CN107311994A - A kind of novel method for synthesizing of the receptor stimulating agent drug molecules of S1P 1 - Google Patents
A kind of novel method for synthesizing of the receptor stimulating agent drug molecules of S1P 1 Download PDFInfo
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- CN107311994A CN107311994A CN201710689810.6A CN201710689810A CN107311994A CN 107311994 A CN107311994 A CN 107311994A CN 201710689810 A CN201710689810 A CN 201710689810A CN 107311994 A CN107311994 A CN 107311994A
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- NMNBCGIZPQXLJW-OAQYLSRUSA-N CCc1cc(-c2n[o]c(-c3cc(C4CCC4)nc(OC)c3)n2)cc(C)c1OC[C@H]1OC(C)(C)OC1 Chemical compound CCc1cc(-c2n[o]c(-c3cc(C4CCC4)nc(OC)c3)n2)cc(C)c1OC[C@H]1OC(C)(C)OC1 NMNBCGIZPQXLJW-OAQYLSRUSA-N 0.000 description 1
- AFLAOKKKMCYTAB-CYBMUJFWSA-N CCc1cc(C(NO)=N)cc(C)c1OC[C@H]1OC(C)(C)OC1 Chemical compound CCc1cc(C(NO)=N)cc(C)c1OC[C@H]1OC(C)(C)OC1 AFLAOKKKMCYTAB-CYBMUJFWSA-N 0.000 description 1
- CFQULHFMXLKXNG-UHFFFAOYSA-N COc1nc(C2CCC2)cc(C(O)=O)c1 Chemical compound COc1nc(C2CCC2)cc(C(O)=O)c1 CFQULHFMXLKXNG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a kind of synthetic method of the receptor stimulating agent drug molecules of S1P 1, belong to medical synthesis technical field.Technical scheme main points are:A kind of synthetic method of the receptor stimulating agent drug molecules of S1P 1, with following structure:
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of S1P-1 receptor stimulating agents drug molecule it is new
Synthetic method.
Background technology
Sphingolipid is the important composition composition of biomembrane, with the effect for protecting intracellular goods and materials.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 also being 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 slough phosphate generation while S1P is formed through the effect of S1P phosphorylases
Sphingol, also can irreversibly be decomposed into phosphatidyl-ethanolamine and palmital 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, a series of downstream signaling pathways generation important physiological functions of activation, the propagation of 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.Cell caused by proinflammatory substance can significantly or even be blocked completely by suppressing SPHK activation
Reaction, such as Ca2+Metabolism, degranulation, the secretion of chemotaxis and cell factor.In addition, S1P can also by with cell surface
S1P acceptors are combined, and acceptor is caved in, and induction of lymphocyte returns nest, suppress lymphocyte from peripheral lymph nodes and Secondary Lymphoid device
The outflow of official, prevents lymphocyte from reaching the position of inflammatory damage or mortifier, with immunoregulation effect.S1P signal paths
Participate in various autoimmune disease develops, such as multiple sclerosis, systemic loupus erythematosus, rheumatoid arthritis, burst
Ulcer colitis etc..Wherein (S) -3- (4- (5- (2- cyclobutyl -6- methoxypyridine -4- bases) -1,2,4- oxadiazoles -3- bases) -
2- ethyl -6- benzyloxies) propane -1,2- glycol is exactly a kind of good S1P-1 receptor stimulating agents.
We by CAD find drug molecule (S) -3- (4- (5- (2- cyclobutyl -6- methoxypyridines -
4- yls) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) and propane -1,2- glycol not only have S1P-1 receptor agonisms live
Property, but also with good antiplatelet aggregative activity, we are carried out to its synthetic method and platelet aggregation inhibitory activity
Research.
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 method for synthesizing of high and reproducible S1P-1 receptor stimulating agents drug molecule.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of S1P-1 receptor stimulating agents drug molecule
Novel method for synthesizing, it is characterised in that concretely comprise the following steps:
The reaction under sodium hydride effect of A, 1,3- dibromopropane and methyl acetoacetate obtains cyclobutyl ethyl ketone;
B, diethy-aceto oxalate and cyclobutyl ethyl ketone react under cryogenic terminates rear and cyanoacetamide generation cyclization instead
2- cyclobutyl -3- carboxyl -6- pyridones should be obtained;
Under thionyl chloride effect first with methanol esterification occurs for C, 2- cyclobutyl -3- carboxyl -6- pyridones, then passes through
Continue occur the carbonyl substitution change chlorine reaction generation chloro- 6- cyclobutane -4- methyl formate pyridines of 2- with thionyl chloride under alkalescence condition;
Substitution reaction generation 2- first occurs with methanol in the basic conditions for the chloro- 6- cyclobutane -4- methyl formates pyridine of D, 2-
Epoxide -6- cyclobutane -4- carboxyl pyridines;
E, 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- methoxyl group -6- cyclobutane -4- carboxyl pyridines prior to thionyl chloride reaction generation 2- methoxyl group -6- cyclobutane -
4- formyl chloropyridines, then with (R) -4- ((2,2- dimethyl-DOX -4- bases) methoxyl group) -3- ethyl-N-hvdroxvs -
Substitution reaction occurs for 5- methylbenzamidines, and finally condensation generation oxazole ring obtains compound (R) -5- (2- cyclobutyl -6- methoxyl group pyrroles
Pyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- evils
Diazole;
G, (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -
4- yls) methoxyl group) -3- ethyl -5- benzyls) and -1,2,4- oxadiazoles hydrolysis obtain (S) -3- (4- (5- (2- cyclobutyl -6- methoxies
Yl pyridines -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
Further limit, step A detailed process is:In reaction bulb, 1,3- dibromopropanes and sodium hydride are added, in nitrogen
50 DEG C are heated slowly under gas shielded;Methyl acetoacetate is slowly added to, keeping temperature is no more than 55 DEG C, at 50 DEG C after dripping
Under the conditions of heating stirring 3h;TLC monitoring raw materials adjust reaction solution pH to 8~9 after having reacted with 1N HCl solutions, maintain the temperature at
60 DEG C of reaction 2h, are then cooled to 40 DEG C;Organic phase is separated, be washed once with saturated nacl aqueous solution, then uses anhydrous magnesium sulfate
Dry, be finally concentrated in vacuo and obtain cyclobutyl ethyl ketone.
Further limit, step B detailed process is:Adding sodium methoxide and THF in the reactor, reaction temperature is down to-
10 DEG C, the mixed liquor of diethy-aceto oxalate and cyclobutyl ethyl ketone is added, keeping temperature is no more than 0 DEG C;Heating is warming up to after dripping
To 15 DEG C of reaction 1h, cyanoacetamide is added, 5h is reacted at ambient temperature;Concentrated under vacuum after adding a certain amount of water
Reaction solution, is then added in glacial acetic acid, the stirring reaction 3h under the conditions of 50 DEG C is dense under vacuum again into concentrated residue
Contracting reaction solution, then adds water in residue, is stirred under the conditions of 10 DEG C, has a large amount of solids to suspend and separates out, filtering and drying to obtain
To 2- cyclobutyl -3- carboxyl -6- pyridones.
Further limit, step C detailed process is:In reaction bulb, 2- cyclobutyl -3- carboxyl -6- pyridones are added
Enter to methanol, add sodium carbonate, thionyl chloride is slowly added dropwise at ambient temperature, TLC monitoring raw material reactions are complete, and vacuum is dense
After contracting reaction solution, DMF and DIPEA are added, nitrogen protection is lower to add thionyl chloride, is slowly heated to backflow, instead
Answering after 2h TLC to monitor raw material, secondary response completely, is concentrated in vacuo reaction solution again, removes the complete thionyl chloride of unreacted, is cooled to 20
DEG C, a certain amount of water is added, is to slowly warm up to after 50 DEG C be cooled to 10 DEG C, there are a large amount of solids to separate out in whipping process, after suction filtration
It is dried to obtain the chloro- 6- cyclobutane -4- methyl formate pyridines of 2-.
Further limit, step D detailed process is:In reaction bulb, the chloro- 6- cyclobutane -4- methyl formate pyrroles of 2-
Pyridine and methanol solution containing sodium hydroxide are heated to 100 DEG C of reaction 2h, and vacuum divides exactly methanol, continues to react 4h, then concentrates
Reaction solution, reacts 2h, again concentration of reaction solution after adding a certain amount of water under the conditions of 80 DEG C, finally under the conditions of 10 DEG C, delays
Slow that the hydrochloric acid solution that concentration is 32% is added dropwise, temperature is no more than 15 DEG C;Drip rear reaction solution tert-butyl acetate 1000mL extractions
Take, separate and be washed with water after organic phase, be concentrated to give 2- methoxyl group -6- cyclobutane -4- carboxyl pyridines.
Further limit, step E 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 be washed once with the mixed solution of water and 1N hydrochloric acid solution, water is finally used
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, 3h is reacted under the conditions of 120 DEG C,
It is cooled to after room temperature and adds methyl tertiary butyl ether(MTBE), be washed with water and wash three times, yellow liquid is obtained after organic phase concentration;Add just
Heptane 1000mL, is stirred under the conditions of 25 DEG C, has 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 F detailed process is:In reaction bulb, 2- methoxyl group -6- cyclobutane -4- carboxyls are added
Pyridine and toluene;Thionyl chloride is added dropwise under the conditions of 20 DEG C, about 20min is added dropwise completely, is stirred for after reaction 30min in 50 DEG C of bars
Reaction solution, the complete thionyl chloride of discharge unreacted are filtered by vacuum under part;Add (R) -4- ((2,2- dimethyl -1,3- dioxies penta
Ring -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines and triethylamine toluene mixture liquid, in no more than 30 DEG C conditions
Lower about 20min is added dropwise complete;Continue to react and backflow be heated to after 15min, the water generated in course of reaction is separated by water knockout drum,
Reaction solution is concentrated in vacuo after reaction 3h, yellow liquid product (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- are obtained
((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles.
Further limit, step G detailed process is:(R) -5- (2- cyclobutyl -6- methoxyl group pyrroles are added in the reactor
Pyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- evils
Diazole and ethanol, are heated to 45 DEG C, add 1N HCl solutions;It is molten that the sodium hydroxide that concentration is 32% is slowly added dropwise in reaction 3h
Liquid, regulation reaction solution pH is neutrality, drips rear concentration of reaction solution, adds ethyl acetate extraction, is washed with water and washs twice, have
Machine obtains product (S) -3- (4- (5- (2- cyclobutyl -6- methoxypyridine -4- bases) -1,2,4- oxadiazoles -3- after mutually concentrating
Base) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
Further limit, products therefrom has particular application as in step G:(S) -3- (4- (5- (2- cyclobutyl -6- methoxyl groups
Pyridin-4-yl) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol has good antiplatelet
Aggtegation.
Embodiment
The above to 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
In reaction bulb, add 1,3- dibromopropanes (200g, 1.0mol) and content for 40% sodium hydride (90g,
1.5mol), 50 DEG C are heated slowly under nitrogen protection;It is slowly added to methyl acetoacetate (116g, 1.0mol), keeping temperature
No more than 55 DEG C, after dripping under the conditions of 50 DEG C heating stirring 3h;TLC monitoring raw materials are adjusted after having reacted with 1N HCl solutions
Reaction solution pH maintains the temperature at 60 DEG C of reaction 2h, is then cooled to 40 DEG C to 8~9;Organic phase is separated, it is molten with saturated sodium-chloride
Liquid 100mL washed once, then be dried with anhydrous magnesium sulfate 5g, is finally concentrated in vacuo and obtains cyclobutyl ethyl ketone 88g, yield is
90%;1H NMR (400M, CDCl3):2.82(s,1H),2.33-2.31(m.4H),2.01(m,2H),1.98(s,3H).
Embodiment 2
Sodium methoxide (60g, 1.1mol) and THF (1000mL) are added in the reactor, and reaction temperature is down to -10 DEG C, addition
The mixed liquor of diethy-aceto oxalate (146g, 1mol) and cyclobutyl ethyl ketone (98g, 1.0mol, 1.0eq), keeping temperature is no more than 0
℃;15 DEG C of reaction 1h are warming up to after dripping, cyanoacetamide (100g, 1.2mol) are added, at ambient temperature instead
Answer 5h;Concentration of reaction solution under vacuum is added after water (600mL), glacial acetic acid 1000mL is then added into concentrated residue,
The stirring reaction 3h under the conditions of 50 DEG C, concentration of reaction solution under vacuum, then adds water (2500mL) in residue again,
Stirred under the conditions of 10 DEG C, there are a large amount of solids to suspend and separate out, filtering and drying to obtain to 183g product 2- cyclobutyl -3- carboxyls -6-
Pyridone, yield is 94%;1H NMR (400M, d6-DMSO):12.65-12.62(m,2H),6.61(s,1H),6.35(s,
1H),2.89-2.88(m,1H),1.95-1.93(m,2H),1.66-1.61(m,4H).
Embodiment 3
In reaction bulb, 2- cyclobutyl -3- carboxyl -6- pyridones (965g, 5.0mol) are added to methanol (6000mL),
Sodium carbonate (320g, 3.0mol) is added, thionyl chloride (360g, 3.0mol) is slowly added dropwise at ambient temperature, TLC monitoring is former
Material reaction is complete, is concentrated in vacuo after reaction solution, adds DMF2000mL and DIPEA (600g, 5.0mol), nitrogen
Protection is lower to add thionyl chloride (600g, 5.0mol), and being slowly heated to TLC monitoring raw material after backflow, reaction 2h, secondary response is complete again
Entirely, reaction solution is concentrated in vacuo, the complete thionyl chloride of unreacted is removed, is cooled to 20 DEG C, add water (2000mL), be to slowly warm up to
10 DEG C are cooled to after 50 DEG C, there are a large amount of solids to separate out, the chloro- 6- cyclobutane -4- methyl formate pyridines of 2- are dried to obtain after suction filtration
1080g, yield is 90%;1H NMR(d6-DMSO):7.71(s,1H),7.62(s,1H),3.97(s,3H),3.23-3.19
(m,1H),2.19-2.17(m,2H),1.86-1.82(m,4H).
Embodiment 4
In reaction bulb, the chloro- 6- cyclobutane -4- methyl formates pyridines (225g, 1.0mol) of 2- and sodium hydroxide
The methanol solution 1500mL of (400g, 10mol) is heated to 100 DEG C of reaction 2h, and vacuum divides exactly methanol 570mL, continues to react 4h, so
Concentration of reaction solution, reacts 2h, again concentration of reaction solution, finally in 10 DEG C of conditions after adding water 1800mL under the conditions of 80 DEG C afterwards
Under, the hydrochloric acid solution 700mL that concentration is 32% is slowly added dropwise, temperature is no more than 15 DEG C;Drip the rear tertiary fourth of reaction solution acetic acid
Ester 1000mL is extracted, and is separated after organic phase and to be washed twice with water 500mL, is concentrated to give 2- methoxyl group -6- cyclobutane -4- carboxyl pyrroles
Pyridine 200g, yield is 96.6%.
Embodiment 5
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 be 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, addition methyl tertiary butyl ether(MTBE) 1000mL after room temperature is cooled to, 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 is 92.8%;1H NMR(d6-DMSO):9.44(s,1H),7.39-7.37(m,2H),
5.69(s,2H),4.45-4.44(m,1H),4.11-4.10(m,1H),3.83-3.82(m,1H),2.66-2.64(m,2H),
2.25 (s, 3H), 1.39 (d, J=12.0Hz, 6H), 1.13 (t, J=8.0Hz, 3H), MS (ESI) m/z:309.4(M+H+).
Embodiment 6
In reaction bulb, 2- methoxyl group -6- cyclobutane -4- carboxyl pyridines (414g, 2.0mol) and toluene 2000mL are added;
Thionyl chloride (240g, 2.0mol) is added dropwise under the conditions of 20 DEG C, about 20min is added dropwise completely, is stirred for after reaction 30min at 50 DEG C
Under the conditions of be filtered by vacuum reaction solution, the complete thionyl chloride of discharge unreacted;Add (R) -4- ((2,2- dimethyl -1,3- dioxies penta
Ring -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines (616g, 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 react and backflow be heated to after 15min,
Reaction solution is concentrated in vacuo after the water generated in course of reaction, reaction 3h are separated by water knockout drum, yellow liquid product (R) -5- is obtained
(2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- second
Base -5- benzyls) -1,2,4- oxadiazoles 950g, yield 94%;1H NMR(d6-DMSO):7.82 (d, J=6.3Hz, 2H), 7.44
(s,1H),7.31(s,1H),4.57-4.56(m,1H),4.23(dd,J1=8.4Hz, J2=6.5Hz, 1H), 4.09-4.06 (m,
4H),3.92-3.90(m,2H),3.27-3.26(m,1H),2.77-2.76(m,2H),2.36(s,3H),2.09-2.07(m,
2H), 1.20-1.97 (m, 2H), 1.74-1.73 (m, 2H), 1.51 (s, 3H), 1.46 (d, J=22.0Hz, 6H), 1.35-1.33
(m, 3H), MS (ESI) m/z:480.6(M+H+).
Embodiment 7
In the reactor add (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,
3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles (960g, 2.0mol) and ethanol 5000mL,
45 DEG C are heated to, 1N HCl (2000mL) are added;It is anti-that the sodium hydroxide solution regulation that concentration is 32% is slowly added dropwise in reaction 3h
Answer liquid pH to neutrality, drip rear concentration of reaction solution, add ethyl acetate 5000mL, washed twice with water 4000mL, it is organic
Mutually concentrate after obtain product (S) -3- (4- (5- (2- cyclobutyl -6- methoxypyridine -4- bases) -1,2,4- oxadiazoles -3- bases) -
2- ethyl -6- benzyloxies) propane -1,2- glycol 865g, yield is 98%;1H NMR(d6-DMSO):7.78(s,2H),7.56-
7.55(m,1H),7.26-7.25(m,1H),4.98(s,1H),4.69(s,1H),3.91-3.89(m,3H),3.82-3.80(m,
2H),3.75-3.74(m,1H),3.53-3.52(m,2H),3.29-3.27(m,1H),2.79-2.77(m,2H),2.32(s,
3H), 1.81-1.78 (m, 4H), 1.67-1.65 (m, 2H), 1.23-1.21 (m, 3H), MS (ESI) m/z:440.5(M+H+).
Embodiment 8
Platelet aggregation inhibitory activity is tested
From healthy male rabbit, random packet.If normal and ticlopidine control group, gastric infusion, dosage 30mg/
kg-1.Normal group gives the CMC-Na that equivalent mass concentration is 0.5%.2h after administration, is injected intraperitoneally 40mg/kg-1Penta bar
Than appropriate sodium (1mL/kg-1) anesthesia, collection rabbit hearts position blood, with the sodium citrate anti-freezing that mass concentration is 3.8%, difference
Platelet rich plasma (PRP) and platelet poor plasma (PPP) are prepared, by adenosine diphosphate (ADP) (final concentration:1.5μmol/L-1) add
With induced platelet aggregation, relative light transmission is detected at 37 DEG C 5 minutes, maximum effect during observation be used to calculate induction
Maximum platelet aggregation rate and inhibiting rate.Inhibiting rate (%)=(aggregation of aggregation maximum-test group of control group is maximum
Value)/control group aggregation maximum * 100%.
As seen from the above table, our (S) -3- (4- (and 5- (2- cyclobutyl -6- methoxypyridine -4- bases) -1,2,4- oxadiazoles -
3- yls) -2- ethyl -6- benzyloxies) propane -1,2- glycol platelet aggregation-against effects are suitable with ticlopidine.
Embodiment above describes general principle, principal character and the advantage of the present invention, 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 (9)
1. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule, it is characterised in that concretely comprise the following steps:
The reaction under sodium hydride effect of A, 1,3- dibromopropane and methyl acetoacetate obtains cyclobutyl ethyl ketone;
B, diethy-aceto oxalate and cyclobutyl ethyl ketone react under cryogenic to be terminated to obtain with cyanoacetamide generation annulation afterwards
To 2- cyclobutyl -3- carboxyl -6- pyridones;
Under thionyl chloride effect first with methanol esterification occurs for C, 2- cyclobutyl -3- carboxyl -6- pyridones, then passes through alkalescence
Under the conditions of continue with thionyl chloride occur carbonyl substitution become chlorine reaction generation the chloro- 6- cyclobutane -4- methyl formate pyridines of 2-;
The chloro- 6- cyclobutane -4- methyl formates pyridine of D, 2- occur in the basic conditions with methanol substitution reaction generation 2- methoxyl groups -
6- cyclobutane -4- carboxyl pyridines;
E, 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- methoxyl group -6- cyclobutane -4- carboxyl pyridines first generate 2- methoxyl group -6- cyclobutane -4- first with thionyl chloride reaction
Acyl chlorides pyridine, then with (R) -4- ((2,2- dimethyl-DOX -4- bases) methoxyl group) -3- ethyl-N-hvdroxv -5- first
Base benzamidine occur substitution reaction, finally condensation generation oxazole ring obtain compound (R) -5- (2- cyclobutyl -6- methoxypyridines -
4- yls) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- evils two
Azoles;
G, (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases)
Methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles hydrolysis obtain (S) -3- (4- (5- (2- cyclobutyl -6- methoxyl group pyrroles
Pyridine -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
2. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step A detailed process is:In reaction bulb, 1,3- dibromopropanes and sodium hydride are added, is heated slowly under nitrogen protection
50℃;Be slowly added to methyl acetoacetate, keeping temperature is no more than 55 DEG C, after dripping under the conditions of 50 DEG C heating stirring 3h;
TLC monitoring raw materials adjust reaction solution pH to 8~9 after having reacted with 1N HCl solutions, maintain the temperature at 60 DEG C of reaction 2h, then drop
Temperature is to 40 DEG C;Organic phase is separated, be washed once with saturated nacl aqueous solution, then is dried with anhydrous magnesium sulfate, is finally concentrated in vacuo
Obtain cyclobutyl ethyl ketone.
3. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step B detailed process is:Sodium methoxide and THF are added in the reactor, and reaction temperature is down to -10 DEG C, adds diethy-aceto oxalate
With the mixed liquor of cyclobutyl ethyl ketone, keeping temperature is no more than 0 DEG C;15 DEG C of reaction 1h are warming up to after dripping, cyano-acetamide is added
Amine, reacts 5h at ambient temperature;Add after a certain amount of water concentration of reaction solution under vacuum, then into concentrated residue plus
Enter in glacial acetic acid, the stirring reaction 3h under the conditions of 50 DEG C, again concentration of reaction solution under vacuum, then added in residue
Water, is stirred under the conditions of 10 DEG C, is had a large amount of solids to suspend and is separated out, filtering and drying to obtain to 2- cyclobutyl -3- carboxyl -6- pyridines
Ketone.
4. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step C detailed process is:In reaction bulb, 2- cyclobutyl -3- carboxyl -6- pyridones are added to methanol, carbonic acid is added
Sodium, is slowly added dropwise thionyl chloride at ambient temperature, and TLC monitoring raw material reactions are complete, are concentrated in vacuo after reaction solution, add DMF
And DIPEA, nitrogen protection is lower to add thionyl chloride, is slowly heated to TLC monitoring raw materials after backflow, reaction 2h
Secondary response completely, is concentrated in vacuo reaction solution again, removes the complete thionyl chloride of unreacted, is cooled to 20 DEG C, adds a certain amount of water,
It is to slowly warm up to after 50 DEG C be cooled to 10 DEG C, there are a large amount of solids to separate out in whipping process, the chloro- 6- rings fourths of 2- is dried to obtain after suction filtration
Alkane -4- methyl formate pyridines.
5. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step D detailed process is:In reaction bulb, the first the chloro- 6- cyclobutane -4- methyl formates pyridines of 2- and containing sodium hydroxide
Alcoholic solution is heated to 100 DEG C of reaction 2h, and vacuum divides exactly methanol, continues to react 4h, then concentration of reaction solution, adds a certain amount of water
2h is reacted under the conditions of 80 DEG C afterwards, again concentration of reaction solution, finally under the conditions of 10 DEG C, the hydrochloric acid that concentration is 32% is slowly added dropwise
Solution, temperature is no more than 15 DEG C;Drip rear reaction solution to be extracted with tert-butyl acetate, separate and be washed with water after organic phase, concentrate
Obtain 2- methoxyl group -6- cyclobutane -4- carboxyl pyridines.
6. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step E 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, be cooled to after room temperature and add first
Base tertbutyl ether, is washed with water and washs three times, and yellow liquid is obtained after organic phase concentration;Normal heptane is added, under the conditions of 25 DEG C
Stirring, has a large amount of solids to separate out, filtering and drying to obtain to white solid (R) -4- ((2,2- dimethyl-DOX -4-
Base) methoxyl group) -3- ethyl-N-hvdroxv -5- methylbenzamidines.
7. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step F detailed process is:In reaction bulb, 2- methoxyl group -6- cyclobutane -4- carboxyl pyridines and toluene are added;In 20 DEG C of bars
Thionyl chloride is added dropwise under part, reaction a period of time is stirred for after being added dropwise completely, reaction solution is filtered by vacuum under the conditions of 50 DEG C, is discharged
The complete thionyl chloride of unreacted;Add (R) -4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyls-N-
The toluene mixture liquid of hydroxy-5-methyl base benzamidine and triethylamine, is added dropwise complete under the conditions of no more than 30 DEG C;When continuing to react one section
Between after be heated to backflow, separate the water generated in course of reaction by water knockout drum, be concentrated in vacuo reaction solution after reaction 3h, obtain Huang
Color liquid product (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4-
Base) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles.
8. a kind of novel method for synthesizing of S1P-1 receptor stimulating agents drug molecule according to claim 1, it is characterised in that
Step G detailed process is:In the reactor add (R) -5- (2- cyclobutyl -6- methoxypyridine -4- bases) -3- (4- ((2,
2- dimethyl-DOX -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- oxadiazoles and ethanol are heated to 45
DEG C, add 1N HCl solutions;The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, during regulation reaction solution pH is
Property, rear concentration of reaction solution is dripped, ethyl acetate extraction is added, is washed with water and washs twice, product is obtained after organic phase concentration
(S) -3- (4- (5- (2- cyclobutyl -6- methoxypyridine -4- bases) -1,2,4- oxadiazoles -3- bases) -2- ethyl -6- benzyloxies)
Propane -1,2- glycol.
9. a kind of S1P-1 receptor stimulating agents drug molecule as claimed in claim 1 is in medicament for resisting platelet aggregation is prepared
Using.
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CN101511827A (en) * | 2006-09-07 | 2009-08-19 | 埃科特莱茵药品有限公司 | Pyridin-4-yl derivatives as immunomodulating agents |
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CN104321311A (en) * | 2012-05-22 | 2015-01-28 | 埃科特莱茵药品有限公司 | New process for the preparation of 2-cyclopentyl-6-methoxy-isonicotinic acid |
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