CN102731429A - 5-arylmethylenethiazolidine-2,4-diketone and synthesis method and application thereof - Google Patents
5-arylmethylenethiazolidine-2,4-diketone and synthesis method and application thereof Download PDFInfo
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Abstract
The invention provides a kind of 5-arylmethylenethiazolidine-2,4-diketones shown by the general formula I, wherein n=1 or 3. Basically all of the 5-arylmethylenethiazolidine-2,4-diketones have the agonist activity of a PPAR (peroxide proliferator-activated receptor); and the relative agonist rate of partial compounds and the existing PPAR (gamma) agonist pioglitazone exceeds 100%. The invention also provides a synthesis method of the compounds; the method has simple technology, mild conditions, low cost and relatively high yield; and the compounds are possibly to be developed into new anti-diabetes medicines, or used as anti-diabetes pilot molecules for further structural optimization.
Description
Technical field
The invention belongs to chemistry and pharmaceutical field, relate to one type of new thiazolidine-2, the 4-cyclohexadione compounds also relates to the compound method of this compounds and the application in pharmacy field.
Background technology
Peroxisome proliferation-activated receptors (PPAR) is the nucleus inner recipient; Be divided into α, β/δ and three kinds of hypotypes of γ; Be activated after part combines; Can combine to form heterodimer with retinoids X acceptor (RXR), the peroxisome proliferation response element (PPRE) with the target gene promoters zone combines again, regulates and control transcribing of target gene.Wherein PPAR α is main relevant with lipid metabolism, is the action target spot of fibrate lipid-lowering medicine; PPAR δ distributes extensively, and effect it be unclear that; PPAR γ has the various biological effect; In sugar metabolism, lipogenesis, adipocyte differentiation, atherosclerosis, Inflammatory response and immunity, play an important role, become the important target of disease therapeuticing medicine screenings such as obesity, mellitus, inflammation, tumour.
Mellitus are a kind of diseases relevant with gene, the chronic metabolism disorders of general such as the relative or definitely not enough sugar that causes, fat, protein owing to Regular Insulin in the body; Mainly be divided into insulin-dependent (1 type; 5%) and non-insulin-depending type (2 types,＞90%).Along with the world population aging, diabetic subject's quantity is soaring rapidly.One of medicine that can more thoroughly improve diabetes B patient body situation at present is an euglycemic agent.Euglycemic agent mainly is divided into: U 25560 (TZD) class and non-TZD class peroxisome proliferation body activated receptor (PPAR γ) agonist, and PPAR α/γ dual agonists.The euglycemic agent of list marketing now only has two kinds: rosiglitazone and pioglitazone are TZD class PPAR gamma agonist.But clinical discovery is taken this two kinds of medicines for a long time, spinoffs such as patient's ubiquity weight increase, edema, the rising of LDL cholesterol levels, and rosiglitazone more has liver toxicity and cardiac toxic.Because most of diabetes B patients are too obese, and often suffer from diabetes hyperlipaemia and coronary heart disease etc., are necessary simultaneously diabetes B patient's blood sugar and lipid to be controlled.Lot of domestic and foreign drugmaker and research institution all drop into the research and development that large quantities of manpower and materials are used for PPAR α/γ dual agonists in recent years; Though there had a plurality of compounds to get into to be clinical; But still do not have a kind of can successfully the listing at present, more have part of compounds the clinical study later stage because of the former of untoward reaction thereby stop research.Therefore, be necessary thiazolidine dione compounds is furtherd investigate and developed, to obtain the antidiabetic medicine of more high-efficiency low-toxicities.
Summary of the invention
In view of this, one of the object of the invention is to provide the thiazolidine dione compounds of one type of novelty, has the PPAR agonist activity, and being expected to exploitation becomes the anti-diabetic new drug, or is used for further composition optimizes as anti-diabetic guide molecule; Two of purpose is to provide the compound method of said thiazolidine dione compounds, and technology is simple, mild condition, with low cost; Three of purpose is to provide the application of said thiazolidine dione compounds in pharmacy field.
After deliberation, the present invention provides following technical scheme:
1. general formula is suc as formula the 5-aryl methylene thiazolidine-2 shown in the I, the 4-diketone:
In the formula,
N=1 or 3.
Further,
N=1 or 3.
Further,
2. said 5-aryl methylene thiazolidine-2; The compound method of 4-diketone is with aromatic formaldehyde shown in the general formula I I, thiazolidine-2, after 4-diketone and sodium acetate, anhydrous mixed grinding are extremely Powdered; The oil bath reacting by heating; Stopped reaction during completely solidified again to solid material fusing promptly generates the aryl methylene of 5-shown in general formula I thiazolidine-2, the 4-diketone; Reaction formula is following:
Among the general formula I I substituent X have with general formula I in the identical definition of substituent X.
Further, said oil bath reacting by heating is 120～140 ℃ of reacting by heating of oil bath.
Aromatic formaldehyde can be buied from the commercial channel shown in the general formula I I, or synthetic according to following method:
Can be that solvent, salt of wormwood are that reacting by heating makes under the condition of acid binding agent at acetonitrile with 3-hydroxy benzaldehyde, 4-hydroxy benzaldehyde or 4-hydroxy 3-methoxybenzene formaldehyde and ethylene bromohyrin.
Can be that solvent, salt of wormwood are that reacting by heating makes under the condition of acid binding agent at acetonitrile with 2-hydroxy benzaldehyde, 3-hydroxy benzaldehyde, 4-hydroxy benzaldehyde or 4-hydroxy 3-methoxybenzene formaldehyde and monobromethane or 1-NBB.
3. said 5-aryl methylene thiazolidine-2, the application of 4-diketone in preparation peroxisome proliferation-activated receptors agonist.
Beneficial effect of the present invention is: the invention provides the novel 5-aryl methylene thiazolidine-2 of a class formation; The 4-diketone is (corresponding to synthetic new compound TM-7-5 among the specification sheets embodiment 2-5, TM-8-4, TM-8-5, TM-9-2～TM-9-4, TM-10-1～TM-10-8); These compounds basically all have the PPAR agonist activity, and wherein part of compounds (TM-9-3 and TM-10-3) surpasses 100% with the exciting relatively rate of existing PPAR gamma agonist pioglitazone; The present invention also provides the compound method of these new compounds, technology is simple, mild condition, with low cost, yield is higher; These compounds might be developed becomes the anti-diabetic new drug, or is used for further composition optimizes as anti-diabetic guide molecule.
Embodiment
In order to make the object of the invention, technical scheme and advantage clearer, carry out detailed description in the face of the preferred embodiments of the present invention down.
Key instrument used in the preferred embodiment is following: accurate micro melting point apparatus (X-6, Beijing Fu Kai Instr Ltd.); Fourier transformation infrared spectrometer (GX, Perkin Elmer, USA); NMR spectrometer with superconducting magnet (AV-300, Bruker, USA); High-resolution mass spectrometer (HRFTIC-MS Varian 7.0, Varian, USA).
Embodiment 1, thiazolidine-2,4-diketone synthetic
In reaction flask, add Mono Chloro Acetic Acid, thiocarbamide and concentrated hydrochloric acid (three's amount ratio is 1mol: 1.1mol: 250ml), reflux 3 hours, the cooling and stirring crystallization filters, crystal use water washing, must 2-imino--4-thiazolone hydrochloride; In crystal, add suitable quantity of water and a certain amount of gac again, reflux m hour, filtered while hot, filtrating cooling and stirring crystallization filters, and crystal is used water washing, and drying promptly gets thiazolidine-2, the 4-diketone.The compound experiment result sees table 1.
Table 1 thiazolidine-2,4-diketone compound experiment result
Thiazolidine-2,4-diketone: white crystal; IR (KBr, cm
-1): 3134 (s, v
NH), 3047 (s, v
=CH), 2949,2825 (s, v
CH2), 1739 (s, v
C=O), 1655 (s, v
C=O), 618.0 (m, v
C-S);
1H NMR (300MHz, CDCl
3, ppm): δ 4.14 (s, 2H, CH
2), 12.02 (bs, 1H, NH).
Can find out return time and whether add the key factor that gac is decision reaction success or failure during recrystallization from table 1.Only refluxed during recrystallization 0.5 hour, and no matter whether added gac, finally all can not obtain thiazolidine-2; The 4-diketone prolongs return time to 12 hour but does not add gac, still can not get thiazolidine-2; The 4-diketone explains that gac is indispensable condition in recrystallization process, the hydrogenchloride that produces in the system that possibly be charcoal absorption; Impel midbody 2-imino--4-thiazolone hydrochloride to thiazolidine-2, the 4-diketone transforms.
Synthetic (the solid phase condensation method) of embodiment 2, target compound TM-7
In mortar, add aldehyde, thiazolidine-2,4-diketone and sodium acetate, anhydrous (three's mol ratio is 1.1: 1.0: 1.0) after mixed grinding is extremely Powdered, change in the reaction flask; 125 ℃ of reactions of oil bath, visible solid material melts retrogradation immediately, stopped reaction when treating completion of cure rapidly; Add an amount of N (DMF) while hot solid is dissolved fully, add elutriation again and go out a large amount of solids, regulate pH5～6 with 2NHCl, stirring at room left standstill in 4 ℃ after 30 minutes; Suction filtration, filter cake is used water washing, and 100 ℃ of dryings disperse to spend the night with ether-ETHYLE ACETATE (volume ratio 2: 1) mixed solvent; Suction filtration, drying promptly gets target compound TM-7.The compound experiment result sees table 2.
The compound experiment result of table 2 target compound TM-7
Through retrieval, target compound TM-7 series is the new compound except TM-7-5, and all the other 36 compounds are known compound.All new compounds through IR,
1H NMR,
13Modern wave spectrum means conclusive evidence such as C NMR and HRMS, the structure of known compound is through conclusive evidences such as fusing point test and IR signs.Concrete data are following:
TM-7-1 5-(4-oil of mirbane methylene radical) thiazolidine-2,4-diketone: khaki color solid; M.p.277.1-278.3 ℃; IR (KBr, cm
-1): 3200 (v
NH), 3050 (v
=CH), 1753,1714 (v
C=O), 1677,1594,1492 (v
C=C), 1536,1348 (v
NO2).
TM-7-2 5-(3-oil of mirbane methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.214.8-216.5 ℃; IR (KBr, cm
-1): 3414 (v
NH), 3 160 (v
=CH), 1744,1699 (v
C=O), 1607,1532,1492 (v
C=C), 1324 (v
NO2).
TM-7-3 5-(2-oil of mirbane methylene radical) thiazolidine-2,4-diketone: purple grape solid; M.p.255.8-257.6 ℃; IR (KBr, cm
-1): 3358 (v
NH), 3165 (v
=CH), 1724,1689 (v
C=O), 1658,1607,1519,1459 (v
C=C), 1344 (v
NO2).
TM-7-4 5-(4-cyanic acid Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid; M.p.290.1-293.2 ℃; IR (KBr, cm
-1): 3446 (v
NH), 3066 (v
=CH), 2229 (v
C ≡ N), 1694,1613 (v
C=O), 1573,1503 (v
C=C).
TM-7-5 5-(3-cyanic acid Ben Yajiaji) thiazolidine-2,4-diketone: light yellow solid; M.p.279.9-281.1 ℃; IR (KBr, cm
-1): 3450 (v
NH), 3072 (v
=CH), 2234 (v
C ≡ N), 1742,1689 (v
C=O), 1634 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 7.70 (t, 1H, J=8.1Hz, Ar-H), 7.79 (s, 1H, Ar-H), 7.84 (d, 1H, J=8.1Hz, Ar-H), 7.90 (d, 1H, J=7.5 Hz, Ar-H), 8.04 (s, 1H ,=CH), 12.73 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 112.7,118.7, and 126.6,129.8,130.9,133.7,134.2,134.7,167.4,167.8; HRMS:C
11H
6N
2O
2S [M-H]
-Calculated value 229.0077, measured value 229.0075.
TM-7-6 5-(4-fluorobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.227.1-229.2 ℃; IR (KBr, cm
-1): 3448 (v
NH), 3047 (v
=CH), 1752,1697 (v
C=O), 1649,1594,1458 (v
C=C).
TM-7-7 5-(3-fluorobenzene methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.179.5-181.5 ℃; IR (KBr, cm
-1): 3446 (v
NH), 3151,3023 (v
=CH), 1747,1695 (v
C=O), 1634,1575,1486 (v
C=C).
TM-7-8 5-(2-fluorobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.226.4-227.5 ℃; IR (KBr, cm
-1): 3450 (v
NH), 3149,3040 (v
=CH), 1736,1687 (v
C=O), 1629,1573,1482 (v
C=C).
TM-7-9 5-(4-trifluoromethyl Ben Yajiaji) thiazolidine-2,4-diketone: white solid; M.p.219.8-221.3 ℃; IR (KBr, cm
-1): 3452 (v
NH), 3203 (v
=CH), 1749,1714 (v
C=O), 1676,1606,1410 (v
C=C), 1317 (v
CF3).
TM-7-10 5-(3-trifluoromethyl Ben Yajiaji) thiazolidine-2,4-diketone: faint yellow solid; M.p.187.1-189.3 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3213 (v
=CH), 1745,1710 (v
C=O), 1606,1431, (v
C=C), 1339 (v
CF3).
TM-7-11 5-(2-trifluoromethyl Ben Yajiaji) thiazolidine-2,4-diketone: white solid; M.p.191.7-192.8 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3154 (v
=CH), 1744,1702 (v
C=O), 1615,1575 (v
C=C), 1317 (v
CF3).
TM-7-12 5-(4-bromobenzene methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.237.5-239.8 ℃; IR (KBr, cm
-1): 3450 (v
NH), 3050 (v
=CH), 1748,1719 (v
C=O), 1610,1579,1483 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 7.62 (d, 2H, J=8.2 Hz, Ar-H), 7.79 (d, 2H, J=8.2Hz, Ar-H), 8.05 (s, 1H ,=CH), 12.63 (s, 1H, NH).
TM-7-13 5-(3-bromobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.201.4-204.0 ℃; IR (KBr, cm
-1): 3447 (v
NH), 3054 (v
=CH), 1744,1673 (v
C=O), 1611,1554,1472 (v
C=C).
TM-7-14 5-(2-bromobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.199.2-200.1 ℃; IR (KBr, cm
-1): 345 1 (v
NH), 3049 (v
=CH), 1740,1699 (v
C=O), 1619,1604 (v
C=C).
TM-7-15 5-(3-bromo-4-fluorobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.231.1-233.6 ℃; IR (KBr, cm
-1): 3450 (v
NH), 3062 (v
=CH), 1739,1713 (v
C=O), 1697,1590,1457 (v
C=C), 1321 (v
CF);
1HNMR (300MHz, DMSO-d
6, ppm): δ 7.51-7.57 (m, 1H, Ar-H), 7.60-7.65 (m, 1H, Ar-H), 7.74 (s, 1H ,=CH), 7.95-7.98 (m, 1H, Ar-H), 12.67 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 109.3,117.8, and 126.5,128.7,130.9,132.1,135.6,160.7,168.6,169.0.
TM-7-16 5-(2-chloro-4-fluorobenzene methylene radical) thiazolidine-2,4-diketone: faint yellow solid; M.p.219.0-221.9 ℃; IR (KBr, cm
-1): 3448 (v
NH), 3147,3053 (v
=CH), 1742,1733 (v
C=O), 1680,1573 (v
C=C), 1396 (v
CF);
1HNMR (300MHz, DMSO-d
6, ppm): δ 7.39-7.44 (m, 1H, Ar-H), 7.59-7.70 (m, 2H, Ar-H), 7.83 (s, 1H ,=CH), 12.75 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d
6, ppm): δ 116.0,118.1, and 118.5,125.5,128.3,131.0,136.2,161.0,168.3,168.4.
TM-7-17 5-(4-chlorobenzene methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.266.3-268.4 ℃; IR (KBr, cm
-1): 3451 (v
NH), 3053 (v
=CH), 1753,1721 (v
C=O), 1611,1587,1487 (v
C=C).
TM-7-18 5-(3-chlorobenzene methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.234.1-236.3 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3053 (v
=CH), 1747,1674 (v
C=O), 1618,1559,1473 (v
C=C).
TM-7-19 5-(2-chlorobenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.204.2-205.5 ℃; IR (KBr, cm
-1): 3452 (v
NH), 3054 (v
=CH), 1736,1713 (v
C=O), 1681,1606 (v
C=C).
TM-7-20 5-(2,4 dichloro benzene methylene radical) thiazolidine-2,4-diketone: faint yellow solid; M.p.223.1-224.3 ℃; IR (KBr, cm
-1): 3451 (v
NH), 3022 (v
=CH), 1754,1708 (v
C=O), 1635,1579,1468 (v
C=C).
TM-7-21 5-(2,3-dichlorobenzene methylene radical) thiazolidine-2,4-diketone: light yellow solid; M.p.230.1-232.2 ℃; IR (KBr, cm
-1): 3451 (v
NH), 3049 (v
=CH), 1747,1735 (v
C=O), 1682,1556 (v
C=C).
TM-7-22 5-(2,6-dichlorobenzene methylene radical) thiazolidine-2,4-diketone: light yellow solid; M.p.165.4-166.2 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3049 (v
=CH), 1745,1697 (v
C=O), 1650,1576 (v
C=C).
TM-7-23 5-(3,4-dichlorobenzene methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.230.8-232.3 ℃; IR (KBr, cm
-1): 3451 (v
NH), 3052 (v
=CH), 1747,1725 (v
C=O), 1611,1592,1491 (v
C=C).
TM-7-24 5-Ben Yajiaji thiazolidine-2,4-diketone: white solid; M.p.257.2-258.9 ℃; IR (KBr, cm
-1): 3413 (v
NH), 3138,3032 (v
=CH), 1739,1689 (v
C=O), 1610,1595,1492 (v
C=C).
TM-7-25 5-(4-methylbenzene methylene radical) thiazolidine-2,4-diketone: light yellow solid; M.p.234.8-236.1 ℃; IR (KBr, cm
-1): 3164 (v
NH), 3051 (v
=CH), 1735,1687 (v
C=O), 1599,15 11 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 7.27 (d, 2H, J=8.0Hz, Ar-H), 7.49 (d, 2H, J=8.1Hz, Ar-H), 7.83 (s, 1H ,=CH), 12.43 (s, 1H, NH).
TM-7-26 5-(3-methylbenzene methylene radical) thiazolidine-2,4-diketone: white solid; M.p.185.4-186.8 ℃; IR (KBr, cm
-1): 3149 (v
NH), 3040 (v
=CH), 1739,1689 (v
C=O), 1605,1577 (v
C=C).
TM-7-27 5-(4-phenol methylene) thiazolidine-2,4-diketone: yellow solid; M.p.297.7-299.5 ℃; IR (KBr, cm
-1): 3427 (v
OH), 3404 (v
NH), 3001 (v
=CH), 1768,1680, (v
C=O), 1593,1574,1510 (v
C=C).
TM-7-28 5-(3-phenol methylene) thiazolidine-2,4-diketone: blush solid; M.p.279.7-281.4 ℃; IR (KBr, cm
-1): 3446 (v
OH, v
NH), 3070 (v
=CH), 1751,1692, (v
C=O), 1638,15931 (v
C=C).
TM-7-29 5-(2-phenol methylene) thiazolidine-2,4-diketone: yellow solid; M.p.285.1-286.9 ℃; IR (KBr, cm
-1): 3428 (v
OH, v
NH), 3037 (v
=CH), 1726,1674 (v
C=O), 1594,1457 (v
C=C).
TM-7-30 5-(4-anisole methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.307.2-309.1 ℃; IR (KBr, cm
-1): 3415 (v
NH), 3095 (v
=CH), 2855 (v
CH3), 1732,1695 (v
C=O), 1638,1590,1510 (v
C=C).
TM-7-31 5-(3-anisole methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.210.5-212.2 ℃; IR (KBr, cm
-1): 3414 (v
NH), 3153 (v
=CH), 2955 (v
CH3), 1733,1683 (v
C=O), 1636,1605 (v
C=C).
TM-7-32 5-(2-anisole methylene radical) thiazolidine-2,4-diketone: yellow-green colour solid; M.p.247.1-248.9 ℃; IR (KBr, cm
-1): 3414 (v
NH), 3032 (v
=CH), 2841 (v
CH3), 1740,1678 (v
C=O), 1637,1543,1486 (v
C=C).
TM-7-33 5-(2,4-dimethoxy Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid; M.p.261.0-263.0 ℃; IR (KBr, cm
-1): 3415 (v
NH), 3009 (v
=CH), 2841 (v
CH3), 1728,1695 (v
C=O), 1637,1580,1462 (v
C=C).
TM-7-34 5-(2,5-dimethoxy Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid; M.p.285.8-287.6 ℃; IR (KBr, cm
-1): 3413 (v
NH), 3126 (v
=CH), 2835 (v
CH3), 1765,1679 (v
C=O), 1638,1591,1469 (v
C=C).
TM-7-35 5-(3,4-dimethoxy Ben Yajiaji) thiazolidine-2,4-diketone: glassy yellow solid; M.p.237.9-239.0 ℃; IR (KBr, cm
-1): 3413 (v
NH), 3226 (v
=CH), 2842 (v
CH3), 1744,1706 (v
C=O), 1637,1592,1466 (v
C=C).
TM-7-36 5-(3,4,5-trimethoxy Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid; M.p.197.5-199.1 ℃; IR (KBr, cm
-1): 3414 (v
NH), 3208 (v
=CH), 2993 (v
CH3), 1748,1699 (v
C=O), 1636,1607,1580 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 3.75 (s, 3H, CH
3O), 3.85 (s, 6H, 2CH
3O), 6.96 (s, 2H, Ar-H), 7.77 (s, 1H ,=CH), 12.64 (s, 1H, NH).
TM-7-37 5-(3-methoxyl group-4-phenol methylene) thiazolidine-2,4-diketone: yellow solid; M.p.235.1-236.5 ℃; IR (KBr, cm
-1): 3460 (v
OH, v
NH), 3036 (v
=CH), 1735,1677 (v
C=O), 1601,1577,1471 (v
C=C);
1HNMR (300MHz, DMSO-d
6, ppm): δ 3.80 (s, 3H, OCH
3), 6.91 (d, 1H, J=8.1Hz, Ar-H), 7.05 (d, 1H, J=8.4Hz, Ar-H), 7.16 (s, 1H, Ar-H), 7.70 (s, 1H ,=CH), 9.95 (s, 1H, ArOH), 12.5 (s, 1H, N-H);
13C NMR (75MHz, DMSO-d
6, ppm) δ 56.0,114.5, and 116.6,119.6,124.6,124.8,133.0,148.4,149.8,167.8,168.5.
Aromatic aldehyde or heterocyclic aldehydes and thiazolidine-2, the Knoevenagel reaction takes place in the active methylene radical of 4-diketone, generates 5-virtue (heterocycle) methylene radical thiazolidine-2, the 4-diketone.The common methods of Knoevenagel reaction has two kinds, and a kind of is the liquid phase condensation method, is about to reactant and is dissolved in organic solvent such as ethanol, the toluene etc., adds catalyzer such as piperidines or pyridine, with the water that produces in the water trap separating reaction, promotes the carrying out of reaction; Another kind is the solid phase condensation method, is about to reactant and sodium acetate porphyrize mixing, heat reaction in the oil bath.Because the solid phase condensation method has short, advantage such as aftertreatment is easy of reaction times, and product purity can reach industrial requirement, therefore, and the preferred solid phase condensation method of the present invention.Can find out from table 2, adopt the solid phase condensation method can successfully synthesize above-mentioned TM-7 series compound, product yield between medium extremely good between, only a few compound yield is on the low side (TM-7-3, TM-7-9 and TM-7-13).What deserves to be mentioned is that general solid phase condensation method only is suitable for synthetic in a small amount, and this experiment is scalable to tens of gram level levels, it is synthetic to help the product mass-producing, thereby has enlarged the range of application of solid phase condensation method.
Embodiment 3, target compound TM-8's is synthetic
1, solid phase condensation method
In mortar, add aldehyde, thiazolidine-2,4-diketone and sodium acetate, anhydrous (three's mol ratio is 1.1: 1.0: 1.0) after mixed grinding is extremely Powdered, change in the reaction flask; 125 ℃ of reactions of oil bath, visible solid material melts retrogradation immediately, stopped reaction when treating completion of cure rapidly; Add an amount of DMF while hot solid is dissolved fully, add elutriation again and go out a large amount of solids, regulate pH 5～6 with 2NHCl, stirring at room left standstill in 4 ℃ after 30 minutes; Suction filtration, filter cake is used water washing, and 100 ℃ of dryings disperse to spend the night with ether-ETHYLE ACETATE (volume ratio 2: 1) mixed solvent; Suction filtration, drying promptly gets target compound TM-8.The compound experiment result sees table 3.
2, liquid phase condensation method
In reaction flask, add aldehyde 1mmol and EtOH 5mL, add piperidinyl-1 .2mmol and thiazolidine-2,4-diketone 1mmol under the stirring at room; Be heated to boiling and make most of thiazolidine-2, the dissolving of 4-diketone, 80 ℃ of back flow reaction then; Tlc monitoring reaction process is to reacting completely, and cooling is filtered; Filter cake is water, methanol wash successively, drying, DMF/H
2The O recrystallization promptly gets target compound TM-8.The compound experiment result sees table 3.
The compound experiment result of table 3 target compound TM-8
Band * compound adopts the liquid phase condensation method synthetic, and the surplus compound of tool adopts the solid phase condensation method synthetic.
Through retrieval, target compound TM-8 series is the new compound except TM-8-4 and TM-8-5, and all the other 7 compounds are known compound.All new compounds through IR,
1H NMR,
13Modern wave spectrum means conclusive evidence such as C NMR and HRMS, the structure of known compound is through conclusive evidences such as fusing point test and IR signs.Concrete data are following:
TM-8-1 5-(thiophene-2-methylene radical) thiazolidine-2,4-diketone: khaki color solid; M.p.262.8-264.5 ℃; IR (KBr, cm
-1): 3414 (v
NH), 3122 (v
=CH), 1769,1685 (v
C=O), 1618,1595 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 7.28-7.31 (m, 1H, SCH=CHCH=C), 7.68 (d, 1H, J=3.3Hz, SCH=CHCH=C), 8.01 (d, 1H, J=4.9Hz, SCH=CHCH=C), 8.07 (s, 1H ,=CH), 12.57 (s, 1H, NH).
TM-8-2 5-(furans-2-methylene radical) thiazolidine-2,4-diketone: white solid; M.p.258.6-260.7 ℃; IR (KBr, cm
-1): 3413 (v
NH), 3033 (v
=CH), 1778,1683 (v
C=O), 1612,1544,1469 (v
C=C);
1H NMR (300 MHz, DMSO-d
6, ppm): δ 6.75-6.77 (m, 1H, OCH=CHCH=C), 7.15 (d, 1H, J=3.3 Hz, OCH=CHCH=C), 7.76 (d, 1H, J=4.9 Hz, OCH=CHCH=C), 8.08 (s, 1H ,=CH), 12.34 (s, 1H, NH).
TM-8-3 5-(1H-indoles-3-methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.312.4-315.7 ℃; IR (KBr, cm
-1): 3414,3225 (v
NH), 3114 (v
=CH), 1721,1693 (v
C=O), 1617,1576,1460 (v
C=C);
1H NMR (300MHz, DMSO-d
6, ppm): δ 7.17-7.28 (m, 2H, Ar-H), 7.51 (d, 1H, J=7.5 Hz, Ar-H), 7.75 (d, 1H, J=3.0Hz, pyrro1e-H), 7.89 (d, 1H, J=7.5 Hz, Ar-H), 8.06 (s, 1H ,=CH), 12.14 (s, 1H, NH), 12.32 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 110.9,112.8, and 116.6,118.7,121.5,123.5,124.9,127.2,129.1,136.6,167.7,168.1.
TM-8-4 5-(anthracene-9-methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.288.1-289.5 ℃; IR (KBr, cm
-1): 3450 (v
NH), 3054 (v
=CH), 1740,1703 (v
C=O), 1625,1556 (v
C=C);
1H NMR (300 MHz, DMSO-d
6, ppm): δ 7.58-7.66 (m, 4H, Ar-H), 8.05 (d, 2H, J=7.2 Hz, Ar-H), 8.19 (d, 2H, J=8.7Hz, Ar-H), 8.64 (s, 1H ,=CH), 8.76 (s, 1H, Ar-H), 12.67 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 125.5,126.2, and 127.4,127.9,128.3,129.3,129.5,130.5,131.1,133.0,166.5,168.2; HRMS:C
18H
11NO
2S [M-H]-calculated value 304.0438, measured value 304.0445.
TM-8-5 5-(6-methoxyl group-2-naphthyl methylene) thiazolidine-2,4-diketone: yellow solid; M.p.267.2-268.9 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3057 (v
=CH), 2946 (v
CH3), 1742,1688 (v
C=O), 1674,1594,1458 (v
C=C);
1HNMR (300 MHz, DMSO-d
6, ppm): δ 3.90 (s, 3H, OCH
3), 7.39 (s, 1H, Ar-H), 7.24 (d, 1H, J=9.0Hz, Ar-H), 7.63 (d, 1H, J=8.4 Hz, Ar-H), 7.89 (s, 1H, Ar-H), 7.93-7.97 (m, 2H, Ar-H), 8.11 (s, 1H ,=CH), 12.54 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d
6, ppm): δ 55.8,106.7, and 120.1,127.0,128.1,128.6,130.8,131.1,135.2,159.3,168.8,168.9; HRMS:C
15H
11NO
3S [M-H]
-Calculated value 284.0387, measured value 284.0385.
TM-8-6 5-(pyridine-4-methylene radical) thiazolidine-2,4-diketone: little yellow solid; M.p.320.2-322.4 ℃; IR (KBr, cm
-1): 3445 (v
NH), 3086 (v
=CH), 1743,1695 (v
C=O), 1601 (v
C=C).
TM-8-7 5-(pyridine-3-methylene radical) thiazolidine-2,4-diketone: white solid; M.p.307.2-309.8 ℃; IR (KBr, cm
-1): 3442 (v
NH), 3069 (v
=CH), 1776,1714 (v
C=O), 1612,1589,1478 (v
C=C).
TM-8-8 5-(pyridine-2-methylene radical) thiazolidine-2,4-diketone: coffee-like solid; M.p.298.0-301.5 ℃; IR (KBr, cm
-1): 3447 (v
NH), 3043 (v
=CH), 1740,1680 (v
C=O), 1618,1580,1471 (v
C=C).
TM-8-9 5-(benzo [d] [1,3] dioxy-5-methylene radical) thiazolidine-2,4-diketone: yellow solid; M.p.263.4-265.2 ℃; IR (KBr, cm
-1): 3449 (v
NH), 3015 (v
=CH), 2917 (v
CH2), 2794,2744 (v
OCH2O), 1737,1680 (v
C=O), 1588,1498 (v
C=C).
The solid phase condensation method requires the fusing point of raw material can not be too high, must with the fusing point coupling of fusing assistant, to guarantee to form molten state when the not too high temperature, be beneficial to accomplish in the short period reaction.For the condensation reaction that above-mentioned aldehyde is participated in, it is synthetic whether to be suitable for the solid phase condensation method, depends primarily on the fusing point of aldehyde, synthetic like the too high solid phase condensation method of then should not using of the fusing point of aldehyde.Physical properties through consulting aldehyde finds, the aldehyde in the table 3 is except that 195 ℃ of the fusing points of indole-3-formaldehyde are higher, and the fusing point of all the other aldehyde is all less than 120 ℃; So in building-up process, indole-3-formaldehyde and thiazolidine-2, the liquid phase condensation method is adopted in the condensation of 4-diketone; All the other aldehyde and thiazolidine-2, the solid phase condensation method is adopted in the condensation of 4-diketone, and product yield is compared with (replacement) phenyl aldehyde series of embodiment 2; Though slightly reduce, overall variation is little.Adopt the solid phase condensation method to realize heterocyclic aldehydes and thiazolidine-2, bibliographical information is not seen in the Knoevenagel reaction of 4-diketone at present as yet.
Embodiment 4, target compound TM-9's is synthetic
1, intermediate compound I M-9's is synthetic
In reaction flask, add aldehyde 10mmol and acetonitrile 10mL, stir and make whole dissolvings, add salt of wormwood 12.5mmol; Stirring at room 30 minutes adds ethylene bromohyrin 20mmol, 85 ℃ of stirring reactions of oil bath; Tlc monitoring reaction process is to reacting completely, and suction filtration distills concentrated; Separate out solid after column chromatography purification or the placement and carry out recrystallization again, drying promptly gets intermediate compound I M-9.The compound experiment result sees table 4.
The compound experiment result of table 4 intermediate compound I M-9
Band * compound obtains pure article through recrystallization, and all the other compounds obtain pure article with column chromatography purification.
2, synthetic (the solid phase condensation method) of target compound TM-9
In reaction flask, add intermediate compound I M-9 Q mmol, thiazolidine-2,4-diketone and sodium acetate, anhydrous (three's mol ratio is 8: 9: 10), 125 ℃ of reactions of oil bath, visible solid material melts rapidly; Retrogradation immediately, stopped reaction when treating completion of cure adds an amount of DMF while hot solid is dissolved fully, adds elutriation again and goes out a large amount of solids; Regulate pH 5～6 with 2NHCl, stirring at room left standstill 10 minutes in 4 ℃ after 1 hour, suction filtration, and filter cake is used water washing; 100 ℃ of dryings are transferred in the reaction flask, disperse to spend the night with ether-ETHYLE ACETATE (volume ratio 1: 1) mixed solvent; Suction filtration, drying promptly gets target compound TM-9.The compound experiment result sees table 5.
The compound experiment result of table 5 target compound TM-9
Through retrieval, target compound TM-9 series is the known compound except TM-9-1, and all the other 3 compounds are new compound.The All new compounds warp
1H NMR,
13Modern wave spectrum means conclusive evidence such as C NMR and HRMS, the structure warp of known compound
1H NMR conclusive evidence.Concrete data are following:
TM-9-1 (5-(2-(2-hydroxyl-oxethyl)-Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 3.77 (t, 2H, J=6.0 Hz, HOCH
2), 4.12 (t, 2H, J=6.0 Hz, OCH
2), 4.96 (bs, 1H, OH), 7.09-7.16 (m, 2H, Ar-H), 7.41-7.46 (m, 2H, Ar-H), 8.01 (s, 1H ,=CH), 12.57 (s, 1H, NH).
TM-9-2 5-(3-(2-hydroxyl-oxethyl) Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 3.74 (m, 2H, HOCH
2), 4.03 (t, 2H, J=5.1 Hz, OCH
2), 4.94 (bs, 1H, OH), 7.06-7.16 (m, 3H, Ar-H), 7.41-7.47 (s, 1H, Ar-H), 7.77 (s, 1H ,=CH), 12.65 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 59.9,70.1, and 116.2,117.2,122.4,124.3,130.8,132.2,134.8,159.5,167.7,168.3; HRMS:C
12H
11NO
4S [M-H]
-Calculated value 264.0336, measured value 264.0335.
TM-9-3 5-(4-(2-hydroxyl-oxethyl) Ben Yajiaji) thiazolidine-2,4-diketone: coffee-like solid;
1H NMR (300MHz, DMSO-d
6, ppm) δ 3.73 (t, 2H, HOCH
2), 4.06 (t, 2H, J=5.1 Hz, OCH
2), 4.95 (bs, 1H, OH), 7.09-7.12 (d, 2H, J=8.7 Hz, Ar-H), 7.54-7.57 (d, 2H, J=8.1 Hz,, Ar-H), 7.76 (s, 1H ,=CH), 12.54 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 59.8,70.3, and 115.8,120.6,125.8,132.2,132.5,160.8,167.9,168.5; HRMS:C
12H
11NO
4S [M-H]
-Calculated value 264.0336, measured value 264.0332.
TM-9-4 5-(4-(2-hydroxyl-oxethyl)-3-anisole methylene radical) thiazolidine-2,4-diketone: golden yellow solid;
1HNMR (300MHz, DMSO-d
6, ppm): δ 3.74 (t, 2H, J=6.0Hz, HOCH
2), 3.81 (s, 3H, OCH
3), 4.03 (t, 2H, J=6.0Hz, OCH
2), 4.93 (bs, 1H, OH), 7.14-7.19 (m, 3H, Ar-H), 7.74 (s, 1H ,=CH), 12.56 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 55.8,59.8, and 70.6,113.3,113.8,121.1,124.1,126.1,132.3,149.4,150.6,168.3,168.6; HRMS:C
13H
13NO
5S [M-H]
-Calculated value 294.0442, measured value 294.0440.
Embodiment 5, target compound TM-10's is synthetic
1, intermediate compound I M-10's is synthetic
In reaction flask, add aldehyde 10mmol and acetonitrile 5mL, stir and make whole dissolvings, add salt of wormwood 20mmol; Stirring at room 20 minutes adds bromoalkane 20mmol, 45 ℃ of stirring reactions of oil bath; Tlc monitoring reaction process is to reacting completely, suction filtration, and the filtrating distillation concentrates; Separate out solid after column chromatography purification or the placement and carry out recrystallization again, drying promptly gets intermediate compound I M-10.The compound experiment result sees table 6.
The compound experiment result of table 6 intermediate compound I M-10
Band * compound obtains pure article with column chromatography purification, and all the other compounds obtain pure article through recrystallization.
2, synthetic (the solid phase condensation method) of target compound TM-10
In reaction flask, add intermediate compound I M-10 Q mmol, thiazolidine-2,4-diketone and sodium acetate, anhydrous (three's mol ratio is 1.1: 1.0: 1.0), 125 ℃ of reactions of oil bath, visible solid material melts rapidly; Retrogradation immediately, stopped reaction when treating completion of cure adds an amount of DMF while hot solid is dissolved fully, adds elutriation again and goes out a large amount of solids; Regulate pH 5～6 with 2NHCl, stirring at room left standstill 10 minutes in 4 ℃ after 30 minutes, suction filtration, and filter cake is used water washing; 100 ℃ of dryings are transferred in the reaction flask, disperse to spend the night with ether-ETHYLE ACETATE (volume ratio 2: 1) mixed solvent; Suction filtration, drying promptly gets target compound TM-10.The compound experiment result sees table 7.
The compound experiment result of table 7 target compound TM-10
Through retrieval, target compound TM-10 series all is new compound, its structure warp
1H NMR,
13Modern wave spectrum means conclusive evidence such as C NMR and HRMS.Concrete data are following:
TM-10-1 5-(2-phenetole methylene radical) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, MDSO-d
6, ppm): δ 1.39 (t, 3H, J=6.9Hz, CH
3), 4.15 (m, 2H, OCH
2), 7.08-7.46 (m, 4H, Ar-H), 8.00 (s, 1H ,=CH), 12.58 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d
6, ppm): δ 14.9,64.4, and 113.0,121.2,122.0,123.7,126.8,128.8,132.8,157.8,167.8,168.5; HRMS:C
12H
11NO
3S [M-H]
-Calculated value 248.0387, measured value 248.0385.
TM-10-2 5-(3-phenetole methylene radical) thiazolidine-2,4-diketone: white solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 1.37 (t, 3H, J=6.9Hz, CH
3), 1.46 (m, 2H, OCH
2), 7.05-7.48 (m, 4H, Ar-H), 7.78 (s, 1H ,=CH), 12.52 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 14.9,64.0, and 116.1,117.1,122.3,124.2,130.8,132.2,134.8,159.3,137.7,168.2; HRMS:C
12H
11NO
3S [M-H]
-Calculated value 248.0387, measured value 248.0384.
TM-10-3 5-(4-phenetole methylene radical) thiazolidine-2,4-diketone: coffee-like solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 1.35 (t, 3H, J=6.9 Hz, CH
3), 1.41 (m, 2H, J=7.2 Hz OCH
2), 7.08 (d, 2H, J=8.7Hz, Ar-H), 7.54 (d, 2H, J=9.0Hz, Ar-H), 7.75 (s, 1H ,=CH), 12.51 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 14.9,64.0, and 115.7,120.5,125.8,132.3,132.6,160.7,167.9,168.4; HRMS:C
12H
11NO
3S [M-H]
-Calculated value 248.0387, measured value 248.0384.
TM-10-4 5-(4-oxyethyl group-3-anisole methylene radical) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 1.36 (t, 3H, J=6.9Hz, CH
3), 3.83 (s, 3H, OCH
3), 4.10 (q, 2H, J=6.9Hz, OCH
2), 7.13-7.20 (m, 3H, Ar-H), 7.76 (s, 1H ,=CH), 12.53 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d
6, ppm): δ 15.0,55.9, and 64.319,113.2,113.8,120.7,124.1,125.95,132.7,149.4,150.5,167.8,168.4; HRMS:C
13H
13NO
4S [M-H]
-Calculated value 278.0493,2 measured values 278.0489.
TM-10-5 5-(2-butyl phenyl ether methylene radical) thiazolidine-2,4-diketone: coffee-like solid;
1H NMR (300MHz, MDSO-d
6, ppm): δ 0.95 (t, 3H, J=7.2 Hz, CH
3), 1.46 (m, 2H, OCH
2CH
2CH
2), 1.76 (m, 2H, OCH
2CH
2), 4.08 (t, 2H, J=6.8Hz, OCH
2), 7.06-7.16 (m, 2H, Ar-H), 7.39-7.46 (m, 2H, Ar-H), 8.02 (s, 1H ,=CH), 12.58 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 14.1,19.2, and 31.0,68.4,113.1,121.2,122.0,123.6,126.7,128.7,132.8,157.9,167.8,168.5; HRMS:C
14H
15NO
3S [M-H]
-Calculated value 276.0700, measured value 276.0695.
TM-10-6 5-(3-butyl phenyl ether methylene radical) thiazolidine-2,4-diketone: white solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 0.96 (t, 3H, J=7.2 Hz, CH
3), 1.46 (m, 2H, OCH
2CH
2CH
2), 1.73 (m, 2H, OCH
2CH
2), 4.03 (t, 2H, J=6.5 Hz, OCH
2), 7.05-7.47 (m, 4H, Ar-H), 7.78 (s, 1H ,=CH), 12.52 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d
6, ppm): δ 14.1,19.2, and 31.1,67.6,116.1,117.2,122.2,124.2,130.8,132.3,134.8,159.5,167.7,168.3; HRMS:C
14H
15NO
3S [M-H]
-Calculated value 276.0700, measured value 276.0701.
TM-10-7 5-(4-butyl phenyl ether methylene radical) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 0.93 (t, 3H, J=7.2Hz, CH
3), 1.43 (m, 2H, OCH
2CH
2CH
2), 1.71 (m, 2H, OCH
2CH
2CH
2), 4.04 (t, 2H, J=6.5Hz, OCH
2), 7.10 (d, 2H, J=9.0Hz, Ar-H), 7.54 (d, 2H, J=8.4Hz, Ar-H), 7.75 (s, 1H ,=CH), 12.52 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 14.0,19.1, and 31.0,67.9,115.7,120.5,125.7,132.3,132.5,160.9,167.8,168.3; HRMS:C
14H
15NO
3S [M-H]
-Calculated value 276.0700, measured value 276.0702.
TM-10-8 5-(4-butoxy-3-anisole methylene radical) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm) δ 0.95 (t, 3H, J=7.2Hz, CH
3), 1.46 (m, 2H, OCH
2CH
2CH
2), 1.73 (m, 2H, OCH
2CH
2CH
2), 3.85 (s, 3H, OCH
3), 4.04 (t, 2H, J=6.3Hz, OCH
2), 7.14-7.20 (m, 3H, Ar-H), 7.76 (s, 1H ,=CH), 12.53 (s, 1H, NH);
13C NMR (75MHz, DMSO-d
6, ppm): δ 14.1,19.2, and 31.1,55.9,68.4,112.3,113.3,113.9,120.7,124.1,125.9,132.7,149.5,150.7,167.8,168.4; HRMS:C
15H
17NO
4S [M-H]
-Calculated value 306.0806, measured value 306.0802.
Embodiment 6, target compound TM-11's is synthetic
1, intermediate compound I M-11's is synthetic
In reaction flask, add aldehyde 12mmol and acetonitrile 6mL, stir and make whole dissolvings, add salt of wormwood 14mmol, stirring at room 30 minutes; Add benzyl bromine 14mmol again, 40 ℃ of stirring reactions of oil bath 4 hours, suction filtration; Filtrating concentrates in 50 ℃ of rotary distillations, separates out solid after the placement, adds sherwood oil-ether (volume ratio 1: 1) mixed solvent 7mL and disperses; Suction filtration, drying promptly gets intermediate compound I M-11.The compound experiment result sees table 8.
The compound experiment result of table 8 intermediate compound I M-11
2, synthetic (the solid phase condensation method) of target compound TM-11
In reaction flask, add intermediate compound I M-11 Q mmol, thiazolidine-2,4-diketone and sodium acetate, anhydrous (three's mol ratio is 1.00: 1.00: 1.05), 125 ℃ of reactions of oil bath, visible solid material melts rapidly; Retrogradation immediately, stopped reaction when treating completion of cure adds an amount of DMF while hot solid is dissolved fully, adds elutriation again and goes out a large amount of solids; Regulate pH 5～6 with 2NHCl, stirring at room left standstill 10 minutes in 4 ℃ after 1 hour, suction filtration, and filter cake washs with less water; 100 ℃ of dryings are transferred in the reaction flask, disperse to spend the night with ether-ETHYLE ACETATE (volume ratio 2: 1) mixed solvent; Suction filtration, drying promptly gets target compound TM-11.The compound experiment result sees table 9.
The compound experiment result of table 9 target compound TM-11
Through retrieval, target compound TM-11 series all is known compound, its structure warp
1H NMR conclusive evidence.Concrete data are following:
TM-11-1 5-((2-benzyloxy) Ben Yajiaji) thiazolidine-2,4-diketone: yellow thick liquid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 5.25 (s, 2H, ArCH
2O), 7.11 (t, 1H, J=7.8 Hz, Ar-H), 7.24 (d, 1H, J=8.1 Hz, Ar-H), 7.36-7.49 (m, 7H, Ar-H), 8.04 (s, 1H ,=CH), 12.60 (s, 1H, NH).
TM-11-2 5-((3-benzyloxy) Ben Yajiaji) thiazolidine-2,4-diketone: white solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 5.19 (s, 2H, ArCH
2O), 7.17 (d, 2H, J=8.4 Hz, Ar-H), 7.34-7.48 (m, 5H, Ar-H), 7.56 (d, 2H, J=8.4 Hz, Ar-H), 8.04 (s, 1H ,=CH), 12.54 (s, 1H, NH).
TM-11-3 5-((4-benzyloxy) Ben Yajiaji) thiazolidine-2,4-diketone: white solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 5.17 (s, 2H, ArCH
2O), 7.12-7.22 (m, 3H, Ar-H), 7.34-7.49 (m, 6H, Ar-H), 7.75 (s, 1H ,=CH), 12.65 (s, 1H, NH).
TM-11-4 5-((4-benzyloxy-3-methoxyl group) Ben Yajiaji) thiazolidine-2,4-diketone: yellow solid;
1H NMR (300MHz, DMSO-d
6, ppm): δ 3.82 (s, 3H, OCH
3), 5.17 (s, 2H, ArCH
2O), 7.14-7.22 (m, 3H, Ar-H), 7.34-7.47 (m, 5H, Ar-H), 7.75 (s, 1H ,=CH), 12.53 (s, 1H, NH).
Embodiment 7,5-virtue (heterocycle) methylene radical thiazolidine-2, the PPAR agonist activity of 4-diketone detects
1, the PPAR agonist activity detects
Entrusting Chengdu Diao Pharmaceutical Group drug screening center to carry out Compound P PAR agonist activity detects.Concrete grammar is following: with the HepG2 liver cancer cell with 1.5 * 10
4After individual/hole is inoculated in 96 orifice plates, with the low sugar DMEM substratum that contains 100U/mL Streptomycin sulphate and penicillium mould, at 37 ℃ of temperature, CO
2The gas volume mark is an overnight cultures under 5% the condition; Carry out plasmid transfection with reference to the transfection reagent specification sheets, the plasmid of transfection comprises plasmid pPPRE-Luc that has PPRE and Photinus pyralis LUC (Luc) reporter gene and the plasmid phRL-TK that has the renilla luciferase reporter gene that is used as the transfection internal reference.The substratum that contains 10 μ g/mL testing samples is used in transfection instead after 24 hours; Set up blank (cell of untransfected), negative control (cells transfected adds the substratum that does not contain sample) and positive control (cells transfected adds the substratum that contains 0.78 μ g/mL pioglitazone) simultaneously; Continue to cultivate after 24 hours and detect uciferase activity, calculate exciting rate according to detected chemiluminescence intensity L value with two luciferase reporter gene detection kit (Promega).Exciting rate=[(L1
Sample-L1
Blank)/(L1
Negative-L1
Blank)]/[(L2
Sample-L2
Blank)/(L2
Negative-L2
Blank)] * 100%, wherein L1 is the chemiluminescence intensity of Photinus pyralis LUC, and L2 is the chemiluminescence intensity of internal reference renilla luciferase, and the result representes with the exciting relatively rate of sample and positive control.Each sample is established two multiple holes, repeats 2 times.The result sees table 10.
Table 10 5-virtue (heterocycle) methylene radical thiazolidine-2, the PPAR agonist activity detected result of 4-diketone
Can find out from table 10; 62 compounds basically all have the PPAR agonist activity, and wherein the exciting relatively rate of 20 compounds and the pioglitazone exciting relatively rate that surpasses 70%, 18 compound surpasses 100%; The exciting relatively rate of compound TM-7-25 and TM-7-9 is the highest; Be respectively 204.70% and 239.77%, these compounds might be developed becomes the anti-diabetic new drug, or is used for further composition optimizes as anti-diabetic guide molecule.18 exciting relatively rates surpass in 100% the compound, have 16 to come from TM-7 series, explain that the PPAR agonist activity of TM-7 series compound is best; In addition; 18 exciting relatively rates surpass in 100% the compound; Have only on the phenyl ring of 1 compound (TM-7-16) 2 substituting groups are arranged, 1 substituting group is all only arranged on the phenyl ring of all the other compounds, have 3 of 2～3 substituted compounds of methoxyl group and phenyl ring to be replaced on TM-8 series compound, the phenyl ring and the compound of 4 substds by methoxyl group; Its PPAR agonist activity is all relatively poor relatively, and this maybe be with sterically hindered relevant.
2, medium effective concentration (EC
50) measure
Get the exciting relatively rate of part PPAR greater than 70% sample, each sample gradient dilution becomes six concentration, and each concentration is established two multiple holes, measures the exciting rate of PPAR, and the 4 Parameter Logistic Model that use again in the Xlfit software calculate EC
50The result sees table 11.
Table 11 part 5-virtue (heterocycle) methylene radical thiazolidine-2, the EC of 4-diketone
50Measure the result
Explanation is at last; Above embodiment is only unrestricted in order to technical scheme of the present invention to be described; Although through invention has been described with reference to the preferred embodiments of the present invention; But those of ordinary skill in the art should be appreciated that and can make various changes to it in form with on the details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (6)
1.5-the aryl methylene thiazolidine-2, the 4-diketone is characterized in that, general formula is suc as formula shown in the I:
In the formula,
N=1 or 3.
2. 5-aryl methylene thiazolidine-2 according to claim 1, the 4-diketone is characterized in that,
N=1 or 3.
3. 5-aryl methylene thiazolidine-2 according to claim 2, the 4-diketone is characterized in that,
4. each said 5-aryl methylene thiazolidine-2 of claim 1 to 3, the compound method of 4-diketone is characterized in that; With aromatic formaldehyde shown in the general formula I I, thiazolidine-2; 4-diketone and sodium acetate, anhydrous mixed grinding after Powdered, oil bath reacting by heating, stopped reaction during completely solidified again to the solid material fusing; Promptly generate the aryl methylene of 5-shown in general formula I thiazolidine-2, the 4-diketone; Reaction formula is following:
Among the general formula I I substituent X have with general formula I in the identical definition of substituent X.
5. according to the said 5-aryl methylene of claim 4 thiazolidine-2, the compound method of 4-diketone is characterized in that, said oil bath reacting by heating is 120～140 ℃ of reacting by heating of oil bath.
6. each said 5-aryl methylene thiazolidine-2 of claim 1 to 3, the application of 4-diketone in preparation peroxisome proliferation-activated receptors agonist.
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| CN106866651A (en) * | 2015-12-12 | 2017-06-20 | 王增涛 | Application of the benzo dioxane derivative in antiepileptic is prepared |
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