CN107337665A - A kind of synthetic method with triazole ring structure immunosuppressive drug - Google Patents
A kind of synthetic method with triazole ring structure immunosuppressive drug Download PDFInfo
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- AIGNUYCCJCXIES-UHFFFAOYSA-N CCc(cc(cc1C)-c2n[nH]c(-c3ccc(C(F)(F)F)nc3)n2)c1OCC1=[O]C(C)(C)OC1 Chemical compound CCc(cc(cc1C)-c2n[nH]c(-c3ccc(C(F)(F)F)nc3)n2)c1OCC1=[O]C(C)(C)OC1 AIGNUYCCJCXIES-UHFFFAOYSA-N 0.000 description 1
- XSCXVYDSZBNCFX-MRXNPFEDSA-N CCc(cc(cc1C)-c2n[nH]c(C3=CC=C(C(F)(F)F)NC3)n2)c1OCC[C@H](CO)O Chemical compound CCc(cc(cc1C)-c2n[nH]c(C3=CC=C(C(F)(F)F)NC3)n2)c1OCC[C@H](CO)O XSCXVYDSZBNCFX-MRXNPFEDSA-N 0.000 description 1
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a kind of synthetic method with triazole ring structure immunosuppressive drug, belong to medical synthesis technical field.Technical scheme main points are：One kind has triazole ring structure immunosuppressive drug, has following structure：
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of with triazole ring structure immunosuppressive drug
Synthetic 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 triazole structure, and the compound has the S1P1 similar with FTY720
Agonist effect, we have studied the synthetic method of the new compound, and transplant mouse skin transplantation model
The survival of grafted skin time 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 novel synthetic method with triazole ring structure immunosuppressive drug of high and structure.
The present invention adopts the following technical scheme that one kind has triazole ring structure immunosupress to solve above-mentioned technical problem
The synthetic method of medicine, it is characterised in that its molecular structure is：
The present invention adopts the following technical scheme that one kind has triazole ring structure immunosupress to solve above-mentioned technical problem
The synthetic method of medicine, 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 continues to react to obtain 6- (trifluoromethyl) with ammoniacal liquor after being oxidized generation carboxyl
Pyridine carboxamide；
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；
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, (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methyl benzyls
Amidine reacts generation chloride compounds prior to thionyl chloride, then is taken in the basic conditions with 6- (trifluoromethyl) pyridine carboxamide
Generation reaction, last cyclic condensation obtain compound (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- triazoles；
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- triazoles hydrolyze to obtain (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -
1,2,4- triazole -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, separate out solid.1h is stirred under ice bath, filters, dry to obtain 2-(aminomethylene)-6,6,6- tri- fluoro- 5- oxos
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) pyridine carboxylic acid.Flow back reaction overnight.Cooling, ice cube is added, and with cryosel water cooling, to anti-under the conditions of 0 DEG C
Answer and ammonia spirit is slowly added dropwise in liquid, temperature is no more than 0 DEG C, gradually separated out during dropwise addition by a large amount of solids, filter drying
Obtain 6- (trifluoromethyl) pyridine carboxamide.
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, (R) -4- ((2,2- dimethyl -1,3- bis- are added
Butyl oxide link -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines and toluene；Thionyl chloride is added dropwise under the conditions of 20 DEG C,
About 20min is added dropwise completely, is stirred for being filtered by vacuum reaction solution, the complete chlorine of discharge unreacted under the conditions of 50 DEG C after reacting 30min
Change sulfoxide；The toluene mixture liquid of 6- (trifluoromethyl) pyridine carboxamides and triethylamine is added, under the conditions of no more than 30 DEG C about
20min 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, react
Reaction solution is concentrated in vacuo after 3h, obtains yellow liquid product (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- triazoles.
Further limit, step H detailed process is：In 30L reactors add (R) -5- (6- trifluoromethylpyridins -
4- yls) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles
And ethanol, 45 DEG C are heated to, adds 1N HCl；The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, makes reaction
Liquid pH reaches neutral, drips rear concentration of reaction solution, adds ethyl acetate extraction, and is washed twice with water, organic phase concentration
After obtain product (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies
Base) propane -1,2- glycol.
Further limit, resulting product has particular application as in step H：Skin graft is into biopsy after being transplanted by mouse skin
Survey and find (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies)
Propane -1,2- glycol has good immunosuppressive activity.
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, ice cube is added, and with cryosel water cooling, to reaction solution under the conditions of 0 DEG C
In ammonia spirit is slowly added dropwise, make temperature be no more than 0 DEG C, gradually separated out during dropwise addition by a large amount of solids, filter drying obtain
6- (trifluoromethyl) pyridine carboxamide.
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(d6-DMSO):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, (R) -4- ((2,2- dimethyl-DOX -4- bases) methoxyl group) -3- ethyls-N- is added
Hydroxy-5-methyl base benzamidine (616g, 2.0mol) and toluene 2000mL；Under the conditions of 20 DEG C be added dropwise thionyl chloride (240g,
2.0mol), about 20min is added dropwise complete, is 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 6- (trifluoromethyl) pyridine carboxamide (440g, 2.0mol) and triethylamine (400g, 4.0mol)
Toluene mixture 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,
The water generated in course of reaction is separated by water knockout drum, reaction solution is concentrated in vacuo after reacting 3h, obtains yellow liquid product (R) -5-
(6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyls -5-
Benzyl) -1,2,4- triazole 910g, yield 92%；1HNMR(400MHz,DMSO-d6)δ:13.3(s,1H),8.58(s,1H),
7.84 (s, 1H), 7.20-7.17 (m, 3H), 4.25 (d, J=8.0Hz, 2H), 3.91 (t, J=8.0Hz, 2H), 3.59-3.56
(m,2H),2.80(s,1H),215(s,3H),1.27(s,6H),1.25(s,3H).MS(ESI)m/z:463.4(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- triazoles (980g, 2.0mol) and ethanol 2000mL are heated to
45 DEG C, add 1N HCl 1500mL；The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, makes the pH of reaction solution
Reach neutral, drip rear concentration of reaction solution, add ethyl acetate 3000mL, washed twice with water 2000mL, organic phase is dense
Product (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyls are obtained after contracting
Epoxide) propane -1,2- glycol 819g, yield 97%；1HNMR(400MHz,DMSO-d6)δ:13.1(s,1H),8.58(s,
1H), 7.88-7.87 (m 1H), 7.20-7.17 (m, 3H), 4.21 (d, J=7.2Hz, 2H), 3.98 (t, J=7.2Hz, 2H),
3.81(s,1H),3.59-3.56(m,2H),2.80(s,2H),215(s,3H),1.25(s,3H),.MS(ESI)m/z:423.4
(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 14.5 days, and 4mg/kg dosage groups are 17.1 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 triazole ring structure immunosuppressive drug, it is characterised in that its molecular structure is：
2. a kind of synthetic method with triazole 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 continues to react to obtain 6- (trifluoromethyl) pyridine with ammoniacal liquor after being oxidized generation carboxyl
Formamide；
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；
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, (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines are first
Generation chloride compounds are reacted in thionyl chloride, then substitution occurs in the basic conditions instead with 6- (trifluoromethyl) pyridine carboxamide
Should, last cyclic condensation obtains compound (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- triazoles；
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- triazoles hydrolyze to obtain (S) -3- (4- (5- (6- trifluoromethylpyridin -4- bases) -1,
2,4- triazole -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
3. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step A detailed process：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.
4. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step B detailed process：Vinyl ethyl ether, pyridine and dichloromethane are sequentially added in reaction bulb, is added phosphoric
Phosphorus, trifluoroacetic acid is added dropwise overnight in ice salt bath constant pressure funnel, is added dropwise and uses water after terminating after stirring reaction at room temperature, reaction
Wash, 10% salt pickling, saturated sodium bicarbonate solution is washed, and is dried, and is filtered, is obtained crude product, recrystallize to obtain 4- ethyoxyls -1,1,1- trifluoros
Butyl- 3- alkene -2- ketone.
5. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step C detailed process：3- aminoacrylonitriles, 4- ethyoxyl -1,1,1- trifluoro butyl- 3- are sequentially added in reaction bulb
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
1h is stirred under ice bath after solid, filters, dry to obtain 2-(aminomethylene)-6,6,6- tri- fluoro- 5- oxos hex- 3- alkene nitrile hydrochloric acid
Salt.
6. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step D detailed process：2-(aminomethylene)-6,6,6-, three fluoro- 5- oxos hex- 3- alkene nitrile salt is added in reaction bulb
Hydrochlorate and DCC, DMSO nitrogen protection reaction system, add phosphorous acid, stirring reaction is certain at room temperature as reaction dissolvent
Time, water is added in reaction system, is extracted with toluene, merge organic phase, twice, saturated common salt is washed once for washing, and drying has
Machine phase, revolving obtain bronzing liquid 6- (trifluoromethyl) nicotinic acid nitrile.
7. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step E detailed process：Water, sulfuric acid and glacial acetic acid are added in reaction bulb, is slowly added to 6- (trifluoromethyl) pyridine first
Acid, flow back reaction overnight, and reaction adds ice cube after terminating, and with cryosel water cooling, is slowly dripped into reaction solution under the conditions of 0 DEG C
The ammonification aqueous solution, temperature is no more than 0 DEG C, gradually separated out during dropwise addition by a large amount of solids, filter drying and obtain 6- (fluoroforms
Base) pyridine carboxamide.
8. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step F detailed process：In reaction bulb, DMAP, 2- methyl -4- cyano group -6- ethyl -phenols and three
Ethamine is added in toluene, and the toluene solution dissolved with methylsufonyl chloride is slowly added dropwise under the conditions of 20 DEG C；One section is reacted after dripping
Time, first it is washed with water once, then washed once with the mixed solution of water and 1N hydrochloric acid solution, finally with water and unsaturated carbonate
The mixed solution of hydrogen sodium washed once；Obtain yellow oily liquid after organic phase concentration, all add in DMF, add (R)-
2,2- dimethyl-DOX -4- methanol, are eventually adding potassium carbonate, react 3h under the conditions of 120 DEG C, be cooled to room temperature
After add methyl tertiary butyl ether(MTBE), be washed with water and wash three times, organic phase concentration after obtain yellow liquid；Add normal 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- diformazans
Base -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines.
9. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step G detailed process：In reaction bulb, (R) -4- ((2,2- dimethyl-DOX -4- bases) methoxies are added
Base) -3- ethyl-N-hvdroxv -5- methylbenzamidines and toluene；Thionyl chloride is added dropwise under the conditions of 20 DEG C, about 20min is added dropwise completely,
It is stirred for being filtered by vacuum reaction solution, the complete thionyl chloride of discharge unreacted under the conditions of 50 DEG C after reacting 30min；Add 6- (three
Methyl fluoride) pyridine carboxamide and triethylamine toluene mixture liquid, about 20min is added dropwise complete under the conditions of no more than 30 DEG C；Continue
It is heated to flowing back after reaction 15min, the water generated in course of reaction is separated by water knockout drum, reaction is concentrated in vacuo after reacting 3h
Liquid, obtain yellow liquid product (R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- dimethyl-DOX -
4- yls) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles.
10. a kind of synthetic method with triazole ring structure immunosuppressive drug according to claim 2, its feature exist
It is in step H detailed process：(R) -5- (6- trifluoromethylpyridin -4- bases) -3- (4- ((2,2- bis- are added in the reactor
Methyl isophthalic acid, 3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles and ethanol are heated to 45 DEG C,
Add 1N HCl；The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, reaction solution pH is reached neutral, drips
Concentration of reaction solution afterwards, ethyl acetate extraction is added, and be washed twice with water, product (S) -3- (4- are obtained after organic phase concentration
(5- (6- trifluoromethylpyridin -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
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