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CAS No. : | 3364-80-5 | MDL No. : | MFCD00626896 |
Formula : | C4H3NOS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WRFKSVINLIQRKF-UHFFFAOYSA-N |
M.W : | 113.14 | Pubchem ID : | 2763214 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 27.5 |
TPSA : | 58.2 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.46 cm/s |
Log Po/w (iLOGP) : | 0.8 |
Log Po/w (XLOGP3) : | 0.75 |
Log Po/w (WLOGP) : | 0.96 |
Log Po/w (MLOGP) : | -0.97 |
Log Po/w (SILICOS-IT) : | 2.32 |
Consensus Log Po/w : | 0.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.48 |
Solubility : | 3.78 mg/ml ; 0.0334 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.55 |
Solubility : | 3.18 mg/ml ; 0.0281 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.18 |
Solubility : | 7.41 mg/ml ; 0.0655 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.81 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H317-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
74.3% | at 0℃; for 1 h; | To a solution of thiazole-4-carboxaldehyde (0.810 ml, 9.67 mmol, Combi-Blocks Inc.) in MeOH (48.3 ml) at 0 °C was added sodium borohydride (0.341 ml, 9.67 mmol, Sigma-Aldrich Chemical Company, Inc.) in portions. The reaction mixture was allowed to stir for 1 hour. Saturated aqueous ammonium chloride solution was carefully added and the reaction mixture was filtered. The filtrate was concentrated in vacuo. The solid was taken up in 10percent MeOH/DCM and filtered through a plug of silica gel to provide thiazol- 4-ylmethanol (0.826 g, 7.18 mmol, 74.3percent yield) as a yellow oil. MS m/z = 116.0 [M+H]+. Calculated for C4H5NOS: 115.009. H NMR (400 MHz, CHLOROFORM -J) δ ppm 2.58 (br. s., 1 H) 4.86 (s, 2 H) 7.27 - 7.30 (m, 1 H) 8.83 (d, J=l .76 Hz, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium metabisulfite In N,N-dimethyl-formamide at 120℃; | General procedure: A solution of substituted o-phenyldiamine (1.0 equiv), thiazole-4-aldehyde or pyridine-2-aldehyde (1.0 equiv) with sodium pyrosulfite in DMF was stirred at 120° C overnight. On completion of the reaction monitored by TLC, the solvent was evaporated and the residue was purified by silica gel chromatography by DCM/MeOH system to afford the final product. If necessary, the crudeproduct could be recrystallized in DCM or dichloroethane to afford pure sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A stirred mixture of 4-CHLOROMETHYLTHIAZOLE (1g, 5.88 MMOL) and hexamine (1.64g, 11.76 mmol, 2eq) in 50percent acetic acid (10 mL) was heated at reflux for 3 hours. The reaction mixture was allowed to cool for five minutes and then concentrated hydrochloric acid (2.5 mL) was added. The resulting reaction mixture was refluxed for a further five minutes prior to dilution of the reaction mixture with water (50 mL). The resulting reaction mixture was extracted with dichloromethane (6 x 50 mL). The extracts were combined and washed once with sodium bicarbonate (50 mL), dried over NA2SO4 AND evaporated to give the title compound as a gum. 'H NMR (CDCI3) : 8 10. 14 (s, 1H), 8.93 (s, 1H), 8.28 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared from 1, 3-thiazole-4-carboxaldehyde (Synthesis, 1987, 998; 1.97 g, 17.5 MMOL) and 2-amino-4-methylpentanoic acid TERT-BUTYL ester, hydrochloride (3.91 g, 17.5 MMOL) in a similar manner to that described for Intermediate 1. | ||
With triethylamine; In dichloromethane; for 20h;Heating / reflux; | A stirred mixture of 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride (2. 1G, 9.38 mmol), 1, 3-thiazole-4-carboxaldehyde (Intermediate b) (1. 06 g, 9.38 MMOL) and triethylamine (1.31 mL, 9.38 MMOL) in dichloromethane (25 mL) was heated under reflux under nitrogen for 20 hours. The reaction mixture was allowed to cool to room temperature, washed twice with water, dried over NA2SO4 and evaporated to give the title compound as an oil. 'H NMR (CDCI3) : 5 8.84 (s, 1H), 8.49 (d, 1 H), 8.01 (s, 1H), 4.00 (dd, 1 H), 1.90-1. 70 (m, 2H), 1.64-1. 56 (m, 1H), 1.47 (s, 9H), 0.96 (d, 3H) and 0.91 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With sodium borohydrid; trifluoroacetic acid; In tetrahydrofuran; | EXAMPLE Q 2-Hydroxy-2-(thiazol-4-yl)ethanamine Prepared analogously to Example P by reaction of 4-formyl-thiazole with sodium borohydride and trifluoroacetic acid in tetrahydrofuran. The product obtained by extraction with methylene chloride is purified on a silica gel column using methanol as eluant. Yield: 19percent of theory 1 H-NMR spectrum (CDCl3 /CD3 OD): delta=4.880 ppm (dd, =CHOH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | Compound 1C (3.3 g, 8.3 mmol) and <strong>[3364-80-5]4-thiazolecarboxaldehyde</strong> (1.4 g, 12.4 mmol) in dichloroethane (16 mL) were stirred for 30 min. under nitrogen. Sodium triacetoxyborohydride (5.3 g, 24.9 mmol) was added and the reaction was stirred for 20 h. The mixture was diluted with CH2CI2 (20 mL) and washed with saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated. Column chromatography (12O g silica gel, eluting with 4percent 7N NH3/MeOH in CH2Cl2) gave 2.01 g ID as a white solid (49percent). 1H NMR (500.333 MHz, CDC13) delta 8.90 (dd, J= 4.1, 1.7 Hz, IH), 8.76 (d, J= 1.9 Hz, IH), 8.11 (dd, J= 8.0, 1.5 Hz, IH), 7.72 (dd, J = 7.3, 2.3 Hz, IH), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, IH), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3.26 (br s, IH), 3.02 (s, 3H), 2.78-2.71 (m, IH), 2.67-2.52 (m, 4H), 2.46-2.37 (m, IH), 2.14-2.04 (m, 2H). TOF MS E+ 499.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 14; To a cooled (-78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (200 mg, 0.7 mmol) in anhydrous toluene (8 mL), TMEDA (110 uL, 0.7 mmol) was added followed by nBuLi (0.47 mL, 0.75 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at -78° C. and a solution of <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (0.32 g, 2.8 mmol) in dichloromethane (1 mL) was added. The mixture was stirred for 16 hrs during which the temperature reached room temperature. The reaction was quenched with water, the resulting mixture was basified by the addition of NH4OH and extracted with EtOAc. The combined organic layers were concentrated and subjected to mass triggered preparative HPLC to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-4-yl-methanol (Compound 14-1) (200 mg). MH+=318.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 120℃; | General procedure: A solution of substituted o-phenyldiamine (1.0 equiv), thiazole-4-aldehyde or pyridine-2-aldehyde (1.0 equiv) with sodium pyrosulfite in DMF was stirred at 120° C overnight. On completion of the reaction monitored by TLC, the solvent was evaporated and the residue was purified by silica gel chromatography by DCM/MeOH system to afford the final product. If necessary, the crudeproduct could be recrystallized in DCM or dichloroethane to afford pure sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-Methyl 3-phenyl-2-(thiazol-4-ylmethylamino)propanoate (34.8.C).L-Phenylalanine methyl ester HCl 34.8.A (2.15 g, 10.0 mmol) was partitioned with DCM and saturated NaHCO3. The aqueous layer was extracted with DCM (2X). The organic layers were combined, dried with sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM (30 ml) and AcOH (571 muL, 10 mmol), thiazole-4-carboxaldehyde 34.8.B (1.13 g, 10 mmol), and NaBH(OAc)3 (4.24 g, 20 mmol) were added and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with NaHCO3(sat) and extracted with DCM. The organic extracts were dried with sodium sulfate, filtered, and concentrated. The resulting residue was partially purified on a silica gel column (120 g, 0-8percent MeOH:DCM) to yield 34.8.C as a crude oil (2.25 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; N,N-dimethyl-formamide; at 25℃; | (2S)-3-(4-fluorophenyl)-N-(l-methyl-3-(2-(methylamino)pyrimidin-4-yl)- lH-pyrazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide (9). The reaction mixture of (2iS)-2-amino-3 -(4-fluorophenyl)-N-( 1 -methyl-3 -(2-(methylamino)pyrimidin-4-yl)- 1 H- pyrazol-5-yl)propanamide, 9.F (20.0 mg, 54.0 mumol), <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (7.4 mg, 65.0 mumol) and sodium triacetoxyborohydride (34.0 mg, 162.0 mumol) in DCE (1.0 ml), DMF (0.1 ml) and sodium acetate (3eqv. 3.0 mg) was stirred at 25 0C overnight. The LCMS indicated compound 9 was formed. The crude mixture was purified by preperative HPLC to give the compound 9. 1H NMR (500 MHz, MeOH) delta ppm 9.13 (1 H, d, J= 2.0 Hz), 8.23 (1 H, d, J= 5.0 Hz), 7.82 (1 H, s), 7.35 (1 H, d, J = 5.0 Hz). 7.32-7.30 (2 H, m), 7.13-7.11 (2 H, m), 6.95 (1 H, s), 4.53-4.46 (2 H, m), 4.37-4.34 (1 H, m), 3.62 (3 H, s), 3.46-3.45(1 H, m), 3.23-3.21(1 H, m), 3.08 (3 H, s). MS ESI (pos.) m/e: 467.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | (2S)-N-(3-(lH-pyrazol-3-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide (12). To a solution of (2S)-N-(3-(lH-pyrazol-3-yl)phenyl)-2- amino-3-phenylpropanamide 12.C (200 mg, 0.65 mmol) in DCM (5 mL) was added thiazole- 4-carbaldehyde (73 mg, 0.65 mmol, available from Combi-Blocks). The mixture was stirred for Ih, then sodium triacetoxyborohydride (207mg, 0.98mmol) was added and the mixture stirred for an additional hour at room temperature. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100percent CH3CN/water + 0.5percent TFA) to afford (2S)-N-(3-(lH-pyrazol-3-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide 12 as a white solid (66.7 mg, 25percent yield). LCMS ESI (pos.) m/e: 404.0 (M+l): IH NMR (500 MHz, MeOH-D4) delta ppm 9.11 (d, J=I .96 Hz, 1 H), 7.82 - 7.87 (m, 1 H), 7.80 (d, J=I.96 Hz, 1 H), 7.74 (d, J=2.20 Hz, 1 H), 7.51 - 7.60 (m, 1 H), 7.21 - 7.38 (m, 7 H), 6.68 (d, J=2.20 Hz, 1 H), 4.50 (d, J=5.38 Hz, 2 H), 4.29 (dd, J=9.29, 5.87 Hz, 1 H), 3.43 (dd, J=13.45, 5.62 Hz, 1 H), 3.27 (dd, J=13.45, 9.29 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | (2S)-N-(2-methoxy-5-(lH-pyrazol-4-yl)pyridin-3-yl)-3-phenyl-2-(thiazol-5- ylmethylamino)propanamide (15.1). To a solution of a 1 :9 mixture of (2S)-2-amino-N-(2- methoxy-5-(lH-pyrazol-4-yl)pyridin-3-yl)-3-phenylpropanamide 15.1. D and (S)-2-amino-N- (2-oxo-5-(lH-pyrazol-4-yl)-l,2-dihydropyridin-3-yl)-3-phenylpropanamide (90 mg, 0.28 mmol) in DCM (1 rnL) was added <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (26 mg, 0.28 mmol) and was then stirred for 1 hour. Sodium triacetoxyborohydride (170 mg, 0.82 mmol) and acetic acid (16 muL, 0.28 mmol) was then added, the mixture was stirred for an additional 1 hour at room temperature, concentrated and the crude product purified by reverse phase chromatography (0-100percent CH3CN/water + 0.5percent TFA) to afford (2S)-N-(2-methoxy-5-(lH-pyrazol-4- yl)pyridin-3-yl)-3-phenyl-2-(thiazol-5-ylmethylamino)propanamide 15.1 (5.7 mg, 57percent) as a white solid. LCMS ESI (pos.) m/e: 435.1 (M+l): IH NMR (500 MHz, MeOH-D4) delta ppm 9.13 (d, J=I.83 Hz, 1 H), 8.50 (d, J=I.83 Hz, 1 H), 8.15 (d, J=I.83 Hz, 1 H), 7.94 (s, 2 H), 7.80 (d, J=I.83 Hz, 1 H), 7.25 - 7.39 (m, 5 H), 4.46 - 4.56 (m, 3 H), 3.91 (s, 3 H), 3.41 (dd, J=13.43, 6.10 Hz, 1 H), 3.24 (dd, J=13.43, 9.16 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | (2S)-3-(4-Fluorophenyl)-N-(l-methyl-3-(2-methylpyridin-4-yl)-lH- pyrazol-5-yl)-2-(thiazol-4-ylmethylamino)propanamide (16.1). To a 100 ml flask was added (2S)-2-amino-3-(4-fluorophenyl)-N-(l-methyl-3-(2 -methylpyridin-4-yl)- lH-pyrazol-5- yl)propanamide TFA (85 mg, 0.182 mmoles), 5 ml of DCE, DIEA (48 mul, 0.27 mmole, Make sure pH = 7), 50 ul of AcOH and <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (16 mg, 0.15 mmole). The reaction was stirred at 65°C for 5 minutes at which time sodium triacetoxyborohydride (116 mg, 0.55 mmoles) was added and stirred at 65 0C for an additional 30 minutes. The solvent was then removed and the crude purified by reverse phase preparative HPLC to give (2S)-2-amino-3- (4-fluorophenyl)-N-( 1 -methyl-3 -(2-methylpyridin-4-yl)- 1 H-pyrazol-5 -yl)propanamide HCl (27.8 mg, 34percent yield) after salt exchange using 1 M HCl in ether (546 ul, 0.55 mmole). LCMS ESI (pos.) m/e: 451.1 (M+l): IH NMR (500 MHz, MeOH-J) delta ppm 9.04 (d, J=I.22 Hz, 1 H) 8.50 (d, J=6.11 Hz, 1 H) 8.16 (s, 1 H) 8.11 (d, J=6.11 Hz, 1 H) 7.78 (s, 1 H) 7.25 (dd, J=8.19, 5.26 Hz, 2 H) 6.95 - 7.10 (m, 3 H) 4.44 (s, 2 H) 4.41 (dd, J=8.93, 5.99 Hz, 1 H) 3.56 (s, 3 H) 3.40 (dd, J=13.33, 5.50 Hz, 1 H) 3.15 (dd, J=13.57, 9.41 Hz, 1 H) 2.70 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | S)-N-(l-Methyl-3-(pyridin-4-yl)-lH-pyrazol-5-yl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide (17.2). To a rt solution of 17.1 (150 mg, 0.47 mmol) and <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (available from Combi-Blocks Inc.) (48 mg, 0.42 mmol) in1 ,2-dichloroethane (5.0 mL) was added 5percent HO Ac/1, 2- dichloroethane (0.1 mL) followed by sodium triacetoxyborohydride (248 mg, 867 mumol). After stirring at 60 0C for 35 mins, the reaction mixture was quenched with saturated NaHCO3 (4 mL), diluted with water (10 mL) and extracted by 1PrOHZCHCl3 (1 :1, 3 x 10 mL). The organic solvent was removed under reduced pressure. After purification of the residue by preparative HPLC (10-90percent CH3CN/water, 30 min), the combined product fractions was treated with saturated aqueous NaHCO3, extracted with 30percent 1PrOH /CHCl3 and concentrated to provide the title product 17.2 (104 mg, 53percent) as white solid. MS ESI (pos.) m/e: 419.1 (M+H); 1H NMR (400 MHz, CD3OD) delta ppm 3.08 (s, 2 H) 3.61 (s, 3 H) 3.68 (s, 1 H), 3.97 (s, 2 H) 6.73 (s, 1 H), 7.28 (m, 6 H), 7.78 (m, 2 H), 8.53 (m, 2 H), 8.97 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2S)-N-(3-(2-Aminopyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide (36). To a solution of tert-butyl (S)-l-(3-(2-aminopyridin-4- yl)phenylamino)-l-oxo-3-phenylpropan-2-ylcarbamate (36.C) (200 mg, 0.46 mmol) in THF (2 mL) was added 4M HCl in dioxane (2 mL, 8 mmol). The mixture was stirred at room temperature for 2 hours and then was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with 4:1 DCM/isopropanol. The organic layers were combined, washed with brine, dried on MgSO4 and concentrated. The residue was dissolved in DCM and then <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (56 mg, 0.50 mmol) was added. The mixture was stirred for Ih at room temperature at which time acetic acid (28 muL, 0.46 mmol) and sodium triacetoxyborohydride (293 mg, 1.38 mmol) were added. The mixture was stirred at room temperature for additional 2 hours, concentrated and the residue purified by reverse phase preparative HPLC to afford (2S)-N-(3-(2-aminopyridin-4-yl)phenyl)-3-phenyl-2- (thiazol-4-ylmethylamino)propanamide 36 (58 mg, 29percent yield) as a white solid. LCMS ESI (pos.) m/e: 430.1 (M+l): IH NMR (400 MHz, MeOH-D4) delta ppm 9.12 (d, J=I.96 Hz, 1 H), 7.91 - 7.97 (m, 2 H), 7.79 (d, J=1.96 Hz, 1 H), 7.42 - 7.57 (m, 3 H), 7.25 - 7.36 (m, 5 H), 7.18 - 7.21 (m, 1 H), 7.13 - 7.17 (m, 1 H), 4.42 - 4.54 (m, 2 H), 4.25 (dd, J=9.39, 5.87 Hz, 1 H), 3.42 (dd, J=13.30, 5.87 Hz, 1 H), 3.25 (dd, J=13.30, 9.00 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | (S)-3-(3-Phenyl-2-(thiazol-5-ylmethylamino)pr opanamido)-5-(pyridin-4- yl)benzoic acid (45.2). To a solution of (S)-3-(2-amino-3-phenylpropanamido)-5-(pyridin-4- yl)benzoic acid (45.1) (181 mg, 0.50 mmol) in DCM (5 mL) was added thiazole-4- carbaldehyde (56 mg, 0.50 mmol). The mixture was stirred for Ih, sodium triacetoxyborohydride (212 mg, 1.00 mmol) was then added and the mixture stirred for an additional 1 hour at room temperature. The reaction mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100percent CHsCN/water + 0.5percent TFA) to afford (S)-3-(3-phenyl-2-(thiazol-5-ylmethylamino)propanamido)-5-(pyridin-4-yl)benzoic acid (45.2) as a white solid (82 mg, 36percent yield). LCMS ESI (pos.) m/e: 459.0 (M+l). IH NMR (500 MHz, MeOH-D4) delta ppm 9.13 (d, J=I.96 Hz, 1 H), 8.93 (d, J=6.85 Hz, 2 H), 8.35 (d, J=I.22 Hz, 1 H), 8.32 - 8.34 (m, 2 H), 8.31 (t, J=I.83 Hz, 1 H), 8.18 - 8.23 (m, 1 H), 7.82 (d, J=I.96 Hz, 1 H), 7.23 - 7.37 (m, 5 H), 4.48 - 4.58 (m, 2 H), 4.35 (dd, J=9.29, 5.87 Hz, 1 H), 3.41 - 3.51 (m, 1 H), 3.24 - 3.30 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 70℃; for 12h; | (S)-3-(4-Chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)-2-(thiazol-4- ylmethylamino)propanamide (3.1). To a 20 ml vial were added (S)-2-amino-3-(4- chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.1.C (50 mg, 0.15 mmole), <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (20 mg, 0.18 mmole), sodium triacetoxyborohydride (62 mg, 0.29 mmole), 5 ml of DCE, and DIEA (97 mul, 0.15 mmole). The reaction was stirred at 700C for 12 hours. The reaction was then partitioned between 10 ml of water and 20 ml of DCM and the solvent was removed by rotary evaporation. The crude was purified using reverse phase preparative HPLC to give 5.55 mg of (S)-3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)isoxazol-5- yl)-2-(thiazol-4-ylmethylamino)propanamide TFA salt 3.1 as a clear film (5.6 mg, 9percent yield). LCMS ESI (pos.) m/e: 440.1 (M+l): IH NMR (500 MHz, MeOH) delta ppm 9.01 (d, J=I.71 Hz, 1 H), 8.76 - 8.78 (m, 2 H), 8.19 (d, J=6.60 Hz, 2 H), 7.69 (dd, J=13.82, 8.68 Hz, 1 H), 7.24 (d, J=I.96 Hz, I H), 7.13 (d, J=8.3 I Hz, 2 H), 6.99 (d, J=8.31 Hz, 2 H), 4.35 - 4.45 (s, 1 H), 4.26 (m, 2 H), 3.34 (dd, J=8.56, 5.87 Hz, 1 H), 3.17 (dd, J=13.69, 5.87 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | (S)-5-(l-(3-Phenyl-2-(thiazol-4-ylmethylamino)propanoyl)-6-(pyridin-4- yl)indolin-4-yl)-l,3,4-oxadiazol-2(3H)-oneTFA salt (57). To a 20 ml flask were added (S)-5-(l-(2-amino-3-phenylpropanoyl)-6-(pyridin-4-yl)indolin-4-yl)-l,3,4-oxadiazol-2(3H)- one TFA salt 57.1.C (80 mg, 0.19 mmole), 10 ml of DCE, DIEA (To pH = 7), thiazole-4- carbaldehyde (21 mg, 0.19 mmole). The reaction was stirred for 2 hour at which time sodium triacetoxyborohydride (119 mg, 0.56 mmole) was added and stirred for an additional 16 hours. The reaction was partitioned between DCM and water. The solvent was removed by rotary evaporation and the crude purified by reverse phase HPLC to (S)-5-(l-(3-phenyl-2- (thiazol-4-ylmethylamino)propanoyl)-6-(pyridin-4-yl)indolin-4-yl)- 1 ,3 ,4-oxadiazol-2(3H)- oneTFA salt 57 as a white solid (7.4 mg, 8 percent yield). IH NMR (400 MHz, MeOH) delta ppm 9.10 (d, J=1.96 Hz, 1 H), 8.81 - 8.87 (m, 3 H), 8.17 (d, J=5.09 Hz, 2 H), 8.03 (d, J=1.56 Hz,1 H), 7.82 (d, J=I.96 Hz, 1 H), 7.31 (s, 5 H), 4.73 (dd, J=IO.17, 5.48 Hz, 1 H), 4.49 - 4.58 (m,2 H), 4.07 (td, J=10.17, 6.26 Hz, 1 H), 3.47 (dd, J=12.91, 5.09 Hz, 1 H), 3.35 - 3.43 (m, 1 H), 3.28 (dd, J=13.11, 9.98 Hz, 1 H), 3.07 - 3.16 (m, 1 H), 2.93 - 3.05 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; In methanol; dichloromethane; at 55℃; for 1h; | (S)-3-Phenyl-l-(6-(pyridin-4-yl)-4-(5-thioxo-4,5-dihydro-l,3,4-oxadiazol-2-yl)indolin-l-yl)-2-(thiazol-4-ylmethylamino)propan-l-one (58). To a flask with (S)-2-amino-3-phenyl-l-(6-(pyridin-4-yl)-4-(5-thioxo-4,5-dihydro-l,3,4-oxadiazol-2- yl)indolin-l-yl)propan-l-one 58.C (41 mg, 0.092 mmol) was added <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (13 mg, 0.111 mmol). Then 1 mL MeOH and 0.8 mL dichloromethane were added followed by sodium cyanoborohydrre (17.5 mg, 0.28 mmol). The reaction was heated to 55 degree for 1 hour. Two drops of water was added and reaction was concentrated and purified on reverse phase HPLC to afford 30 mg (42percent) TFA salt of 58. IH NMR (400 MHz, MeOH) delta ppm 9.08 (d, J=1.96 Hz, 1 H) 8.81 - 8.91 (m, 3 H) 8.21 (d, J=6.65 Hz, 2 H) 8.11 (d, J=1.56 Hz, 1 H) 7.81 (d, J=1.96 Hz, 1 H) 7.26 - 7.34 (m, 5 H) 4.73 (dd, J=10.17, 5.09 Hz, 1 H) 4.47 - 4.59 (m,2 H) 4.08 (td, J=10.07, 6.46 Hz, 1 H) 3.47 (dd, J=12.91, 5.48 Hz, 1 H) 3.35 - 3.44 (m, 1 H) 3.22 - 3.30 (m, 1 H) 3.12 (td, J=9.88, 5.67 Hz, 1 H) 2.93 - 3.07 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 70℃; for 76h; | (S)-l-(3-Phenyl-2-(thiazol-4-ylmethylamino)propanoyl)-6-(pyridin-4- yl)indoline-4-carboxamide (60). To a 100 ml flask were added (S)-l-(2-amino-3- phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxamide 61.C (49 mg, 0.13 mmole), thiazole-5-carbaldehyde (16 mg, 0.14 mmole), sodium triacetoxyborohydride (49 mg, 0.23 mmole), 20 ml of DCE, and DIEA (30 mul, 0.17 mmole). The reaction was stirred at 7O0C for 4 hours at which time an additional 50 mg of sodium triacetoxyborohydride was added and stirred for an additional 72 hours. The reaction mixture was then partitioned between CH2Cl2 and water and the solvent was removed from the organic layer by rotary evaporation. The crude product was purified by reverse phase preparative HPLC to give (S)- l-(3-phenyl-2-(thiazol-4-ylmethylamino)propanoyl)-6-(pyridin-4-yl)indoline-4-carboxamide TFA salt 60 as light yellow solid (6.6 mg, 12 percent yield). LCMS ESI (pos.) m/e: 484.1 (M+l) IH NMR (500 MHz, MeOH) delta ppm IH NMR (500 MHz, MeOH), delta ppm 9.10 (d, J=1.96 Hz, 1 H), 8.87 - 8.96 (m, 3 H), 8.37 (d, J=6.85 Hz, 2 H), 8.03 (d, J=I.71 Hz, 1 H), 7.83 (d, J=I.96 Hz, 1 H), 7.24 - 7.37 (m, 5 H), 4.74 (dd, J=10.27, 5.14 Hz, 1 H), 4.46 - 4.60 (m, 2 H), 3.96 - 4.07 (m, 1 H), 3.48 (dd, J=12.96, 4.89 Hz, 1 H), 3.35 - 3.41 (m, 1 H), 3.28 (dd, J=12.96, 10.27 Hz, 1 H), 2.97 - 3.07 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | (S)-2-(3-(3-(4-Chlorophenyl)-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)-2-methylpropanoic acid (63.1). To a 100 ml flask were added (S)-2-(3-(2-amino-3-(4-chlorophenyl)propanamido)-5-(pyridin-4-yl)phenyl)-2- methylpropanoic acid TFA salt 63.1.C (200 mg, 0.36 mmole), <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (33 mg, 0.21 mmole) , sodium triacetoxyborohydride (154 mg , 0.73 mmole), 20 ml of DCE, 1 ml MeOH and DIEA (95 mul, 0.54 mmole). The reaction was stirred at 70 0C for 2 hours at which time sodium cyanotrihydroborate (46 mg, 0.73 mmole) was added and stirred at 70 0C for an additional 1 hour. The reaction mixture was then partitioned between CH2Cl2 and water and the solvent was removed from the organic layer by rotary evaporation. The crude product was purified by reverse phase preparative HPLC to give (S)-2-(3-(3-(4- chlorophenyl)-2-(thiazol-4-ylmethylamino)propanamido)-5-(pyridin-4-yl)phenyl)-2- methylpropanoic acid TFA salt 63.1 as an off white solid (72.5 mg, 60percent yield). LCMS ESI (pos.) m/e: 535.2 (M+l): IH NMR (500 MHz, MeOH) delta ppm 9.14 (d, J=1.96 Hz, 1 H), 8.79 - 8.91 (m, 2 H), 8.14 - 8.25 (m, 2 H), 7.99 (t, J=I.71 Hz, 1 H), 7.82 (d, J=I.96 Hz, 1 H), 7.69 (t, J=I.59 Hz, 1 H), 7.52 (t, J=I.71 Hz, 1 H), 7.35 (m, 2 H), 7.27 (m, 2 H), 4.43 - 4.63 (m, 2 H), 4.28 (dd, J=9.29, 5.87 Hz, 1 H), 3.45 (dd, J=13.45, 5.62 Hz, 1 H), 3.24 (dd, J=13.33, 9.41 Hz, 1 H), 1.65 (d, J=6.85 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | (2S)-N-(2-hydroxy-5-(2-methylpyridin-4-yl)phenyl)-3-phenyl-2-(thiazol-4- ylmethylamino)propanamide (64.D). Amine 64.C (310 mg, 0.9 mmol), thiazole-4- carboxaldehyde (101 mg, 0.9 mmol), AcOH (51 muL, 0.9 mmol), and NaBH(OAc)3 were stirred in DCM (10 ml) overnight. The reaction mixture was diluted with DCM and neutralized with NaHCO3 (sat). The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 64.D (330 mg, 83percent). LC-MS (+esi, M+H+=445.1). IH NMR (400 MHz, DMSO-J6) delta ppm 10.43 (br. s., 1 H) 9.88 (s, 1 H) 8.99 (d, J=I.96 Hz, 1 H) 8.53 (d, J=2.45 Hz, 1 H) 8.44 (d, J=5.38 Hz, 1 H) 7.41 (s, 1 H) 7.33 - 7.40 (m, 3 H) 7.18 - 7.31 (m, 5 H) 6.97 (d, J=8.31 Hz, 1 H) 3.74 - 3.89 (m, 2 H) 3.53 - 3.62 (m, 1 H) 3.10 (dd, J=13.69, 4.89 Hz, 1 H) 2.87 (dd, J=13.69, 8.31 Hz, 1 H) 2.68 (d, J=6.36 Hz, 1 H) 2.51 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 70℃; for 12h; | 3.3.C 3.3[0210] (S)-3-Phenyl-N-(3-(pyridin-4-yl)isoxazol-5-yl)-2-(thiazol-4- ylmethylamino)propanamide (3.3). To a 20 ml vial were added (S)-2-amino-3-phenyl-N- (3-(pyridin-4-yl)isoxazol-5-yl)propanamide 3.3.C (40 mg, 0.13 mmole), thiazole-4- carbaldehyde (18 mg, O.lbetammole), sodium triacetoxyborohydride (55 mg, 0.26mmole) and 10 ml of DCE. The reaction was stirred at 700C for 12 hours. The crude material was partitioned between DCM and water and then purified by reverse phase preparative HLPC to give (S)-3-phenyl-N-(3-(pyridin-4-yl)isoxazol-5-yl)-2-(thiazol-4- ylmethylamino)propanamide TFA salt 3.3 as a white solid (14.2 mg, 27 percent yield). LCMS ESI (pos.) m/e: 406.1 (M+l): IH NMR (500 MHz, MeOH-J) delta ppm 9.09 (d, J=I.96 Hz, 1 H), 8.87 (br. s., 2 H), 8.27 (d, J=5.38 Hz, 2 H), 7.77 (d, J=I.96 Hz, 1 H), 7.27 - 7.35 (m, 3 H), 7.20 - 7.25 (m, 2 H) 7.07 (s, 1 H), 4.42 - 4.55 (m, 2 H), 4.35 (dd, J=8.80, 5.87 Hz, 1 H), 3.44 (dd, J=13.57, 5.99 Hz, 1 H), 3.26 (dd, J=13.69, 8.80 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 60℃; for 0.5h; | (S)-3-Phenyl-N-(2-(pyridin-4-yl)thiazol-4-yl)-2-(thiazol-4- ylmethylamino)propanamide (4). To a rt solution of 4.C (100 mg, 0.31 mmol) and <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (available from Combi-Blocks Inc.) (34.9 mg, 0.31 mmol) in 1 ,2-dichloroethane was added sodium triacetoxyborohydride (available from Fluka Chemie GmbH) (196 mg, 0.93 mmol) followed by 5percent HOAc/1,2- dichloroethane (50 muL). After stirring at 60 0C for 30 min, the reaction mixture was poured into saturated aqueous NaHCO3 (1.0 mL), diluted with water (5 mL), and extracted with 30percent 1PrOHZCHCl3 (3 x 10 mL). The organic solvent was removed under reduced pressure. After purification of the residue by preparative HPLC (10-90percent CH3CN/water, 30 min), the title product 2 (30 mg, 23percent) was obtained as colorless TFA salt. MS ESI (positve.) m/e: 422.0 (M+H); 1U NMR (400 MHz, CD3OD) delta ppm 2.86 - 3.05 (m, 1 H), 3.12 (dd, J=13.30, 6.26 Hz, 1 H), 3.65 (dd, J=7.83, 6.26 Hz, 1 H), 3.79 - 4.03 (m, 2 H), 7.13 - 7.36 (m, 6 H), 7.84 (s, 1 H), 7.89 - 7.99 (m, 2 H), 8.64 (dd, J=4.50, 1.76 Hz, 2 H), 8.90 (d, J=2.35 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 4h; | (S)-3-Phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)-2-(thiazol-4-ylmethylamino)- propanamide (5.3). To a mixture of (S)-2-amino-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5- yl)propanamide (0.075 g, 0.23 mmol), <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (0.026 g, 0.23 mmol) and N,N-dimethylformamide (0.500 ml, 0.23 mmol) in 1 ,2-dichloroethane (1.000 ml, 0.23 mmol) was added sodium triacetoxyborohydride (0.17 g, 0.81 mmol). The resulting mixture was allowed to stir at room temperature for 4 hours. Upon completion, the mixture was directly subjected to HPLC purification give 10 mg of (S)-3-phenyl-N-(2-(pyridin-4-yl)thiazol-5-yl)- 2-(thiazol-4-ylmethylamino)-propanamide 5.3. 400 MHz 1H NMR (CD3OD) delta: 9.30 (d, IH), 8.81 (d, 2H), 8.07 (d, 2H), 7.95 (d, IH), 7.76 (s, IH), 7.28 - 7.37 (m, 3H), 7.24 (dd, J = 8.0, 4.0 Hz, 2H), 4.49 (d, J = 16 Hz, IH), 4.44 (d, J = 16 Hz, IH), 4.43 (dd, J = 12, 8.0 Hz, IH), 3.49 (dd, J = 12, 4.0 Hz, IH), 3.23 (dd, J = 12, 8.0 Hz, IH). LCMS (ES+) m/z 422. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | (2S)-N-(5-(2-methylamino)pyridine-4-yl)-l,3,4-thiadiazol-2-yl)-3-phenyl- 2-(thiazol-4-ylmethylamino)propanamide (8.1). To a flask with 69 mg of 8.1.F (0.19 mmol) was added <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (23 mg, 0.2 mmol), 2 niL MeOH and 1 mL dichloromethane. Then sodium cyanoborohydride (24 mg, 0.49 mmol) was added. The reaction mixture was heated at 50 0C for 1 hour. 2 drops of water were added and the reaction was concentrated and purified on reverse phase HPLC column to afford 32 mg of 8.1 (37percent yield). IH NMR (400 MHz, MeOH) delta ppm 8.90 (d, J=I.96 Hz, 1 H) 8.06 (d, J=4.70 Hz, 1 H) 7.31 (d, J=I.96 Hz, 1 H) 7.16 - 7.28 (m, 5 H) 7.03 (dd, J=5.48, 1.56 Hz, 1 H) 6.96 - 7.00 (m, 1 H) 3.92 (d, J=5.09 Hz, 2 H) 3.78 (t, J=7.04 Hz, 1 H) 3.10 (dd, J=12.00, 8.00 Hz, 1 H) 3.01 (dd, J=12.00, 8.00 Hz, 1 H) 2.92 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 36; 4-((Z)-2-Tritylthioethen-1-yl)thiazole; a) 4-Ethynylthiazole; Bromomethyltriphenylphosphonium bromide (9.83 g) was added to 100 ml of a suspension of 7.27 g of potassium-t-butoxide in THF under ice cooling, the suspension was stirred at the same temperature for 10 min, and 2.44 g of 4-formylthiazole was further added thereto. The mixture was stirred at room temperature for 2 hr. Thereafter, 100 ml of ethyl acetate and 100 ml of semi-saturated brine were added thereto, followed by separation. The organic layer was then washed with semi-saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:hexane=3:2) to give 614 mg of 4-ethynylthiazole. NMR (CDCl3) delta: 3.15 (1H, s), 7.58 (1H, d, J=2.0 Hz), 8.78 (1H, d, J=2.0 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.3% | With methanol; sodium tetrahydroborate; at 0℃; for 1h; | To a solution of thiazole-4-carboxaldehyde (0.810 ml, 9.67 mmol, Combi-Blocks Inc.) in MeOH (48.3 ml) at 0 °C was added sodium borohydride (0.341 ml, 9.67 mmol, Sigma-Aldrich Chemical Company, Inc.) in portions. The reaction mixture was allowed to stir for 1 hour. Saturated aqueous ammonium chloride solution was carefully added and the reaction mixture was filtered. The filtrate was concentrated in vacuo. The solid was taken up in 10percent MeOH/DCM and filtered through a plug of silica gel to provide thiazol- 4-ylmethanol (0.826 g, 7.18 mmol, 74.3percent yield) as a yellow oil. MS m/z = 116.0 [M+H]+. Calculated for C4H5NOS: 115.009. H NMR (400 MHz, CHLOROFORM -J) delta ppm 2.58 (br. s., 1 H) 4.86 (s, 2 H) 7.27 - 7.30 (m, 1 H) 8.83 (d, J=l .76 Hz, 1 H) |
With methanol; sodium tetrahydroborate; at 0 - 20℃; for 2h; | To a solution of sodium borohydride (502 mg, 13.3 mmol) in methanol (20 mL) was added a solution of l,3-<strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (1.0 g, 8.8 mmol) in methanol (5 mL) at 0°C. The mixture was stirred for 2 hours at room temperature. The solvent was evaporated, water was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, l,3-thiazole-4-ylmethanol was obtained as a yellow oil (596 mg, 58percent yield) and used in the next step without purification; 1HNMR (400 MHz, CDCl3): delta 2.67 (bs, IH), 4.85 (d, J = 5.9 Hz, 2H), 7.28 (s, IH), 8.81 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In ethanol; at 20℃; | Example 3A2-Amino-6-sulfanyl-4-(1,3-thiazol-4-yl)pyridine-3,5-dicarbonitrile492 mg (4.349 mmol) of <strong>[3364-80-5]1,3-<strong>[3364-80-5]thiazole-4-carbaldehyde</strong></strong>, 871 mg (8.697 mmol) of 2-cyanoethanethioamide and 880 mg (8.697 mmol) of N-methylmorpholine were dissolved in 10 ml of ethanol.The reaction mixture was stirred at room temperature overnight, the solvent was removed under reduced pressure and acetonitrile was added to the residue.The solid was filtered off and washed with acetonitrile, and the filter cake was dried under reduced pressure.This gave 181 mg (14percent of theory, 86percent pure) of the target compound.LC-MS (Method 1): Rt=0.76 min; MS (ESIpos): m/z=260 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[623] Example 158 - 3-ri-Methyl-5-(4-methyl-cvclohexyl)-l,2,3,6-tetrahydro-pyridin-4-yl1-5-r4-; [624] A mixture of 4-bromobenzyl bromide (1.00 g, 4.00 mmol) and triphenylphosphine (1.70 g, 6.00 mmol) in toluene (10 mL) was stirred at 80 °C overnight. The reaction mixture wasconcentrated, followed by sonication in hexane, filtration, and a subsequent hexane wash gave a white solid, which was dried in vacuo. This white solid (906 mg, 1.77 mmol) was dissolved in THF (10 mL), cooled to 0 °C, and lithium hexamethyl disilazide (1 M) in THF (1.95 mL, 1.95 mmol) was added. After 0.5 hr, thiazole-4-carboxaldehyde (200 mg, 1.77 mmol) was added, the ice bath was removed, and the mixture stirred for 0.5 hr. The reaction mixture was quenched by the addition of water, extracted with EtOAc (2x30 mL), the organic layer was washed with brine, dried over MgS04, concentrated and filtered through a silica plug using 30percent -100percent EtOAc/hexane to give 158A as a clear oil. MS calcd: M+H)+ = 267. + = 267. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 2h; | [374] Example 61 - 3-ri-Ethyl-5-(4-methyl-cyclohexyl -l,2,3,6-tetrahydro-pyridin-4-yl1-5-|4-; [375] Thiazole-4-carbaldehyde (17 mg, 0.11 mmole), sodium triacetoxyborohydride (70 mg, 0.33 mmole), and 018B (48 mg, 0.11 mmole) were mixed in 10 mL of DCE. The reaction was stirred at RT for 2 hr. The reaction mixture was then partitioned between CH2C12 and water. The organic layer was concentrated, and the resulting crude product was purified by column chromatography to give 161A. MS calc + = 536. MS found: (M+H)+ = 536. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; for 16h; | Step 1 : To a solution of (5-amino-6-aminomethyl-pyridin-2-yl)-(2,4-dimethoxy-benzyl)- carbamic acid tert-butyl ester (Example 20, product from Step 3) (422 mg, 1.1 mmol, 1 equiv), 1 ,3-<strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (150 mg, 1.3 mmol, 1.2 equiv.) and acetic acid (32 muIota_, 2.2 mmol, 2 equiv) in DCE (5 mL) was added sodium triacetoxyborohydride (400 mg, 1.87 mmol, 1.7 equiv) and the reaction mixture was stirred for 16 h. Saturated NaHC03 was added and the product was extracted with dichloromethane. The organic phase was dried (MgS04), filtered and the solvent evaporated. The crude material was purified by column chromatography (S1O2, eluted with dichloromethane - MeOH/NH30-10percent) to afford (5-amino- 6-[(thiazol-4-ylmethyl)-amino]-methyl}-pyridin-2-yl)-(2,4-dimethoxy-benzyl)-carbamic acid tert-butyl ester (157 mg). MS: [M+H]+ = 486. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 65℃; for 16h; | A mixture of <strong>[3364-80-5]thiazole-4-carbaldehyde</strong> (0.1 15 g; 1.016 mmol) and 4-amino-2- methoxypyridine (0.126 g; 1.016 mmol) in ethanol (1 mL) was stirred at 65°C for 16 h. The solvent was evaporated and the residue was dried under reduced pressure to give quantitatively 2-methoxy-/V-(thiazol-4-ylmethylene)pyridin-4-amine which was used without further purification. ESI/APCI (+): 220 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium metabisulfite; In N,N-dimethyl-formamide; at 120℃; | General procedure: A solution of substituted o-phenyldiamine (1.0 equiv), thiazole-4-aldehyde or pyridine-2-aldehyde (1.0 equiv) with sodium pyrosulfite in DMF was stirred at 120° C overnight. On completion of the reaction monitored by TLC, the solvent was evaporated and the residue was purified by silica gel chromatography by DCM/MeOH system to afford the final product. If necessary, the crudeproduct could be recrystallized in DCM or dichloroethane to afford pure sample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium methylate; In methanol; at 20℃; for 4h; | General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5percent methanol in dichloromethane) or column chromatography (2percent methanol in dichloromethane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium methylate; In methanol; at 20℃; for 18h; | General procedure: Method A [31]: To a solution of the starting aldehyde (1.5 mmol) and ketone (0.75 mmol) in methanol (10 mL) was added the solution of sodium methoxide in methanol (5.4 M, 0.14 mL,0.75 mmol), and the mixture was stirred for 4-18 h and monitored with TLC. When the reaction was completed, the following two work-up procedures were applied. Procedure 1: if precipitate was observed, the precipitate was filtered and rinsed with cold methanol. Procedure 2: if no precipitate was observed, then saturated solution of ammonium chloride was added, and the subsequent mixture was extracted with dichloromethane. The organic layer was dried over anhydrous MgSO4. The solvent was evaporated under vacuum to give a crude product, which was purified by preparative TLC (3e5percent methanol in dichloromethane) or column chromatography (2percent methanol in dichloromethane). |
Tags: 3364-80-5 synthesis path| 3364-80-5 SDS| 3364-80-5 COA| 3364-80-5 purity| 3364-80-5 application| 3364-80-5 NMR| 3364-80-5 COA| 3364-80-5 structure
[ 20949-84-2 ]
2-Methylthiazole-4-carbaldehyde
Similarity: 0.80
[ 261710-79-6 ]
5-Methylthiazole-4-carbaldehyde
Similarity: 0.78
[ 133047-46-8 ]
2-Isopropylthiazole-4-carbaldehyde
Similarity: 0.68
[ 82294-70-0 ]
4-Methylthiazole-5-carbaldehyde
Similarity: 0.67
[ 20949-84-2 ]
2-Methylthiazole-4-carbaldehyde
Similarity: 0.80
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P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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