CN102492004A - Preparation method and application of 2-(4-beta-D-allose pyranoside-phenyl)-2,3-dihydroquinoline-4(1H) and 2-(4-(2,3,4,6-tetrabenzyl)-beta-D-allose pyranoside-phenyl)-2,3-benzodihydropyran - Google Patents
Preparation method and application of 2-(4-beta-D-allose pyranoside-phenyl)-2,3-dihydroquinoline-4(1H) and 2-(4-(2,3,4,6-tetrabenzyl)-beta-D-allose pyranoside-phenyl)-2,3-benzodihydropyran Download PDFInfo
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Abstract
The invention relates to a preparation method and an application of 2-(4-beta-D-allose pyranoside-phenyl)-2,3-dihydroquinoline-4(1H) (1) and 2-(4-(2,3,4,6-tetrabenzyl)-beta-D-allose pyranoside-phenyl)-2,3-benzodihydropyran (2). The invention discloses helicide derivatives with a central nervous system improving function, and a preparation method thereof. The compounds provided by the invention have good sedative, sleep-promoting, and convulsion-inhibiting functions. The compounds are collected in a Year 2000 version of Pharmacopoeia of PRC with a medicine name of helicide tablets. The helicide derivative novel medicines are represented by chemical formulas (1) and (2), wherein R1 can be hydrogen and acetyl, and R2 can be semicarbazide, hydroxylamine, and methoxylamine. Acording to the helicide derivatives provided by the invention, a plant active monomer helicide with sedative, sleep-promoting, and convulsion-inhibiting functions is adopted as a matrix compound, structural modification is carried out according to a medicine efficacy molecular principle, and compounds with high activities for improving central nervous system functions are designed and prepared.
Description
Technical field
The present invention be to have calmness, the active vegetable active monomer helicidum of sleeping peacefully carries out structural modification, obtains the verivate of the helicidum of a series of better efficacy.
Background technology
Helicidum be 4-formylphenyl-beta-D-allopyranosid-(4-fornylphenl-β-D-Allosupranoside) be Chen Weixin etc. at Liebigs.Ann.Chem.,
1981,(10) effective constituent that reported first extracts from the fruit of Yunnan Province of China Proteaceae radish plant tree (Helicia Nilagirica Beed, different name Helicia Erratica Hook) in, its structure as shown in:
At present, helicidum is more as the report of preparation, and to apply for a patent.At publication number is among the CN1535690, has reported helicidum soft capsule and preparation method thereof; Publication number is among the CN1535691 a kind of Helicid powder injection and preparation method thereof to be provided; Publication number is to disclose a kind of being applicable among the CN1586494 to alleviate neurosal headache, giddy and somnopathy, the Helicidum oral disintegation tablet of assisting therapy primary headache; Publication number is that a kind of helicidum soft capsule is provided among the CN1596903; Publication number is to disclose a kind of helicidum capsule among the CN1640410; Publication number is that a kind of adopt slow, controlled release preparation slow, that controlled-release technology makes helicidum are provided among the CN1478482; Publication number is that a kind of Hilieidum quick-release tablet and preparation method thereof is provided among the CN1454600.
Existing a lot of report about the helicidum pharmacological action.Like " the preliminary discussions of helicidum analgesic activity " such as Chen Zhaoxi<b >(</b><<the Xue Bao > of No.1 Military Medical Univ.;>,<b >1985</b>, 5 [3]<b >)</b>Sha Jingshu etc. " new drug evaluation: helicidum (Hilieidum) "<b >(</b><<pharmacy circular>>,<b >1987</b>, 22 [1]<b >)</b>Zhong Yuguo etc. " "<b >(</b><<the Xue Bao > of Sichuan medical college;>,<b >1984</b>, 15 [1]<b >)</b>Liu Ping etc. " helicidum is to the rat early stage neurobehavioral toxicity in young generation "<b >(</b><<zhong Chengyao>>,<b >2002</b>, 24 [4]<b >)</b>Tang Fuqin etc. " Hilieidum sheet treatment neurasthenia disease crowd's clinical observation "<b >(</b><<china combination of Chinese tradiational and Western medicine Za Zhi>>,<b >1998</b>, 18 [3]<b >)</b>Li Jian etc. " the neurobehavioral teratogenic effect of helicidum "<b >(</b><<hygiene Toxicology Za Zhi>>,<b >2001</b>, 15 [2]<b >)</b>Han Yumei etc. " Chinese medicine is to the influence of excitatory neurotransmitter L-glutamic acid "<b >(</b><<the Xue Bao > of Jiangxi Medical College;>,<b >1996</b>, 36 [1]<b >)</b>
Helicidum with possess effect acumen, transformation period weak point, good effect, side reaction judgement criteria few, that especially do not influence outstanding hypnotic and sedatives such as patient's cerebration memory certain gap still arranged; As: Wu Deyu etc. " progress of soporific " (science and technology and engineering 2005; 5 (17); 1286), also influenced this medicine in clinical applying.
Summary of the invention
One of the object of the invention is to be lead compound with the helicidum, thereby to the synthetic a series of new calming soporifics with better pharmacologically active of its structural modification, anticonvulsion type of medicine.Make doctor and patient to the control of disease the time, can increase selection to available medicine.
The present invention is lead compound with the helicidum, and to its structural modification synthetic compound, its structural formula is suc as formula 1. and 2.:
① ②
Wherein, formula 1. and 2. in R
1Can be hydrogen, ethanoyl; R
2Can for Urea,amino-, azanol, methoxyl group amine.With the helicidum being the synthetic above-claimed cpd of the present invention of raw material 1. and 2. the time, can adopt preparation in the following method.
Step: 1. aldehyde radical of (1) helicidum and o-aminoacetophenone reaction obtains 3a.
(2) 3a has synthesized 3b-3d with methoxyl group amine, azanol, Urea,amino-reaction respectively; 3a and acetic anhydride synthesize 4a.
(3) 4a has synthesized 4b-4d with methoxyl group amine, azanol, Urea,amino-reaction respectively.
2. (1) helicidum and benzyl bromine reaction synthetic 3.(2) 3 have synthesized alpha, beta-unsaturated ketone 2a with o-aminoacetophenone reaction.(3) alpha, beta-unsaturated ketone 2a reacts under the catalysis of sodium acetate and has generated 5a.(4) 5a has synthesized 5b-5d with methoxyl group amine, azanol, Urea,amino-reaction respectively.Be appreciated that by foregoing 1. the above-mentioned synthesis mode of employing prepares the said compound of the present invention, route is very simple, and cost is lower, and the yield of product is higher, can be suitable for industriallization and the needs that enlarge production.
Instance 1:2-(4-
β-D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-ketone (3a)
In the round-bottomed flask of 50mL, 0.6mmol L-proline(Pro) is dissolved in the absolute anhydrous methanol of 20mL, adds behind helicidum 2mmol, the o-aminoacetophenone 2mmol at room temperature stirring reaction then successively 5 days.(methylene dichloride: methyl alcohol=8:1) separation and purification gets yellow-green colour solid 3a to bullion after reaction finishes through column chromatography.Productive rate: 60%, m.p. 115-117 ℃;
1H NMR (400MHz, DMSO-d
6)
δ: 6.61 ~ 7.59 (m, 8H), 5.15 (d,
J=8.0 Hz, 1H), 5.07 (d,
J=6.4 Hz, 1H), 4.95 (d,
J=3.6 Hz, 1H), 4.65 ~ 4.71 (m, 2H), 4.49 (t,
J=4.0 Hz, 1H), 3.66 ~ 3.92 (m, 3H), 3.36 ~ 3.47 (m, 4H), 2.59 ~ 2.85 (m, 2H); IR (KBr)
ν: 3382,2920,1657,1609,1507,1479,1329,1082,1037,912,836,763; HRMS (ESI) calcd for C
21H
23NO
7[M+H]
+: 402.1547, found 402.1562; [M+Na]
+: 424.1367, found 424.1368.
Instance 2:2-(4-
β-
D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-methoxyl group amine (3b)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add methoxy amine hydrochlorate (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (methylene dichloride: methyl alcohol=8:1) separation and purification gets yellow solid 3b, productive rate: 90%, m.p. 114-116 ℃;
1H NMR (400MHz, DMSO-d
6) δ: 7.64 (d,
J=8.0 Hz, 1H), 7.35 (d,
J=8.4 Hz, 2H), 7.10 (t,
J=8.0 Hz, 1H), 7.00 (d,
J=8.0 Hz, 2H), 6.77 (d,
J=8.0 Hz, 1H), 6.59 (t,
J=8.0 Hz, 1H), 6.40 (s, 1H), 5.07 ~ 5.12 (m, 2H), 4.95 (d,
J=2.0 Hz, 1H), 4.66 (d,
J=7.6 Hz, 1H), 4.49 (t,
J=5.6 Hz, 1H), 4.31 (m, 1H), 3.92 (d,
J=2.0 Hz, 1H), 3.84 (s, 3H), 3.66 (m, 2H), 3.36 ~ 3.47 (m, 4H), 3.10 (m, 1H); IR (KBr) ν: 3370,2930,2810,1614,1509,1478,1420,1324,1230,1083,1041,914,876,834,756; HRMS (ESI) calcd for C
22H
26N
2O
7[M+H]
+: 431.1813, found 431.1813; [M+Na]
+: 453.1632, found 453.1634.
Instance 3:2-(4-
β-
D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-oxyamine (3c)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add hydroxylamine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (methylene dichloride: methyl alcohol=8:1) separation and purification gets yellow solid 3c, productive rate: 80%, 118 ~ 120 ℃ of m.p.;
1H NMR (400MHz, DMSO-d
6)
δ: 10.86 (s, 1H), 7.64 (d,
J=8.0 Hz, 1H), 7.35 (d,
J=8.4 Hz, 2H), 7.06 (t,
J=7.6 Hz, 1H), 7.00 (d,
J=8.2 Hz, 2H), 6.76 (d,
J=8.2 Hz, 1H), 6.59 (t,
J=7.6 Hz, 1H), 6.31 (s, 1H), 5.07 ~ 5.12 (m, 2H), 4.97 (s, 1H), 4.68 (d,
J=7.2 Hz, 1H), 4.49 ~ 4.51 (m, 1H), 4.27 ~ 4.30 (m, 1H), 3.92 (s, 1H), 3.66 (d,
J=8.4 Hz, 2H), 3.39 ~ 3.7 (m, 4H, OH), 3.10 (d,
J=16.4 Hz, 1H)); IR (KBr)
ν: 3378,2925,1627,1509,1480,1417,1324,1230,1084,1036,940,835,758; HRMS (ESI) calcd for C
21H
24N
2O
7[M+H]
+: 417.1656, found 417.1666; [M+K]
+: 455.1215, found 455.1197.
Instance 4:2-(4-
β-
D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-Urea,amino-(3d)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add carbamylhydrazine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (methylene dichloride: methyl alcohol=8:1) separation and purification gets white solid 3d, productive rate: 80%, 126 ~ 128 ℃ of m.p.;
1H NMR (400MHz, DMSO-d
6)
δ: 9.18 (s, 1H), 7.96 (d,
J=7.2 Hz, 1H), 7.37 (d,
J=8.2 Hz, 2H), 7.00 ~ 7.07 (m, 3H), 6.75 (d,
J=8.0 Hz, 1H), 6.60 (t,
J=7.6 Hz, 1H), 6.42 (s, 2H), 6.31 (s, 1H), 5.08 ~ 5.13 (m, 2H), 4.96 (s, 1H), 4.66 (d,
J=5.6 Hz, 1H), 4.50 (m, 1H), 4.30 ~ 4.33 (m, 1H), 3.92 (s, 1H), 3.66 ~ 3.68 (m. 2H), 3.41 ~ 3.47 (m, 4H), 3.0 ~ 3.03 (m, 1H); IR (KBr)
ν: 3352,2922,1672,1615,1572,1508,1477,1418,1326,1231,1082,1037,909,836,759; HRMS (ESI) calcd for C
22H
26N
4O
7[M+H]
+: 459.1874, found 459.1870: [M+Na]
+: 481.1694, found 481.1686.
Instance 5:2-(4-(2,3,4,6-is tetra-acetylated)-
β-D-Allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-ketone (4a)
In the round-bottomed flask of 25mL, 3a 2.5mmol and triethylamine 12mmol are dissolved among the 2mL DMF, and (2mmol rises to room temperature, stirred overnight after reaction for some time under ice bath under ice bath stirs, slowly to add diacetyl oxide.After reaction stopped, reaction solution was poured in the frozen water of 50mL, has solid to separate out immediately, filtered, and promptly got yellow-green colour solid 4a with water washing.Productive rate: 98%, 112 ~ 114 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.87 (dd,
J=1.2 Hz,
J=8.0 Hz, 1H), 7.30 ~ 7.45 (m, 3H), 7.02 ~ 7.10 (m, 2H), 6.80 (t,
J=8.0 Hz, 1H), 6.71 (d,
J=8.2 Hz, 1H), 5.75 (t,
J=2.8 Hz, 1H), 5.37 (d,
J=8.0 Hz, 1H), 5.17 (dd,
J=3.2 Hz,
J=8.0 Hz, 1H), 5.02 ~ 5.10 (m, 1H), 4.73 (dd,
J=4.0 Hz,
J=13.2 Hz, 1H), 4.49 (s, 1H), 4.20 ~ 4.30 (m, 3H), 2.70 ~ 2.90 (m, 2H), 2.02 ~ 2.20 (m, 12H); IR (KBr)
ν: 3473,3350,2958,1752,1672,1609,1507,1482,1372,1223,1090,1044,949,911,764; HRMS (ESI) calcd for C
29H
31NO
11[M+H]
+: 570.1970, found 570.1965; [M+Na]
+: 592.1789, found 592.1802.
Instance 6:2-(4-(2,3,4,6-is tetra-acetylated)-
β-D-Allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-methoxyl group amine (4b)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add methoxy amine hydrochlorate (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (acetone: sherwood oil=1:4) separation and purification gets yellow solid 4b, productive rate: 93%, 88 ~ 89 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.89 (d,
J=7.2 Hz, 1H), 7.38 (d,
J=8.4 Hz, 2H), 7.14 ~ 7.18 (m, 1H), 7.03 (d,
J=8.4 Hz, 2H), 6.78 (m, 1H), 6.64 (d,
J=7.2 Hz, 1H), 5.75 (t,
J=2.8 Hz, 1H), 5.36 (dd,
J=1.6 Hz,
J=8.0 Hz, 1H), 5.16 (dd,
J=2.8 Hz,
J=8.0 Hz, 1H), 5.05 ~ 5.08 (m, 1H), 4.35 (dd,
J=3.6 Hz,
J=12 Hz, 1H), 4.22 ~ 4.26 (m, 3H), 3.95 (s, 3H), 3.36 (dd,
J=3.6 Hz,
J=16.8,1H), 2.50 ~ 2.53 (m, 1H), 2.03 ~ 2.17 (m, 12H); IR (KBr)
ν: 3425,2933,1753,1615,1509,1480,1372,1224,1092,1046,948,909,757; HRMS (ESI) calcd for C
30H
34N
2O
11[M+H]
+: 599.2235, found 599.2234.
Instance 7:2-(4-(2,3,4,6-is tetra-acetylated)-
β-D-Allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-azanol (4c)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add hydroxylamine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (acetone: sherwood oil=1:2) separation and purification gets white solid 4c, productive rate: 81%, 104 ~ 106 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.82 (d,
J=7.2 Hz, 1H), 7.39 (d,
J=8.4 Hz, 2H), 7.16 ~ 7.20 (m, 1H), 7.05 (d,
J=8.4 Hz, 2H), 6.76 ~ 6.79 (m, 1H), 6.65 (d,
J=7.6 Hz, 1H), 5.75 (t,
J=2.8 Hz, 1H), 5.37 (dd,
J=1.2 Hz,
J=8.4 Hz, 1H), 5.17 (dd,
J=3.2 Hz,
J=8.0 Hz, 1H), 5.05 ~ 5.08 (m, 1H), 4.39 (dd,
J=3.6 Hz,
J=12.4 Hz, 1H), 4.26 ~ 4.27 (m, 3H), 3.46 (dd,
J=3.6 Hz,
J=12.4 Hz, 1H), 2.53 ~ 2.64 (m, 1H), 2.03 ~ 2.17 (m, 12H); IR (KBr)
ν: 3369,1752,1606,1510,1481,1429,1373,1224,1092,1043,943,835,757; HRMS (ESI) calcd for C
29H
32N
2O
11[M+H]
+: 585.2079, found 585.2081; [M+Na]
+: 607.1898, found 607.1894.
Instance 8:2-(4-(2,3,4,6-is tetra-acetylated)-
β-D-Allopyranosid--phenyl)-2,3-EEDQ-4 (1
HSynthesizing of)-Urea,amino-(4d)
Add 3a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add carbamylhydrazine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (methylene dichloride: methyl alcohol: sherwood oil=5:0.5:5) separation and purification gets white solid 4d, productive rate: 80%, 124 ~ 126 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.91 (d,
J=8.0 Hz, 1H), 7.38 (d,
J=8.6 Hz, 2H), 7016 ~ 7.20 (m, 1H), 7.06 (d,
J=8.6 Hz, 2H), 6.79 ~ 6.83 (m, 1H), 6.66 (d,
J=8.1 Hz, 1H), 5.75 (t,
J=2.8 Hz, 1H), 5.38 (d,
J=8.0 Hz, 1H), 5.17 (dd,
J=3.1 Hz,
J=8.0 Hz, 1H), 5.05 ~ 5.09 (m, 1H), 4.43 (dd,
J=2.8 Hz,
J=11.6 Hz, 1H), 4.21 ~ 4.3 (m, 3H), 2.88 ~ 2.98 (m, 1H), 2.43 ~ 2.59 (m, 1H), 2.10 ~ 2.20 (m, 12H); IR (KBr)
ν: 3466,3363,3194,2920,1752,1690,1615,1577,1509,1479,1435,1372,1225,1093,1043,948,911,836,760; HRMS (ESI) calcd for C
30H
34N
4O
11[M+H]
+: 627.2297, found 627.2300; [M+K]
+: 665.1856, found 665.1890.
Instance 9:2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-flavanone (5a) is synthetic
(1) 4-(2,3,4, the 6-benzyloxy-4)-
β-D-Synthesizing of allopyranosid--phenyl aldehyde 3
The helicidum that in the round-bottomed flask of 50mL, adds 7mmol is dissolved in 20mLDMF, under ice bath, stirs also slowly to add 30mmolNaH, stirs after 1 hour, under ice bath stirs, adds 28mmol benzyl bromine, and reaction is used ethyl acetate extraction after finishing, and organic layer is used anhydrous Na
2SO
4Drying is revolved to steam to remove and is desolvated, and (ETHYLE ACETATE: sherwood oil=1:6) separation and purification gets white solid 3 to bullion, productive rate 70% through column chromatography.
(2)
E-4-(2,3,4, the 6-benzyloxy-4)-
β-D-Synthesizing of allopyranosid--styryl-2-hydroxyl benzophenone (2a)
The THF, 3 1mmol, the o-hydroxyacetophenone 1mmol that in the round-bottomed flask of 50mL, add 10mL successively under the stirring at room, drip 10mmolNaOH (40%) aqueous solution, add 10mL ethanol then, stir 12h at 40 ℃.Reaction finishes postcooling to room temperature, with 30% hydrochloric acid adjusting pH to 6, and with ethyl acetate extraction three times, anhydrous Na
2SO
4Drying is revolved to do and is promptly got crude product, and gets yellow solid 2a with V (ethanol): V (ether)=1:4 recrystallization.Productive rate: 70%, m.p. 111-113 ℃;
1H NMR (400MHz, CDCl
3)
δ: 6.93 ~ 7.94 (m, 30H), 5.57 (d,
J=8.0 Hz, 1H), 4.49 ~ 4.91 (m, 8H), 4.24 ~ 4.28 (m, 1H), 4.19 (t,
J=2.4 Hz, 1H), 3.54 ~ 3.84 (m, 4H); IR (KBr)
ν: 3441,3029,2874,1639,1577,1508,1489,1449,1372,1344,1240,1201,1156,1098,1060,1023,978,913,833,743,697,664; HRMS (ESI) calcd for C
49H
46O
8[M+H]
+: 763.3265, found 763.3281; [M+Na]
+: 785.3085, found 785.3107.
(3) 2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-flavanone (5a) is synthetic
In the round-bottomed flask of 100mL, 2a 1.3mmol, anhydrous sodium acetate 13mmol are dissolved in 15mL ethanol, stirring and refluxing 6h, and reaction is revolved ethanol after finishing, and is dissolved in ETHYLE ACETATE, and with water washing 3 times, organic layer is used anhydrous Na
2SO
4Drying is revolved to steam to remove and is desolvated, and (ETHYLE ACETATE: sherwood oil=1:8) separation and purification gets yellow solid 5a to bullion through column chromatography.Productive rate: 65%, m.p. 48-50 ℃;
1H NMR (400MHz, CDCl
3)
δ: 7.90 ~ 7.96 (m, 1H), 7.02 ~ 7.55 (m, 27H), 5.50 ~ 5.57 (m, 1H), 5.42 (dd,
J=2.8 Hz,
J=13.6 Hz, 1H), 4.35 ~ 4.95 (m, 8H), 4.20 ~ 4.27 (m, 1H), 4.18 (t,
J=2.4 Hz, 1H), 3.80 (dd,
J=1.6 Hz,
J=10.8 Hz, 1H), 3.70 (dd,
J=4.8 Hz,
J=9.6 Hz, 1H), 3.52 ~ 3.60 (m, 2H), 3.05 ~ 3.15 (m, 1H), 2.8 ~ 2.9 (m, 1H); IR (NaCl)
ν: 3030,2903,1689,1607,1511,1464,1368,1228,1094,908,828,736; HRMS (ESI) calcd for C
49H
46O
8[M+Na]
+: 785.3085, found 785.3076.
Instance 10:2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-dihydrobenzopyrans-4-methoxyl group amine (5b) is synthetic
Add 5a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add methoxy amine hydrochlorate (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (ETHYLE ACETATE: sherwood oil=1:7) separation and purification gets yellow solid 5b, productive rate: 95%, m.p.44-46 ℃;
1H NMR (400MHz, CDCl
3)
δ: 7.90 ~ 7.98 (m, 1H), 7.09 ~ 7.41 (m, 25H), 6.96 (t,
J=7.8 Hz, 2H), 5.53 (dd,
J=1.6 Hz,
J=7.6 Hz, 1H), 5.02 (dd,
J=2.8 Hz,
J=12.0 Hz, 1H), 4.36 ~ 4.96 (m, 8H), 4.14 ~ 4.26 (m, 2H), 3.99 (s, 3H), 3.79 (d,
J=10.1,1H), 3.69 (dd,
J=4.8 Hz,
J=10.8 Hz, 1H), 3.50 ~ 3.60 (m, 2H), 3.28 ~ 3.45 (m, 1H), 2.60 ~ 2.75 (m, 1H); IR (NaCl)
ν: 3062,3030,2927,1735,1614,1570,1511,1456,1369,1230,1098,918,886,737; HRMS (ESI) calcd for C
50H
49NO
8[M+H]
+: 792.3531, found 792.3541; [M+Na]
+: 814.3350, found 814.3330.
Instance 11:2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-dihydrobenzopyrans-4-azanol (5c) is synthetic
Add 5a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add hydroxylamine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (ETHYLE ACETATE: sherwood oil=1:7) separation and purification gets white solid 5c, productive rate: 90%, 53 ~ 54 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.87 (d,
J=8.4 Hz, 1H), 7.15 ~ 7.45 (m, 23H), 7.12 (d,
J=8.4 Hz, 2H), 6.94 ~ 7.00 (m, 2H), 5.53 (d,
J=8.0 Hz, 1H), 5.05 (dd,
J=2.8 Hz,
J=12.4 Hz, 1H), 4.35 ~ 4.95 (m, 8H), 4.15 ~ 4.28 (m, 2H), 3.80 (d,
J=10.8 Hz, 1H), 3.70 (dd,
J=4.8 Hz,
J=10.4 Hz, 1H), 3.45 ~ 3.60 (m, 3H), 2.75 (dd,
J=12.8 Hz,
J=17.2 Hz, 1H); IR (KBr)
ν: 3432,2918,1629,1511,1456,1312,1115,903,821,733,696; HRMS (ESI) calcd for C
49H
47NO
8[M+Na]
+: 785.3085, found 785.3076.
Instance 12:2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-dihydrobenzopyrans-4-Urea,amino-(5d) is synthetic
Add 5a 2mmol in the round-bottomed flask of 25mL and be dissolved in the ethanol of 10mL, under agitation add carbamylhydrazine hydrochloride (being neutralized into neutrality with dilute NaOH solution before adding) 2mmol then, add back backflow 2h.Revolve after reaction stops and desolvating, be dissolved in ETHYLE ACETATE, use water washing, extraction liquid is used anhydrous Na
2SO
4Drying is revolved steam to remove and is desolvated, bullion through column chromatography (ETHYLE ACETATE: sherwood oil=1:7) separation and purification gets white solid 5d, productive rate: 85%, 88 ~ 89 ℃ of m.p.;
1H NMR (400MHz, CDCl
3)
δ: 7.88 ~ 7.95 (m, 1H), 7.35 ~ 7.40 (m, 23H), 7.09 (d,
J=8.8 Hz, 2H), 6.94 ~ 7.05 (m, 2H), 5.53 (d,
J=8.0 Hz, 1H), 4.95 ~ 5.10 (m, 1H), 4.35 ~ 4.95 (m, 8H), 4.15 ~ 4.25 (m, 2H), 3.81 (d,
J=10.8 Hz, 1H), 3.70 (dd,
J=4.4 Hz,
J=10.8 Hz, 1H), 3.45 ~ 3.60 (m, 2H), 3.10 (t,
J=16.0 Hz, 1H), 2.60 ~ 2.75 (m, 1H); IR (KBr)
ν: 3468,3205,2901,1693,1614,1573,1512,1456,1416,1310,1096,909,826,736; HRMS (ESI) calcd for C
50H
49N
3O
8[M+H]
+: 820.3592, found 820.3609; [M+Na]
+: 842.3412, found 842.3406.
Instance 13: biological activity test
Experimental technique
Get 90 of healthy Kunming mouses, be divided into 15 groups at random by sex, body weight, 6 every group, male and female half and half.Before the administration each group mouse is positioned over respectively in the box of spontaneous activity recording unit, makes its 5min that conforms, then the opening entry time, the numeral that shows on observation and the record 5min charactron is as the control value of spontaneous activity in mice number of times before the administration.After all mouse assay is accomplished, the grouping administration.The every mouse of negative group is irritated stomach and gives 0.05%CMC 0.4ml/20g, and stable group (positive controls) is injected 0.4ml/20g with 0.05% diazepam solution to mouse peritoneal, all the other respectively organize mouse all by join 1.0% suspension give mouse stomach 0.4ml/20g.Each is organized each mouse and is administered once, and 40min, 50min, 60min and 80min after the administration measure the spontaneous activity number of times of respectively organizing mouse 5min with method, and the gained data are carried out statistical treatment with spss.13 software, and the significant difference between comparative group.
The biological activity test result sees table 1.The result shows that 3b-3d, 4b-4d, 5c obviously suppress the spontaneous activity number of times of mouse, relatively have significantly and the highly significant gender gap with control group; Compare with the parent compound helicidum, 4c and 5 further furthers investigate well afoot to have shortened the onset time of medicine.
Table 1 target compound is measured the result to spontaneous activity in mice
Claims (3)
1. 2-(4-
β-D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
H) 1. and 2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-1. and 2. allopyranosid--phenyl)-2, the 3-dihydrobenzopyrans is preparation method and application 2., and its structure is suc as formula,
① ②
Wherein, formula 1. and 2. in R
1Can be hydrogen, ethanoyl; R
2Can for Urea,amino-, azanol, methoxyl group amine.
2. according to claims 1, be the compound method of the compound of representative 1. and 2. with chemical formula, it is characterized in that 1. through helicidum and o-aminoacetophenone Synthetic 2-(4-under the catalysis of L-proline(Pro)
β-D-allopyranosid--phenyl)-2,3-EEDQ-4 (1
H)-ketone, more respectively with ethanoyl, Urea,amino-, azanol, methoxyl group amine is synthetic obtains; 2. through helicidum at first with the benzyl bromine reaction obtain 2-4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl aldehyde, 2-4-(2,3,4, the 6-tetrabenzyl)-
β-D-The Shimdt-Claisen condensation takes place and obtains α in allopyranosid--phenyl aldehyde and adjacent amino-benzene ketone in the sodium hydroxide solution of ethanol and THF; Alpha, beta-unsaturated ketone; Again the Michael addition is taken place in alpha, beta-unsaturated ketone under the catalysis of sodium acetate and 2-(4-(2,3; 4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-dihydrobenzopyrans-4-ketone, last 2-(4-(2,3,4, the 6-tetrabenzyl)-
β-D-Allopyranosid--phenyl)-2,3-dihydrobenzopyrans-4-ketone respectively with Urea,amino-, azanol, methoxyl group amine are synthetic obtains.
3. according to claims 1, The compounds of this invention can be made tablet, pill, granule, capsule and injection or other clinical acceptable suitable dosage forms.
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| CN104974200A (en) * | 2015-04-30 | 2015-10-14 | 苏州晶云药物科技有限公司 | Eutectic crystals of Helicid and L-proline and preparation method thereof |
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| CN104974200A (en) * | 2015-04-30 | 2015-10-14 | 苏州晶云药物科技有限公司 | Eutectic crystals of Helicid and L-proline and preparation method thereof |
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