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CAS No. : | 3972-36-9 | MDL No. : | MFCD00798341 |
Formula : | C11H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GTOFKXZQQDSVFH-VIFPVBQESA-N |
M.W : | 208.21 | Pubchem ID : | 446168 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.27 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 54.18 |
TPSA : | 74.6 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.71 cm/s |
Log Po/w (iLOGP) : | 1.17 |
Log Po/w (XLOGP3) : | 1.21 |
Log Po/w (WLOGP) : | 1.4 |
Log Po/w (MLOGP) : | 1.57 |
Log Po/w (SILICOS-IT) : | 1.39 |
Consensus Log Po/w : | 1.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.86 |
Solubility : | 2.88 mg/ml ; 0.0138 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.37 |
Solubility : | 0.881 mg/ml ; 0.00423 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.01 |
Solubility : | 2.04 mg/ml ; 0.00979 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.9 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | 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 |
---|---|---|
17.9 g | With ethylenediaminetetraacetic acid; (R)-1-phenyl-ethyl-amine; sodium carbonate; In ethanol; water; at 20 - 25℃; for 5h; | The containing 100g2-benzyl succinate R- alpha-phenethylamine salt (R/S = 85/15) ethanol solution of reduced pressure concentration recovery ethanol, then added to the remaining system 500 ml water, 61g sodium carbonate stirring to dissolve. The aqueous phase is extracted twice with methylene chloride, combined methylene chloride, and recovered methylene chloride (R)-alpha-phenethylamine. Adding to the aqueous phase 0.4gEDTA, then heating to 20-25 o C insulation 5h, in high-efficiency liquid detection system (R)-2-benzyl succinate and (S)-2-benzyl succinate ratio of 1:1, stop heating, cooling to 0-10 oC, in to the system by adding hydrochloric acid to pH= 1-2, for 0-10 o C insulation 2h, filtering the system, solid drying. Yield 95.4%. The resulting 2-benzyl succinate and R- alpha-phenethylamine in ethanol into the salt crystal. According to the embodiment 1 of the method for processing, S-benzyl succinate to 17.9g, total yield racemation 38.8%, ee value 99.5%, purity 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In water; at 60℃; for 0.333333h; | A mixture of the product of step D (7 g, 33.6 mmol) in conc. H2SO4(20 mL) was stirred at 60 for 20 min. The reaction mixture was poured into ice-H2O (150 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brined, dried over Na2SO4and concentrated to give the target compound (6.3 g, 100) as a white solid, which was directly used to the next step.1H NMR (400 MHz, DMSO-d6) delta 12.48 (s, 1H) , 7.85 (dd, J7.6, 1.2 Hz, 1H) , 7.60-7.53 (m, 1H) , 7.37 (dd, J16.0, 8.0 Hz, 2H) , 3.28-3.12 (m, 3H) , 2.79 (d, J8.8 Hz, 2H) ppm. MS: M/e 191 (M +1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; thionyl chloride; triethylamine; In ethyl acetate; | Reference Example 1 (S)-2-Benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid Triethylamine 42.5 g was dissolved in ethyl acetate 250mL, and imidazole 14.3 g and (S)-benzylsuccinic acid 20.8 g were added to the solution with stirring. Thionyl chloride 25.0 g was added to the solution at -15C with stirring, and the mixture was allowed to react for 4 hours at -15 to 0C. cis-Hexahydroisoindoline 12.5 g was added to the reaction mixture, and the mixture was allowed to react overnight at 0C to room temperature. To the reaction mixture was added 1N hydrochloric acid 200 mL, and the organic layer was separated, washed with water and extracted with 1N aqueous sodium hydroxide solution. The aqueous layer was washed with ethyl acetate, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give (S)-2-benzyl-3-(cis-hexahydro-2-isoindonylcarbonyl)propionic acid 30.6 g as a colorless viscous oil. Chemical purity: 93.2% 1H-NMR (CDCl3, 270MHz) delta ppm: 1.15-1.7 (8H, m), 2.05-2.3 (2H, m), 2.35-2.55 (2H, m), 2.65-3.5 (7H, m),7.1-7.4 (5H, m) IR(neat): 1735, 1605 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.12 g | In acetic anhydride; toluene; for 1h;Reflux; | Into a 100mL three-necked flask were successively added <strong>[3972-36-9](S)-2-benzylsuccinic acid</strong> 30.40g (0.16mol), 20mL of acetic anhydride, 50mL toluene, the reaction was stirred at reflux for 1h, the reaction was completed, cooling and crystallization, filtration, drying, white flaky crystal 26.12g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dihydrogen peroxide; lithium hydroxide; In tetrahydrofuran; water; at 0℃; | To a stirred solution of the product of Step C (12.9 g, 34.96 mmol) in THF (50 mL) was added dropwise aq. H2O2(30, 15 mL) at 0, followed by a solution of LiOH (2.5 g, 104 mmol) in H2O (20 mL) . After the addition, the reaction was stirred overnight. The reaction mixture was quenched with aq. Na2SO3(50 mL) , most THF was removed to give the aqueous layer, then extracted with EtOAc (50 mL x 3) . The aqueous layer was acidified to pH34 with aq. HCl (2.0 M) , and extracted with EtOAc (50 mL x 3) . The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the target compound (7 g, 100) as a white solid.1H NMR (400 MHz, DMSO-d6) delta 12.22 (s, 2H) , 7.35-7.13 (m, 5H) , 2.98-2.84 (m, 2H) , 2.81-2.67 (m, 1H) , 2.42 (dd, J16.8, 8.8 Hz, 1H) , 2.24 (dd, J16.8, 4.4 Hz, 1H) ppm. MS: M/e 207 (M-1)- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In dichloromethane; at 35 - 42℃; for 2h; | (41.6 g, 0.2 mol) of (S) -benzylsuccinic acid and 416 ml of dichloromethane were placed in a round bottom flask, and then 50 g (0.42 mol) of thionyl chloride was added thereto. The mixture was refluxed at 35 to 42 C for 2 hours to complete the reaction Thereafter, the temperature of the solution containing (S)-BSCl was cooled to 10 to 20 C. | |
The 41.6 g S - benzyl succinic acid (0.2 muM), 0.6 g triethylamine, 220 ml dichloromethane are added to a 500 ml three-neck bottle in, stir at room temperature 20 min, heating to reflux state. Weighing 52.0 g thionyl chloride (0.44 muM) slowly dropping, then completing, stirring and reflux 3 h, cooling to room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at -10℃; for 5h; | To the reaction flask was added 81.7 g of N,N'-carbonyldiimidazole, 500 mL of methylene chloride solution cooled to -10 C, 50.0 g (240 mmoL) of <strong>[3972-36-9](S)-benzylsuccinic acid</strong> was added, and the reaction was carried out for 5 hours. A solution of 39.2 g (242 mmoL) of cis-perhydroisoindole hydrochloride in 80 mL of dichloromethane was added dropwise -10 C reaction, TLC point plate to complete reaction, add 6N HCl to the reaction flask to adjust the pH to 1 ~ 2, stir for 1 hour,The organic phase is separated, The organic phase was washed with distilled water to give a solution of (2S)-2-benzyl-3-(cis-hexahydroisoindoline-2-carbonyl)propionic acid in dichloromethane. | |
In ethyl acetate; at 0 - 5℃; for 3h; | ethyl acetate was added to the reaction flask, cooled to 0 ~ 5 , to which was added 1,1'-carbonyl diimidazole; 6 times was added at 0 ~ 10 S-2- benzyl succinate To the reaction flask acid, stirred for 20min after each added; after are added at 0 ~ 5 stirred for 3h, maintaining 0 ~ 5 , was added cis-hexahydro-isoindole hydrochloride, the reaction temperature was raised to 25 ~ 30 , stirring 8H; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In a 500-L reaction vessel, ethyl acetate (225 L), triethylamine (1.8 kg),Imidazole (9.8 kg)And intermediates2 (15kg),Cooled to -10 C with stirring,Thionyl chloride (17.2 kg) was added dropwise and the addition was complete. Stirring was continued at -10 C to -5 C6h,Cis-all-iso-isoindoline (9kg) was added dropwise, and the reaction was stirred at room temperature for 18h,1N hydrochloric acid was added to the reaction solution(150L) After stirring for 1h,Liquid separation, organic layer washed,It was extracted with 1N sodium hydroxide solution (100 L × 3)The combined aqueous layers were washed with ethyl acetate (50 L). The aqueous layer was adjusted to pH = 3 with 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate (100 mL x 3)The organic layer was washed with saturated brine (50 L × 3), the organic layer was dried over anhydrous Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure to give an oil19.8 kg, Intermediate 3 yield: 87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With Ru(OCOCH3)2{(S)-2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl)}; hydrogen; In methanol; at 50℃; under 760.051 Torr; for 10h;Molecular sieve; Inert atmosphere; Large scale; | 200L high pressure hydrogenation reactor airtight,Intermediate 1 (19 kg),Methanol (95L) and molecular sieves containing 5% Ru (OAc) 2 [(S) -BINAP](SBA-15) supported catalyst (0.95kg, self-made) into the reaction vessel,Replace the reactor with N2 air, heated to 50 , atmospheric pressure hydrogen 10h,Cool, filter and filtrate was concentrated to dryness under reduced pressure. The resulting solid was treated with acetic acidEthyl ester recrystallized and dried in vacuo to give a white solid 15.5kg, intermediate 2, yield 81%, chiral purity 99.5% e.e .. |
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