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CAS No. : | 6000-44-8 | MDL No. : | MFCD00062543 |
Formula : | C2H4NNaO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WUWHFEHKUQVYLF-UHFFFAOYSA-M |
M.W : | 97.05 | Pubchem ID : | 4684308 |
Synonyms : |
Sodium glycinate
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 14.26 |
TPSA : | 66.15 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.17 cm/s |
Log Po/w (iLOGP) : | -8.37 |
Log Po/w (XLOGP3) : | -3.21 |
Log Po/w (WLOGP) : | -2.3 |
Log Po/w (MLOGP) : | -3.58 |
Log Po/w (SILICOS-IT) : | -1.04 |
Consensus Log Po/w : | -3.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.65 |
Solubility : | 4300.0 mg/ml ; 44.3 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 2.39 |
Solubility : | 23900.0 mg/ml ; 246.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 0.83 |
Solubility : | 659.0 mg/ml ; 6.79 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P362-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-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 |
---|---|---|
96.7% | With sodium hydroxide In water at 160℃; | 10 g (calculated on the basis of the dry substance) of a Pd-doped copper catalyst on active carbon (Degussa AG, CE 1015 OY/W) suspended in water was placed first analogously to example 1 in an autoclave and 61 g ethanolamine and 272 g sodium hydroxide solution (15percent by weight) were added. The autoclave was closed and the contents were heated to 160° C. The pressure was kept at 12 bar (absolute) and the hydrogen that formed was continuously discharged by a pressure control valve. After the end of the reaction (which is evident from the decrease in gas release) it was cooled to 90° C. and the catalyst was removed from the product solution by filtration. 315 g filtrate which contained 29.8 g percent by weight Na glycinate was obtained (corresponds to a yield of 96.7percent of theory).The filtered catalyst was suspended in 10 g water and fed back into subsequent batches. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide In glycerol at 120℃; for 1 h; | EXAMPLE 1Synthesis of Sodium Glvcinate Reagent CompositionA glass reactor vessel was charged with 25g glycerol, 13.5g of glycine and 7.0g of sodium hydroxide pellets. These were heated together at 120°C for one hour. Water was continuously distilled from the resultant reagent composition. This reagent composition provided a 100percent yield of sodium glycine in glycerol. This composition can be prepared as a pre-mix as herein described and then charged to a reactor with a fatty acid ester to conduct a reaction to produce cocoyi glycinate. Alternatively, the sodium glycine slurry and and glycerol can be formed in situ as is described in the following reaction scheme. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99 %Spectr. | With C20H28ClN2OPRu; sodium hydroxide In 1,4-dioxane; water at 125℃; for 24 h; Inert atmosphere; Glovebox; Schlenk technique | General procedure: In a glove box, a 25 mL Schlenk flask was charged with a stirring bar, catalyst (0.005-0.01 mmol), NaOH or KOH (5.5-10 mmol), amino alcohol (1-5 mmol), water (0.3-0.5 mL) and dioxane (0-0.5 mL) under an atmosphere of nitrogen (see Table 9 for specific amounts used). The flask was taken out of the glove box, equipped with a condenser and the solution was refluxed (oil bath temperature 125° C.) with stirring in an open system under a flow of argon for 24 h. After cooling to room temperature, 1-5 mmol of pyridine was added to the crude reaction mixture as an internal standard. 0-2 mL water was added, leading to a homogeneous solution. Then 0.05 mL of the solution was dissolved in D2O for determination of the conversion of amino alcohol and the yield of amino acid salt by 1H NMR spectroscopy. Isolation of alanine is given as a specific example. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.134 g (18%) | In water; ethyl acetate; N,N-dimethyl-formamide; | N-(4-Fluoro-5-methyl-2-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (0.550 g. 3.18 mmol) in DMF (5.0 mL) was added dropwise a solution of sodium glycinate (0.308 g, 3.18 mmol, Aldrich, used as received) in water (1.0 mL). The resulting suspension was stirred at 28 C. overnight. The solid was filtered and dried under vacuum to give 0.168 g (23%) of crude product. It was purified as follows. 0.150 g material was boiled in ethyl acetate (5.0 mL) and filtered while hot to give 0.134 g (18%) of the pure (1 H NMR) title compound as a yellow powder. 1 H NMR (DMSO-d6): 2.213 (s, 3H), 3.428 (d, 2H, J=3.9 Hz), 6.765 (d, 1H, J=6.9 Hz), 7.700 (d, 1H, J=10.5 Hz), 8.728 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.360 g (46%) | In water; N,N-dimethyl-formamide; | N-(4'-Chloro-5'-methyl-2'-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[170098-88-1]2-chloro-5-fluoro-4-nitrotoluene</strong> (0.605 g, 3.19 mmol, as prepared above) in DMF (3.0 mL) at 70 C., was added dropwise, a solution of sodium glycinate (0.310 g, 3.19 mmol, Aldrich, used as received) in water (3.0 mL). The resulting suspension was stirred overnight at 70 C. The suspension was cooled to room temperature and the resulting red solid was filtered, washed with chloroform (10 mL) and dried under vacuum to give 0.360 g (46%) pure (1 H NMR) title compound as a red powder; 1 H NMR (DMSO-d6): delta2.276 (s, 3H), 3.431 (d, 2H, J=4.2 Hz), 6.848 (s, 1H), 7.963 (s, 1H), 8.773 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.005 g (37%) | In water; N,N-dimethyl-formamide; | N-(5'-Chloro-4'-methyl-2'-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[112108-73-3]2-chloro-4-fluoro-5-nitrotoluene</strong> (2.080 g, 10.97 mmol, as prepared above) in DMF (11.0 mL) at 70 C., was added dropwise, a solution of sodium glycinate (1.065 g, 10.97 mmol, Aldrich, used as received) in water (11.0 mL). The resulting suspension was stirred overnight at 70 C., cooled to room temperature, and the resulting red solid was filtered, washed with acetone (35 mL), and dried under vacuum to give 1.005 g (37%) of the pure (1 H NMR) title compound as a red powder; 1 H NMR (DMSO-d6): delta2.184 (s, 3H), 3.396 (d, 2H, J=4.2 Hz), 6.852 (s, 1H), 7.991 (s, 1H), 8.671 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.932 g (45%) | In water; N,N-dimethyl-formamide; | N-(4'-Bromo-5'-methyl-2'-nitrophenyl)glycine sodium salt: To a stirred solution of <strong>[170098-98-3]2-bromo-5-fluoro-4-nitrotoluene</strong> (1.662 g, 7.102 mmol, as prepared above) in DMF (7.0 mL) at 70 C., was added, dropwise, a solution of sodium glycinate (0.690 g, 7.11 mmol, Aldrich, used as received) in water (7.0 mL). The resulting suspension was stirred overnight at 70 C. The suspension was cooled to room temperature and the red solid was filtered, washed with acetone, and dried under vacuum to give 0.932 g (45%) of the pure (1 H NMR) title compound as a red powder; 1 H NMR (DMSO-d6): delta2.306 (s, 3H), 3.452 (d, 2H, J=3.9 Hz), 6.874 (s, 1H), 8.125 (s, 1H), 8.779 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; at 55 - 60℃; for 4h; | One mole of a soluble ferrous salt is reacted with two moles of <strong>[6000-44-8]sodium glycinate</strong> and one mole of ascorbic acid in an aqueous solution to produce ferrous bisglycinate ascorbic acid chelate. Specifically, two moles of <strong>[6000-44-8]sodium glycinate</strong> (194.1 g) and one mole of ascorbic acid (176.1 g) were dissolved in one liter of water, and the mixture was brought to 55-60 C. Next, 1.0 mole (126.8 g) of ferrous chloride was added to the mixture, and the mixture was allowed to react for a total of 4 hours. After the 4 hour reaction time, the composition was cooled 40 C. and spray dried to obtain about 380.1 g of ferrous bisglycinate ascorbate at 100% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With citric acid; In water; at 55 - 60℃; for 1.0h; | One mole of ferrous oxide is reacted with two moles of sodium glycinate in the presence of citric acid in an aqueous solution to form ferrous bisglycinate. The ferrous bisglycinate is further reacted in a 1:1 molar ratio with citric acid to form ferrous bisglycinate citric acid chelate. Specifically, two moles of sodium glycinate (194.1 g) were dissolved in one liter of 0.5 M citric acid, and the mixture was brought to 55-60° C. Next, 1.0 mole (71.8 g) of ferrous oxide was added to the mixture, and the mixture was allowed to react for 1 hour forming ferrous bisglycinate. Next, one mole of citric acid (192.1 g) was added to the reaction mixture. After a 4 hour reaction time, the composition was cooled 40° C. and spray dried to obtain about 394.0 g of ferrous bisglycinate citrate at 100percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; at 55 - 60℃; for 4h; | One mole of iron acetate is reacted with two moles of glycine in an aqueous solution to produce ferrous bisglycinate acetic acid chelate. Specifically, one mole of ferrous acetate (173.9 g) and two moles of <strong>[6000-44-8]sodium glycinate</strong> (194.1 g) were dissolved in one liter of water, and the mixture was brought to 55-60 C. After a 4 hour reaction time, the composition was cooled 40 C. and spray dried to obtain about 368.0 g of ferrous bisglycinate acetate at 100% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol; at 150℃; for 0.333333h;Microwave irradiation; | A mixture of the compound from Example 6b) (0.060 g, 0.20 mmol) and <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.039 g, 0.40 mmol) in ethanol (3.0 mL) was heated to 150 0C for 20 minutes in a Biotage Initiator microwave synthesizer. The reaction was quenched with water (10 mL) and neutralized with IN aqueous HCl. The resulting precipitate was collected and dried in vacuo to afford the title compound as brown solid (0.051 g, 78%). 1H NMR (400 MHz, OMSO-d6) delta ppm 12.8 (s, 1 H) 12.5 (s, 1 H) 10.2 (t, J=5.6 Hz, 1 H) 8.21 (s, 1 H) 7.65 (d, J=6.8 Hz, 2 H) 7.57 (t, J=7.6 Hz, 2 H) 7.49 (t, J=7.2 Hz, 1 H) 4.10 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 329 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.5%Chromat.; 1.1%Chromat.; 2.3%Chromat.; 16.7%Chromat. | A sample of HMPA self-esters, prepared as described above in example 8 from 0.066 g (0.48 mmol) of (OH)2P(O)CH2OH.1.4H2O, was stirred with an excess of sodium glycinate (0.482 g, 4.97 mmol) in 2 ml of acetonitrile for about ten minutes, followed by removal of the solvent. The flask was immersed in an oil bath and heated to 180 C. for 16 hours with vigorous stirring. At the end of this time the reaction mixture was hydrolyzed by 24% HBr (10 ml) at 110 C. for 6 hours to give, according to HPLC, 16.7% glyphosate, 1.1% AMPA, 2.3% H3PO4, and 1.5% H3PO3 at 20% HMPA conversion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7%Chromat.; 1.2%Chromat.; 1.7%Chromat.; 2.2%Chromat.; 15.1%Chromat. | A sample of HMPA self-esters, prepared as described above in example 8 from 0.106 g (0.775 mmol) of (OH)2P(O)CH2OH.1.4H2O was vigorously stirred with an excess of sodium glycinate (0.480 g, 4.96 mmol) in 1.5 ml of sulfolane at 180 C. for 16 hours. At the end of this time the reaction mixture was hydrolyzed by 24% HBr (10 ml) at 110 C. for 6 hours to give, according to HPLC, 15.1 % glyphosate, 1.2% AMPA, 2.2% H3PO4, 0.7% H3PO3, and 1.7% glyphosine at 20% HMPA conversion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8%Chromat.; 1.9%Chromat.; 1.9%Chromat.; 18%Chromat. | A sample of HMPA self-esters, prepared as described above in example 8 from 0.077 g (0.56 mmol) of (OH)2P(O)CH2OH.1.4H2O was vigorously stirred with an excess of sodium glycinate (0.488 g, 5.03 mmol) in 2 ml of 15-crown-5 ether at 178 C. for 16 hours. At the end of this time the reaction mixture was hydrolyzed by 24% HBr (10 ml) at 110 C. for 6 hours to give, according to HPLC, 18.0% glyphosate, 1.8% AMPA, 1.9% H3PO4, and 1.9% glyphosine at 23% HMPA conversion. | |
2.5%Chromat.; 0.7%Chromat.; 4.7%Chromat.; 30.3%Chromat. | A sample of HMPA self-esters, prepared as described above in example 8 from 0.064 g (0.47 mmol) of (OH)2P(O)CH2OH.1.4H2O was vigorously stirred with excess of sodium glycinate (0.475 g, 4.90 mmol) in 2 ml of sulfolane in the presence of 0.219 g (1.46 mmol) of Nal at 150 C. for 94 hours. At the end of this time the reaction mixture was hydrolyzed by 24% HBr (10 ml) at 110 C. for 6 hours to give, according to HPLC, 30.3% glyphosate, 2.5% AMPA, 4.7% H3PO4, and 0.7% glyphosine at 36% HMPA conversion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | 17-CarboxvmethYlamino-17-demethoxvgeldanamycin (13) (+) -Geldanamycin (3.1 mg, 5. 5 umol) was stirred at room temperature with <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (10.7 mg, 0.11 mmol) in a mixture of ethanol (1.2 ml) and water (0.3 ml). Upon the complete conversion of GA shown by thin layer chromatography (3 hours), the purple mixture was acidified with diluted hydrochloric acid and partitioned between chloroform and distilled water. The organic phase was dried over anhydrous sodium sulfate and concentrated. Separation by flash column chromatography on silica gel (ethyl acetate/methanol) gave the product as a purple solid (3.2 mg, 96%). IR (KBr) (cm'') 3446, 3305,2929, 2875,1734, 1693,1655, 1618, 1574,1485, 1394,1319, 1267,1139, 1072 ;'H NMR (CDC13, 500 MHz) 8 8.91 (s, 1H), 7.25 (s, 1H), 6.83 (bs, 1H), 6.80 (bd, J= 11.5 Hz, 1H), 6.60 (bdd, J= 11.5, 11.0 Hz, 1H), 5.86-5. 80 (m, 2H), 5.16 (s, 1H), 4.95 (bs, 2H), 4.33-4. 21 (m, 2H), 4.27 (bd, J= 10.0 Hz, 1H), 3.54 (dd, J= 9.0, 2.0 Hz, 1H), 3.42 (ddd, J= 9.0, 3.0, 3.0 Hz, 1H), 3.33 (s, 3H), 3.25 (s, 3H), 2.70 (dqd, J= 9. 5,7. 0,2. 0 Hz, 1H), 2.59 (d, J= 14.0 Hz, 1H), 2.27 (dd, J= 14.0, 11.0 Hz, 1H), 2.07 (bs, 3H), 1.80-1. 75 (m, 2H), 1.62-1. 54 (m, 1H), 1.77 (bs, 3H), 0.98 (d, J= 7.0 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H); HRMS (FAB) found 604.2867 [M+H] +, calcd. 604.2870 for C3OH42N3OIo |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.4% | With hydrogenchloride; | Example 10 After 50 ml of 2M-NaOH aqueous solution and 7.1 g (0.10 mol) of glycin were charged in a 200 mL four-necked glass flask having a reflux condenser, a thermometer, a nitrogen inlet adapter, and an agitator and were stirred at room temperature so that the glycin can be completely dissolved in the solution to prepare a solution of glycin sodium salt. Sequentially, 45.6 g (0.30 mol) of methylphenyl carbonate was added to the solution and was allowed to react with it at 50 C. for eight hours under stirring vigorously. Thereafter, the reaction mixture was poured into a separating funnel to separate an organic layer and hydrochloric acid was added to the aqueous layer to adjust the pH of the aqueous layer to pH3. The aqueous layer was extracted with ethyl acetate and ethyl acetate was washed with water. From the quantitative analysis of the ethyl acetate solution using the gas chromatography, it was found that N-methoxycarbonyl glycin was produced at the yield of 91.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.673 g (64%) | In ethanol; water; | N-(5'-Chloro-4'-fluoro-2'-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[578-28-9]1-chloro-2,5-difluoro-4-nitrobenzene</strong> (0.825 g, 4.26 mmol) in ethanol (8.0 mL), was added a solution of sodium glycinate (0.415 g, 4.27 mmol) in water (1.5 mL). The resulting suspension was refluxed for 60 h. The solution was cooled to room temperature and the precipitated bright orange solid was filtered, washed with cold ethanol (5 mL), and dried under vacuum to give 0.673 g (64%) title compound as a bright orange powder; 1 H NMR (DMSO-d6) delta3.50 (d, 2H, J=3.6 Hz), 7.04 (d, 1H, J=6.6 Hz), 8.01 (d, 1H J=9.9 Hz), 8.74 (s, 1H). The unreacted <strong>[578-28-9]1-chloro-2,5-difluoro-4-nitrobenzene</strong> was recovered almost quantitatively from the filtrate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.438 g (38%) | In water; N,N-dimethyl-formamide; | N-(4'-Chloro-5'-fluoro-2'-nitrophenyl)glycine and N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt: To a stirred solution of <strong>[1481-68-1]1-chloro-2,4-difluoro-5-nitrobenzene</strong> (1.000 g, 5.167 mmol, as prepared above) in DMF (10.0 mL), was added, dropwise, a solution of sodium glycinate (0.502 g, 5.17 mmol, Aldrich, used as received) in water (2.0 mL). The solution was stirred at 70° C. for 16 h and cooled to room temperature. The precipitated solid was filtered, washed with acetone (10 mL), and dried under vacuum to give 0.438 g (38percent) of a red solid as a mixture of the title compounds in a ratio of 1.0:0.3 as judged by 1 H NMR; 1 H NMR (DMSO-d6): delta3.474 (d, 2H, J=4.5 Hz), 3.523 (d, 2H, J=3.9 Hz), 6.535 (d, 1H, J=14.7 Hz), 6.871 (d, 1H, J=12.3 Hz), 6.976 (s, 1H), 8.068 (d, 1H, J=7.8 Hz), 8.168 (d, 1H, J=7.8 Hz), 8.867 (s, 1H). The separation of the mixture was not feasible at this stage; hence, it was used as such for the next reaction. |
0.438 g (38%) | In water; N,N-dimethyl-formamide; | N-(4'-Chloro-5'-fluoro-2'-nitrophenyl)glycine and N-(2'-chloro-5'-fluoro-4'-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[1481-68-1]1-chloro-2,4-difluoro-5-nitrobenzene</strong> (1.000, 5.167 mmol) in DMF (10.0 mL), was added dropwise, a solution of sodium glycinate (0.502 g, 5.17 mmol) in water (2.0 mL). The solution was stirred at 70° C. for 16 h. The resulting suspension was then cooled to room temperature and the precipitated solid was filtered, washed with acetone (10 mL), and dried under vacuum to give 0.438 g (38percent) red solid as a mixture of title compounds in a ratio of 3:1 (1 H NMR); 1 H NMR (DMSO-d6) delta3.474 (d, 2H, J=4.5 Hz), 3.523 (d, 2H, J=3.9 Hz), 6.535 (d, 1H, J=14.7 Hz), 6.871 (d, 1H; J=12.3 Hz), 6.976 (s, 1H), 8.068 (d, 1H, J=7.8 Hz), 8.168 (d, 1H, J=7.8 Hz), 8.867 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of the compound from Example 58b) (0.279 g, 0.727 mmol) in ethanol (3.0 mL) was added <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.074 g, 0.764 mmol) and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), filtered, and washed with water to give the title compound as a pale yellow solid (0.217 g, 72%). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.6 (t, J=5.3 Hz, 1 H), 7.41 (s, 1 H), 7.16 - 7.37 (m, 5 H), 6.92 (s, 1 H), 5.60 (s, 2 H), 4.10 (d, J=5.6 Hz, 2 H), 3.82 (s, 3 H), 3.76 (s, 3 H). MS(ES+) m/e 413 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | To a solution of the compound from Example 60b) (0.073 g, 0.19 mmol) in ethanol (3.0 mL) was added <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.020 g, 0.200 mmol) and the solution was heated to 180 0C for 30 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), filtered, washed with water and triturated with Et2O. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded the title compound as a pale orange solid (0.023 g, 30%). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.8 (t, J=5.3 Hz, 1 H), 7.49 (d, J=9.6 Hz, 1 H), 7.32 (t, J=7.3 Hz, 2 H), 7.24 (d, J=7.1 Hz, 1 H), 7.17 - 7.22 (m, 3 H), 5.52 (br. s., 1 H), 4.13 (d, J=5.8 Hz, 2 H), 3.81 (s, 3 H), 3.78 (s, 3 H). MS(ES+) m/e 413[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A mixture of the compound from Example 75b) (0.387 g, 1.08 mmol) and <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong>(0.157 g, 1.62 mmol) in ethanol (2.0 mL) was heated to 160 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with water and acidified with 6M aqueous hydrochloric acid. Following stirring at ambient temperature for 5 min., the precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a white solid (0.385 g, 92%). 1H NMR (400 MHz, DMSOd6) delta ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.07 (dd, J=10.2, 9.2 Hz, 1 H), 7.64 (dd, J=12.8, 6.7 Hz, 1 H), 7.33 (t, J=7.5 Hz, 2 H), 7.27 (t, J=7.3 Hz, 1 H), 7.23 (d, J=7.1 Hz, 2 H), 5.53 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 389 [M+H]+. EPO <DP n="69"/> |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To a solution of the compound from Example 82c) (0.050 g, 0.140 mmol) in ethanol (1.0 mL) was added <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.014g, 0.146 mmol). The solution was heated to 1600C for 25 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was poured into water and then acidified with IM aqueous hydrochloric acid. The clear solution was stirred for 18 h and the resulting precipitate was filtered and washed with Et2O to afford the title compound as a pale yellow solid (0.017 g, 32%). 1H NMR (400 MHz, DMSOd6) delta ppm 10.4 (t, J=5.4 Hz, 1 H), 8.14 (dd, J=8.1, 1.5 Hz, 1 H), 7.84 (tt, J=7.3, 1.5 Hz, 1 H), 7.59 (d, J=8.6 Hz, 1 H), 7.41 (t, J=7.6 Hz, 1 H), 5.60 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 3.17 (s, 3 H), 2.47 (s, 3 H). MS(ES+) m/e 388 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In ethanol; at 160℃; for 0.333333h;Microwave; | A mixture of the compound from Example 100a) (0.100 g, 0.296 mmol) and <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.032 g, 0.325 mmol) in ethanol (2.0 mL) was heated to 160 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with water, acidified with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo to afford the title compound as a pale yellow solid (0.100 g, 92%). 1H NMR (400 MHz, DMSOd6) delta ppm 12.9 (br. s., 1 H), 10.4 (t, J=4.7 Hz, 1 H), 8.07 (d, J=8.1 Hz, 1 H), 7.96 (d, J=8.3 Hz, 1 H), 7.78 (t, J=7.5 Hz, 1 H), 7.47 (d, J=7.1 Hz, 2 H), 7.35 (d, J=7.1 Hz, 2 H), 7.25 - 7.40 (m, 2 H)5 6.53 (t, J=6.2 Hz, 1 H), 4.17 (d, J=5.1 Hz, 2 H), 4.07 (br. s., 2 H). MS(ES+) m/e 368 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | To a solution of the compound from Example 109b) (0.050 g, 0.130 mmol) in ethanol (1.0 mL) was added <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.013g, 0.136 mmol). The solution was heated to 150 0C for 15 min. in a Biotage Initiator microwave synthesizer. The resulting solid was filtered, washed with ethyl acetate, dissolved in water and treated with 6M aqueous hydrochloric acid. The resulting solid was EPO <DP n="97"/>filtered, washed with hexanes, and dried in vacuo to afford the title compound as a pale orange solid (0.013 g, 25%). 1H NMR (400 MHz, DMSO-d6) delta ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.4 Hz, 1 H), 7.74 (dd, J=8.7, 1.6 Hz, 1 H), 7.59 - 7.68 (m, 2 H), 7.20 - 7.32 (m, 4 H), 7.13 - 7.20 (m, 1 H), 4.27 (t, J=7.3 Hz, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 2.73 (t, J=7.7 Hz, 2 H), 1.84 - 1.96 (m, 2 H). MS(ES+) m/e 399 [M+H]+- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | A mixture of the compound from Example 1 Ia) (0.03 g, 0.095 mmol) and <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.014 g, 0.14 mmol) in ethanol (3.0 iriL) was heated to 180 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, IM aqueous HCl (2.0 mL) was added. The precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a yellow solid (0.025 g, 76%). 1H NMR (400 MHz, DMSOd6) delta ppm 12.9 (s, 1 H) 10.6 (s, 1 H) 8.11 (dd, 7=7.8, 1.5 Hz, 1 H) 7.91 (br. s., 1 H) 7.74 - 7.82 (m, 1 H) 7.36 (t, /=7.7 Hz, 1 H) 4.13 (d, 7=5.6 Hz, 2 H) 2.40 - 2.71 (m, 3 H) 1.85 (d, J=ILl Hz, 2 H) 1.69 (d, 7=11.4 Hz, 3 H) 1.41 - 1.56 (m, 2 H) 1.16 - 1.36 (m, 1 H). MS(ES+) m/e 345 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | EXAMPLE 7 N-[(4-hydroxy-2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)carbonyl]glycine A solution of ethyl 3-aminoisonicotinate (0.071 g, 0.43 mmol) in methylene chloride (2.0 mL) was treated with triethylamine (1.00 mL, 7.17 mmol) followed by ethyl malonyl chloride (0.060 mL, 0.47 mmol). The mixture was stirred overnight at ambient temperature, followed by concentration in vacuo. The residue was dissolved in ethanol (2.0 mL), treated with sodium ethoxide (0.158 mL, 0.43 mmol, 21% solution in ethanol) at ambient temperature, and stirred overnight. The solution was concentrated in vacuo, and the resulting residue was dissolved in ethanol (2.0 mL) and treated with <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.030 g, 0.43 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.060 mL, 0.43 mmol) and heated to 180 C. for 30 min. in a Biotage Initiator microwave synthesizer. The reaction was diluted with water, acidified with 1 N aqueous hydrochloric acid, and the resulting precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a light brown solid (0.034 g, 30%). 1H NMR (400 MHz, DMSO-d6 delta ppm 12.4 (s, 2 H), 10.4 (s, 2 H), 8.88 (s, 1 H), 7.89 (s, 1 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 264 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | 6b) N-[4-hydroxy-2-oxo-1-(phenylmethyl)-1,2-dihydro-1,7-naphthyridin-3-yl]carbonyl}glycine A solution of the compound from Example 6a) (0.500 g, 1.90 mmol) in methylene chloride (20.0 mL) was treated with (4-dimethylamino)pyridine (0.040 mL, 0.38 mmol) followed by ethyl malonyl chloride (0.260 mL, 2.09 mmol). The mixture was stirred overnight at ambient temperature, followed by addition of triethylamine (1.00 mL, 7.17 mmol). Following stirring 1 h at ambient temperature, the reaction mixture was concentration in vacuo. The residue was dissolved in ethanol (2.0 mL), treated with sodium ethoxide (0.700 mL, 1.90 mmol, 21% solution in ethanol) at ambient temperature, and stirred overnight. The solution was concentrated in vacuo, filtered through a plug of silica with ethyl acetate, and concentrated in vacuo. The resulting residue was dissolved in ethanol (3.0 mL) and treated with <strong>[6000-44-8]<strong>[6000-44-8]glycine sodium</strong> salt</strong> (0.110 g, 1.54 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.230 mL, 1.54 mmol) and heated to 180 C. for 3 min. in a Biotage Initiator microwave synthesizer. The reaction was diluted with water, acidified with 1 N aqueous hydrochloric acid, and the resulting precipitate was filtered, washed with methanol, and dried in vacuo to afford the title compound as a light brown solid (0.175 g, 32%). 1H NMR (400 MHz, METHANOL-d4) delta ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.75 (dd, J=4.7, 1.9 Hz, 1 H), 8.54 (dd, J=8.0, 1.9 Hz, 1 H), 7.31-7.43 (m, 3 H), 7.14-7.30 (m, 3 H), 5.75 (s, 2 H), 4.20 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 354 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | 17c) N-[(1-[4-(1,1-dimethylethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)carbonyl]glycine Glycine sodium salt (0.030 g, 0.35 mmol) was added to a solution of the compound from Example 17b) (0.130 g, 0.33 mmol) in ethanol (2.0 mL). The mixture was heated to 160 C. for 1 h in a Biotage Initiator microwave synthesizer. The reaction was quenched with 6 N aqueous hydrochloric acid and the resulting precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as an off-white solid (0.090 g, 68%). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.4 (t, J=5.6 Hz, 1 H), 8.81 (dd, J=4.7, 1.9 Hz, 1 H), 8.51 (dd, J=7.8, 1.8 Hz, 1 H), 7.46 (dd, J=8.0, 4.7 Hz, 1 H), 7.27-7.33 (m, 2 H), 7.17-7.22 (m, 2 H), 5.62 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 410 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | A stirred mixture of ethyl 6-cyclohexyl-5-hydroxy-3-oxo-2- (phenylmethyl)-2,3-dihydro-4-pyridazinecarboxylate (0.095 g, 0.267 mmol), anhydrous glycine, sodium salt (0.053 g, 0.544 mmol) and 2-methoxyethanol (3 mL) was heated under reflux under nitrogen for 2 h, then cooled and diluted with water (30 mL). IM aqueous hydrochloric acid was added slowly until the pH had dropped to 2. After 60 h, the solid was filtered, washed with water and dried to leave the title compound (0.095 g, 92%) as a white solid. IH NMR (400 MHz, DMSO-(i6) delta ppm 1.12 - 1.28 (m, 1 H) 1.28 - 1.49 (m, 4 H) 1.63 - 1.72 (m, 1 H) 1.74 - 1.81 (m, 2 H) 1.83 - 1.91 (m, 2 H) 2.82 - 2.94 (m, 1 H) 4.09 (d, J=5.56 Hz, 2 H) 5.25 (s, 2 H) 7.25 - 7.31 (m, 3 H) 7.31 - 7.38 (m, 2 H) 10.19 (t, J=5.18 Hz, 1 H) 12.97 (br. s., 1 H) 15.86 (br. s., 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.6% | To a 5 mL mircrowave tube was added ethyl 5-hydroxy-3-oxo-6-(2-thienyl)-2,3-dihydro-4- pyridazinecarboxylate (60 mg, 0.225 mmol) and Glycine Sodium Salt (54.7 mg, 0.563 mmol) in 2- methoxyethanol (2 ml) and the mixture was irradiated at 150 0C for 20 minutes. The mixture was diluted with water (10 ml) and acidified with IN HCl. The precipitate was collected by filtration and recrystallized in ethanol to afford the title compound, N-[5-hydroxy-3-oxo-6-(2-thienyl)-2,3- dihydro-4-pyridazinyl]carbonyl}glycine (30 mg, 0.101 mmol, 44.6 % yield), as an off white solid. IH NMR (400 MHz, DMSO-</6) d ppm 13.41 (s, 1 H), 13.00 (s, 1 H), 10.25 (t, J=5.81 Hz, 1 H), 7.79 - 7.97 (m, 1 H), 7.70 (d, J=4.55 Hz, 1 H), 7.18 (dd, J=5.05, 3.79 Hz, 1 H), 4.16 (d, J=5.81 Hz, 2 H). MS(ES+) m/e 296 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Glycine, sodium salt (28 mg, 0.29 mmol) was added to a solution of the compound from example 19d) (65 mg, 0.15 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes to give the title compound (19 mg, 28%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.02 (s, 1 H) 10.26 (t, J=4.93 Hz, 1 H) 7.87 (dd, J=8.72, 5.68 Hz, 2 H) 7.60 - 7.69 (m, 4 H) 7.42 - 7.51 (m, 4 H) 7.29 - 7.40 (m, 3 H) 5.41 (s, 2 H) 4.14 (d, J=5.81 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Glycine, sodium salt (55 mg, 0.57 mmol) was added to a <n="38"/>solution of the compound from example 20c) (125 mg, 0.28 mmol) in 2-methoxyethanol at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes. The product was purified by precipitation from CH2C12/Hexanes to give the title compound as a white solid (69 mg, 52%). IH NMR (400 MHz, DMSO-^6) delta ppm 10.24 (t, J=6.06 Hz, 1 H) 7.84 (d, J=8.59 Hz, 2 H) 7.57 (d, J=8.59 Hz, 2 H) 7.33 - 7.41 (m, 2 H) 7.26 - 7.33 (m, 2 H) 5.32 (s, 2 H) 4.12 (d, J=5.81 Hz, 2 H) 1.25 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Glycine, sodium salt (53 mg, 0.55 mmol) was added to a solution of the compound from example 21a) (126 mg, 0.27 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to <n="39"/>precipitate the product. The solid was filtered and washed with HoO and Hexanes. The product was purified by precipitation from CH2C12/Hexanes to give the title compound (90 mg, 67%). IH NMR (400 MHz, DMSO-^6) delta ppm 13.03 (s, 1 H) 10.25 (t, J=5.43 Hz, 1 H) 7.80 - 7.89 (m, 2 H) 7.65 (ddd, J=6.88, 3.09, 1.64 Hz, 4 H) 7.58 (ddd, J=9.09, 2.53, 2.27 Hz, 2 H) 7.42 - 7.50 (m, 4 H) 7.32 - 7.40 (m, 1 H) 5.41 (s, 2 H) 4.14 (d, J=5.56 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Glycine, sodium salt (71 mg, 0.73 mmol) was added to a solution of the compound from example 22a) (147 mg, 0.37 mmol) in 2-methoxyethanol (2 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with HoO and Hexanes. The product was redissolved in hot CH2Cl2, dried (MgSOzt) and filtered. The solution was cooled to 0 C and Hexanes added to precipitate the product. The product was filtered to give the title compound as a pale pink solid (107 mg, 68%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.03 (s, 1 H) 10.20 (t, <n="40"/>J=4.29 Hz, 1 H) 7.76 - 7.86 (m, 2 H) 7.52 (dd, J=7.58, 1.52 Hz, 1 H) 7.27 - 7.41 (m, 4 H) 7.20 - 7.27 (m, 1 H) 5.45 (s, 2 H) 4.14 (d, J=5.56 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Glycine, sodium salt (83 mg, 0.85 mmol) was added to a solution of the compound from example 23a) (179 mg, 0.43 mmol) in 2-methoxyethanol at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes to give the title compound (153 mg, 80%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.03 (s, 1 H) 10.19 (t, J=4.80 Hz, 1 H) 7.74 - 7.83 (m, 2 H) 7.55 (ddd, J=8.91, 2.53, 2.21 Hz, 2 H) 7.52 (dd, J=7.71, 1.39 Hz, 1 H) 7.28 - 7.39 (m, 2 H) 7.21 - 7.26 (m, 1 H) 5.45 (s, 2 H) 4.13 (d, J=5.81 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Glycine, sodium salt (26 mg, 0.27 mmol) was added to a solution of the compound from example 25a) (47 mg, 0.14 mmol) in 2-methoxyethanol (0.8 mL) at room temperature. The reaction was heated to reflux and stirred for 3 h. The reaction was cooled back to room temperature and IN HCl was added to precipitate the product. The solid was filtered and washed with Hexanes and Et2O to give the title compound as a pale pink solid (21 mg, 40%). IH NMR (400 MHz, DMSO-^6) delta ppm 13.02 (s, 1 H) 10.28 - 10.39 (m, 1 H) 7.79 - 7.88 (m, 2 H) 7.29 - 7.38 (m, 2 H) 4.25 (t, J=7.07 Hz, 2 H) 4.15 (d, J=5.56 Hz, 2 H) 1.68 (q, J=7.07 Hz, 2 H) 0.65 - 0.79 (m, 1 H) 0.40 (ddd, J=7.89, 5.75, 4.04 Hz, 2 H) 0.02 (td, J=5.24, 4.17 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Glycine, sodium salt (43 mg, 0.44 mmol) was added to a solution of the compound from example 26d) (102 mg, 0.22 mmol) in 2-methoxyethanol (1.4 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes which partially dissolved the product. EtOAc was added and the layers separated. The aqueous layer was backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO^, filtered and concentrated to give the title compound as a tan solid (57 mg, 53%). IH NMR (400 MHz, DMSO-^6) delta ppm 16.29 (s, 1 H) 13.00 (s, 1 H) 10.27 (t, J=5.56 Hz, 1 H) 7.72 (d, J=8.59 Hz, 2 H) 7.51 (d, J=8.59 Hz, 2 H) 7.34 - 7.41 (m, 2 H) 7.27 - 7.33 (m, 2 H) 5.31 (s, 2 H) 4.13 (d, J=5.81 Hz, 2 H) 1.32 (s, 9 H) 1.25 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Glycine, sodium salt (52 mg, 0.54 mmol) was added to a solution of the compound from example 27a) (118 mg, 0.27 mmol) in 2-methoxyethanol at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with HoO and Hexanes. The product was purified by precipitation from CH2C12/Hexanes to give the title compound as a white solid (100 mg, 79%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.01 (s, 1 H) 10.22 (t, J=5.18 Hz, 1 H) 7.64 - 7.71 (m, 2 H) 7.46 - 7.54 (m, 3 H) 7.28 - 7.40 (m, 2 H) 7.20 - 7.26 (m, 1 H) 5.45 (s, 2 H) 4.14 (d, J=5.56 Hz, 2 H) 1.30 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Glycine, sodium salt (68 mg, 0.70 mmol) was added to a solution of the compound from example 29a) (153 mg, 0.35 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O, Hexanes and Et2O to give the title compound as a pale pink solid (71 mg, 44%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 15.75 (s, 1 H) 12.99 (s, 1 H) 10.03 (t, J=5.18 Hz, 1 H) 8.11 (dd, J=8.08, 1.26 Hz, 1 H) 7.69 (td, J=7.64, 1.39 Hz, 1 H) 7.59 (td, J=7.71, 1.26 Hz, 1 H) 7.23 (dd, J=7.83, 1.01 Hz, 1 H) 5.56 (s, 2 H) 4.09 (d, J=5.81 Hz, 2 H) 2.24 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Glycine, sodium salt (48 mg, 0.50 mmol) was added to a solution of the compound from example 30c) (105 mg, 0.25 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes to give the title compound (81 mg, 72%). IH nuMR (400 MHz, OMSO-d6) delta ppm 13.03 (s, 1 H) 10.13 - 10.21 (m, 1 H) 7.47 - 7.55 (m, 3 H) 7.37 - 7.44 (m, 1 H) 7.34 (ddd, J=UJS, 7.45, 1.77 Hz, 2 H) 7.23 - 7.29 (m, 1 H) 5.47 (s, 2 H) 4.13 (d, J=5.56 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Glycine, sodium salt (40 mg, 0.41 mmol) was added to a solution of the compound from example 3 Id) (85 mg, 0.21 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes. The product was purified by precipitation from CH2Cl2/Hexanes to give the title compound (59 mg, 65%). IH NMR (400 MHz, DMSO-^6) delta ppm 13.03 (s, 1 H) 10.24 (t, J=4.93 Hz, 1 H) 7.67 - 7.77 (m, 2 H) 7.51 (dd, J=7.71, 1.64 Hz, 1 H) 7.28 - 7.39 (m, 2 H) 7.23 (dd, J=7.45, 1.89 Hz, 1 H) 7.03 (ddd, J=9.41, 2.78, 2.46 Hz, 2 H) 5.44 (s, 2 H) 4.13 (d, J=5.56 Hz, 2 H) 3.80 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Glycine, sodium salt (112 mg, 1.16 mmol) was added to a solution of the compound from example 32a) (241 mg, 0.58 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and E^O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes to give the title compound (220 mg, 85%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.08 (br. s., 1 H) 10.23 (t, J=5.43 Hz, 1 H) 7.72 - 7.78 (m, 2 H) 7.18 (tt, J=9.38, 2.37 Hz, 1 H) 7.01 - 7.12 (m, 4 H) 5.37 (s, 2 H) 4.13 (d, J=5.56 Hz, 2 H) 3.81 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Glycine, sodium salt (137 mg, 1.41 mmol) was added to a solution of the compound from example 35c) (316 mg, 0.71 mmol) in 2-methoxyethanol (2.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with H2O and Hexanes to give the title compound (266 mg, 79%). IH NMR (400 MHz, OMSO-d6) delta ppm 13.00 (s, 1 H) 10.18 (t, J=5.31 Hz, 1 H) 7.80 (d, J=7.83 Hz, 1 H) 7.64 (t, J=7.45 Hz, 1 H) 7.53 (t, J=7.71 Hz, 1 H) 7.23 - 7.45 (m, 4 H) 6.99 - 7.11 (m, 1 H) 5.55 (s, 2 H) 4.13 (d, J=5.81 Hz, 2 H) 3.77 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Glycine, sodium salt (129 mg, 1.33 mmol) was added to a solution of the compound from example 36a) (275 mg, 0.66 mmol) in 2-methoxyethanol (2.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with HoO and Hexanes to give the title compound (232 mg, 79%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 13.02 (s, 1 H) 10.21 (t, J=4.29 Hz, 1 H) 7.48 - 7.57 (m, 1 H) 7.24 - 7.42 (m, 6 H) 7.02 - 7.08 (m, 1 H) 5.46 (s, 2 H) 4.14 (d, J=5.56 Hz, 2 H) 3.77 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Glycine, sodium salt (35 mg, 0.36 mmol) was added to a solution of the compound from example 37c) (75 mg, 0.18 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 1.5 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered then redissolved in MeOH. The solution was concentrated and Et2O added. The product was filtered to give the title compound as an off-white <n="57"/>solid (38 mg, 48%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.76 (s, 1 H) 12.98 (s, 1 H) 10.12 (t, J=5.68 Hz, 1 H) 7.41 - 7.56 (m, 2 H) 7.30 - 7.40 (m, 2 H) 7.29 (dd, J=7.33, 1.77 Hz, 1 H) 7.09 - 7.22 (m, 2 H) 7.04 (td, J=7.45, 0.76 Hz, 1 H) 5.42 (s, 2 H) 4.11 (d, J=5.81 Hz, 2 H) 3.76 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Glycine, sodium salt (74 mg, 0.76 mmol) was added to a solution of the compound from example 38a) (146 mg, 0.38 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (124 mg, 79%). IH NMR (400 MHz, OMSO-d6) delta ppm 15.83 (s, 1 H) 13.09 (s, 1 H) 10.21 (t, J=5.56 Hz, 1 H) 7.49 - 7.57 (m, 2 H) 7.36 - 7.47 (m, 1 H) 5.47 (s, 2 H) 4.11 (d, J=5.56 Hz, 2 H) 3.04 (sept, J=6.78 Hz, 1 H) 0.93 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Glycine, sodium salt (57 mg, 0.59 mmol) was added to a solution of the compound from example 39a) (98 mg, 0.29 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (86 mg, 82%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.87 (s, 1 H) 12.98 (s, 1 H) 10.18 (t, J=5.18 Hz, 1 H) 7.36 (ddd, J=I 1.87, 5.31, 2.78 Hz, 2 H) 7.10 - 7.24 (m, 2 H) 5.23 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 3.18 (sept, J=6.82 Hz, 1 H) 1.20 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Glycine, sodium salt (69 mg, 0.71 mmol) was added to a solution of the compound from example 40a) (137 mg, 0.36 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (136 mg, 91%). IH nuMR (400 MHz, DMSO-^6) delta ppm 10.19 (t, J=3.92 Hz, 1 H) 7.78 (d, J=7.83 Hz, 1 H) 7.62 (t, J=7.33 Hz, 1 H) 7.51 (t, J=7.58 Hz, 1 H) 7.13 (d, J=7.83 Hz, 1 H) 5.42 (s, 2 H) 4.04 (d, J=5.56 Hz, 2 H) 3.19 (sept, J=7.07 Hz, 1 H) 1.13 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Glycine, sodium salt (54 mg, 0.56 mmol) was added to a solution of the compound from example 41a) (95 mg, 0.28 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (49 mg, 47%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.92 (s, 1 H) 12.97 (s, 1 H) 10.13 (t, J=5.3 I Hz, 1 H) 7.73 - 7.82 (m, 2 H) 7.52 - 7.66 (m, 2 H) 5.31 (s, 2 H) 4.09 (d, J=5.56 Hz, 2 H) 3.18 (sept, J=6.95 Hz, 1 H) 1.19 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Glycine, sodium salt ( 107 mg, 1.10 mmol) was added to a solution of the compound from example 42a) (200 mg, 0.55 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (157 mg, 73%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.94 (s, 1 H) 12.98 (s, 1 H) 10.08 (t, J=5.43 Hz, 1 H) 8.10 (dd, J=8.08, 1.26 Hz, 1 H) 7.72 (td, J=7.58, 1.26 Hz, 1 H) 7.55 - 7.64 (m, 1 H) 7.31 (dd, J=7.58, 1.01 Hz, 1 H) 5.57 (s, 2 H) 4.10 (d, J=5.56 Hz, 2 H) 3.16 (sept, J=6.78 Hz, 1 H) 1.13 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Glycine, sodium salt (64 mg, 0.66 mmol) was added to a solution of the compound from example 43a) (110 mg, 0.33 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (108 mg, 90%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.90 (s, 1 H) 12.96 (s, 1 H) 10.15 (t, J=5.56 Hz, I H) 7.32 - 7.41 (m, 1 H) 7.13 - 7.30 (m, 3 H) 5.31 (s, 2 H) 4.10 (d, J=5.56 Hz, 2 H) 3.17 (sept, J=6.86 Hz, 1 H) 1.17 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Glycine, sodium salt (69 mg, 0.71 mmol) was added to a solution of the compound from example 44a) (125 mg, 0.35 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (112 mg, 84%). IH NMR (400 MHz, OMSO-d6) delta ppm 15.92 (s, 1 H) 12.97 (s, 1 H) 10.12 (t, J=5.56 Hz, 1 H) 7.29 (td, J=9.22, 4.55 Hz, 1 H) 7.17 - 7.25 (m, 1 H) 7.12 (ddd, J=8.91, 5.62, 3.16 Hz, 1 H) 5.29 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 3.17 (sept, J=6.86 Hz, 1 H) 1.16 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Glycine, sodium salt (49 mg, 0.51 mmol) was added to a solution of the compound from example 45d) (93 mg, 0.25 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (79 mg, 81%). IH NMR (400 MHz, OMSO-d6) delta ppm 16.43 (s, 1 H) 12.99 (s, 1 H) 10.26 (t, J=5.56 Hz, 1 H) 7.44 - 7.53 (m, 1 H) 7.28 - 7.39 (m, 2 H) 7.18 - 7.24 (m, 1 H) 5.34 (s, 2 H) 4.11 (d, J=5.56 Hz, 2 H) 1.28 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Glycine, sodium salt (54 mg, 0.55 mmol) was added to a solution of the compound from example 49a) (107 mg, 0.28 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (68 mg, 59%). IH NMR (400 MHz, OMSO-d6) delta ppm 16.36 (s, 1 H) 12.98 (s, 1 H) 10.30 (t, J=5.43 Hz, 1 H) 7.37 (ddd, J=8.46, 2.15, 2.02 Hz, 2 H) 7.25 (d, J=8.34 Hz, 2 H) 5.19 (s, 2 H) 4.09 (d, J=5.56 Hz, 2 H) 1.35 (s, 9 H) 1.25 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Glycine, sodium salt (45 mg, 0.46 mmol) was added to a solution of the compound from example 53c) (86 mg, 0.23 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (43 mg, 47%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.87 (s, 1 H) 12.97 (s, 1 H) 10.19 (t, J=5.56 Hz, 1 H) 7.08 - 7.25 (m, 3 H) 7.02 (d, J=7.07 Hz, 1 H) 5.25 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 2.80 - 2.94 (m, 1 H) 2.38 (s, 3 H) 1.63 - 1.91 (m, 5 H) 1.12 - 1.45 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Glycine, sodium salt (32 mg, 0.33 mmol) was added to a solution of the compound from example 54a) (61 mg, 0.16 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (30 mg, 46%). IH NMR (400 MHz, OMSO-d6) delta ppm 15.90 (s, 1 H) 12.96 (s, 1 H) 10.14 (t, J=5.68 Hz, I H) 7.31 - 7.41 (m, I H) 7.11 - 7.29 (m, 3 H) 5.30 (s, 2 H) 4.09 (d, J=5.56 Hz, 2 H) 2.78 - 2.93 (m, 1 H) 1.61 - 1.91 (m, 5 H) 1.08 - 1.44 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Glycine, sodium salt (45 mg, 0.47 mmol) was added to a solution of <n="74"/>the compound from example 55a) (99 mg, 0.23 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (49 mg, 47%). IH NMR (400 MHz, OMSO-d6) delta ppm 10.40 (br. s., 1 H) 7.70 (d, J=8.08 Hz, 2 H) 7.46 (d, J=8.08 Hz, 2 H) 5.27 (s, 2 H) 3.93 (d, J=5.31 Hz, 2 H) 2.81 - 2.97 (m, 1 H) 1.61 - 1.90 (m, 5 H) 1.12 - 1.45 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Glycine, sodium salt (44 mg, 0.45 mmol) was added to a solution of the compound from example 56a) (96 mg, 0.23 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the <n="75"/>title compound (77 mg, 74%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.91 (s, 1 H) 12.98 (s, 1 H) 10.12 (t, J=5.56 Hz, 1 H) 7.62 (d, J=8.08 Hz, 1 H) 7.58 (d, J=2.02 Hz, 1 H) 7.26 (dd, J=8.34, 2.02 Hz, 1 H) 5.25 (s, 2 H) 4.09 (d, J=5.81 Hz, 2 H) 2.76 - 2.93 (m, 1 H) 1.62 - 1.93 (m, 5 H) 1.10 - 1.50 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Glycine, sodium salt (52 mg, 0.53 mmol) was added to a solution of the compound from example 68a) (108 mg, 0.27 mmol) in 2-methoxyethanol (2 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and washed with H2O and Hexanes. The product was purified by recrystallization from hot AcOH to give the title compound (44 mg, 37%). IH NMR (400 MHz, OMSO-d6) delta ppm 16.40 (s, 1 H) 12.97 (s, 1 H) 10.31 (t, J=5.43 Hz, 1 H) 7.59 - 7.70 (m, 4 H) 7.39 - 7.50 (m, 4 H) 7.31 - 7.39 (m, 1 H) 5.28 (s, 2 H) 4.11 (d, J=5.56 Hz, 2 H) 1.36 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Glycine, sodium salt (29 mg, 0.30 mmol) was added to a solution of the compound from example 69b) (66 mg, 0.15 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 1.5 h. The reaction was <n="85"/>cooled back to room temperature and H2O was added followed by IN HCl to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound (61 mg, 86%). IH NMR (400 MHz, DMSO-^6) delta ppm 13.02 (s, 1 H) 10.19 (t, J=5.18 Hz, 1 H) 7.52 (dd, J=7.71, 1.64 Hz, 1 H) 7.30 - 7.40 (m, 2 H) 7.24 - 7.30 (m, 1 H) 7.10 - 7.20 (m, 2 H) 6.95 (dt, J=I 1.05, 2.31 Hz, 1 H) 5.46 (s, 2 H) 4.14 (d, J=5.56 Hz, 2 H) 4.04 (q, J=6.99 Hz, 2 H) 1.33 (t, J=6.95 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | To a 20 mL microwave tube was added the product of example70a) (0.125 g, 0.318 mmol) and Glycine Sodium Salt (0.046 g, 0.477 mmol) in 2-methoxyethanol (2ml) and the mixture was irradiated at 150 0C for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with IN HCl. The gelatinous aqueous solution was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound (84.0 mg, 0.199 mmol, 62 % <n="86"/>yield) as an off white powder. IH NMR (400 MHz, DMSO-(Z6) d ppm 15.83 (s, 1 H), 12.94 (s, 1 H), 10.09 (t, J=5.68 Hz, 1 H), 7.29 - 7.50 (m, 7 H), 7.22 - 7.28 (m, 1 H), 7.10 - 7.16 (m, 1 H), 5.25 (s, 2 H), 4.07 (d, J=5.56 Hz, 2 H), 3.13 (sept, J=6.78 Hz, 1 H), 1.13 (d, J=6.82 Hz, 6 H). MS(ES+) m/e 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a 20 mL microwave tube was added the product of example 18a (0.125 g, 0.318 mmol) and Glycine Sodium Salt (0.046 g, 0.477 mmol) in MethoxyEthanol (2ml) and the mixture was irradiated at 150 0C for 20 minutes. The reaction mixture was diluted with water (4 ml), acidified with IN HCl, and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound (94.0 mg, 0.223 mmol, 70 % yield) as an off white powder. IH NMR (400 MHz, DMSO-(Z6) d ppm 15.88 (s, 1 H), 12.97 (br. s., 1 H), 10.19 (t, J=5.56 Hz, 1 H), 7.54 - <n="87"/>7.70 (m, 4 H), 7.40 - 7.51 (m, 3 H), 7.37 (tt, J=7.33, 1.26 Hz, 1 H), 7.28 (d, J=7.83 Hz, 1 H), 5.33 (s, 2 H), 4.09 (d, J=5.81 Hz, 2 H), 3.19 (sept, J=6.82 Hz, 1 H), 1.21 (d, J=6.82 Hz, 6 H). MS(ES+) m/e 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Glycine, sodium salt (37 mg, 0.38 mmol) was added to a solution of the compound from example 72a) (66 mg, 0.19 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was then cooled to room temperature and HoO was added. The solution was filtered and IN HCl was added to precipitate the product. The product was filtered and purified by precipitation from CH2Cl2/Hexanes to give the title compound as an off- white solid (54 mg, 75%). IH nuMR (400 MHz, DMSO-(Z6) delta ppm 12.99 (s, 1 H) 10.31 (t, J=5.43 Hz, 1 H) 7.07 - 7.23 (m, 4 H) 5.25 (s, 2 H) 4.10 (d, J=5.56 Hz, 2 H) 2.37 (s, 3 H) 1.31 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Glycine, sodium salt (40 mg, 0.412 mmol) was added to a solution of the compound from example 73a) (94 mg, 0.207 mmol) in 2-methoxyethanol (1.5 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with HoO and Hexanes. The product was purified by recrystallization from hot CH2CI2 to give the title compound as a white solid (39 mg, 39%). IH nuMR (400 MHz, DMSO-^6) delta ppm 13.03 (s, 1 H) 10.07 - 10.18 (m, 1 H) 7.81 (d, J=7.58 Hz, 1 H) 7.64 (t, J=7.45 Hz, 1 H) 7.47 - 7.59 (m, 3 H) 7.41 (tt, J=9.32, 2.31 Hz, 1 H) 7.29 (d, J=7.83 Hz, 1 H) 5.57 (s, 2 H) 4.12 (d, J=5.81 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Glycine, sodium salt (45 mg, 0.464 mmol) was added to a solution of the compound from example 74a) (98 mg, 0.232 mmol) in 2-methoxyethanol (1.5 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product. The solid was filtered and washed with HoO and Hexanes. The product was purified by recrystallization from hot CH2Cl2 to give the title compound as a white solid (53 mg, 51%). IH NMR (400 MHz, DMSO-</6) delta ppm 13.01 (s, I H) 10.15 (t, J=5.18 Hz, 1 H) 7.50 - 7.62 (m, 2 H) 7.41 (tt, J=9.25, 2.37 Hz, 1 H) 7.19 (tt, J=9.47, 2.27 Hz, 1 H) 7.05 - 7.15 (m, 2 H) 5.39 (s, 2 H) 4.13 (d, J=5.56 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Glycine, sodium salt (61 mg, 0.629 mmol) was added to a solution of the compound from example 75a) (125 mg, 0.314 mmol) in 2-methoxyethanol (2 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added. The solution was filtered and IN HCl was added to precipitate the product as a tan gum. The gum was filtered and washed with H2O and Hexanes. The product was purified by recrystallization from hot CH2Cl2 to give the title compound as a white solid (103 mg, 77%). IH nuMR (400 MHz, OMSO-d6) delta ppm 12.98 (s, 1 H) 10.23 (t, J=5.31 Hz, 1 H) 7.79 (d, J=7.83 Hz, 1 H) 7.64 (t, J=7.33 Hz, 1 H) 7.53 (t, J=7.58 Hz, 1 H) 7.21 (d, J=7.83 Hz, 1 H) 5.43 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 1.28 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Glycine, sodium salt (29 mg, 0.299 mmol) was added to a solution of the compound from example 76a) (56 mg, 0.150 mmol) in 2-methoxyethanol (2.5 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled to room temperature and H2O was added. The solution was filtered and IN HCl added to precipitate the product. The solid was filtered and washed with H2O and Hexanes. The product was purified by precipitation from CE^C^/Hexanes to give the title compound as a pale yellow solid (41 mg, 68%). IH nuMR (400 MHz, DMSO-(Z6) d ppm 1.22 (d, J=6.82 Hz, 6 H) 3.14 - 3.29 (m, 1 H) 4.10 (d, J=5.56 Hz, 2 H) 5.70 (s, 2 H) 7.41 - 7.48 (m, 1 H) 7.48 - 7.56 (m, 1 H) 7.96 - 8.04 (m, 1 H) 8.06 - 8.12 (m, 1 H) 10.07 (t, J=5.43 Hz, 1 H) 12.99 (s, 1 H) 16.06 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Glycine, sodium salt (27 mg, 0.365 mmol) was added to a solution of the compound from example 77a) (75 mg, 0.180 mmol) in 2-methoxyethanol (2 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was then cooled to room temperature and HoO added. The solution was filtered and IN HCl added to precipitate the product. The solid was filtered then redissolved in a IN NaOH solution in MeOH/THF. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure and H2O was added. IN HCl was added to precipitate the product, which was filtered as a tan gum. The gum was dissolved in hot CH9CI9 and the solution concentrated to give the title compound as an off-white solid (60 mg, 75%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 10.23 (t, J=5.31 Hz, 1 H) 7.69 (dd, J=9.09, 2.78 Hz, 1 H) 7.53 (td, J=8.46, 2.78 Hz, 1 H) 7.34 (dd, J=8.59, 5.31 Hz, 1 H) 5.39 (s, 2 H) 4.09 (d, J=5.81 Hz, 2 H) 1.26 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | To a 20 mL microwave tube was added ethyl 2-[(2- bromophenyl)methyl]-5-hydroxy-6-(l-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (1.2 g, 3.04 mmol) and Glycine Sodium Salt (0.589 g, 6.07 mmol) in 2-methoxyethanol (8 ml) and the mixture was irradiated at 150 0C for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with IN HCl to give a off-white precipitate that was collected by filtration and washed with water, hexanes and ether to give N- [2-[(2-bromophenyl)methyl]-5-hydroxy-6- (l-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (1.06 g, 2.499 mmol, 82 % yield). IH NMR (400 MHz, DMSO-^6) d ppm 15.94 (s, 1 H), 12.99 (s, 1 H), 10.15 (t, J=5.43 Hz, <n="94"/>1 H), 7.67 (dd, J=7.83, 1.26 Hz, 1 H), 7.35 (td, J=7.52, 1.14 Hz, 1 H), 7.26 (td, J=7.58, 1.77 Hz, 1 H), 7.08 (dd, J=7.71, 1.64 Hz, 1 H), 5.31 (s, 2 H), 4.10 (d, J=5.81 Hz, 2 H), 3.17 (sept, J=6.82 Hz, 1 H), 1.14 (d, J=6.82 Hz, 6 H). MS(ES+) m/e 425 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.9% | To a 20 mL microwave tube was added ethyl 2-[(3- bromophenyl)methyl]-5-hydroxy-6-(l-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (700 mg, 1.771 mmol) and Glycine Sodium Salt (172 mg, 1.771 mmol) in MethoxyEthanol (8 ml) and the mixture was irradiated at 150 0C for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with IN HCl to give a off- white precipitate that was collected by <n="95"/>filtration and washed with water, hexanes and ether to give N-[2-[(3-bromophenyl)methyl]-5- hydroxy-6-(l-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (270 mg, 0.636 mmol, 35.9 % yield). IH NMR (400 MHz, OMSO-d6) d ppm 15.91 (s, 1 H), 12.98 (s, 1 H), 10.15 (t, J=5.43 Hz, 1 H), 7.53 (t, J=1.52 Hz, 1 H), 7.50 (dt, J=7.58, 1.77 Hz, 1 H), 7.32 (t, J=7.71 Hz, 1 H), 7.28 (ddd, J=7.71, 1.39, 1.26 Hz, 1 H), 5.25 (s, 2 H), 4.10 (d, J=5.56 Hz, 2 H), 3.19 (sept, J=6.78 Hz, 1 H), 1.20 (d, J=7.07 Hz, 6 H). MS(ES+) m/e 425 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Glycine, sodium salt (41 mg, 0.422 mmol) was added to a solution of the compound from example 80a) (101 mg, 0.210 mmol) in 2-methoxyethanol (2 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled back to room temperature and H2O was added followed by IN HCl to precipitate the product. The solid was filtered and washed with HoO and <n="96"/>Hexanes. The product was purified by recrystallization from hot EtOH to give the title compound as a white solid (77 mg, 72%). IH NMR (400 MHz, DMSO-<i6) delta ppm 13.01 (s, 1 H) 10.15 (t, J=5.18 Hz, 1 H) 7.81 (d, J=7.58 Hz, 1 H) 7.64 (t, J=7.45 Hz, 1 H) 7.54 (t, J=7.58 Hz, 1 H) 7.29 (d, J=7.83 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 6.95 (dt, J=10.93, 2.37 Hz, 1 H) 5.56 (s, 2 H) 4.13 (d, J=5.81 Hz, 2 H) 4.05 (q, J=6.91 Hz, 2 H) 1.33 (t, J=6.95 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Glycine, sodium salt (71 mg, 0.732 mmol) was added to a solution of the compound from example 87a) (128 mg, 0.363 mmol) in 2-methoxyethanol (2 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was then cooled to room temperature and HoO added. The solution was filtered and IN HCl was added to precipitate the product. The product was purified by recrystallization from hot EtOH to give the title compound as a white solid (61 mg, 44%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 15.90 (s, 1 H) 12.97 (s, 1 H) 10.14 (t, J=5.56 Hz, 1 H) 7.37 (td, J=8.53, 6.69 Hz, 1 H) 7.27 (ddd, J=10.42, 9.41, 2.65 Hz, 1 H) 7.02 - 7.12 (m, J=8.53, 8.53, 2.53, 0.88 Hz, 1 H) 5.27 (s, 2 H) 4.09 (d, J=5.81 Hz, 2 H) 3.17 (m, 1 H) 1.16 (d, J=7.07 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Glycine, sodium salt (68.0 mg, 0.701 mmol) was added to a solution of the compound from example 88a) (135 mg, 0.350 mmol) in 2-methoxyethanol (2.5 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was then cooled to room temperature and H2O added. The solution was filtered and IN HCl added to precipitate the product. The product was filtered then purified by recrystallization from hot EtOH to give the title compound as a pale pink solid (81 mg, 56%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 15.92 (s, 1 H) 12.98 (s, 1 H) 10.13 (t, J=5.31 Hz, 1 H) 7.62 (d, J=8.08 Hz, 1 H) 7.59 (d,J=I.77 Hz, 1 H) 7.27 (dd, J=8.34, 2.02 Hz, 1 H) 5.25 (s, 2 H) 4.09 (d, J=5.56 Hz, 2 H) 3.18 (sept, J=6.82 Hz, 1 H) 1.19 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Glycine, sodium salt (35 mg, 0.361 mmol) was added to a solution <n="105"/>of the compound from example 91a) (90 mg, 0.234 mmol) in Ethanol (3 ml) at room temperature. The reaction was heated in the microwave at 150 C for 20 minutes. The reaction was cooled and HoO was added followed by IN HCl to precipitate the product. The product was filtered and washed several times with H2O and Hexanes to give the title compound as a white solid (72 mg, 74%). IH NMR (400 MHz, OMSO-d6) delta ppm 15.96 (s, 1 H) 12.98 (s, 1 H) 10.11 (t, J=5.43 Hz, 1 H) 7.61 (dd, J=8.08, 1.52 Hz, 1 H) 7.34 (t, J=7.83 Hz, 1 H) 7.12 (dd, J=7.83, 1.26 Hz, 1 H) 5.37 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 3.17 (m, 1 H) 1.14 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Glycine, sodium salt (49 mg, 0.505 mmol) was added to a solution of the compound from example 94a) (94 mg, 0.255 mmol) in Ethanol (3 ml) at room temperature. The reaction was heated in the microwave at 150 C for 20 minutes. The reaction was cooled and H2O added. The solution was filtered and IN HCl added to precipitate the product. The product was filtered and purified by recrystallization from hot EtOH to give the title compound as a white solid (48 mg, 47%). IH NMR (400 MHz, DMSO-^6) delta ppm 15.92 (s, 1 H) 12.97 (s, 1 H) 10.12 (t, J=5.56 Hz, 1 H) 7.47 (dd, J=9.98, 1.89 Hz, 1 H) 7.22 - 7.36 (m, 2 H) 5.28 (s, 2 H) 4.10 (d, J=5.56 Hz, 2 H) 3.16 (qq, J=6.85, 6.69 Hz, 1 H) 1.16 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Glycine, sodium salt (44 mg, 0.453 mmol) was added to a solution of the compound from example 96a) (88 mg, 0.228 mmol) in 2-methoxyethanol (2 ml) at room temperature. The reaction was heated to refluxed for 2h. The reaction was then cooled to room temperature and HoO added. The solution was filtered and IN HCl added to precipitate the product. The product was filtered and washed several times with H2O and Hexanes to give the title compound as an off-white solid (43 mg, 45%). IH NMR (400 MHz, DMSO-(Z6) delta ppm 15.94 (s, 1 H) 12.98 (s, 1 H) 10.12 (t, J=5.56 Hz, 1 H) 7.68 (d, J=2.02 Hz, 1 H) 7.41 (dd, J=8.34, 2.27 Hz, 1 H) 7.21 (d, J=8.34 Hz, 1 H) 5.32 (s, 2 H) 4.10 (d, J=5.81 Hz, 2 H) 3.16 (sept, J=6.78 Hz, 1 H) 1.14 (d, J=6.82 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Glycine, sodium salt (19 mg, 0.196 mmol) was added to a solution of the compound from example 98c) (30 mg, 0.097 mmol) in 2-methoxyethanol (1 ml) at room temperature. The reaction was heated to reflux and stirred for 2 h. The reaction was cooled and diluted with H2O. The solution was filtered and IN HCl added to precipitate the product. The product was filtered and washed with H2O and Hexanes to give the title compound as a white solid (24 mg, 73%). IH NMR (400 MHz, OMSO-d6) delta ppm 15.77 (s, 1 H) 13.01 (s, 1 H) 10.35 (t, J=4.80 Hz, 1 H) 4.67 - 4.83 (m, 1 H) 4.11 (d, J=5.56 Hz, 2 H) 3.18 (sept, J=6.86 Hz, 1 H) 1.55 - 1.91 (m, 7 H) 1.31 - 1.48 (m, 2 H) 1.20 (d, J=6.82 Hz, 6 H) 1.14 - 1.25 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Glycine, sodium salt (58 mg, 0.598 mmol) was added to a solution of the compound from example 99c) (97 mg, 0.301 mmol) in 2-methoxyethanol (1.5 mL) at room temperature. The reaction was heated to reflux and stirred for 1.5 h. The reaction was then cooled to room temperature and H2O was added. The solution was filtered and IN HCl added to precipitate the product. The product was filtered and redissolved in CH2CI2. The solution was concentrated under reduced pressure and Hexanes added. The product was filtered to give the title compound as an off-white solid (79 mg, 75%). IH NMR (400 MHz, DMSO-^6) delta ppm 16.27 (s, 1 H) 13.01 (s, 1 H) 10.45 (t, J=5.43 Hz, 1 H) 4.66 - 4.83 (m, 1 H) 4.12 (d, J=5.56 Hz, 2 H) 1.57 - 1.89 (m, 7 H) 1.36 - 1.52 (m, 2 H) 1.34 (s, 9 H) 1.05 - 1.30 (m, 1 H). |
[ 70161-44-3 ]
Sodium 2-((hydroxymethyl)amino)acetate
Similarity: 0.70
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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 |
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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. |
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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. |
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H311 | Toxic in contact with skin |
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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 |
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H351 | Suspected of causing cancer |
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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 |
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H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
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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 |
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