Structure of 14190-59-1
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CAS No. : | 14190-59-1 |
Formula : | C4H3NO2S |
M.W : | 129.14 |
SMILES Code : | S1C=CN=C1C(=O)O |
MDL No. : | MFCD02094169 |
InChI Key : | IJVLVRYLIMQVDD-UHFFFAOYSA-N |
Pubchem ID : | 2762733 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 29.07 |
TPSA ? Topological Polar Surface Area: Calculated from |
78.43 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.73 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.81 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.77 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.63 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.55 |
Solubility | 3.66 mg/ml ; 0.0283 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.04 |
Solubility | 1.18 mg/ml ; 0.00915 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.63 |
Solubility | 30.3 mg/ml ; 0.235 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.51 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.01 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | (116c) A 2 N aqueous solution of KOH (3.5 mL, 5 eq) was added to ethyl thiazole-2-carboxylate (213 mg, 1.355 mmol) in ethanol (3 mL). After 2 h at room temperature, the mixture was acidified with 2 N HCl (3.5 mL). Upon sitting overnight, a needle crystal was formed, which was collected by filtration to give thiazole-2-carboxylic acid (43.3 mg, 25percent). | |
Step 3 : Thiazole-2-carboxylic acid; A solution of ethyl thiazole-2-carboxylate (1.46g; 9.29mmol), obtained using a literature method (HeIv. Chim Acta 1945, 28, p. 924), in EtOH (10 ml) was placed in a sealable vessel and treated with KOH (3.07g; 46.4mmol). The vessel was sealed and heated at 120°C for 30min. After cooling, the solution was poured into water (50mL) and the pH adjusted to 4.0 with con. HCl. The now turbid mixture was extracted with iPrOAc (50mL), dried over magnesium sulfate, filtered and evaporated to a brown oil. The oil was dissolved in CH2Cl2 and filtered, then evaporated to afford the title compound as a brown pasty solid. | ||
Step 3: Thiazole-2-carboxylic acid; A solution of ethyl thiazole-2 -carboxylate (1.46g; 9.29mmol), obtained using a literature method (HeIv. Chim Acta 1945, 28, p. 924), in EtOH (10 ml) was placed in a sealable vessel and treated with KOH (3.07g; 46.4mmol). The vessel was sealed and heated at 1200C for 30min. After cooling, the solution was poured into water (5OmL) and the pH adjusted to 4.0 with con. HCl. The now turbid mixture was extracted with iPrOAc (5OmL), dried over magnesium sulfate, filtered and evaporated to a brown oil. The oil was dissolved in CH2Cl2 and filtered, then evaporated to afford the title compound as a brown pasty solid. |
Example 226; (R)-N-(2-(l-(4-fluorophenyl)-5-methyl-4,5-dihydro-lH-indazol-5- yl)ethyl)thiazole-2-carboxamide; [00447] (226a) To an ethanol (3 mL) solution of thiazole-2-carboxylic acid ethyl ester (213 mg, 1.355 mmol) was added aqueous KOH (2 M, 3.5 mL). The mixture EPO <DP n="130"/>was stirred at room temperature for 2 h then concentrated, acidified with aqueous HCl (2 M, 3 mL). The resulting white needle crystal (43 mg) was collected from the solution by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Synthesis of Carboxylic acid 187 as Illustrated in FIG. 29 Ethyl bromopyruvate (1.66 mL, 13.2 mmol, 1 equiv) and thioacetamide (1.05 g, 13.9 mmol, 1.05 equiv) are dissolved in 95percent aqueous ethanol (14 mL, 1 M) and heated at reflux for 5 minutes. Completion of the reaction is indicated by TLC. The reaction mixture is then cooled to room temperature, concentrated in vacuo, suspended in CHCl3 (20 mL) and washed with saturated aqueous NaHCO3 (2*20 mL) and with H2O (20 mL). Drying (MgSO4) and concentration is followed by flash chromatographic purification (silica gel, EtOAc) to yield the corresponding ethyl ester of acid 7 (2.26 g, 100percent). This ester is dissolved in THF-H2O (1:1; 14 mL, 1 M) and submitted to the action of lithium hydroxide (1.66 g, 39.6 mmol, 3.0 equiv). After stirring at room temperature for 45 min TLC indicates the disappearance of starting material. The mixture is poured into H2O (20 mL) and extracted with ether (2*20 mL). Acidification to pH~2 to 3 with aqueous 4 N HCl is followed by extractions with EtOAc (6*20 mL). Drying (MgSO4) and concentration gives pure carboxylic acid 187 (1.36 g, 72percent). | |
(3) Thiazole ester (4) (470 mg) as produced above (1) is dissolved in dichloromethane (15 ml), mixed with anisole (0.611 ml) and trifluoroacetic acid (1.22 ml), and stirred at 0° C. for 2 hours. After concentrating to dryness, the mixture is triturated in a mixture of ether and hexane (1:1) to give thiazolecarboxylic acid (5) (336 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;Molecular sieve; | Compound 1 (3 mmol), compound 2 (3 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (3.3 mmol) and N,N-dimethylpyridine (DMAP) (0.3 mmol) were mixed with a molecular sieve, and the resulted mixture was cooled in ice bath (0° C.). Then DMF and pyridine (4.5 mmol) were added in turn. The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water and extracted with EtOAc. The solvent was removed completely by concentration. Then compound 3 was obtained through column chromatograph (yield 60percent). Subsequently, compound 3 (0.3 mmol) was mixed with ammonium acetate (NH4OAc) (15 mmol) and sodium acetate (NaOAc) (30 mmol) and heated to 130° C., and the progress of reaction was tracked by TLC. Then the reactant was cooled to room temperature, and diluted with water, extracted with ethyl acetate. The solvent was removed completely by concentration. Then compound 4i (Wang279-1) was obtained by separation through column chromatograph with petroleum ether/ethyl acetate (volume ratio 1:1) (yield 31percent). |
60% | With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;Molecular sieve; | Compound 1 (3mmol), compound 2 (3mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (3.3mmol) and N,N-dimethyl pyridine (DMAP) (0.3mmol) were mixed with a molecular sieve, and the resulted mixture was cooled in ice bath (0°C). Then DMF and pyridine (4.5mmol) were added in turn. The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water and extracted with EtOAc. The solvent was removed completely by concentration. Then compound 3 was obtained through column chromatograph (yield 60percent). Subsequently, compound 3 (0.3mmol) was mixed with ammonium acetate (NH4OAc) (15mmol) and sodium acetate (NaOAc) (30mmol) and heated to 130°C, and the progress of reaction was tracked by TLC. Then the reactant was cooled to room temperature, and diluted with water, extracted with ethyl acetate. The solvent was removed completely by concentration. Then compound 4i (Wang279-1) was obtained by separation through column chromatograph with petroleum ether/ ethyl acetate (volume ratio 1:1) (yield 31percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃; | Benzoic aldehyde (25 mmol) was added to the 25percent ammonia water solution (20 mL) containing potassium cyanide (KCN) (30 mmol) and ammonium chloride (37.5 mmol). The resulted mixture was stirred for 56 hours, and the reaction was tracked by TLC. The reactant was extracted with dichloromethane. Then the extract was dried over magnesium sulphate (MgSO4), and the solvent was concentrated to obtain compound 9 (2.9 g, yield 90percent). Compound 9 (6 mmol) was mixed with EDC (7.8 mmol), DMAP (0.6 mmol) and thiazole-2-formic acid (6 mmol). The resulted mixture was cooled under ice bath (0° C.), subsequently DMF was added thereto (15 mL). The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water, and extracted with ethyl acetate. The solvent was removed completely by concentration, and compound 10 was obtained by separation through column chromatograph (0.76 g, yield 50). Compound 10 (3.1 mmol) was mixed with triphenylphosphine (Ph3P) (7.75 mmol) and carbon tetrachloride (CCl4) (7.75 mmol), and the resulted mixture was dissolved in acetonitrile (20 mL). The reaction was conducted at 45° C. and tracked by TLC. After the reaction was completed, the solvent was removed by concentration, and compound 11 (Wang261) (yield 60percent) was obtained by separation through column chromatograph with petroleum ether/ethyl acetate (volume ratio 5:1). The following compounds were synthesized by the same method: |
50% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃; | Benzoic aldehyde (25mmol) was added to the 25percent ammonia water solution (20mL) containing potassium cyanide (KCN) (30mmol) and ammonium chloride (37.5mmol). The resulted mixture was stirred for 56 hours, and the reaction was tracked by TLC. The reactant was extracted with dichloromethane. Then the extract was dried over magnesium sulphate (MgSO4), and the solvent was concentrated to obtain compound 9 (2.9g, yield 90percent). Compound 9 (6mmol) was mixed with EDC (7.8mmol), DMAP (0.6mmol) and thiazole-2-formic acid (6mmol). The resulted mixture was cooled under ice bath (0°C), subsequently DMF was added thereto (15mL). The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water, and extracted with ethyl acetate. The solvent was removed completely by concentration, and compound 10 was obtained by separation through column chromatograph (0.76g, yield 50). Compound 10 (3.1mmol) was mixed with triphenylphosphine (Ph3P) (7.75mmol) and carbon tetrachloride (CCl4) (7.75mmol), and the resulted mixture was dissolved in acetonitrile (20mL). The reaction was conducted at 45°C and tracked by TLC. After the reaction was completed, the solvent was removed by concentration, and compound 11 (Wang261) (yield 60percent) was obtained by separation through column chromatograph with petroleum ether/ ethyl acetate (volume ratio 5:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; HATU; In tetrahydrofuran; | Thiazole-2-carboxylic acid (3-acetyl-2, 4-difluoro-phenyl)-amide, which has the structural formula was made as follows. To <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (491 mg, 3.80 mmol ; Metzger, et AL., Bull. Soc. Chim. Fr. , 708-709 (1953) and FOR 1H NMR, see Borgen et AL., Acta. Chem. Scand. , 20; 2593-2600 (1966) ) in THF (2 mL) was added 0- (7- AZABENZOTRIAZOL-1-YL)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU; 1.45 g, 3.81 MMOL), followed by addition of 3'-amino-2', 6 -DIFLUORO-ACETOPHENONE (from Example H (1) ; 542 mg, 3.36 MMOL) and triethylamine (0.88 mL, 6.3 MMOL). The mixture stirred under argon overnight, then partitioned between ethyl acetate and sat. aq. NA2CO3. The organic layer was separated, washed with 1 N HCI, dried over NA2SO4, and concentrated to afford a residue that was purified via column chromatography to afford 823 mg (92percent yield) of white solid, which was used without further purification. 1H NMR: 8 9. 33 (1H, bs), 8.54 (1H, td, J = 5.7, 9.0 Hz), 7.96 (1H, d, J = 3.1 Hz), 7.67 (1H, d, J = 3. 1 Hz), 7.02 (1H, td, J = 1. 8,9. 0 HZ), 2.64 (3H, t, J = 1. 8 HZ). THIAZOLE-2-CARBOXYLIC acid [3- (2-BROMOACETYL)-2, 4-DIFLUORO-PHENYL]-AMIDE, which has the structural formula was made as follows. To THIAZOLE-2-CARBOXYLIC acid [3- (2- ACETYL)-2, 4-difluoro-phenyl]-amide (530 mg, 1.88 MMOL) in HOAC (5 mL) was added pyridinium tribromide (600 mg, 1.88 MMOL). The mixture was heated at 70 C for a half hour, allowed to cool, and partitioned between ether and water. The organic layer was separated, washed with water and sat. aq. NaHCO3, dried over MGS04, and concentrated in vacuo to give 645 mg (95percent) of white solid, which was used without further purification. 1H NMR: No. 9.53 (1H, bs), 8.63 (1H, td, J = 5.8, 9.0 Hz), 7.96 (1H, d, J = 3.1 Hz), 7.69 (1H, d, J = 3. 1 Hz), 7.07 (1H, td, J = 1. 9,9. 0 HZ), 4.38 (2H, d, J = 0. 8 HZ). The title compound was made analogously to 4- [4-AMINO-5- (2, 6-DIFLUORO-BENZOYL)- thiazol-2-ylamino]-benzenesulfonyl fluoride from Example A (1). 4-ISOTHIOCYANATO- benzenesulfonamide (142 mg, 0.663 MMOL) and <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> [3- (2-bromoacetyl)- 2, 4-difluoro-phenyl]-amide (300 mg, 0. 831 MMOL) gave 245 mg (69percent yield) of a yellow solid. 1H NMR (DMSO-d6) : 8 11.19 (1 H, s), 10.60 (1 H, s), 8.45 (2H, bs), 8.17 (1H, d, J = 3.1 Hz), 8.13 (1H, d, J = 3. 1 Hz), 7.80 (1H, d, J = 9. 2 HZ), 7.76 (1H, d, J = 9. 2 HZ). HRESIMS : calcd. for C20H5F2N603S3 : 537.0285. Found: 537.0272. ANAL. CALCD. for C20HA4F2N604S3 0. 4 H2ONo.0. 1 EtOH : C, 44.24 ; H, 2.83 ; N, 15. 33; S, 17.54. Found: C, 44.23 ; H, 2.64 ; N, 15.16 ; S, 17.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; | Preparation 107: 1, 3-thiazole-2-carbonyl CHLORIDE 1,3 <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (Preparation 92,5. 0 g, 39 MMOL) was added to a solution containing sodium hydroxide (1.55 g), in water (26 ml). The solution was evaporated to dryness and the resultant solid was triturated with diethyl ether, filtered and dried in an oven at 60 C for 6 h to give a brown solid (5.5 g). The solid was added to thionyl chloride (25 ML) and heated on a steam bath for 2 h. The excess thionyl chloride was removed in vacuo and the resultant oil was triturated with petroleum ether (40-60,3 x 30 ml) to give the title compound as an oily solid upon filtration and evaporation (4.0 g, 70percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 1-hydroxy-7-aza-benzotriazole; PS-DCC; N-ethyl-N,N-diisopropylamine; In dichloromethane; | Example 37 { (S)-3- [3- (4-Fluoro-phenyl)-l, 2, 4-oxadiazol-5-yl]-piperidin-1-yl}-thiazol-2-yl- methanone The compound was prepared following the procedure described in the Example 36, using <strong>[14190-59-1]2-<strong>[14190-59-1]thiazolecarboxylic acid</strong></strong> as the acid of choice and S-3- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl] -piperidine hydrochloride (prepared as described in the Example 12). Yield: 55 percent (off-white powder); mp=94-95°C ; [a] D20 = +127° (c=0. 9, CHCl3) ; LCMS (Tr): 5.54 min (Method A); MS (ES+) gave m/z : 359. 1. H-NMR (CDC13, 300 MHz), 8 (ppm): 8.05 (m br, 2H); 7. 89 (m br, 1H); 7.53 (m br, 1H); 7.15 (dd, 2H); 5.41, 4.94, 4.38, 4.04 and 3.44 (m br, 3H); 3.34 (m br, 2H); 2.36 (m, 1H); 2.13-1. 92 (m br, 2H); 1.78 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; water; | Preparation 92: 1,3 thiazole-2-carboxylic acid To a solution of 2-bromothiazole (16.4 g, 0.1 mol) in anhydrous diethyl ether (50 ml) AT-70 C was added slowly n-butyl lithium (1.6 M solution in hexane, 75 ML). The reaction mixture was stirred AT-70 C for 20 min and was then added portion-wise to powdered solid carbon dioxide (500 g). The reaction mixture was stirred for 18 h, and the resultant mixture was dissolved in water (70 ML) FILTERED and extracted with diethyl ether (3 x 75 ml). The aqueous layer was acidified by the addition of sulphuric acid (10 M solution) and cooled to 0 C. A solid crystallised out and was removed by filtration, washed with cold water, and dried at 50 C for 6 h to give the title compound as a light brown solid (5.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With n-butyllithium; carbon dioxide; | Example 105 ETHYL 2-[N-(1'-AMINOCITRACONAMIDO)]-4-(2'-THIAZOLYL)PYRIMIDINE-5-CARBOXYLATE 2-Bromothiazole (8.25 g, 0.05 moles) in anhydrous ether (60 mL) is added dropwise to a solution of nBuLi (34 mL, 1.5M solution, 0.051 mmol) in anhydrous ether (60 mL) cooled to -78° C. and stirred for 30 minutes. Carbon dioxide is bubbled into the solution and after saturation is achieved, the reaction mixture is poured over dry-ice. H2 O (10 mL) is added and the mixture basified to pH=9 with NaOH (1N). The aqueous layer is acidified with concentrated HCl to pH <3 then extracted into ether, dried (MgSO4) and concentrated to provide the thiazole-2-carboxylic acid in 57percent yield (3.2 g); 1 H NMR (MeOD) delta 8.00 (d, 1H); 7.94 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; triethylamine; In tetrahydrofuran; N-methyl-acetamide; dichloromethane; water; | EXAMPLE 11 STR27 To an ice-cooled and stirred solution of 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-<strong>[14190-59-1]thiazolecarboxylic acid</strong> (5.00 g, 14.0 mmoles) and dimethylformamide (1.03 g, 14.1 mmoles) in methylene chloride (200 ml) was added dropwise oxalyl chloride (3.93 g, 31.0 mmoles) and the mixture was stirred for 40 minutes. On the other hand, hydroxylamine hydrochloride (3.91 g, 56.3 mmoles) in water (5 ml) and triethylamine (8.55 g, 84.5 mmoles) were dissolved in tetrahydrofuran (100 ml), and to the mixture was added dropwise the above-mentioned reacted solution of <strong>[14190-59-1]thiazolecarboxylic acid</strong>. After stirring for 30 minutes, the reaction mixture was acidified to pH 4 with 1M hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolecarbohydroxamic acid (2.50 g, 6.73 mmoles, 48percent) as a light brown amorphous product. m.p. 118° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water; | EXAMPLE 20 9.8 g of <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> and 12.3 g of 1,1'-carbonyldiimidazole were stirred at 70° for 1 hour in 35 ml of tetrahydrofuran. To this solution were then added dropwise 12.2 g of N-(t-butoxycarbonyl)ethylenediamine in 20 ml of tetrahydrofuran and the mixture was left to stir at 70° for a further 1/2 hour. The reaction mixture was subsequently cooled to room temperature and concentrated to about 1/4 of the volume on a rotary evaporator under reduced pressure, taken up in water and extracted three times with ethyl acetate. The ethyl acetate extracts, dried over magnesium sulfate, were evaporated completely, whereby t-butyl [2-(thiazole-2-carboxamido)ethyl]carbamate was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 72h; | EDCI (257 mg, 1.34 mmol) and HOAt (152 mg, 1.12 mmol) were added to a stirred solution of 22 (200 mg, 1.12 mmol) in CH2Cl2 (10 mL) and dry DMF (1 mL). The resulting solution was stirred at room temperature for 3 days. Then, the reaction mixture was partitioned between CH2Cl2 and IN NaHCO3. The organic layer was successively washed with IN NH4Cl, and water, dried (Na2SO4), and evaporated. Purification by flash chromatography (gradient AcOEt/heptane, 10:90 to 50:50) afforded 62 mg (19percent) of the target product 23: m/z = 291 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20℃; | Example 66 (2Z)-2-(3-butyl-5-methyl-1.3.4-thiadiazol-2(3H)-ylidene)-l-(1.3-thiazol-4- yPethanoneIn a 20 mL vial <strong>[14190-59-1]thiazole-2-carboxylic acid</strong> (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-l,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1 : 1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) delta ppm psi.89 (t, 3 H) 1.25 - 1.38 (m, 2 H) 1.69 - 1.82 (m, 2 H) 2.46 (s, 3 H) 4.12 - 4.20 (m, 2 H) 6.81 (s, 1 H) 8.24 (s, 1 H) 9.15 (s, 1 H); MS (ESI) m/z 282 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 4h; | Step 4: tert-Butyl-1'- {4-[(1,3-thiazol-2-ylcarbonyl)amino]phenyl}-4,4'-bipiperidine-1-carboxylate.; A solution of the product of Example 12.29, Step 2 above (50mg; 0.139mmol) and Example 12.29, Step 3 (36mg; 0.278mmol) in DMF (1 ml) was treated with PyBOP (145 mg; 0.278mmol). The reaction was stirred at ambient temperature for 4hr. The reaction was partitioned between iPrOAc (50mL) and pH7 <n="77"/>phosphate buffer (10mL). The organic was washed twice more with pH7 buffer (2x10mL). The wet organic was evaporated and repartitioned between CH2CI2 and water. The organic was dried over magnesium sulfate, filtered and evaporated. The derived residue was digested in refluxing MTBE. The red-brown supernatant was found to be enriched in the title compound. The solution was evaporated to an oil and chromatographed (PTLC; 20: 1 CH2Cl2/MeOH). The title compound was a rust colored solid. The material was rechromatographed (PTLC; MTBE). The baseline band was recovered giving the title compound as a light rust colored powdery solid. LRMS calc: 470.2 obs: 471.2 (M+H), 371.3 (M-BOC+H). | |
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 4h; | Step 4: /er/-Butyl-r-{4-[(l,3-thiazol-2-ylcarbonyl)amino]phenyl}-4,4'-bipiperidine-l -carboxylate.; <n="75"/>A solution of the product of Example 12.29, Step 2 above (50mg; 0.139mmol) and Example 12.29, Step 3 (36mg; 0.278mmol) in DMF (1 ml) was treated with PyBOP (145 mg; 0.278mmol). The reaction was stirred at ambient temperature for 4hr. The reaction was partitioned between iPrOAc (5OmL) and pH7 phosphate buffer (1OmL). The organic was washed twice more with pH7 buffer (2x1 OmL). The wet organic was evaporated and repartitioned between CH2CI2 and water. The organic was dried over magnesium sulfate, filtered and evaporated. The derived residue was digested in refluxing MTBE. The red-brown supernatant was found to be enriched in the title compound. The solution was evaporated to an oil and chromatographed (PTLC; 20: 1 CF^C^/MeOH). The title compound was a rust colored solid. The material was rechromatographed (PTLC; MTBE). The baseline band was recovered giving the title compound as a light rust colored powdery solid. LRMS calc: 470.2 obs: 471.2 (M+H), 371.3 (M-BOC+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Thiazole-2-carboxylic acid (5 g, 38.7 mmol) and CDMT (7.47 g, 42.6 mmol) were suspended in THF under N2 at O0C. After 15 min NMM (11.7 g, 12.76 mL, 116 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hr at RT, and then N- <n="23"/>methoxymethanamine hydrochloride was added at 0 0C. The reaction mixture was stirred over night at room temperature and was then concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the solution was washed with water and brine, dried over anhydrous sodium sulfate. The residue after evaporation of solvents was purified by column chromatography eluting with 30percent EtOAc/hexanes to give 4.6 g (70percent) of the desired product as pale yellow oil. |
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