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CAS No. : | 302-84-1 | MDL No. : | MFCD00064223 |
Formula : | C3H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MTCFGRXMJLQNBG-UHFFFAOYSA-N |
M.W : | 105.09 | Pubchem ID : | 617 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 22.18 |
TPSA : | 83.55 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) : | -9.12 cm/s |
Log Po/w (iLOGP) : | 0.19 |
Log Po/w (XLOGP3) : | -3.07 |
Log Po/w (WLOGP) : | -1.61 |
Log Po/w (MLOGP) : | -3.91 |
Log Po/w (SILICOS-IT) : | -1.45 |
Consensus Log Po/w : | -1.97 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 3.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.57 |
Solubility : | 3950.0 mg/ml ; 37.5 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.88 |
Solubility : | 7970.0 mg/ml ; 75.9 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 1.3 |
Solubility : | 2080.0 mg/ml ; 19.8 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
94.2% | for 19 h; Cooling with ice; Reflux | In 100 ml of methanol is added in three-mouth bottle 30 ml, under the condition of the mechanical stirring ice-water bath, slow adds by drops two chlorine Asia sulphone 6.6 ml, after dripping, continue to stir 1h, the (II) 6.00g DL-serine (57mmol) inputs in three-mouth bottle, heating reflux reaction, reaction time 18h rear, reduced pressure distillation to remove the solvent, obtained after drying (III) 8.32g DL-serine methyl ester hydrochloride, yield 94.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With thionyl chloride at 0 - 20℃; | |
90% | With thionyl chloride at 0℃; for 3h; Reflux; Inert atmosphere; | 1. methyl 2-amino-3-hydroxypropanoate (2) In inert atmosphere DL-Serine (9.59 mmol) was dissolved in methanol (2 mL / mmol) and cooled to < 0° C (salt/ice). Thionyl chloride (56.69 mmol, 5.9 eq.) was added slowly by syringe, reaction mixture was refluxed for 3 h, TLC was monitored in BuOH: Acetic acid: Water (3:1:1) system and then concentrated, coevaporated with ether. Product obtained (2) was white crystalline solid (90 % yield). |
With hydrogenchloride man verdampft unter geringem Druck, zersetzt das entstandene Hydrochlorid durch eine 2prozentige Loesung von Natrium in Methylalkohol und verdampft das Filtrat unter geringem Druck bei gewoehnlicher Temp.; |
With hydrogenchloride | ||
With thionyl chloride | ||
With thionyl chloride for 48h; Ambient temperature; | ||
With hydrogenchloride In water | ||
With acetyl chloride at 70℃; for 1h; | ||
With thionyl chloride at 0 - 20℃; for 48h; | 40.I Step I: To a solution of serine (10.5 g, 100 mmol) in MeOH (100 mL) at 0° C. was added thionyl chloride (8.3 g, 5.1 mL, 70 mmol) over 5 minutes. After the reaction mixture was allowed to warm to room temperature and stirred for 48 hours, it was concentrated to a solid through repetitive evaporation with MeOH (3×20 mL), toluene (1×20 mL), and hexane (20 mL). The crude white solid was dissolved in acetyl chloride (120 mL), chilled to 0° C., and phosphorus pentachloride (22.5 g, 107 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred for an additional 9 hours. Then the reaction mixture was cooled, and the solid precipitate was filtered and collected to yield 13.5 g of a light-yellow solid. This solid was suspended in THF (100 mL) and water (5 mL) at 0° C. and reacted with potassium carbonate (27 g, 195 mmol) and benzoyl chloride (26.6 g, 22 mL, 190 mmol) for 1 hour at 0° C. The reaction was stirred for 4 hours at room temperature, then diluted with water (600 mL) and chilled to 0° C. overnight. The solid formed in this reaction mixture was filtered off and dried to yield methyl 2-benzamido-3-chloro-propanoate ( AR1) (11 g, 42%). LC/MS: calc'd 242 (MH+), exp 242 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cis-nitrous acid | ||
With hydrogenchloride; sodium nitrite In water at 0 - 20℃; for 17.0833h; Schlenk technique; Inert atmosphere; | Methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (8) D/L-Serine (25.0 g, 238 mmol, 1.0 eq.) and NaNO2 (32.8 g, 476 mmol, 2.0 eq.) were dissolved in H2O (1.15 L)and cooled to 0 °C. HCl (37% in H2O, 39.7 mL) was added to the mixture over a period of 5 minutes and thereaction was allowed to warm to rt followed by stirring for 17 h. The solvent was removed under reducedpressure and the resulting gum was freeze-dried overnight. After dissolving the residue in MeOH (314 mL),the solution was cooled to 0 °C and acetyl chloride (13.5 mL, 190 mmol, 0.8 eq.) in MeOH (100 mL) wasadded, followed by trimethyl orthoformate (84.0 mL, 952 mmol, 4.0 eq.). The solution was warmed to rt andstirred for 42 h, while the reaction mixture gradually turned into a yellow suspension with a whiteprecipitate. After removal of the solvent in vacuo, the residue was suspended in EtOAc (400 mL) and the solidwas removed by filtration The solution was concentrated (30 °C, 40 mbar) to give an orange oil which was directly dissolved in 2,2-dimethoxypropane (238 mL). p-TsOH (1.36 g, 7.14 mmol, 0.03 eq.) was added andthe reaction was stirred for 3 h 20 min at rt. Thereafter, NaHCO3 (2.86 g, 34.0 mmol, 0.145 eq.) was added andthe reaction was continued for 1 h. The solid was removed by filtration and the filtercake was rinsed withEt2O (200 mL). After removal of the solvent in vacuo (30 °C, 100 mbar), the oil was purified by vacuumdistillation (76 °C, 15 mbar; oil bath temperature: 95 - 100 °C) using a distillation apparatus equipped with15 cm vigreux column to obtain methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (8, 17.3 g, 108 mmol, 45%over 3 steps) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: serin; benzenesulfonyl chloride With sodium hydroxide In water at 0 - 20℃; for 18.5h; Stage #2: With hydrogenchloride In water at 0℃; | 2.1 Example 2; (RS)-1-Benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-3-phenyl-imidazolidin-2-oneStep 1: DL-serine (1.051 g) was dissolved in a 1 M aqueous NaOH solution (20 ml). Benzenesulfonyl chloride (1.77 g) was added at 0° C. After 30 min the ice bath was removed and the mixture was stirred for 18 h at room temperature. The mixture was again placed in an ice bath. The mixture was acidified to pH 1 using 25% aqueous HCl. The colorless precipitate was collected by filtration, washed with 1 M HCl and dried to give (RS)-2-benzenesulfonylamino-3-hydroxy-propionic acid (1.23 g) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide | ||
With methyloxirane In tetrahydrofuran at 20℃; for 2h; | Synthesis of (3,5-Dinitrobenzoyl)-protected amino acids (compounds 6-9) (1): General procedure: 3,5-Dinitrobenzoyl chloride (2.3 g, 10 mmol) was added to a suspension of amino acids (12 mmol) in dry THF and propylene oxide(1.40 mL, 20 mmol) was added dropwise. After stirring for 2 h at room temperature, the solution was filtered, and the solvent wasremoved under reduced pressure to give the desired products. Injection samples were prepared by dissolving each of racemic analytesin methanol at a concentration of 1 mg/mL. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With thionyl chloride; for 19h;Cooling with ice; Reflux; | In 100 ml of methanol is added in three-mouth bottle 30 ml, under the condition of the mechanical stirring ice-water bath, slow adds by drops two chlorine Asia sulphone 6.6 ml, after dripping, continue to stir 1h, the (II) 6.00g DL-serine (57mmol) inputs in three-mouth bottle, heating reflux reaction, reaction time 18h rear, reduced pressure distillation to remove the solvent, obtained after drying (III) 8.32g DL-serine methyl ester hydrochloride, yield 94.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In methanol; water monomer at 25℃; Resolution of racemate; | ||
With R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 coated C18 silica gel column at 25℃; Resolution of racemate; | ||
With C9H20N(1+)*C5H8NO2(1-); copper (II) acetate In water monomer at 10℃; Resolution of racemate; |
With capillary electrochromatography open-tubular column coated with 1-allylimidazolium-β-cyclodextrin In aq. acetate buffer at 20℃; Resolution of racemate; | ||
With (R,R)-BINOL2-C/PDAN-based chiral covalent organic frameworks covered silica gel packed HPLC column In methanol; water monomer at 25℃; Resolution of racemate; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | INTERMEDIATE 57 (METHOD W)JV-BenzylserineRacemic serine (14.7 g, 140 mmol) was dissolved in 2M NaOH (70 niL) and benzaldehyde (14.64 g, 14.0 mL, 138 mmol) added with stirring. The mixture was stirred EPO <DP n="59"/>at r.t. for 1 h before cooling to 50C. Sodium borohydride (1.5 g, 40 mmol) was added portionwise such that an internal temperature of between 6 and 100C was maintained. After addition the reaction mixture was allowed to stir at 50C for 30 minutes and then at r.t. for 1 h. The reaction mixture was cooled to 50C and a further portion of sodium borohydride (1.5 g, 40 mmol) added portionwise such that an internal temperature <10C was maintained. The ice bath was removed on completion of addition and the reaction stirred at r.t. for 16 h. The reaction mixture was extracted with Et2O (3 x 100 mL) and the aqueous phase acidified to pH 5 with concentrated hydrochloric acid. The resultant white precipitate was filtered and washed with water. The product was dried in vacuo to give the title compound (24.0 g, 88%). deltaH (DMSOd6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (IH, t, J5.8 Hz). Some exchangeable protons were not observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With thionyl chloride Reflux; | 1.1 Step 1 The 5.00g serine added to the 50 ml isopropanol in, dropping 11.32g SOCl2. Reaction refluxing overnight after directly concentrated, to obtain 8.47g white serine isopropyl ester hydrochloride, yield 96.9%. |
92% | With hydrogenchloride | |
With hydrogenchloride at 85℃; for 12h; | 7 Example 7. (2/?)-2-Amino-2-Deutero-3-Hydroxy-Propanoic Acid (Compound 100) 237] The detailed synthesis of racemic 2-amino-2-deutero-3-hydroxy-propanoic acid followed by resolution to obtain (2f?)-2-amino-2-deutero-3 -hydroxy -propanoic acid (Compound 100) in high e.e. (enantiomeric excess) and with high % D is shown in Scheme 2 below. (0459) Scheme 2 (0460) o pou (0461) [238] As depicted in Scheme 2, Compound 100 was prepared from non-deuterated D,L- serine. Proton NMR and mass spectral data were consistent with the structure shown above for Compound 100: MS (M+H): 107.2; MS (M-H): 105.2; -NMR (400 MHz, D2O): d 3.90 (dd, Ji=2A Hz, .72=19.2 Hz, 2H). Deuterium incorporation was determined by proton NMR to be approximately 96%. SFC (supercritical fluid chromatography) analysis of the benzyloxycarbonylamino derivative of Compound 100 revealed no trace of the S-enantiomer. |
With hydrogenchloride at 85℃; for 12h; | ||
With hydrogenchloride at 85℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 7.6 % Chromat. 2: 39.1 % Chromat. 3: 7.4 % Chromat. 4: 0.9 % Chromat. 5: 2.7 % Chromat. 6: 0.6 % Chromat. | With oxygen; ozone In water for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With acetic acid at 75℃; for 2h; | |
Stage #1: serin; acetic anhydride With acetic acid at 45℃; for 3h; Stage #2: 7-chloro-1H-indole Heating; | General procedure for the synthesis of N-acetyl-benztryptophan methyl ester (8) General procedure: dl-Serine (2.0 mol equiv) was added to acetic acid (0.2 M) and acetic anhydride (9.5 mol equiv), and the mixture was stirred for 3 h at 45 °C. To the reaction mixture, compound 7 (1.0 mol equiv) was added and stirred under the conditions shown in Scheme 2. After pouring into water, the mixture was concentrated in vacuo, the residue was extracted with ethyl acetate. The combined organic layers were washed with 30% NaOH aq and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in methanol (0.37 M) and ethyl acetate (0.16 M), 2.0 M trimethylsilyldiazomethane in toluene solution (2.6 mol equiv) was added dropwise, and the mixture was stirred for 1 h. After the addition of acetic acid (4.0 mol equiv), the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; In acetic acid; for 24h;Under N2; Heating / reflux; | Intermediate 32 Preparation of N-acetyltryotophan acetic anhydride (0.5 ML, 5.2 mmol) was added to a slurry of Intermediate 31 (0.575 g, 2.6 mmol) and DL-serine (0.270 g, 2.6 mmol) in anhydrous acetic acid (5 ML) at room temperature under a nitrogen blanket.The resulting orange solution was heated to reflux and stirred for 24 hours.The cooled mixture then was concentrated under reduced pressure to provide the intermediate N-acetyltryptophan as dark red oil, which was used immediately without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
acetic anhydride; In acetic acid; at 80℃; for 24h;Under N2; | Intermediate 17 Preparation of N-Acetyl-6-carboxytryptophan A mixture of <strong>[1670-82-2]indole-6-carboxylic acid</strong> (5.0 g, 31 mmol), DL-serine (3.25 g, 31 mmol), and acetic anhydride (8.8 ML, 93 mmol) in glacial acetic acid (50 ML) was heated under a nitrogen blanket at 80 C. for 24 hours.The resulting brown solution was cooled to room temperature, then the solvent was removed under reduced pressure to provide Intermediate 17 as a brown foam, which was used without further purification (11.0 g): 1H NMR (300 MHz, D2O): delta 8.08 (s, 1H), 7.72 (s, 2H), 7.40 (s, 1H), 4.61-4.53 (m, 1H), 3.45-3.35 (m, 1H), 3.23-3.13 (m, 1H), 1.92 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine In dichloromethane at 0 - 25℃; for 12h; | 3-Hydroxy-2- [2- (4-methoxy-phenyl)-acetylamino]-propionic acid methyl ester: to a suspensionofDL-serineHCl (2.0 g, 12.8 mmol) in dichloromethane (10 mL) at0 C were added dropwise triethylamine (3.58 mL, 25.7 mmol) and (4-methoxyphenyl) -acetyl chloride (1.96 mL, 12.8 mmol). The mixture was stirred at25 C for 12 hours. The reaction mixture was washed with a saturated aqueous sodium chloride solution, separated, and evaporated to dryness and purified by column chromatography (hexanes: ethyl acetate from 25 to 100%). 3-Hydroxy-2-[2- (4-methoxy-phenyl)-acetylamino]-propionic acid methyl ester was isolated as a white solid (2g, 58 %). ESI-MSm/z calc. 267.3, found 268.2(M+1) +. Retention time of 1.83 minutes NMR (400 MHz,CDC13) 8 3.64 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 3.93 (qd, J = 14.6 and 4.0 Hz,2H), 4.66 (m, 1H), 6.40 (m, 1H), 7.01 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In diethyl ether; chloroform; | Example 13 A solution of 16.9 g (100 mmol) of ethyl serinate hydrochloride obtained according to the method described in Example 1, but starting with serine, in 150 ml of chloroform, is cooled to 0-5 C. 500 ml of Et2O and 10.12 g (100 mmol) of triethylamine are added. The medium is stirred for 2 hours at 0 C. It is filtered and evaporated to dryness. 11.98 g of a colourless oil (90%) are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: serin With sulfuric acid; sodium nitrite In water at 5 - 20℃; Stage #2: With lithium hydroxide In water | 3.a; 5.e Example 3; N, N', N"-Tris-{2,4,6-triiodo-3[N-methyl-N-(2,3- dihydroxypropyl)aminocarbonyl]-5-(2,3-dihydroxy-butyrylamino)phenyl}- carbamoylethyl methane. Following the synthetic scheme depicted below and the procedure described in steps a) to g) the title compound was obtained. a) Synthesis of lithium 2.3-dihvdroxypropanoate; D,L-Serine (115.5 g, 1.10 mole) was added to a mixture of cone, sulfuric acid (75 g) in water (1.25 L) and the mixture was cooled to ca 5°C. Sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 3h while temperature was kept at 5°-10°C. Then sulfuric acid (60 g) dissolved in water (200 ml) and cooled to ca 5°C in a ice/water mixture, was added. A new portion of sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 2h, while temperature was kept at 5°-10°C. The mixture was stirred at ambient temperature over night and then concentrated to a volume of ca 700 ml. Lithium hydroxide (22.7 g, 0.95 mole), dissolved in water (100 ml) was added. The mixture was now poured into a stirred mixture of methanol (1 L) and acetone (0.3 L). The precipitate formed was filtered off and washed with methanol/acetone (1/0.3 100 ml). The combined filtrates were now evaporated to a small volume (ca. 300 ml) and pH was adjusted to 7 by addition of a 5M solution of lithium hydroxide (ca. 200 ml). The mixture was evaporated to dryness and abs. ethanol (600 ml) was added, the product dissolved by heating and the mixture evaporated to dryness. The residue was then co evaporated twice with toluene (2 * 300 ml), and pumped in vacuo. There was of a gum like product 130 g. Identity was checked by 1H NMR in D2O.; e) Synthesis of lithium 2,3-dihvdroxypropanoate (13); D,L-Serine (115.5 g, 1.10 mole) was added to a mixture of cone, sulfuric acid (75 g) in water (1.25 L) and the mixture was cooled to ca 5°C. Sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 3h while temperature was kept at 5°-100C. Then sulfuric acid (60 g) dissolved in water (200 ml) and cooled to ca 50C in a ice/water mixture, was added. A new portion of sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 2h, while temperature was kept at 5°-10°C. The mixture was stirred at ambient temperature over night and then concentrated to a volume of ca 700 ml. Lithium hydroxide (22.7 g, 0.95 mole), dissolved in water (100 ml) was added. The mixture was now poured into a stirred mixture of methanol (1 L) and acetone (0.3 L). The precipitate formed was filtered off and washed with methanol/acetone (1/0.3 100 ml). The combined filtrates were now evaporated to a small volume (ca. 300 ml) and pH was adjusted to 7 by addition of a 5M solution of lithium hydroxide (ca. 200 ml). The mixture was evaporated to dryness and abs. ethanol (600 ml) was added, the product dissolved by heating and the mixture evaporated to dryness. The residue was then co evaporated twice with toluene (2 * 300 ml), and pumped in vacuo. There was of a gum like product 130 g. Identity was checked by 1H NMR in D2O. | |
Stage #1: serin With sulfuric acid; sodium nitrite In water at 5 - 20℃; Stage #2: With lithium hydroxide In water | K D,L-Serine (115.5 g, 1.10 mole) was added to a mixture of conc. sulfuric acid (75 g) in water (1.25 L) and the mixture was cooled to ca 5° C. Sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 3 h while temperature was kept at 5°-10° C. Then sulfuric acid (60 g) dissolved in water (200 ml) and cooled to ca 5° C. in a ice/water mixture, was added. A new portion of sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 2 h, while temperature was kept at 5°-10° C. The mixture was stirred at ambient temperature over night and then concentrated to a volume of ca 700 ml. Lithium hydroxide (22.7 g, 0.95 mole), dissolved in water (100 ml) was added. The mixture was now poured into a stirred mixture of methanol (1 L) and acetone (0.3 L). The precipitate formed was filtered off and washed with methanol/acetone (1/0.3 100 ml). The combined filtrates were now evaporated to a small volume (ca. 300 ml) and pH was adjusted to 7 by addition of a 5M solution of lithium hydroxide (ca. 200 ml). The mixture was evaporated to dryness and abs. ethanol (600 ml) was added, the product dissolved by heating and the mixture evaporated to dryness. The residue was then co evaporated twice with toluene (2×300 ml), and pumped in vacuo. There was of a gum like product 130 g. Identity was checked by 1H NMR in D2O. | |
Stage #1: serin With sulfuric acid; water; sodium nitrite at 5 - 20℃; Stage #2: With lithium hydroxide In water | F D,L-Serine (115.5 g, 1.10 mole) was added to a mixture of cone, sulfuric acid (75 g) in water (1.25 L) and the mixture was cooled to ca 5°C. Sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 3h while temperature was kept at 5°-10°C. Then sulfuric acid (60 g) dissolved in water (200 ml) and cooled to ca 5°C in a ice/water mixture, was added. A new portion of sodium nitrite (68.3 g, 0.99 mole) dissolved in water (500 ml) was added slowly during 2h, while temperature was kept at 5°-10°C. The mixture was stirred at ambient temperature over night and then concentrated to a volume of ca 700 ml. Lithium hydroxide (22.7 g, 0.95 mole), dissolved in water (100 ml) was added. The mixture was now poured into a stirred mixture of methanol (1 L) and acetone (0.3 L). The precipitate formed was filtered off and washed with methanol/acetone (1/0.3 100 ml). The combined filtrates were now evaporated to a small volume (ca. 300 ml) and pH was adjusted to 7 by addition of a 5M solution of lithium hydroxide (ca. 200 ml). The mixture was evaporated to dryness and abs. ethanol (600 ml) was added, the product dissolved by heating and the mixture evaporated to dryness. The residue was then co evaporated twice with toluene (2 * 300 ml), and pumped in vacuo. There was of a gum like product 130 g. Identity was checked by 1H NMR in D2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In N,N-dimethyl-formamide at 20℃; for 12h; | 4.1 (1) Synthesis of carboxylic acid (11); In a 50 ml three-necked flask, 100 mg (0.21 mmol) of an oxadiazolopyridine carboxylic acid (9) and 26 mg (0.25 mmol) of serine were dissolved in 20 ml of DMF. After dropping, the mixture was stirred for 12 hours at room temperature. Under reduced pressure, DMF was distilled off. The residue was isolated and purified by silica gel column chromatography (chloroform:methanol=7:3) to obtain 79 mg (yield: 81%) of a carboxylic acid (11). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In ethanol; water for 24h; | 12 Example 12 Vanillin (30.4 grams, 0.20 moles) was dissolved in 100 mL of ethanol, and then Serine (10.5 grams, 0.1 moles) dissolved in 100 mL of water was added. As soon as the Serine was added the solution turned yellow forming a precipitate in the ethanol/water solvent. Three grams of a 5% Pd on carbon catalyst was added to the solution. The reaction mixture was placed in a hydrogenation flask and 35 psi of Hydrogen was added while the, flask was shaken for 24 hours. The mixture was filtered to remove the 5% Pd/C, and then placed on a rotary evaporator to remove most of the water and ethanol. The reaction mixture was cooled to O0C overnight and 34 grams of crystal product was isolated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: serin With hydrogen bromide; potassium bromide In water at -15 - -12℃; for 0.25h; Stage #2: With sodium nitrite In water for 2h; | 4.1.9 2-bromo-3-hydroxypropanoic acid (29) To a mixture of D,L-serine (33) (95.24mmol, 10g) and potassium bromide (322.69mmol, 38.4g) in 100ml of distilled water, 23.8ml of hydrogen bromide was added. The solution was cooled, and the temperature was maintained between-15°C and-12°C; after 15min, NaNO2 (11.68mmol, 8.08g) was added in portions of 1.01g to the solution for 2h. Subsequently, nitrogen was removed using the ultrasonic. When the reaction was completed, the aqueous phase was acidified with 1mL concentrated HCl. The product was extracted in ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried over Na2SO4, and evaporated. The resulting oil was quenched with dry methylene chloride and allowed to purify by crystallization at-30°C to yield 33 (12.86g, 80%, Rf=0.5 (DCM/methanol/AcOH 8:2:0.5) as colorless crystals that were stored under argon at a temperature below zero due to strong hygroscopicity and low melting point. 1H NMR (D2O): δ ppm 3,83 (d, 1H, CH2’), 4,62-4,67 (m, 2H, CH2”, CHBr). 13C NMR (D2O): δ=172,30 (COOH), 62,85 (CH2), 46,67 (CHBr). Formula C3H5BrO3. |
63% | With hydrogen bromide; potassium bromide; sodium nitrite In water at -10 - 20℃; for 20.5h; | |
63% | With hydrogen bromide; potassium bromide; sodium nitrite In water at -10 - 20℃; for 16h; Inert atmosphere; | Synthesis of 2-Bromo-3-hydroxypropionic acid Synthesis of 2-Bromo-3-hydroxypropionic acid 2-Bromo-3-hydroxypropionic acid was synthesized in 50-63% yield as in the following example. Sodium nitrite (12 g, 0.17 mol) was added in portions over 270 min to a solution of D, 23 L-serine (10 g, 0.10 mol), 24 HBr (26 mL, 48% aq. w/w, 0.23 mol) and 25 potassium bromide (40 g, 0.33 mol) in 11 water (88 mL) at -10 to 0° C. After stirring at room temperature for 16 h, the light-greenish solution was saturated with 26 NaCl and extracted five times with ethyl acetate (50 mL each). The combined organic extracts were washed five times with saturated aqueous NaCl (50 mL each) and dried over Na2SO4. After filtration and removing the solvent by trap-to-trap distillation, the residue was recrystallized from CH2Cl2 to obtain 10 g (63%) of 20 2-bromo-3-hydroxypropionic acid as a white solid. 1H NMR (CDCl3/DMSO-d6): 2.01 (broad s, OH), 3.77 (m, CH2OH), 4.10 (t, CHBr), 7.20 (broad s, COOH). 13C NMR (CDCl3/DMSO-d6): 45.6 (CBr), 64.0 (COH), 171.0 (C═O). Anal. C, H: calcd. 21.32, 2.98; found 20.95, 2.90. |
With hydrogen bromide; potassium bromide; sodium nitrite In water at -5 - 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
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58% | With hydrogenchloride; potassium chloride; sodium nitrite In water at -10 - 20℃; for 27h; Inert atmosphere; | |
58% | With hydrogenchloride; potassium chloride; sodium nitrite In water at -10 - 20℃; Inert atmosphere; | Synthesis of 2-chloro-3-hydroxypropionic acid Synthesis of 2-chloro-3-hydroxypropionic acid In a 3-necked 1000 ml. RB flask, sodium nitrite (68.4 g, 0.99 mol) was added in small batches to the aqueous solution of a mixture of DL-serine (52.4 g, 0.50 mol), potassium chloride (130.4 g, 1.75 mol) and HCl (116.0 g of 36.5%-38% w/v aq. sol., 1.21 mol) (taken together in 490 mL of water) at 0° C.-10° C. After complete addition, reaction mixture brought to room temperature and kept overnight for the reaction. Solution turned from clear and off-white to clear and light green. The product was salted out with NaCl and extracted with 5 times of 100 mL of ethyl acetate. Organic phase was washed 5 times with saturated NaCl aqueous solution (50 mL each) and then dried over anhy. Na2SO4. Solution was filtered and solvent was evaporated by trap-to-trap distillation method followed by drying in the vacuum chamber. Product was recrystallized in CH2Cl2. Yield=36.5 g (58%). 1H NMR (CDCl3/DMSO-d6): 2.01 (br s, OH), 3.98 (m, CH2OH), 4.42 (t, CHCl), 7.20 (br s, COOH). 13C NMR (CDCl3/DMSO-d6): 57.8 (CCl), 64.3 (COH), 170.4 (C=O). Anal. C, H: calcd. 28.94, 4.04; found 28.60, 3.80. |
36.5 g (58%) | With hydrogenchloride; potassium chloride; sodium nitrite In water; ethyl acetate | Examples Synthesis of 2-chloro-3-hydroxypropionic acid. In a 3-necked 1000 ml. RB flask, sodium nitrite (68.4 g, 0.99 mol) was added in small batches to the aqueous solution of a mixture of DL-serine (52.4 g, 0.50 mol), potassium chloride (130.4 g, 1.75 mol) and HCl (116.0 g of 36.5%-38% w/v aq. sol., 1.21 mol) (taken together in 490 mL of water) at 0° C.-10° C. After complete addition, reaction mixture brought to room temperature and kept overnight for the reaction. Solution turned from clear and off-white to clear and light green. The product was salted out with NaCl and extracted with 5 times of 100 mL of ethyl acetate. Organic phase was washed 5 times with saturated NaCl aqueous solution (50 mL each) and then dried over anhy. Na2SO4. Solution was filtered and solvent was evaporated by trap-to-trap distillation method followed by drying in the vacuum chamber. Product was recrystallized in CH2Cl2. Yield=36.5 g (58%). 1H NMR (CDCl3/DMSO-d6): 2.01 (br s, OH), 3.98 (m, CH2OH), 4.42 (t, CHCl), 7.20 (br s, COOH). 13C NMR (CDCl3/DMSO-d6): 57.8 (CCl), 64.3 (COH), 170.4 (C=O). Anal. C, H: calcd. 28.94, 4.04; found 28.60, 3.80. |
Yield | Reaction Conditions | Operation in experiment |
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42% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 4.1.23. Synthesis of d,l-2,2-[6'-(4-sulfamoylphenethylamino)-1',3',5'-triazine-2',4'-diyl]bis(azanediyl)bis(3-hydroxypropanoic acid) 23 4-[6-(4',6'-Dichloro-1',3',5'-triazin-2'-ylamino)ethyl]benzenesulfonamide 3 (0.1 g, 1.0 equiv) and d,l-serine (4.2 equiv) were dissolved in dry DMF (15 ml) and DIPEA (5.0 equiv) was added. The reaction was stirred under a nitrogen atmosphere at rt until starting material was consumed (TLC monitoring) and treated according to the procedure reported above to afford the title product as a white solid.d,l-2,2-[6'-(4-Sulfamoylphenethylamino)-1',3',5'-triazine-2',4'-diyl]bis(azanediyl)bis(3-hydroxypropanoic acid) 23: 42% yield; mp 278-280 °C with decomposition; νmax (KBr) cm-1, 3342, 2830, 1710 (CO, acid), 1562 (aromatic); δH (400 MHz, DMSO-d6) 2.88 (2H, br m, 5-H2), 3.34 (4H, m, 6-H2, 2 × 3-HH), 3.77 (2H, br m, 2 × 2-H), 4.40 (2H, m, 2 × 3-HH), 7.32 (2H, s, SO2NH2, exchange with D2O), 7.45 (2H, d, J 8.2, 2 × 3-H), 7.76 (2H, d, J 8.2, 2 × 2-H), 8.00 (2H, br s, CHNH-, exchange with D2O); δC (100 MHz, DMSO-d6) 174.9, 165.3, 164.0, 145.0, 141.4, 129.0, 127.5, 69.4, 58.0, 44.2, 36.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The peptone medium (500 mL) was inoculated with F. nucleatum cell suspension from one agar plate and incubated for 24 h. The damp cells (approximately 2.5 g) were harvested aseptically in air by centrifugation (8200g, 15 min) and resuspended with gentle magnetic stirring in defined medium containing dl-serine (50 mL). Samples (300 muL) were removed at various times and centrifuged (15,400g, 10 min). Supernatants were stored at -15 C for HPLC analysis. 4.5. Identification of metabolic end-products. The supernatant from a serine resuspension experiment (800 mM, 48 h incubation) was titrated to pH 9.5 with 5 M NaOH and lyophilized. A portion of the lyophilzed residue (ca. 100 mg) was dissolved in D2O for NMR analysis. Resonances in the NMR spectra were assigned by chemical shift comparisons with standard samples. The relative amounts of the end-products were calculated from the integrated areas of the 1H NMR signals for the methyl groups of acetate, butyrate and lactate at delta 1.84, 0.81 and 1.26 ppm, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With sodium hydroxide In water monomer at 0 - 27℃; | 3 To a slurry of D,L-serine (500 g, 4.76 mol) in 1,4-dioxane (2.5 L) at 0-5°C was slowly added a solution of sodium hydroxide (400 g, 10 mol) in water (2.5 L), followed by di-tert-butyl dicarbonate (1639 mL, 7.14 mol). The temperature was then raised to 25-27°C, and the reaction mixture was maintained at that temperature overnight. The solvent was evaporated under reduced pressure to approximately one-third of the total reaction mass, then the reaction mixture was filtered through Celite to remove the salts. The aqueous layer was washed with ethyl acetate (2 x 2.5 L), cooled to 0-5°C, then acidified with a solution of citric acid (4.4 kg, 23.15 mol) in water (3.6 L), and the pH was adjusted to ∼2. The residue was extracted with ethyl acetate (5 x 2.5 L), then the combined organic layers were washed with brine (1 L) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to afford a pale yellow viscous liquid (925 g, 94.7%). HPLC purity: 78.03%. To a mixture of this material (500 g, 2.4 mol) in toluene (2.5 L) was added tetrabutylammonium bromide (39.2 g). The reaction mixture was cooled to 0-5°C, then dimethyl sulphate (946.5 mL, 9.7 mol) and a solution of sodium hydroxide (878 g, 21.9 mol) in water (2.17 L) were simultaneously added at 0-5°C. The reaction mixture was maintained at 0-5°C for 30 minutes, then the temperature was raised to 25-27°C and the reaction mixture was maintained at that temperature overnight. The reaction mixture was allowed to settle, and separated into two layers. The aqueous layer was washed with toluene (2.5 L), cooled to 0-5°C, then acidified with a solution of citric acid (1.85 kg, 9.7 mol) in water (1.34 L), to pH ∼3 at 0-5°C. The residue was extracted with dichloromethane (6 x 2.5 L), then the combined organic layers were washed with brine (1.8 L) and dried over sodium sulphate. The solvent was evaporated under vacuum to afford an offwhite solid (281 g, 52.6%). HPLC purity: 81.1%. To a mixture of this material (385 g, 1.75 mol) in acetone (1925 mL) was added potassium carbonate (358 g, 2.6 mol) slowly at 0-5°C, followed by slow addition of benzyl bromide (210 mL, 1.75 mmol). The temperature was maintained at 0-5°C for 30 minutes, then raised to 25-27°C and the reaction mixture was maintained at that temperature overnight. The reaction mass was filtered to remove the inorganic salts, and the salts were then washed with acetone. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed twice with water, followed by brine. The organic layer was dried over sodium sulphate. The solvent was evaporated completely to provide a brick red-coloured liquid (540 g, 98.7%). To a mixture of this material (300 g, 0.97 mol) in tetrahydrofuran (1.5 L) at 0-5°C was slowly added a solution of conc. hydrochloric acid (793 mL) in water (1.6 L). The temperature was maintained at 0-5°C for 30 minutes, then raised to 25-27°C and the reaction mixture was maintained at that temperature for 30 h. The solvent was evaporated completely and the aqueous layer was washed five times with dichloromethane. The aqueous layer was basified (pH∼10) with sodium carbonate (700 g) at 0-5°C. The residue was extracted four times into dichloromethane, and the organic layer was dried over sodium sulphate. The solvent was evaporated completely under vacuum to afford the title compound (122 g, 60%) as a pale yellow liquid. HPLC purity: 95.17%. |
78% | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 72h; | 4-(Methoxy-methyl-carbamoyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester 35 Di-tert-butyl dicarbonate (9.85 g, 45.1mmol) in 1,4-dioxane (35 ml) was added to a stirred solution of DL-serine (3.95 g, 37.6 mmol) in 1M NaOH (75 ml) at 0 oC. The reaction was warmed to room temperature and stirred for 3 days, maintaining the pH at 9 by the addition, when necessary, of 1M NaOH. The mixture was concentrated to about half volume under reduced pressure, cooled to 0 oC and carefully treated with 1M H2SO4 (~38 ml) until pH 2-3 was achieved. The solution was saturated with solid NaCl, and extracted with ethyl acetate (6 x 50 ml). The combined organic extracts were concentrated in vacuo to give 2-tert-butoxycarbonylamino-3-hydroxy-propionic acid as a thick colourless oil (6.05 g, 78 %), Rf (ethyl acetate) 0.04; umax (film)/cm-1 3332 (br, -OH, NH, CO2H), 2977, 2934, 1701, 1682, 1511, 1456, 1393, 1367, 1280, 1248, 1155, 1056, 850, 778, 752; δH (300 MHz, D6-DMSO) 6.71 (1H, d, J 8.1 Hz), 3.96 (1H, ddd, J 8.1, 4.9, 4.9 Hz), 3.62 (2H, d, J 4.9 Hz), 1.38 (9H, s); δC (75.5 MHz, CDCl3) 172.8, 155.7,78.5, 61.8, 56.5, 28.5; m/z (EI) 204 (M-H)+, 194, 160, 150, 132, 119, 104, 74, 57. |
68% | Stage #1: serin With sodium hydroxide In water monomer at 0℃; Stage #2: di-<i>tert</i>-butyl dicarbonate In water monomer at 20℃; for 4h; | 3.2.2. General procedure for the synthesis of (R,S)-2-tertbutoxycarbonylamino-propanoic acids General procedure: 50 mmol of either (R,S)-2-amino-3-mercaptopropanoic acid or(R,S)-2-amino-3-hydroxypropanoic acid were dissolved in 21 mL ofdistilled water and then 21 mL of NaOH 2.5 N were added. Themixture was stirred at 0 C, afterwards a solution of di-tert-butyldicarbonate (51.3 mmol in 27 mL of acetone) was added dropwise.The reaction was then stirred at room temperature for 4 h. Acetonewas evaporated under vacuum, the aqueous residue was acidifiedto pH 2 using citric acid 10% (110 mL), extracted using ethyl acetate(EtOAc, 3 x 200 mL) and the resulting organic layer was washedwithwater (1 x 300 mL) and brine (1 x 300 mL), dried on anhydrousNa2SO4, filtered and concentrated, affording the crude product. 3.2.3 |
68% | Stage #1: serin With sodium hydroxide In water monomer at 0℃; Stage #2: di-<i>tert</i>-butyl dicarbonate In water monomer at 20℃; for 4h; | 3.2.2. General procedure for the synthesis of (R,S)-2-tertbutoxycarbonylamino-propanoic acids General procedure: 50 mmol of either (R,S)-2-amino-3-mercaptopropanoic acid or(R,S)-2-amino-3-hydroxypropanoic acid were dissolved in 21 mL ofdistilled water and then 21 mL of NaOH 2.5 N were added. Themixture was stirred at 0 C, afterwards a solution of di-tert-butyldicarbonate (51.3 mmol in 27 mL of acetone) was added dropwise.The reaction was then stirred at room temperature for 4 h. Acetonewas evaporated under vacuum, the aqueous residue was acidifiedto pH 2 using citric acid 10% (110 mL), extracted using ethyl acetate(EtOAc, 3 x 200 mL) and the resulting organic layer was washedwithwater (1 x 300 mL) and brine (1 x 300 mL), dried on anhydrousNa2SO4, filtered and concentrated, affording the crude product. 3.2.3 |
With sodium hydroxide In water monomer at 0 - 27℃; Industry scale; | 3 To a slurry of D,L-serine (500 g, 4.76 mol) in 1,4-dioxane (2.5 L) at 0-5°C was slowly added a solution of sodium hydroxide (400 g, 10 mol) in water (2.5 L), followed by di-tert-butyl dicarbonate (1639 mL, 7.14 mol). The temperature was then raised to 25- 27°C, and the reaction mixture was maintained at that temperature overnight. The solvent was evaporated under reduced pressure to approximately one-third of the total reaction mass, then the reaction mixture was filtered through Celite to remove the salts. The aqueous layer was washed with ethyl acetate (2 x 2.5 L), cooled to 0-5°C, then acidified with a solution of citric acid (4.4 kg, 23.15 mol) in water (3.6 L), and the pH was adjusted to ~2. The residue was extracted with ethyl acetate (5 x 2.5 L), then the combined organic layers were washed with brine (1 L) and dried over sodium sulphate. The solvent was evaporated under reduced pressure to afford a pale yellow viscous liquid (925 g, 94.7%). HPLC purity: 78.03%. | |
With sodium hydroxide In 1,4-dioxane; water monomer at 0 - 20℃; for 8h; | ||
With sodium hydroxide In 1,4-dioxane; water monomer at 20℃; for 24.5h; Cooling with ice; | N-(tert-Butoxycarbonyl)-L-serine (4) To a solution of L-serine (3) (2.00 g, 19.0 mmol) in 1 M NaOH (22 mL)cooled on an ice bath was slowly added a solution of di-tert-butyl dicarbonate (5.4 mL, 23.5 mmol) in 1,4-dioxane (16 mL). After stirring for 30 min on an ice bath, the mixture was stirred for 24 h at rt. The reactionmixture was evaporated to remove solvent, and the resulting solution was extracted with diethyl ether toremove ether-soluble byproducts. A 1 M potassium hydrogen sulfate solution was added to the aqueous layer,and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, andevaporated to give 4 as a colorless oil (3.90 g, 99%). The spectral data of 4 were identical to those in theliterature.25 The purity was confirmed by 1H NMR. | |
Stage #1: serin; di-<i>tert</i>-butyl dicarbonate With sodium hydroxide In 1,4-dioxane at 20℃; for 24h; Inert atmosphere; Stage #2: With sulfuric acid Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.0 mg | With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 2h; Inert atmosphere; | P169 Preparation of Product P169: 2-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-3- hydroxypropanoic acid A solution of 2-amino-3-hydroxypropanoic acid (15.67 mg, 0.149 mmol) was prepared in DMSO (1.0 mL) and N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (50 mg, 0.149 mmol) added. The solution was then treated with sodium hydride (60% dispersion in oil, 5.96 mg, 0.149 mmol) and the reaction stirred under nitrogen for 2 hours. The mixture was then quenched with isopropanol (0.5 mL) and water (0.5 mL) and the solvent removed in vacuo. The sample was partitioned between water (5 mL) and dichloromethane (5 mL) and the organics separated (hydrophobic frit). The crude was purified by MDAP (Method A) to give the required product 1.0 mg. LCMS (M+l) 421, RT 1.17 mins. |
1 mg | With sodium hydride In dimethyl sulfoxide; mineral oil for 2h; Inert atmosphere; | Preparation of Product P169: 2-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-3-hydroxypropanoic acid Preparation of Product P169: 2-((4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)amino)-3-hydroxypropanoic acid [0261] A solution of 2-amino-3-hydroxypropanoic acid (15.67 mg, 0.149 mmol) was prepared in DMSO (1.0 mL) and N-(2,4-dimethylphenyl)-4-fluoro-N-isobutylbenzenesulfonamide (50 mg, 0.149 mmol) added. The solution was then treated with sodium hydride (60% dispersion in oil, 5.96 mg, 0.149 mmol) and the reaction stirred under nitrogen for 2 hours. The mixture was then quenched with isopropanol (0.5 mL) and water (0.5 mL) and the solvent removed in vacuo. The sample was partitioned between water (5 mL) and dichloromethane (5 mL) and the organics separated (hydrophobic frit). The crude was purified by MDAP (Method A) to give the required product 1.0 mg. LCMS (M+1) 421, RT 1.17 mins. |
Yield | Reaction Conditions | Operation in experiment |
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62% | Stage #1: serin With sodium hydrogencarbonate In water Heating; Stage #2: salicylaldehyde In methanol; water for 5h; Reflux; | 3.1 2.3.1 Sodium (E)-3-hydroxy-2-((2-hydroxybenzylidene)amino)propanoate (L1H2Na) L1H2Na was prepared by stirring a methanolic solution (30 mL) of 2-hydroxybenzaldehyde (1.15 g, 9.49 mmol) and sodium 2-amino-3-hydroxypropanoate that was generated in situ from a hot aqueous solution (10 mL) of NaHCO3 (0.79 g, 9.40 mmol) and 2-amino-3-hydroxypropanoic acid (l-serine) (1.00 g, 9.51 mmol). A yellow color developed almost immediately, and stirring was continued for 1 h, followed by reflux for 4 h. After removal of the volatile components, the residue was washed thoroughly with hot hexane, filtered and dried in vacuo. After extraction into anhydrous methanol followed by filtration, the resulting solution was concentrated to a minimum and allowed to cool to room temperature, affording the crude product. Repeated recrystallization from methanol yielded pure L1H2Na (1.35 g, 62% yield). M.p.: >250 °C. IR (cm-1): 1653 ν(OCO)asym. |
Yield | Reaction Conditions | Operation in experiment |
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80% | Stage #1: 2-[1-(3-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 1h; Stage #2: serin In tetrahydrofuran for 4h; | 7 4.1.6. General procedure for the preparation of 1,5-diarylpyrrole-3-acetic amides (2a-d, 5a-d) General procedure: PyBOP (0.93 mmol) and triethylamine (3 mmol) were added in sequence to a solution of 7a,b (0.78 mmol) in THF (20 mL) at rt and the mixture stirred for 1 h. Then the amino acid (10a,b, 11a-b) (1.5 mmol) was added over 5 min. After 4 h the mixture was concentrated in vacuo and the oily residue was treated with 1 N KOH (10 mL). The solution was filtered through a paper filter. The liquid was collected, cooled to 0 °C and 5 N HCl was added dropwise till a white precipitate was formed. The solid obtained was filtered and dried. After re-crystallization from ethanol/petroleum ether the product was obtained in quite good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-[1-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrol-3-yl]acetic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In tetrahydrofuran at 20℃; for 1h; Stage #2: serin In tetrahydrofuran for 4h; | 7 4.1.6. General procedure for the preparation of 1,5-diarylpyrrole-3-acetic amides (2a-d, 5a-d) General procedure: PyBOP (0.93 mmol) and triethylamine (3 mmol) were added in sequence to a solution of 7a,b (0.78 mmol) in THF (20 mL) at rt and the mixture stirred for 1 h. Then the amino acid (10a,b, 11a-b) (1.5 mmol) was added over 5 min. After 4 h the mixture was concentrated in vacuo and the oily residue was treated with 1 N KOH (10 mL). The solution was filtered through a paper filter. The liquid was collected, cooled to 0 °C and 5 N HCl was added dropwise till a white precipitate was formed. The solid obtained was filtered and dried. After re-crystallization from ethanol/petroleum ether the product was obtained in quite good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: serin With nitric acid In dichloromethane at 0℃; for 0.833333h; Stage #2: With acetic anhydride In 1,4-dioxane for 0.75h; | 23 4.1.22. General procedure for the preparation of nitro-oxyalkyl amines (9a,b) and amino acids (11a,b) General procedure: Fuming nitric acid (3 mL) was added to dichloromethane in a 100 mL round-bottomed flask. The solution was allowed to reach 0 °C and then hydroxyalkylamine (8a-b) (or amino acid 10a-b) (16 mmol) was added dropwise. After 50 min of stirring, acetic anhydride (2 mL) was added dropwise over 2 min. After 45 min a precipitate was formed and then filtered. The solid was then crystallized with hot chloroform/ethanol to give the product as nitrate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 3-acetylindole With iodine; dimethyl sulfoxide at 110℃; for 0.75h; Stage #2: serin at 110℃; for 0.25h; | 11 General procedure: A mixture of 1-(1H-indol-3-yl)ethanone1(0.5mmol), I2(1.0mmol) in DMSO (3.0mL) was stirred at 110°C for 45min till almost full conversion of the substrates was indicated by TLC analysis, then added 2-aminobutanoic acid2b(1.0mmol) and stirred at 110°C for 15min. Then added 50mL water and 30mL saturated brine solution to the mixture and extracted with EtOAc three times (3×50mL). The extract was washed with 10% Na2S2O3solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc=4:1) to afford the product3bas a yellow solid. 4.3.2 2-Ethyl-5-(1H-indol-3-yl)oxazole (3b pimprinethine) 4.3.11 (5-(1H-Indol-3-yl)oxazol-2-yl)methanol (3k) Yield 73%; yellow solid; mp=189-190 °C; IR (KBr): 3440, 1637, 1427, 1386, 1115, 1079 cm-1. 1H NMR (600 MHz, DMSO-d6) δ (ppm) 11.55 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.35 (s, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.2 Hz, 1H), 5.66 (t, J=6.6 Hz, 1H), 4.53 (d, J=6.0 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ (ppm) 160.92, 147.97, 136.42, 123.64, 123.32, 122.22, 120.17, 119.58, 119.16, 103.82, 56.03. HRMS (ESI): m/z [M+H]+ calcd for C12H11N2O2: 215.0815; found: 215.0813. |
Yield | Reaction Conditions | Operation in experiment |
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55% | With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction; | General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35°C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With Novozym 435 lipase on resin In acetone at 35℃; for 8h; Green chemistry; Enzymatic reaction; | General procedure: A representative synthetic procedure is given hereafter: To 500mg (1.5mmol) of DPA ethyl ester as an oil were added 100mg of Novozym 435 lipase on resin and 5 equiv (7.5mmol) of serinol. A minimum amount of acetone was then added to decrease viscosity (1mL). The mixture was magnetically stirred for 4-18h at 35°C until TLC indicated complete disappearance of the ethyl ester (to be noted, LC-MS methods with UV detection are not useful to follow these reactions owing to the very low absorbance of the chromophores). The reaction was then filtered, acetone was evaporated then water added. The mixture was extracted with a minimal amount of diethyl ether (1mL) thrice. The organic phase was dried with magnesium sulfate, filtered then evaporated under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate to give the desired amide 25 as a colorless oil in 60% yield (>90% purity by 1H NMR). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In water; at 20℃; for 6h; | The DL-SeriniumHSq was synthesized using the following procedure:0.315 g (3 mmol) of DL-Serine and 0.456 g (3 mmol) of H2Sqwere dissolved in 45 ml of water. The mixture was stirred continuouslyat room temperature for 6 h. After the complete dissolutionof the <strong>[2892-51-5]squaric acid</strong> the reaction mixture was set aside to crystallize.The product was purified by multiple recrystallizations fromdistilled water. The yield of the product was 81%. Crystals suitablefor X-ray diffraction were grown by slow evaporation from amixture of methanol-water (1:3 v/v). After several weeks, colourlesscrystals are isolated, filtered and dried at room temperature.The most intensive signal in the positive ESI mass spectrum ofcompound studied is the peak at m/z, corresponding to the singlycharged cation [C3H9NO2] with a molecular weight of 88.20. TGAanalysis in the range 350e500 K showed an absence of the solventmolecules in the crystal structure. |
Yield | Reaction Conditions | Operation in experiment |
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48.9% | Stage #1: formaldehyd; serin With sodium hydrogencarbonate In water at 20℃; for 2h; Stage #2: curcumin In methanol; water at 20℃; for 2h; | 11 Preparation of curcumin-serine conjugate Take 0.95 [(9.1111111101) serine and 0.76] sodium bicarbonate (9.1111111101), dissolved in 6111] ^ deionized water, A 1.5 mL formaldehyde aqueous solution (37%, 18.0 mmol) was added and the reaction was stirred at room temperature for 2 hours, The reaction solution was diluted with 50 mL of methanol, and then 1.1 lg (3. Ommol) of curcumin was added, The reaction was stirred at room temperature for 2 hours, and the TLC was monitored until the curcumin reacted completely Add the appropriate amount of 0.5M dilute hydrochloric acid and sodium bicarbonate, the reaction product was separated by silica gel column chromatography, dichloromethane / methanol / glacial acetic acid Mixed solvent to obtain curcumin - serine conjugate 1.13g, yield 48.9% (synthetic route shown in Figure 20). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate In 1,4-dioxane; water at 20℃; for 1h; Cooling with ice; | N-(9-Fluorenylmethoxycarbonyl)-L-serine (10) To a solution of L-serine (3) (103 mg, 0.98 mmol) in aqueous10% sodium carbonate (3 mL) cooled on an ice bath was slowly added a solution of 9-fluorenylmethoxycarbonyl chloride (245 mg, 0.95 mmol) in 1,4-dioxane (3 mL). After stirring for 1 h at rt, themixture was washed with EtOAc to remove byproducts, added with 1M HCl, and extracted with EtOAc. Theorganic layer was washed with brine, dried over MgSO4, and evaporated to give 10 as a white solid (284 mg,88%). The spectral data of 10 were identical to the literature.33 The purity was confirmed by 1H NMR. | |
Stage #1: serin With sodium carbonate In 1,4-dioxane; water Cooling with ice; Stage #2: (fluorenylmethoxy)carbonyl chloride In 1,4-dioxane; water at 20℃; for 5h; | General procedure: The N-FMOC derivatizedracemic and L-amino acids and methyl esters were preparedaccording to conventional methods.22 Racemic or L-α-amino acid (5 mmol) was dissolved in 10% aqueoussodium carbonate solution (12.5 mmol). Dioxane (7.5 mL)was then added and the mixture was stirred in an ice-bath.After that, 9-FMOC chloride (5 mmol) was added slowlyand stirred at room temperature for 5 h. Now, the reactionmixture was poured into water and extracted with ether.The aqueous solution obtained was acidified with c-HCl inan ice-bath. Finally, the resulting N-FMOC α-amino acidwas filtered and dried under vacuum. In order to prepareracemic or L-FMOC α-amino acid methyl ester, the correspondingFMOC α-amino acid (1 mmol) synthesized in theprevious step was dissolved in 5 mL of anhydrous methanolwith N,N0-dicyclohexylcarbodiimide (1.1 mmol). Themixture was stirred at room temperature for 12 h, filteredand dried under vacuum to get N-FMOC α-amino acidmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
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43% | Stage #1: serin; nickel(II) acetate tetrahydrate In water at 25℃; for 0.5h; Stage #2: 2-Picolinic acid With sodium hydroxide In water at 25℃; for 0.5h; | System Ni(II)-Hpic-Ser Nickel acetate tetrahydrate (252.1mg; 1.01mmol) and serine (106.1mg; 1.01mmol) were dissolved in water (5mL) and the mixture was magnetically stirred for 30min. Picolinic acid (124.3mg; 1.01mmol) was added to the previous solution, upon which the green solution turned light blue. A solution of NaOH (5%) was added dropwise, to adjust the pH of the Ni(II)-Hpic-ser system to approximately 5.7, thus observing the precipitation of a light blue solid. The mixture was stirred for 30min. The solid was filtered off, washed with cold water (3 portions of 2mL each), acetone (5mL) and diethyl ether (5mL), and dried on air. Characterization was performed on this solid. The mother liquor was reserved on a Petri dish, to allow for the slow crystallization of the compound. After a few days, dark blue rectangular crystals were obtained. Yield of the solid: 122.5mg, 43%. Anal. Calc. for C9H10N2NiO5·C2H4O2·2H2O: C, 34.68; H, 4.76; N, 7.35. Found: C, 33.68; H, 4.62; N, 7.46. 1H NMR (300.2MHz, D2O, 25°C): δ [ppm]=54.48 (br), 46.01 (br), 41.98 (br), 34.35 (br), 20.33 (br), 15.99 (br), 2.53 (br, acetic acid solvate). IR (KBr disk, ν in cm-1): 3166 br, 1701m, 1636s, 1597s, 1570s, 1481m, 1447m, 1378s, 1300m, 1247m, 1052m, 1026m, 862 w, 767s, 705s, 647m, 451m. UV-Vis (DMSO, λmax in nm): 619, ε=5.95Lmol-1cm-1. |
Yield | Reaction Conditions | Operation in experiment |
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84% | Stage #1: serin With sodium hydroxide In water Stage #2: nickel(II) chloride hexahydrate In water at 25℃; for 1h; | Binary Systems Ni(II)-L2 (L = pic, ser, phe) General procedure: Nickel chloride hexahydrate (594.2 mg; 2.00 mmol) was dissolved in water (5 mL). Accordingly, picolinic acid (492.4 mg, 4.00 mol), serine (420.4 mg, 4.00 mmol) or phenylalanine (660.8 mg; 4.00 mmol) were treated with NaOH (4.00 mL from stock solution 1.0 M, 4.00 mmol) in water (6 mL). The ligand basic solution was added to the nickel precursor. The mixture was stirred at room temperature for one hour. For Ni(pic)2 and Ni(phe)2 a pale blue precipitate was formed within minutes. The solid was filtrated and washed with cold water (3 portions of 4 mL each) and acetone (3 portions of 4 mL each). For Ni(ser)2 a deep blue solution was obtained and it was placed on a Petri dish, to allow for the slow crystallization of the compound. After a few days, dark blue rectangular crystals were obtained. The crystals were filtrated and washed with cold water (3 portions of 4 mL each) and acetone (3 portions of 4 mL each). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: serin With potassium carbonate In water at 20℃; for 1h; Stage #2: 4-chloro-benzoyl chloride In tetrahydrofuran; water at 20℃; for 1.5h; | 78-1 (78-1) (78-1) Synthesis of 2-[(4-chlorophenyl)formamide]-3-hydroxypropionic acid (Compound 78-1) Water (100 mL) was added to DL-serine (10g, 95 mmol) and potassium carbonate (13.2 g, 95 mmol), and the mixture was stirred at room temperature for 1 hour, then a THF (20 mL) solution of 4-chlorobenzoyl chloride (12.2 mL, 95 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, the aqueous layer was acidified with concentrated hydrochloric acid, and stirred at 0 °C to precipitate crystals. The obtained crystals were collected by filtration and washed with water to obtain the title compound (15.4 g, yield 67%). Ms m/z (APCI) [M+H]+ = 244. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.4% | With methylamine In water at 150℃; for 10h; Autoclave; Inert atmosphere; | 4 Example 4: Preparation of 2-amino-3-hydroxypropionic acid A 2-L autoclave was charged with 86 g (1 mol) of 2-amino-3-hydroxypropionitrile, and 620 g of a 40% strength aqueous methylamine solution was added thereto.Water 1068g was added, nitrogen gas was charged to 3MPa, and the mixture was heated to 150°C for 10 hours. The reaction solution was concentrated under reduced pressure to recover a methylamine aqueous solution.Distillation residue was added 400g methanol 80 ° C reflux 2h, cooling, crystal precipitation, filtration, vacuum drying 120 ° C 4h 2-amino-3-hydroxypropionic acid, purity 98%, yield 89.4%. |
87.9% | Stage #1: 2-amino-3-hydroxypropionitrile With calcium hydroxide; ammonia In water at 180 - 190℃; for 4h; Stage #2: With ammonium bicarbonate In water at 40 - 50℃; for 1h; | 6 Example 6: Synthesis of 2-amino-3-hydroxypropionic acid Into a 1L autoclave was added 86 g (1 mol) of 2-amino-3-hydroxypropionitrile, 136 g of 25% aqueous ammonia and 110 g of calcium hydroxide (1?5 mol), 3 g of triethylbenzylammonium sulfate, 500 g of water, and heated to 180_190. °C, pressure 2 • 5 ~ 3 • OMPa, reaction 4h, dropped to 40-50 °C, ammonium bicarbonate was added 118g (1.5mol), stirred lh, filtered, the mother liquor was concentrated under reduced pressure, the residue was added 150g methanol reflux 2h , cooling, crystal precipitation. After filtration and drying at 120° C. for 4 h, 92.3 g of 2-amino-3-hydroxypropionic acid was obtained with a purity of 96% and a yield of 87.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.23% | With triethylamine In water; acetonitrile at 20℃; for 24h; | 12 General method for synthesis of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) General procedure: A solution of N-acylbenzotriazole derivative (5, 0.005 mol) and the appropriate amino acid (0.005 mol) in acetonitrile/water mixture (3:1) containing triethylamine (0.0075 mol) was stirred at room temperature for 24h, then acetonitrile was evaporated under reduced pressure and the residual water solution was then acidified with 1N HCl to pH∼5 and the resultant precipitate was then filtered, dried and crystalized from methanol to give the titled compounds (6 a-m and 7) in 32.18-78.47% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NAD In aq. buffer at 37℃; Enzymatic reaction; | 2.6 Cascade Enzyme Reactions General procedure: Enzyme reactions were carried out at 37 °C in water bath without stirring. Reaction volume was 0.2 mL and the reactions were carried out in 50 mM Tris buffer (pH 7.0). 10-μLaliquots of the reaction mixture were taken at predetermined reaction times and diluted five fold with water, followed by addition of 10 μL of 5 N HCl to stop the reaction. The resulting mixture was centrifuged at 13,000 rpm for 15 min andthen the supernatant was used for quantitative chiral HPLC analysis of amino acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In methanol at 30℃; for 28h; diastereoselective reaction; | 3.26 General procedure for synthesis of pyrrolidinyldispirooxindole 44.3.1 General procedure: Isatin (1, 0.20mmol, 1 equiv.), amino acid (2, 0.40 mmol, 2 equiv.), methyleneindolinone (3, 0.2mmol, 1 equiv.) and MeOH (0.2 mL or 1 mL) were well mixed and stirred at 30°C. Once the reaction was completed (monitored by TLC), the resulting residue was purified by flash column chromatography on silica gel to yield the corresponding product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate In water at 70 - 80℃; for 1h; | 2-[({4-[(2,4-Dioxo-1,3-thiazolidin-5-ylidene)methyl] phenyl} sulfonyl) amino] alkanoic acidanalogus (3a to 3h) General procedure: An aqueous sodium carbonate solution (10 ml,1.2 mmol) was added drop wise to the stirred solution of amino acid (1 mmol). Compound 2 was added (0.3g,1 mmol) to the above mixture, stirred vigorously and the reaction mixture was heated at 70-80° for 1-2 hr. The resulting solution was allowed to cool and the pH was brought to 2.5 by adding hydrochloric acid under stirring. The product was separated by filtration and washed with cold water. The progress and completion of the reaction was monitored by TLC. The analytical parameters were recorded in Table-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.2% | Stage #1: serin; C26H24O5 With acetic acid In methanol; dichloromethane at 10 - 30℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 12h; | Synthesis of compound 56 Embodiment 56 (E)-2-(4-(3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylstyryl)-2,6-dimet hoxybenzylamino)-3-hydroxypropanoic acid 56 Synthetic route Synthesis of compound 56 Compound 15-a (150mg, 0.47mmol) and 2-amino-3-hydroxypropionic acid (76mg, 0.72mmol) were dissolved in a mixed solvent of methanol (15mL) and dichloromethane (15mL), followed by addition of glacial acetic acid (0.04mL, 0.72mmol). The reaction solution was stirred at room temperature for 2 hours. Then sodium cyanoborohydride (38mg, 0.6mmol) was added and the resulting mixture was stirred for another 12 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 22%-55%) to give compound 56 as a white solid (79mg, yield 33.2%). LC-MS (ESI): m/z = 504 [M-H]+. 1H NMR (400 MHz, DMSO-d6) δ: 7.62-7.57 (m, 2H), 7.27- 7.24 (t, J=6 Hz, 1H), 7.11-7.08 (m, 2H), 6.99 (s, 2H), 6.93-6.91 (d, J=6.8 Hz, 1H), 6.79-6.75 (m, 2H), 4.29 (s, 4H), 4.17-4.08 (m, 2H), 3.87 (s, 6H), 3.78-3.75 (m, 1H), 3.61-3.57 (m, 1H), 3.13-3.10 (m, 1H), 2.30 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.2% | Stage #1: serin; C25H24O4 With acetic acid In methanol; dichloromethane at 10 - 30℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane at 10 - 30℃; for 12h; | Synthesis of compound 48 Synthesis of compound 48 Compound 48-a (170mg, 0.44mmol) and 2-amino-3-hydroxypropionic acid (104mg, 0.88mmol) were dissolved in a mixed solvent of methanol (15mL) and dichloromethane (15mL), followed by addition of glacial acetic acid (0.05mL, 0.88mmol). The reaction solution was stirred at room temperature for 2 hours, followed by addition of sodium cyanoborohydride (110mg, 1.75mmol), and the resulting mixture was stirred for another 12 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 25%-55% (the initial mobile phase was 25% water and 75% acetonitrile, and the final mobile phase was 55% water and 45% acetonitrile, where % refers to percent of volume)) to give compound 48 as a white solid (20mg, yield 9.2%). LC-MS (ESI): m/z = 476 [M-H]+. 1H NMR (400 MHz, DMSO-d6) δ: 7.66-7.62 (m, 2H), 7.31-7.27 (m, 3H), 7.14-7.13 (m, 2H), 7.05-7.03 (m, 4H), 4.06 (s, 2H), 3.87 (s, 6H), 3.79 (s, 3H), 3.65-3.63 (d, J = 8.8 Hz, 1H), 3.54-3.52 (d, J = 8.8 Hz, 1H), 2.29 (s, 3H), 1.26 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: serin; C25H22N2O3 With acetic acid In methanol; dichloromethane at 10 - 30℃; for 6h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane at 10 - 30℃; for 12h; | Synthesis of compound 60 Synthesis of compound 60 Compound 60-a (90mg, 0.22mmol) and 2-amino-3-hydroxypropionic acid (42mg, 0.68mmol) were dissolved in a mixed solvent of methanol (7mL) and dichloromethane (7mL), followed by addition of two drops of glacial acetic acid. The reaction solution was stirred at room temperature for 6 hours, followed by addition of sodium cyanoborohydride (43mg, 0.68mmol), and the resulting mixture was stirred for another 12 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 25%-55%) to give compound 60 as a white solid (18mg, yield 16%). LC-MS (ESI): m/z = 486 [M-H]+. 1H NMR: (400 MHz, CD3OD) δ: 8.58 (s, 1H), 7.93 (s, 1H), 7.47-7.42 (m, 3H), 7.39-7.34 (m, 3H), 7.30 (t, J = 6.4, 1H), 7.26 (s, 2H), 7.20 (d, J = 6.4, 1H), 4.46-4.39 (q, 2H), 4.03 (s, 6H), 4.02-4.00 (m, 1H), 3.87-3.83 (dd, J1 = 6.0, J2 = 9.6, 1H), 3.56-3.54 (m, 1H), 2.31 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.3% | Stage #1: serin; C24H21NO3 With acetic acid In methanol; dichloromethane at 10 - 30℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane at 10 - 30℃; for 12h; | Synthesis of compound 69 Synthesis of compound 69 Compound 69-a (220mg, 0.59mmol) and serine (125mg, 1.18mmol) were dissolved in a mixed solvent of methanol (15mL) and dichloromethane (15mL), followed by addition of glacial acetic acid (0.07mL, 1.18mmol). The reaction solution was stirred at room temperature for 2 hours, followed by addition of sodium cyanoborohydride (91mg, 1.4mmol), and the resulting mixture was stirred for another 12 hours. The reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (50mL) and water (50mL). The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 15%-65% (the initial mobile phase was 15% water and 85% acetonitrile, and the final mobile phase was 65% water and 35% acetonitrile, where % refers to percent of volume)) to give compound 69 as a white solid (31mg, yield 11.3%). LC-MS (ESI): m/z = 461 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.43 (s, 1H), 8.07-8.04 (d, J=12 Hz, 1H), 7.75-7.74 (d, J=6 Hz, 1H), 7.64 (s, 1H), 7.33-7.25 (m, 2H), 7.14-7.13 (m, 1H), 6.92-6.91 (m, 1H), 6.77-6.75 (m, 2H), 4.28 (s, 4H), 3.99-3.96 (d, J=10.8Hz, 1H), 3.89-3.86 (d, J=10.8Hz, 1H), 3.70-3.67 (m, 1H), 3.64-3.61 (m, 1H), 3.18-3.16 (t, J=4.4 Hz, 1H), 2.44 (s, 3H), 2.28 (s,3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | Stage #1: serin With sodium hydroxide In water at 61.5℃; for 1.25h; Stage #2: chloroacetic acid In water at 62 - 65℃; for 2.5h; Stage #3: With potassium iodide In water at 92℃; for 5.5h; | 11 Example 11 Preparation method of N,N-bis(carboxymethyl)serine trisodium salt Into a 1000 mL three-necked flask, 260.0 g of deionized water was added in sequence.105.0g of serine, magnetic stirring was started, and the pH was adjusted to 9.3-9.8 by adding lye (m/m=50.0%).After stirring at this temperature for 1.0 h, the temperature was raised to 61.5 ° C, and the remaining aqueous sodium hydroxide solution (m/m = 50.0%) was added dropwise.After 15 minutes, 283.5 g of aqueous chloroacetic acid (m/m = 70.0%) was added dropwise, maintaining the temperature at 62.0-65.0 °C, and the addition was completed in about 2.5 h. 0.2 g of potassium iodide was added, and stirring was continued at this temperature for 4.0 h.Then, the temperature is raised to 92.0 ° C for the incubation reaction for 1.5 h, and after the reaction is finished, the temperature is lowered to room temperature.Filtration, the filtrate is a N,N-bis(carboxymethyl)serine trisodium salt solution.After testing, the content of N,N-bis(carboxymethyl)serine trisodium salt in the obtained mixture was 26.0%.The yield was 96.9% (calculated as serine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.6% | With triethylamine In ethanol at 25℃; for 72h; Darkness; | 1.2 Preparation of Linoleyl Serine (Compound 15, named NIS) Take the obtained intermediate A1 and dissolve it in 45mL of 65% ethanol, and add 3mL (21.52mmol)Triethylamine, then add 0.896g (8.53mmol) serine, and stir at 25 ° C in the dark for 72h;After the reaction was completed, the mixture was evaporated under reduced pressure to remove a large amount of ethanol.Add an appropriate amount of distilled water to the concentrate, adjust the pH = 2 with concentrated HCl, add an appropriate amount of ethyl acetate, and take the upper ethyl acetate layer.Dry over anhydrous sodium sulfate and concentrate. Silica gel column chromatography,The mobile phase was eluted with dichloromethane / methanol (10/1).1.30 g of light yellow oily product was obtained with a yield of 50.60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic anhydride; acetic acid at 75℃; for 12h; Inert atmosphere; | 1.1 (1) Synthesis of 2-amino-3-(4-methyl-1H-indol-3-yl)propionic acid Under the protection of nitrogen, dissolve 4-methyl-1H-indole (1.3g, 10.0mmol), DL-serine (1.1g, 10.0mmol), and acetic anhydride (3mL, 30.0mmol) in 50mL of glacial acetic acid. Heat and stir at 75°C for 12h, then remove the solvent in the reaction solution, add the resulting residue to 10% sodium hydroxide solution (20mL), then heat to 60°C, after 6h, cool in ice bath, adjust pH=5 with acetic acid, and extract with ethyl acetate , Dry with anhydrous magnesium sulfate. Spin off most of the solvent, and purify by silica gel column chromatography, using dichloromethane/methanol (V/V=20/1)Elution gave 2-amino-3-(4-methyl-1H-indol-3-yl)propionic acid (1.9 g), yield: 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.8% | Stage #1: serin; C25H19F3O3 With acetic acid In methanol; dichloromethane at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 12h; | 1 Synthesis of compound 1 Compound 1-a (200 mg, 0.40 mmol) and serine (99 mg, 0.94 mmol) were dissolved in a mixed solution of methanol (15 mL) and dichloromethane (15 mL), and glacial acetic acid (0.05 mL, 0.94 mmol) was added. After the reaction solution was stirred at room temperature for 2 hours, sodium cyanoborohydride (119 mg, 1.89 mmol) was added and stirring was continued for 12 hours.The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL), and then washed with water (20 mL) and saturated brine (20 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Phase chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 15%-65% (the initial mobile phase is 15% water-85% acetonitrile, at the end the mobile phase is 65% water-35% acetonitrile) , Where% refers to volume percentage)) after purification to obtain compound 1 (12 mg, yield: 5.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | Stage #1: serin; C24H19FO3 With acetic acid In methanol; dichloromethane at 20℃; for 6h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 18h; | 12 Synthesis of compound 12 At room temperature, add glacial acetic acid (0.04mL, 0.65mmol) to a mixed solution of 12-a (140mg, 0.37mmol) and serine (77.7mg, 0.74mmol) in methanol (5mL) and dichloromethane (5mL), The reaction solution was stirred at room temperature for 6 hours. Then, sodium cyanoborohydride (70 mg, 1.1 mmol) was added and stirred for 18 hours.Concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 30%-60% (the initial mobile phase was 30% water-70% acetonitrile), and flow at the end The phase is 60% water-40% acetonitrile, where% refers to volume percentage)) after purification to obtain compound 12 (18 mg, yield: 11%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: serin; C23H15F5O With acetic acid In methanol; dichloromethane at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 12h; | 15 Synthesis of compound 15 At room temperature, add glacial acetic acid (0.04mL, 0.65mmol) to the mixed solution of 15-a (120mg, 0.3mmol) and serine (63mg, 0.6mmol) in methanol (10mL) and dichloromethane (10mL). The solution was stirred at room temperature for 2 hours.Then, sodium cyanoborohydride (56.7 mg, 0.9 mmol) was added and stirred for 12 hours. Concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 40%-70% (initial mobile phase was 40% water-60% acetonitrile, flow at the end) The phase is 70% water-30% acetonitrile, where% refers to volume percentage)) after purification to obtain compound 15 (26 mg, yield: 18%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.8% | Stage #1: serin; C23H19F3O With acetic acid In methanol; dichloromethane at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 16h; | 18 Synthesis of compound 18 At room temperature, add glacial acetic acid (0.03mL, 0.54mmol) to a mixed solution of 18-a (100mg, 0.27mmol) and serine (57mg, 0.54mmol) in methanol (10mL) and dichloromethane (10mL). The solution was stirred at room temperature for 2 hours. Then, sodium cyanoborohydride (68 mg, 1.08 mmol) was added and stirred for 16 hours.Concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (mobile phase: water (10mM ammonium bicarbonate), acetonitrile; gradient: 40%-70% (initial mobile phase was 40% water-60% acetonitrile), flow at the end The phase is 70% water-30% acetonitrile, where% refers to volume percentage)) after purification to obtain compound 18 (17 mg, yield: 13.8%). |
13.8% | Stage #1: serin; C23H19F3O With acetic acid In methanol; dichloromethane at 10 - 30℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 16h; | 18 Synthesis of compound 18 To a mixed solution of 18-a (100 mg, 0.27 mmol) and serine (57 mg, 0.54 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added acetic acid (0.03 mL, 0.54 mmol) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Then, to the reaction solution was added sodium cyanoborohydride (68 mg, 1.08 mmol) and was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 40% to 70% (the initial mobile phase was 40% water and 60% acetonitrile, and the final mobile phase is 70% water and 30% acetonitrile, wherein, % refers to volume percentage) to obtain compound 18 (17 mg, yield: 13.8%). LC-MS (ESI): m/z = 456 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium carbonate; copper(II) sulfate In water for 2h; Reflux; | 19 Synthesis of compound 19-a To a 500 ml reaction flask were added serine (2.95 g, 28 mmol), anhydrous copper sulfate (0.96 g, 6 mmol), sodium carbonate (11.9 g, 112 mmol), 37% aqueous formaldehyde solution (20 mL) and 400 ml water.The mixture was heated to reflux for 2 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in an appropriate amount of water. After adjusting the pH to 3 with 4M hydrochloric acid, the aqueous solution was purified on a Dowex-50X ion exchange column (6.0cm×40cm). ,200400 mesh, hydrogen type). Rinse with water first, after the pH of the effluent turns from acidic to neutral, rinse with 250 ml of water fully, then elute the product with 2M ammonia water, and detect with ninhydrin color reagent.The effluent that developed to ninhydrin was collected and concentrated under reduced pressure. The residue was added with absolute ethanol (10 mL) and stirred vigorously, filtered, and the filter cake was vacuum dried to obtain α-(hydroxymethyl)serine (2.2 g, yield: 58%). |
58% | With sodium carbonate; copper(II) sulfate In water for 2h; Reflux; | 19 Synthesis of compound 19-a (E)-2-(3-(2-(2-methylbiphenyl-3-yl)vinyl)-4-(trifluoromethyl)benzylamino)-3-hydroxy-2-hydroxymethylpropanoic acid (compound 19) Synthesis route: Synthesis of compound 19-a To a 500 mL reaction flask were added serine (2.95 g, 28 mmol), anhydrous copper sulfate (0.96 g, 6 mmol), sodium carbonate (11.9 g, 112 mmol), 37% aqueous formaldehyde (20 mL) and 400 mL of water. The mixture was heated to reflux for 2 hours, cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with an appropriate amount of water. After the pH of the aqueous solution was adjusted to 3 with 4 M hydrochloric acid, the aqueous solution was purified on a Dowex-50X ion exchange column (6.0 cm * 40 cm, 200 ∼ 400 mesh, hydrogen type). The ion exchange column was first rinsed with water, and rinsed with 250 mL of water after the pH value of the effluent was changed from acidic to neutral, and then the product was eluted with 2M ammonia and detected with ninhydrin chromogenic agent. The effluent which was colored on ninhydrin was collected and concentrated under reduced pressure. To the residue was added anhydrous ethanol (10 mL) and stirred vigorously, filtered, and the filter cake was dried in vacuum to obtain α-(hydroxymethyl) serine (2.2 g, yield: 58%). 1H NMR (500 MHz, CD3OD) δ: 3.90 (d, J = 14.0 Hz, 2H), 3.76 (d, J = 14.0 Hz, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: serin; C23H15F5O With acetic acid In methanol; dichloromethane at 10 - 30℃; for 2h; Stage #2: With sodium cyanoborohydride In methanol; dichloromethane for 12h; | 15 Synthesis of compound 15 To a mixed solution of 15-a (120 mg, 0.3 mmol) and serine (63 mg, 0.6 mmol) in methanol (10 mL) and dichloromethane (10 mL) was added acetic acid (0.04 mL, 0.65 mmol) at room temperature, and the reaction solution was stirred at room temperature for 2 hours. Then, to the reaction solution was added sodium cyanoborohydride (56.7 mg, 0.9 mmol) and was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (mobile phase: water (10 mM ammonium bicarbonate), acetonitrile; gradient: 40% to 70% (the initial mobile phase was 40% water and 60% acetonitrile, and the final mobile phase was 70% water and 30% acetonitrile, wherein % refers to volume percentage)) to obtain compound 15 (26 mg, yield: 18%). LC-MS (ESI): m/z = 492 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In dichloromethane at 20℃; for 27h; Cooling with ice; | 4.1.5. Synthetic routes for compounds 11-21 General procedure: A dichloromethane solution of compound 4 (1mmol, 50 ml) was drop wisely added to a cold and stirred dichloromethane solution (50 ml) of free amino acid (1mmol, obtained by the addition of two equivalents amount of triethylamine (2mmol) to the amino acid to a stirred and cold dichloromethane, 50 ml) in ice bath. The obtained mixture was additionally stirred for extra 3 h in ice bath, then for 24 h at room temperature, washed with distilled water, 1N sodium bicarbonate, 1N potassium hydrogen sulphate and dis- tilled water then dried for (24 h at 0 °C) over sodium sulphate an- hydrous. The volatile materials were evaporated till drought then triturated with petroleum ether (B.P. = 40-60 °C) to get residual material. The obtained precipitate was collected, and then recrys- tallized from methanol to gain the compounds 11-21 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Stage #1: serin; 3,3‴-dimethoxy-2′,2″-dimethyl[1,1':3′,1'':3″,1‴-quaterphenyl]-4,4‴-dicarbaldehyde In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: With sodium cyanoborohydride; acetic acid In N,N-dimethyl-formamide at 20℃; | General procedure D General procedure: (for the synthesis of compounds A1-A5, A7-A9, B1, B7-B12, 36, 37, 39 and C3-C15) To a flask was added benzaldehydes (0.119mmol), amines (0.659mmol) and DMF (6mL). The reaction was stirred for 1h at room temperature. Then sodium cyanoborohydride (41mg, 0.659mmol) and acetic acid (41μL, 0.6mmol) were added and the reaction was stirred at room temperature overnight. After it was fully reacted, the mixture was diluted with water (50mL) and extracted with ethyl acetate (50mL×3), washed by saturated brine (25mL×2) and dried over anhydrous sodium sulfate. After solvent removal, the crude product was purified by column chromatography to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In water; acetone | 4.1. General Procedure General procedure: A four-dram vial was charged with palladium(II) acetate and 3.0 mL of 50/50 (v/v)acetone/water. The mixture was stirred until completely dissolved. To this was added theappropriate amino acid and left to stir overnight. All reaction solutions turned from a darkred orange to a clear yellow with a pale yellow-white precipitate on overnight stirring. Anodor of acetic acid was noted when the vial was opened. The supernatant was transferredvia pipette to a clean vial and allowed to evaporate to give clear yellow needles sometimessuitable for X-ray crystallography. The pale-yellow precipitate was washed with cold waterand dried under vacuum. The original reaction precipitate and the material obtainedfrom evaporation were combined and weighed to determine a final yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In ethanol for 9h; Reflux; | General method: General procedure: The Schiff bases 3-20 were synthesized by the condensation of a carbonyl compound(3-(4-acetylphenyl)-2-phenylquinazolin-4(3H)-one and/or indol-3-carboxaldehyde) (1 mmol) and derivatives of amino acids (1 mmol) after stirringfor 30 min with Et3N dissolved in dry ethanol (10 mL). The resulting reaction mixturewas stirred and refluxed for 9 h (TLC control) and then allowed to cool overnight. Theprecipitated Schiff bases were filtered, washed with cold ethanol several times, anddried at room temperature. The solid products were then recrystallized with ethanol[31]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine In ethanol for 9h; Reflux; | General method: General procedure: The Schiff bases 3-20 were synthesized by the condensation of a carbonyl compound(3-(4-acetylphenyl)-2-phenylquinazolin-4(3H)-one and/or indol-3-carboxaldehyde) (1 mmol) and derivatives of amino acids (1 mmol) after stirringfor 30 min with Et3N dissolved in dry ethanol (10 mL). The resulting reaction mixturewas stirred and refluxed for 9 h (TLC control) and then allowed to cool overnight. Theprecipitated Schiff bases were filtered, washed with cold ethanol several times, anddried at room temperature. The solid products were then recrystallized with ethanol[31]. |
[ 6003-05-0 ]
(S)-2-Aminopropanoic acid hydrochloride
Similarity: 0.88
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