CN107382965A - The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity - Google Patents
The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity Download PDFInfo
- Publication number
- CN107382965A CN107382965A CN201710689844.5A CN201710689844A CN107382965A CN 107382965 A CN107382965 A CN 107382965A CN 201710689844 A CN201710689844 A CN 201710689844A CN 107382965 A CN107382965 A CN 107382965A
- Authority
- CN
- China
- Prior art keywords
- reaction
- bases
- added
- methoxyl group
- under
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 *c1cc(*)nc(C2CCCC2)c1 Chemical compound *c1cc(*)nc(C2CCCC2)c1 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity, belong to medical synthesis technical field.Technical scheme main points are:A kind of receptor stimulating agent drug molecules of new S1P 1 with antitumor activity, have following structure:
Description
Technical field
The invention belongs to medical synthesis technical field, and in particular to a kind of new S1P-1 acceptors with antitumor activity
The synthetic method of anti-depressant medications molecule.
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, suppressing SPHK activation significantly or even can block cell caused by proinflammatory substance anti-completely
Should, such as Ca2+Metabolism, the secretion of degranulation, chemotaxis and cell factor.In addition, S1P can also pass through the S1P with cell surface
Acceptor combines, and acceptor is caved in, and induction of lymphocyte returns nest, suppresses lymphocyte from peripheral lymph nodes and secondary lymphatic organ
Outflow, 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 arthritis, exedens
Colitis etc..
In terms of tumour, ceramide and sphingol mainly cause cell-cycle arrest and promote Apoptosis, and S1P is then led
Promote cell survival.The key enzyme SPH1 of S1P productions is catalyzed due to the oncogene characteristic with tumour and thin in kinds of tumors
High expression in born of the same parents, the carcinogenicity of cell can be strengthened by raising SPHK1 expression, so the balance between S1P and sphingol determines
The destiny of cell, SPHK have turned into the target spot of oncotherapy.
We are found that a kind of compound that 1,2,4- triazole structures are linked with pyridine by CAD
Molecule, the compound molecule have S1P-1 receptor agonist activities, it has been found that the compound molecule is to some tumour cells
With certain inhibitory action.
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 synthetic method of the novel new S1P-1 receptor stimulating agents drug molecule with antitumor activity of high and structure.
The present invention for solve above-mentioned technical problem adopt the following technical scheme that, have antitumor activity new S1P-1 by
The synthetic method of body anti-depressant medications molecule, it is characterised in that its molecular structure is:
The present invention for solve above-mentioned technical problem adopt the following technical scheme that, have antitumor activity new S1P-1 by
The synthetic method of body anti-depressant medications molecule, it is characterised in that concretely comprise the following steps:
A, the reaction under sodium hydride effect obtains cyclopentylethanone to 1,4- dibromobutanes with methyl acetoacetate;
B, diethy-aceto oxalate and cyclopentylethanone react under cryogenic terminates rear and cyanoacetamide generation cyclization instead
2- cyclopenta -3- carboxyl -6- pyridones should be obtained;
C, 2- cyclopenta -3- carboxyl -6- pyridones and dimethyl suflfate react generation 2- methoxyl group -6- pentamethylene -
Continue after 4- carboxyl pyridines and ammoniacal liquor reaction generation 2- methoxyl group -6- pentamethylene -4- formamido pyridines;
D, 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;
E, (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 with 2- methoxyl group -6- pentamethylene -4- formamido pyridines in alkaline bar
Substitution reaction occurs under part, last cyclic condensation obtains compound (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3-
(4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles;
F, (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -
4- yls) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles hydrolyze to obtain (S) -3- (4- (5- (2- cyclopenta -6- methoxies
Yl pyridines -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
Further limit, step A detailed process is:In reaction bulb, Isosorbide-5-Nitrae-dibromobutane 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 use 1N HCl solutions regulation reaction solution pH to 8~9 after having reacted, maintain the temperature at
60 DEG C of reaction 2h, are then cooled to 40 DEG C;Organic phase is separated, washed once with saturated nacl aqueous solution, then uses anhydrous magnesium sulfate
Dry, be finally concentrated in vacuo and obtain cyclopentylethanone.
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 cyclopentylethanone 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, reacts 5h at ambient temperature;Concentrated under vacuum after adding a certain amount of water
Reaction solution, then added into concentrated residue in glacial acetic acid, the stirring reaction 3h under the conditions of 50 DEG C is dense under vacuum again
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- cyclopenta -3- carboxyl -6- pyridones.
Further limit, step C detailed process is:In reaction bulb, dimethyl suflfate is first added, is warming up to 80 DEG C,
2- cyclopenta -3- carboxyl -6- pyridones are added portionwise again, reaction temperature is no more than 85 DEG C, TLC monitoring raw material reactions are complete
Afterwards, a certain amount of water is added into reaction solution under the conditions of 0 DEG C, then ammonia spirit is slowly added dropwise, temperature is no more than 0 DEG C, drop
Gradually separated out during adding by a large amount of solids, filter drying and obtain 2- methoxyl group -6- pentamethylene -4- formamido pyridines.
Further limit, step D 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 E 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 2- methoxyl group -6- pentamethylene -4- formamido pyridines and triethylamine is added, no more than 30 DEG C
Under the conditions of about 20min be added dropwise it is complete;Continue to be heated to flowing back after reacting 15min, separated in course of reaction and generated by water knockout drum
Water, react 3h after be concentrated in vacuo reaction solution, obtain yellow liquid product (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -
3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles.
Further limit, step F detailed process is:(R) -5- (2- cyclopenta -6- methoxies are added in 30L reactors
Yl pyridines -4- bases) -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, add 1N HCl;It is molten that the sodium hydroxide that concentration is 32% is slowly added dropwise in reaction 3h
Liquid, reaction solution pH is reached neutral, drip rear concentration of reaction solution, add ethyl acetate extraction, and be washed twice with water, have
Machine obtains product (S) -3- (4- (5- (2- cyclopenta -6- methoxypyridine -4- bases) -1,2,4- triazoles -3- after mutually concentrating
Base) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
Further limit, step F product has particular application as:Target compound (S) -3- (4- (5- (2- cyclopenta -6- first
Epoxide pyridin-4-yl) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol is to breast cancer cell
MCF-7 and liver cancer HepG2 have certain inhibitory 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
In reaction bulb, add Isosorbide-5-Nitrae-dibromobutane (216g, 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 to 8~9,60 DEG C of reaction 2h are maintained the temperature at, are then cooled to 40 DEG C;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 cyclopentylethanone 102g, yield is
91%;1H NMR(400M,CDCl3):2.86(m,1H),2.15(s.3H),1.68(m,8H)
Embodiment 2
Sodium methoxide (60g, 1.1mol) and THF (1000mL) are added in the reactor, and reaction temperature is down to -10 DEG C, adds
The mixed liquor of diethy-aceto oxalate (146g, 1mol) and cyclopentylethanone (112g, 1.0mol, 1.0eq), keeping temperature are no more than 0
℃;15 DEG C of reaction 1h are warming up to after dripping, add cyanoacetamide (100g, 1.2mol), 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 195g product 2- cyclopenta -3- carboxyls -6-
Pyridone, yield 94%;1H NMR(400M,DMSO-d6):12.67(br,2H),6.63(s,1H),6.38(s,1H),2.89
(m,1H),1.98(m,2H),1.63(m,6H),MS(ESI)m/z:206.2(M-H+).
Embodiment 3
In reaction bulb, dimethyl suflfate (630g, 5.0mol) is first added, is warming up to 80 DEG C, then 5 batches add 2- rings penta
Base -3- carboxyl -6- pyridones (1000g, 5.0mol), reaction temperature is set to be no more than 85 DEG C, after TLC monitoring raw material reactions completely,
A certain amount of water is added into reaction solution under the conditions of 0 DEG C, then ammonia spirit is slowly added dropwise, temperature is no more than 0 DEG C, was added dropwise
Gradually separated out in journey by a large amount of solids, ammoniacal liquor, which is added dropwise, makes reaction solution pH reach 8, filters reaction solution, and drying filter cake obtains 2- methoxies
Base -6- pentamethylene -4- formamido pyridine 1050g, yield 95%.
Embodiment 4
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 5
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 2- methoxyl group -6- pentamethylene -4- formamido pyridines (440g, 2.0mol) and triethylamine
The toluene mixture liquid 2000mL of (400g, 4.0mol), 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- (2- cyclopenta -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxies penta
Ring -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazole 910g, yield 92%;1H NMR(400M,DMSO-d6):
13.2 (s, 1H), 7.57-7.55 (m, 2H), 6.85 (s, 1H), 6.01 (s, 1H), 4.55 (t, J=4.0Hz, 2H), 4.01 (s,
1H),3.94-3.92(m,2H),3.80(dd,J1=8.0Hz, J2=3.0Hz, 3H), 2.79 (s, 1H), 2.15 (s, 3H),
1.96-1.94 (m, 4H), 1.77-1.75 (m, 4H), 1.40 (s, 3H), 1.27 (s, 6H), 1.32 (t, J=7.5Hz, 3H), MS
(ESI)m/z:493.6(M+H+).
Embodiment 6
In the reactor add (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,
3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles (980g, 2.0mol) and ethanol 2000mL,
45 DEG C are heated to, adds 1N HCl 1500mL;The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, makes reaction
The pH of liquid reaches neutral, drips rear concentration of reaction solution, adds ethyl acetate 3000mL, is washed twice, had with water 2000mL
Machine obtains product (S) -3- (4- (5- (2- cyclopenta -6- methoxypyridine -4- bases) -1,2,4- triazoles -3- after mutually concentrating
Base) -2- ethyl -6- benzyloxies) propane -1,2- glycol 861g, yield 95%;1H NMR(400M,DMSO-d6):13.5(s,
1H), 7.51-7.48 (m, 2H), 6.81 (s, 1H), 6.01 (s, 1H), 4.55 (t, J=4.0Hz, 2H), 4.01 (s, 1H),
3.94-3.92(m,2H),3.80(dd,J1=8.0Hz, J2=4.0Hz, 3H), 3.58 (s, 1H), 3.45 (s, 1H), 2.79 (s,
1H), 2.15 (s, 3H), 1.96-1.94 (m, 4H), 1.77-1.75 (m, 4H), 1.40 (s, 3H), 1.36 (s, 3H), MS (ESI)
m/z:453.5(M+H+).
Embodiment 7
Antitumor activity is tested
Growth period breast cancer cell MCF-7 and liver cancer HepG2 are collected, the active anticancer of compound is determined with MTS methods,
By cell with (every milliliter 4 × 10 of debita spissitudo4Individual cell) it is added in 96 porocyte culture plates and (must trains containing 10% tire calf serum
Nutrient solution is made into individual cells suspension), after cultivating 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of with various concentrations
Compound effects 72 hours, then by MTS (final mass concentration 2mg/mL) and DMS (final 30 μM of molar concentration) mixing
Thing is directly added into celliferous culture medium, continues to put incubator incubation 4h.After acting on 4h, abandoning supernatant, 150 are added per hole
μ LDMSO, vibration, suction of the metabolin that cell survival rate is acted on MTS by it under enzyme linked immunological monitor 490nm wavelength
Yield determines.
Preliminary biological activity test shows that the compound has suppression to make breast cancer cell MCF-7 and liver cancer HepG2
With, but be better than the inhibitory action to breast cancer cell MCF-7 to the inhibitory action of hepatocellular carcinoma H22, its action effect with
Tarceva approaches.
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 (9)
1. the synthetic method of the new S1P-1 receptor stimulating agents drug molecule with antitumor activity, it is characterised in that its molecule
Structure is:
2. the synthetic method of the new S1P-1 receptor stimulating agents drug molecule with antitumor activity, it is characterised in that specific step
Suddenly it is:
A, the reaction under sodium hydride effect obtains cyclopentylethanone to 1,4- dibromobutanes with methyl acetoacetate;
B, diethy-aceto oxalate and cyclopentylethanone react under cryogenic terminates to obtain with cyanoacetamide generation annulation afterwards
To 2- cyclopenta -3- carboxyl -6- pyridones;
C, 2- cyclopenta -3- carboxyl -6- pyridones react with dimethyl suflfate and generate 2- methoxyl group -6- pentamethylene -4- carboxylics
Continue after yl pyridines and ammoniacal liquor reaction generation 2- methoxyl group -6- pentamethylene -4- formamido pyridines;
D, 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;
E, (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 with 2- methoxyl group -6- pentamethylene -4- formamido pyridines in the basic conditions
Generation substitution reaction, last cyclic condensation obtain compound (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3- (4-
((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles;
F, (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3- (4- ((2,2- dimethyl -1,3- dioxolanes -4- bases)
Methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles hydrolyze to obtain (S) -3- (4- (5- (2- cyclopenta -6- methoxyl group pyrroles
Pyridine -4- bases) -1,2,4- triazole -3- bases) -2- ethyl -6- benzyloxies) propane -1,2- glycol.
3. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step A detailed process is:In reaction bulb, Isosorbide-5-Nitrae-dibromobutane and sodium hydride are added, is protected in nitrogen
Under be heated slowly to 50 DEG C;Methyl acetoacetate is slowly added to, 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 use 1N HCl solutions regulation reaction solution pH to 8~9 after having reacted, maintain the temperature at 60 DEG C instead
2h is answered, is then cooled to 40 DEG C;Organic phase is separated, washed once with saturated nacl aqueous solution, then is dried with anhydrous magnesium sulfate, most
It is concentrated in vacuo afterwards and obtains cyclopentylethanone.
4. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step B detailed process is:Add sodium methoxide in the reactor and THF, reaction temperature are down to -10 DEG C, add
Enter the mixed liquor of diethy-aceto oxalate and cyclopentylethanone, keeping temperature is no more than 0 DEG C;15 DEG C are warming up to after dripping instead
1h is answered, cyanoacetamide is added, reacts 5h at ambient temperature;Concentration of reaction solution under vacuum is added after a certain amount of water,
Then added into concentrated residue in glacial acetic acid, the stirring reaction 3h under the conditions of 50 DEG C, again concentration reaction under vacuum
Liquid, water is then added in residue, 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 2- rings
Amyl group -3- carboxyl -6- pyridones.
5. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step C detailed process is:In reaction bulb, dimethyl suflfate is first added, is warming up to 80 DEG C, then in batches
2- cyclopenta -3- carboxyl -6- pyridones are added, reaction temperature is no more than 85 DEG C, after TLC monitoring raw material reactions completely, at 0 DEG C
Under the conditions of a certain amount of water is added into reaction solution, then ammonia spirit is slowly added dropwise, temperature is no more than 0 DEG C, during dropwise addition
Gradually separated out by a large amount of solids, filter drying and obtain 2- methoxyl group -6- pentamethylene -4- formamido pyridines.
6. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step D detailed process is:In reaction bulb, DMAP, 2- methyl -4- cyano group -6- second
Base phenol 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;Drip
After react 2h, be first washed with water once, then washed once with the mixed solution of water and 1N hydrochloric acid solution, finally with water and saturation
The mixed solution of sodium acid carbonate washed once;Yellow oily liquid is obtained after organic phase concentration, all adds in DMF, adds
(R) -2,2- dimethyl-DOX -4- methanol, is eventually adding potassium carbonate, reacts 3h under the conditions of 120 DEG C, be cooled to
Methyl tertiary butyl ether(MTBE) is added after room temperature, is washed with water and washs three times, yellow liquid is obtained after organic phase concentration;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.
7. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step E detailed process is:In reaction bulb, (R) -4- ((2,2- dimethyl -1,3- dioxies penta are added
Ring -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 chlorination of discharge unreacted under the conditions of 50 DEG C after reacting 30min
Sulfoxide;The toluene mixture liquid of 2- methoxyl group -6- pentamethylene -4- formamido pyridines and triethylamine is added, in no more than 30 DEG C bars
About 20min is added dropwise complete under part;Continue to be heated to flowing back after reacting 15min, separate what is generated in course of reaction by water knockout drum
Water, reaction solution is concentrated in vacuo after reacting 3h, obtains yellow liquid product (R) -5- (2- cyclopenta -6- methoxypyridine -4- bases) -3-
(4- ((2,2- dimethyl -1,3- dioxolanes -4- bases) methoxyl group) -3- ethyl -5- benzyls) -1,2,4- triazoles.
8. the synthesis side of the new S1P-1 receptor stimulating agents drug molecule according to claim 2 with antitumor activity
Method, it is characterised in that step F detailed process is:(R) -5- (2- cyclopenta -6- methoxypyridines -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- triazoles and
Ethanol, 45 DEG C are heated to, add 1N HCl;The sodium hydroxide solution that concentration is 32% is slowly added dropwise in reaction 3h, makes reaction solution
PH reaches neutral, drips rear concentration of reaction solution, adds ethyl acetate extraction, and is washed twice with water, after organic phase concentration
Obtain product (S) -3- (4- (5- (2- cyclopenta -6- methoxypyridine -4- bases) -1,2,4- triazole -3- bases) -2- ethyls -6-
Benzyloxy) propane -1,2- glycol.
9. the new S1P-1 receptor stimulating agents drug molecule with antitumor activity is preparing anti-swell as claimed in claim 1
Application in tumor medicine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710689844.5A CN107382965A (en) | 2017-08-14 | 2017-08-14 | The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710689844.5A CN107382965A (en) | 2017-08-14 | 2017-08-14 | The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity |
Publications (1)
Publication Number | Publication Date |
---|---|
CN107382965A true CN107382965A (en) | 2017-11-24 |
Family
ID=60355690
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710689844.5A Pending CN107382965A (en) | 2017-08-14 | 2017-08-14 | The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107382965A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112574215A (en) * | 2020-12-15 | 2021-03-30 | 河南科技大学第一附属医院 | Preparation method and application of benzoxazole compound for hospital disinfection |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1403439A (en) * | 2001-08-31 | 2003-03-19 | 蝉真有限公司 | Phytosphingosine derivate with antitumor activity |
CN102471328A (en) * | 2009-07-16 | 2012-05-23 | 埃科特莱茵药品有限公司 | Pyridin-4-yl derivatives |
CN102741232A (en) * | 2009-09-29 | 2012-10-17 | 阿勒根公司 | Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors |
WO2013036530A1 (en) * | 2011-09-08 | 2013-03-14 | Allergan, Inc. | 3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy)propan-2-ol derivatives as sphingosine-1 phosphate receptors modulators |
CN103313981A (en) * | 2011-01-19 | 2013-09-18 | 埃科特莱茵药品有限公司 | 2-methoxy-pyridin-4-yl derivatives |
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 |
CN105051037A (en) * | 2013-02-20 | 2015-11-11 | 株式会社Lg生命科学 | Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent |
-
2017
- 2017-08-14 CN CN201710689844.5A patent/CN107382965A/en active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1403439A (en) * | 2001-08-31 | 2003-03-19 | 蝉真有限公司 | Phytosphingosine derivate with antitumor activity |
CN102471328A (en) * | 2009-07-16 | 2012-05-23 | 埃科特莱茵药品有限公司 | Pyridin-4-yl derivatives |
CN102741232A (en) * | 2009-09-29 | 2012-10-17 | 阿勒根公司 | Condensed ring pyridine compounds as subtype-selective modulators of sphingosine-1-phosphate-2 (s1p2) receptors |
CN103313981A (en) * | 2011-01-19 | 2013-09-18 | 埃科特莱茵药品有限公司 | 2-methoxy-pyridin-4-yl derivatives |
WO2013036530A1 (en) * | 2011-09-08 | 2013-03-14 | Allergan, Inc. | 3-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenoxy)propan-2-ol derivatives as sphingosine-1 phosphate receptors modulators |
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 |
CN105051037A (en) * | 2013-02-20 | 2015-11-11 | 株式会社Lg生命科学 | Sphingosine-1-phosphate receptor agonists, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent |
Non-Patent Citations (2)
Title |
---|
GUNTHER SCHMIDT,等: "Practical Synthesis of a S1P Receptor 1 Agonist via a Guareschi− Thorpe Reaction", 《ORG. PROCESS RES. DEV.》 * |
张彩霞,等: "鞘氨醇激酶与肿瘤", 《药学学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112574215A (en) * | 2020-12-15 | 2021-03-30 | 河南科技大学第一附属医院 | Preparation method and application of benzoxazole compound for hospital disinfection |
CN112574215B (en) * | 2020-12-15 | 2021-08-10 | 河南科技大学第一附属医院 | Preparation method and application of benzoxazole compound for hospital disinfection |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11192879B2 (en) | Chemokine receptor modulators and uses thereof | |
CN102209714A (en) | Triazine, pyrimidine and pyridine analogs and their use as therapeutic agents and diagnostic probes | |
CN105732615B (en) | Cdk kinase inhibitors | |
JP2023531503A (en) | Aromatic compound and its use in antitumor drug | |
CN106478633A (en) | One class bruton's tyrosine kinase inhibitor | |
CN104072493B (en) | One class contains 2-mercaptobenzothiazole and the naphthalimide compound of triazole heterocycle, its preparation method and application thereof | |
CN106478605A (en) | Pyrimidines, its preparation method and medical usage | |
CN101967140A (en) | Deuterated crizotinib as well as derivant, preparation method and application thereof | |
US9029403B2 (en) | Treatment of ovarian cancer with benzylidenebenzohydrazides | |
CN102333781B (en) | Tricyclic pyrazolopyrimidine derivative | |
CN104230905A (en) | Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs | |
CN111269104A (en) | Chalcone analogue and application thereof | |
CN107382965A (en) | The synthetic method of the receptor stimulating agent drug molecules of new S1P 1 with antitumor activity | |
CN106674242A (en) | Curcumol derivatives with anti-tumor activity, and preparation method and application of curcumol derivatives | |
CN104771392B (en) | Class I histone deacetylase inhibitor and application | |
CN1931869B (en) | Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use | |
CN105669823A (en) | Piperazine-framework-containing glycyrrhetinic acid derivatives, and preparation method and application thereof | |
CN102603712A (en) | S-type and R-type tetrahydro-naphthalene amides antitumor compound and pharmaceutically acceptable salt or pro-drug thereof, preparation method and application | |
CN104530018B (en) | Indole compounds containing alpha-methylene-gamma-butyrolactone structures, preparation method and application thereof | |
CN107235994B (en) | Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole | |
CN104130250B (en) | Deuterated Dasatinib and its preparation method and application | |
CN103709135B (en) | Ton ketone derivatives and its preparation method and application | |
CN107337665A (en) | A kind of synthetic method with triazole ring structure immunosuppressive drug | |
CN105612157B (en) | The cyclopenta amine derivative that 3- replaces | |
CN107382989A (en) | A kind of synthetic method with oxazole ring structure immunosuppressive drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171124 |
|
RJ01 | Rejection of invention patent application after publication |