CN107382989A - A kind of synthetic method with oxazole ring structure immunosuppressive drug - Google Patents

A kind of synthetic method with oxazole ring structure immunosuppressive drug Download PDF

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CN107382989A
CN107382989A CN201710689842.6A CN201710689842A CN107382989A CN 107382989 A CN107382989 A CN 107382989A CN 201710689842 A CN201710689842 A CN 201710689842A CN 107382989 A CN107382989 A CN 107382989A
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李起华
陈昊
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First Affiliated Hospital of Henan University of Science and Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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Abstract

The invention discloses a kind of synthetic method with oxazole ring structure immunosuppressive drug, belong to medical synthesis technical field.Technical scheme main points are：Technical scheme main points are：One kind has oxazole ring structure immunosuppressive drug, has following structure：

Description

A kind of synthetic method with oxazole ring structure immunosuppressive drug
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of conjunction with oxazole ring structure immunosuppressive drug Into method.
Background technology
Sphingolipid is the important composition composition of biomembrane, has the function that the intracellular goods and materials of protection.In recent years, with biology The development of technology and the complication of human diseases spectrum, the mankind deepen continuously to the understanding of sphingolipid., it is now thought that sphingolipid is not Only it is the important composition composition of biomembrane, while is also played a significant role in cell activities signal transduction.Sphingol -1- Phosphoric acid (S1P) is the bioactive lipid with important physiological function of discovered in recent years, is widely present in blood, lymph, Red blood cell, neutrophil leucocyte, platelet cell can act on through S1P phosphorylases while S1P is formed and slough phosphate generation Sphingol, also phosphatidyl-ethanolamine and palmital can be irreversibly decomposed into through S1P lyases, so as to ensure that Human Physiology ring S1P dynamic equilibrium in border.S1P can be used as second messenger and directly act on intracellular target, can also be transported through transport protein Combined to extracellular with corresponding acceptor, activate a series of downstream signaling pathways and produce important physiological functions, propagation such as cell, Migration, survival, apoptosis and cell communication etc., participate in immunological regulation, hematopoietic regulation, allograft reaction, glycometabolism regulation With inflammation regulation etc. different physiological roles.In recent years, medicament research and development based on S1P signal paths turned into autoimmune disease, The study hotspot of the association areas such as tumour.In immune system, suppression SPHK activation significantly or even can block proinflammatory completely Cell effect caused by material, such as Ca2+Metabolism, the secretion of degranulation, chemotaxis and cell factor.In addition, S1P can also pass through Combined with the S1P acceptors of cell surface, acceptor is caved in, induction of lymphocyte returns nest, suppresses lymphocyte from peripheral lymph nodes And the outflow of secondary lymphatic organ, prevent lymphocyte from reaching the position of inflammatory damage or mortifier, there is immunoregulation effect. S1P signal paths participate in the occurrence and development of various autoimmune disease, such as multiple sclerosis, systemic loupus erythematosus, rheumatoid Property arthritis, ulcerative colitis etc..For example, FTY720 (fingolimod, FTY720) is the prodrug class of first discovery S1P1 activators, in vivo by SHPK2 phosphorylations, turn into active phosphate form D TY720-P, then by being incorporated into T, B leaching The S1P1 acceptors of bar cell surface, cause acceptor to cave in and the degraded of follow-up ubiquitination, cause Lymphocyte Membrane surface S1P1 miss status so that lymphocyte, which can not flow out secondary lymphatic organ, enters peripheral blood circulation.FTY720 is exactly Acted on by this unique induction of lymphocyte " going back to the nest ", in the case of not killer cell, play immunosupress effect Should, therefore received much concern in the treatment use of autoimmune type disease and organ transplant rejection etc..We calculate The research of machine Computer Aided Design is found that the new compound with oxazole structure, and there is the compound S1P1 similar with FTY720 to swash Dynamic agent effect, we have studied the synthetic method of the new compound, and carry out transplanting skin to mouse skin transplantation model The piece time-to-live is studied.
The content of the invention
Present invention solves the technical problem that there is provided it is a kind of operation is simple, raw material is cheap and easy to get, reaction efficiency compared with A kind of high and reproducible synthetic method with oxazole ring structure immunosuppressive drug.
The present invention adopts the following technical scheme that one kind has oxazole ring structure immunosuppressive drug to solve above-mentioned technical problem The synthetic method of thing, it is characterised in that concretely comprise the following steps：
A, cyanoacetic acid reacts under carbonyl reduction catalyst action with ammoniacal liquor generates 3- aminoacrylonitriles；
B, vinyl ethyl ether and trifluoroacetic acid generate 4- ethyoxyl -1,1,1- trifluoros under pyridine and phosphorus pentachloride effect Butyl- 3- alkene -2- ketone；
C, 3- aminoacrylonitriles obtain 2-(ammonia with the generation substitution reaction of 4- ethyoxyl-1,1,1- trifluoro butyl- 3- alkene-2- ketone Methylene) the fluoro- 5- oxos hex- 3- alkene nitrile hydrochlorides of -6,6,6- three；
D, 2-(aminomethylene)-6,6,6-, three fluoro- 5- oxos hex- 3- alkene nitrile hydrochlorides are under DCC and phosphorous acid effect Itself cyclization obtains 6- (trifluoromethyl) nicotinic acid nitrile；
E, 6- (trifluoromethyl) nicotinic acid nitrile is oxidized and obtains 6- (trifluoromethyl) pyridine carboxylic acid；
F, 2- methyl -4- cyano group -6- ethyl -phenols first with methylsufonyl chloride occur substitution reaction activated hydroxyl groups, then with (R) - Substitution reaction generation (R) -4- ((2,2- dimethyl -1,3- dioxies penta occur for 2,2- dimethyl -1,3- dioxolanes -4- methanol Ring -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines；
G, 6- (trifluoromethyl) pyridine carboxylic acids react prior to thionyl chloride generates 6- (trifluoromethyl) pyridinecarboxylic chloride, then with (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines substitute Reaction, finally condensation generation oxazole ring obtain compound (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- diformazans Base -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles；
H, (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) first Epoxide) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles hydrolyze to obtain (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) - 1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
Further limit, step A detailed process is：Cyanoacetic acid and methanol are added in reaction bulb, adds carbonyl Reducing catalyst NaBH (OAc)3, nitrogen protection reaction system, ammoniacal liquor is slowly added dropwise, controls temperature to be no more than 60 during dropwise addition DEG C, heating reflux reaction after completion of dropwise addition, TLC monitoring raw material reactions are complete, filtering reacting liquid, add dichloromethane extraction, have Machine is mutually washed with saturated sodium bicarbonate solution, until aqueous phase PH=8, is washed 2 times, organic phase is dried, and revolving obtains 3- ammonia except solvent Base acrylonitrile.
Further limit, step B detailed process is：Vinyl ethyl ether, pyridine and dichloro are sequentially added in reaction bulb Methane.Phosphorus pentachloride is added in there-necked flask, trifluoroacetic acid is added dropwise overnight in ice salt bath constant pressure funnel, is added dropwise after room temperature Lower stirring reaction.Reaction system is washed with water, and 10% salt pickling, saturated sodium bicarbonate solution is washed, and is dried, and is filtered, is obtained crude product, tie again It is brilliant to obtain 4- ethyoxyl -1,1,1- trifluoro butyl- 3- alkene -2- ketone.
Further limit, step C detailed process is：Sequentially added in reaction bulb 3- aminoacrylonitriles, 4- ethyoxyls- 1,1,1- trifluoros butyl- 3- alkene -2- ketone and toluene.Heating reflux reaction adds n-hexane while hot after for a period of time, adds certain The watery hydrochloric acid of amount, 1h is stirred under ice bath after separating out solid, filters, dry to obtain 2-(aminomethylene)-6,6,6- tri- fluoro- 5- oxygen For hex- 3- alkene nitrile hydrochlorides.
Further limit, step D detailed process is：It is fluoro- that 2-(aminomethylene)-6,6,6- three are added in reaction bulb 5- oxos hex- 3- alkene nitrile hydrochlorides and DCC, DMSO protect reaction system, add phosphorous acid as reaction dissolvent, nitrogen, in Stirring reaction certain time at room temperature.Add water in reaction system, extracted with toluene, merge organic phase, twice, saturation is eaten for washing Salt is washed once, dries organic phase, and revolving obtains bronzing liquid 6- (trifluoromethyl) nicotinic acid nitrile.
Further limit, step E detailed process is：Water, sulfuric acid and glacial acetic acid are added in reaction bulb, is slowly added to 6- (trifluoromethyl) nicotinic acid nitrile, flow back reaction overnight.Cooling, add ice cube, and use cryosel water cooling, precipitation white solid；Filtering, filter Liquid is extracted with ethyl acetate, and merges organic phase, twice, organic phase dries revolving for washing, and pickling decolourizes to obtain beige solid 6- (trifluoromethyl) pyridine carboxylic acid.
Further limit, step F detailed process is：In reaction bulb, DMAP, 2- methyl -4- cyanogen Base -6- ethyl -phenols and triethylamine are added in toluene, and the toluene solution dissolved with methylsufonyl chloride is slowly added dropwise under the conditions of 20 DEG C； 2h is reacted after dripping, is first washed with water once, then washed once with the mixed solution of water and 1N hydrochloric acid solution, finally uses water It washed once with the mixed solution of saturated sodium bicarbonate；Yellow oily liquid is obtained after organic phase concentration, is all added in DMF, (R) -2,2- dimethyl-DOX -4- methanol is added, potassium carbonate is eventually adding, reacts 3h under the conditions of 120 DEG C, Methyl tertiary butyl ether(MTBE) is added after being cooled to room temperature, is washed with water and washs three times, yellow liquid is obtained after organic phase concentration；Add just Heptane 1000mL, stirred under the conditions of 25 DEG C, there are a large amount of solids to separate out, filtering and drying to obtain to white solid (R) -4- ((2,2- Dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines.
Further limit, step G detailed process is：In reaction bulb, 6- (trifluoromethyl) pyridine carboxylic acids and first are added Benzene；Thionyl chloride is added dropwise under the conditions of 20 DEG C, and about 20min is added dropwise completely, and the vacuum under the conditions of 50 DEG C is stirred for after reaction 30min Filter reaction solution, the complete thionyl chloride of discharge unreacted；Add (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) first Epoxide) -3- ethyl-N-hvdroxv -5- methylbenzamidines and triethylamine toluene mixture liquid, the about 20min under the conditions of no more than 30 DEG C It is added dropwise complete；Continue to be heated to flowing back after reacting 15min, the water generated in course of reaction is separated by water knockout drum, after reacting 3h Be concentrated in vacuo reaction solution, obtain yellow liquid product (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl - 1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles.
Further limit, step H detailed process is：(R) -5- (6- trifluoromethylpyridins -4- are added in the reactor Base) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles and Ethanol, 45 DEG C are heated to, add 1N HCl solutions；The sodium hydroxide solution that concentration is 32%, regulation is slowly added dropwise in reaction 3h Reaction solution pH is neutrality, drips rear concentration of reaction solution, adds ethyl acetate extraction, is washed with water and washs twice, organic phase is dense Product (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyls are obtained after contracting Epoxide) propane -1,2- glycol.
Further limit, the step H product that obtains has particular application as：(S) -3- (4- (5- (6- trifluoromethylpyridins -4- Base) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol has good immunosuppressive action.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair Bright scope.
Embodiment 1
Cyanoacetic acid 170g (2mol) and methanol 200mL is added in 2000mL reaction bulbs, adds carbonyl reduction catalysis Agent NaBH (OAc)310g, nitrogen protection reaction system, is slowly added dropwise ammoniacal liquor 800mL, controls temperature to be no more than during dropwise addition 60 DEG C, heating reflux reaction after completion of dropwise addition, TLC monitoring raw material reactions are complete, filtering reacting liquid, add dichloromethane 500mL Extractive reaction liquid twice, merges organic phase, and organic phase is washed with saturated sodium bicarbonate solution, until aqueous phase PH=8, is washed with water 2 times, organic phase is dried, and revolving obtains 3- aminoacrylonitrile 125g, yield 92% except solvent.
Embodiment 2
Vinyl ethyl ether 375.9g (5.23mol), pyridine 826.8g, dichloromethane are sequentially added in 10L there-necked flask 5000mL.Phosphorus pentachloride 1084.2g is added in there-necked flask, trifluoroacetic acid 444.6g is added dropwise overnight in ice salt bath constant pressure funnel (3.89mol), it is added dropwise after stirring reaction 48h at room temperature.Reaction system is washed with water, 10% salt pickling, unsaturated carbonate hydrogen Sodium solution is washed, and is dried, and is filtered, is obtained crude product, recrystallizes to obtain sterling 4- ethyoxyls -1,1,1- trifluoro butyl- 3- alkene -2- ketone 602.0g, Yield is 92.1%.
Embodiment 3
3- aminoacrylonitriles 136g (2mol), 4- ethyoxyl -1,1,1- trifluoro butyl- are sequentially added in 10L there-necked flask 3- alkene -2- ketone 370g (2.2mol) and toluene 1800mL.Heating reflux reaction 48h, n-hexane 3900mL is added while hot, is added Dilute hydrochloric acid solution 1000mL, solid is separated out after cooling.1h is stirred under ice bath, filters, dry to obtain 2-(aminomethylene)-6,6,6- Three fluoro- 5- oxos hex- 3- alkene nitrile hydrochloride 410g, yield 91%.
Embodiment 4
2-(aminomethylene)-6,6,6-, three fluoro- 5- oxos hex- 3- alkene nitrile hydrochloric acid is sequentially added in 10L there-necked flask Salt 450g (2.0mol), DCC400g (2mol) and DMSO 1000mL stirring reactions.Under nitrogen protection, it is slowly added dropwise dissolved with Asia Phosphoric acid 20g DMSO100mL, stirring reaction 2h, TLC monitoring raw material reactions are complete at room temperature.Add water in reaction system 10L, extracted with toluene, merge organic phase, twice, saturated common salt is washed once for washing, dries organic phase, and revolving obtains bronzing Liquid 6- (trifluoromethyl) nicotinic acid nitrile 300g, yield 88%.
Embodiment 5
Water 1420g, sulfuric acid 2440g, glacial acetic acid 150mL are added in 10L there-necked flask, is slowly added to 6- (trifluoromethyl) Nicotinic acid nitrile 870g (5mol).Flow back reaction overnight.Cooling, add ice cube, and use cryosel water cooling, precipitation white solid.Filtering, filter Liquid is extracted with ethyl acetate, and merges organic phase, twice, organic phase dries revolving for washing, and pickling decolourizes to obtain beige solid 6- (trifluoromethyl) pyridine carboxylic acid 930g, yield 97.3%.
Embodiment 6
In reaction bulb, DMAP DMAP (12g, 0.1mol), 2- methyl -4- cyano group -6- ethyl -phenols (161g, 1.0mol), and triethylamine (133mL, 1.0mol) are added in toluene 300mL, be slowly added dropwise under the conditions of 20 DEG C dissolved with The toluene solution 250mL of methylsufonyl chloride (114g, 1.0mol)；2h is reacted after dripping, first washed once with water 200mL, then It washed once with water 130mL and 1N hydrochloric acid solution 70mL mixed solution, finally with water 130mL and saturated sodium bicarbonate 70mL Mixed solution washed once；Yellow oily liquid is obtained after organic phase concentration, all adds in DMF 500mL, adds (R) -2,2- dimethyl-DOX -4- methanol (158g, 1.2mol), is eventually adding potassium carbonate (276g, 2.0mol), 3h is reacted under the conditions of 120 DEG C, methyl tertiary butyl ether(MTBE) 1000mL is added after being cooled to room temperature, then is washed three times with water 1000mL, Yellow liquid is obtained after organic phase concentration；Normal heptane 1000mL is added, is stirred under the conditions of 25 DEG C, there are a large amount of solids to separate out, Filtering and drying to obtain to white solid (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyls-N- Hydroxy-5-methyl base benzamidine 286g, yield 92.8%；1H NMR(400M,DMSO-d6):9.46(s,1H),7.36(m,2H), 5.69 (s, 2H), 4.42 (m, 1H), 4.11 (m, 1H), 3.80 (m, 1H), 2.63 (m, 2H), 2.25 (s, 3H), 1.35 (d, J= 18Hz, 6H), 1.17 (t, J=7.5Hz, 3H), MS (ESI) m/z:309.4(M+H+).
Embodiment 7
In reaction bulb, 6- (trifluoromethyl) pyridine carboxylic acid (442g, 2.0mol) and toluene 2000mL are added；In 20 DEG C of bars Thionyl chloride (240g, 2.0mol) is added dropwise under part, about 20min is added dropwise completely, is stirred for after reaction 30min under the conditions of 50 DEG C very Sky filters reaction solution, the complete thionyl chloride of discharge unreacted；Add (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) Methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines (616g, 2.0mol) and triethylamine (400g, 4.0mol) toluene mixing Liquid 2000mL, about 20min is added dropwise complete under the conditions of no more than 30 DEG C；Continue to be heated to flowing back after reacting 15min, by dividing water Device separates the water generated in course of reaction, is concentrated in vacuo reaction solution after reacting 3h, obtains yellow liquid product (R) -5- (6- fluoroforms Base-pyridin-4-yl) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2, 4- oxadiazoles 871g, yield 93.7%；1H NMR(400M,DMSO-d6):8.58(s,1H),7.88-7.87(m,1H),7.55 (d, J=8.0Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.35 (s, 1H), 4.42 (s, 1H), 4.20-4.19 (m, 1H), 3.95-3.94 (m, 2H), 3.63 (s, 1H), 2.60 (s, 2H), 1.35 (d, J=8.0Hz, 3H), 1.28 (s, 6H), 1.25 (t, J =4.0Hz, 3H), MS (ESI) m/z:464.5(M+H+).
Embodiment 8
(R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxies are added in the reactor Penta ring -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles (926g, 2.0mol) and ethanol 5000mL are heated to 45 DEG C, add 1N HCl (2000mL)；Reaction 3h is slowly added dropwise the sodium hydroxide solution that concentration is 32% and adjusts reaction solution pH To neutrality, rear concentration of reaction solution is dripped, adds ethyl acetate 5000mL, is washed twice with water 4000mL, organic phase concentration After obtain product (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies Base) propane -1,2- glycol 806g, yield 95%；1H NMR(400M,DMSO-d6):8.58(s,1H),7.83(m,1H), 7.54 (d, J=8.0Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.39 (s, 1H), 4.20-4.19 (m, 1H), 3.95-3.94 (m, 1H), 3.65 (s, 1H), 3.58 (s, 1H), 3.63 (s, 1H), 2.60 (s, 2H), 1.35 (d, J=8.0Hz, 3H), 1.25 (t, J=4.0Hz, 3H), MS (ESI) m/z:424.4(M+H+).
Embodiment 9
Influence of the target compound to the mouse skin transplantation model skin grafts time-to-live
C57BL/6 mouse and each 15 of BALB/c mouse are taken, after intraperitoneal injection yellow Jackets (45mg/kg) anesthesia, is taken Place is used as field of operation on the right side at back of the body middle part；Chaeta is shaved off, with 75% ethanol disinfection, full thickness skin is wiped out with eye scissors and forms 1cm* The 1cm surface of a wound, the fascia layer of skin graft is wiped out, it is standby as allogeneic skin graft using after normal saline flushing, by its surface of a wound As transplant bed.Mouse back skin graft is taken out from physiological saline and is laid in plant bed as graft, with adhesive bandage and medical adhesive Cloth, around wrapping, appropriate pressurization, is in close contact skin graft and plant bed by thorax abdomen.C57BL/6 mouse enter with BALB/c mouse The two-way transplanting of row.30 mouse are randomly divided into 3 groups, dermatoplasty solvent control group (gives distilled water), target compound 2 and 4mg/kg dosage groups, gastric infusion, one time a day, every group of C57BL/6 mouse and each 5 of BALB/c (totally 10).Observe daily small Mouse skin growth situation, until experiment terminates.Shift or come off if any skin graft in postoperative 4 days, think operative failure, do not charge to In experimental data.Remove wrapping within postoperative 6th day, observe graft color, hardness, incrustation and dropping situations day by day, become with skin graft Blacking is hard, incrustation comes off and is set to repulsion terminal, records the Graft survival time.If skin-grafting and the back of host are healed, color and luster one Cause, no inflammation and hyperemia, the skin and hair well-grown of hairiness, then it is assumed that rejection does not occur.The incrustation of more than 50% skin graft, It is hardened, is downright bad, comes off as repulsion standard.The 20th day after the transfer, processing animal terminated to test, and carries out data statistics.Experiment As a result represented with mean ± SD, and administration group and solvent control group are subjected to t inspections.
Gavage, which gives mouse target compound, can be obviously prolonged the survival of grafted skin time.The control group survival of grafted skin time is averaged For 7.2 days, and target compound 2mg/kg dosage groups were 13.2 days, and 4mg/kg dosage groups are 15.7 days, are had compared with control group aobvious Write difference (table 1).
Influence of the target compound of table 1 to the mouse skin transplantation model skin grafts time-to-live
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within In the scope of protection of the invention.

Claims (10)

1. a kind of synthetic method with oxazole ring structure immunosuppressive drug, it is characterised in that concretely comprise the following steps：
A, cyanoacetic acid reacts under carbonyl reduction catalyst action with ammoniacal liquor generates 3- aminoacrylonitriles；
B, vinyl ethyl ether and trifluoroacetic acid generate 4- ethyoxyl -1,1,1- trifluoro butyl- 3- under pyridine and phosphorus pentachloride effect Alkene -2- ketone；
C, 3- aminoacrylonitriles obtain 2-(amino Asia with the generation substitution reaction of 4- ethyoxyl-1,1,1- trifluoro butyl- 3- alkene-2- ketone Methyl) the fluoro- 5- oxos hex- 3- alkene nitrile hydrochlorides of -6,6,6- three；
D, 2-(aminomethylene)-6,6,6-, three fluoro- 5- oxos hex- 3- alkene nitrile hydrochlorides DCC and phosphorous acid effect under itself Cyclization obtains 6- (trifluoromethyl) nicotinic acid nitrile；
E, 6- (trifluoromethyl) nicotinic acid nitrile is oxidized and obtains 6- (trifluoromethyl) pyridine carboxylic acid；
F, 2- methyl -4- cyano group -6- ethyl -phenols first with methylsufonyl chloride occur substitution reaction activated hydroxyl groups, then with (R) -2,2- Substitution reaction generation (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- occur for dimethyl -1,3- dioxolanes -4- methanol Base) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines；
G, 6- (trifluoromethyl) pyridine carboxylic acids prior to thionyl chloride react generation 6- (trifluoromethyl) pyridinecarboxylic chloride, then with (R)- It is anti-that substitution occurs for 4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines Should, finally condensation generation oxazole ring obtains compound (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- diformazans Base -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles；
H, (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxies Base) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles hydrolyze to obtain (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1, 2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
A kind of 2. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step A detailed process is：Cyanoacetic acid and methanol are added in reaction bulb, adds carbonyl reduction catalyst n aBH (OAc)3, nitrogen protection reaction system, ammoniacal liquor is slowly added dropwise, controls temperature to be no more than 60 DEG C, after completion of dropwise addition during dropwise addition Heating reflux reaction, TLC monitoring raw material reactions are complete, filtering reacting liquid, add dichloromethane extraction, organic phase unsaturated carbonate Hydrogen sodium solution is washed, until aqueous phase PH=8, is washed 2 times, organic phase is dried, and revolving obtains 3- aminoacrylonitriles except solvent.
A kind of 3. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step B detailed process is：Vinyl ethyl ether, pyridine and dichloromethane are sequentially added in reaction bulb, adds phosphorus pentachloride, Trifluoroacetic acid is added dropwise overnight in ice salt bath constant pressure funnel, is added dropwise and is washed with water after stirring reaction at room temperature, reaction after terminating, 10% salt pickling, saturated sodium bicarbonate solution are washed, and are dried, and are filtered, are obtained crude product, recrystallize to obtain 4- ethyoxyls -1,1,1- trifluoro butyl- 3- alkene -2- ketone.
A kind of 4. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step C detailed process is：Sequentially added in reaction bulb 3- aminoacrylonitriles, 4- ethyoxyl -1,1,1- trifluoro butyl- 3- alkene - 2- ketone and toluene, heating reflux reaction add n-hexane while hot after for a period of time, add a certain amount of watery hydrochloric acid, separate out solid Body, filtered under ice bath after stirring a period of time, dry to obtain 2-(aminomethylene)-6,6,6- tri- fluoro- 5- oxos hex- 3- alkene nitriles Hydrochloride.
A kind of 5. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step D detailed process is：2-(aminomethylene)-6,6,6-, three fluoro- 5- oxos hex- 3- alkene nitrile hydrochloric acid is added in reaction bulb Salt and DCC, DMSO nitrogen protection reaction system, add phosphorous acid, the timing of reaction one are stirred at room temperature as reaction dissolvent Between, reaction adds water after terminating, and is extracted with toluene, merges organic phase, and twice, saturated common salt is washed once for washing, dries organic phase, Revolving obtains bronzing liquid 6- (trifluoromethyl) nicotinic acid nitrile.
A kind of 6. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step E detailed process is：Water, sulfuric acid and glacial acetic acid are added in reaction bulb, is slowly added to 6- (trifluoromethyl) nicotinic acid nitrile, is flowed back Reaction overnight；Reaction adds ice cube after terminating, and uses cryosel water cooling, precipitation white solid, filtrate ethyl acetate after filtering Extraction, merge organic phase, twice, organic phase dries revolving for washing, and pickling decolourizes to obtain beige solid 6- (trifluoromethyl) pyrrole Pyridine formic acid.
A kind of 7. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step F detailed process is：In reaction bulb, DMAP, 2- methyl -4- cyano group -6- ethyl -phenols and three second Amine is added in toluene, and the toluene solution dissolved with methylsufonyl chloride is slowly added dropwise under the conditions of 20 DEG C；2h is reacted after dripping, is first used Water washing washed once once, then with the mixed solution of water and 1N hydrochloric acid solution, finally mixed with water and saturated sodium bicarbonate Solution is closed to washed once；Yellow oily liquid is obtained after organic phase concentration, all adds in DMF, adds (R) -2,2- diformazans Base-DOX -4- methanol, is eventually adding potassium carbonate, reacts 3h under the conditions of 120 DEG C, first is added after being cooled to room temperature Base tertbutyl ether, it is washed with water and washs three times, yellow liquid is obtained after organic phase concentration；Normal heptane 1000mL is added, at 25 DEG C Under the conditions of stir, there are a large amount of solids to separate out, filtering and drying to obtain to white solid (R) -4- ((2,2- dimethyl -1,3- dioxies penta Ring -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines.
A kind of 8. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step G detailed process is：In reaction bulb, 6- (trifluoromethyl) pyridine carboxylic acids and toluene are added；It is added dropwise under the conditions of 20 DEG C Thionyl chloride, about 20min are added dropwise completely, are stirred for being filtered by vacuum reaction solution under the conditions of 50 DEG C after reacting 30min, discharge is not anti- The thionyl chloride answered；Add (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N- hydroxyls The toluene mixture liquid of base -5- methylbenzamidines and triethylamine, about 20min is added dropwise complete under the conditions of no more than 30 DEG C；Continue to react It is heated to flowing back after 15min, the water generated in course of reaction is separated by water knockout drum, is concentrated in vacuo reaction solution after reacting 3h, obtains To yellow liquid product (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) Methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles.
A kind of 9. synthetic method with oxazole ring structure immunosuppressive drug according to claim 1, it is characterised in that Step H detailed process is：(R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- diformazans are added in the reactor Base-DOX -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles and ethanol are heated to 45 DEG C, then Add 1N HCl solutions；The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, and regulation reaction solution pH is neutrality, is added dropwise Concentration of reaction solution after complete, ethyl acetate extraction is added, is washed with water and washs twice, product (S) -3- is obtained after organic phase concentration (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- two Alcohol.
10. a kind of as claimed in claim 1 have oxazole ring structure immunosuppressive drug in immunosuppressive drug is prepared Using.
CN201710689842.6A 2017-08-14 2017-08-14 A kind of synthetic method with oxazole ring structure immunosuppressive drug Withdrawn CN107382989A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109467532A (en) * 2018-12-17 2019-03-15 浙江工业大学上虞研究院有限公司 The preparation method of 4- trifluoromethyl nicotinic acid

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109467532A (en) * 2018-12-17 2019-03-15 浙江工业大学上虞研究院有限公司 The preparation method of 4- trifluoromethyl nicotinic acid

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