* 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.
With potassium permanganate In water at 55℃; for 22 h;
4-methylthiazole (19.8 g, 0.2 mol),200 mL of water and potassium permanganate (173.8 g, 1.1 mol) were placed in a 500 mL three-neck reaction flask and heated to 55° C. for 22 h with stirring and heating.The reaction solution was then cooled and then filtered. The filter cake (manganese dioxide) was washed with hot water at 50°C, and the filtrate was adjusted to pH 3 with dilute hydrochloric acid.A solid precipitated and was filtered. The filter cake was washed with a small amount of water. The product was dried to give 18.1 g, yield 70.2percent, melting point 196-198°C.
Stage #1: at 40℃; for 5 h; Stage #2: With hydrogenchloride; sodium nitrite In water for 2 h;
A method for preparing thiazole-4-carboxylic acid,Include the following steps: Mix ethyl bromopyruvate, thiourea, and water,Raise the temperature to 40°C, incubate and stir for 5 hours, then add concentrated hydrochloric acid, and add 30 wtpercent sodium nitrite aqueous solution dropwise.The mixture was further stirred for 2 hours, and the filter cake was filtered to obtain thiazole-4-carboxylic acid. The molar ratio of ethyl bromopyruvate to thiourea was1:1.05, the molar ratio of ethyl bromopyruvate to sodium nitrite is 1:1.5, and the weight ratio of ethyl bromopyruvate to water is1.95:10, the volume ratio of water to concentrated hydrochloric acid is 1:1.
Reference：
[1] Patent: CN107417639, 2017, A, . Location in patent: Paragraph 0023; 0029; 0030; 0031; 0032; 0033; 0034-0041
5
[ 1113-59-3 ]
[ 77287-34-4 ]
[ 3973-08-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 2, p. 511 - 522
6
[ 115-08-2 ]
[ 1113-59-3 ]
[ 3973-08-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 8, p. 2035 - 2044
7
[ 89791-92-4 ]
[ 3973-08-8 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 689,696
8
[ 22358-80-1 ]
[ 3973-08-8 ]
Reference：
[1] Yakugaku Zasshi, 1953, vol. 73, p. 126[2] Chem.Abstr., 1953, p. 12358
[3] Helvetica Chimica Acta, 1937, vol. 20, p. 204
[4] Helvetica Chimica Acta, 1942, vol. 25, p. 1075
9
[ 14527-43-6 ]
[ 3973-08-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2929 - 2932
10
[ 100367-77-9 ]
[ 3973-08-8 ]
Reference：
[1] Helvetica Chimica Acta, 1942, vol. 25, p. 1075
11
[ 89791-92-4 ]
[ 3973-08-8 ]
[ 89379-29-3 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 689,696
12
[ 7113-13-5 ]
[ 3973-08-8 ]
Reference：
[1] Journal of the Chemical Society. Perkin transactions 1, 1966, vol. 16, p. 1357 - 1360
13
[ 89379-29-3 ]
[ 3973-08-8 ]
Reference：
[1] Journal of the Chemical Society, 1957, p. 689,696
[2] Helvetica Chimica Acta, 1948, vol. 31, p. 1342,1348
14
[ 635-46-1 ]
[ 22358-80-1 ]
[ 3973-08-8 ]
Reference：
[1] Helvetica Chimica Acta, 1948, vol. 31, p. 924,925
15
[ 22358-80-1 ]
[ 108-24-7 ]
[ 3973-08-8 ]
Reference：
[1] Helvetica Chimica Acta, 1937, vol. 20, p. 204
16
[ 7647-01-0 ]
[ 89379-29-3 ]
[ 3973-08-8 ]
Reference：
[1] Helvetica Chimica Acta, 1948, vol. 31, p. 1342,1348
17
[ 67-56-1 ]
[ 3973-08-8 ]
[ 59418-09-6 ]
Reference：
[1] Organic Letters, 2008, vol. 10, # 13, p. 2909 - 2912
[2] Chemistry - A European Journal, 2011, vol. 17, # 51, p. 14450 - 14463
[3] Yakugaku Zasshi, 1953, vol. 73, p. 126[4] Chem.Abstr., 1953, p. 12358
[5] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 64 - 73
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 5 h;
General procedure: 2.5mmol thiazole-4-carboxyli acid and 2.0mmol alcohol were dissolved in 25mL dichloromethane (DCM) in a dry flask with continuous stirring, followed by the addition of 2.5mmol 3-(3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride. When the temperature of the reaction system cooled to 0°C, 0.2mmol 4-dimethylaminopyridine was added dropwise and reacted for 1hat 0°C. Then the temperature was elevated to room temperature for another 4h reaction. The reaction was stopped by adding 25mL saturated NaHCO3 solution and extracted twice with 20mL dichloromethane (2×20mL). The extracted organic layers were first dried by anhydrous Na2SO4, and then filtered and concentrated under vacuum distillation, obtaining the crude products. Finally, the crude products were further purified using column chromatography (ethy lacetate:petroleum ether, 1:5).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 64 - 73
20
[ 3973-08-8 ]
[ 95-54-5 ]
[ 148-79-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: at 150℃; Inert atmosphere Stage #2: at 230℃; for 2 h; Inert atmosphere
O-phenylenediamine (10.8 g, 0.1 mol) and polyphosphoric acid (21 g, 0.062 mol) were added to the reaction flask.Nitrogen protection, the oil bath was quickly heated under stirring to 150 deg.] C,Then thiazole-4-carboxylic acid (12.9 g, 0.1 mol) was added and the temperature was raised to 230°C and the reaction was incubated for 2 h.The reaction was stopped, slightly cooled and poured into 200 g of ice-water mixture while hot, and the mixture turned into a dark brown liquid.When 40percent sodium hydroxide solution was used to neutralize to pH=5-6, a large amount of purple gray precipitated out, solid was filtered off, and washed with 20mL*4 water to obtain a purple-gray solid, namely thiabendazole crude product.The crude product is dissolved in 10 times the quality of the water, adjusted with dilute hydrochloric acid pH = 1-2, add activated carbon reflux decolorization, filtration,The filtrate was warmed to weak basic pH with a saturated aqueous solution of sodium bicarbonate (pH = 7-8), then filtered and dried to give 17.7 g of a white crystalline solid. The yield was 88percent. Melting point 304-306C.
Reference：
[1] Patent: CN104557902, 2018, B, . Location in patent: Paragraph 0055; 0064; 0065; 0078; 0091; 0104
[2] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2305 - 2310
21
[ 3973-08-8 ]
[ 75-65-0 ]
[ 1235406-42-4 ]
Yield
Reaction Conditions
Operation in experiment
94%
With diphenyl phosphoryl azide; triethylamine In <i>tert</i>-butyl alcohol for 16 h; Inert atmosphere; Reflux
5.80 ml (41.84 mmol) of triethylamine and subsequently, with ice-bath cooling, 9.10 ml (42.19 mmol) of diphenyl azidophosphate are introduced into a solution of 4.85 g (37.55 mmol) of 4-thiazolecarboxylic acid in 180 ml of tert-butanol under nitrogen, and the reaction mixture is heated under reflux for 16 h. The solvent is removed in vacuo, the residue is taken up in dichloromethane and washed twice with water and saturated NaCl solution. The organic phase is dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 7.07 g (35.30 mmol, 94percent) of tert-butyl N-(1,3-thiazol-4-yl)carbamate as beige crystals; ESI-MS: m/e: 201 ([M+H]+).
60.6%
at 0 - 90℃;
2.1 tert-butyl thiazo 1-4-ylcarbamate DPPA (1.19 g, 4.34 mmol) was added dropwise to a mixture of thiazole-4- carboxylic acid (0.5 g, 3.87 mmol) and triethylamine (0.44 g, 4.30 mmol) in tert-BuOH (50 mL) at 0 °C -5 °C. The mixture was heated to 90 °C for overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried with Na2S04, concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel (EA/heptane=l/10) to give the title compound (0.47 g, 2.35 mmol, 60.6percent) as a white solid. LC-MS : m/z 201 (M+H), RT=1.28 min; 1H NMR (400 MHz, CDC13): δ = 8.59 (d, J =2.4 Hz, 2H), 7.31 (s, 1H), 1.54 (s, 9H).
51.5%
With diphenylphosphoranyl azide; triethylamine In <i>tert</i>-butyl alcohol at 90 - 100℃; for 72 h;
Thiazol-4-carboxylic acid (5.0 g, 38.8 mmol) was dissolved in t-BuOH (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL, 1.5 eq.) were added thereto. While maintaining the internal temperature at 90 to 100°C, the reaction mixture was stirred for 3 days, and then the completion of the reaction was confirmed by TLC. The product was concentrated under reduced pressure, distilled water (50 mL) was added, and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, dried and then filtered. The filtrate was concentrated under reduced pressure, and the residue was added to a small amount of EA and slurried. The resulting solid was filtered to obtain a white title compound (4.0 g, 51.5percent). 1H NMR (MeOD): 8.73(s, 1H), 7.24(s, 1H), 1.52(s, 9H)
27%
at 100℃; for 17 h;
A mixture of thiazole-4-carboxylic acid (8.16 g, 63.2 mmol) and triethylamine (9.7 mL, 70 mmol) in tert-butanol (320 mL) was treated with diphenyl phosphoryl azide (15 mL, 70 mmol) and heated gradually in an oil bath to 100° C. and stirred for 17 h. Once cooled, the crude reaction mixture was concentrated under reduced pressure to remove most of the volatiles. The residue was transferred to a 1.0-L separatory funnel with ethyl acetate (300 mL) and the organic layer was washed with water (2×200 mL) and brine (2×100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified silica gel chromatography, eluting from 0percent to 50percent ethyl acetate in heptanes. The resultant gummy solid was triturated with heptanes, filtered, washed with heptanes and dried under high vacuum to afford tert-butyl thiazol-4-ylcarbamate (3.42 g, 27percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.54 (s, 9H), 7.30 (br. s, 1H), 8.33 (br. s, 1H), 8.58 (d, J=2.3 Hz, 1H). [M-C4H8+H]+=145.1.
With potassium permanganate; In water; at 55℃; for 22h;
4-methylthiazole (19.8 g, 0.2 mol),200 mL of water and potassium permanganate (173.8 g, 1.1 mol) were placed in a 500 mL three-neck reaction flask and heated to 55° C. for 22 h with stirring and heating.The reaction solution was then cooled and then filtered. The filter cake (manganese dioxide) was washed with hot water at 50°C, and the filtrate was adjusted to pH 3 with dilute hydrochloric acid.A solid precipitated and was filtered. The filter cake was washed with a small amount of water. The product was dried to give 18.1 g, yield 70.2percent, melting point 196-198°C.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h;
A solution of (4-Amino-3-nitro-phenyl) -carbamic acid tert-butyl ester (1-3,0. 409 g, 1.832 mmol), thiazole 4-carboxylic acid (0.226 g, 1.832 mmol) and diisopropylethylamine (0.81 ML, 4.03 mmol) in N, N DIMETHYLFORMAMIDE (10 ML) was reacted at the ambient temperature with BENZOTRIAZOL-1-YLOXYTRIPYRROLIDINOPHOSPHONIUM hexafluorophosphate (PyBop, 1.05 g, 2.02 mmmol). After 3 h stirring at the same temperature, the reaction mixture was concentrated under the reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and aqueous 0.5N-NaOH solution (70 mL). The organic layer was washed with brine, separated, dried (MGS04) and concentrated III VACUO. The resulting crude product was triturated with ethyl acetate (5 mL), collected by filtration, and dried under the reduced pressure. The mixture of the intermediate products (1-4a and 1-4b) was dissolved in aqueous 20percent (V/V)-ACETIC acid (50 mL) and heated at reflux for 2 h. The reaction mixture was cooled to the ambient temperature and concentrated IN VACUO. The resulting crude thick oil was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was washed with brine, separated, dried (MGS04) and concentrated in vacuo. The crude product was triturated with ethyl acetate (15 mL) and hexanes (2 mL). The resulting solid, 2- thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5), was collected by filtration and dried under the reduced pressure ; 1H NMR (500 MHz, DMSO-D6) 8 12.34 (s, 1 H), 9.27 (s, 1 H), 8.24 (s, 1 H), 7.27 (bs, 1 H), 6.66 (s, 1 H), 6.54 (d, 1 H, J = 7.5 Hz), 4.96 (bs, 2 H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 12.1667h;
To a solution of thiazole-4-carboxylic acid (2.25 g, 17.6 mmol) and HOBt (2.60 g, 19.2 mmol) in anhydrous DMF (80 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.69 g, 19.2 mmol) followed by the dropwise addition of a solution of Example 17D (5.07 g, 16 mmol) in anhydrous DMF (50 mL) over 10 minutes, after which anhydrous triethylamine (4.45 mL, 32 mmol) was added to the mixture via syringe. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and H2O (30 mL). The aqueous layer was extracted with ethyl acetate (2*50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The yellow solid was crystallized from ethyl acetate (30 mL). The white crystals were dried under vacuum at 40° C. for 12 hours to provide a white powder (4.8 g) as the titled compound. MS (ESI) m/e 427 (M+H)+, 425 (M-H)-; 1H NMR (500 MHz, CD3OD) delta ppm 1.41 (s, 5 H) 1.44(s, 4H), 1.66 (m, 1 H), 2.49 (m, 1 H), 2.59 (m, 1 H), 3.03 (m, 1 H), 3.13 (m, 1 H), 3.21 (m, 1 H), 3.48 (m, 2 H) 3.75 (m, 2 H) 3.85 (m, 1 H) 4.53 (m, 2 H) 4.66 (m, 1 H), 8.25 (s, 1 H), 8.99 (s, 1 H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 12.1667h;
Example 55A (2S, 4R)-4-[(Thiazole-4-carbonyl)-amino]-methyl}-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of thiazole-4-carboxylic acid (2.25 g, 17.6 mmol) and HOBt (2.60 g, 19.2 mmol) in anhydrous DMF (80 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.69g, 19.2 mmol) followed by the dropwise addition of a solution of Example 17D (5.07 g, 16 mmol) in anhydrous DMF (50 mL) over 10 minutes, after which anhydrous triethylamine (4.45 mL, 32 mmol) was added to the mixture via syringe. The mixture was allowed to stir for 12 hours at room temperature, concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and H2O (30 mL). The aqueous layer was extracted with ethyl acetate (2*50 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The yellow solid was crystallized from ethyl acetate (30 mL). The white crystals were dried under vacuum at 40° C. for 12 hours to provide a white powder (4.8 g) as the titled compound. MS (ESI) m/e 427 (M+H)+, 425 (M-H)-; 1H NMR (500 MHz, CD3OD) delta ppm 1.41 (s, 5H) 1.44(s, 4H), 1.66 (m, 1H), 2.49 (m, 1H), 2.59 (m, 1H), 3.03 (m, 1H), 3.13 (m, 1H), 3.21 (m, 1H), 3.48 (m, 2H) 3.75 (m, 2H) 3.85 (m, 1H) 4.53 (m, 2H) 4.66 (m, 1H), 8.25 (s, 1H), 8.99 (s, 1H).
N-[4-(4-Piperidinomethyl-pyridin-2-yloxy)-cis-2-butenyl]thiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
EXAMPLE 26 N-[4-(4-Piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]thiazole-4-carboxamide Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 4-thiazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 68percent yield. Nuclear Magnetic Resonance Spectrum (CDCl3), delta ppm: 1.36-1.52 (2H, multiplet); 1.52-1.67 (4H, multiplet); 2.24-2.53 (4H, multiplet); 3.43 (2H, singlet); 4.26 (2H, triplet, J=6.4 Hz); 4.98 (2H, doublet, J=6.4 Hz); 5.72-5.81 (1H, multiplet); 5.86-5.96 (1H, multiplet); 6.75 (1H, singlet); 6.90 (1H, doublet, J=5.4 Hz); 7.40-7.58 (1H, broad); 8.11 (1H, doublet, J=5.4 Hz); 8.18 (1H, doublet, J=2.4 Hz); 8.75 (1H, doublet, J=2.4 Hz). Infrared Absorption Spectrum (liquid film), numax cm-1: 2936, 1664, 1611, 1560, 1540, 1481, 1420, 1403, 1313, 1288.
With dimethylsulfide borane complex; In tetrahydrofuran; at 0℃; for 24h;
164 2-( 1 H-Indazol-4-yl V4-morpholin-4-yl-6-(4-thiazol-4-ylmethyl-piperazin- 1 - ylmethyl)-thieno[3,2-d1pyrimidine.Via 2-chloro-4-mophiholin-4-yl-6-(4-thiazol-4-ylmethyl-piperazin- 1 - ylmethyl)-thieno[3,2-d]pyrimidine, prepared from l-thiazol-4-ylmethyl-pirhoerazine, via 2-chloro-4-morpholin-4-yl-6-(4-thiazol-4-ylmethyl-piperazin- 1 -ylmethyl)- thieno[3,2-d]pyrimidine, prepared according to the following procedure: to a suspension of 4-thiazolecarboxylic acid (500mg) in THF (1OmL) was added borane- dimethylsulfide complex (0.73mL). After 24 h the mixture was cooled to O0C and quenched by the addition of 2M hydrochloric acid and extracted into ethyl acetate. The organic layers were washed with brine and dried (MgSO4). The solvent was evaporated and the residue stirred in DCM/MeOH overnight. The mixture was concentrated and the residue purified by flash chromatography to give thiazol-4-yl- methanol (173mg). To a solution of thiazol-4-yl-methanol (168mg) in DCM (5mL) was added triethylamine (0.33mL) followed by methanesulfonyl chloride (0.17mL) at O0C. The mixture was stirred at room temperature for 10 min and diluted with DCM, washed with brine and dried (MgSO4). The crude product was purified by flash chromatography to give methanesulfonic acid thiazol-4-yl methyl ester (263 mg). To a solution of 2-chloro-4-morpholin-4-yl-6-piperazin-l-ylmethyl-thieno[3,2- d]pyrimidine (300mg) and methanesulfonic acid thiazol-4-yl methyl ester (213 mg) in MeCN (1OmL) was added potassium carbonate (164 mg) and the mixture heated at 80 °C for 8 h. The cooled mixture was filtered, the solvent evaporated and the residue partitioned between DCM and water. The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography to give the desired product (249mg). EPO <DP n="88"/>1H NMR (400MHz, CDCl3) 2.57 (br s, 4H), 3.71 (s, 2H), 3.79 (s, 2H), 3.85 (t, J=4.8Hz, 4H), 4.02 (t, J=4.8Hz, 4H), 7.13 (s, IH), 7.30 (s, IH), 7.43 (t, J=7.8Hz, IH), 7.51 (d, J=8.3Hz, IH), 8.21 (d, J=6.9Hz, IH), 8.71 (d, J=2.0Hz, IH), 8.95 (s, IH), 10.10 (br s, IH); MS (ESI+) 533.25 (MH+).
Example 11 : 2-(lH-Indol-4-vI)-4-morpholin-4-yl-6-(4-thiazoI-4-vImethvI- piperazin-l-ylmethyl)-thieno[3,2-d1pyrimidine; To a suspension of 4-thiazolecarboxylic acid (500 mg) in tetrahydrofuran (10 mL) was added borane-dimethylsulfide complex (0.73 mL). After 24 hours the mixture was cooled to 0 °C and quenched by the addition of 2M hydrochloric acid and extracted into ethyl acetate. The organic layers were washed with brine and dried (MgSO4). The solvent was evaporated and the residue stirred in dichloromethane- methanol overnight. The mixture was concentrated and the residue purified by flash chromatography to give thiazol-4-yl-methanol (173 mg).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 15h;
Example 2Preparation of Compound 2To a solution of thiazole-5-carboxylic acid (0.050 mmol, 10 mg), N1N- diisopropylethylamine (0.20 mmol, 26 mg) and HATU (0.050 mmol, 19 mg) in DMF (1 mL) was added 4-(2-aminophenyl)-piperazine-1 -carboxylic acid te/t-butyl ester (0.10 mmol, 28 mg). The resulting reaction was heated to 80 0C and allowed to stir at this temperature for 15 h, after which time the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was reacted with TFA (0.5 mL) for 10 minutes. The TFA solution was then concentrated in vacuo to provide a crude residue which was purified using reverse phase HPLC to provide Compound 2.
[628] Example 159 - 3-r5-(4-Methyl-cyclohexyl -l,2,3,6-tetrahydro-pyridin-4-yl1-5-|4-r(thiazole- 4-carbonyiyaminol -phenyl I -thiophene-2-carboxylic acid; [629] <strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (1.42 g, 11 mmol) in DCM (20 mL) was treated with oxallyl chloride (8 mL, 2 M solution in DCM), followed by 2 drops of DMF. After 1 hr at RT, solvent was evaporated, and the residue was redissolved in DCM (20 mL). To the solution was added 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzenamine (2.20 g, 10 mmol) and TEA (2 mL). After 30 min at RT, the reaction mixture was diluted with ether (100 mL), washed with water, sodium bicarbonate, and brine. The organic layer was dried over anhydrous MgS04, filtered and concentrated to give 15
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h;
Example A5: Preparation of compound A5b A solution of A4a (1.0 g, 4.6 mmol, Oakwood) in DMF (10 mL) is treated with Ala (766.3 mg,6.0 mmol, Combi Blocks), DIPEA (2.0 mL, 11.4 mmol) and HATU (2.4 g, 6.4 mmol). Thereaction mixture is stirred for 30 mm, and then partitioned between water (30 mL) and EtOAc(50 mL). The layers are separated and the organic layer is washed with brine, dried over MgSO4and concentrated. The crude residue is triturated in water (40 mL) by sonication for 15 mm. Thesuspension is filtered and rinsed with water (25 mL). The residue is dried under high vacuumand nitrogen flow for 1 h to provide A5b.
To thiazole 4-carboxylic acid (2.5 g) was added dry DMF (68 ml_), DIPEA (6.67 ml.) and HATU (13.1 g). The reaction was stirred at room temperature for 1 hour under a nitrogen atmosphere. 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (5.1 g) was added and stirring continued for 24 hours. The cooled reaction was partitioned between EtOAc and saturated sodium bicarbonate. The phases were separated and the combined organic fractions washed further with saturated sodium bicarbonate, then water, then 2N HCI (x2) and then saturated brine. The organic fraction was passed through a hydrophobic frit and concentrated. The crude material was purified using a 330 g silica Biotage cartridge, eluting a 0% to 100% EtOAc in cyclohexane gradient to give the title compound. MS calcd for (Ci6H19BN2O3S + H)+ : 331 MS found (electrospray) : (M+H)+ = 331
To 1 ,3-thiazole-4-carboxylic acid (2.5 g) was added dry DMF (68 ml_), DIPEA (6.67 ml.) and HATU (13.1 g). The reaction was stirred at room temperature for 1 h under nitrogen. (4- Aminophenyl)boronic acid (5.1 g) was added and the reaction was stirred for 24 h, then partitioned between EtOAc and saturated sodium bicarbonate solution. The organic phases were washed further with saturated sodium bicarbonate solution, water, 2N HCI (x 2) and brine. The organic phases were passed through a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 0-100% EtOAc in cyclohexane to give the title compound. MS calcd for (Ci0H9BN2O3S + H)+: 331 MS found (electrospray): (M+H)+ = 331
1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (200 mg) was dissolved in DMF (6 ml_). HATU (650 mg) and DIPEA (0.539 ml.) were added and the reaction mixture was stirred at room temperature for 15 mins. 4-lodoaniline (508 mg) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in DCM. This was washed with sodium bicarbonate solution (x 2) followed by 2N HCI (x 2). The DCM was separated, dried using a hydrophobic frit and was evaporated in vacuo to give the title compound. MS calcd for (C10H7IN2O5 + H)+: 331 <n="43"/>MS found (electrospray): (M+H)+ = 331
{4-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-[(methyloxy)carbonyl]-2-thienyl}boronic acid[ No CAS ]
methyl 3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{6-[(1,3-thiazol-4-ylcarbonyl)amino]-3-pyridinyl}-2-thiophenecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (93 mg) was dissolved in DMF (4 ml_). HATU (293 mg) and DIPEA (248 mg) were added and the mixture was stirred at room temperature for 10 mins. A solution of Intermediate 4 (200 mg) in DMF (2 ml.) was added and the reaction mixture stirred at room temperature for 3 days. The reaction mixture was evaporated in vacuo and the residue partitioned between DCM and saturated sodium bicarbonate solution. The organic phase was separated and dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion.(TM). silica chromatography, eluting with a gradient of 3-100percent EtOAc in cyclohexane to give the title compound. MS calcd for (C26H30N4O4S2 + H)+: 526 MS found (electrospray): (M+H)+ = 526
methyl 5-(6-amino-5-methyl-3-pyridinyl)-3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2-thiophenecarboxylate[ No CAS ]
methyl 3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{5-methyl-6-[(1,3-thiazol-4-ylcarbonyl)amino]-3-pyridinyl}-2-thiophenecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 92h;
A solution of 1 ,3-thiazole-4-carboxylic acid (45 mg), Intermediate 93 (150 mg), DIPEA (135 mg) and HATU (160 mg) in DMF (2 ml.) was stirred at room temperature under nitrogen for 16 h. The reaction mixture was left for a further 2 days. 1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (23 mg) and HATU (67 mg) was added to the reaction mixture which was stirred for 1 day. 1 ,3- <strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (135 mg) were added and stirred for 1 day. The reaction was evaporated in vacuo and partitioned between HCI and DCM. The organic phase was washed with sodium bicarbonate, separated and evaporated in vacuo. The crude material <n="85"/>was purified using a 12 g ISCO Companion.(TM). silica cartridge eluting with a gradient of EtOAc in cyclohexane to give the title compound. MS calcd for (C27H32N4O4S2+ H)+ : 541 MS found (electrospray) : (M+H)+ = 541
methyl 5-(4-amino-3-chlorophenyl)-3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2-thiophenecarboxylate[ No CAS ]
methyl 5-{3-chloro-4-[(1,3-thiazol-4-ylcarbonyl)amino]phenyl}-3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2-thiophenecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (65 mg) was dissolved in DMF (4 ml.) then HATU (867 mg) and DIPEA (0.175 ml.) were added. The reaction was stirred for 15 mins then Intermediate 28 (250 mg) was added. The reaction was stirred at room temperature overnight, then at 7O0C for 4 h. DMAP (4 mg) was added and the reaction was stirred at 7O0C for 18 h. The reaction was evaporated in vacuo and was partitioned between DCM and sodium bicarbonate solution. The organic phases were dried by passing through a hydrophobic frit and were evaporated in vacuo. The crude material was purified by ISCO Companion.(TM). silica chromatography, eluting with a gradient 5-100percent EtOAc in cyclohexane to give the title compound. MS calcd for (C27H30CIN3O4S2 + H)+: 560/562 <n="54"/>MS found (electrospray): (M+H)+ = 560/562
methyl 5'-amino-4-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2,2'-bithiophene-5-carboxylate[ No CAS ]
methyl 4-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5'-[(1,3-thiazol-4-ylcarbonyl)amino]-2,2'-bithiophene-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1 ,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (40.9 mg) was dissolved in DMF (5 ml_). HATU (132 mg) and DIPEA (150 mg) were added and the mixture was stirred at room temperature for 15 mins. Methyl 5'-amino-4-[[(frans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2,2'- bithiophene-5-carboxylate (130 mg, a synthesis of which is described as Intermediate 33) was added and the reaction mixture was stirred at room temperature over a weekend. The reaction was evaporated in vacuo and was partitioned between DCM and sodium bicarbonate solution. The organic phases were dried by passing through a hydrophobic frit and were evaporated in vacuo. The crude material was purified by ISCO Companion.(TM). silica chromatography, eluting with a gradient 5-100percent EtOAc in cyclohexane to give the title compound.MS calcd for (C25H29N3O4S3 + H)+: 532 MS found (electrospray): (M+H)+ = 532
To a solution of 4-thiazolecarboxylic acid (0.24 g) and HATU (0.70 g) in N, N- dimethylformamide (5 ml.) was added DIPEA (0.80 ml.) and the reaction was stirred at room temperature under nitrogen for 10 mins. 4-Bromo-2-(methyloxy)phenyl]amine (0.31 g) was added and the reaction stirred at room temperature under nitrogen for 20 h. The reaction mixture was evaporated in vacuo and loaded onto a 5 g aminopropyl cartridge in DCM. The cartridge was eluted with DCM (3 column volumes) and methanol (3 column volumes). The fractions were evaporated in vacuo. The crude material was purified using a 40 g silica Silicycle cartridge eluting with a gradient of 0 - 100percent EtOAc in cyclohexane to give the title compound.MS calcd for (C28H30F3N3O4S2 + H)+ : 313/315 MS found (electrospray) : (M+H)+ = 313/315
Example 240; N-{ 6- [5- ( { [3- (1-cyano-l-methylethyl) phenyl] carbonyl} amino) -2- methylphenoxy] [1, 2, 4] triazolo [1, 5-a]pyridin-2-yl}-l, 3-thiazole-4- carboxamide; 20To a solution of 1, 3-thiazole-4-carboxylic acid (121 mg, 938 mumol) in tetrahydrofuran (3 mL) were added oxalyl chloride (102 muL, 1.17 mmol) and N,N-dimethylformamide (20 muL) and the25 mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue and N-{3- [ (2-amino[l,2, 4] triazolo[l, 5-a]rhoyridin-6- yl)oxy]-4-methylphenyl}-3- (1-cyano-l-methylethyl) benzamide (200 mg, 0.469 mmol) were dissolved in pyridine (5 mL) , and the30 mixture was stirred at room temperature for 16 hr. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl <n="403"/>acetate (20 mL, 5 mL) . The combined organic layer was washed with saturated brine (5 mL) , and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0--->99/l) , and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration, and dried to give the title compound (206 mg, 82percent) as a colorless powder.1H-NMR (DMSO-de, 300 MHz) delta 1.71 (6H, s) , 2.23 (3H, s) , 7.27 - 7.36 (2H, m), 7.50 - 7.62 (3H, m) , 7.71 (IH, ddd, J = 7.9, 2.0, 1.0 Hz), 7.80 - 7.89 (2H, m) , 7.96 (IH, t, J = 1.7 Hz), 8.61 (IH, d, J = 2.0 Hz), 8.89 (IH, dd, J = 2.3, 0.8 Hz), 9.28 (IH, d, J = 2.0 Hz), 10.25 (IH, s) , 10.72 (IH, s) .
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃;
To a mixture of thiazole-4-carboxylic acid (1 g, 7.74 mmol), N,O-dimethylhydroxylamine (1.51 g, 15.5 mmol), and HATU (3.83 g, 10.07 mmol) in CH2Cl2 (25 mL) was added TEA (4.84 mL, 34.85 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The organics were concentrated and purified by chromatography (60-70percent EtOAc/hexanes) to yield N-methoxy-N-methylthiazole-4-carboxamide as a clear oil. 1H NMR (CDCl3) delta: 8.83 (s, 1H), 8.10 (s, 1H), 3.79 (s, 3H), 3.46 (s, 3H)
With triethylamine; HATU; In dichloromethane; at 20℃;
STEP 1: N-methoxy-N-methylthiazole-4-carboxamide To a mixture of thiazole-4-carboxylic acid (1 g, 7.74 mmol), N,O-dimethylhydroxylamine (1.51 g, 15.5 mmol), and HATU(3.83 g, 10.07 mmol) in CH2Cl2 (25 mL) was added TEA (4.84 mL, 34.85 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 and water. The organics were concentrated and purified by chromatography (60-70percent EtOAc/hexanes) to yield N-methoxy-N-methylthiazole-4-carboxamide as a clear oil. 1H NMR (CDCl3) delta: 8.83 (s, 1H), 8.10 (s, 1H), 3.79 (s, 3H), 3.46 (s, 3H)
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 12h;
A mixture of 2-(3-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-4-amine (13; 0.28 g, 1.0 mmol), thiazole-4-carboxylic acid (14; 0.15 g, 1.2 rnmol), DIEA (0.42 mL, 2.4 mmol) and HATU (0.79 g, 2.07 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. A saturated aqueous solution OfNaHCO3 (5 mL) was added and the mixture was filtered. The residue was washed with ethyl acetate (3x15 mL) and the aqueous layer was extracted with ethyl acetate (3x15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ethepiethyl acetate = 10: 1 ) to give N-(2-(3-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-4-yl)thiazole-4-carboxamide (Compound 332) (0.30 g, 0.77 mmol, 77 percent) as a colorless solid. MS (ESI) calcd for Ci8Hj 1F3N4OS: 388.06; found: 389 [M+H].
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
Step 3) Preparation ofN-(2-(3-(trifluoromethoxy)phenyl)benzo[d]oxazol-4- yl)thiazole-4-carboxamide (Compound 104): 2-(3-(Trifluoromethoxy)phenyl)benzo[d]oxazol-4-amine (3; 68 mg, 0.23 mmol) was taken up in 2 mL of DMF along with thiazole-4-carboxylic acid (51; 30 mg, 0.23 mmol), HATU (175 mg, 0.46 mmol) and DIEA (80 muL, 0.46 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and dilute aqueous NaHCO3 (10 mL) was. The resulting solids were collected by filtration, washed with water, aqueous MeOH (1:1), and dried to afford the product as an off-white solid. An analytically pure sample of N-(2-(3-(trifluoromethoxy)phenyl)benzo[d]oxazol-4-yl)thiazole-4-carboxamide (Compound 104) could be obtained by additional purification using reverse phase HPLC employing a mixture of aqueous CH3CN that has been buffered with 0.1percent TFA. MS (ESI) calcd for Ci8Hi0F3N3O3S: 405.04; found: 406 [M+H]. Additional compounds shown in Table 1 were prepared by using the appropriate carboxylic acid according to the general amide coupling procedure shown in this step.
Exam ple 1K: Com pound 1010Step 1: Stir a mixture of 1cS (28 mg, O.O.euro..euro. mmol), TEA (46 muL, 0.33 mmol), TBTU (27 mg, 0084 mmol), 1 r3'thiazole-4~carboxy1kappa: acid (18 mg, 0.13 mmol} in DMSO (15 mL) for about 18 h. Add 5 N NaOH (aqueous, Q Z mL) and heat to 45°C for about 1 h. Acidify to approximately pH<=2 with TFA, purify and lysigmapitize the volatiles to afford 1010.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;
Step 3. Preparation of N-(4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromen-8- yl)thiazole-4-carboxamide: 8-amino-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one (178) (70 mg, 0.23 mmol) was taken up in 2 mL of DMF along with thiazole-4-carboxylic acid 3 (30 mg, 0.23 mmol), EtaATU (175 mg, 0.46 mmol) and DIEA (80 muL, 0.46 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with 5 mL of H2O. The resulting solids were collected by filtration, washed successively with a solution of dilute NaHCO3ZMeOH (1:1), aqueous MeOH, dilute 1 N HCl/MeOH (1:1), aqueous MeOH, and then pure MeOH. After drying under high vacuum, 28 mg of Compound 204 was obtained as an off-white solid. MS (ESI) calcd for C20HnF3N2O3S: 416.04; found: 417 [M+H].
1 ,3-thiazole-4-carboxylic acid (0.775 g, 6 mmol, commercially available from e.g. Sigma-AIdrich, Apollo or Fluorochem) was dissolved in dichloromethane (DCM) (50 ml_), and the solution was cooled to 0 0C. To this was added oxalyl chloride (0.578 ml_, 6.60 mmol) and 5 drops of DMF (cat.) and the solution was stirred, under argon, for 3 hours. The solvent was then removed in vacuo, and the remaining residue was redissolved in dichloromethane (DCM) (50 ml_), before 1 ,1-dimethylethyl hydrazinecarboxylate (0.872 g, 6.60 mmol) and DIPEA (1.258 ml_, 7.20 mmol) were added. The solution was stirred under argon for 2 hours, LCMS and TLC confirmed product formation, thus the solvent was evaporated in vacuo. The remaining residue was then partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (20 ml). The aqueous phase was then further extracted with ethyl acetate (2 x 30 mL) and the combined extracts were washed with brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was then evaporated in vacuo to yield the product in 1.308 g.
9-amino-8-methoxy-1-thiophen-2-yl-5,6-dihydro-imidazo[5,1-a]isoquinoline-3-carboxylic acid tert-butyl-methyl-amide hydrochloride[ No CAS ]
[ 1256776-78-9 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 2h;
A mixture of the product of example 6b (60 mg), thiazole-4-carboxylic acid (25 mg), N- ethylmorpholine (40 mul) and TBTU (50 mg) in DMF (1 ml) was stirred at room temperature for 2 h. The reaction mixture was poured in an aqueous NaHCO3 solution (5percent). The mixture was extracted with ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in dichloromethane/ethyl acetate as eluent. The fractions with product were combined and concentrated in vacuo. The residue was treated with diethyl ether and dried in vacuo (50 0C). Yield: 45 mg. LC/MS-ESI: [M+H]+ = 522.1; TLC Rf = 0.16 (heptane/ethyl acetate 1 :1); Mp: 240-242 0C; 1H-NMR (DMSO-d6) delta 1.48 (s, 9H, terf-butyl), 3.05 (m, 3H + 2H, N CH3 + C(6)H2), 3.97 (s, 3H, O CH3), 4.18 (t, 2H, C(5)H2), 7.1, 7.48 and 7.51 (3xm, 3H, thiophene), 7.21 (s, IH, H7-Ar), 8.90 (s, IH, HlO-Ar), 8.52, 9.25 (2xd, H2 and H5- thiaz), 9.78 (s, IH, NH); hFSHRago (CHO luc) EC50 = 13 nM
With N-ethylmorpholine;; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Example 11 8-Methoxy-9-[(thiazole-4-carbonyl)-amino]-1-thiophen-2-yl-5,6-dihydro-imidazo[5,1-a]isoquinoline-3-carboxylic acid tert-butyl-methyl-amide A mixture of the product of example 6b (60 mg), thiazole-4-carboxylic acid (25 mg), N-ethylmorpholine (40 mul) and TBTU (50 mg) in DMF (1 ml) was stirred at room temperature for 2 h. The reaction mixture was poured in an aqueous NaHCO3 solution (5percent). The mixture was extracted with ethyl acetate. The organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in dichloromethane/ethyl acetate as eluent. The fractions with product were combined and concentrated in vacuo. The residue was treated with diethyl ether and dried in vacuo (50° C.). Yield: 45 mg. LC/MS-ESI: [M+H]+=522.1; TLC Rf=0.16 (heptane/ethyl acetate 1:1); Mp: 240-242° C.; 1H-NMR (DMSO-d6) delta 1.48 (s, 9H, tert-butyl), 3.05 (m, 3H+2H, NCH3+C(6)H2), 3.97 (s, 3H, OCH3), 4.18 (t, 2H, C(5)H2), 7.1, 7.48 and 7.51 (3*m, 3H, thiophene), 7.21 (s, 1H, H7-Ar), 8.90 (s, 1H, H10-Ar), 8.52, 9.25 (2*d, H2 and H5-thiaz), 9.78 (s, 1H, NH); hFSHRago (CHO luc) EC50=13 nM.
With triethylamine; HATU; In N,N-dimethyl acetamide; at 150℃; for 0.5h;microwave irradiation; Sealed tube;
General procedures for Example 147-159; To a solution of 147a (13 mg, 0.02 mmol) in DMA in a 4 ml vial was added the acid monomer (0.025 mmol) dissolved in DMA followed by a solution of HATU (0.025 mmol) in DMA and then triethylamine (0. 4 mmol) neat. The vial was capped and microwaved at 150 °C for 30 minutes. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in MeOH:DMSO (1:1 v:v, 1.5 ml) and purified by reverse phase HPLC.HPLC condition: Samples were purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100A AXIA column (30mm x 75mm). A gradient of methanol (A) and 0.1percenttrifluoroacetic acid in water (B) was used, at a flow rate of 50mL/min (0-0.5 min 20percent A, 0.5- 6.0 min linear gradient 20-100percent A, 6.0-7.0 min 100percent A, 7.0-8.0 min linear gradient 100- 10percent A).; Exam le 147N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-ethyl-7-fluoroquinoxalin-2-yloxy)-14a-(l- methylcyclopropylsulfonylcarbamoyl)-5,16-dioxo- 1,2,3, 5,6,7, 8, 9, 10, 11, 13a, 14,14a, 15,16, 16a-hexadecahydrocyclopropa[e]pyrrolo[l, 2- a][l,4]diazacyclopentadecin-6-yl)thiazole-4-carboxamide; The title compound 147 was prepared according to the general procedure used for Example 147-159, using thiazole-4-carboxylic acid as the acid monomer. MS (ESI): m/z = 768.2 [M+H].
Step A: To thiazole-4-carboxylic acid (1 g, 7.7 mmol) in THF (30 mL) at 0 °C was added TEA (1.08 mL, 7.7 mmol) followed by dropwise addition of ethyl chloroformate (0.74 mL, 7.7 mmol). The mixture was stirred at 0 °C for 15 min and then sodium azide (3.77 g, 57.9 mmol) was added. The mixture was stirred for 15 min and then partitioned between water and EtOAc. The organic layer was separated, dried over Na2S04, and concentrated under reduced pressure to afford thiazole-4- carbonyl azide (940 mg, 79percent). 1H NMR (300 MHz, DMSO-t/6) delta 9.23 (s, 1H), 8.76 (s, 1H).
[370] l,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (100 mg) was dissolved in DMF (3 mL). To it were added HATU (325 mg) and DIPEA (0.35 mL) and the reaction mixture was stirred at RT for 15 min.Compound 059A (168 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT for 4 hr. The reaction mixture was evaporated in vacuo and the residue was dissolved in DCM (50 mL). This was washed with sodium bicarbonate solution (2 x10 mL) followed by brine. The organic layer was concentrated and purified by column chromatography with 0-5percent MeOH in DCM as eluent to give pure 059B. MS calcd: (M+H)+ = 554. MS found: (M+H)+ = 554.
[529] 122B is stirred in DCM (3 mL) and trifluoroacetic acid (TFA, 1 mL) at RT under N2 for 1 hr. The reaction is evaporated in vacuo. The residue is dissolved in DMF (2 mL), and to it is added HATU (0.2 mmol), TEA (0.5 mmol), and l,3-thiazole-4-carboxylic acid (0.2 mmol). After the reaction is stirred at RT for 15 hr, the mixture is diluted with EtOAc (50 mL), washed with water (2x10 mL) and brine (10 mL), dried over MgS04, and concentrated. The residue is purified by column chromatography with 0-10percent MeOH in DCM to give ester 122C. Purification and subsequent hydrolysis of 122C, and extraction to recover the resulting acid, are conducted generally as described for 112, to give 122.
[249] Example 13 - 3 1-Methyl-5-(4-methyl-cvclohexyl)-l,2,3,6-tetrahvdro-pyridin-4-yl1-5-|4-; [250] l,3-<strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (100 mg) was dissolved in DMF (3 mL). 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU; 325 mg) and diisopropylethylamine (DIPEA; 0.35 mL) were added and the reaction mixture was stirred at RT for 15 min. Compound 004B (161 mg, 0.38 mmol) was added and the reaction mixture was stirred at RT for 1 hr. The reaction mixture was evaporated in vacuo and the residue was dissolved in DCM. This was washed with NaHC03 solution (2x) followed by 2 N HC1 (2x). The DCM was separated and concentrated to obtain the compound as a brown oil, which was purified by column chromatography to give 013A. MS cal + = 536. MS found: (M+H)+ = 536.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
5-(2,9-Diazaspiro[5.5]undec-2-yl)- 1 -(2,2-dimethylpropyl)-3-methyl- 1 ,3-dihydro- 2H-imidazo[4,5-.pound.]pyridin-2-one (22-2, 20 mg, 0.054 mmol) was added to anhydrousdimethylformamide (354 Thiazole-3-carboxylic acid (6.95 mg, 0.054 mmol), EDC (10.32 mg, 0.054 mmol), EtaOmicronBetaTau (8.24 mg, 0.054 mmol) and triethylamine (15 0.108 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100percent, 0.1percent TFA in H20:acetonitrile) to give l-(2,2- dimethylpropyl)-3-methyl-5-[9-(l,3-thiazol-4-ylcarbonyl)-2,9-diazaspiro[5.5]undec-2-yl]-l,3- dihydro-2H-imidazo[4,5-3/4]pyridin-2-one (22-3) as a white solid. MS m/z (Mu+Eta): calculated = 483.2537; observed = 483.2530.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
5-(2,7-Diazaspiro[4.5]dec-7-yl)-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro- 2H-imidazo[4,5-.pound.]pyridin-2-one (23-2, 20 mg, 0.056 mmol) was added to anhydrousdimethylformamide (368 Thiazole-3-carboxylic acid (7.22 mg, 0.056 mmol), EDC (10.72 mg, 0.056 mmol), EtaOmicronBetaTau (8.57 mg, 0.056 mmol) and triethylamine (11 0.112 mmol) were added sequentially and the resulting reaction mixture was allowed to stir at room temperature for 18 h. Following this duration, the contents were filtered and the resulting filtrate was purified via reverse-phase HPLC (10-100percent, 0.1percent TFA in H20:acetonitrile) to give l-(2,2- dimethylpropyl)-3-methyl-5-[2-(l,3-thiazol-4-ylcarbonyl)-2,7-diazaspiro[4.5]dec-7-yl]-l,3- dihydro-2H-imidazo[4,5-b]pyridin-2-one (23-3) as a white solid. MS m/z (M+H): calculated = 469.2380; observed = 469.2373.
N-(4-(2-(4-(pyridin-2-ylmethylene)piperidine-1-carboxamido)thiazol-5-yl)phenyl)thiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h;
The compound (70 mg, 179 mumol) obtained in Example 25 (2) was dissolved in DMF (3 mL), and then HOBt (38 mg, 250 mumol), WSC (48 mg, 250 mumol) and thiazole-4-carboxylic acid (32 mg, 250 mg) were added thereto, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and the precipitate was collected by filtration. The obtained crude product was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:50), thereby giving the title compound (38 mg, 42percent) as a pale brown solid. 1H-NMR (DMSO-d6): delta (ppm) 2.38 (t, J=4.8 Hz, 2H), 2.98 (t, J=4.8 Hz, 2H), 3.59 (t, J=4.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 2H), 6.39 (s, 1H), 7.18 (dd, J=5.2, 8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.71-7.76 (m, 2H), 7.90 (d, J=8.4 Hz, 2H), 8.51 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 9.27 (s, 1H)
O-phenylenediamine (10.8 g, 0.1 mol) and polyphosphoric acid (21 g, 0.062 mol) were added to the reaction flask.Nitrogen protection, the oil bath was quickly heated under stirring to 150 deg.] C,Then thiazole-4-carboxylic acid (12.9 g, 0.1 mol) was added and the temperature was raised to 230°C and the reaction was incubated for 2 h.The reaction was stopped, slightly cooled and poured into 200 g of ice-water mixture while hot, and the mixture turned into a dark brown liquid.When 40percent sodium hydroxide solution was used to neutralize to pH=5-6, a large amount of purple gray precipitated out, solid was filtered off, and washed with 20mL*4 water to obtain a purple-gray solid, namely thiabendazole crude product.The crude product is dissolved in 10 times the quality of the water, adjusted with dilute hydrochloric acid pH = 1-2, add activated carbon reflux decolorization, filtration,The filtrate was warmed to weak basic pH with a saturated aqueous solution of sodium bicarbonate (pH = 7-8), then filtered and dried to give 17.7 g of a white crystalline solid. The yield was 88percent. Melting point 304-306C.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;Ionic liquid;
General procedure: To a solution of the benzoxazole core (1.0 eq) in DMF (10 mL/mmol of limiting reagent) was added the carboxylic acid (1.2 eq), HBTU (1.2 eq) and triethylamine (5.0 eq). The solution was stirred under nitrogen at 45 °C overnight. The solution was extended with ethyl acetate, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide.
4-chloro-3-(oxazolo[4,5-b]pyridin-2-yl)benzenamine[ No CAS ]
[ 1448806-17-4 ]
Yield
Reaction Conditions
Operation in experiment
83%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 45℃;Inert atmosphere;
General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 45℃;Inert atmosphere;
General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 45℃;Inert atmosphere;
General procedure: To a solution of the benzoxazole core (1.0 eq) in DCM (2 mL) was added the carboxylic acid (1.2 eq), EDCI (1.2 eq) and DMAP (0.1 eq). The solution was stirred under nitrogen at 45 °C overnight. Work-up 1 (W1): The solution was extended with DCM, a saturated solution of sodium bicarbonate was added and the mixture was extracted three times with DCM. The combined organic layers were then washed with brine, dried with sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting ethyl acetate/cyclohexane 50:50 led to the desired carboxamide. Work-up 2 (W2): Water (approximately 2 mL) was added to the reaction mixture and it was transferred to the fridge overnight. The resulting precipitate was filtered and gave the desired carboxamide.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 90℃; for 12h;Inert atmosphere;
General procedure: A mixture of compound 5 (0.13 mmol), the appropriate acid (0.17 mmol), HOBt (0.17 mmol), and EDCI (0.19 mmol) in dry DMF was cooled to 0 °C under nitrogen atmosphere. To the reaction mixture, triethylamine (0.16 mmol) was added at 0 °C. The mixture was then stirred at 90 °C for 12 h. The reaction mixture was cooled and then partitioned between water and ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. After evaporation of the organic solvent, the residue was purified by column chromatography to afford the corresponding compounds 1a-l.
N-[4-(2-pyridinyl)-1,3-thiazol-2-yl]thiazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
General procedure: EDCI (1.7 mmol) was added in small batches to a solution of the carboxylic acid (1.4 mmol) and HOBt (1.7 mmol) in dry DCM or DMF (5 ml), and the reaction mixture was stirred for 10 minutes at room temperature. A solution of the appropriate amine (1.1 mmol) in 5 ml of dry DCM or DMF was added in small portions and the reaction mixture left to stir for 24 hr at room temperature (monitored by TLC until completion). The reaction mixture was then washed with saturated aqueous sodium bicarbonate (3 x 10ml), saturated aqueous sodium chloride (2 x 10ml), dried with anhydrous Na2SO4 and concentrated under reduced pressure. Purification by column silica gel chromatography (EtOAc/Hexane, 40:60) afforded the products as solids
General procedure: 5.1.3. General procedure C. To the carboxylic acid substrate (0.42 mmol, 1.2 equiv) in DMF (1.5 mL) was added CDI (0.50 mmol, 1.1equiv) and DBU (0.67 mmol, 1.9 equiv). The reaction was stirred for 30 min at 23 °C. Next, 2-amino-4-(2-pyridyl)thiazole 20 (0.35 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 16 h at 23 °C. A small amount of silica gel was added to the reaction mixture, which was concentrated in vacuo under reduced pressure. The crude product impregnated on the silica gel was purified by silica gel flash chromatography (0?10percent MeOH?CH2Cl2) to afford the title compound.
4-amino-1-((2R,3R,4R,5R)-5-(aminomethyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyrimidin-2(1H)-one[ No CAS ]
C37H37N5O7S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;
To a solution of 1 (0.25 g, 0.428 mmol) and Et3N (0.04 g, 0.428 mmol) in DMF (2 ml) was added a solution of HOBT (0.07 g, 0.428 mmol), HBTU (0.16 g, 0.428 mmol) and 4-thiazolecarboxylic acid (0.06 g, 0.428 mmol) in DMF(3ml). The resulting solution was allowed to stir overnight at rt. Purification by flash chromatography (Et3N/MeOH/EtOAc = 1/10/89) yielded protected intermediate which was taken directly to the next step without further characterization. Started from the protected intermediate, CH3CN (1.5 ml), H2O (1.5 ml) and TFA (1.3 ml) was added to the reaction mixture. The resulting solution was allowed to stir overnight at rt. The volatiles were removed in vacuo and the reaction mixture was subjected to reverse phase chromatograph, followed by lyophilization yielding 6 as a white solid (0.10 g, 40percent).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;
Step 1:A solution of DIPEA (1.2 mL, 7.0 mmol), A17a (Aldrich, 530 mg, 3.5 mmol) and Ala (300 mg, 2.3 mmol) in DMF (14 mL) is treated with HATU (1.3 g, 3.5 mmol). The mixture is stirred for 2 h and then is diluted with water and EtOAc. The organic layer is separated, washed with water (2 x) and passed through a phase separator. The filtrate is evaporated to dryness and the residue is purified by Combif lash to give A17b.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2.58333h;
Step 4:A solution of DIPEA (0.050 mL, 0.29 mmol), Ala (10 mg, 0.077 mmol) and A3e (20 mg, 0.54mmol) in DMF (1 mL) at RT is treated with HATU (36 mg, 0.095 mmol). The reaction mixture is stirred for 2 h. In a separate reaction vessel, a solution of DIPEA (0.050 mL, 0.29 mmol) andAla (10 mg, 0.077 mmol) in DMF (1 mL) at RT is treated with HATU (36 mg, 0.095 mmol). This mixture is stirred for 5 mm before being added to the original reaction mixture. The reactionmixture is stirred for 30 mm and then is diluted with AcOH (500 jiL). The residue is purified by preparative HPLC to give compound 1016.
With N-ethyl-N,N-diisopropylamine; HATU; In water; N,N-dimethyl-formamide; for 0.75h;
To a solution of 4-am inophenylboronic acid pinacol ester A4a (500 mg, 2.3 mmol, Oakwood) in DMF (5 mL) is added 1,3-thiazole-4-carboxylic acid Ala (383.1 mg, 3.0 mmol, Combi Blocks), DIPEA (993.8 iL, 5.7 mmol) and HATU (1 .2 g, 3.2 mmol). The reaction mixture is stirred for 45 mm, and then water (15 mL) is added and the suspension is stirred overnight. The precipitate is filtered and rinsed with water (10 mL) and DCM (10 mL). The residue is dried under high vacuum and nitrogen flow for 15 mm to afford A4b which is used as such in subsequent steps.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 2h;
Step 1:A solution of DIPEA (1.2 mL, 7.0 mmol), Al5a (Aldrich, 530 mg, 3.5 mmol) and Ala (300 mg,2.3 mmol) in DMF (14 mL) is treated with HATU (1 .3 g, 3.5 mmol). The mixture is stirred for 2 hand then is diluted with water and EtOAc. The organic layer is separated and washed with water(2 x). The organic layer is passed through a phase separator and the filtrate evaporated todryness. The product is purified by Combif lash to give A15b.
{4-[(thiazole-4-carbonyl)-amino]-phenyl}-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;Inert atmosphere;
A solution of DIPEA (13 mL, 72 mmol), A1a (4.8 g, 37 mmol) and B1 a (6.0 g, 29 mmol, Senn Chemicals AG) in DMF (60 mL) is treated with HATU (15 g, 40 mmol) at RT. The reaction is stirred for 1 h and then is diluted with water and EtOAc. The organic layer is separated, washed with water (2x), dried over MgS04 and evaporated to dryness. The product is purified by Combiflash to give B1 b.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;Inert atmosphere;
Compound A1a (5.0 g, 26 mmol) and B7a (Lancaster, 4.3 g, 33 mmol) and DIPEA (14 mL, 79 mmol) are dissolved in DMF (100 mL) and HATU (14 g, 36 mmol) is added. The reaction is stirred overnight and then is poured into water. The resulting precipitate is collected by filtration to give B7b
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;Inert atmosphere;
Compound A1a (580 mg, 4.5 mmol, Combi Blocks) and B8a (750 mg, 4.5 mmol) and DIPEA (1 .7 ml_, 9.5 mmol) are dissolved in DMF (30 ml_). TBTU (1 .6 g, 5.0 mmol) is added and the reaction is stirred overnight. The resulting solution of B8b is then used for the subsequent step.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;Inert atmosphere;
Compound A1a (3.4 g, 26 mmol, Combi Blocks) and B9a (Aldrich, 4.0 g, 26 mmol) and DIPEA (9.1 ml_, 52 mmol) are dissolved in DMF (60 ml.) and HATU (9.4 g, 25 mmol) is added. The reaction is stirred overnight and then is partitioned between EtOAc and saturated NaHC03. The organic layer is washed with water and then brine, dried over MgS04 and concentrated. The residue is purified by Combiflash to give B9b.
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