CN102276548A - Method for synthesizing 2-iminothiazolidine-4-one and derivatives thereof - Google Patents
Method for synthesizing 2-iminothiazolidine-4-one and derivatives thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 2-iminothiazolidine-4-one and derivatives thereof. The method comprises the following steps of: reacting water or ethanol serving as a solvent and 1 molar part of thiourea or N,N'-disubstituted thiourea and 1 to 1.5 molar parts of chloroacetic acid which are taken as reaction raw materials at the temperature of between 40 and 100 DEG C for 1 to 10 hours; and thus obtaining the 2-iminothiazolidine-4-one or the derivatives thereof after reaction. In the method, the water or the ethanol is taken as the solvent, and the chloroacetic acid is a reaction substrate and also a reaction catalyst; and the acidity of the chloroacetic acid is smartly utilized to self-catalyze the reaction, thiazole heterocycles can be formed through cyclization at higher reaction yield (32.5 to 86.4 percent) under the condition that additional catalysts are not used, and the process that a fussy esterification or amidation reaction is used for derivatization of the chloroacetic acid and the aftertreatment process of waste acid obtained after reaction are avoided. The method for synthesizing the 2-iminothiazolidine-4-one and the derivatives thereof is an environment-friendly synthetic process, is easy to operate, and is particularly suitable for industrialized clean production, and design thought is ingenious.
Description
Technical field
The invention belongs to the thiazolium compounds synthesis technical field, the synthetic method of particularly a kind of 2-imido grpup thiazolidin-4-one and derivative thereof.
Background technology
Most of clinical application all is the compound that contains heterocycle structure that is got by chemosynthesis, some natural crossing cyclic cpdss also are clinical commonly used drugs, many compounds relevant with vital movement contain heterocycle more, and in a word, the activity of medicine often depends on the heterocycle in the structure.This may be because heterogeneous ring compound than cycloaliphatic ring or aromatic cycle compound is more difficult is in vivo decomposed by metabolism, and has better biocompatibility with body.
Contain N, the heterogeneous ring compound of S atom extensively is present in nature, and has wide biological activity, especially occupies critical role in medicines such as antitumor, antiviral, antibiotic, anti-inflammatory, anti-diabetic, antipsychotic, antihistamine and cardiovascular and cerebrovascular.Contain N, the thiazole heterocycle of S is widely used in drug research, and the one, as the basic structure parent nucleus that constitutes pharmacophore, adapting to the space requirement of medicine special role target spot, the 2nd, produce corresponding biological activity as the integral part of active substituent or ring system.
The thiazoles heterocycle structure not only extensively is present in nature, and also occupies critical role in chemotherapeutic agent.2-imido grpup thiazolidin-4-one compounds is a kind of thiazole derivative with special construction, and the compound that contains this class formation parent nucleus usually has and wide biological activity (Rajanarendar, E.; Rao, E.K.; Shaik, F.P.; Et al., J.Sulfur Chem., 2010,31 (4), 263-274; Al-Zaydi, K.M.J.Saudi Chem.Soc., 2010,14,91-95; Vicini, P.; Geronikaki, A.; Anastasia, K.; Et al., Bioorg.Med.Chem., 2006,14,3859-3864; Chen, S.; Chen, L.; Le, N.T.; Et al., Bioorg.Med.Chem.Lett., 2007,17 (8), 2134-2138).As: suppress nitricoxide synthase (magnify forever, to China, Xu Yungen, etc., Acta Pharmaceutica Sinica, 2006,41 (9), 825-829), tuberculosis (Srivastava, T.; Gaikwad, A.K.; Haq, W.; Et al., Arkivoc., 2005, ii, 120-130), anticonvulsion (Captan, G; Ulusoy, N.; Ergenc, N.; Et al., Farmaco, 1996,51,729-732), anti-inflammatory (Rovnyak, G.C.; Narayanan, V.L.; Haugwitz, R.D.USP 1977,4053613), antimycotic (Khan, H.M.; Tiwari, S.; Begum, K.; Et al., Indian J.Chem., 1998,37B, 1075-1079; ), antibiotic (Pan, B.; Huang, R.-Z.; Han S.-Q.; Et al., Bioorg.Med.Chem.Lett., 2010,2O (8), 2461-2464), antimicrobial (Gazzar, A.-R.E.B.A.; Gaffar, A.-E.-D.M.; Ali, A.S.J.SulfurChem., 2008,5,549-558; ), antiviral (Shukle, S.K.; Singh, S.P.; Awasthi, L.P.; Et al., Indian J.Pharm.Sci., 1982,44,153-155), arrestin tyrosine phosphorylation enzyme (Ottan à, R.; Maccari, R.; Ciurleo, R.; Et al., Bioorg.Med.Chem., 2009,17,1928-1937), anti-diabetic (Li, X.; Abell, C.; Wattington, B.H.; Etal., Org.Biomol.Chem., 2003,1,392-4395; ), immunoregulation effect (Bolli, M.H.; Abele, S.; Binkert, C.; Et al., J.Med.Chem., 2010,53,4198-4211), or the like.
The prior synthesizing method of at present relevant 2-imido grpup-thiazolidin-4-one compounds mainly contains following several:
1. acid catalyzed ring-closure reaction
Adopting inorganic acid as catalyzer, as in the presence of hydrochloric acid or sulfuric acid, be starting raw material by 2-Mono Chloro Acetic Acid and thiocarbamide, carry out the ring-closure reaction under the acid catalysis, can get unsubstituted 2-imido grpup thiazolidin-4-one (Meng, G. on the imido grpup; Li, Z.Y; Zheng, M.L.Org.Prep.Proced.Int., 2008,40 (6), 572-574; Hendry, C.M.J.Am.Chem.Soc., 1958,80,973-976; Zhang Ruiren, Qu Youle, Wang Xu. Chinese Journal of Pharmaceuticals, 2002,33,578).
2. the ring-closure reaction of base catalysis
The organic bases of catalyzed cyclization reaction can be pyridine (Bolli, M.H.; Abele, S.; Binkert, C.; J.Med.Chem., 2010,53 (10), 4198-4211), triethylamine also can be used as catalyzer (Ottan à, R.; Maccari, R.; Ciurleo, R.; Et al., Bioorg.Med.Chem., 2009,17,1928-1937).The catalyzed reaction of described employing organic bases must at first become Mono Chloro Acetic Acid acyl chlorides or ester, then again and two substituting thioureido derivative cyclizations; But mineral alkali is this ring-closure reaction of catalysis also, all can be used as catalyzer (Pan, B. as sodium hydrogen or sodium acetate; Huang, R.-Z.; Han S.-Q.; Et al., Bioorg.Med.Chem.Lett., 2010,2O (8), 2461-2464; Hegazi, B.; Mohamed, H.A.; Dawood, K.M.; Et al., Chem.Pharm.Bull., 2010,58 (4), 479-483; Sule E.; Ilknur, D.J.Org.Chem., 2007,72,2494-2450) etc., adopt mineral alkali catalysis directly in ethanol, methyl alcohol equal solvent, to reflux and get final product with Mono Chloro Acetic Acid and thiocarbamide.
3. carry out ring-closure reaction by the Mono Chloro Acetic Acid derivative
3.1 Mono Chloro Acetic Acid is become cyclization behind the ester
Adopt the reaction of ethyl chloroacetate and Sodium Thiocyanate 99, can get product, but product purity and yield all not high (Wang Shaojie, Zhang Xing, Qi Yingbo. Chinese pharmaceutical chemistry magazine, 2000,1O, 291-292).
3.2 Mono Chloro Acetic Acid is become cyclization behind the acid amides
This method at first generates nitrogen-chloro acetanilide with aniline and halo Acetyl Chloride 98Min. (bromine) reaction, replaces isocyanate reaction with alkyl again, and cyclization under sodium hydride catalysis forms dibasic Thiazolinone derivative (Bolli, M.H.; Abele, S.; Binkert, C.; Et al., J.Med.Chem., 2010,53 (10), 4198-4211).
By chlor(o)acetamide and KSCN reaction through chemical combination and Dimroth reset 2-substituted imido thiazolidone (Al-Zaydi, K.M.; Al-Shamary, A.; Elnagdi, M.H.J.Chem.Res., 2006, (6), 408-411).
Utilization N-chloracetyl-1,2,3, Synthetic 2-Fang imido grpup-4-thiazolidone compounds (magnifies forever but 4-tetrahydroisoquinoline or N-chloracetyl phthalic imidine and substituting thioureido react also, to China, Xu Yungen, etc., Acta Pharmaceutica Sinica, 2006,41 (9), 825-829).
4. carry out cyclization by Thiovanic acid
With 2 mercaptopropionic acid and N, N-DIC (DIC) is a raw material, can get product (Monforte, P. through ring-closure reaction; Fenech, G.; Basile, M.; Et al., J.Heterocyclic Chem., 1979,16 (2), 341-345), cost an arm and a leg but this method is raw materials used.
5. solvent-free ring-closure reaction
Thiocarbamide and N-replacement maleinamide are got thiazolidinone derivatives through the addition of Michael's type under condition of no solvent, productive rate is higher, belongs to method (Shimo, the T. of environmental protection; Matsuda, Y.; Iwanaga, T.; Etal., Heterocycles, 2007,71 (5), 1053-1058), but, not unsubstituted active methylene radical with 5-substd in this method products therefrom structure, can't do further structural modification by condensation reaction.
Above-mentioned synthetic method more or less has various defectives, thereby has limited that its heavy industrialization is clean to be produced, and bigger as agents useful for same toxicity, aftertreatment is loaded down with trivial details, and product does not contain methylene radical, (Nekrasov, D.D. such as can't further modify; Obukhova, A.S.Chem.Heterocylclic Compd., 2006,42,1109).
Based on as can be known to the analysis of above-mentioned various synthetic methods, adopt nontoxic environmental protection technology, synthetic effectively 5 still unsubstituted 2-imido grpup thiazolidin-4-ones and derivative thereof have become one of current urgency problem to be solved.
Summary of the invention
The problem that the present invention solves is to provide the synthetic method of a kind of 2-imido grpup thiazolidin-4-one and derivative thereof, and this method is a kind of green synthesis method, and technology is simple, the good purity height of product yield.
The present invention is achieved through the following technical solutions:
The synthetic method of a kind of 2-imido grpup thiazolidin-4-one and derivative thereof may further comprise the steps:
1) in molfraction, as solvent, add 1 part thiocarbamide or N with water or ethanol, the Mono Chloro Acetic Acid of N '-two substituting thioureido and 1～1.5 part reacted 1～10 hour under 40～100 ℃ of conditions;
2) thiocarbamide and fusing point are lower than 100 ℃ N, and when N '-two substituting thioureido was reaction raw materials, used water was a solvent, and fusing point is higher than 100 ℃ N, when N '-two substituting thioureido is reaction raw materials, are solvent with ethanol then.
3) with water be the reaction of solvent, after reaction is finished, the hydro-oxidation sodium solution is regulated pH to 10～12, extract with ethyl acetate or chloroform then, wash with saturated nacl aqueous solution after collecting organic phase, with after the siccative removal moisture, filter again, obtain target product behind the recovery organic solvent;
With ethanol is the reaction of solvent, and reaction is separated out if any precipitation after finishing, and then is precipitated as target product, cooling back suction filtration, and the washing with alcohol filter cake gets target product with recrystallization from ethyl acetate/petroleum ether again; As do not have precipitation and separate out column chromatography for separation (sherwood oil: ethyl acetate 10: 1; 5: 1 gradient elutions), collect the main product object point, get target product through recrystallization again.
Described N, the substituting group of N-two substituting thioureidos are the aromatic group or the heterocyclic radical of alkyl, ethylenic unsaturation alkyl, aromatic group, various replacements.
Described alkyl is methyl, ethyl or propyl group; The ethylenic unsaturation alkyl is an allyl group; Aromatic group is phenyl, ortho position substituted-phenyl, a position substituted-phenyl, para-orientation phenyl, di-substituted-phenyl, trisubstd phenyl; Heterocyclic radical is thiazolyl, thiazolamine base or 4-methylthiazol base.
Described N, N '-two substituting thioureido is N, N '-diethyl thiourea, N, N '-di-isopropyl thiourea, N, N '-di-n-butyl thiocarbamide, N, N '-diphenyl thiourea, N, N '-two (p-methylphenyl) thiocarbamide, N, N '-two (p-methoxyphenyl) thiocarbamide, N, N '-two (2-methyl-3-chloro-phenyl-) thiocarbamide, N, N '-two (m-trifluoromethylphenyl) thiocarbamide, N, N '-two (adjacent fluorophenyl) thiocarbamide, N, N '-two (fluorophenyl) thiocarbamide, N, N '-two (to fluorophenyl) thiocarbamide.
Described recrystallization is to carry out recrystallization with the ethyl acetate/petroleum ether mixed solvent, and the volume ratio of ethyl acetate and sherwood oil is 1: 1～10.
Described is the reaction of solvent with ethanol, and when having precipitation to separate out, cooling back suction filtration is used the washing with alcohol filter cake then, gets target product with ethyl acetate/petroleum ether mixed solvent recrystallization again, and the volume ratio of ethyl acetate and sherwood oil is 1: 1～10.
Described sherwood oil: the ethyl acetate gradient elution is that the volume ratio of sherwood oil and ethyl acetate was from 10: 1 to 5: 1 gradient elution.
Described is the reaction of solvent with ethanol, does not have to precipitate when separating out, and after silica gel thin-layer chromatography launched, the pairing product of point that launches back area maximum on the silica gel thin-layer plate was a target product; Separate with silica gel column chromatography then, use sherwood oil: the ethyl acetate gradient elution, collect target fraction, recrystallization can get target product.
Compared with prior art, the present invention has following beneficial technical effects:
1, as solvent, and Mono Chloro Acetic Acid itself both can be used as catalyzer with water (or ethanol) in the present invention, also was reaction substrate simultaneously; Utilized Mono Chloro Acetic Acid itself to have certain acidity cleverly, ionizablely gone out acid ion, had autocatalysis, can not rely on extra catalyzer fully and just can promote ring-closure reaction, and can avoid loaded down with trivial details one-tenth ester or become step such as acid amides reaction.Compare with existing synthetic method, this synthetic method not only can be avoided the corrosive nature of strong inorganic acid (as the concentrated hydrochloric acid and the vitriol oil) to equipment, also can avoid the complicated processes of the aftertreatment of a large amount of acid waste liquids simultaneously.
Synthetic method provided by the invention is the synthetic and eco-friendly synthesis technique of a kind of green, mentality of designing is ingenious, simple to operate, make water or innoxious solvent ethanol do green and environment-friendly solvent, except that reaction raw materials, do not need to add especially acid or alkali as catalyzer, overcome yet and utilized the Mono Chloro Acetic Acid derivative to carry out the defective of ring-closure reaction, be particularly suitable for the clean production of industrialization.
2, the prepared 2-imido grpup thiazolidin-4-one of the present invention is when cyclization, and the S of its thiazole ring, N come from thiocarbamide or thiourea derivative, and 2-position imido grpup comes from thiocarbamide; And the derivative of 2-imido grpup thiazolidin-4-one is when cyclization, 2-position substituted imine base comes from the N substitutive derivative (N-substituting thioureido) of thiocarbamide, and utilize N, when N '-two substituting thioureido carries out cyclization, then generating 2-position substituted imine base and 3-position accordingly replaces, its substituting group all comes from N, N '-two substituting thioureido.
So, can be by synthesizing single substituting thioureidos of various N-or N in advance, N-two substituting thioureido derivatives then by synthetic method provided by the present invention, have good diversity thereby the feasible functional group that 2-substituted imine base, 3-position are replaced carries out structure of modification.
Because by changing N, the substituent type of N '-two substituting thioureido derivative, can effectively change the substituting group of 2-and 3-position on the thiazole ring, can make up by effective ways provided by the present invention and to design and synthesize multiple 2-imido grpup thiazolidin-4-one derivatives, be used for new drug development and screening.
Embodiment
The present invention is described in further detail below in conjunction with specific embodiment, and the explanation of the invention is not limited.
The present invention with Mono Chloro Acetic Acid, various thiocarbamide or derivatives thereof and water (or ethanol) mix all with after, in react under the condition of ice bath finish after, the separation and purification target product gets final product.Institute's its structural formula of synthetic compound can be expressed as:
Wherein R is-H, Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, tert-Bu ,-CH
2CH=CH
2,-CH
2CH
2N (CH
3)
2, Ph, 4-CH
3-Ph, 4-CH
3O-Ph, 3-Cl-2-CH
3-Ph, 3-CF
3-Ph, 2-F-Ph, 3-F-Ph, a kind of among the 4-F-Ph.
The synthetic route general formula of target compound is as follows:
R＝Et，n-Bu，i-Pr，Ph，4-CH
3-Ph，4-CH
3O-Ph，3-Cl-2-CH
3-Ph，3-CF
3-Ph，2-F-Ph，3-F-Ph，4-F-Ph
Provide concrete compound and synthetic embodiment thereof below:
Synthesizing of embodiment 1:2-imido grpup thiazolidin-4-one hydrochloride (1)
In reactor, add Mono Chloro Acetic Acid (9.46g successively, 100mmol), and thiocarbamide (7.61g, 100mmol) and water (10mL), under the room temperature condition, fully stir and make Mono Chloro Acetic Acid, after thiocarbamide is dissolved in the water fully, place 40 ℃ of water-bath stirring reactions again, exothermic heat of reaction, reaction system becomes clarification back system temperature rapidly and rises, top temperature reaches 72 ℃, and after this system temperature descends gradually, and white solid increases, reacted 1 hour, temperature of reaction is constant in 40 ℃, adopts TLC (developping agent: monitoring reaction process chloroform-methanol 10: 1), the dyeing of iodine cylinder, demonstration reacts completely, the system for the treatment of naturally cools to room temperature, and suction filtration, collecting precipitation are also with a small amount of frozen water washing, dry, get white crystal (9.15g), be 2-imido grpup thiazolidin-4-one hydrochloride, yield is 60.2% (in Mono Chloro Acetic Acid).Products therefrom mp.197-198 ℃/206-213 ℃ (dec.), lit.256-258 ℃ of (Allen, C.F.H.; Van Allen, J.A.Org.Synth., 1955, CV3,751-752; Mackie, A.; Misra, A.L.J.Chem.Soc., 1955,1030-1031).
Synthesizing of embodiment 2:2-(ethyl imido grpup)-3-ethyl-thiazolidin-4-one (2)
In flask, add Mono Chloro Acetic Acid (2.35g successively, 25.0mmol), 1,3-diethyl thiourea (3.05g, 23.0mmol) and water (10mL), place oil bath pan to stir and make and dissolve fully, be heated to 100 ℃, back flow reaction 5 hours is with TLC (developping agent: monitoring reaction process chloroform-methanol 20: 1); Question response is cooled to room temperature with reaction system after finishing, hydro-oxidation sodium water solution (2mol/L) regulation system pH to 12, and ethyl acetate extraction, after the gained organic phase is washed with saturated sodium-chloride, anhydrous sodium sulfate drying.Filter, reclaim organic solvent, get yellow oily liquid, after room temperature left standstill, the needle-like crystal (3.43g) that congeals into gradually was 2-(ethyl imido grpup)-3-ethyl-thiazolidin-4-one, and yield is 86.4% (in Mono Chloro Acetic Acid).Products therefrom mp.38 ℃, lit.38 ℃ of (van Allan, J.A.J.Org.Chem., 1956,21,24-27; Loomans, J.; Demoen, P.Mededelingen van de Vlaamse Chemische Vereniging, 1964,26 (3), 80-86).
1H?NMR(400MHz，CDCl
3)δ：3.78(q，4H，CH
3CH
2NR
1R
2?&thiazolidine-5-H)，3.35(q，2H，J＝8.0Hz，CH
3CH
2N＝)，1.25(t，3H，CH
3CH
2NR
1R
2)，1.20(t，3H，CH
3CH
2N＝).
Synthesizing of embodiment 3:3-normal-butyl-2-(normal-butyl imido grpup) thiazolidin-4-one (3)
In flask, add successively Mono Chloro Acetic Acid (2.35g, 25.0mmol), 1, (4.7g 25.0mmol) and water (15mL), is heated to 100 ℃ to 3-di-n-butyl thiocarbamide, back flow reaction 7.5 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 5: 1), reaction finishes, and treats that the system cold is to room temperature, there is oily matter to separate out in the system, ethyl acetate extraction, saturated sodium-chloride washing, anhydrous sodium sulfate drying.Filter, steam and remove organic solvent, get yellow oily liquid (3.7g), yield is 64.9% (in Mono Chloro Acetic Acid).MS：228.1(25)[M]
+；
1H?NMR(400MHz，CDCl
3)δ：3.92(s，1H，HO-CH＝)，3.76(s，2H，R
1R
2NCH
2CH
2CH
2CH
3)，3.69(t，2H，R
1R
2NCH
2CH
2CH
2CH
3)，3.59(t，2H，R
1R
2NCH
2CH
2CH
2CH
3)，3.25(t，2H，CH
3CH
2CH
2CH
2N＝)，1.58(m，2H，CH
3CH
2CH
2CH
2N＝)，1.35(m，2H，CH
3CH
2CH
2CH
2N＝)，0.90(m，6H，2×(CH
3)).
Synthesizing of embodiment 4:3-sec.-propyl-2-(hydroxyl imido grpup) thiazolidin-4-one (4)
Take by weighing compound Mono Chloro Acetic Acid (2.19g, 20mmol), N, (3.2g 20mmol) places clean 100mL three-necked bottle to N '-di-isopropyl thiourea, add ethanol (20mL), be heated to 100 ℃, back flow reaction 5.5 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 5: 1), after reaction finishes, separate (sherwood oil: ethyl acetate 10: 1 through silica gel column chromatography; 5: 1 gradient elutions), collect the main product object point (after silica gel thin-layer chromatography launches, developping agent: petroleum ether-ethyl acetate 5: 1, the point of area maximum after launching on the silica gel thin-layer plate is judged as the main product object point), must slightly yellowy solid (1.3g), recrystallization gets white crystal (0.56g), and thick productive rate is 32.5% (in Mono Chloro Acetic Acid).m.p.60-61℃。MS：175.0(50)[M]
+；
1H?NMR(400MHz，CDCl
3)δ：5.25(m，1H，R
1R
2NCH(CH
3)
2)，3.85(s，2H，thiazolidine-5-H)，1.49(t，6H，R
1R
2NCH(CH
3)
2).
Synthesizing of embodiment 5:3-phenyl-2-(phenyl imine base) thiazolidin-4-one (5)
In flask, add successively Mono Chloro Acetic Acid (0.47g, 5.0mmol), 1, (1.14g 5.0mmol) and ethanol (20mL), is heated to 100 ℃ to the 3-diphenyl thiourea, back flow reaction 5.0 hours, and TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), reaction finishes, treat that the system cold to room temperature, separates out solid, decompress filter, the small amount of ethanol washing, get white solid (0.53g), filtrate discards, and yield is 40.0% (in Mono Chloro Acetic Acid).mp.175-176℃，lit.172℃(Singh，H.；Singh，H.；Ahuja，A.S.；et?al.J.Chem.Soc.，Perkin?Transactions?1：Org.Bio-Org.Chem.(1972-1999)1982，(3)，653-656.)；174-175℃(Finzi，C.；Angelini，C.Annali?di?Chimica(Rome，Italy)1953，43，832-838；CA?1955，49：32367)；176-177.5℃(Shirai，H.；Yashiro，T.；Miwa，I.Nagoya-shiritsu?Daigaku?Yakugakubu?Kenkyu?Nenpo(1964-1992)(1966)，14，63-65?CA?1968，68：87240)；176℃(Bhargava，P.N.Bulletin?of?theChemical?Society?of?Japan(1951)，2451-2.CA，1952，46：67019)。
1H?NMR(400MHz，CDCl
3)δ：7.56(t，2H，R
1R
2N-Ar-2，6-H)，7.40(q，3H，＝N-Ar-3，4，5-H)，7.36(t，2H，＝N-Ar-2，6-H)，7.16(t，1H，R
1R
2N-Ar-4-H)，6.96(d，J＝12Hz，2H，R
1R
2N-Ar-3，5-H)，3.99(s，2H，thiazolidine-5-H).
Synthesizing of embodiment 6:3-(p-methylphenyl)-2-(p-methylphenyl imido grpup) thiazolidin-4-one (6)
Take by weighing Mono Chloro Acetic Acid (0.20g, 2.0mmol), 1, (0.52g 5.0mmol) and ethanol (10mL), is heated to 80 ℃ to 3-di-p-tolyl thiocarbamide, refluxed 5.5 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), stopped reaction separates (sherwood oil: ethyl acetate 10: 1 through silica gel column chromatography; 5: 1 gradient elutions), collect the main product object point (after silica gel thin-layer chromatography launches, developping agent: petroleum ether-ethyl acetate 5: 1, the point of expanded area maximum on the silica gel thin-layer plate is judged as the main product object point), get thick product (0.35g), recrystallization from ethyl acetate/petroleum ether gets white needle-like crystals (0.30g), and thick productive rate is 59.0% (in Mono Chloro Acetic Acid).m.p.127℃，lit.127℃(Bhargava，PN；Chitteyya，B.Journal?of?the?Indian?Chemical?Society?(1955)，32，797-8.CA：1956，50：60248)；124-126℃(Fischer，E；Hartmann，I；Priebs，H.Zeitschrift?fuer?Chemie?(1975)，15(12)，480-1.CA：1976，84：150553)；145℃(Merja，B.C.；Joshi，A.M.；Parikh，K.A.；et?al.Indian?Journal?of?Chemistry，Section?B：Organic?Chemistry?Including?Medicinal?Chemistry?(2004)，43B(4)，909-912.CA：2004，142：38180)。
1HNMR(400MHz，CDCl
3)δ：9.78(s，1H，HO-CH＝)，7.44(d，J＝8.0Hz，2H，Ar-H)，7.44(d，J＝8.0Hz，2H，Ar-H)，7.07(d，J＝8.0Hz，2H，Ar-H)，3.35(s，4H)，2.49(s，1H，HO-CH＝)，2.22(s，3H，R
1R
2N-Ar-CH
3)，2.00(s，3H，＝N-Ar-CH
3).
Synthesizing of embodiment 7:3-(p-methoxyphenyl)-2-(p-methoxyphenyl imido grpup) thiazolidin-4-one (7)
In flask, add Mono Chloro Acetic Acid (0.19g successively, 2.0mmol), 1, and 3-two (p-methoxyphenyl) thiocarbamide (0.58g, 2mmol), and ethanol (20mL), be heated to 80 ℃, back flow reaction 7.0 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), reaction finishes, and separates (sherwood oil: ethyl acetate 10: 1 through silica gel column chromatography; 5: 1 gradient elutions), collect the main product object point, get light gray solid (0.35g), recrystallization from ethyl acetate/petroleum ether gets white needle-like crystals (0.28g), thick productive rate 53.3% (in Mono Chloro Acetic Acid).m.p.117-119℃，lit.113℃(Fischer，E；Hartmann，I；Priebs，H.Zeitschrift?fuerChemie(1975)，15(12)，480-1.CA：1976，84：150553)。
1H?NMR(400MHz，CDCl
3)δ：7.52(d，J＝8.0Hz，2H，R
1R
2N-Ar-H)，7.05(d，J＝8.0Hz，2H，R
1R
2N-Ar-H)，6.90(s，4H，＝N-Ar-H)，3.94(s，2H，thiazolidine-5-H)，3.84(s，3H，R
1R
2N-Ar-OCH
3)，3.81(s，3H，＝N-Ar-OCH
3).
Synthesizing of embodiment 8:3-(3-chloro-2-aminomethyl phenyl)-2-(3-chloro-2-aminomethyl phenyl imido grpup) thiazolidin-4-one (8)
Take by weighing compound Mono Chloro Acetic Acid (0.19g, 2.0mmol), 1,3-two (3-chloro-2-aminomethyl phenyl) thiocarbamide (0.65g, 2.0mmol) placing a clean reaction flask, ethanol (6.0mL) is heated to 80 ℃, refluxed 3.5 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), stopped reaction, the question response system is chilled to room temperature, the velvet-like solid of adularescent is separated out, suction filtration gets white solid (0.25g), m.p.127-128 ℃, mother liquor reclaims white solid (0.15g), thick productive rate 54.8%.MS：363.9[M+H]
+；
1H?NMR(400MHz，CDCl
3)δ：7.42(d，J＝8.0Hz，1H，Ar-H)，7.28(s，1H，Ar-H)，7.24(d，J＝8.0Hz，1H，Ar-H)，6.96(t，1H，Ar-H)，6.86(d，J＝8.0Hz，1H，Ar-H)，6.63(d，J＝8.0Hz，1H，Ar-H)，5.55(s，3H，R
1R
2N-Ar-CH
3)，4.15(s，2H，thiazolidine-5-H)，2.26(s，3H，＝N-Ar-2-CH
3).
Synthesizing of embodiment 9:3-(m-trifluoromethylphenyl)-2-(m-trifluoromethylphenyl imido grpup) thiazolidin-4-one (9)
In flask, add Mono Chloro Acetic Acid (0.68g successively, 7.2mmol), 1, (2.73g 7.2mmol) and ethanol (20mL), is heated to 80 ℃ to 3-two (m-trifluoromethylphenyl) thiocarbamide, back flow reaction 5 hours, TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), reaction finishes, and separates (sherwood oil: ethyl acetate 10: 1 through silica gel column chromatography; 5: 1 gradient elutions) collect the main product object point, get product (1.18g), recrystallization from ethyl acetate/petroleum ether gets white velvet-like crystal 0.63g, and thick productive rate is 45.0% (in Mono Chloro Acetic Acid).m.p.85-86℃。MS：403.9(100)[M]
+；
1H?NMR(400MHz，CDCl
3)δ：7.71(m，3H，Ar-H)，7.63(d，J＝8.0Hz，1H，Ar-H)，7.48(t，J＝8.0Hz，1H，Ar-H)，7.42(d，J＝8.0Hz，1H，Ar-H)，7.22(s，1H，Ar-H)，7.14(d，J＝8.0Hz，1H，Ar-H)，4.07(s，2H，thiazolidine-5-H).
Synthesizing of embodiment 10:3-(adjacent fluorophenyl)-2-(adjacent fluorophenyl imido grpup) thiazolidin-4-one (10)
In flask, add successively Mono Chloro Acetic Acid (0.945g, 10mmol), 1, (2.64g 10mmol) and ethanol (10mL), is heated to 80 ℃ to 3-two (adjacent fluorophenyl) thiocarbamide, back flow reaction 4 hours, and TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), question response finishes, reaction system is cooled to room temperature, separate out a large amount of white solids, suction filtration, filter cake washs with small amount of ethanol, the dry white solid (1.50g) that gets, yield is 49.3% (in Mono Chloro Acetic Acid).m.p.170-171℃。
1H?NMR(400MHz，CDCl
3)δ：7.47(m，2H，Ar-H)，7.30(m，2H，Ar-H)，7.15(m，3H，Ar-H)，6.98(m，1H，Ar-H)，4.07(d，2H，J＝12.0Hz，thiazolidine-5-H).
Synthesizing of embodiment 11:3-(fluorophenyl)-2-(a fluorophenyl imido grpup) thiazolidin-4-one (11)
Take by weighing Mono Chloro Acetic Acid (1.81g, 20.0mmol), 1, and 3-two (fluorophenyl) thiocarbamide (5.07g, 18.0mmol) and ethanol (10mL), be heated to 80 ℃, back flow reaction 4 hours, and TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), reaction finishes, the question response system is chilled to room temperature, separates (sherwood oil: ethyl acetate 10: 1 through silica gel column chromatography; 5: 1 gradient elutions) collect the main product object point, get product (3.00g), get white needle-like crystals (0.80g) with recrystallization from ethyl acetate/petroleum ether, m.p.82-83 ℃, thick productive rate is 54.8% (with 1,3-two (fluorophenyl) thiocarbamide meter).MS：303.9(100)[M]
+；
1H?NMR(400MHz，CDCl
3)δ：7.52(m，1H，Ar-H)，7.30(m，1H，Ar-H)，7.20(m，3H，Ar-H)，6.87(m，1H，Ar-H)，6.74(d，1H，J＝8.0Hz，Ar-H)，6.69(m，1H，Ar-H)，4.07(s，2H，thiazolidine-5-H).
Synthesizing of embodiment 12:3-(to fluorophenyl)-2-(to the fluorophenyl imido grpup) thiazolidin-4-one (12)
Take by weighing compound Mono Chloro Acetic Acid (0.95g, 10.0mmol), 1, and 3-two (to fluorophenyl) thiocarbamide (2.64g, 10.0mmol) and ethanol (15mL), be heated to 80 ℃, back flow reaction 2 hours, and TLC (developping agent: monitoring reaction process petroleum ether-ethyl acetate 3: 1), question response finishes, reaction system is chilled to room temperature, through column chromatography for separation (sherwood oil: ethyl acetate 10: 1; 5: 1 gradient elutions) collect the main product object point, product (1.80g), recrystallization from ethyl acetate/petroleum ether gets light grey crystal (1.29g), m.p.122-123 ℃, mother liquor reclaim solid (0.51g), total thick productive rate is 59.2%.
1H?NMR(400MHz，CDCl
3)δ：7.39(m，1H，Ar-H)，7.38(m，1H，Ar-H)，7.23(m，2H，Ar-H)，7.04(m，2H，Ar-H)，6.92(m，1H，Ar-H)，6.89(m，1H，Ar-H)，4.01(s，2H，thiazolidine-5-H).
More than concrete each compound productive rate, fusing point, and the data statistics of document fusing point is as shown in table 1:
Table 1. target compound synthesizes related data
Annotate: h: hour; NCE: new chemical entities (New Chemical Entity)
Claims (8)
1. the synthetic method of 2-imido grpup thiazolidin-4-one and derivative thereof is characterized in that, may further comprise the steps:
1) in molfraction, as solvent, add 1 part thiocarbamide or N with water or ethanol, the Mono Chloro Acetic Acid of N '-two substituting thioureido and 1～1.5 part fully stirs, and after treating to dissolve fully, back flow reaction is 1～10 hour under 40～100 ℃ of conditions;
Thiocarbamide and fusing point are lower than 100 ℃ N, and when N '-two substituting thioureido was reaction raw materials, water was as solvent; Fusing point is higher than 100 ℃ N, when N '-two substituting thioureido is reaction raw materials, uses ethanol as solvent;
2) if to be the reaction of solvent, after reaction is finished, regulate pH to 10～12 as water, with ethyl acetate or chloroform extraction, collect organic phase then, again with after the siccative removal moisture afterwards with the saturated nacl aqueous solution washing, filter, obtain target product behind the recovery organic solvent;
3) as if being the reaction of solvent with ethanol, reaction is separated out if any precipitation after finishing, and then is precipitated as target product, and cooling back suction filtration gets target product again behind recrystallization;
As do not have precipitation and separate out, separate through silica gel column chromatography, use sherwood oil: the ethyl acetate gradient elution, collect target fraction, recrystallization gets target product;
The gained target product is 2-imido grpup thiazolidin-4-one or 2-(substituted imine base)-3-replacement-thiazolidin-4-one.
2. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof is characterized in that, described N, the substituting group of N '-two substituting thioureido are the aryl radical or the heterocyclic radical of alkyl, ethylenic unsaturation alkyl, aromatic group, replacement.
3. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 2 and derivative thereof is characterized in that, described alkyl is methyl, ethyl or propyl group; The ethylenic unsaturation alkyl is an allyl group; Aromatic group is phenyl, ortho position substituted-phenyl, a position substituted-phenyl, para-orientation phenyl, di-substituted-phenyl, trisubstd phenyl; Heterocyclic radical is thiazolyl, thiazolamine base or 4-methylthiazol base.
4. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof, it is characterized in that, described N, N '-two substituting thioureido is N, N '-diethyl thiourea, N, N '-di-isopropyl thiourea, N, N '-di-n-butyl thiocarbamide, N, N '-diphenyl thiourea, N, N '-two (p-methylphenyl) thiocarbamide, N, N '-two (p-methoxyphenyl) thiocarbamide, N, N '-two (2-methyl-3-chloro-phenyl-) thiocarbamide, N, N '-two (m-trifluoromethylphenyl) thiocarbamide, N, N '-two (adjacent fluorophenyl) thiocarbamide, 1,3-two (fluorophenyl) thiocarbamide or N, N '-two (to fluorophenyl) thiocarbamide.
5. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof is characterized in that, described recrystallization is to carry out recrystallization with the ethyl acetate/petroleum ether mixed solvent, and the volume ratio of ethyl acetate and sherwood oil is 1: 1～10.
6. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof, it is characterized in that, with ethanol is the reaction of solvent, when having precipitation to separate out, cooling back suction filtration, use the washing with alcohol filter cake then, get target product with ethyl acetate/petroleum ether mixed solvent recrystallization again, the volume ratio of ethyl acetate and sherwood oil is 1: 1～10.
7. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof is characterized in that, described sherwood oil: the ethyl acetate gradient elution is that the volume ratio of sherwood oil and ethyl acetate was from 10: 1 to 5: 1 gradient elution.
8. the synthetic method of 2-imido grpup thiazolidin-4-one as claimed in claim 1 and derivative thereof, it is characterized in that, described is the reaction of solvent with ethanol, do not have and precipitate when separating out, after silica gel thin-layer chromatography launched, the pairing product of point that launches back area maximum on the silica gel thin-layer plate was a target product; Separate with silica gel column chromatography then, use sherwood oil: the ethyl acetate gradient elution, collect target fraction, recrystallization can get target product.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103289922A (en) * | 2013-05-17 | 2013-09-11 | 浙江工业大学 | Yokenella sp. and application thereof in preparing alpha, beta-unsaturated enol and aromatic alcohol |
| CN104059060A (en) * | 2014-05-30 | 2014-09-24 | 西安交通大学 | 5-(1H-indolyl-3-methylene)-1,3-thiazolidinyl-4-one derivatives, and synthesis method and application thereof |
| CN106432131A (en) * | 2016-09-22 | 2017-02-22 | 青岛科技大学 | Preparation method of tri-imine thiazole derivative |
| CN109776520A (en) * | 2018-12-14 | 2019-05-21 | 延边大学 | A kind of 1,3- diaryl pyrazole azole PTP1B inhibitor of the structure of rhodanine containing carboxyalkyl and its preparation and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008260725A (en) * | 2007-04-13 | 2008-10-30 | Ohara Yakuhin Kogyo Kk | Method for producing 2-imino-4-thiazolidinone |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103289922A (en) * | 2013-05-17 | 2013-09-11 | 浙江工业大学 | Yokenella sp. and application thereof in preparing alpha, beta-unsaturated enol and aromatic alcohol |
| CN104059060A (en) * | 2014-05-30 | 2014-09-24 | 西安交通大学 | 5-(1H-indolyl-3-methylene)-1,3-thiazolidinyl-4-one derivatives, and synthesis method and application thereof |
| CN106432131A (en) * | 2016-09-22 | 2017-02-22 | 青岛科技大学 | Preparation method of tri-imine thiazole derivative |
| CN106432131B (en) * | 2016-09-22 | 2018-06-05 | 青岛科技大学 | A kind of preparation method of three imines thiazole |
| CN109776520A (en) * | 2018-12-14 | 2019-05-21 | 延边大学 | A kind of 1,3- diaryl pyrazole azole PTP1B inhibitor of the structure of rhodanine containing carboxyalkyl and its preparation and application |
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