CN1478770A - 1,3-dicarbonyl compound and its preparation and use - Google Patents

1,3-dicarbonyl compound and its preparation and use Download PDF

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CN1478770A
CN1478770A CNA021367159A CN02136715A CN1478770A CN 1478770 A CN1478770 A CN 1478770A CN A021367159 A CNA021367159 A CN A021367159A CN 02136715 A CN02136715 A CN 02136715A CN 1478770 A CN1478770 A CN 1478770A
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methyl
compound
dicarbonyl compounds
reaction
alkyl
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杨玉社
汤磊
嵇汝运
陈凯先
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Institute of Materia Medica of CAS
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Institute of Materia Medica of CAS
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Abstract

A 1,3-bicarbonyl compound is prepared through the condensation reaction between 4[2-(N-methyl-2-pyridinamino)ethoxy] benzaldehyde and C1-C4 alkyl, alkoxy, alkoxyamino, or heterocycleamino substituted 1,3-bicarbonyl derivative in different solvents, or the reaction between N-methylindoalkyl alcohol and 2-(4-hydroxybenzyl)-dimethyl malonate. Said compound has the activity to sensitize insulin, so it can be used for the medicines to treat B-type diabetes, obesity and hyperlipomia.

Description

One class 1,3-dicarbonyl compound and its preparation and purposes
Technical field
The present invention relates to a class 1, the medicine that synthesizes and can be used as treatment type ii diabetes, obesity, hyperlipidemia of 3-dicarbonyl compound.
Background technology
Type ii diabetes is a kind of metabolism disorder disease, and patient mainly shows as blood sugar concentration rising (fasting plasma glucose concentration is greater than 130mg/dL) and glycosuria.The hyperglycemia that continues can cause the generation of many complication, as retina, kidney, nervous system lesion and cardiovascular complication.Especially cardiovascular complication is the deadly major cause of morbidity [Shinkai, H.Exp.Opin.Ther.Patents.2000,10:596] of diabetic subject.So the control blood glucose level in patients is for delaying or to block the generation of complication very important.Type ii diabetes is generally by dietary control, and physical activity or application ofhypoglycemic medicine improve blood glucose level in patients.Use long anti-type ii diabetes medicine of time clinically and comprise sulfonylureas and biguanides.Sulfonylureas passes through to stimulate the beta Cell of islet uelralante and controlling blood sugar as tolbutamide, Glipizide etc.But a shortcoming of this class medicine is that hypoglycemic incidence is higher, and former of the part patient and secondary effect are relatively poor.Biguanide compound example hydrochloric acid N1,N1-Dimethylbiguanide also is the class medicine that present diabetic is used morely.But biguanide compound can cause lacticemia and produce the enteron aisle side effect.
Because the major cause of Regular Insulin type ii diabetes morbidity is intravital insulin resistance and the beta Cell of islet nonfunction of inducing generation thereof, so the research of euglycemic agent also is an importance of anti-type ii diabetes drug research.Since nineteen eighty-two thiazolidine dione compounds ciglitazone be proved have insulin-sensitizing activity in animal body since [Sohda, T et al, Chem.Pharm.Bull.1982,30,3580], the researchist has synthesized several ten thousand thiazolidine dione compounds altogether to seek the better euglycemic agent of controlling blood sugar.First thiazolidinediones euglycemic agent troglitazone went on the market up to 1997.Then there are rosiglitazone and piglitazone to be used for the treatment of type ii diabetes again in this compounds.But the thiazolidinediones medicine has all shown hepatotoxicity in various degree [Henry, R.R.Endocrinol.Metab.Clin.NorthAm.1997,26,553] after listing, and wherein troglitazone is withdrawn from market because of liver toxicity is big.Because the toxicity of this compounds is under a cloud relevant with the thiazolidinedione ring in the structure, so the research of non-thiazolidinediones euglycemic agent becomes a main direction of anti-type ii diabetes drug research gradually.
Summary of the invention
An object of the present invention is to seek a class and have insulin-sensitizing activity and do not have 1 of hepatotoxicity, the 3-dicarbonyl compound, and used as using in anti-type ii diabetes, obesity, the high blood cholesterol drug.Another purpose provides the preparation method of this compounds.
A class 1 involved in the present invention, the 3-Dicarbonyl derivatives can be used following general formula:
Wherein
Figure A0213671500061
R 1, R 2=C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH-,-O-C (CH 2) 2-O-
R 3＝-CH 2OH，-CO 2CH 3，-CH 2OCHO，-CH 2O 2CH 3，H
R 4=2 or 3 join
Figure A0213671500062
And
R 5=H, C 1-C 4Alkoxyl group, substituted aryl
n＝1-4
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-; R 3During for H;
R 4For
Figure A0213671500064
n＝1-4
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-; R 3During for H;
R 4For
Figure A0213671500071
And
Figure A0213671500072
R 5Be H, C1-C4 alkoxyl group
n＝1-4
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-,
R 4For
Figure A0213671500073
R 3For-CH 2OH ,-CO 2CH 3,-CH 2OCHO ,-CH 2O 2CH 3
n＝1-4
Of the present invention 1, the 3-dicarbonyl compound is mainly by following method preparation:
Compound 1-7,12-17,19 synthetic as follows:
Figure A0213671500074
A NaH, 4-hydroxy benzaldehyde, DMF; B acetic acid piperidinium salt toluene refluxes: c H 2, 10% Pd-C.
1 is raw material with 2-chloropyridine and 2-methylethylolamine, presses currently known methods [Cantello BCC et al.J.Med.Chem.1994,37:3977] through some steps reaction synthetic intermediate 4-[2-(N-methyl-2-pyridine amino) oxyethyl groups] phenyl aldehyde.
2 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 1,3 identical or different C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group replace 1, the 3-Dicarbonyl derivatives, at benzene, toluene, in chloroform or the ethanol in room temperature to 150 ℃ scope internal reaction 2-24 hour.Condensation obtains compound 1-7,12-17,19.Compound 8-11,21-22's is synthetic
A 5 equiv of hydroxylamine hydrochlorides or 85% hydrazine hydrate, Na2CO3 refluxes;
B NaH, methyl-chloroformate or Vinyl chloroformate;
C methylamine hydrochloride or cyclopropylamine
3 compounds 1 obtain compound 8 or 9 with normal oxammonium hydrochloride of 1-2 or hydrazine hydrate reaction.Compound 1 obtains compound 10 or 11 with normal oxammonium hydrochloride of 3-10 or hydrazine hydrate reaction.
4 compounds 1 and the normal methylamine hydrochloride of 2-100 or cyclopropylamine are at salt of wormwood, and yellow soda ash obtained compound 18 or 20 in 24-72 hour in room temperature to 70 ℃ scope internal reaction under the existence of sodium hydroxide or potassium hydroxide.
5 compounds 1 are at dimethyl formamide, and with sodium hydride, sodium methylate or sodium ethylate are alkali in the aprotic solvent such as tetrahydrofuran (THF), obtain compound 21,22 with methyl-chloroformate or Vinyl chloroformate reaction.
Compound 26-32's is synthetic
Figure A0213671500082
(a) triphenyl phosphorus, diethyl azodiformate, ether; (b) 10% Pd-C, formic acid.
6 is raw material with 2-aminopyridine and methyl acrylate, and reference literature method [Gerald R.et al.J.Org.Chem.1958,23,1358] makes 4-[2-(N-propyloic-2-pyridine amino) oxyethyl group through some steps reactions] phenyl aldehyde.The latter makes compound 25 with reference to the method for preparing compound 1.
7 with the 4-trifluoromethyl-benzyl-alcohol, 2-(4-hydroxybenzyl)-dimethyl malonate, the normal triphenylphosphine (Ph of 1-1.5 3P) and the normal diethylazodicarboxylate of 1-1.5 (DEAD) in anhydrous diethyl ether, made compound 23 in 6-48 hour in 0-30 ℃ of reaction.
8 2-(1-indoles) ethanol and 2-(4-hydroxybenzyl)-dimethyl malonate make compound 24 with reference to the method for preparing compound 23.
N-methyl on 92 or 3-indolyl alcohol makes compound 26-32,34 with 2-(4-hydroxybenzyl)-dimethyl malonate with reference to the method for preparing compound 23.
11 compounds 31 got compound 33 in 2-6 hour with 0.5-3 times of (w/w) 10% Pd-C 70 ℃ of reactions in 98% formic acid.
The structural formula of compound that the present invention relates to sees Table 1-2.Table 1
Figure A0213671500091
Numbering R 1R 2R 3
1 OMe OMe H
2 O-i-Pr O-i-Pr H
3 O-t-Bu O-t-Bu H
4 -O-CMe 2-O-
5 Me OEt H
6 Me OMe H
7 n-Pr OEt H
8 NHOH NHOH H
9 NHNH 2 NHNH 2 H
10 -NH-O-
11 -NH-NH-
12 OMe NH-2-Py H
13 OMe NH-3-Py H
14 OMe NH-4-Py H
15 OEt NH-2-Py H
16 OEt NH-3-Py H
17 OEt NH-4-Py H
18 NHMe NHMe H
19 NHPh NHPh H
20 cyclopropylamino cyclopropylamino H
21 OMe OMe CO 2Me
22 OMe OMe CO 2Et table 2
Figure A0213671500101
Numbering R 4N numbers R 4N23 1 29 124 2 30
Figure A0213671500105
125
Figure A0213671500106
2 31 226 1 32
Figure A0213671500109
127 1 33 228
Figure A02136715001012
1 34 4 annotate: the R in the table 2 3Be H
Biological activity determination: adipocyte broke up to adipocyte before euglycemic agent can impel, and was index with the differentiation situation of cell, filtered out euglycemic agent.Our reference method [Kletzein BF.Mol.Pharm.1991,41,393] is a model with adipocyte before the 3T3-L1, with the index of triglyceride growing amount in the cell as the reacting cells differentiation, the insulin-sensitizing activity of compound is estimated.
The 3T3-L1 cell cultures went down to posterity once in the DMEM that contains 10%NBS (new-born calf serum) (Dulbecco ' s modifiedEagle ' s medium) nutrient solution in per 3 days.Cell is in 24 well culture plates, covering with the back uses 0.5mM IBMX (isobutylmethylxanthine) and 1 μ M DEX (dexamethasone) and 1.0 μ Minsulin to handle 48 hours, what add various dose simultaneously is subjected to the reagent thing, continues to be cultured to experiment and finishes.Collecting cell with triglyceride and the protein content in the colorimetric method for determining cell, calculates after the administration increasing amount of triglyceride in the cell.
Positive controls is rosiglitazone.The solvent control group is the nutrient solution that contains 0.1%DMSO.
The increasing amount of the triglyceride under three different concns (0.01,0.1,1 μ M) of each compound sees Table 3.As shown in Table 3, compound 2,5,26,27,28,31,33 grades have stronger insulin-sensitizing activity.Involved in the present invention 1, the 3-Dicarbonyl derivatives can be used for controlling the type ii diabetes blood glucose level in patients, also can be used for anti-obesity and reducing blood-fat.
Compound involved in the present invention does not have the thiazolidinedione group, and has the insulin-sensitizing activity similar with thiazolidine dione compounds, so these compounds might become novel treatment diabetes medicament, and anti-obesity medicine and blood lipid-lowering medicine.The increase per-cent of triglyceride level in the table 3.3T3-L1 cell a
Compound concentration (μ M)
Numbering
0.01 0.1 1
1 31.34 45.53 39.8
2 14.06 71.07 73.73
3 5.17 -8.87 -3.56
4 ND b ND ND
5 -0.16 24.28 55.79
6 -8.1 -7.06 14.25
7 -9.69 9.57 31.9
8 1.88 2.67 8.21
9 0.27 0.44 3.24
10 -9.54 -11.51 7.54
11 -16.86 0.29 8.59
12 -2.81 10.52 13.85
13 3.08 12.48 20.6
14 3.64 14.75 18.91
15 -6.88 4.34 17.01
16 6.36 19.57 18.87
17 6.23 14.06 24.47
18 ND 16.09 3.20
19 5.38 13.17 11.11
20 2.53 -5.68 11.09
21 1.20 3.73 2.36
22 -4.77 21.60 25.83
23 10.46 6.82 19.44
24 2.01 20.1 23.36
25 ND ND ND
26 26.24 54.36 50.14
27 13.78 50.66 57.01
28 13.27 34.81 41.18
29 -5.49 -2.85 12.85
30 -5.03 13.09 16.04
31 3.95 17.01 53.3
32 2.29 3.07 12.64
33 15.64 34.56 48.38
34 20.97 23.83 31.46rosiglitazone c 31.45±16.57 40.07±13.77 38.99±11.67 amean，n＝3； bND：not?done； cmean±SD，n＝22.
Embodiment
Further the present invention is described below, but it does not limit the present invention with embodiment.
Fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct. 1H-NMR Varian Mercury400 nuclear magnetic resonance analyser record, chemical shift is represented with δ (ppm).Mass spectrum is measured with the MAT-95 mass spectrograph.Ultimate analysis is measured with Vario EL elemental analyser, and the result is with the weight percent meter of each element atom.Separate with silica gel if the undeclared 200-300 order that is.Embodiment 1:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] dimethyl malonate (1)
4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde 6.6g (25.8mmol) and dimethyl malonate 3.4g (25.8mmol) are in 150mL toluene, and adding an amount of acetic acid piperidines is catalyzer, reflux water-dividing reaction 4 hours.Remove toluene under reduced pressure, raffinate is with sherwood oil: ethyl acetate=silica gel column chromatography got 2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group in 3: 1] Ben Yajiaji] dimethyl malonate 8.1g.
2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] Ben Yajiaji] dimethyl malonate 6.15g is in the mixed solvent of 15mL methyl alcohol and 50mL dioxane, and with 0.6g 10%Pd-C mixing, the normal pressure hydrogenation reaction is to no longer inhaling till the hydrogen.Filtering Pd-C removes solvent under reduced pressure, and residue is with sherwood oil: ethyl acetate=2: 1 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, 4.3g, two step yields 59.1%. 1H NMR (CDCl 3): δ=3.10 (s, 3H, NCH 3), 3.13 (d, J=7.9Hz, 2H, PhCH2-), 3.60 (t, J=7.9Hz, 1H ,-CH-), 3.63 (s, 6H, OCH 3), 3.90 (t, J=5.5Hz, 2H, NCH 2-), 4.10 (t, J=5.5Hz, 2H ,-CH 2O), 6.50 (m, 2H, Py-H), 6.75 (d, J=8.5Hz, 2H, Ph-H), 7.08 (d, J=8.5Hz, 2H, Ph-H), 7.40 (m, 1H, Py-H), 8.10 (m, 1H, Py-H); Ultimate analysis, C 20H 24N 2O 5(372): calculated value: C, 64.51; H, 6.45; N, 7 52. measured values: C, 64.26; H, 6.47; N, 7.21; IR (KBr): 2952.5,1735.6,1596.8,1511.9,1425.2,1247.7,1155.2,1027.9,771.4cm -1Embodiment 2:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] Diisopropyl malonate (2)
With the Diisopropyl malonate is raw material, and other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=4: 1 is an eluent, and it is the light green solid that silica gel column chromatography is got product, two step yields 43.4%.m.p.39-40℃。 1H NMR (CDCl 3): δ=1.15 (d, J=6.3Hz, 6H), 1.18 (d, J=6.3Hz, 6H), 3.08 (d, J=7.8Hz, 2H), 3.12 (s, 3H), 3.50 (t, J=7.8Hz, 1H), 3.96 (t, J=5.5Hz, 2H), 4.13 (t, J=5.5Hz, 2H), 4.99 (m, 2H), 6.52 (m, 2H), 6.77 (d, J=8.5Hz, 2H), 7.08 (d, J=8.5Hz, 2H), 7.46 (m, 1H), 8.12 (m, 1H); Ultimate analysis, C 24H 32N 4O 5(428): calculated value: C, 67.29; H, 7.48; N, 6.54. measured value: C, 67.23; H, 7.50; N, 6.42; IR (KBr): 2983.4,2946.7,2861.9,1741.4,1726,1604.5,1506.2,1429,1322.9,1230.4,1168.7,1097.3,1002.8,811.9,783,530.3cm-1; EI-MS (m/z): 428 (4, M +), 121 (100).Embodiment 3:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] propanedioic acid di tert butyl carbonate (3)
With the propanedioic acid di tert butyl carbonate is raw material, and other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=4: 1 is an eluent, and it is the light green solid that silica gel column chromatography is got product, two step yields 23.7%.m.p.31-32℃。 1H NMR (CDCl 3): δ=1.40 (s, 18H), 3.02 (d, J=7.9Hz, 2H), 3.15 (s, 3H), 3.38 (t, J=7.9Hz, 1H), 3.97 (t, J=5.5Hz, 2H), 4.15 (t, J=5.5Hz, 2H), 6.57 (m, 2H), 6.78 (d, J=8.6Hz, 2H), 7.08 (d, J=8.5Hz, 2H), 7.48 (m, 1H), 8.15 (m, 1H); Ultimate analysis, C 26H 36N 2O 5(456): calculated value C, 68.42; H, 7.89; N, 6.14. measured value C, 68.28; H, 7.96; N, 6.04; IR (KBr): 2979.5,1737.6,1722.1,1604.5,1504.2,1369.2,1340.3,1272.8,1242,1153.2,1135.9,1020.2,850.5,773.6cm-1; EI-MS (m/z): 456 (3, M +), 121 (83), 135 (100). embodiment 4:5-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-2,2-dimethyl-4,6-
Dioxo-1,3-diox (4)
4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde 0.25g (0.97mmol) and 2,2-dimethyl-4,6-dioxo-1,3-diox (Meldrum ' s acid) 0.125g (0.87mmol) is in 5mL toluene, add an amount of 3A molecular sieve and acetic acid piperidines, room temperature reaction 5 hours.The filtering molecular sieve, toluene washs with water 3mL, the saturated common salt washing, remove toluene behind the anhydrous sodium sulfate drying under reduced pressure, raffinate is with sherwood oil: ethyl acetate=2.5: 1 is an eluent, and silica gel column chromatography is got 2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] Ben Yajiaji]-2,2-dimethyl-4,6-dioxo-1,3-diox 0.19g.
2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] Ben Yajiaji]-2,2-dimethyl-4,6-dioxo-1,3-diox 0.19g is in the mixed solvent of 2mL methyl alcohol and 4mL dioxane, with 0.05g 10%Pd-C mixing, the normal pressure hydrogenation reaction stops to inhaling hydrogen.Filtering Pd-C removes solvent under reduced pressure, and residue is with sherwood oil: ethyl acetate=1: 1 is an eluent, and it is a light green oily matter that silica gel column chromatography is got product, 83mg, two step yields 25.2%. 1H NMR (CDCl 3): δ=1.50 (s, 3H), 1.70 (s, 3H), 3.20 (s, 3H), 3.40 (d, J=4.7Hz, 2H), 3.70 (t, J=4.7Hz, 1H), 4.00 (t, J=5.2Hz, 2H), 4.19 (t, J=5.2Hz, 2H), 6.60 (m, 2H), 6.80 (d, J=8.8Hz, 2H), 7.20 (d, J=8.8Hz, 2H), 7.50 (m, 1H), 8.20 (m, 1H); Ultimate analysis, C 21H 24N 2O 5H 2O (402): calculated value C, 62.69; H, 6.47; N, 6.87. measured value C, 63.03; H, 6.42; N, 6.54; EI-MS (m/z): 384 (0.1, M +), 121 (100). embodiment 5:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] methyl aceto acetate (5)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and methyl aceto acetate be raw material, other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=2: 1 is an eluent, and it is light green oily matter that silica gel column chromatography gets product, two step yields 37.3%. 1H NMR (CDCl 3): δ=1.20 (t, J=7.0Hz, 3H), 2.20 (s, 3H), 3.08 (d, J=7.7Hz, 2H), 3.10 (s, 3H), 3.70 (t, J=7.5Hz, 1H), 3.98 (t, J=5.5Hz, 2H), 4.20 (m, 4H), 6.55 (m, 2H), 6.80 (d, J=8.4Hz, 2H), 7.05 (d, J=8.4Hz, 2H), 7.46 (m, 1H), 8.12 (m, 1H); Ultimate analysis, C 21H 26N 2O 4(370): calculated value C, 68.11; H, 7.03; N, 7.57. measured value C, 67.96; H, 6.83; N, 7.48; IR (KBr): 2935.2,1716.4,1739.5,1596.8,1511.9,1425.2,1247.7,1159,1035.6,771.4,526.5cm -1EI-MS (m/z): 370 (4, M +), 121 (100). embodiment 6:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] methyl acetoacetate (6)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and methyl acetoacetate be raw material, other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=2: 1 is an eluent, and it is light green oily matter that silica gel column chromatography gets product, two step yields 41.2%. 1H NMR (CDCl 3): δ=2.20 (s, 3H), 3.08 (d, J=7.6Hz, 2H), 3.13 (s, 3H), 3.75 (t, J=7.5Hz, 1H), 3.98 (t, J=5.5Hz, 2H), 4.20 (t, J=5.5Hz, 2H), 4.33 (s, 2H), 6.55 (m, 2H), 6.84 (d, J=8.4Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 7.46 (m, 1H), 8.15 (m, 1H); Ultimate analysis, C 20H 24N 2O 4(356): calculated value C, 67.42; H, 6.74; N, 7.87. measured value C, 67.25; H, 6.49; N, 7.67; IR (KBr): 2950.6,1743.4,1716.4,1596.8,1560.2,1498.4,1425.2,1359.6,1247.7,1159,987.4,771.4,734.8,526.5cm -1EI-MS (m/z): 356 (6, M +), 121 (84), 149 (100). embodiment 7:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] ethyl butyrylacetate (7)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and ethyl butyrylacetate be raw material, reflux in toluene is divided water reaction 16 hours.Other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=2: 1 is an eluent, and it is light green oily matter that silica gel column chromatography is got product, two step yields 18.8%.1HNMR (CDCl 3): δ=0.83 (t, J=7.3Hz, 3H), 1.20 (t, J=7.1Hz, 3H), 1.53 (m, 2H), 2.29 (m, 1H), 2.48 (m, 1H), 3.05 (d, J=7.9Hz, 2H), 3.12 (s, 3H), 3.70 (t, J=7.9Hz, 1H), 3.97 (t, J=5.5Hz, 2H), 4.12 (m, 4H), 6.57 (m, 2H), 6.78 (d, J=8.5Hz, 2H), 7.03 (d, J=8.5Hz, 2H), 7.48 (m, 1H), 8.15 (m, 1H); Ultimate analysis, C 23H 30N 2O 4(398): calculated value C, 69.35; H, 7.54; N, 7.04. measured value C, 68.90; H, 7.59; N, 6.95; IR (KBr): 2933.2,2962.2,1741.4,1714.4,1596.8,1511.9,1425.2,1247.7,1159,1035.6,771.4cm -1EI-MS (m/z): 398 (6, M +), 121 (100). embodiment 8:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] the third two hydroximic acids (8)
0.41g (7.03mmol) the potassium hydroxide thermosol is in 1mL methyl alcohol, mixes with the solution of 0.326g (4.69mmol) oxammonium hydrochloride in 2mL methyl alcohol after being chilled to room temperature, is chilled to 0 ℃.Add the solution of compound 1 0.436g (1.17mmol) in 2mL methyl alcohol, the filtering insolubles.Filtrate was in stirring at room 14 hours, and steaming desolventizes.Residue is dissolved in 2mL water, adds 1.25N aqueous acetic acid 1.9mL, is settled out white solid.Suction filtration, solid are with ethyl acetate: the mixed solvent recrystallization of methyl alcohol=10: 1.Get product 0.3g, yield 46.8%.m.p.152-154℃。 1H NMR (DMSO-d6): δ=2.90 (d, J=7.2Hz, 2H), 3.08 (m, 4H), 3.90 (t, J=5.7Hz, 2H), 4.10 (t, J=5.7Hz, 2H), 6.55 (t, J=5.5Hz, 1H), 6.63 (d, J=8.6Hz, 1H), 6.80 (d, J=8.2Hz, 2H), 7.10 (d, J=8.1Hz, 2H), 7.50 (m, 1H), 8.05 (d, J=4.7Hz, 1H), 8.85 (s, 1H), 10.3 (s, 1H); Ultimate analysis, C 18H 22N 4O 5(374): calculated value C, 57.75; H, 5.88; N, 14.97. measured value C, 57.51; H, 5.89; N, 14.67; IR (KBr): 3253.4,2927.5,1656.6,1511.9,1608.4,1245.8,767.5cm -1EI-MS (m/z): 373 (0.2, M +-1), 121 (100). embodiment 9:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] malonyl-hydrazine (9)
Compound 1 0.42g (1.13mmol) and 0.28g (5.6mmol) hydrazine hydrate back flow reaction 24 hours in the mixed solvent of 3ml methyl alcohol and 6ml tetrahydrofuran (THF).Remove solvent under reduced pressure.Residue is with ethyl acetate: the mixed solvent recrystallization of methyl alcohol=10: 1.Get product 0.31g, yield 73.8%.m.p.138-140℃。 1H NMR (DMCO-d6): δ=3.10 (m, 8H), 3.96 (t, J=5.7Hz, 2H), 4.10 (t, J=5.7Hz, 2H), 4.45 (t, J=7.1Hz, 2H), 5.00 (t, 1H), 6.60 (m, 2H), 6.82 (d, J=8.4Hz, 2H), 7.15 (d, J=8.4Hz, 2H), 7.50 (m, 1H), 8.06 (d, J=4.73Hz, 1H); Ultimate analysis, C 18H 24N 6O 3(372): calculated value C, 58.06; H, 6.45; N, 22.58. measured value C, 57.82; H, 6.26; N, 22.19; IR (KBr): 3284.2,1668.2,1598.7,1510,1425.2,1245.8,981.6,765.6cm -1EI-MS (m/z): 372 (0.6, M +), 121 (100). embodiment 10:4-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] isoxazole alkyl-3,5-diketone (10)
Compound 1 0.345g (0.927mmol) and 0.33g (4.7mmol) oxammonium hydrochloride add anhydrous sodium carbonate 0.5g (4.7mmol), back flow reaction 9 hours in 20mL methyl alcohol.Be chilled to 0 ℃, suction filtration, filtrate decompression is steamed and is desolventized.Residue is dissolved in the 1mL water, adds methyl alcohol 10mL, separates out white solid.Suction filtration, the gained white solid is with recrystallizing methanol.Get product 0.16g, yield 40.8%.M.p.198-200 ℃ (degraded). 1H NMR (D 2O): δ=3.00 (m, 5H), 3.38 (t, J=7.0Hz, IH), 3.82 (t, J=4.8Hz, 2H), 4.22 (t, J=4.7Hz, 2H), 6.65 (m, 2H), 6.65 (d, J=8.0Hz, 1H), 6.73 (d, J=8.1Hz, 2H), 7.55 (t, J=7.7Hz, 1H), 7.97 (d, J=4.4Hz, 1H); IR (KBr): 3386.4,2935.2,1681.6,1652.7,1598.7,1511.9,1425.2,1351.9,1251.6,767.5cm -1EI-MS (m/z): 121 (100), 135 (64). embodiment 11:4-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl] pyrazolidine-3,5-diketone (11)
Compound 1 0.37g (1mmol) and 0.058g (1mmol) hydrazine hydrate (85% aqueous solution) are in methyl alcohol: the mixed solvent 18mL of tetrahydrofuran (THF)=1: 2 adds anhydrous sodium carbonate 0.25g (2.35mmol), back flow reaction 24 hours.Be chilled to 0 ℃, suction filtration, filtrate decompression is steamed and is desolventized.Residue is dissolved in the 2mL dehydrated alcohol, adds ethyl acetate 10mL, separates out white solid, and suction filtration gets product 0.14g, yield 35%.M.p.240-241 ℃ (degraded). 1H?NMR(D 20)：δ＝3.08(m，6H)，3.40(s，2H)，3.90(t，J＝5.3Hz，2H)，4.30(t，J＝5.3Hz，2H)，6.71(m，2H)，6.86(d，J＝8.5Hz，2H)，7.18(d，J＝8.5Hz，2H)，7.63(m，1H)，8.04(d，J＝5.2Hz，1H)；IR(KBr)：3390.3，2923.6，1664.3，1600.7，1558.2，1510，1425.2，1249.7，769.5cm -1。Embodiment 12:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(2-pyridine) amino-3-oxo methyl propionate (12)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(2-pyridine) amino-3-oxo methyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=2: 3 is an eluent, and it is light green oily matter that the silica gel H column chromatography is got product, two step yields 22.7%. 1H NMR (CDCl 3): δ=3.12 (s, 3H), 3.24 (d, J=7.3Hz, 2H), 3.58 (t, J=7.2Hz, 2H), 3.66 (s, 3H), 3.96 (t, J=5.3Hz, 2H), 4.12 (t, J=5.3Hz, 2H), 6.53 (m, 2H), 6.75 (d, J=8.1Hz, 2H), 7.03 (m, 2H), 7.43 (t, J=7.9Hz, 1H), 7.68 (t, J=7.8Hz, 1H), 8.05 (m, 2H), 8.22 (d, J=4.2Hz, 1H), 8.73 (s, 1H, amide NH); Ultimate analysis, C 24H 26N 4O 41/2H 2O (443): calculated value C, 65.01; H, 6.09; N, 12.64. measured value C, 65.22; H, 6.17; N, 12.43; IR (KBr): 3313.2,3008.5,2950.6,1747.2,1695.1,1596.8,1511.9,1134.8,1299.8,1247.7,1151.3,771.4,520.7cm -1EI-MS (m/z): 434 (8, M +), 121 (100).Embodiment 13:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(3-pyridine) amino-3-oxo methyl propionate (13)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(3-pyridine) amino-3-oxo methyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Ethyl acetate: methyl alcohol=10: 1 is eluent, and it is colorless oil that silica gel column chromatography is got product, two step yields 28.2%. 1H NMR (CDCl 3): δ=3.12 (s, 3H), 3.26 (m, 2H), 3.62 (t, J=7.2Hz, 1H), 3.70 (s, 3H), 3.98 (t, J=5.3Hz, 2H), 4.12 (t, J=5.3Hz, 3H), 6.53 (m, 2H), 6.77 (d, J=8.4Hz, 2H), 7.06 (d, J=8.5Hz, 2H), 7.45 (t, J=6.6Hz, 1H), 8.10 (m, 2H), 8.33 (d, J=4.2Hz, 1H), 8.52 (s, 1H), 8.81 (s, 1H, amide NH); Ultimate analysis, C 24H 26N 4O 41/3H 2O (440): calculated value C, 65.45; H, 5.91; N, 12.72. measured value C, 65.51; H, 6.12; N, 12.47; IR (KBr): 2950.6,1745.3,1693.2,1596.8,1546.7,1511.9,1425.2,1324.9,1247.7,1161,756cm -1EI-MS (m/z): 434 (0.2, M +), 121 (100).Embodiment 14:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(4-pyridine) amino-3-oxo methyl propionate (14)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(4-pyridine) amino-3-oxo methyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Ethyl acetate is an eluent, and it is colorless oil that silica gel column chromatography is got product, two step yields 26.4%. 1H NMR (CDCl 3): δ=3.10 (s, 3H), 3.27 (m, 2H), 3.68 (m, 4H), 3.98 (t, J=5.5Hz, 3H), 4.15 (t, J=5.5Hz, 2H), 6.57 (m, 2H), 6.75 (d, J=8.1Hz, 2H), 7.03 (d, J=8.4Hz, 2H), 7.52 (m, 3H), 8.10 (s, 1H), 8.48 (d, J=5.9Hz, 2H), 9.20 (s, 1H); Ultimate analysis, C 24H 26N 4O 42/3H 2O (446): calculated value C, 64.57; H, 6.28; N, 12.55. measured value C, 65.07; H, 6.62; N, 12.66; IR (KBr): 2952.5,1747.2,1702.9,1596.8,1511.9,1425.2,1427.7,1161,829.3,756,536.1cm -1EI-MS (m/z): 434 (0.2, M +), 121 (100).Embodiment 15:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(2-pyridine) amino-3-oxo ethyl propionate (15)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(2-pyridine) amino-3-oxo ethyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=1: 1 is an eluent, and it is colorless oil that silica gel column chromatography is got product, two step yields 12.4%. 1H NMR (CDCl 3): δ=1.20 (t, J=7.1Hz, 3H), 3.11 (s, 3H), 3.26 (m, 2H), 3.58 (t, J=7.7Hz, 1H), 3.96 (t, J=5.2Hz, 2H), 4.16 (m, 2H), 6.53 (m, 2H), 6.80 (d, J=8.3Hz, 2H), 7.04 (m, 3H), 7.48 (m, 1H), 7.66 (m, 1H), 8.13 (m, 2H), 8.32 (d, J=3.8Hz, 1H), 8.86 (s, 1H); Ultimate analysis, C 25H 28N 4O 41/2H 2O (457): calculated value C, 65.65; H, 6.35; N, 12.25. measured value C, 65.70; H, 6.41; N, 12.06; IR (KBr): 3315.1,2981.5,2937.1,1739.5,1695.1,1596.8,1511.9,1434.8,1298.8,1247.7,1151.3,1047.2,989.3,771.4,520.7cm -1EI-MS (m/z): 448 (8, M +), 121 (100).Embodiment 16:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(3-pyridine) amino-3-oxo ethyl propionate (16)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(3-pyridine) amino-3-oxo ethyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Sherwood oil: ethyl acetate=3: 1 is an eluent, and it is colorless oil that silica gel column chromatography is got product, two step yields 53.3%. 1H NMR (CDCl 3): δ=1.20 (t, J=7.1Hz, 3H), 3.11 (s, 3H), 3.20 (m, 2H), 3.60 (t, J=7.7Hz, 1H), 3.96 (t, J=5.4Hz, 2H), 4.16 (m, 4H), 6.57 (m, 2H), 6.78 (d, J=8.2Hz, 2H), 7.05 (d, J=8.2Hz, 2H), 7.28 (m, 1H), 7.49 (m, 1H), 8.10 (m, 2H), 8.32 (d, J=3.8Hz, 1H), 8.54 (s, 1H), 8.88 (s, 1H); Ultimate analysis, C 25H 28N 4O 41/2H 2O (457): calculated value C, 65.64; H, 6.35; N, 12.25. measured value C, 65.65; H, 6.51; N, 11.88; IR (KBr): 3311.2,2933.2,2115.6,1739.5,1693.2,1596.8,1504.2,1423.2,1245.8,1159,1045.2,771.4,707.8,530.3cm -1EI-MS (m/z): 448 (0.6, M +), 121 (100). embodiment 17:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-3-(4-pyridine) amino-3-oxo ethyl propionate (17)
With 4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde and 3-(4-pyridine) amino-3-oxo ethyl propionate is a raw material, other operation steps is similar to the synthetic of compound 1.Chloroform: methyl alcohol=100: 4 is eluent, and it is colorless oil that silica gel column chromatography is got product, two step yields 39.6%. 1H NMR (CDCl 3): δ=1.20 (t, J=7.1Hz, 3H), 3.11 (s, 3H), 3.22 (m, 2H), 3.64 (t, J=7.7Hz, 1H), 3.96 (t, J=5.5Hz, 2H), 4.16 (m, 4H), 6.52 (m, 2H), 6.75 (d, J=8.0Hz, 2H), 7.03 (d, J=8.2Hz, 2H), 7.52 (m, 3H), 8.08 (d, J=4.6Hz, 1H), 8.48 (d, J=5.7Hz, 2H), 9.31 (s, 1H); C 25H 28N 4O 41/2H 2O (457): calculated value C, 65.64; H, 6.35; N, 12.25. measured value C, 65.87; H, 6.49; N, 11.77; IR (KBr): 3164.7,1739.5,1594.9,1504.2,1423.2,1247.7,1045.2,1000.9,827.3,771.4,734.8,543.2cm -1EI-MS (m/z): 448 (0.3, M +), 121 (100). embodiment 18:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-N, N '-dimethyl propylene diamide (18)
Compound 10.66g (1.77mmol) is dissolved in the mixed solvent of 5mL methyl alcohol and 2mL tetrahydrofuran (THF).Get methylamine hydrochloride 0.9g (13.2mmol) and be dissolved in the 2mL water, add sodium hydroxide 0.48g (12.0mmol), add the solution of above-claimed cpd 1 again, stirring at room 24 hours.The white solid that suction filtration generated, the water wash product.With ethyl alcohol recrystallization, get product 0.45g, yield 68.2% again.m.p.168-169℃。 1H NMR (CDCl 3): δ=2.72 (d, J=5.0Hz, 6H), 3.05 (m, 3H), 3.21 (s, 3H), 4.00 (t, J=5.5Hz, 2H), 4.20 (t, J=5.7Hz, 2H), 6.47 (s, 2H, NH), 6.60 (m, 2H), 6.80 (d, J=8.5Hz, 2H), 7.06 (d, J=8.5Hz, 2H), 7.50 (m, 1H), 8.19 (m, 1H); Ultimate analysis, C 20H 28N 4O 3(370): calculated value C, 64.86; H, 7.03; N, 15.14. measured value C, 64.79; H, 7.00; N, 14.64; IR (KBr): 3320.9,2937.1,1658.5,1598.7,1560.2,1504.2,1427.1,1247.7,1159,769.5,547.7cm -1EI-MS (m/z): 370 (6, M +), 121 (100).Embodiment 19:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-N, N '-diphenylprop diamide (19)
4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenyl aldehyde 0.14g (0.55mmol) and N, N '-diphenylprop diamide 0.14g (0.55mmol) is in 10mL toluene, and adding an amount of acetic acid piperidines is catalyzer, reflux water-dividing reaction 5 hours.Remove toluene under reduced pressure, get the yellowish brown solid.Add DMF10mL, with 0.04g 10%Pd-C mixing, normal pressure stirs inhales H-H reaction to no longer inhaling till the hydrogen.Filtering Pd-C adds entry 40mL, the white solid that suction filtration generated, water wash product.With ethyl alcohol recrystallization, get product 0.18g again, two step yields 72.0%.m.p.172-173℃。 1H NMR (CDCl 3): δ=3.10 (s, 3H), 3.25 (d, J=7.6Hz, 2H), 3.56 (t, J=7.6Hz, 1H), 3.90 (t, J=5.5Hz, 2H), 4.05 (t, J=5.5Hz, 2H), 6.53 (m, 2H), 6.69 (d, J=8.5Hz, 2H), 7.09 (m, 4H), 7.30 (m, 4H), 7.48 (m, 5H), 8.13 (d, J=5.1Hz, 1H), 9.00 (s, 2H); Ultimate analysis, C 30H 30N 4O 3(494): calculated value C, 72.87; H, 6.07; N, 11.34. measured value C, 72.84; H, 6.03; N, 11.07; IR (KBr): 3280.4,1675.9,1598.7,1511.9,1442.5,1425.2,1249.7,754,690.4cm -1EI-MS (m/z): 494 (8, M +), 121 (100).Embodiment 20:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-N, N '-two cyclopropyl Malonamide (20)
Compound 1 1.0g (2.7mmol) mixes the back and stirred 72 hours in 35 ℃ with cyclopropylamine 3.0g (52mmol).Remove excessive cyclopropylamine under reduced pressure.Residue and ethyl acetate 5mL stir evenly, and suction filtration gets white solid 0.73g, yield 64.0%.M.p.183-184 ℃ (degraded). 1H NMR (CDCl 3): δ=0.38 (m, 4H), 0.70 (m, 4H), 2.60 (m, 2H), 3.00 (m, 3H), 3.20 (s, 3H), 3.98 (t, J=5.3Hz, 2H), 4.17 (t, J=5.3Hz, 2H), 6.58 (s, 4H), 6.77 (d, J=8.5Hz, 2H), 7.02 (d, J=8.5Hz, 2H), 7.50 (m, 1H), 8.13 (d, J=4.4Hz, 1H); Ultimate analysis, C 24H 30N 4O 3(422): calculated value C, 68.25; H, 7.11; N, 13.17. measured value C, 68.01; H, 7.31; N, 12.85; IR (KBr): 3291.9,1664.3,1600.7,1504.2,1425.2,1243.9,771.4cm -1EI-MS (m/z): 422 (9, M +), 135 (100). embodiment 21:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-2-methoxycarbonyl dimethyl malonate (21)
Compound 1 0.43g (1.16mmol) is dissolved in the 5mL anhydrous tetrahydro furan.0 ℃ adds sodium hydride (60% solid) 0.028g (1.16mmol), is stirred to no bubble and produces.Drip methyl-chloroformate 0.125g (1.16mmol), temperature rising reflux reaction 1 hour.Remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=3: 2 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, 0.255g, yield 51.2%. 1H NMR (CDCl 3): δ=3.16 (s, 3H), 3.45 (s, 3H), 3.72 (s, 9H), 3.95 (t, J=5.5Hz, 2H), 4.15 (t, J=5.5Hz, 2H), 6.53 (m, 2H), 6.75 (d, J=8.7Hz, 2H), 7.11 (d, J=8.6Hz, 2H), 7.48 (m, 1H), 8.13 (d, 1H); Ultimate analysis, C 22H 26N 2O 7(430): calculated value C, 61.40; H, 6.05; N, 6.51. measured value C, 60.94; H, 6.17; N, 6 38; IR (KBr): 2952.5,1747.2,1596.8,1500.4,1425.2,1276.7,1247.7,1180.2,1060.7,771.4cm -1EI-MS (m/z): 430 (8, M +), 135 (100).Embodiment 22:2-[4-[2-(N-methyl-2-pyridine amino) oxyethyl group] phenmethyl]-2-ethoxycarbonyl dimethyl malonate (22)
With compound 1 and Vinyl chloroformate is raw material, and the preparation method is similar to compound 24, sherwood oil: it is a colorless oil that ethyl acetate=5: 3 silica gel column chromatographies get product, yield 62.1%. 1H NMR (CDCl 3): δ=1.21 (t, J=7.3Hz, 4H), 3.25 (s, 3H), 3.42 (s, 2H), 3.70 (m, 7H), 4.15 (m, 6H), 6.88 (m, 2H), 6.71 (d, J=8.2Hz, 2H), 7.12 (d, J=8.2Hz, 2H), 7.58 (m, 1H), 8.16 (m, 1H); Ultimate analysis, C 23H 28N 2O 71/3H 2O (450): calculated value C, 61.33; H, 6.37; N, 6.22. measured value C, 61.19; H, 6.34; N, 6.17; IR (KBr): 2952.5,1743.4,1596.8,1500.4,1425.2,1247.7,1180.2,1114.7,1058.7,840.8,771.4,567cm -1EI-MS (m/z): 444 (5, M +), 135 (100). embodiment 23:2-[4-(4-trifluoromethyl) benzyloxy phenmethyl] dimethyl malonate (23)
4-trifluoromethyl-benzyl-alcohol 70 μ L (0.5mmol) and 2-(4-hydroxybenzene methyl) dimethyl malonate 0.118g (0.5mmol) are in the 8mL ether, add triphenylphosphine 0.19g (0.75mmol), 0 ℃ slowly drips DAD (diethylazodicarboxylate) 120 μ L (0.75mmol).Stirring at room 24 hours.Remove solvent under reduced pressure, the lithium hydroxide hydrolysis gets target compound 0.09g, yield 45.5%. 1H NMR (CDCl 3): δ=3.12 (d, J=7.3Hz, 2H), 3.70 (m, 7H), 5.10 (s, 2H), 6.80 (d, J=8.5Hz, 2H), 7.08 (d, J=8.5Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 7.60 (d, J=8.5Hz, 2H); Ultimate analysis, C 20H 19F 3O 51/3H 2O (402): calculated value C, 59.70; H, 4.89.Measured value C, 59.95; H, 4.70; IR (KBr): 2962.2,1751.1,1737.6,1511.9,1442.5,1326.8,1236.2,1170.6,1126.2,1068.4,1016.3,823.5,530.3cm -1EI-MS (m/z): 396 (9, M +), 159 (100).
2-(4-hydroxybenzene methyl) dimethyl malonate is synthetic with the method that is similar to compound 1 by p-Hydroxybenzaldehyde and dimethyl malonate.Embodiment 24:2-[4-[2-(1 indoles)] oxyethyl group] phenmethyl] dimethyl malonate (24)
2-(1-indoles) ethanol 0.2g (1.24mmol) and 2-(4-hydroxybenzene methyl) dimethyl malonate 0.293g (1.24mmol) add triphenylphosphine 0.47g (1.9mmol) in the 15mL anhydrous diethyl ether, 0 ℃ slowly drips DAD300 μ L (1.9mmol).Stirring at room 24 hours.Remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=3: 1 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, 0.29g, yield 62.9%. 1HNMR (CDCl 3): δ=3.10 (d, J=8.0Hz, 2H), 3.58 (t, J=8.0Hz, 1H), 3.65 (s, 6H), 4.20 (t, J=5.4Hz, 2H), 4.50 (t, J=5.4Hz, 2H), 6.50 (d, J=3.2Hz, 1H), 6.70 (d, J=8.5Hz, 2H), 7.05 (m, 3H), 7.20 (m, 2H), 7.39 (d, J=8.4Hz, 1H), 7.60 (d, J=7.6Hz, 1H); Ultimate analysis, C 22H 23NO 5(381): calculated value C, 69.29; H, 6.04; N, 3.67. measured value C, 69.52; H, 6.24; N, 3.62; IR (KBr): 2952.5,1735.6,1612.2,1511.9,1463.7,1436.7,1315.2,1243.9,1153.2,1064.5,1027.9,744.4cm -1EI-MS (m/z): 381 (52, M +), 130 (100). embodiment 25:2-[4-[2-[N-propyloic-N-(2-pyridine) amino] oxyethyl group] phenmethyl] dimethyl malonate (25)
3-(2-pyridine) alanine 0.78g (4.7mmol) is with in the 12mL dry DMF, and 0 ℃ adds sodium hydride (60% solid) 0.423g (10.3mmol), is stirred to no bubble and produces.Add the solution of 4-(2-bromine oxethyl) phenyl aldehyde 1.08g (4.7mmol) in the 5mL dry DMF.60 ℃ were stirred 12 hours.Add water 70mL, transfer pH to 7 with 1N hydrochloric acid, ethyl acetate 30mL+30mL extraction is washed with water 40mL behind the combined ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=1: 1 is an eluent, and silica gel column chromatography is got 4-[2-[N-propyloic-N-(2-pyridine) amino] oxyethyl group] phenyl aldehyde is a colorless oil, 0.58g, yield 39.2%. 1H?NMR(CDCl 3)：δ＝2.68(t，J＝6.2Hz，2H)，3.63(m，2H)，4.12(t，J＝4.6Hz，2H)，4.45(t，J＝4.6Hz，2H)，6.38(d，J＝8.2Hz，1H)，6.58(m，1H)，7.00(d，J＝8.6Hz，2H)，7.39(m，1H)，7.80(d，J＝8.7Hz，2H)，8.05(m，1H)。
4-[2-[N-propyloic-N-(2-pyridine) amino] oxyethyl group] phenyl aldehyde and dimethyl malonate be raw material, to be similar to the method for compound 1, sherwood oil: ethyl acetate=1: 3 is an eluent, and it is a colorless oil that silica gel column chromatography gets 28, two step yields 46.5%. 1H?NMR(CDCl 3)：δ＝2.68(t，J＝6.2Hz，2H)，3.15(d，J＝7.9Hz，2H)，3.70(m，9H)，4.12(t，J＝4.6Hz，2H)，4.42(t，J＝4.6Hz，2H)，6.35(d，J＝8.2Hz，1H)，6.55(m，1H)，6.80(d，J＝8.8Hz，2H)，7.10(d，J＝8.7Hz，2H)，7.39(m，1H)，8.05(m，1H)；IR(KBr)：3411.5，2954.5，1727.9，1608.4，1513.9，1436.7，1344.2，1243.9，1178.3，1060.7，775.3，538.1cm -1；EI-MS(m/z)：430(2，M +)，151(100)；HRMS：430.1741(C 22H 26N 2O 7)。Embodiment 26:2-[4-(N-methyl-2-indoles methoxyl group) phenmethyl] dimethyl malonate (26)
N-methyl-2-indole-alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Product is with re-crystallizing in ethyl acetate, yield 13.5%.m.p.98-100℃。 1HNMR (DMCO-d6): δ=3.10 (d, J=8.0Hz, 2H), 3.62 (s, 6H), 3.70 (t, J=8.1Hz, 1H), 3.82 (s, 3H), 5.28 (s, 2H), 6.60 (s, 1H), 7.01 (m, 3H), 7.18 (m, 3H), 7.40 (dd, J=8.0Hz, 0.8Hz, 1H), 7.55 (dd, J=8.1Hz, 1.1Hz, 1H); Ultimate analysis, C 22H 23NO 5(381): calculated value C, 69.29; H, 6.04; N, 3.67. measured value C, 69.29; H, 6.03; N, 3.79; IR (KBr): 2956.4,1731.8,1511.9,1434.8,1238.1,1161,1008.6,752.1cm -1EI-MS (m/z): 381 (2, M +), 144 (100). embodiment 27:2-[4-(N-methyl-5-methoxyl group-2-indoles methoxyl group) phenmethyl] dimethyl malonate (27)
N-methyl-5-methoxyl group-2-indole-alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Product is with re-crystallizing in ethyl acetate, yield 26.2%.m.p.120-121℃。 1H NMR (DMCO-d6): δ=3.10 (d, J=8.0Hz, 2H), 3.62 (s, 6H), 3.70 (t, J=8.1Hz, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H), 6.50 (s, 1H), 6.80 (dd, J=8.8Hz, 2.2Hz, 1H), 6.96 (d, J=8.8Hz, 2H), 7.05 (d, J=2.2Hz, 1H), 7.16 (d, J=8.8Hz, 2H), 7.30 (d, J=8.8Hz, 1H); Ultimate analysis, C 23H 25NO 6(411): calculated value C, 67.15; H, 6.08; N, 3.41. measured value C, 67.20; H, 6.11; N, 3.49; IR (KBr): 2956.4,1733.7,1510,1488.8,1436.7,1292.1,1230.4,1178.3,1029.8,1000,844.7,813.8cm -1EI-MS (m/z): 411 (16, M +), 174 (100).Embodiment 28:2-[4-(N-methyl-2-indoline methoxyl group) phenmethyl] dimethyl malonate (28)
N-methyl-2-indoline methyl alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=5: 2 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, yield 29.1%. 1H?NMR(DMCO-d6)：2.81(dd，J＝15.8Hz，9.5Hz，1H)，2.82(s，3H)，3.10(d，J＝8.8Hz，2H)，3.17(dd，J＝15.7Hz，9.1Hz，1H)，3.62(s，6H)，3.66-3.78(m，2H)，4.14(dd，J＝9.9Hz，5.1Hz，1H)，4.20(dd，J＝9.9Hz，5.8Hz，1H)，6.49(d，J＝8.4Hz，1H)，6.59(t，J＝7.6Hz，1H)，6.90(d，J＝8.4Hz，2H)，6.98-7.04(m，1H)，7.1-7.17(m，3H)；IR(KBr)：2952.5，1753，1735.6，1610.3，1513.9，1486.9，1436.7，1245.8，1153.2，1038.7，829.3，752.1cm -1；EI-MS(m/z)：383(1，M +)，121(100)；HRMS：383.1724(C 22H 25NO 5)。Embodiment 29:2-[4-(N-methyl-5-methoxyl group-2-indoline methoxyl group) phenmethyl] dimethyl malonate (29)
N-methyl-5-methoxyl group-2-indoline methyl alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=5: 2 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, yield 57.8%. 1H NMR (DMCO-d6): 2.76-2.84 (m, 4H), 2.98-3.16 (m, 3H), 3 64 (s, 6H), 3.69 (s, 3H), 3.72 (t, J=8.8Hz, 1H), 4.14 (dd, J=9.9Hz, 5.1Hz, 1H), 4.23 (dd, J=9.9Hz, 5.5Hz, 1H), 4.24-4.30 (m, 1H), 6.45 (d, J=8.5Hz, 1H), 6.62 (dd, J=8.5Hz, 1.4Hz, 1H), 6.71 (d, J=1.4Hz, 1H), 6.90 (d, J=8.4Hz, 2H), 7.18 (d, J=8.4Hz, 2H); Ultimate analysis, C 23H 27NO 6(413): calculated value C, 66.83; H, 6.54; N, 3.39. measured value C, 67.22; H, 6.22; N, 2.82; IR (KBr): 3457.8,2952.5,1735.6,1612.2,1513.9,1492.7,1436.7,1346.1,1240,1151.3,1031.7,846.6,545.8cm -1EI-MS (m/z): 413 (18, M +), 107 (100).Embodiment 30:2-[4-(N-methyl-5-methoxyl group-3-indoles methoxyl group) phenmethyl] dimethyl malonate (30)
N-methyl-5-methoxyl group-3-indole-alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=3: 1 is an eluent, and it is a reddish-brown oily matter that silica gel column chromatography is got product.Yield 8.5%. 1H?NMR(DMCO-d6)：δ＝3.10(d，J＝7.6Hz，2H)，3.67(s，6H)，3.73(t，J＝7.9Hz，1H)，3.80(s，6H)，5.22(s，2H)，6.85(dd，J＝8.8Hz，2.4Hz，1H)，6.71(d，J＝8.5Hz，2H)，7.17(m，3H)，7.18(d，J＝9.1Hz，1H)。IR(KBr)：3428.9，2952.5，2833.0，1735.6，1616.1，1515.8，1488.8，1436.7，1349.9，1228.5，1151.3，1033.7，756.0cm -1；EI-MS(m/z)：411(5，M +)，107(100)；HRMS：411.1659(C 23H 25NO 6)。Embodiment 31:2-[4-[2-(N-methyl-3-indoles)] oxyethyl group] phenmethyl] dimethyl malonate (31)
2-(N-methyl-3-indoles) ethanol and 2-(4-hydroxybenzene methyl) dimethyl malonate are raw material, and be synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=2: 1 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, yield 45.2%. 1H NMR (DMCO-d6): δ=3.10 (d, J=7.7Hz, 2H), 3.20 (t, J=6.9Hz, 2H), 3.62 (s, 6H), 3.70 (t, J=7.7Hz, 1H), 3.80 (s, 3H), 4.20 (t, J=6.9Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 7.12 (t, J=8.1Hz, 1H), 7.15 (m, 4H), 7.37 (m, 1H), 7.65 (d, J=8.1Hz, 1H); Ultimate analysis, C 23H 25NO 5(395): calculated value C, 69.87; H, 6.33; N, 3.55. measured value C, 69.87; H, 6.33; N, 3.54; IR (KBr): 3457.8,2950.6,1735.6,1612.2,1511.9,1473.4,1434.8,1243.9,1155.2,1027.9,829.3,742.5cm -1EI-MS (m/z): 395 (6, M +), 121 (100). embodiment 32:2-[4-(N-methyl-3-indoles methoxyl group) phenmethyl] dimethyl malonate (32)
N-methyl-3-indole-alcohol and 2-(4-hydroxybenzene methyl) dimethyl malonate is a raw material, and is synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=3: 1 is an eluent, and it is a solid that the silica gel H column chromatography is got product, yield 10.2%.m.p.53-55℃。 1H NMR (DMCO-d6): 3.11 (d, J=7.7Hz, 2H), 3.62 (s, 6H), 3.72 (t, J=7.7Hz, 1H), 3.80 (s, 3H), 5.22 (s, 2H), 6.98-7.03 (m, 3H), 7.12-7.18 (m, 3H), 7.22 (s, 1H), 7.32-7.39 (m, 1H), 7.55 (dd, J=8.1Hz, 0.7Hz, 1H); Ultimate analysis, C 22H 23NO 53/4H 2O (393): calculated value C, 66.92; H, 6.21; N, 3.55. measured value C, 67.08; H, 6.24; N, 3.71; IR (KBr): 3442.4,2954.5,1727.9,1749.1,1612.2,1511.9,1440.6,1278.6,1222.7,1170.6,987.4,968.1,742.5cm -1EI-MS (m/z): 381 (15, M +), 144 (100). embodiment 33:2-[4-[2-(N-methyl-3-indoline)] oxyethyl group] phenmethyl] dimethyl malonate (33)
Compound 34 83mg (0.23mmol) are dissolved in 98% formic acid 2.5mL, add 10%Pd-C 61mg, the following 70 ℃ of reactions of nitrogen protection 3 hours.Filtering Pd-C removes solvent under reduced pressure, adds saturated sodium bicarbonate aqueous solution 5mL, and ethyl acetate 5mL+5mL extraction is washed with water 6mL behind the combined ethyl acetate, saturated common salt washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, residue is with sherwood oil: ethyl acetate=3: 1 is an eluent, and it is a colorless oil that silica gel column chromatography is got product, 37mg, yield 44.5%. 1H NMR (DMCO-d6): 1.90-1.98 (m, 1H, HC-C-O-), 2.20-2.30 (m, 1H, HC-C-O-), 2.70 (s, 3H, H 3CN-), 3.02 (dd, J=8.8Hz, 7.6Hz, 1H, 2-H), 3.10 (d, J=7.7Hz, 2H, PhCH 2-), 3.30-3.38 (m, 1H, 3-H), 3.48 (t, J=8.4Hz, 1H, 2-H), 3.62 (s, 6H), 3.71 (t, J=7.7Hz, 1H), 4.02-5.02 (m, 2H, CH 2O-), 6.48 (d, J=8.0Hz, 1H), 6.59-6.64 (m, 1H), 6.82 (d, J=8.8Hz, 2H), 7.00-7.07 (m, 2H), 7.15 (d, J=8.8Hz, 2H); Ultimate analysis, C 23H 27NO 5(397): calculated value C, 69.52; H, 6.80; N, 3.53. measured value C, 69.34; H, 6.86; N, 3.53; IR (KBr): 2950.6,2858.0,1731.8,1608.4,1513.9,1490.7,1434.8,1243.9,1153.2,1022.1,829.3,750.2cm -1EI-MS (m/z): 397 (8, M +), 121 (100); HRMS:397.1873 (C 23H 27NO 5).Embodiment 34:2-[4-[4-(N-methyl-3-indoles)] butoxy] phenmethyl] dimethyl malonate (34)
4-(N-methyl-3-indoles) butanols and 2-(4-hydroxybenzene methyl) dimethyl malonate are raw material, and be synthetic with the method that is similar to compound 27.Sherwood oil: ethyl acetate=3: 1 is an eluent, and it is a solid that silica gel column chromatography is got product, yield 27.8%. 1H NMR (DMCO-d6): δ=1.80-1.88 (m, 4H), 2.80 (t, J=6.6Hz, 2H), 3.10 (d, J=8.0Hz, 2H), 3.62 (s, 6H), 3.70 (t, J=8.1Hz, 1H), 3.75 (s, 3H), 3.98 (t, J=6.3Hz, 2H), 6.80 (d, J=8.8Hz, 2H), and 6.97-7.02 (m, 2H), 7.10-7.14 (m, 3H), 7.29-7.32 (m, 1H), 7.53-7.55 (m, 1H); Ultimate analysis, C 25H 29NO 51/3H 2O (429): calculated value C, 69.92; H, 6.92; N, 3.26. measured value C, 69.90; H, 6.79; N, 3.09; IR (KBr): 3041.2,2954.5,1,756 9,1739.5,1612.2,1513.9,1434.8,1280.5,1245.8,1149.4,1018.2,844.7,779.1,732.8,541.9,428cm -1EI-MS (m/z): 423 (15, M +), 121 (100).

Claims (10)

1, a class has 1,3 dicarbonyl compounds of following structure
Wherein
R 1, R 2=C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH-,-O-C (CH 2) 2-O-
R 3＝-CH 2OH，-CO 2CH 3，-CH 2OCHO，-CH 2O 2CH 3，H
R 4=2 or 3 join And
R 5=H, C 1-C 4Alkoxyl group, substituted aryl,
n＝1-4
2,1,3 dicarbonyl compounds according to claim 1 is characterized in that
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-;
R 3During for H
R 4For
Figure A0213671500024
n＝1-4
3,1,3 dicarbonyl compounds according to claim 1 is characterized in that
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-;
R 3During for H
R 4For
Figure A0213671500031
R 5Be H, C1-C4 alkoxyl group
n＝1-4
4, according to described 1,3 dicarbonyl compounds of claim 1, it is characterized in that
Work as R 1, R 2Be C 1-C 4Alkyl, alkoxyl group, alkylamino, heterocyclic amino group, diazanyl, hydroxylamino ,-NH-O-,-NH-NH ,-O-C (CH 2) 2-O-,
R 4For The time
R 3For-CH 2OH ,-CO 2CH 3,-CH 2OCHO ,-CH 2O 2CH 3
n＝1-4
5, the preparation method of 1,3 dicarbonyl compounds as claimed in claim 1 is characterized in that the oxyethyl group with 4-[2-(N-methyl-2-pyridine chloro)] phenyl aldehyde is raw material and 1,3 identical or different C 1-C 4Alkyl, alkoxyl group, alkylamino, 1 of heterocyclic amino group replacement, the 3-Dicarbonyl derivatives, condensation obtains target compound.
6, according to the preparation method of described 1,3 dicarbonyl compounds of claim 5, the solvent that it is characterized in that condensation reaction is a benzene, toluene, and chloroform, ethanol, temperature of reaction is a room temperature to 150 ℃, the reaction times is 2-24 hour.
7,, it is characterized in that Compound I and certain density oxammonium hydrochloride, hydrazine hydrate, methylamine hydrochloride, cyclopropylamine reaction obtain condenses separately according to described 1,3 dicarbonyl compounds of claim 5.
8, the preparation method of 1,3 dicarbonyl compounds according to claim 5, it is characterized in that reactant 1 is in the presence of salt of wormwood, yellow soda ash, sodium hydroxide or potassium hydroxide, temperature of reaction is a room temperature to 70 ℃, reaction times is 24-72 hour, or compound 1 is at aprotic solvent such as dimethyl formamide, in the tetrahydrofuran (THF), with sodium hydride, sodium methylate or sodium ethylate are alkali, react separately target compound with methyl-chloroformate or Vinyl chloroformate.
9, it is characterized in that according to described 1,3 dicarbonyl compounds of claim 5 room temperature reaction in dehydrated alcohol makes R at a certain amount of triphenylphosphine and diethylazodicarboxylate with the N-skatole alkyl alcohol on 2 or 3 and 2-(4-hydroxybenzyl)-dimethyl malonate 4Purpose compound for substituted heterocycle.
10, according to described 1,3 dicarbonyl compounds of claim 1, it is characterized in that they are euglycemic agents, can in treatment type ii diabetes, obesity, high fat of blood medicine, use.
CNA021367159A 2002-08-29 2002-08-29 1,3-dicarbonyl compound and its preparation and use Pending CN1478770A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010111905A1 (en) * 2009-03-31 2010-10-07 江苏恒瑞医药股份有限公司 Pharmaceutical composition for treatment of 2 type dabetes
JP2015514754A (en) * 2012-04-20 2015-05-21 メディシナル バイオコンバージェンス リサーチ センター Use of novel aminopyridine derivatives for cancer prevention or treatment
CN107597018A (en) * 2017-09-11 2018-01-19 陕西莱特光电材料股份有限公司 A kind of double-hydrophilic parents oil-based surfactant and preparation method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010111905A1 (en) * 2009-03-31 2010-10-07 江苏恒瑞医药股份有限公司 Pharmaceutical composition for treatment of 2 type dabetes
US8476272B2 (en) 2009-03-31 2013-07-02 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for treatment of type 2 diabetes
JP2015514754A (en) * 2012-04-20 2015-05-21 メディシナル バイオコンバージェンス リサーチ センター Use of novel aminopyridine derivatives for cancer prevention or treatment
CN107597018A (en) * 2017-09-11 2018-01-19 陕西莱特光电材料股份有限公司 A kind of double-hydrophilic parents oil-based surfactant and preparation method thereof

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