Structure of H-DL-β-Pro-OH
CAS No.: 59378-87-9
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CAS No. : | 59378-87-9 |
Formula : | C5H9NO2 |
M.W : | 115.13 |
SMILES Code : | O=C(C1CNCC1)O |
MDL No. : | MFCD01318699 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 32.52 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.96 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-3.25 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.38 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.22 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.63 |
Log S (ESOL):? ESOL: Topological method implemented from |
1.56 |
Solubility | 4180.0 mg/ml ; 36.3 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
2.79 |
Solubility | 70200.0 mg/ml ; 610.0 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.13 |
Solubility | 85.7 mg/ml ; 0.745 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-9.31 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.67 |
* 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 |
---|---|---|
39% | With potassium carbonate; In butan-1-ol; at 120℃; for 1h;Microwave irradiation; | Step 1 A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline, (350 mg, 1.03 mmol), potassium carbonate (436 mg, 3.16 mmol), and 3-pyrrolidine carboxylic acid (236 mg, 2.05 mmol) in n-butanol (10.0 mL) was heated in the microwave at 120 C. for 60 minutes. The reaction mixture was cooled to room temperature, filtered, rinsed with ethyl acetate, and the filtrate was concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 25S column eluding with chloroform containing 0.1% acetic acid/methanol (0.5-7%) to afford 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (152 mg, 39%). 1H NMR (400 MHz, DMSO-d6) delta ppm 2.72-2.81 (m, 1H) 2.81-2.91 (m, 1H) 3.77-3.87 (m, 1H) 4.12-4.31 (m, 2H) 4.32-4.44 (m, 2H) 6.51 (s, 2H) 8.12 (dd, J=8.34, 4.29 Hz, 1H) 8.35 (dd, J=8.84, 2.02 Hz, 1H) 8.53 (d, J=1.52 Hz, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.83 (s, 1H) 8.95 (dd, J=8.34, 1.01 Hz, 1H) 9.48 (dd, J=4.17, 1.64 Hz, 1H) 12.97 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 120℃; for 18h; | (a) 1-[3-Chloro-5-(ethoxycarbonyl)pyridin-2-yl]pyrroIidine-3-carboxylic acid; 5,6-Dichloro- nicotinic acid ethyl ester (0.765 g, 0.35 mmol) and 3-pyrrolidine carboxylic acid (0.060 g, 0.52 mmol) were suspended in DMA (3 mL). DIPEA (0.18 1.041) was added to the system heated at 120 C for 18. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the crude material. The crude material was partitioned between DCM (70mL) and IN HCl (40mL) and the organics separated. The organics were dried (Mg5O4) and concentrated under reduced pressure to afford 1-[3-chloro-5-(ethoxycarbonyl)pyridin-2-yl]<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> as a solid crude product, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;palladium on charcoal; In acetic acid; | EXAMPLE 13 1-(t-Butyloxycarbonyl)-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> A solution of 205 g. (1 mol.) of N-benzyl<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (CA, 64 14173d) is dissolved in glacial acetic acid (1 l.) and hydrogenated in the presence of 40 g. of 10% palladium on charcoal until no more starting material is detected by TLC. The catalyst is filtered off and the filtrate is concentrated to dryness in vacuo. The residual 3-pyrrolidine carboxylic acid is dissolved in a mixture of DMF-H2 O (2:1) (2 liters), triethylamine (1 mol.), t-butoxycarbonyl azide (1.5 mol.) is added and the mixture is stirred at room temperature for two days. Periodically the pH is tested with pH paper, and after twenty-four hours more azide (0.5 mol.) is added. The solvent is concentrated in vacuo to remove the DMF, the aqueous phase is acidified with citric acid (to pH 2-3) and extracted with ethyl acetate. The organic phase is concentrated to dryness in vacuo to yield the product 1-(t-butyloxycarbonyl)-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; In 1,4-dioxane; | 3-(4-Chloro-benzylcarbamoyl)-pyrrolidine-1-carboxylic Acid Tert-Butyl Ester To a solution of di-tert-butyl-dicarbonate (1.86 g, 8.5 mmol) in dioxane (100 mL) was added 3-pyrrolidine carboxylic acid (1.0 g, 8.5 mmol) and 1 N NaOH (5 mL). The solution was stirred at rt for 12 h. The reaction was concentrated down and partitioned between EtOAc/1N HCl. The reaction was quenched with 1N HCl and extracted with EtOAc (3*), and the organic layers were collected together, dried over MgSO4 and evaporated in vacuo. The residue was was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (ABCR Product List; 36.0 mg, 0.312 mmol), and sodium hydride (60%; 9.99 mg, 0.250 mmol) in dimethyl sulfoxide (DMSO) (2 ml) were stirred at room temperature for 30 min. 1-Chloro-5-(5-{3-chloro-4-[(1- methylethyl)oxy]phenyl}-1 ,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was left to stir at 12O0C under nitrogen for 3 hours. The cooled reaction mixture was loaded onto an SCX column. The column was flushed with methanol and then the desired product was eluted with 2M ammonia in methanol. The solvent was removed in vacuo from the appropriate fractions to give a yellow solid. Lithium hydroxide (2.99 mg, 0.125 mmol), methanol (2.00 ml), water (1 ml) and tetrahydrofuran (THF) (2.00 ml) were added and the mixture stirred at 8O0C for 1 hour. The solvent was removed in vacuo to give an orange solid which was triturated under ether and filtered. The solid was dissolved in water and then extracted with ether. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as a yellow solid (9 mg).MS (ES) C25H2335CIN4O4 requires 478; found 479 [M+H]+. 1 H NMR (DMSO-d6) Shift: 12.46 (br. s., 1 H), 8.47 (d, J = 8.5 Hz, 1 H), 8.42 (d, J = 7.5 Hz, 1 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.16 (dd, J = 9.0, 2.0 Hz, 1 H), 8.09 (d, J = 6.0 Hz, 1 H), 7.96 (d, J = 6.0 Hz, 1 H), 7.67 (t, J = 8.5, 7.5 Hz, 1 H), 7.47 (d, J = 9.0 Hz, 1 H), 4.90 (spt, J = 6.0 Hz, 1 H), 3.90 - 4.02 (m, 2H), 3.77 - 3.89 (m, 2H), 3.19 (quin, J = 7.0 Hz, 1 H), 2.1 1 - 2.27 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 80℃; for 2h; | Example 6l-(2-Hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)phenyl)ethyl)<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong>[00201] To a mixture of 2-bromo-l-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-l,2,4- oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and pyrrolidine-3- carboxylic acid (22.81 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80 0C for 2 hours. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge Cl 8, 19 x 100 mm, 5-mum particles; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5, acetonitrile:water with 0.05% TFA; Gradient: 25-100% B over 10 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of l-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-l,2,4- oxadiazol-3-yl)phenyl)ethyl) <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> was 16.3 mg, and its purity was 96%. 1H NMR (400 MHz, MeOH-d3) delta ppm 8.21 (2 H, d, J=8.35 Hz), 7.81 (2 H, dd, J=8.02, 1.65 Hz), 7.69 (2 H, d, J=8.35 Hz), 7.54-7.66 (3 H, m), 5.10-5.22 (1 H, m), 3.39- 3.54 (4 H, m), 3.24-3.27 (3 H, m), 3.00-3.10 (2 H, m), 2.23-2.57 (2 H, m), 1.70-1.83 (2 H, m), 1.05 (3 H, t, J=7.36 Hz). MS (m+1) = 489. HPLC Peak RT = 2.08 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 441-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> trifluoroacetate (E44)To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (100 mg, 0.258 mmol) (D11) in Ethanol (10 mL) stirred at room temperature was added <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (119 mg, 1.034 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and dissolved in THF. The residue was purified by Mass Directed AutoPrep to afford 1-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (E44) (58 mg) as a TFA salt (off-white solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 121-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> trifluoroacetate (E12)To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (73 mg) and <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (72.4 mg) in dichloromethane (DCM) (10 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (66.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, the residue was purified by Mass Directed AutoPrep to give 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (E12) (27 mg) as a TFA salt (off-white solid). deltaH (DMSO-d6, 400 MHz): 1.13 (3H, t), 1.35 (6H, d), 2.23 (1H, m), 2.86 (2H, m), 3.10 (2H, m), 3.22 (2H, m), 3.48 (4H, m), 3.72 (1H, m), 3.87 (1H, m), 4.84 (1H, m), 7.39 (2H, dd), 7.50 (2H, m), 7.96 (1H, dd), 8.10 (1H, d), 9.95 (1H, br s), 12.97 (1H, br s). deltaF (DMSO-d6, 376 MHz): -73.5. MS (ES): C26H30ClN3O3S requires 499. found 500.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 481-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (E48)To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (100 mg, 0.266 mmol) in Ethanol (10 mL) stirred at room temperature was added <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (123 mg, 1.065 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (E48) (55 mg) as a off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2- ethylbenzaldehyde (100 mg, 0.258 mmol) (D11) in Ethanol (10 mL) stirred at room temperature was added <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (119 mg, 1.034 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was queched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2S04. The dried solution was filtered and concentrated, and dissolved in THF. The residue was purified by Mass Directed AutoPrep to afford 1-[3-(5-{3-chloro-4-[(1- methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3- pyrrolidinecarboxylic acid (E44) (58 mg) as a TFA salt (off-white solid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2- ethylphenyl]acetaldehyde (D15) (73 mg) and <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (72.4 mg) in dichloromethane (DCM) (10 ml_) stirred at room temperature was added AcOH (0.15 ml_). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (66.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2S04. The dried solution was filtered and concentrated, the residue was purified by Mass Directed AutoPrep to give 1-{2-[3-(5- {3-chloro-4-[(1-methylethyl)oxy]phenyl}-1 ,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-3- pyrrolidinecarboxylic acid (E12) (27 mg) as a TFA salt (off-white solid). deltaEta (DMSO-cfe, 400MHz): 1.13 (3H, t), 1.35 (6H, d), 2.23 (1 H, m), 2.86 (2H, m), 3.10 (2H, m), 3.22 (2H, m), 3.48 (4H, m), 3.72 (1 H, m), 3.87 (1 H, m), 4.84 (1 H, m), 7.39 (2H, dd), 7.50 (2H, m), 7.96 (1 H, dd), 8.10 (1 H, d), 9.95 (1 H, br s), 12.97 (1 H, br s). 8F (DMSO- 6, 376MHz): -73.5. MS (ES): C26H30CIN3O3S requires 499; found 500.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1 ,3,4-thiadiazol-2-yl]-2-(2- methylpropyl)benzonitrile (D27) (100 mg, 0.266 mmol) in Ethanol (10 ml_) stirred at room temperature was added <strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (123 mg, 1.065 mmol) and AcOH (0.15 ml_, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (1 10 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was queened with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2S04. The dried solution was filtered and concentrated, and purified by Mass Directed AutoPrep to afford 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1 ,3,4- thiadiazol-2-yl}-2-ethylphenyl)methyl]-<strong>[59378-87-9]3-pyrrolidinecarboxylic acid</strong> (E48) (55 mg) as a off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[01012] Synthesis of Compound B-31 : N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-l -isopropyl-6-(l -(l -methylpyiiOlidine-3-carbonyl)-l,2,3,6-tetrahydropyridin-4- yl)-l H-pyrazolo[3,4-b]pyridine-4-carboxamideCompound B-31[01013] Step 1 : Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l - isopropyl-6-(l -(pyrrolidine-3-carbonyl)- 1,2,3, 6-tetrahydropyridin-4-yl)-lH-pyrazolo [3,4- b]pyridine-4-carboxamide[01014] N-((4,6-Dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-l -isopropyl-6-(l , 2,3,6- tetrahydropyridin-4-yl)-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to it Et3N (3 equiv.) and pyrrol idine-3-carboxylic acid (2 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2S04; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 5-(di-tert-butylphosphino)-1?, 3?, 5?-triphenyl-1?H-[1,4?]bipyrazole; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In water; at 100℃; for 12h;Inert atmosphere; | Step 1: Preparation of l-(l-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-lH-indazol-3- yl)<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (1C). To a solution of bippyphos (lOmg, 0.019mmol) in tert-amyl alcohol (0.8ml) was added Pd2(dba)3 (lOmg, 0.0095mmol) and a drop of water to maintain a homogeneous reaction mixture. After 15 min of stirring, (3-bromo-4-fluoro-lH- indazol-l-yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone (40mg, 0.095mmol), <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (14mg, 0.117mmol) and Cs2C03 (93mg, 0.284mmol) was added and the mixture was purged with N2, then it was heated to 100C for 12hr in oil bath. The mixture was diluted with H20, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3x1 OmL). The combined organics were dried over anhydrous Na2S04, and concentrated. The residue was purified by prep-TLC (Petroleum/EtOAc, 2/1) to afford 17 mg (40 %) of the title compound. LCMS (ESI) calc'd for C20Hi4ClF4N3O3 [M+H]+: 456, found: 456. 1HNMR (400MHz, CDC13) delta 8.44 (IH, d, J=8.0Hz), 7.64-7.67 (2H, m), 7.51-7.60(2H, m), 7.04-7.09 (IH, m), 3.56-3.75 (4H, m), 3.17-3.20 (IH, m), 2.24-2.30 (2H, m |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With 5-(di-tert-butylphosphino)-1?, 3?, 5?-triphenyl-1?H-[1,4?]bipyrazole; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In pentan-1-ol; water; at 100℃; for 12.25h;Inert atmosphere; | Example 1 C: Preparation of 1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1H-indazol-3-yl)<strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (1C).To a solution of bippyphos (10mg, 0.Ol9mmol) in tert-amyl alcohol (0.8m1) was added Pd2(dba)3 (10mg, 0.OO9Smmol) and a drop of water to maintain a homogeneous reaction mixture. The mixture was stirred for 15 mm, followed by the addition of(3-bromo-4-fluoro-1 H-indazol- 1 -yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone (40mg, 0. O9Smmol), pyrroli dine-3-carboxylic acid (14mg, 0.ll7mmol) and Cs2CO3 (93mg, 0.284mmo1). The mixture was purged with N2 and then heated at 100C for l2hr. The mixture was diluted with H20, and the organic layer was separated. The aqueous layer was extracted with EtOAc (3x 1 OmL). The combined organics were dried over anhydrous Na2SO4, and concentrated. The residuewas purified by prep-TLC (PetroleumlEtOAc, 2/1) to afford 17 mg (40 %) of the title compound. LCMS (ESI) calc?d for C20H14C1F4N303 [M+H]: 456, found: 456. ?HNMR(400MHz, CDC13) oe 8.44 (1H, d, J=8.OHz), 7.64-7.67 (2H, m), 7.51-7.60(2H, m), 7.04-7.09 (1H, m), 3.56-3.75 (4H, m), 3.17-3.20 (1H, m), 2.24-2.30 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With triethylamine; In tetrahydrofuran; water; at 60℃; for 2.5h; | General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct The title compound was prepared following general procedure B, except <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> was the amine reactant, and contents were heated to 60 C for 2.5 h as a solution in THF/water (1:1). The solution was diluted with iN hydrochloric acid solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate and 5:1 dichloromethane/isopropyl alcohol. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The crude material was purified via reverse phase HPLC (5-75% acetonitrile in water with 0.1% triefluoroacetic acid, 20 minute gradient) to deliver the desired compound, Compound 1-76 (ii mg, 45% yield) as a white solid.1H-NMR (400 MHz, CD3OD) oe 8.83 (m, 1H), 8.29-8.27 (m, 1H), 7.63 (s, 1H), 7.33-7.29 (m, 1H), 7.13-7.05 (m, 2H), 6.99-6.96 (m, 2H), 6.03 (s, 2H), 4.23-4.03 (m, 5H), 2.34 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
600 mg | With thionyl chloride; In ethanol; at 0 - 80℃; | Thionyl chloride (5 mL) was added to a cold (0 C.) stirred solution of pyrrolidine-3-carboxylicacid (500 mg, 4.34 mmol) in EtOH (25 mL) and continued stirring at 80 C. for 12-16 h. The reaction mixture was concentrated under reduced pressure to afford 600 mg (crude) of ethyl pyrrolidine-3-carboxylate, which was used as such in the next step without purification. MS (ESI): m/z 144 (M+H). |
With thionyl chloride; at 0 - 40℃; for 10h; | General procedure: To a solution of ethanol (150 mL), SOCl2 (10.34 g, 86.86 mmol) was added at 0 C. Afterwards,-proline (5.0 g, 43.43 mmol) was added in several separated portions at 0 C. The mixture wasstirred for 10 h at 40 C and then evaporated in vacuo. The residue was used immediately withoutfurther purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In isopropyl alcohol; at 80℃; | Step 1: 1-(4-Aminopyrimidin-2-yl) <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> 102a A 100 mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with <strong>[59378-87-9]pyrrolidine-3-carboxylic acid</strong> (1.20 g, 10 mmol), 2-chloropyrimidin-4-amine (1.30 g, 10 mmol), isopropyl alcohol (IPA, 40 mL), and TEA (6 mL). The mixture was heated at 80 C. overnight (O/N). After this time the reaction was cooled to room temperature (r.t.). It was then filtered and the filter cake was washed with DCM to afford 102a (1.4 g, 67%) as a pale yellow solid. MS: [M+H]+ 209.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 8h;Inert atmosphere; | [000393j To a solution of Compound 1A (0.5 g, 4.3 mmol) in DMF (20 mL) was added 1-chloro-4-iodobenzene (1.0 g, 4.3 mmol), Cul (100mg, 0.5 mmol) and K2C03 (1.2 g, 8.6 mmol). The mixture was stirred for 8 h at 100 C under N2. The mixture was diluted with aq NH4C1 (40 mL), extracted with ethyl acetate (50 mL x 2), washed with brine (100 mL x 2), and evaporated. The crude product was purified by silica gel column chromatography (methanol in dichloromethane, 10% v/v) to give Compound lB. LC-MS (mlz): 224 [M-lf. |
Tags: 59378-87-9 synthesis path| 59378-87-9 SDS| 59378-87-9 COA| 59378-87-9 purity| 59378-87-9 application| 59378-87-9 NMR| 59378-87-9 COA| 59378-87-9 structure
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