CN101735048A - Salicylic acid compounds with insulin-sensitizing activity and preparation method thereof - Google Patents
Salicylic acid compounds with insulin-sensitizing activity and preparation method thereof Download PDFInfo
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- CN101735048A CN101735048A CN200810202270A CN200810202270A CN101735048A CN 101735048 A CN101735048 A CN 101735048A CN 200810202270 A CN200810202270 A CN 200810202270A CN 200810202270 A CN200810202270 A CN 200810202270A CN 101735048 A CN101735048 A CN 101735048A
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- ethyl acetate
- solvent evaporated
- anhydrous
- adds
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 230000000694 effects Effects 0.000 title abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 198
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 80
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- 239000002904 solvent Substances 0.000 claims description 55
- 238000006243 chemical reaction Methods 0.000 claims description 44
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 40
- 238000001035 drying Methods 0.000 claims description 35
- 238000005406 washing Methods 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 20
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 20
- 239000012044 organic layer Substances 0.000 claims description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 20
- UIAFKZKHHVMJGS-UHFFFAOYSA-N 2,4-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1O UIAFKZKHHVMJGS-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 15
- 238000004440 column chromatography Methods 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- 239000012312 sodium hydride Substances 0.000 claims description 10
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- PGTANUNIOXCVLE-UHFFFAOYSA-N CC.[Br] Chemical compound CC.[Br] PGTANUNIOXCVLE-UHFFFAOYSA-N 0.000 claims description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 31
- 150000001875 compounds Chemical class 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
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- 206010012601 diabetes mellitus Diseases 0.000 description 18
- 229940095102 methyl benzoate Drugs 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 13
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- OXOWWPXTTOCKKU-UHFFFAOYSA-N 2-propoxybenzoic acid Chemical compound CCCOC1=CC=CC=C1C(O)=O OXOWWPXTTOCKKU-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
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- OUJMXIPHUCDRAS-UHFFFAOYSA-N 2-(5-ethylpyridin-2-yl)ethanol Chemical compound CCC1=CC=C(CCO)N=C1 OUJMXIPHUCDRAS-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
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- CIFXXSVGKCRQHZ-UHFFFAOYSA-N methyl 2-propoxybenzoate Chemical class CCCOC1=CC=CC=C1C(=O)OC CIFXXSVGKCRQHZ-UHFFFAOYSA-N 0.000 description 4
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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Landscapes
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Abstract
The invention provides salicylic acid compounds with a structure shown as the following formula (I). In the formula (I), R1 refers to substituted alkyl having 1 to 6 carbon atoms, substituted aryl alkyl, or substituted aromatic heterocyclic alkyl; R2 refers to ethyl or acetyl; and R3 refers to hydrogen atom or methyl. The invention also provides two preparation methods for the salicylic acid compounds with the structure of the formula (I). The salicylic acid compounds have insulin-sensitizing activity.
Description
Technical field
The present invention relates to salicylic acid compounds of tool insulin-sensitizing activity and preparation method thereof, belong to pharmaceutical chemistry and diabetes B therapeutics field.
Background technology
Diabetes are that a kind of absolute or relative deficiency causes the metabolic disease of hyperglycemia owing to the body insulin secretion.It is the chronic complicating diseases of important foundation with the vascular lesion that long-term hyperglycemia can cause a series of, causes the patient disabled or dead, and the serious harm human beings'health has become the third-largest sick kind the after cardiovascular and cerebrovascular diseases, malignant tumour.The World Health Organization (WHO) studies show that since the 1980s, diabetic subject's number increases year by year with about 10% average growth rate.Global diabetic subject add up to 1.71 hundred million (2.85%) in 2000, and according to the WHO prediction, to the year two thousand thirty, global diabetic subject will reach 3.66 hundred million (6.1%).Clinical diabetes mainly is divided into type 1 diabetes and diabetes B, and the latter accounts for more than 90%.Because diabetes are not still had ideal radical cure means at present, how effectively controlling blood sugar delays especially developing of vascular complication of complication, has become the focus that people pay close attention to.
Along with going deep into that diabetes are familiar with, it is found that improving insulin resistant (InsulIn resIstance, IR refer to that body reduces insulin sensitivity) and alleviating the islet cells infringement is two importances of control diabetes B.IR is the important foundation of diabetes B morbidity, and there has been IR in Most patients when no hyperglycemia, and improving IR in early days is prevention and the key that delays diabetes and complication thereof.Increase the susceptibility of body target cell, but except that lowering blood glucose, the islet tissue that can also make the patient be subjected to overstimulation obtains resting and reorganizing to Regular Insulin.Therefore, the emphasis of diabetes B clinical application also gradually from the medicine of insulin secretion accelerating, has turned to euglycemic agent.Discover that traditional biguanides hypoglycemic agents metformin has certain insulin-sensitizing effect, is used widely in recent years clinically.In addition; thiazolidinediones (ThIazolIdInedIones; TZDs) euglycemic agent such as rosiglitazone, pioglitazone etc.; the insulin resistant effect that improves with its uniqueness enjoys clinical attention, and such medicine also has beneficial effects such as the lipid metabolism of improvement, prevention vascular complication and protection islet cells simultaneously.But no matter be metformin or TZDs, still will stand the test of aspects such as untoward reaction, long-term efficacy, also can not satisfy clinical needs far away, seeking more antidiabetic medicines safely and effectively is pendulum urgent tasks in face of the pharmacy researcher.From the angle of theoretical investigation, metformin and TZDs improve the mechanism of insulin resistant and other beneficial effect and do not illustrate fully as yet.Therefore, in the new drug research process,, compare with existing clinical medicine simultaneously by further investigation to mechanism of action, can be illustrating of medicine anti-diabetic and complication mechanism of action thereof experimental data is provided, and be that further the pharmaceutically-active novel targets of discovery is given a clue.
TZDs is the brand-new anti-diabetes B medicine of a class that grows up the phase at the end of the nineties in last century, discovered afterwards that peroxisome proliferation-activated receptors γ (peroxIsome prolIferator-actIved receptor, PPAR γ) was its significant feature target spot.PPAR γ belongs to PPAR nuclear hormone receptor superfamily, mainly expresses in adipocyte, and it is the important transcription factor of regulating the adipocyte differentiation.It with nuclear in another acceptor RXR (retInoId X receptor, Vogan-Neu acid X acceptor) after the combination, under the effect of a series of co-activation factor, (PPRE) combines with the PPAR response element, regulate a series of participation glucose and generate, transport, utilize and the insulin response gene transcription relevant, thereby improve the susceptibility of body Regular Insulin with fatty acid metabolism.Because, also may there be the unsafe factor to medication person such as increase of persistence Q volume of blood and liver toxicity except that causing the weight increase in TZDs, therefore, people turn to sight the research of non-TZDs PPAR gamma agonist again.The nearly more than ten years, external each big drugmaker fell over each other to study the PPAR gamma agonist, had successively found the agonist of hundreds of various structure types, and a plurality of compound listings was arranged or enter clinical experimental stage.The like product that China goes back the complete autonomous innovation of none at present, have an independent intellectual property rights comes into the market.
Summary of the invention
An object of the present invention is to provide salicylic acid compounds with insulin-sensitizing activity.
Another object of the present invention provides the preparation method of this compounds.
In order to achieve the above object, technical scheme of the present invention is for providing a kind of salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2Expression ethyl or ethanoyl;
R
3Expression hydrogen atom or methyl.
Unless dated especially, term used herein has as giving a definition:
" fragrant heterocyclic radical " expression contains 1-4 heteroatomic five yuan or six membered heteroaryl that is selected from Sauerstoffatom, nitrogen-atoms or sulphur atom, as furyl, thienyl, pyrryl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl etc., or contain heteroatomic nine yuan or ten yuan and the ring heteroaryl that 1-4 is selected from oxygen Sauerstoffatom, nitrogen-atoms or sulphur atom, as indyl, benzopyranyl, quinoline base and the different quinoline base etc. of giving repeated exhortations of giving repeated exhortations.In these groups, be the best with pyridyl, indyl, oxazolyl He isoxazolyl.
Saturated or unsaturated, the replacement that contains 1-6 carbon atom that " fragrant heterocyclic radical alkyl " expression is replaced by fragrant heterocyclic radical or straight chain, the branched alkane hydrocarbon chain of non-replacement, wherein the definition of " fragrant heterocyclic radical " is the same, alkyl is the best with methylene radical and ethylene.
" alkyl of replacement ", " cycloalkyl of replacement ", " aryl of replacement " and " fragrant heterocyclic radical of replacement " represent respectively above-mentioned " alkyl ", " cycloalkyl ", " aryl " and " fragrant heterocyclic radical " can randomly be selected from halogen atom, alkyl, alkoxyl group, acyloxy ,-OH ,-NH
2,-NO
2The group of ,-NHAc replaces.
Salicylic acid compounds is preferably shown in the formula of the present invention (I):
(1) 2-acetoxyl group-4-n-butoxy phenylformic acid;
(2) 2-acetoxyl group-4-n-butoxy methyl benzoate;
(3) 2-acetoxyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] phenylformic acid;
(4) 2-acetoxyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl benzoate;
(5) 2-acetoxyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] phenylformic acid;
(6) 2-acetoxyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl benzoate;
(7) 2-acetoxyl group-4-[2-(1-indoles) oxyethyl group] phenylformic acid;
(8) 2-acetoxyl group-4-[2-(1-indoles) oxyethyl group] methyl benzoate;
(9) 2-acetoxyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid;
(10) 2-acetoxyl group-4-[3-methyl-3-(2-pyridine)] the propoxy benzoic acid methyl esters;
(11) 2-oxyethyl group-4-n-butoxy phenylformic acid;
(12) 2-oxyethyl group-4-n-butoxy methyl benzoate;
(13) 2-oxyethyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] phenylformic acid;
(14) 2-oxyethyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl benzoate;
(15) 2-oxyethyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] phenylformic acid;
(16) 2-oxyethyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl benzoate;
(17) 2-oxyethyl group-4-[2-(1-indoles) oxyethyl group] phenylformic acid;
(18) 2-oxyethyl group-4-[2-(1-indoles) oxyethyl group] methyl benzoate;
(19) 2-oxyethyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid;
(20) 2-oxyethyl group-4-[3-methyl-3-(2-pyridine)] the propoxy benzoic acid methyl esters.
The structural formula of above compound is as follows:
Wherein, the R of compound 1-20
1, R
2, R
3See the following form:
The present invention also provides three kinds of preparation methods of salicylic acid compounds (I):
First kind of preparation method's step comprises:
The first step: with 2, the 4-resorcylic acid is suspended in the mixed solution of acetic anhydride and acetic acid, adding volume ratio is 1: 1 the 98wt% sulfuric acid and the mixed solution of 37wt% hydrochloric acid, sealing also is warming up to 85-95 ℃ of reaction 0.5-1.5h, hot suction filtration, filtrate places ice bath cooling to separate out solid, filter, with filter residue in 55-65 ℃ of following drying under reduced pressure;
Add Anhydrous potassium carbonate and dry N in above-mentioned filter residue, dinethylformamide drips cylite, room temperature reaction 2-3h, filter, filtrate adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (II);
Wherein, 2,4-resorcylic acid and acetic anhydride, acetic acid, sour mixed solution, Anhydrous potassium carbonate, N, the mass ratio of dinethylformamide, cylite and ethyl acetate was respectively 5: 4: 5: 1.5: 2.7: 42.6: 3.9: 72.9;
Second step: intermediate (II) with the anhydrous diethyl ether dissolving, is added aromatic alkyl alcohol R
1OH and triphenylphosphine, under-3--8 ℃ cryosel bath condition, drip diethyl azodiformate, room temperature is carried out Mi Qu and is spreaded out reaction 15-20h, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, through anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (III);
Wherein, 2,4-resorcylic acid and anhydrous diethyl ether, aromatic alkyl alcohol R
1The mass ratio of OH, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.36-1.05: 1.65: 1.12: 41;
The 3rd step: (III) dissolves with tetrahydrofuran (THF) with intermediate, the Pd-C catalyzer that adds 8-12wt% is inhaled H-H reaction 20-30h, wherein intermediate (III) was respectively 12.5: 134 with the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer: 1-1.5, filter, solvent evaporated obtains salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2The expression ethanoyl;
R
3Expression hydrogen atom or methyl.
Second kind of preparation method's step comprises:
The first step: with 2, the 4-resorcylic acid is dissolved in dry N, in the dinethylformamide, adds Anhydrous potassium carbonate, drip cylite, room temperature reaction 1-3h adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (IV);
Wherein, 2,4-resorcylic acid and N, the mass ratio of dinethylformamide, Anhydrous potassium carbonate, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: intermediate (IV) with the anhydrous diethyl ether dissolving, is added aromatic alkyl alcohol R
1OH and triphenylphosphine drip diethyl azodiformate, room temperature reaction 15-20h under cryosel bath condition, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtain intermediate (V);
Wherein, intermediate (IV) and anhydrous diethyl ether, aromatic alkyl alcohol R
1The mass ratio of OH, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.36-1.05: 1.65: 1.12: 41;
The 3rd step: (V) uses dry N with intermediate, the dinethylformamide dissolving, add sodium hydride, dripping bromine ethane, 45-55 ℃ of reaction 5-7h, add ethyl acetate, water successively, 0.8-1.2mol/L sodium hydroxide solution, the saturated common salt washing, the organic layer anhydrous sodium sulfate drying, solvent evaporated, with the tetrahydrofuran (THF) dissolving, the Pd-C catalyzer that adds 8-12wt% is inhaled H-H reaction 20-30h, wherein, intermediate (V) and N, dinethylformamide, sodium hydride, monobromethane, ethyl acetate, the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer is 2: 47.5: 0.3: 1.1: 180: 16: 1, to filter, and solvent evaporated obtains salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2The expression ethyl;
R
3Expression hydrogen atom or methyl.
Above-mentioned two kinds of preparation methods also can comprise for the 4th step:
Under condition of ice bath, dripping thionyl chloride in through the exsiccant anhydrous methanol adds the 3rd step products therefrom then, stirring at room 5-7h, and solvent evaporated adds ethyl acetate, water, saturated common salt washing successively, anhydrous sodium sulfate drying, solvent evaporated;
Wherein, the mass ratio of the 3rd step products therefrom and anhydrous methanol, sulfur oxychloride and ethyl acetate was respectively 1: 39.5: 2: 180.
Among above-mentioned two kinds of preparation methods, intermediate (II), (III), (IV) and structural formula (V) are as follows:
Wherein, R wherein
1Expression:
The biological activity determination of salicylic acid compounds of the present invention is as follows:
Adipocyte broke up to adipocyte before euglycemic agent can impel, and was index with the differentiation situation of cell, can specificly filter out euglycemic agent.With adipocyte before the 3T3-L1 is model, with the index of triglyceride level growing amount in the cell as the reacting cells differentiation, the insulin-sensitizing activity of compound is estimated.
With the 3T3-L1 cell inoculation in 96 orifice plates, treating that cytogamy was changed after 2 days contains 10%FBS (new-born calf serum), 5 μ g/ml INS (Regular Insulin), 1 μ mol/L DEX (dexamethasone, dexamethasone) and 0.5mmol/L IBMX (isobutyl methylxanthine, high glycoform DMEM nutrient solution IsobutylmethylxanthIne) (Dulbecco ' s modIfIed Eagle ' s medIum) and the dosing of dividing into groups simultaneously.Be subjected to reagent and positive drug rosIglItazone all to establish two concentration of 10-9M, 10-6M, establish DMSO (dimethyl sulfoxide (DMSO)) control group simultaneously.Change the DMEM nutrient solution that contains 10%FBS, 5 μ g/ml INS after 2 days and, change the DMEM nutrient solution and the dosing that only contain 10%FBS later on every other day with the method dosing.Break up and measured lipid content in the cell with the oil red O stain method on the 8th day, key step be cell with 10% formaldehyde fixed 1h, use 0.2% oil red O solution-dyed 2h then, unnecessary oil red O dyestuff is removed in washing, oil red O in the Virahol dissolved cell, survey 510nm OD value.Same experiment repeats 3～4 times.The increase percentage of the interior lipid content of 3T3-L1 cell after the different concns compound effects (
N=3 or 4) see the following form:
As seen from the above table, compound 9,15,16 etc. has stronger insulin-sensitizing activity, and other compound also obviously increases content of triglyceride in the cell, has insulin-sensitizing effect.Therefore salicylic acid compounds involved in the present invention can be used for controlling the formation of diabetes B blood glucose level in patients and inhibition complication, so these compounds might become novel treatment diabetes B medicine by development.
The invention has the beneficial effects as follows: therefore the compound of this patent can be used to prepare anti-diabetes B medicine because of having insulin-sensitizing activity, reduces the generation of the blood sugar concentration and the inhibition diabetic complication of diabetic.
Embodiment
Further the present invention is described below, but it does not limit the present invention with specific embodiment.
Synthesizing of embodiment 1:2-acetoxyl group-4-n-butoxy phenylformic acid (compound 1)
The first step: with 2,4-resorcylic acid 5g is suspended in the mixed solution of acetic anhydride and acetic acid, add nitration mixture [98% sulfuric acid: 37% hydrochloric acid=1: 1] (V: V), sealing also is warming up to 85 ℃ of reaction 0.5h, hot suction filtration, filtrate places ice bath cooling to separate out solid, filter, with filter residue in 55 ℃ of following drying under reduced pressure;
In above-mentioned filter residue, add Anhydrous potassium carbonate and dry N, dinethylformamide, drip cylite, room temperature reaction 2h filters, filtrate adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying is with sherwood oil: ethyl acetate=3: 1 (V: V) be eluent, silica gel column chromatography separates solvent evaporated, obtains intermediate (II);
Wherein, 2,4-resorcylic acid and acetic anhydride, acetic acid, nitration mixture Anhydrous potassium carbonate, N, the mass ratio of dinethylformamide, cylite and ethyl acetate was respectively 5: 4: 5: 1.5: 2.7: 42.6: 3.9: 72.9;
Second step: (II) dissolves with anhydrous diethyl ether with intermediate, add propyl carbinol and triphenylphosphine, drip diethyl azodiformate under-3 ℃ of cryosel bath conditions, room temperature is carried out Mi Qu and is spreaded out reaction 15h, solvent evaporated, add ethyl acetate, water and saturated common salt washing successively is through anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=5: 1 (V: V) be eluent, silica gel column chromatography separates, and solvent evaporated obtains intermediate (III);
Wherein, 2, the mass ratio of 4-resorcylic acid and anhydrous diethyl ether, propyl carbinol, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.36: 1.65: 1.12: 41;
The 3rd step: intermediate (III) is dissolved with tetrahydrofuran (THF), and the Pd-C catalyzer that adds 8wt% is inhaled H-H reaction 20h, filters solvent evaporated;
Wherein intermediate (III) was respectively 12.5: 134: 1 with the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer.
Products therefrom yield 89.65%,
1H NMR (DMSO-d
6): δ=0.96 (t, 3H), 1.35 (m, 2H), 1.71-1.73 (m, 2H), 2.10 (s, 3H), 3.95 (t, 2H), 6.77 (s, 1H), 6.92 (d, J=8.8Hz, 1H), 7.86 (d, J=8.8Hz, 1H).
Synthesizing of embodiment 2:2-acetoxyl group-4-n-butoxy methyl benzoate (compound 2)
Under condition of ice bath, dripping thionyl chloride in anhydrous methanol adds 5g compound 1, stirring at room 5h then, thin-layer chromatography (TLG) monitoring reaction finishes, and solvent evaporated adds ethyl acetate, water, saturated common salt washing successively, anhydrous sodium sulfate drying, solvent evaporated;
Wherein, the mass ratio of the 3rd step products therefrom and anhydrous methanol, sulfur oxychloride and ethyl acetate was respectively 1: 39.5: 2: 180.
Products therefrom yield 90.2%,
1H NMR (CDCl
3): δ=0.86 (t, 3H), 1.29 (m, 2H), 1.72 (m, 2H), 2.12 (s, 3H), 3.68 (s, 3H), 3.90 (t, 2H), 6.78 (s, 1H), 6.93 (d, J=8.8Hz, 1H), 7.82 (d, J=8.8Hz, 1H).
Embodiment 3:2-acetoxyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] phenylformic acid (compound 3) synthetic
The first step: with 2,4-resorcylic acid 5g is suspended in the mixed solution of acetic anhydride and acetic acid, add nitration mixture [98% sulfuric acid: 37% hydrochloric acid=1: 1] (V: V), sealing also is warming up to 95 ℃ of reaction 1.5h, hot suction filtration, filtrate places ice bath cooling to separate out solid, filter, with filter residue in 65 ℃ of following drying under reduced pressure;
In above-mentioned filter residue, add Anhydrous potassium carbonate and dry N, dinethylformamide, drip cylite, room temperature reaction 3h filters, filtrate adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying is with sherwood oil: ethyl acetate=3: 1 (V: V) be eluent, silica gel column chromatography separates solvent evaporated, obtains intermediate (II);
Wherein, 2,4-resorcylic acid and acetic anhydride, acetic acid, Anhydrous potassium carbonate, N, the mass ratio of dinethylformamide, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: (II) dissolves with anhydrous diethyl ether with intermediate, add 5-ethyl 2-pyridine ethanol and triphenylphosphine, drip diethyl azodiformate under-8 ℃ of cryosel bath conditions, room temperature is carried out Mi Qu and is spreaded out reaction 20h, solvent evaporated, add ethyl acetate, water and saturated common salt washing successively is through anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=5: 1 (V: V) be eluent, silica gel column chromatography separates, and solvent evaporated obtains intermediate (III);
Wherein, 2, the mass ratio of 4-resorcylic acid and anhydrous diethyl ether, 5-ethyl 2-pyridine ethanol, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.78: 1.65: 1.12: 46;
The 3rd step: intermediate (III) is dissolved with tetrahydrofuran (THF), and the Pd-C catalyzer that adds 12wt% is inhaled H-H reaction 30h, filters solvent evaporated;
Wherein intermediate (III) was respectively 10: 134: 1.5 with the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer.
Products therefrom yield 85.5%,
1H NMR (DMSO-d
6): δ=1.25 (t, 3H), 2.15 (s, 3H), 2.65 (m, 2H), 3.26 (t, J=6.4Hz, 2H), 4.37 (t, J=6.4Hz, 2H), 6.77 (s, 1H), 6.92 (d, J=8.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.62 (d, J=7.6Hz, 1H), 7.86 (d, J=8.8Hz, 1H), 8.56 (s, 1H).
Embodiment 4:2-acetoxyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl benzoate (compound 4) synthetic
Under condition of ice bath, dripping thionyl chloride in anhydrous methanol adds 5g compound 3 then, stirring at room 7h, and the TLC monitoring reaction finishes, and solvent evaporated adds ethyl acetate, water, saturated common salt washing successively, anhydrous sodium sulfate drying, solvent evaporated;
Wherein, the mass ratio of the 3rd step products therefrom and anhydrous methanol, sulfur oxychloride and ethyl acetate was respectively 1: 39.5: 2: 180.
Products therefrom yield 85.5%,
1H NMR (CDCl
3): δ=1.23 (t, 3H), 2.13 (s, 3H), 2.65 (m, 2H), 3.26 (t, J=6.4Hz, 2H), 3.85 (s, 3H), 4.37 (t, J=6.4Hz, 2H), 6.77 (s, 1H), 6.90 (d, J=8.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 8.49 (s, 1H).
Embodiment 5:2-acetoxyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] phenylformic acid (compound 5) synthetic
The first step: with 2,4-resorcylic acid 5g is suspended in the mixed solution of acetic anhydride and acetic acid, add nitration mixture [98% sulfuric acid: 37% hydrochloric acid=1: 1] (V: V), sealing also is warming up to 90 ℃ of reaction 1h, hot suction filtration, filtrate places ice bath cooling to separate out solid, filter, with filter residue in 60 ℃ of following drying under reduced pressure;
In above-mentioned filter residue, add Anhydrous potassium carbonate and dry N, dinethylformamide, drip cylite, room temperature reaction 2.5h filters, filtrate adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying is with sherwood oil: ethyl acetate=3: 1 (V: V) be eluent, silica gel column chromatography separates solvent evaporated, obtains intermediate (II);
Wherein, 2,4-resorcylic acid and acetic anhydride, acetic acid, Anhydrous potassium carbonate, N, the mass ratio of dinethylformamide, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: (II) dissolves with anhydrous diethyl ether with intermediate, add 2-(5-methyl-2-phenyl-4-oxazole) ethanol and triphenylphosphine, drip diethyl azodiformate under-5 ℃ of cryosel bath conditions, room temperature is carried out Mi Qu and is spreaded out reaction 16h, solvent evaporated, add ethyl acetate, water and saturated common salt washing successively is through anhydrous sodium sulfate drying, with sherwood oil: ethyl acetate=5: 1 (V: V) be eluent, silica gel column chromatography separates, and solvent evaporated obtains intermediate (III);
Wherein, 2, the mass ratio of 4-resorcylic acid and anhydrous diethyl ether, 2-(5-methyl-2-phenyl-4-oxazole) ethanol, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 1.05: 1.65: 1.12: 46;
The 3rd step: intermediate (III) is dissolved with tetrahydrofuran (THF), and the Pd-C catalyzer that adds 10wt% is inhaled H-H reaction 24h, filters solvent evaporated;
Wherein intermediate (III) was respectively 10: 134: 1 with the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer.
Products therefrom
1H NMR (DMSO-d
6) δ=2.19 (s, 3H), 2.34 (s, 3H), 2.93 (t, J=11.6Hz, 2H), 4.27 (t, J=11.6Hz, 2H), 6.77 (s, 1H), 6.92 (d, 1H), 7.47-7.49 (m, 3H), 7.85-7.90 (m, 3H).
Embodiment 6:2-acetoxyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl benzoate (compound 6) synthetic
Under condition of ice bath, dripping thionyl chloride in anhydrous methanol adds 5g compound 5 then, stirring at room 6h, and the TLC monitoring reaction finishes, and solvent evaporated adds ethyl acetate, water, saturated common salt washing successively, anhydrous sodium sulfate drying, solvent evaporated;
Wherein, the mass ratio of the 3rd step products therefrom and anhydrous methanol, sulfur oxychloride and ethyl acetate was respectively 1: 39.5: 2: 180.
Products therefrom yield 87.0%.
1H?NMR(CDCl
3)：δ＝1.25(t，3H)，2.10(s，3H)，2.65(m，2H)，3.25(t，J＝6.4Hz，2H)，3.88(s，3H)，4.38(t，J＝6.4Hz，2H)，6.78(s，1H)，6.92(d，J＝8.8Hz，1H)，7.20(d，J＝7.6Hz，1H)，7.63(d，J＝7.6Hz，1H)，7.88(d，J＝8.8Hz，1H)，8.57(s，1H)。
Embodiment 7:2-acetoxyl group-4-[2-(1-indoles) oxyethyl group] phenylformic acid (compound 7) synthetic
Be similar to embodiment 1, replace propyl carbinol with 2-(1-indoles) ethanol and carry out condensation reaction, other class of operation obtain title compound together.
1H?NMR(DMSO-d
6)：δ＝2.01(s，3H)，3.76(t，J＝5.2Hz，2H)，4.12(t，J＝5.3Hz，2H)，6.52(d，1H)，6.77(s，1H)，6.92(d，J＝8.8Hz，1H)，7.09-7.20(m，2H)，7.24(dd，J＝8.2Hz，7.7Hz，1H)，7.38(d，J＝8.3Hz，1H)，7.64(d，J＝7.9Hz，1H)，7.86(d，J＝8.8Hz，1H)。
Embodiment 8:2-acetoxyl group-4-[2-(1-indoles) oxyethyl group] methyl benzoate (compound 8) synthetic
With compound 7 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 86.5%
1H NMR (DMSO-d
6): δ=2.05 (s, 3H), 3.85 (t, J=5.2Hz, 2H), 3.90 (s, 3H), 4.16 (t, J=5.3Hz, 2H), 6.48 (d, 1H), 6.78 (s, 1H), 6.92 (d, J=8.8Hz, 1H), 7.09-7.20 (m, 2H), 7.24 (dd, J=8.2Hz, 7.7Hz, 1H), 7.35 (d, J=8.3Hz, 1H), 7.59 (d, J=7.9Hz, 1H), 7.83 (d, J=8.8Hz, 1H).
Embodiment 9:2-acetoxyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid (compound 9) synthetic
Be similar to embodiment 1, with 3-methyl-3-(2-pyridine)] propyl alcohol replacement propyl carbinol generation condensation reaction, other class of operation obtain title compound together.
1H?NMR(DMSO-d
6)：δ＝1.35(d，3H)，1.98(m，2H)，2.08(s，3H)，2.95(m，1H)，3.97(t，2H)，6.77(s，1H)，6.92(d，J＝8.8Hz，1H)，7.23(m，1H)，7.29(d，1H)，7.65-68(m，1H)，7.86(d，J＝8.8Hz，1H)，8.56(m，1H)。
Embodiment 10:2-acetoxyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid methyl esters (compound 10) synthetic
Being similar to embodiment 6, is raw material with compound 9, obtains title compound, yield 82.5%.
1HNMR(CDCl
3)：δ＝1.38(d，3H)，2.01(m，2H)，2.12(s，3H)，2.92-2.93(m，1H)，3.79(s，3H)，3.99(t，2H)，6.79(s，1H)，6.95(d，J＝8.8Hz，1H)，7.27(m，1H)，7.32(d，1H)，7.65-68(m，1H)，7.86(d，J＝8.8Hz，1H)，8.62(m，1H)。
Synthesizing of embodiment 11:2-oxyethyl group-4-n-butoxy phenylformic acid (compound 11)
The-step: with 2,4-resorcylic acid 5g is dissolved in dry N, in the dinethylformamide, adds Anhydrous potassium carbonate, drip cylite, room temperature reaction 1h adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (IV);
Wherein, 2,4-resorcylic acid and N, the mass ratio of dinethylformamide, Anhydrous potassium carbonate, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: (IV) dissolves with anhydrous diethyl ether with intermediate, add propyl carbinol and triphenylphosphine, under cryosel bath condition, drip diethyl azodiformate, room temperature reaction 15h, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtain intermediate (V);
Wherein, intermediate (IV) was respectively 5: 21.3: 0.36 with the mass ratio of anhydrous diethyl ether, propyl carbinol, triphenylphosphine, diethyl azodiformate and ethyl acetate: 1.65: 1.12: 41;
The 3rd step: (V) uses dry N with intermediate, and the dinethylformamide dissolving adds sodium hydride, dripping bromine ethane, 45 ℃ of reaction 5h add ethyl acetate, successively water, 0.8mol/L sodium hydroxide solution, saturated common salt washing, the organic layer anhydrous sodium sulfate drying, solvent evaporated, with the tetrahydrofuran (THF) dissolving, the Pd-C catalyzer that adds 8wt% is inhaled H-H reaction 20h, filter solvent evaporated;
Wherein, intermediate (V) and N, the mass ratio of dinethylformamide, sodium hydride, monobromethane, ethyl acetate, tetrahydrofuran (THF) and Pd-C catalyzer is 2: 47.5: 0.3: 1.1: 180: 16: 1.
Products therefrom yield 56.0%.It is title compound.
1H?NMR(DMSO-d
6)：δ＝0.96(t，3H)，1.35(m，2H)，1.38(t，3H)，1.74(m，2H)，3.95(t，2H)，4.05(m，2H)，6.50(s，1H)，6.58(d，J＝8.8Hz，1H)，7.90(d，J＝8.8Hz，1H).
Embodiment 12:2-oxyethyl group-4-n-butoxy methyl benzoate (compound 12)
With compound 11 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 89.0%.
1H?NMR(CDC1
3)：δ＝0.98(t，3H)，1.38(m，2H)，1.40(t，3H)，1.72-73(m，2H)，3.85(s，3H)，3.95(t，2H)，4.02(m，2H)，6.56(s，1H)，6.72(d，J＝8.8Hz，1H)，7.92(d，J＝8.8Hz，1H).
Embodiment 13:2-oxyethyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] phenylformic acid (compound 13)
The first step: with 2,4-resorcylic acid 5g is dissolved in dry N, in the dinethylformamide, adds Anhydrous potassium carbonate, drip cylite, room temperature reaction 3h adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (IV);
Wherein, 2,4-resorcylic acid and N, the mass ratio of dinethylformamide, Anhydrous potassium carbonate, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: (IV) dissolves with anhydrous diethyl ether with intermediate, add 5-ethyl 2-pyridine ethanol and triphenylphosphine, under cryosel bath condition, drip diethyl azodiformate, room temperature reaction 20h, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtain intermediate (V);
Wherein, intermediate (IV) was respectively 5: 21.3: 1.05 with the mass ratio of anhydrous diethyl ether, 5-ethyl 2-pyridine ethanol, triphenylphosphine, diethyl azodiformate and ethyl acetate: 1.65: 1.12: 41;
The 3rd step: (V) uses dry N with intermediate, and the dinethylformamide dissolving adds sodium hydride, dripping bromine ethane, 55 ℃ of reaction 7h add ethyl acetate, successively water, 1.2mol/L sodium hydroxide solution, saturated common salt washing, the organic layer anhydrous sodium sulfate drying, solvent evaporated, with the tetrahydrofuran (THF) dissolving, the Pd-C catalyzer that adds 12wt% is inhaled H-H reaction 30h, filter solvent evaporated;
Wherein, intermediate (V) and N, the mass ratio of dinethylformamide, sodium hydride, monobromethane, ethyl acetate, tetrahydrofuran (THF) and Pd-C catalyzer is 2: 47.5: 0.3: 1.1: 180: 16: 1.
Products therefrom
1H NMR (DMSO-d
6): δ=1.23 (t, 3H), 1.35 (t, 3H), 2.65 (m, 2H), 3.26 (t, J=6.4Hz, 2H), 4.01 (m, 2H), 4.37 (t, J=6.4Hz, 2H), 6.77 (s, 1H), 6.92 (d, J=8.8Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.85 (d, J=8.8Hz, 1H), 8.53 (s, 1H).
Embodiment 14:2-oxyethyl group-4-[2-(5-ethyl-2-pyridine) oxyethyl group] methyl benzoate (compound 14)
With compound 13 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 87.0%.
1H?NMR(CDCl
3)：δ＝1.25(t，3H)，1.34(t，3H)，2.68(m，2H)，3.26(t，J＝6.4Hz，2H)，3.86(s，3H)，4.05(m，2H)，4.33(t，J＝6.4Hz，2H)，6.75(s，1H)，6.90(d，J＝8.8Hz，1H)，7.20(d，J＝7.6Hz，1H)，7.60(d，J＝7.6Hz，1H)，7.86(d，J＝8.8Hz，1H)，8.50(s，1H).
Embodiment 15:2-oxyethyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] phenylformic acid (compound 15)
The first step: with 2,4-resorcylic acid 5g is dissolved in dry N, in the dinethylformamide, adds Anhydrous potassium carbonate, drip cylite, room temperature reaction 2h adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (IV);
Wherein, 2,4-resorcylic acid and N, the mass ratio of dinethylformamide, Anhydrous potassium carbonate, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: (IV) dissolves with anhydrous diethyl ether with intermediate, add 2-(5-methyl-2-phenyl-4-oxazole) ethanol and triphenylphosphine, under cryosel bath condition, drip diethyl azodiformate, room temperature reaction 16h, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtain intermediate (V);
Wherein, intermediate (IV) was respectively 5: 21.3: 0.98 with the mass ratio of anhydrous diethyl ether, 2-(5-methyl-2-phenyl-4-oxazole) ethanol, triphenylphosphine, diethyl azodiformate and ethyl acetate: 1.65: 1.12: 41;
The 3rd step: (V) uses dry N with intermediate, and the dinethylformamide dissolving adds sodium hydride, dripping bromine ethane, 50 ℃ of reaction 6h add ethyl acetate, successively water, 1mol/L sodium hydroxide solution, saturated common salt washing, the organic layer anhydrous sodium sulfate drying, solvent evaporated, with the tetrahydrofuran (THF) dissolving, the Pd-C catalyzer that adds 10wt% is inhaled H-H reaction 24h, filter solvent evaporated;
Wherein, intermediate (V) and N, the mass ratio of dinethylformamide, sodium hydride, monobromethane, ethyl acetate, tetrahydrofuran (THF) and Pd-C catalyzer is 2: 47.5: 0.3: 1.1: 180: 16: 1.
Products therefrom
1H NMR (DMSO-d
6): δ=1.35 (t, 3H), 2.35 (s, 3H), 2.92 (t, J=11.6Hz, 2H), 3.95 (m, 2H), 4.25 (t, J=11.6Hz, 2H), 6.78 (s, 1H), 6.93 (d, 1H), 7.47-7.49 (m, 3H), 7.85-7.90 (m, 3H).
Embodiment 16:2-oxyethyl group-4-[2-(5-methyl-2-phenyl-4-oxazole) oxyethyl group] methyl benzoate (compound 16)
With compound 15 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 82.5%.
1H?NMR(CDCl
3)：δ＝1.33(t，3H)，2.30(s，3H)，2.93(t，J＝11.6Hz，2H)，3.72(s，3H)，3.98(m，2H)，4.23(t，J＝11.6Hz，2H)，6.79(s，1H)，6.93(d，1H)，7.47-7.49(m，3H)，7.87-7.93(m，3H).
Embodiment 17:2-oxyethyl group-4-[2-(1-indoles) oxyethyl group] phenylformic acid (compound 17)
Be similar to embodiment 15, replace 2-(5-methyl-2-phenyl-4-oxazole) ethanol with 2-(1-indoles) ethanol and carry out condensation reaction, other class of operation obtain title compound together.
1H?NMR(DMSO-d
6)：δ＝1.35(t，3H)，3.75(t，J＝5.2Hz，2H)，3.95(m，2H)，4.12(t，J＝5.3Hz，2H)，6.52(d，1H)，6.75(s，1H)，6.90(d，J＝8.8Hz，1H)，7.09-7.23(m，2H)，7.26(dd，J＝8.2Hz，7.7Hz，1H)，7.35(d，J＝8.3Hz，1H)，7.56(d，J＝7.9Hz，1H)，7.85(d，J＝8.8Hz，1H).
Embodiment 18:2-oxyethyl group-4-[2-(1-indoles) oxyethyl group] methyl benzoate (compound 18)
With compound 17 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 85.0%.
1H?NMR(DMSO-d
6)：δ＝1.37(t，3H)，3.70(t，J＝5.2Hz，2H)，3.80(s，3H)，3.95(m，2H)，4.09(t，J＝5.3Hz，2H)，6.48(d，1H)，6.78(s，1H)，6.95(d，J＝8.8Hz，1H)，7.09-7.20(m，2H)，7.23(dd，J＝8.2Hz，7.7Hz，1H)，7.36(d，J＝8.3Hz，1H)，7.56(d，J＝7.9Hz，1H)，7.89(d，J＝8.8Hz，1H).
Embodiment 19:2-oxyethyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid (compound 19)
Be similar to embodiment 11, with 2-[N-methyl-N-(2-pyridine) amino] ethanol replaces 2-(5-methyl-2-phenyl-4-oxazole) ethanol and carries out condensation reaction, other class of operation with, obtain title compound.
1H?NMR(DMSO-d
6)：δ＝1.32(t，3H)，1.36(d，3H)，1.98(m，2H)，2.95(m，1H)，3.97(t，2H)，4.02(m，2H)，6.50(s，1H)，6.61(d，J＝8.8Hz，1H)，7.23(m，1H)，7.29(d，1H)，7.65-68(m，1H)，7.86(d，J＝8.8Hz，1H)，8.56(m，1H).
Embodiment 20:2-oxyethyl group-4-[3-methyl-3-(2-pyridine)] propoxy benzoic acid methyl esters (compound 20)
With compound 19 is raw material, obtains title compound with the method that is similar to embodiment 6, yield 83.5%.
1H?NMR(CDCl
3)：δ＝1.30(t，3H)，1.38(d，3H)，2.02(m，2H)，2.94(m，1H)，3.86(s，3H)，3.92(t，2H)，4.06(m，2H)，6.50(s，1H)，6.63(d，J＝8.8Hz，1H)，7.25(m，1H)，7.29(d，1H)，7.67-68(m，1H)，7.83(d，J＝8.5Hz，1H)，8.63(m，1H)。
Claims (5)
1. a salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2Expression ethyl or ethanoyl;
R
3Expression hydrogen atom or methyl.
2. salicylic acid compounds as claimed in claim 1 is characterized in that, described R
1For
3. the preparation method of a salicylic acid compounds is characterized in that, concrete steps are:
The first step: with 2, the 4-resorcylic acid is suspended in the mixed solution of acetic anhydride and acetic acid, adding volume ratio is 1: 1 the 98wt% sulfuric acid and the mixed solution of 37wt% hydrochloric acid, sealing also is warming up to 85-95 ℃ of reaction 0.5-1.5h, hot suction filtration, filtrate places ice bath cooling to separate out solid, filter, with filter residue in 55-65 ℃ of following drying under reduced pressure;
Add Anhydrous potassium carbonate and dry N in above-mentioned filter residue, dinethylformamide drips cylite, room temperature reaction 2-3h, filter, filtrate adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (II);
Wherein, 2,4-resorcylic acid and acetic anhydride, acetic acid, sour mixed solution, Anhydrous potassium carbonate, N, the mass ratio of dinethylformamide, cylite and ethyl acetate was respectively 5: 4: 5: 1.5: 2.7: 42.6: 3.9: 72.9;
Second step: intermediate (II) with the anhydrous diethyl ether dissolving, is added aromatic alkyl alcohol R
1OH and triphenylphosphine, under-3--8 ℃ cryosel bath condition, drip diethyl azodiformate, room temperature is carried out Mi Qu and is spreaded out reaction 15-20h, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, through anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (III);
Wherein, 2,4-resorcylic acid and anhydrous diethyl ether, aromatic alkyl alcohol R
1The mass ratio of OH, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.36-1.05: 1.65: 1.12: 41;
The 3rd step: (III) dissolves with tetrahydrofuran (THF) with intermediate, the Pd-C catalyzer that adds 8-12wt% is inhaled H-H reaction 20-30h, wherein intermediate (III) was respectively 12.5: 134 with the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer: 1-1.5, filter, solvent evaporated obtains salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2The expression ethanoyl;
R
3Expression hydrogen atom or methyl.
4. the preparation method of a salicylic acid compounds is characterized in that, concrete steps are:
The first step: with 2, the 4-resorcylic acid is dissolved in dry N, in the dinethylformamide, adds Anhydrous potassium carbonate, drip cylite, room temperature reaction 1-3h adds ethyl acetate, water and saturated common salt washing successively, the organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtains intermediate (IV);
Wherein, 2,4-resorcylic acid and N, the mass ratio of dinethylformamide, Anhydrous potassium carbonate, cylite and ethyl acetate was respectively 5: 4: 5: 2.7: 42.6: 3.9: 72.9;
Second step: intermediate (IV) with the anhydrous diethyl ether dissolving, is added aromatic alkyl alcohol R
1OH and triphenylphosphine drip diethyl azodiformate, room temperature reaction 15-20h under cryosel bath condition, solvent evaporated adds ethyl acetate, water and saturated common salt washing successively, organic layer anhydrous sodium sulfate drying, column chromatography for separation, solvent evaporated obtain intermediate (V);
Wherein, intermediate (IV) and anhydrous diethyl ether, aromatic alkyl alcohol R
1The mass ratio of OH, triphenylphosphine, diethyl azodiformate and ethyl acetate was respectively 5: 21.3: 0.36-1.05: 1.65: 1.12: 41;
The 3rd step: (V) uses dry N with intermediate, the dinethylformamide dissolving, add sodium hydride, dripping bromine ethane, 45-55 ℃ of reaction 5-7h, add ethyl acetate, water successively, 0.8-1.2mol/L sodium hydroxide solution, the saturated common salt washing, the organic layer anhydrous sodium sulfate drying, solvent evaporated, with the tetrahydrofuran (THF) dissolving, the Pd-C catalyzer that adds 8-12wt% is inhaled H-H reaction 20-30h, wherein, intermediate (V) and N, dinethylformamide, sodium hydride, monobromethane, ethyl acetate, the mass ratio of tetrahydrofuran (THF) and Pd-C catalyzer is 2: 47.5: 0.3: 1.1: 180: 16: 1, to filter, and solvent evaporated obtains salicylic acid compounds (I):
In the formula (I):
R
1Expression replaces or unsubstituted C
1-6Alkyl replaces or unsubstituted arylalkyl, or replacement or unsubstituted fragrant heterocyclic radical alkyl;
R
2The expression ethyl;
R
3Expression hydrogen atom or methyl.
5. as the preparation method of claim 3 or 4 described salicylic acid compounds, it is characterized in that the 3rd step back also had for the 4th step:
Under condition of ice bath, dripping thionyl chloride in through the exsiccant anhydrous methanol adds the 3rd step products therefrom then, stirring at room 5-7h, and solvent evaporated adds ethyl acetate, water, saturated common salt washing successively, anhydrous sodium sulfate drying, solvent evaporated;
Wherein, the mass ratio of the 3rd step products therefrom and anhydrous methanol, sulfur oxychloride and ethyl acetate was respectively 1: 39.5: 2: 180.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019050749A1 (en) * | 2017-09-08 | 2019-03-14 | Eli Lilly And Company | Pharmaceutical combinations comprising insulin and at least an agent selected from meloxicam, bromfenac sodium, acetylsalicylic acid, salicylic acid and paracetamol |
Citations (3)
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| CN1315320A (en) * | 2000-01-11 | 2001-10-03 | 寿制药株式会社 | Ether and amide compounds as medicide for treating glycuresis and preparing process thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019050749A1 (en) * | 2017-09-08 | 2019-03-14 | Eli Lilly And Company | Pharmaceutical combinations comprising insulin and at least an agent selected from meloxicam, bromfenac sodium, acetylsalicylic acid, salicylic acid and paracetamol |
| US11510967B2 (en) | 2017-09-08 | 2022-11-29 | Eli Lilly And Company | Pharmaceutical combinations comprising insulin and at least an agent selected from meloxicam, bromfenac sodium, acetylsalicylic acid, salicyclic acid and paracetamol |
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