CN102079732B - Method for synthesizing 2-amino-4-methylthiazole-5-carboxylate and derivatives thereof - Google Patents
Method for synthesizing 2-amino-4-methylthiazole-5-carboxylate and derivatives thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 2-amino-4-methylthiazole-5-carboxylate and derivatives thereof, which comprises: based on molar part, adding acetoacetic ester and N-bromosuccinimide into a solvent made of water and tetrahydrofuran, heating the solution to allow the acetoacetic ester and the N-bromosuccinimide to react, adding various N-mono-substituted thiourea derivatives, heating the solution in a water bath to perform reactions to obtain various salts of 2-substituted amino-4-methylthiazole-5-formate thiazole; and alkalifying the salts by ammonia water and purifying the products of alkalization to obtain various target products. In the invention, products which are readily available in commerce or intermediates which can be synthesized easily are used as initiative raw materials, synthesis is performed by a one-pot boiling effective method of bromination and cyclization reactions, the complex bromination operation and cyclization operation are simplified, the process is simple, the product yield and purity are high, an effective, simple and convenient synthesis method is provided for various 2-substituted aminothiazole heterocyclic compounds, part of the obtained target compounds can be used in the study and active screening of antitumor and anti-human immunodeficiency virus(HIV) medicaments.
Description
Technical field
The invention belongs to the thiazolium compounds synthesis technical field, particularly the synthetic method of a kind of 2-amino-4-methylthiazole-5-carboxylate 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 widely biological activity, especially occupies critical role in the 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 consists of 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.
2-amino-4-methylthiazol-5-formic acid ester and derivative thereof are very important heterocycle compounds, use very important (Pratt, J. in organic synthesis; Jae, H.S.; Rosenberg, S.; Et al.Bioorg.Med.Chem.Lett.1994,4,169), this compounds can be used for synthetic 4-methyl-5-formyl thiazole, and 4-methyl-5-formyl thiazole then is important intermediate (a) Raju of synthetic antibiotic Cefditoren pivoxil Cephalosporins, S.A.; Karadi, A.B.; Manjunath, S.Asian J.Res.Chem., 2009,2,270.b) Wellington, K.; Curran, M.P. Drugs 2004,64,2597.c) Bai, N.; Sha, Y.W.; Meng, G.Molecules, 2008,13,943.d) Nishimura, T.; Tabuki, K.; Aoki, S.; Et al.Jap.J.Antibiotics 1993,46,629).Other has bibliographical information 2-amino-4-methylthiazol-5-formic acid ester and derivative thereof also to have antileukemie activity (Nikolova, A.; Ivanov, D.; Bontchev, P.; Et al.Arzneimittel Forsch.2004,54,323-329).
The molecular structure of 2-aromatic base substituted amido-4-methylthiazol-5-formic acid ester derivative is owing to have the aromatic ring structure on two fragrant planes, basic pharmacophore structural framework with Anti-HIV-1 Active, mutually mate with the binding pocket of the substrate binding site of HIV1-RT (RT), be expected to the X.T. for HIV-1RT inhibitor design (a) Tian; Qin B.J.; Wu Z.Y.; Et al.J.Med.Chem., 2010,53 (23), 8287-8297.b) Qin B.J.; Jiang X.K.; Lu H.; Et al.J.Med.Chem., 2010,53 (13), 4906-4916.c) Meng G.; Chen F.-E.; De Clerco E.; Et al.Chem.Pharm.Bull., 2003,51 (7), 779-789).In addition, phenylpropyl alcohol isothiazolones analog derivative (Benzisothiazolones, BITA) have anti-HIV-1 nucleocapsid protein (CA) and suppress effect, this is because this compounds has coordinative activity constitutional features (the Loo J.A. that the zinc finger protein in CA is combined; Holler T.P.; Sanchez J.D.; Et al.J.Med.Chem., 1996,39 (21), 4313-4320).
Studies show that: a series of compounds that contain the rhodanic acid heterocycle structure have biological activity (a) Cutshall that suppresses HIV-intergrase (IN), N.S.; O ' Day, C.; Prezhdo, M.Bioorg.Med.Chem.Lett.2005,15,3374-3379; B) Irvine, M.W.; Patrick, G.L.; Kewney, J.; Et al.Bioorg.Med.Chem.Lett.2008,18,2032-2037) its contain N, S heterocycle structure can with the structure type of HIV-1 intergrase (IN) inhibitor, IN metal-chelating center magnesium ion generation sequestering action (Boros, E.E.; Edwards, C.E.; Foster, S.A.; Et al.J.Med.Chem.2009,52,2754-2761).
For synthesizing of 2-amino-4-methylthiazol-5-formic acid ester compound, the traditional method of bibliographical information is used " two-step reaction synthesis method " and " iodide reaction one kettle way "." two-step reaction synthesis method " is take methyl aceto acetate and NBS as raw material, methylene dichloride is solvent, room temperature reaction 20 hours, with obtaining liquid concentration behind hydrochloric acid (1mol/L) cleaning product, often need just can get intermediate yellow transparent liquid 2-bromo-acetoacetic ester after the column chromatography for separation.And then above-mentioned intermediate slowly added ethanol and thiocarbamide, and room temperature was placed 12 hours, and temperature is controlled at 40 ℃, react after 6 hours, filters to get light yellow solid, after the solid after concentrated with filtrate merges, with getting target compound behind the dehydrated alcohol recrystallization.In a word, this method this method reaction is total consuming time longer, and the purifying of intermediate needs column chromatography for separation, and working method and post-processing step are comparatively loaded down with trivial details, and total recovery lower (less than 11%) is unsuitable for industrialization (a) Meshram, H.M.; Reddy, P.N.; Vishnu, P.; Et al.Tetrahedron Lett.2006,47,991; Sreedhar, B.; Reddy P.S.; Madhavi, M.Synth.Commun.2007,37,4149)." iodo single step reaction method " is though directly take methyl aceto acetate and thiocarbamide as raw material, but need to add a large amount of iodines (being about 1: 1.1 with the mol ratio of substrate), temperature of reaction is 120 ℃, reacted 25 hours, reaction can not be carried out fully always, the existence of a large amount of iodines has a strong impact on observation and the monitoring of reaction process, and can not effectively obtain target product according to the working method of document description.The operation circulation ratio of this method is relatively poor in a word, and uses a large amount of elemental iodines, not only the operator is damaged, and has polluted environment, is unsuitable for suitability for industrialized production (Lin J.L.; Zhao, H.Acta Cryst.2009, E65, o1753).
Therefore, the pharmaceutical chemistry research field still needs a kind of effective and easy synthetic method, be used for synthesizing various replacement 2-amino-4-methylthiazol-5-formic acid ester derivative, satisfy the demand of the screening of new drug development with the compound for preparing various structure diversities, thus the more efficiently lead compound of more convenient searching.
Summary of the invention
The problem that the present invention solves is to provide the synthetic method of a kind of 2-amino-4-methylthiazole-5-carboxylate and derivative thereof, synthesize through the method that bromo, cyclization two-step reaction " are treated different things alike ", simplified the two steps operation of loaded down with trivial details bromo and cyclization, technique is simple, the good purity of product yield is high.
The present invention is achieved through the following technical solutions:
The synthetic method of a kind of 2-amino-4-methylthiazol-5-formic acid ester and derivative thereof may further comprise the steps:
1) in molfraction, as solvent, adds 1 part acetylacetic ester with after 1～1.5 part N-bromo-succinimide mixes, at 0～5 ℃ of reaction 1～2h with water and tetrahydrofuran (THF); And then add 1～1.5 part thiocarbamide or N-substituting thioureido, and be heated to 80～90 ℃ of reaction 1～20h, obtain the intermediate product thiazole salt;
2) cooled and filtered, filtrate have Precipitation after with ammonia neutralization; Perhaps filtrate is extracted with ethyl acetate, Precipitation is arranged after organic addition water; Filter, collecting precipitation obtains target compound 2-amino-4-methylthiazol-5-formic acid ester or 2-substituted-amino thiazole-4-methyl-5-manthanoate.
The volume ratio of described water and tetrahydrofuran (THF) is 2～3: 1, and the volume ratio of solvent and acetylacetic ester is 20～50: 1.。
Described acetylacetic ester is methyl aceto acetate, and 2-amino-4-methylthiazol-5-formic acid ester is the 2-amino-4-methylthiazole-5-carboxylate, and 2-substituted-amino thiazole-4-methyl-5-manthanoate is 2-substituted-amino thiazole-4-methyl-5-ethyl formate.
The substituting group of described N-substituting thioureido is alkyl, ethylenic unsaturation alkyl, aromatic group or heterocyclic radical.
Described alkyl is methyl, ethyl or propyl group; The ethylenic unsaturation alkyl is allyl group; Aromatic group is phenyl, ortho position substituted-phenyl, m-phenylcnc, para-orientation phenyl, di-substituted-phenyl, trisubstd phenyl; Heterocyclic radical is thiazolyl, thiazolamine base or 4-methylthiazol base.
Described N-substituting thioureido is alkyl substituting thioureido, thiosinamine, N-phenylthiourea, N-p-methylphenyl thiocarbamide, N-p-nitrophenyl thiocarbamide, N-(3-chloro-2-tolyl) thiocarbamide, N-(4-sulfabenz amido) thiocarbamide or 4-methyl-2-(thioformamide base) thiazole-5-ethyl formate substituting thioureido.
Being prepared as of described N-substituting thioureido:
In molfraction, with 1 part thiocyanic acid amine, 1～2 part acetone with after 1～2 part Benzoyl chloride at room temperature mixes, after the reflux 15～20 minutes, the aromatic amine, aminothiazole or the sulfanilamide (SN) that add again 1～1.5 part conduct replacement, behind reflux 30～45min, then cool off in the water with reactant transfer to 0～5 ℃, filter and also collect filtrate; Filtrate adds the sodium hydroxide solution hydrolysis, use again in the hydrochloric acid and after, separate out precipitation, collecting precipitation obtains the N-substituting thioureido.
2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-preparation method of 4-methylthiazol base-5-ethyl formate, may further comprise the steps:
1) with water and tetrahydrofuran (THF) as solvent, add 1 part methyl aceto acetate with after 1～1.5 part NBS mixes, reacting below 0 ℃ 1～2 hour; And then add 4-methyl-2-(thioformamide base) thiazole-5-ethyl formate of 1～1.5 part, be heated to 80～90 ℃ of reactions 1～20 hour;
2) filtration after reaction is finished is separated out solid precipitation after the filtrate cooling, and collecting precipitation obtains 2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-4-methylthiazol base-5-ethyl formate.
A kind of derivative of 2-amino-4-methylthiazole-5-carboxylate, its chemical name are 2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-4-methylthiazol base-5-ethyl formate, structural formula is:
Compared with prior art, the present invention has following useful technique effect:
1, the present invention is starting raw material by the product that is easy to get take commerce or the intermediate that synthesizes easily, and the effective ways of " treating different things alike " through bromo, cyclization two-step reaction synthesize.With various acetylacetic esters, tetrahydrofuran (THF) and water mix all with after, under condition of ice bath, add NBS, react complete after, add respectively the single substituting thioureido derivative of various N-, the heating in water bath certain hour can get the salt of various 2-substituted-aminos-4-methyl-5-manthanoate thiazole, and purifying gets all types of target product behind liquid ammonia alkalinization.
2, the prepared 2-substituted-amino thiazole of the present invention-4-methyl-5-manthanoate is when cyclization, the S of its thiazole ring, N come from thiocarbamide or thiourea derivative, 2-position substituted-amino comes from the substituting group on the thiourea derivative, so can be by the single substituting thioureido derivative of pre-synthesis various N-, then the effective ways by " treating different things alike " provided by the present invention form the amino that replace 2 of thiazole ring, substituted-amino comprises that alkylamino, aromatic amino or thiazole are amino, thereby has good diversity so that 2-replacement functional group is carried out structure of modification.Ester bond on the thiazole ring 5-position comes from methyl aceto acetate or methyl acetoacetate, can form different substituting groups 5 of thiazole ring by changing the ester kind, mainly comprise ethyl formate, methyl-formiate, even can also be the tert-butyl ester and COOH (hydrolysis of ester group can be arranged and get) etc., thereby make the transformation of 5-bit architecture have certain diversity.
Because by changing the substituent type of the single substituting thioureido derivative of N-, or the ester group structure type of change acetylacetic ester, can effectively change the substituting group of 2-and 5-position on the thiazole ring, can make up by effective ways provided by the present invention and to design and synthesize multiple 2-substituted-amino thiazole-4-methyl-5-manthanoate, be used for new drug development and screening.
3, compare with " two-step reaction synthesis method ", the reaction of the present invention by bromo, cyclization two-step reaction " are treated different things alike ", avoided the chromatographic separation of intermediate 2-bromo-acetoacetic ester, and the defective of loaded down with trivial details treatment step, improved yield (reaching as high as 76.0%), simple to operate, be easy to suitability for industrialized production.
4, compare with " the iodide reaction one kettle way " of bibliographical information, the present invention does not need to add volatile iodine, because the use of iodine can have a strong impact on observation and the monitoring of reaction process, this law not only can be avoided this defective, also can avoid the hazardness to contaminate environment.By comparison, this law reaction conditions gentleness is controlled, and operation is better repeatable, and yield is higher, reliable product quality.
5, in view of containing N, the heterogeneous ring compound of S atom is the medical of the molecular structure of biological activity and antiviral basic pharmacophore widely, the present invention especially carries out various designs with bioactive 2-amino-4-methylthiazol-5-formic acid ester derivative by the single substituting thioureido derivative of N-: such as, 2-sulfahydantoin thiazole-4-methyl-5-ethyl formate is except having the structural framework adaptive with HIV-1RT, also have and the similar constitutional features of BITA and main pharmacodynamics group, the coordination combination with zinc finger protein metal ion center can be participated in, HIV-1CA can be suppressed.Further, because the compound that synthesized has the N of containing, S heterocycle structure, structurally with the similar of rhodanic acid, can suppress HIV-1IN.Therefore, carry out triple inhibitor that the designed compound that goes out of structure of modification is expected to become HIV-1CA, HIV-1RT and HIV-1IN on the heterocycle skeleton structure basis of 2-aromatic base substituted amido-4-methylthiazol.
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 various acetylacetic esters, tetrahydrofuran (THF) and water mix all with after, under condition of ice bath, add NBS, react complete after, add respectively the single substituting thioureido derivative of various N-, heating in water bath for reaction, through synthesizing that bromo, cyclization two-step reaction " are treated different things alike ", the compound that is synthesized is take the heterocycle structure of 2-substituted-amino-4-methylthiazol-5-formic acid ester as core, difference according to 2 substituted-aminos, can be divided into following three types: alkylamino, aromatic amino, heterocycle (thiazole) amino, its structural formula is expressed as respectively:
(1) R in the formula
1For-C
2H
5,-CH
3R
2For-H, Me, Et, i-Pr, n-Pr, n-Bu, i-Bu, tert-Bu ,-CH
2CH=CH
2,-CH
2CH
2N (CH
3)
2
(2) R in the formula
1For-C
2H
5,-CH
3R
2For-H, 2-Me, 3-Me, 4-Me, 2-Cl, 3-Cl, 4-Cl, 2-CF
3, 3-CF
3, 4-CF
3, 2-F, 3-F, 4-F, 2-NO
2, 3-NO
2, 4-NO
2, 2-Br, 3-Br, 4-Br, 2-COOH, 3-COOH, 4-COOH, 2-Me, 3-Cl, 3-F, 4-F, 3-Cl, 4-F, 2-Cl, 5-Cl, 3-Cl, 4-Cl, 3-CF
3, 5-CF
3, 4-SO
2NH
2, 4-(Et)
2NCH
2CH
2OCO-, 2-MeO, 4-NO
2, 2-Me, 5-NO
2, 2-NO
2, 4-MeO, 2-NO
2, 4-Me, 2-MeO, 5-NO
2, 2-MeO, 5-PhNHCO-
2, 2-NO
2, 4-Cl, 2-MeO, 5-Cl.
(3) R in the formula
1For-C
2H
5,-CH
3R
2For-C
2H
5,-CH
3
The below provides concrete compound and synthetic embodiment thereof:
Synthesizing of embodiment 12-amino-4-methylthiazole-5-carboxylate
Add methyl aceto acetate (1.3g, 100mmol), water (20mL) and tetrahydrofuran (THF) (10mL) in the there-necked flask of 150mL, ice bath adds NB S (2.2g, 110mmol) to 0-3 ℃, reacts 1 hour; And then adding thiocarbamide (0.76g, 100mmol), bath temperature is 80 ℃ of reactions 1 hour, obtains 2-amino-4-methyl-5-ethyl formate thiazole salt;
The impurity that the cooled and filtered place to go is insoluble, filtrate with ammonia neutralization to pH be 7, filter, collect the gained precipitation, and to get light yellow solid with re-crystallizing in ethyl acetate be target product 2-amino-4-methylthiazole-5-carboxylate (1.3g), productive rate is 72.0%.
Its physico-chemical property is: mp=178-179 ℃; Proton nmr spectra is:
1H NMR (CDCl
3, 400MHz): δ 1.19 (s, 3H, CH
3), 2.36 (s, 3H, thiazole-4-CH
3), 4.13 (q, 2H, CH
2), 7.69 (br, 2H, thiazole-2-NH
2); Carbon-13 nmr spectra is:
13C NMR (CDCl
3, 400MHz): δ 14.32 (thiazole-4-CH
3), 17.12 (CH
2CH
3), 59.72 (CH
2CH
3), 107.34 (thiazole-4-C), 159.34 (thiazole-4-C), 161.95 (O=C), 170.21 (thiazole-2-C).
Synthesizing of embodiment 22-allyl amido thiazole-4-methyl-5-ethyl formate
Add methyl aceto acetate (1.3g, 100mmol), water (30mL) and tetrahydrofuran (THF) (10mL) in the there-necked flask of 150mL, ice bath adds NB S (2.2g, 110mmol) to 0-3 ℃, reacts 1 hour; And then adding thiosinamine (1.06g, 100mmol), bath temperature is 90 ℃ of reactions 16 hours, obtains 2-allyl amido-4-methyl-5-ethyl formate thiazole salt;
The impurity that the cooled and filtered place to go is insoluble, filtrate with ammonia neutralization to pH be 6～7, Precipitation is arranged, filter, collecting precipitation also gets soil Red product 2-allyl amido thiazole-4-methyl-5-ethyl formate (1.72g) with re-crystallizing in ethyl acetate, and mp=109-110 ℃, productive rate is 76.0%.
Synthesizing of embodiment 32-anilino thiazole-4-methyl-5-ethyl formate
1) the intermediate N phenylthiourea is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (4.2g, 51mmol), acetone (25mL), slowly add Benzoyl chloride (7.2g under the room temperature, 50mmol), then temperature rises to 56 ℃ of backflows 15 minutes, adds aniline (4.6g again, 50mmol), after continuing to reflux 30 minutes, the product cooling is poured in the cold water (375mL), separate out a large amount of yellow solids; With sodium hydroxide solution [sodium hydroxide (7.5g), water (65mL)] hydrolysis, use again hydrochloric acid (10%) neutralization after filtering, separate out white solid, dehydrated alcohol recrystallization, drying, get synthetic (5.3g) of white crystal N-phenylthiourea, productive rate is 70.0%.
Its physico-chemical property is: mp=178-179 ℃; Proton nmr spectra is:
1H NMR (DMSO-d
6, 400MHz): δ 2.49 (br, 2H ,-NH
2), 7.10 (d, 2H, ArH-2,6), 7.31 (dd, 2H, ArH-3,5), 7.45 (dd, 1H, ArH-4), 9.66 (br, 1H, NH); Carbon-13 nmr spectra is:
13C NMR (DMSO-d
6, 400MHz): δ 123.01 (Ar-C-4), 124.38 (Ar-C-2,6), 128.67 (Ar-C-3,5), 139.06 (Ar-C-1), 180.99 (C=S).
2) 2-anilino thiazole-4-methyl-5-ethyl formate is synthetic
Add methyl aceto acetate (1.3g, 100mmol), water (25mL) and tetrahydrofuran (THF) (10mL) in the there-necked flask of 150mL, ice bath to 0～5 ℃ add NB S (2.0g, 100mmol), react 1 hour; And then adding N-phenylthiourea (2.47g, 120mmol), 90 ℃ of bath temperatures obtain 2-phenyl amino-4-methyl-5-ethyl formate thiazole salt for reaction 20 hours;
Cold filtration falls insoluble impurity, filtrate with ammonia neutralization to pH be 6～7, Precipitation is arranged, filter collecting precipitation, the precipitation of collecting is got incarnadine product 2-anilino thiazole-4-methyl-5-ethyl formate (0.9g) with re-crystallizing in ethyl acetate, and mp=191-192 ℃, productive rate is 50.0%.
Synthesizing of embodiment 42-para-totuidine base thiazole-4-methyl-5-ethyl formate
1) intermediate N p-methylphenyl thiocarbamide is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (4.2g, 50mmol), acetone (25mL), slowly add Benzoyl chloride (7.2g under the room temperature, 50mmol), then temperature rises to 56 ℃ of backflows 15 minutes, adds monomethylaniline (5.35g again, 50mmol), after continuing to reflux 30 minutes, the product cooling is poured in the cold water (375mL), separate out a large amount of yellow solids, use sodium hydroxide solution [sodium hydroxide (7.5g) after filtering, water (65mL)] hydrolysis, white solid, dehydrated alcohol recrystallization are separated out in cooling, dry, get white crystal (5.0g), mp=201-202 ℃, productive rate is 60.0%.Proton nmr spectra is:
1H NMR (DMSO-d
6, 400MHz): δ 2.25 (s, 3H, CH
3), 2.49 (br, 1H ,-NH), 7.11 (d, 2H, ArH-2,6), 7.23 (d, 2H, ArH-3,5), 9.55 (br, 2H, NH
2); Carbon-13 nmr spectra is:
13C NMR (DMSO-d
6, 400MHz): δ 20.47 (4-CH
3), 123.33 (Ar-C-3,5), 129.16 (Ar-C-2,6), 133.70 (Ar-C-4), 136.40 (Ar-C-1), 180.94 (C=S).
2) 2-(para-totuidine base)-thiazole-4-methyl-5-ethyl formate is synthetic
In the there-necked flask of 150mL, add methyl aceto acetate (1.3g, 100mmol), water (28mL) and tetrahydrofuran (THF) (10mL), below the ice bath to 0 ℃, add NB S (3.0g, 150mmol), reaction adds N-p-methylphenyl thiocarbamide (309g, 150mmol) after 1 hour again, bath temperature is 90 ℃ of reactions 16 hours, obtains 2-para-totuidine base-4-methyl-5-ethyl formate thiazole salt;
Cold filtration is removed insoluble impurities, filtrate with ammonia neutralization to pH be 6-7, Precipitation is arranged, filter collecting precipitation, the precipitation of collecting is got pale yellow crystals (1.8g) with re-crystallizing in ethyl acetate, mp=150-155 ℃, productive rate is 65.0%.
Synthesizing of embodiment 5:2-(p-nitrophenyl amido)-thiazole-4-methyl-5-ethyl formate
1) intermediate N p-nitrophenyl thiocarbamide is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (4.2g, 51mmol), acetone (25mL), slowly add Benzoyl chloride (7.2g under the room temperature, 50mmol), then temperature rises to 56 ℃ of backflows 15 minutes, add again p-Nitroaniline (6.9g, 50mmol), after continuing to reflux 30 minutes, the product cooling is poured in the 375mL cold water, separate out a large amount of yellow solids, use sodium hydroxide solution [sodium hydroxide (7.5g) after filtering, water (65mL)] hydrolysis, be cooled to room temperature after, being neutralized to pH with hydrochloric acid (10%) is 4, separate out yellow mercury oxide, collecting precipitation also gets yellow crystals (19.2g) with the dehydrated alcohol recrystallization, and mp=120-123 ℃, productive rate is 65%.
2) 2-(p-nitrophenyl amido) thiazole-4-methyl-5-ethyl formate is synthetic
In the there-necked flask of 150mL, add methyl aceto acetate (1.3g, 100mmol), water (20mL) and tetrahydrofuran (THF) (10mL), below the ice bath to 0 ℃, add NB S (2.2g, 110mmol), reaction adds N-p-nitrophenyl thiocarbamide (3.94g, 100mmol) after 1 hour again, bath temperature is 90 ℃ and refluxed 18 hours, obtains the salt of 2-(paranitraniline base) thiazole-4-methyl-5-ethyl formate;
Cold filtration falls insoluble impurity, filtrate with ammonia neutralization to pH be 6-7, Precipitation is arranged, filter, collecting precipitation also gets light yellow product (0.64g) with re-crystallizing in ethyl acetate, mp=125-128 ℃, productive rate is 21.0%.
Synthesizing of embodiment 6:2-(3-chloro-2-methyl aniline base) thiazole-4-methyl-5-ethyl formate
1) intermediate N (3-chloro-2-tolyl) thiocarbamide is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (4.5g, 50mmol), acetone (25mL), slowly add Benzoyl chloride (7.2g under the room temperature, 50mmol), reflux 15 minutes adds 3-chloro-2-methyl aniline (4.6g, 50mmol) again, reflux after 30 minutes, after the product cooling, pour in the cold water (375mL), separate out a large amount of yellow solids, use sodium hydroxide solution [sodium hydroxide (7.5g) after filtering, water (65mL)] hydrolysis, a small amount of yellow solid (3.9g) is separated out in cooling, and being neutralized to pH with hydrochloric acid (10%) is 4, separate out white solid (5.1g), the solid that obtains for twice is products therefrom, after product merging (altogether 9.0g), gets white crystal (8.2g) with the dehydrated alcohol recrystallization, mp=190-192 ℃, productive rate is 81.0%.Proton nmr spectra is:
1H NMR (DMSO-d
6, 400MHz): δ 2.20 (s, 3H, CH
3), 3.32 (s, 2H ,-NH
2), 7.19 (m, 1H, ArH-5), 7.34 (d, 1H, ArH-6), 7.54 (d, 1H, ArH-6), 9.37 (br, 1H, NH); Carbon-13 nmr spectra is:
13C NMR (DMSO-d
6, 400MHz): δ 15.05 (2-CH
3), 126.97 (Ar-C-6), 127.09 (Ar-C-4), 127.34 (Ar-C-5), 133.18 (Ar-C-3), 133.87 (Ar-C-1), 138.79 (Ar-C-2), 181.86 (C=S).
2) 2-(3-chloro-2-methyl aniline base) thiazole-4-methyl-5-ethyl formate is synthetic
In the there-necked flask of 150mL, add methyl aceto acetate (1.3g, 100mmol), water (20mL) and tetrahydrofuran (THF) (10mL), below the ice bath to 0 ℃, add NB S (2.2g, 110mmol), reaction adds N-(3-chloro-2-tolyl) thiocarbamide (2.4g, 100mmol) after 20 hours again, bath temperature is 90 ℃ and refluxed 18 hours, obtains the salt of 2-(3-chloro-2-methyl aniline base) thiazole-4-methyl-5-ethyl formate; Then the ethyl acetate that adds 50mL extracts, and with the concentrated organic phase of Rotary Evaporators, and then the elutriation of adding 10mL goes out yellow mercury oxide, collecting precipitation is also used the sherwood oil recrystallization, white solid (0.7g) is separated out in cooling, and mp=110-120 ℃, productive rate is 23.0%.
Embodiment 7:2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-4-methylthiazol base-5-ethyl formate synthetic
1) intermediate 4-methyl-2-(thioformamide base) thiazole-5-ethyl formate is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (0.9g, 12mmol), acetone (20mL), slowly add Benzoyl chloride (1.44g under the room temperature, 10mmol), reflux 15 minutes, add thiazolamine-4-methyl-5-ethyl formate (1.9g, 10mmol), reflux is after 30 minutes again, (temperature is 0-5 ℃ with pouring cold water into after the product cooling, 500mL), separate out a large amount of yellow solids, use sodium hydroxide solution [sodium hydroxide (1.7g) after filtering, water (20mL)] be hydrolyzed, it is 4 that cooling is neutralized to pH with hydrochloric acid (10%), separates out white precipitate (2.1g), filters, be precipitated 4-methyl-2-(thioformamide base) thiazole-5-ethyl formate, and using the dehydrated alcohol recrystallization, mp=236-256 ℃, productive rate is 88.0%.
2) 2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-4-methylthiazol base-5-ethyl formate synthetic
In the there-necked flask of 150mL, add methyl aceto acetate (0.6g; 5.0mmol); water (10mL) and tetrahydrofuran (THF) (5mL); ice bath is to 0-3 ℃; add NB S (1.2g; 6.0mmol); react after 1 hour; add 4-methyl-2-(thioformamide base) thiazole-5-ethyl formate (1.3g, 5.0mmol), bath temperature is raised to 90 ℃ of reactions 22 hours again; remove by filter insoluble impurities; after the filtrate cooling, separate out a small amount of light yellow solid (0.1g), be 2-[5-(ethoxycarbonyl)-4-methylthiazol base-2-amido]-4-methylthiazol base-5-ethyl formate; mp=88-118 ℃, productive rate is 6.0%.
Synthesizing of embodiment 82-(4-sulfabenz amido) thiazole-4-methyl-5-ethyl formate
1) intermediate N (4-sulfanilamide (SN) phenyl) thiocarbamide is synthetic
In the there-necked flask of 150mL, add successively thiocyanic acid amine (4.5g, 52mmol), acetone (25mL), slowly add Benzoyl chloride (7.2g under the room temperature, 50mmol), temperature rises to 56 ℃ and refluxed 15 minutes, add again sulfanilamide (SN) (8.6g, 50mmol), after continuing to reflux 30 minutes, after the product cooling, pour in the cold water (375mL), separate out a large amount of yellow solids, with sodium hydroxide solution [sodium hydroxide (7.5g), water (65mL)] hydrolysis, it is 4 that cooling is neutralized to pH with hydrochloric acid (10%) after filtering, separate out white solid (7.36g), the water recrystallization gets white crystal (5.9g), and mp=212-215 ℃, productive rate is 51.0%.
2) 2-(4-sulfabenz amido) thiazole-4-methyl-5-ethyl formate is synthetic
In the there-necked flask of 150mL, add methyl aceto acetate (1.3g, 100mmol), water (20mL) and tetrahydrofuran (THF) (10mL), below the ice bath to 0 ℃, add NB S (2.2g, 110mmol), react and add again N-(4-sulfabenz amido) thiocarbamide (2.3g after 20 hours, 100mmol), bath temperature is raised to 90 ℃ of reaction 18h, insolubles filters uses re-crystallizing in ethyl acetate, field gray solid (2.1g) is separated out in cooling, and mp=235-247 ℃, productive rate is 62.0%.
Synthesizing of embodiment 92-amino-4-methylthiazol-5-formic acid methyl esters
Add methyl acetoacetate (1.16g, 100mmol), water (20mL) and tetrahydrofuran (THF) (10mL) in the there-necked flask of 150mL, ice bath adds NB S (2.2g, 110mmol) to 0-5 ℃, reacts 1 hour; And then adding thiocarbamide (0.76g, 100mmol), bath temperature is raised to 80 ℃ of reactions 1 hour, obtains 2-amino-4-methyl-5-ethyl formate thiazole salt;
The impurity that the cooled and filtered place to go is insoluble, filtrate is 6-7 with ammonia neutralization to pH, the filtration under diminished pressure collecting precipitation, and use re-crystallizing in ethyl acetate, getting white crystal is target product 2-amino-4-methylthiazol-5-formic acid methyl esters (1.2g).Its physico-chemical property is: mp=171-174 ℃, have irritating smell, and productive rate is 70.0%.
Claims (3)
1. the synthetic method of 2-amino-4-methylthiazol-5-formic acid ester and derivative thereof is characterized in that, may further comprise the steps:
1) in molfraction, as solvent, adds 1 part acetylacetic ester with after 1～1.5 part N-bromo-succinimide mixes, at 0～5 ℃ of reaction 1～2h with water and tetrahydrofuran (THF); And then add 1～1.5 part thiocarbamide or N-substituting thioureido, and be heated to 80～90 ℃ of reaction 1～20h, obtain the intermediate product thiazole salt;
2) cooled and filtered, filtrate have Precipitation after with ammonia neutralization; Perhaps filtrate is extracted with ethyl acetate, Precipitation is arranged after organic addition water; Filter, collecting precipitation obtains target compound 2-amino-4-methylthiazol-5-formic acid ester or 2-substituted-amino thiazole-4-methyl-5-manthanoate;
Described N-substituting thioureido is thiosinamine, N-phenylthiourea, N-p-methylphenyl thiocarbamide, N-p-nitrophenyl thiocarbamide, N-(3-chloro-2-tolyl) thiocarbamide or N-(4-amino-sulfonyl phenyl) thiocarbamide;
Described acetylacetic ester is methyl aceto acetate, and 2-amino-4-methylthiazol-5-formic acid ester is the 2-amino-4-methylthiazole-5-carboxylate, and 2-substituted-amino thiazole-4-methyl-5-manthanoate is 2-substituted-amino thiazole-4-methyl-5-ethyl formate.
2. the synthetic method of 2-amino as claimed in claim 1-4-methylthiazol-5-formic acid ester and derivative thereof is characterized in that, the volume ratio of described water and tetrahydrofuran (THF) is 2～3:1; The volume ratio of solvent and acetylacetic ester is 20～50:1.
3. the synthetic method of 2-amino as claimed in claim 1-4-methylthiazol-5-formic acid ester and derivative thereof is characterized in that, being prepared as of described N-substituting thioureido:
In molfraction, with 1 part thiocyanic acid amine, 1～2 part acetone with after 1～2 part Benzoyl chloride at room temperature mixes, after the reflux 15～20 minutes, the aromatic amine or the sulfanilamide (SN) that add again 1～1.5 part conduct replacement, behind reflux 30～45min, then cool off in the water with reactant transfer to 0～5 ℃, filter and also collect filtrate; Filtrate adds the sodium hydroxide solution hydrolysis, use again in the hydrochloric acid and after, separate out precipitation, collecting precipitation obtains the N-substituting thioureido.
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| M.K.ROUT et al.Preparation of 2-Substituted-4-methyl-5-carbethoxythiazoles.Condensation of Ethyl Acetoacetate with Substituted Thioureas.《Journal of the American Chemical Society》.1953,第75卷(第16期),4057-4058. * |
| Ze Li et al.Design, Synthesis, and Biological Evaluation of Antiviral Agents Targeting Flavivirus Envelope Proteins.《Journal of Medicinal Chemistry》.2008,第51卷(第15期),4660-4671. * |
| 钟为慧等.4-甲基-5-甲酰基噻唑的合成工艺研究.《高校化学工程学报》.2009,第23卷(第3期),486-490. * |
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