1equiv) is put in 500mL eggplant-shape bottle successively, stir 10 minutes, Acetyl Chloride 98Min. (10.1mL, 0.142mol, 1.2equiv) is dripped in reaction solution, within 10 minutes, dropwise, stirring at room temperature 4 hours.React complete, distilled water wash reaction solution (150mL × 3), anhydrous sodium sulfate drying, steams solvent, obtains 24.02g, yield 95.9%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(14-2) 4-((4-acetyl bromide) phenyl) phenylium ester
By 4-phenylphenoxy acetic ester (1.00g, 4.7mmol, 1equiv), dry methylene chloride (20mL), bromoacetyl bromide (0.41mL, 4.7mmol, 1equiv) put into successively in 100mL three-necked bottle, ice bath is cooled to 0 DEG C, adds aluminum chloride (1.25g, 9.4mmol in batches, 2equiv), maintain the temperature at 0-5 DEG C, after aluminum chloride adds, stirring at room temperature reacts 2 hours.React complete, poured into by reaction solution and add in the 2N hydrochloric acid of ice cube, stir 2 hours, separatory, which floor washed with dichloromethane water layer (30mL × 3), is associated with, and anhydrous slufuric acid is dry, steams solvent, obtains 0.957g white solid, yield 61.1%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(14-3) 2-(4-((4-acetoxyl group) phenyl) phenyl)-2-oxoe thyl acetate
By 4-((4-acetyl bromide) phenyl) phenylium ester (9.00g; 27.0mmol; 1equiv), acetonitrile (50mL), acetic acid (3.09mL; 54.0mmol; 2equiv), triethylamine (7.53mL, 54.0mmol; 2equiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 5 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 5.75g faint yellow solid, yield 68.2%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(14-4) 2-methyl-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole
By 2-(4-((4-acetoxyl group) phenyl) phenyl)-2-oxoe thyl acetate (5.75g, 18.4mmol, 1equiv), dimethylbenzene (50mL), ethanamide (5.43g, 92mmol, 5equiv), boron trifluoride diethyl etherate (0.92mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 1.50g faint yellow solid, yield 27.8%.ESI-MS:294.114。Fusing point: 170.5-172 DEG C. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(14-5) 2-methyl-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole
By 2-methyl-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole (1.33g, 4.53mmol, 1equiv), dehydrated alcohol (15mL), distilled water (2mL), sodium hydroxide (199mg, 4.98mmol, 1.1equiv) put in 100mL eggplant-shape bottle successively, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 1.00g white solid, yield 87.9%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(14-6) 2-methyl-4-methylol-4-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (1.566mg, 5.97mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (2.71mL, 5.97mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (1.155g, 7.96mmol, 2equiv), 2-methyl-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole (1.00g, 3.98mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 575mg white solid, yield 38.2%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(14-7) 2-amino-2-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-4,5-dihydro-oxazole (700mg, 1.77mmol, 1equiv), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (78mg, 1.95mmol, 1.1equiv) is dropped in reaction flask, be warming up to back flow reaction 12 hours.React complete, regulate pH to 2-3, flash column chromatography with ethanol solution of hydrogen chloride, obtain 400mg white solid, yield 57.8%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 15
This experiment demonstrates 2-amino-2-(4-(4-((2-ethyl base) oxazole-4-base) phenyl) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(15-1) 2-(4-((4-acetoxyl group) phenyl) phenyl)-2-oxoethyl propionic ester
By 4-((4-acetyl bromide) phenyl) phenylium ester (9.00g; 27.0mmol; 1equiv), acetonitrile (50mL), propionic acid (4.03mL; 54.0mmol; 2equiv), triethylamine (7.53mL, 54.0mmol; 2equiv) put into successively in 100mL eggplant-shape bottle, stirring at room temperature reacts 5 hours.React complete, suction filtration, steams solvent, and residue from dichloromethane dissolves, and flash column chromatography, obtains 7.31g white solid, yield 83.0%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(15-2) 2-ethyl-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole
By 2-(4-((4-acetoxyl group) phenyl) phenyl)-2-oxoethyl propionic ester (7.31g, 22.4mmol, 1equiv), dimethylbenzene (50mL), ethanamide (6.62g, 112mmol, 5equiv), boron trifluoride diethyl etherate (1.1mL) is put in 100mL eggplant row bottle successively, is warming up to back flow reaction, reacts 30 hours.React complete, steam dimethylbenzene, residue from dichloromethane dissolves, and distilled water wash dichloromethane layer, anhydrous sodium sulfate drying, steams solvent, flash column chromatography, obtains 1.00g yellow solid, yield 16.8%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(15-3) 2-ethyl-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole
By 2-ethyl-4-(4-((4-acetoxyl group) phenyl) phenyl) oxazole (4.22g, 13.7mmol, 1equiv), dehydrated alcohol (15mL), distilled water (2mL), sodium hydroxide (604mg, 15.1mmol, 1.1equiv) put in 100mL eggplant-shape bottle successively, back flow reaction 10 minutes.React complete, be cooled to room temperature, add 50mL distilled water, dichloromethane extraction, anhydrous sodium sulfate drying, steam solvent, obtain 3.49g white solid, yield 96.0%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(15-4) 2-methyl-4-methylol-4-(4-(4-((Ethyl-Methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (1.485mg, 5.66mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (2.57mL, 5.66mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (1.095g, 7.54mmol, 2equiv), 2-ethyl-4-(4-((4-hydroxyl) phenyl) phenyl) oxazole (1.00g, 3.77mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 490mg white solid, yield 33.1%. 1h NMR (300MHz, CDCl 3) 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 DEG C.
(15-5) 2-amino-2-(4-(4-((2-ethyl base) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((Ethyl-Methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-4,5-dihydro-oxazole (490mg, 1.25mmol, 1equiv), anhydrous methanol (10mL), 2N hydrochloric acid (1.5mL) is put in 50mL eggplant-shape bottle successively, stirring at room temperature 3 hours.React complete, add 40mL distilled water to reaction solution, with sodium hydroxide solution, pH regulator is extremely neutral, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steams solvent.By obtained material 15mL dissolve with methanol, sodium hydroxide (55mg, 1.38mmol, 1.1equiv) is dropped in reaction flask, be warming up to back flow reaction 12 hours.React complete, regulate pH to 2-3, flash column chromatography with ethanol solution of hydrogen chloride, obtain 260mg white solid, yield 51.4%. 1h NMR (300MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 16
This experiment demonstrates 2-amino-2-(4-((4-phenyl) phenoxy group) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(16-1) 4-((4-hydroxyl) phenoxy group) preparation of trifluoromethanesulfonic acid phenyl ester
By 4,4 ,-phenyl ether diphenol (10.00g, 49.5mmol, 1equiv), acetonitrile (100mL) is put in 500mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips trifluoromethanesulfanhydride anhydride (10.0mL in reaction solution, 59.4mmol, 1.2equiv), within 1.5 hours, dropwise, room temperature reaction 0.5 hour.Reaction is finished, and steams solvent, dissolves resistates with methylene dichloride, distilled water wash, suction filtration, organic over anhydrous dried over sodium sulfate, Flash column chromatography, obtain 8.99g colorless oil, yield 54.3%. 1H NMR(400MHz,CDCl 3)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 argon shield, by 4-((4-hydroxyl) phenoxy group) preparation (1.20g of trifluoromethanesulfonic acid phenyl ester, 3.59mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (208mg, 0.180mmol, 0.05equiv), aqueous sodium carbonate (761mg sodium carbonate+3ml) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (441mg, 3.59mmol, 1equiv), phenyl-boron dihydroxide (526mg, 4.31mmol, 1.2equiv) is put in reaction flask, is warming up to back flow reaction, reacts 8 hours.Reaction is finished, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (2.014g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.56g white solid, yield 59.5%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(16-3) 2-methyl-4-methylol-4-(4-((4-phenyl) phenoxy group) benzene Oxymethylene base)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (748mg, 2.85mmol, 1.5equiv), toluene (50mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.30mL, 2.85mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (0.552g, 3.80mmol, 2equiv), 4-((4-phenyl) phenoxy group) phenol (500mg, 1.90mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 270mg white solid, yield 36.7%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(16-4) 2-amino-2-(4-((4-phenyl) phenoxy group) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-((4-phenyl) phenoxy group) benzene Oxymethylene base)-4,5-dihydro-oxazoles (350mg), dehydrated alcohol (5mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, drops into 6N hydrochloric acid (5mL) in reaction flask, is warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 255mg white solid, yield 70.3%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 17
This experiment demonstrates 2-amino-2-(4-(4-(4-((4-methyl) phenyl) phenoxy group base) benzene Oxymethylene)) preparation of-1,3-PD hydrochloride
(17-1) 4-(4-((4-methyl) phenyl) phenoxy group) phenol
Under argon shield, by 4-((4-hydroxyl) phenoxy group) trifluoromethanesulfonic acid phenyl ester (1.20g, 3.59mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (208mg, 0.180mmol, 0.05equiv), aqueous sodium carbonate (761mg sodium carbonate+3mL) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (441mg, 3.59mmol, 1equiv), p-methylphenyl boric acid (586mg, 4.31mmol, 1.2equiv) is put in reaction flask, is warming up to back flow reaction, reacts 8 hours.Reaction is finished, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (2.014g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.58g white solid, yield 58.5%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(17-2) 2-methyl-4-methylol-4-(4-(4-((4-methyl) phenyl) phenoxy group) benzene Oxymethylene)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (713mg, 2.72mmol, 1.5equiv), toluene (40mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.24mL, 2.72mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (0.525g, 3.62mmol, 2equiv), 4-(4-((4-methyl) phenyl) phenoxy group) phenol (500mg, 1.81mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 240mg white solid, yield 32.9%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(17-3) 2-amino-2-(4-(4-(4-((4-methyl) phenyl) phenoxy group base) benzene Oxymethylene))-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-methyl) phenyl) phenoxy group) benzene Oxymethylene)-4,5-dihydro-oxazole (245mg), dehydrated alcohol (5mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 180mg white solid, yield 71.3%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 18
This experiment demonstrates 2-amino-2-(4-(4-((4-methoxyl group) phenyl) phenoxy group base) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(18-1) 4-(4-((4-methoxyl group) phenyl) phenoxy group) phenol
Under argon shield, by 4-((4-hydroxyl) phenoxy group) trifluoromethanesulfonic acid phenyl ester (1.20g, 3.59mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (208mg, 0.180mmol, 0.05equiv), aqueous sodium carbonate (761mg sodium carbonate+3mL) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (441mg, 3.59mmol, 1equiv), p-methylphenyl boric acid (655mg, 4.31mmol, 1.2equiv) is put in reaction flask, is warming up to back flow reaction, reacts 8 hours.Reaction is finished, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (2.014g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.56g white solid, yield 53.4%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(18-2) 2-methyl-4-methylol-4-(4-(4-((4-methoxyl group) phenyl) phenoxy group) benzene Oxymethylene)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (863mg, 3.29mmol, 1.5quiv), toluene (40mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.50mL, 3.29mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (636mg, 4.38mmol, 2equiv), 4-(4-((4-methoxyl group) phenyl) phenoxy group) phenol (640mg, 2.19mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 320mg white solid, yield 34.8%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(18-3) 2-amino-2-(4-(4-((4-methoxyl group) phenyl) phenoxy group base) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-methoxyl group) phenyl) phenoxy group) benzene Oxymethylene)-4,5-dihydro-oxazole (265mg), dehydrated alcohol (5mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 183mg white solid, yield 67.0%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 19
This experiment demonstrates 2-amino-2-(4-(4-((4-trifluoromethyl) phenyl) phenoxy group base) benzene Oxymethylene) preparation of-1,3-PD hydrochloride
(19-1) 4-(4-((4-trifluoromethyl) phenyl) phenoxy group) phenol
Under argon shield, by 4-((4-hydroxyl) phenoxy group) trifluoromethanesulfonic acid phenyl ester (1.20g, 3.59mmol, 1equiv), glycol dimethyl ether (20mL), four triphenylphosphines close palladium (208mg, 0.180mmol, 0.05equiv), aqueous sodium carbonate (761mg sodium carbonate+3mL) is put in 100mL eggplant-shape bottle successively, stirring at room temperature 5 minutes; By two water lithiumbromides (441mg, 3.59mmol, 1equiv), p-trifluoromethyl phenyl boric acid (819mg, 4.31mmol, 1.2equiv) is put in reaction flask, is warming up to back flow reaction, reacts 8 hours.Reaction is finished, reaction solution is cooled to room temperature, drops into potassium hydroxide aqueous solution (2.014g potassium hydroxide+20mL water) in reaction flask, 60 DEG C are reacted 1 hour, 6N hydrochloric acid is dropped in reaction flask, regulate pH to 3-4, dichloromethane extraction (20mL × 3), anhydrous sodium sulfate drying, steam solvent, flash column chromatography, obtains 0.57g white solid, yield 48.1%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(19-2) 2-methyl-4-methylol-4-(4-(4-((4-trifluoromethyl) phenyl) phenoxy group) benzene Oxymethylene)-4,5-dihydro-oxazoles
Under argon shield, by triphenylphosphine (740mg, 2.82mmol, 1.5equiv), toluene (40mL) is put in 100mL eggplant-shape bottle successively, ice bath is cooled to 0 DEG C, the toluene solution (1.41mL, 2.82mmol, 1.5equiv) of diethyl azodiformate is dripped in reaction flask, within 15 minutes, dropwise, stir 1 hour under ice bath; By 2-methyl-4,4-dihydroxymethyl-4,5-dihydro-oxazole (546mg, 3.76mmol, 2equiv), 4-(4-((4-trifluoromethyl) phenyl) phenoxy group) phenol (620mg, 1.88mmol, 1equiv) put into successively in reaction flask, be warming up to back flow reaction, react 36 hours.React complete, steam toluene, residue from dichloromethane dissolves, and flash column chromatography, obtains 410mg white solid, yield 47.7%. 1h NMR (400MHz, CDCl 3) 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 DEG C.
(19-3) 2-amino-2-(4-(4-((4-trifluoromethyl) phenyl) phenoxy group base) benzene Oxymethylene)-1,3-PD hydrochloride
By 2-methyl-4-methylol-4-(4-(4-((4-trifluoromethyl) phenyl) phenoxy group) benzene Oxymethylene)-4, (285mg) of 5-dihydro-oxazole, dehydrated alcohol (5mL), put in 50mL eggplant-shape bottle successively, dissolution of solid, in reaction flask, drop into 6N hydrochloric acid (5mL), be warming up to 70 DEG C of reactions 1 hour.Reaction is finished, and reaction solution is cooled to room temperature, and separate out white solid, concentrated solvent, suction filtration, obtains 189mg white solid, yield 64.5%. 1h NMR (400MHz, CD 3oD) 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, CD 3oD) 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 DEG C.
Embodiment 20
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-methoxyl group) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD-1-phosphoric acid ester
(20-1) 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-methoxyl group) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD
By 2-amino-2-(4-(4-(4-((4-methyl) phenyl) thiophenyl) benzene Oxymethylene))-1, ammediol hydrochloride (100mg, 0.231mmol), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add 40 μ L chloroformic acid benzyl esters, stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 127mg colorless oil, yield 95.6%. 1h NMR (300MHz, Acetone-d 6) 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. fusing point: 108-109 DEG C.
(20-2) 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-methoxyl group) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-O, O-dibenzyl phosphate
By 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-methoxyl group) phenyl) thiophenyl) benzene Oxymethylene))-1, ammediol (105mg, 0.198mmol, 1equiv), 10mL methylene dichloride, pyridine (32 μ L, 0.396mmol, 2equiv), chlorine phosphate dibenzyl ester (64 μ L, 0.277mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 38mg colorless oil, 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 group) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1402P-b(27mg, 0.034mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (24 μ L in reaction solution, 0.17mmol, 5equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 12mg white solid, yield 57.9%.
Embodiment 21
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-ethyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD-1-phosphoric acid ester
(21-1) 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-ethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD
By SYL1406(100mg, 0.231mmol), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (35 μ L, 0.246mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oil, 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-ethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-O, O-dibenzyl phosphate
By SYL1406P-a(100mg, 0.184mmol, 1equiv), 10mL methylene dichloride, pyridine (30 μ L, 0.368mmol, 2equiv), chlorine phosphate dibenzyl ester (60 μ L, 0.258mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 39mg colorless oil, 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-ethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1406P-b(39mg, 0.049mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (35 μ L in reaction solution, 0.245mmol, 5equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 12mg white solid, yield 49.1%.
Embodiment 22
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-((4-phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD-1-phosphoric acid ester
(22-1) 2-benzyloxy-formyl base amino-2-(4-(4-((4-phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD
By SYL1407(95mg, 0.227mmol), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (36 μ L, 0.250mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 105mg colorless oil, 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-PD-1-O, O-dibenzyl phosphate
By SYL1407P-a(116mg, 0.225mmol, 1equiv), 10mL methylene dichloride, pyridine (36 μ L, 0.45mmol, 2equiv), chlorine phosphate dibenzyl ester (73 μ L, 0.315mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 39mg colorless oil, 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-PD-1-phosphoric acid ester
Under argon shield, by SYL1407P-b(40mg, 0.052mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (66 μ L in reaction solution, 0.468mmol, 9equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 23mg white solid, yield 74.3%.
Embodiment 23
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD-1-phosphoric acid ester
(23-1) 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD
By SYL1408(100mg, 0.206mmol, 1equiv), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (32 μ L, 0.227mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 111mg colorless oil, 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-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-O, O-dibenzyl phosphate
By SYL1408P-a(109mg, 0.187mmol, 1equiv), 10mL methylene dichloride, pyridine (30 μ L, 0.374mmol, 2equiv), chlorine phosphate dibenzyl ester (61 μ L, 0.262mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 34mg colorless oil, 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-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1408P-b(30mg, 0.035mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (26 μ L in reaction solution, 0.18mmol, 5equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 16mg white solid, yield 64.8%.
Embodiment 24
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene)) preparation of-1,3-PD-1-phosphoric acid ester
(23-1) 2-benzyloxy-formyl base amino-2-(4-(4-(4-((4-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD
By SYL1409(100mg, 0.223mmol, 1equiv), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (35 μ L, 0.245mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oil, 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-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-O, O-dibenzyl phosphate
By SYL1409P-a(100mg, 0.183mmol, 1equiv), 10mL methylene dichloride, pyridine (29 μ L, 0.366mmol, 2equiv), chlorine phosphate dibenzyl ester (59 μ L, 0.256mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 34mg colorless oil, 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-trifluoromethyl) phenyl) thiophenyl) benzene Oxymethylene))-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1409P-b(27mg, 0.034mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (24 μ L in reaction solution, 0.17mmol, 5equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 12mg white solid, yield 71.8%.
Embodiment 25
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene) preparation of-1,3-PD-1-phosphoric acid ester
(23-1) 2-benzyloxy-formyl base amino-2-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD
By SYL1414(80mg, 0.205mmol, 1equiv), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (32 μ L, 0.226mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 66mg colorless oil, 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-base) phenyl) benzene Oxymethylene)-1,3-PD-1-O, O-dibenzyl phosphate
By SYL1414P-a(145mg, 0.194mmol, 1equiv), 10mL methylene dichloride, pyridine (31 μ L, 0.388mmol, 2equiv), chlorine phosphate dibenzyl ester (62 μ L, 0.266mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 54mg colorless oil, yield 37.2%.
(23-3) 2-benzyloxy-formyl base amino-2-(4-(4-((2-methyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1414P-b(35mg, 0.047mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (60 μ L in reaction solution, 0.423mmol, 9equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 14mg yellow solid, yield 68.6%.
Embodiment 26
This experiment demonstrates 2-benzyloxy-formyl base amino-2-(4-(4-((2-ethyl) oxazole-4-base) phenyl) benzene Oxymethylene) preparation of-1,3-PD-1-phosphoric acid ester
(23-1) 2-benzyloxy-formyl base amino-2-(4-(4-((2-ethyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD
By SYL1415(100mg, 0.247mmol, 1equiv), 10mL ethyl acetate, 4mL saturated sodium bicarbonate aqueous solution is put in 50mL eggplant-shape bottle successively, stirs 10 minutes; After dissolution of solid, add chloroformic acid benzyl ester (39 μ L, 0.272mmol, 1.1equiv), stirring at room temperature reacts 3 hours; React complete, add 20mL ethyl acetate in reaction solution, which floor (20mL × 3) distilled water wash has, anhydrous sodium sulfate drying.Solvent evaporated obtains 108mg colorless oil, 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-ethyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD-1-O, O-dibenzyl phosphate
By SYL1415P-a(100mg, 0.199mmol, 1equiv), 10mL methylene dichloride, pyridine (32 μ L, 0.398mmol, 2equiv), chlorine phosphate dibenzyl ester (65 μ L, 0.279mmol, 1.4equiv) put in 25mL eggplant-shape bottle successively, room temperature reaction 10 hours; React complete, add 10mL methylene dichloride in reaction solution, 10% copper sulfate solution washing (15mL), distilled water wash (10mL), anhydrous sodium sulfate drying, steams solvent, obtains 43mg colorless oil, 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-ethyl) oxazole-4-base) phenyl) benzene Oxymethylene)-1,3-PD-1-phosphoric acid ester
Under argon shield, by SYL1415P-b(25mg, 0.0328mmol, 1equiv), 10ml methylene dichloride is put in 25mL eggplant-shape bottle successively, and ice bath is cooled to 0 DEG C, drips Iodotrimethylsilane (47 μ L in reaction solution, 0.328mmol, 10equiv), stir 1 hour at 0 DEG C; React complete, decompression steams solvent, adds 5mL methyl alcohol, and drip 10% sodium thiosulfate solution wherein in resistates, and separate out until no longer include solid, suction filtration, obtains 11mg yellow solid, yield 74.8%.
Pharmacological evaluation
One, 1.1 S1P1 receptor stimulant is observed on the impact of experimental rat venous blood lymph quantity.
1.2 experiment material
The configuration of medicine: accurately take the above-mentioned medicine of 10mg and be placed in mortar, measures the 4ml Xylo-Mucine (CMC-Na) of 5 ‰, is developed into homogenous suspension (if not soluble in mortar, 1 tween-80 can be added), dosage 10mg/Kg, administration volume 0.4ml/100g, gavage.
Laboratory animal: SD rat, male, cleaning grade, tieing up laboratory animal company limited of tonneau China by Beijing provides, conformity certification SCXK(capital) 2006-0009; Wista rat, male, cleaning grade, is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences's breeding field, conformity certification number: SCXK(capital) 2005-0013.The all each administration group of above animal 3.
Plant and instrument: Japanese photoelectricity five is classified automatic hemacytometer, model: 7222K, provides paid service by Beijing Jian Hao medical science development corporation, Ltd. that coordinates.Diluent, DH-640, by East Lake, Shanghai, biomedical company limited provides service, lot number: 081225.
1.3 test method
Laboratory animal enters after clean environment stablizes 24 hours, gets blood 10 μ L, is diluted in rapidly in 2mL diluent, adopt automatic hemacytometer counting lymphocyte quantity in tail vein.After getting blood, gavage (p.o.) gives the sample that laboratory animal configures.After 24h time point, animal takes off cervical vertebra and puts to death.See the following form in detail.
Two, S1P1, S1P3 receptor-selective test
Table 1.S1P1 receptor stimulant is on the impact of SD rat serum medium size lymphocyte quantity
Note: " △ % "=(after administration prolymphocyte-administration lymphocyte)/administration prolymphocyte;
Table 2S1P1, S1P3 extracorporeal receptor Choice tests

Claims (13)

1. acceptable salt and ester in the compound as shown in formula I and pharmacodynamics thereof:
Wherein
R is selected from hydrogen, C1-6 alkyl, C1-6 acyl group, sulfonate group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-6 alkyl;
R 1be selected from hydrogen, substituted or non-substituted C1-6 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino;
R 2be selected from hydrogen, substituted or non-substituted C1-8 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is selected from the integer of 1-4;
R 3be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-6, the alkene of C2-6;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from Sauerstoffatom, sulphur atom or singly-bound, represents that phenyl is directly connected with phenyl when X is singly-bound;
When X is selected from Sauerstoffatom, sulphur atom; Y is selected from the alkyl of C0-8, the alkoxyl group of C1-8, C2-8 alkene, five yuan or hexa-atomic aromatic ring, fragrant heterocycle, and described fragrant heterocycle is five-ring, six-ring, and can containing 1,2 or 3 heteroatomss, contained heteroatoms can be identical or different, described heteroatoms is selected from N, O, S; When Y is selected from the alkyl of C0, represent Y disappearance, namely Z is directly connected with phenyl ring;
When X is selected from singly-bound; It is five-ring that Y is selected from aromatic ring described in five yuan or hexa-atomic aryl, fragrant heterocycle, six-ring, and can containing 1,2 or 3 heteroatomss, and contained heteroatoms can be identical or different, and described heteroatoms is selected from N, O, S; When Y is selected from the alkyl of C0, represent Y disappearance, namely Z is directly connected with phenyl ring;
Z is selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylthio; C1-6 alkylamino is comprising single alkylamino and two alkylamino, C1-6 acyl group; C1-6 acyloxy; C1-6 amide group; C1-6 haloalkyl, the alkene of C2-6.
2. acceptable salt and ester in compound according to claim 1 and pharmacodynamics thereof, is characterized in that, as shown in general formula I A
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group, sulfonate group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl, C1-4 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is selected from the integer of 1 to 4;
R 3for hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from Sauerstoffatom, sulphur atom;
C ring is selected from
R 4be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
3. acceptable salt and ester in compound according to claim 1 and pharmacodynamics thereof, is characterized in that, as shown in general formula I B
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, sulfonate group;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is the integer of 1 to 3;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
R 3for hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6;
X is selected from Sauerstoffatom, sulphur atom;
R 4be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino is comprising the alkene of the haloalkyl of the amide group of the acyloxy of the acyl group of single alkylamino and two alkylamino, C1-4, C1-4, C1-4, C1-4, benzyl, C2-4.
4. acceptable salt and ester in compound according to claim 1 and pharmacodynamics thereof, is characterized in that, as shown in general formula I C
R is selected from hydrogen, C1-4 alkyl, C1-4 acyl group ,-P (=O) (OR ') (OR "), wherein OR ' and OR " identical or different, R ' and R " be independently selected from hydrogen, C1-4 alkyl, C1-4 acyl group;
R 1be selected from hydrogen, substituted or non-substituted C1-4 alkyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino;
R 2be selected from hydrogen, substituted or non-substituted C1-6 alkoxy acyl, and substituting group is selected from halogen, carbonyl, hydroxyl, sulfydryl, cyano group, amino, phenyl;
M is the integer of 1 to 4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
R 3be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino; C1-6 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-6, the acyloxy of C1-6, the amide group of C1-6, the haloalkyl of C1-61, the alkene of C2-6.
D ring is selected from
R 5be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
5. acceptable salt and ester in compound according to claim 2 and pharmacodynamics thereof, is characterized in that, shown in following general formula
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 51be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 52be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 53be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 54be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 55be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
W is selected from Sauerstoffatom, sulphur atom or nitrogen-atoms;
X is selected from oxygen or sulphur;
R 56be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
6. acceptable salt and ester in compound according to claim 5 and pharmacodynamics thereof, is characterized in that, shown in following general formula
R 51be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 62be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 63be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 64be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 65be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 66be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl.
7. acceptable salt and ester in compound according to claim 5 and pharmacodynamics thereof, is characterized in that, shown in following general formula
R 71be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 72be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 73be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 74be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 75be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl,
R 76be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, fluorine, chlorine, bromine, nitro, cyano group, methyl, ethyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ring propoxy-, n-butoxy, isobutoxy, tert.-butoxy, methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, ring rosickyite base, positive butylthio, isobutylthio, tertiary butylthio, methylamino, ethylamino-, third is amino, isopropylamine base, cyclopropyl amino, n-butylamine-based, isobutyl amine, TERTIARY BUTYL AMINE base, formyl radical, ethanoyl, propionyl, iso-propionyl, ring propionyl, positive butyryl radicals, isobutyryl, tertiary butyryl radicals, formamido-, acetamido, propionamido-, Isopropamide base, ring propionamido-, positive amide-based small, isobutyl amide, t-butyl carboxamide base, vinyl, propenyl, allyl group, butenyl.
8. acceptable salt and ester in compound according to claim 4 and pharmacodynamics thereof, is characterized in that, shown in following general formula
R 51be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
R 52be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
R 52be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, C1-4 alcoxyl C1-4 alkyl, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
R 54be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
R 55be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio, C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4;
R 55be selected from hydrogen, hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group, C1-4 alkyl, C1-4 alkoxyl group, C1-4 alkylthio; C1-4 alkylamino comprising single alkylamino and two alkylamino, the acyl group of C1-4, the acyloxy of C1-4, the amide group of C1-4, the haloalkyl of C1-4, the alkene of C2-4.
9. acceptable salt and ester in compound as claimed in one of claims 1-8 and pharmacodynamics thereof, it is characterized in that, described compound is selected from following cohort:
10. the preparation method of compound any one of claim 1-9, is characterized in that, comprises following method:
Method (one), wherein X selects chlorine or bromine; N is the integer of 0-2,
Method (two), wherein X is Sauerstoffatom or singly-bound, and Y is chlorine or bromine,
Method (three), wherein X is Sauerstoffatom or sulphur atom, R be 0 ?the alkyl of 2 carbon,
11. 1 kinds of pharmaceutical compositions, is characterized in that, containing the compound according to any one of claim 1-9 and pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
12. the compound according to any one of claim 1-9 is preparing the application in immunomodulator.
Compound according to any one of 13. claim 1-9 is in preparation treatment immunologic derangement, hypoimmunity immunosuppression, application after organ transplantation in rejection and/or autoimmune disease medicine.
CN201410053128.4A 2014-02-17 2014-02-17 Amido propylene glycol derivative, preparation method and its pharmaceutical composition and purposes Active CN104844486B (en)

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CN107827716A (en) * 2017-09-28 2018-03-23 大连天源基化学有限公司 The residual processing method of kettle in the production of 1 (4 phenoxy phenoxy base) 2 propyl alcohol
CN111087358A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Prisamod
CN111087356A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Iguratimod
CN111087359A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Iguratimod

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CN100351244C (en) * 2002-05-27 2007-11-28 诺瓦提斯公司 Bis-aromatic alkanols
WO2005014525A2 (en) * 2003-08-12 2005-02-17 Mitsubishi Pharma Corporation Bi-aryl compound having immunosuppressive activity
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827716A (en) * 2017-09-28 2018-03-23 大连天源基化学有限公司 The residual processing method of kettle in the production of 1 (4 phenoxy phenoxy base) 2 propyl alcohol
CN111087358A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Prisamod
CN111087356A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Iguratimod
CN111087359A (en) * 2018-10-24 2020-05-01 中国医学科学院药物研究所 Preparation method of Iguratimod
CN111087356B (en) * 2018-10-24 2022-06-21 中国医学科学院药物研究所 Preparation method of Iguratimod
CN111087359B (en) * 2018-10-24 2022-06-21 中国医学科学院药物研究所 Preparation method of Iguratimod
CN111087358B (en) * 2018-10-24 2022-06-21 中国医学科学院药物研究所 Preparation method of Prisamod

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