* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Example 17Compound 16 (3.0 g, 15.05 mmol) was added to a suspension of thiourea (1.4 g, 18.10 mmol) in ethanol. The reaction mixture was refluxed for 8h. After cooling, solvent was concentrated and residue was subjected to purification with DCM/MeOH to give 17 as yellow solid (2.3 g, 80percent). 1H NMR (400 MHz, DMSO-d6) δ 9.37 (bs, 2H, NH2), 7.82 (s,1Η, Ar-H), 7.58-7.34 (m, 6Η, Ar-H); ESI-MS: calcd for (C9Η8N2S) 176, found 177[M+H] .
80%
for 8 h; Reflux; Inert atmosphere
Compound 12 (3.0 g, 15.05 mmol) was added to a suspension of thiourea (1.4 g, 18.10 mmol) in ethanol. The reaction mixture was refluxed for 8h. After cooling, solvent was concentrated and residue was subjected to purification with DCM/MeOH to give compound 13 as yellow solid (2.3 g, 80percent). 1H NMR (400 MHz, DMSOd6) δ 9.37 (bs, 2H, NH2), 7.82 (s, I H3 Ar-H), 7.58-7.34 (m, 6H, Ar-H); ESI-MS: calculated for (C9H8N2S) 176, found 177 [M+H]+.
66%
at 20 - 80℃; for 8 h; Inert atmosphere
[000319] Synthesis of 5-phenylthiazol-2-amine (397): To a stirred solution of 2-bromo-2- phenylacetaldehyde 394 (860 mg, crude) in EtOH (20 mL) under inert atmosphere was added thiourea (658 mg, 8.64 mmol) at RT; heated at 80 °C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The pH of the residue was neutralized with 10percent aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-3percent MeOH/ CH2C12 to afford compound 397 (500 mg, 66percent) as an off-white solid. TLC: 5percent MeOH/ CH2C12 (Rj 0.6); 1H NMR (400 MHz, DMSO-d6): ö 7.43-7.38 (m, 3H), 7.32 (t, J= 7.8 Hz, 2H), 7.17 (tt, J 7.5, 0.9 Hz, 1H), 7.12 (s, 2H).
35.3%
Heating / reflux
A mixture of bromo-phenyl-acetaldehyde (47.5g, 0.239mol), thiourea (36.7g, 0.48mol) and ethanol (17OmL) was heated to reflux overnight. The mixture was then cooled and the resulting precipitate filtered. The filtered precipitate was then washed with aqueous NaHCC^. Recrystallization from methanol-water returned the title compound (15g, 35.3percent) as a yellow solid. 1H NMR(SOOMHZ, DMSO-J6): 8.52(s, IH), 7.68 (s,lH), 7.50 (m, 2H), 7.39 (m, 2H), 7.29 (m, IH)
A mixture of 2-chloro-2-phenylacetaldehyde (1.7 g, 11.28 mmol) and thiourea (0.86 g, 11.28 mmol) in ethanol (5 mL) was stirred at 70-80 ° C overnight. The reaction mixture was diluted with water and then an aqueous ammonia solution was added thereto to obtain a basic solution. The reaction mixture was extracted with dichloromethane. The separated organic layer was dehydrated with anhydrous magnesium sulfate. The reaction was concentrated under reduced pressure to remove the solvent and then separated by chromatography. The purified product was recrystallized from hexane-ethyl acetate to give pale yellow crystalline 5-phenylthiazol-2-amine (907.5 mg, 45.6percent).
Reference：
[1] Patent: KR101688978, 2016, B1, . Location in patent: Paragraph 0052-0054
[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1957, vol. 245, p. 1321
[3] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 6, p. 1463 - 1464
[4] ChemMedChem, 2016, vol. 11, # 13, p. 1406 - 1409
3
[ 14371-25-6 ]
[ 17356-08-0 ]
[ 39136-63-5 ]
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 6, p. 2292 - 2300
4
[ 122-78-1 ]
[ 17356-08-0 ]
[ 39136-63-5 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 4007,4009
[2] Journal of Medicinal Chemistry, 1983, vol. 26, # 8, p. 1158 - 1163
5
[ 122-78-1 ]
[ 39136-63-5 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1957, vol. 245, p. 1321
[2] Patent: WO2015/138895, 2015, A1,
6
[ 932-87-6 ]
[ 39136-63-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 7, p. 1208 - 1212
7
[ 2612-36-4 ]
[ 17356-08-0 ]
[ 39136-63-5 ]
Reference：
[1] , 1979, vol. 15, p. 2129 - 2133[2] Zhurnal Organicheskoi Khimii, 1979, vol. 15, p. 2351 - 2356
With copper dichloride; isopentyl nitrite; In acetonitrile; at 20℃;
To a mixture of <strong>[39136-63-5]5-phenyl-thiazol-2-ylamine</strong> (13g, 74mmol), CuCl2 (2Og, 148mmol) in CH3CN (50OmL) was added isoamyl nitrite (17.3g, 148mmol) in a dropwise fashion at room temperature. The mixture was then stirred overnight at ambient temperature. The mixture was then concentrated in vacuo to remove CH3CN and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC^ and concentrated in vacuo to give crude title compound (8.5g, 58.9%) as a brown solid. The crude product was purified via flash column chromatography eluting with petroleum ethe?ethyl acetate 100:1 to give title compound (7.8g, 54.0% ) as a yellow solid. 1H NMR(SOOMHZ, DMSO-J6): 8.13(s, IH), 7.65 (m,2H), 7.43 (m, 3H); ES-MS: 196(M+H+)
3 g
Step a. To a stirring solution of <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (5.0 g, 28.3 mmol, 1.0 eq) in HC1 (40 ml) and AcOH (40 ml) was added NaN02 (2.3 g, 33.9 mmol, 1.2 eq) in water (10 ml) slowly at 0C. After stirring at 0C for 0.5 h, CuCl2 (7.6 g, 56.5 mmol, 2.0 eq) was added to the solution, and the mixture was stirred for 16 h at rt. The reaction mixture was extracted with DCM (400 ml x3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EtOAc = 100: 1 to 40: 1) to yield 2- chloro-5-phenylthiazole (3.0 g, 99.0% purity) as yellow crystals.
3-methyl-N-(5-phenyl-thiazol-2-yl)-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17.7%
In pyridine; at 20℃;
5-Phenyl-thiazol-2-ylamine (35.2 mg, 0.200 mmol) and 4-methyl-benzoyl chloride (30.9 mg, 0.200 mmol) were dissolved in 1 mL of pyridine. The reaction mixture was stirred at room temperature overnight and then purified by reverse-phase preparative liquid chromatography (10.4 mg, 0.0353 mmol, 17.7 %). ESI-MS M/Z calc. 294.1, found 295.4 (M+1) + Retention time 3.40 minutes.
General procedure: C. Synthesis of key intermediates Synthesis of 2-aminothiazoles (5). Method A [0204] [0205] To a mixture of 5-dibromo-2,2-dimethyl-[1,3] dioxane-4,6-dione (0.012 mol) and corresponding aldehyde 27 (0.024 mol) in anhydrous ether (50 ml) bromine (0.2 ml) was added. The reaction mixture was stirred at room temperature overnight. The resulting solution was washed consequently with the solution of sodium bicarbonate and brine. The organic layer was concentrated in vacuo to give the crude bromoaldehyde 28, which was used on next step without purification. [0206] A solution of 28 and thiourea (0.012 mol) in anhydrous ethanol (20 ml) was refluxed for 6 h (TLC control). After cooling to room temperature water (60 ml) and aqueous ammonia (2 ml) were added, followed by extraction with dichloromethane (2X50 ml). The combined organic phases were dried over anhydrous sodium sulfate; the solvent was removed in vacuo. The title thiazole 5 was purified by column chromatography on silica gel.
The 2-bromophenylacetaldehyde obtained from the previous step and thiourea (3.81 g, 50 mmol) were refluxed in ethanol (45 mL) for 2 hours. The solvent was removed and the residue was dissolved in ethyl acetate (60 mL) and washed with 10% aqueous NaHCO3 (3*40 mL). The organic layer was dried over Na2SO4, and the filtrate evaporated under reduced pressure. Column chromatography (Ethyl Acetate:Hexanes=3:2) of the residue gave 5-phenyl-1,3-thiazole-2-ylamine (2.7 g).
20
[ 39136-63-5 ]
[ 7758-99-8 ]
[ 133311-51-0 ]
Yield
Reaction Conditions
Operation in experiment
18.6 parts (98.0%)
With sodium bromide; phosphoric acid; nitric acid; sodium nitrite; In water;
Example 7 To a stirred and cooled (-10C) solution of 13.9 parts of <strong>[39136-63-5]5-phenyl-2-thiazolamine</strong> (this product is described in J. Am. Chem. Soc. 71 , 4007, 1949) and 119 parts of phosphoric acid were added dropwise 37.5 parts of nitric acid. Upon complete addition, a solution of 7.85 parts of sodium nitrite in 12.4 parts of water was added dropwise during 35 minutes at -5C. Upon completion, the thus obtained solution was added dropwise to a cooled (-5C) mixture of 13.2 parts of copper(II)sulfate, 51.4 parts of sodium bromide and 275 parts of water. Upon completion, the reaction mixture was allowed to stand overnight to reach room temperature. The whole was neutralized with sodium carbonate (exothermic reaction, the temperature rose to 40C). After cooling, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 18.6 parts (98.0%) of 2-bromo-5-phenylthiazole as a residue (interm. 19).
Example 17Compound 16 (3.0 g, 15.05 mmol) was added to a suspension of thiourea (1.4 g, 18.10 mmol) in ethanol. The reaction mixture was refluxed for 8h. After cooling, solvent was concentrated and residue was subjected to purification with DCM/MeOH to give 17 as yellow solid (2.3 g, 80%). 1H NMR (400 MHz, DMSO-d6) delta 9.37 (bs, 2H, NH2), 7.82 (s,1Eta, Ar-H), 7.58-7.34 (m, 6Eta, Ar-H); ESI-MS: calcd for (C9Eta8N2S) 176, found 177[M+H] .
80%
In ethanol; for 8h;Reflux; Inert atmosphere;
Compound 12 (3.0 g, 15.05 mmol) was added to a suspension of thiourea (1.4 g, 18.10 mmol) in ethanol. The reaction mixture was refluxed for 8h. After cooling, solvent was concentrated and residue was subjected to purification with DCM/MeOH to give compound 13 as yellow solid (2.3 g, 80%). 1H NMR (400 MHz, DMSOd6) delta 9.37 (bs, 2H, NH2), 7.82 (s, I H3 Ar-H), 7.58-7.34 (m, 6H, Ar-H); ESI-MS: calculated for (C9H8N2S) 176, found 177 [M+H]+.
66%
In ethanol; at 20 - 80℃; for 8h;Inert atmosphere;
[000319] Synthesis of 5-phenylthiazol-2-amine (397): To a stirred solution of 2-bromo-2- phenylacetaldehyde 394 (860 mg, crude) in EtOH (20 mL) under inert atmosphere was added thiourea (658 mg, 8.64 mmol) at RT; heated at 80 C and stirred for 8 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The pH of the residue was neutralized with 10% aqueous NaHCO3 solution (10 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through flash column chromatography using 2-3% MeOH/ CH2C12 to afford compound 397 (500 mg, 66%) as an off-white solid. TLC: 5% MeOH/ CH2C12 (Rj 0.6); 1H NMR (400 MHz, DMSO-d6): oe 7.43-7.38 (m, 3H), 7.32 (t, J= 7.8 Hz, 2H), 7.17 (tt, J 7.5, 0.9 Hz, 1H), 7.12 (s, 2H).
35.3%
In ethanol;Heating / reflux;
A mixture of bromo-phenyl-acetaldehyde (47.5g, 0.239mol), thiourea (36.7g, 0.48mol) and ethanol (17OmL) was heated to reflux overnight. The mixture was then cooled and the resulting precipitate filtered. The filtered precipitate was then washed with aqueous NaHCC^. Recrystallization from methanol-water returned the title compound (15g, 35.3%) as a yellow solid. 1H NMR(SOOMHZ, DMSO-J6): 8.52(s, IH), 7.68 (s,lH), 7.50 (m, 2H), 7.39 (m, 2H), 7.29 (m, IH)
Example Al 9; a) Preparation of intermediate 53; A mixture of intermediate 48 (2.17 g; 0.004 mol), <strong>[39136-63-5]5-phenyl-2-thiazolamine</strong> (2.115 g; 0.012 mol) and 50 ml of ethanol was stirred at 75C for 18 hours. The product was precipitated, filtered off, washed with DIPE and dried, yielding 1.8 g of intermediate53.
With N-ethyl-N,N-diisopropylamine; In chloroform; at 0 - 20℃; for 0.333333h;
Intermediate 59-Synthesis of N-(5-Phenyl-thiazol-2-yl)-malonamic acid To a stirred solution of <strong>[39136-63-5]5-phenyl-thiazol-2-ylamine</strong> (0.4 g, 0.0022 mol) and DIEA (0.73 g, 0.0056 mol) in chloroform (4 mL) was added mono-ethylmalonyl chloride (0.375 g, 0.0024 mol) dropwise at 0 C. and the resulting mixture was stirred at ambient temperature for 20 minutes. The reaction mixture was then diluted with cold water and the product was extracted with chloroform. The chloroform was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.3 g (46%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester. To a solution of N-(5-phenyl-thiazol-2-yl)-malonamic acid ethyl ester (0.292 g, 0.001 mol) in the mixture of methanol (1 mL), THF (1.5 mL) and H2O (1 mL) was added LiOH.H2O (0.084 g, 0.002 mol) and the resulting mixture was stirred for 1 hour. The reaction mixture was then concentrated. The residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethylacetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 0.23 g (87%) of N-(5-phenyl-thiazol-2-yl)-malonamic acid.
Step A: (3-Hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added 1,1'-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C. for 2 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)-1H-imidazole-1-carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65 C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3=375.33).
In acetonitrile; at 65℃; for 2h;
Step A: (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added Iota, Gamma-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C for 2 hours. The precipitate was filtered and washed with acetonitrile (2 x 20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)- ^-imidazole-l- carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-l-ammoniobicyclo[2.2.2]octan-l- yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65 C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2- yl)thioureido)methyl)-l-ammoniobicyclo[2.2.2]octan-l-yl)trihydroborate (.85 g, 2.19 mmol, 74.4 % yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1-BH3= 375.33).
In acetonitrile; at 65℃; for 2h;
To <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (0.52 g, 2.9 mmol) inacetonitrile (6 mL) was added 1,1'-thiocarbonyldiimidazole(0.68 g, 3.8 mmol). The reaction mixture was stirred at 65 C.for 2 hours. The precipitate was filtered and washed withacetonitrile (2x20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)_1H-imidazole-I-carbothioamide. The intermediatewas taken up in N,N-dimethylformamide (30 mL) andtreated with (3-(aminomethyl)-3-hydroxy-I-ammoniobicyclo[2.2.2]octan-I-yl)trihydroborate (0.5 g, 2.9 mmol). Thereaction mixture was stirred for 5 hours at 65 C. The reactionwas concentrated in vacuo and purified via silica gel chromatography(30-100% ethyl acetate/hexane). The product fractionswere combined and concentrated in vacuo to yield(3-hydroxy-3-((3-(5-phenylthiazol-2-yI)thioureido)methy1)l-ammoniobicyclo[2.2.2]octan-I-yl)trihydroborate (0.85 g,2.19 mmol, 74.4% yield) as a white powder.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 48h;Inert atmosphere;
3-(furan-2-yl)propionic acid (150mg, 1.07mmol) was dissolved in DCC (220mg, 1.07mmol), in anhydrous dichloromethane in the HOBT (14.4mg, 0.107mmol) successively at room temperature under a nitrogen condition, <strong>[39136-63-5]5-phenylthiazol-2-amine</strong> (188.5 mg, 1.07 mmol) was added and the mixture was stirred for two days and then the reaction was terminated by using dichloromethane and distilled water. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent and then separated by chromatography. The purified product was recrystallized from ethanol to obtain white solid (3-(furan-2-yl)-N-(5-phenylthiazol-2-yl)propanamide (Compound 1c) (74.8 mg, 23.5%).
Example 19To a solution of cyanuric chloride (230 mg, 1.25 mmol) in THF (16 mL) was added benzylamine (0.14 mL, 1.25 mmol) and DIPEA (0.20 mL, 1.25 mmol) at 0 C. The reaction mixture was let to stir at 0 C to room temperature for 2h. 3-amino-5- phenylthiazole (compound 17) (220 mg, 1.25 mmol) and DIPEA (0.20 mL, 1.25 mmol) were added to the above mixture and the resulting mixture was heated with microwave initiator at 150 C for 10 minutes. 1 -methylpiperazine (0.28 mL, 2.50 mmol) and DIPEA (0.44 mL, 2.50 mmol) were added to the mixture and the mixture was heated with microwave initiator at 60 C for 10 minutes. Saturated NaHCO3 in water was added and the mixture was extracted by ethyl acetate (3 x 50 mL). The combined organic was washed by brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a silica gel column eluted with 0-5 % MeOH/DCM afforded 19 as white solid (16 mg, 3 %). 1H NMR (400 MHz, DMSO-d6) delta 12.56 (bs, 1H, NH), 9.20 (bs, 1Eta, NH), 7.75-5.96 (m, 9Eta, Ar-H), 3.71 (bs, 4Eta, 2CH2), 2.33 (s, 4Eta, 2CH2), 2.21 (s, 3Eta, CH3); ESI-MS: calcd for (C24Eta26N8S) 458, found 459 [M+H]+. HPLC: retention time: 7.89 min. purity: 97%.
DIPEA (0.13 mL, 0.65 mmol) and 5-(phenyll)thiazol-2-amine (103 mg, 0.586 mmol) was added to a suspension of compound 4 (0.2g, 0.588 mmol) in THF (12 mL) . The mixture was heated at 150 0C for 10 minutes using microwave initiator. A solution of N- Methylpiperazine (70.4 mg, 0.703 mmol) and DIPEA ((0.13 mL, 0.65 mmol) in THF (5 mL) was added to the above vial at room temperature. The mixture was heated at 60 0C for 0.2 hours. After cooling to room temperature, saturated NaHCO3 in water was added to the flask and the mixture was extracted with dichloromethane (3 x25 ml) and washed by brine, dried over sodium sulfate and concentrated. The resulting crude product was purified by Teledyne- Isco flash system by using DCM/MeOH, 0 to 15% of Methanol in dichloromethane to provide compound 32 as a white solid (31 mg, 1 1%). IH NMR (400 MHz, DMSO-d6) 6 1 1.55 (brs, I H), 10.25 (brs, IH), 7.95 (s, IH,), 7.49-7.05 (m, 9H), 3.45 (m, 4H), 2.39 (m, 4H), 2.20 (s, 3H), 1.45 (m, IH), 0.85 (m, 4H) ; ESI-MS: calculated for (C27H28N80S2) 544, found 545 (MH+). HPLC: retention time: 16 min. purity: 98%.
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