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CAS No. : | 3262-72-4 | MDL No. : | MFCD00037243 |
Formula : | C8H15NO5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FHOAKXBXYSJBGX-YFKPBYRVSA-N |
M.W : | 205.21 | Pubchem ID : | 98766 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 48.02 |
TPSA : | 95.86 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) : | -7.64 cm/s |
Log Po/w (iLOGP) : | 1.5 |
Log Po/w (XLOGP3) : | -0.13 |
Log Po/w (WLOGP) : | -0.04 |
Log Po/w (MLOGP) : | -0.3 |
Log Po/w (SILICOS-IT) : | -0.69 |
Consensus Log Po/w : | 0.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.63 |
Solubility : | 47.6 mg/ml ; 0.232 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.43 |
Solubility : | 7.64 mg/ml ; 0.0372 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.09 |
Solubility : | 167.0 mg/ml ; 0.813 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.7 |
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 |
---|---|---|
80% | With NaH In water; ethyl acetate; N,N-dimethyl-formamide; mineral oil | Example 36 N-tert-Butoxycarbonyl-O-benzyl-L-serine 39: To a solution of Boc-L-serine (15 g, 73.09 mmol) in DMF (300 mL) at 0° C. was added NaH (6.43 g, 160.80 mmol, 60percent in mineral oil) and stirred for 1.5 h at 0° C. After the addition of benzyl bromide (13.75 g, 80.40 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in H2O. The crude product was partitioned between H2O and Et2O. The aqueous phase was acidified to pH<4 with 3 N HCl and extracted with EtOAc three times. The combined EtOAc solution was washed with H2O, dried with Na2SO4, filtered, and concentrated to give the N-tert-butoxycarbonyl-O-benzyl-L-serine (17.27 g, 80percent). |
80% | With NaH In water; ethyl acetate; N,N-dimethyl-formamide; mineral oil | Example H36 N-tert-Butoxycarbonyl-O-benzyl-L-serine 39: To a solution of Boc-L-serine (15 g, 73.09 mmol) in DMF (300 mL) at 0° C. was added NaH (6.43 g, 160.80 mmol, 60percent in mineral oil) and stirred for 1.5 h at 0° C. After the addition of benzyl bromide (13.75 g, 80.40 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in H2O. The crude product was partitioned between H2O and Et2O. The aqueous phase was acidified to pH<4 with 3 N HCl and extracted with EtOAc three times. The combined EtOAc solution was washed with H2O, dried with Na2SO4, filtered, and concentrated to give the N-tert-butoxycarbonyl-O-benzyl-L-serine (17.27 g, 80percent). |
75% | Stage #1: With sodium hydride In N,N-dimethyl-formamide at -15℃; for 2 h; Stage #2: at -15 - 20℃; |
To a stirring solution of 2S-Z (50 g, 245 mmol) in DMF (650 mL) was added NaH (60percent) (23 g, 563 mmol) at -15 °C and stirred for 2 h. Benzyl bromide (32.8 mL, 269 mmol) was slowly added. The reaction mixture temperature was warmed to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was poured into chilled water (200 mL) and extracted with diethylether (2x 250 mL). The aqueous layer was acidified with citric acid (pH~4) and extracted with EtOAc (2x500 mL). The combined organic layers were washed with water (3x250 mL). The organic extracts were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford 2S-AA (54 g, 75percent) as brown syrup. H-NMR: (400 MHz, CDC13): δ 7.32-7.26 (m, 5H), 5.43 (d, J = 7.6 Hz, 1H), 4.70-4.46 (m, 1H), 4.45 (s, 2H), 4.13-3.91 (m, 1H), 3.73-3.70 (m, 1H), 1.44 (s, 9H). |
75% | Stage #1: at -15℃; for 2 h; Stage #2: at 20 - 25℃; for 12 h; |
To a stirring solution of Int A (50 g, 245 mmol) in DMF (650 mL) was added NaH (60percent) (23 g, 563 mmol) at -15 °C and stirred for 2 h. After adding benzyl bromide (32.8 mL, 269 mmol) slowly, the reaction mixture was warmed to RT and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was poured into chilled water (200 mL) and extracted with diethylether (2x 250 mL). The aqueous layer was acidified with citric acid (pH~4) and extracted with EtOAc (2x500 mL). The combined organic layers were washed with water (3 x 250 mL). The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford Int B (54 g, 75percent) as a brown syrup. (0569) 1H NMR: (400 MHz, CDCl3): δ 7.32-7.26 (m, 5H), 5.43 (d, J = 7.6 Hz, 1H), 4.70-4.46 (m, 1H), 4.45 (s, 2H), 4.13-3.91 (m, 1H), 3.73-3.70 (m, 1H), 1.44 (s, 9H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 4.5 h; Cooling with ice | To a solution of 4 (1.26 g, 6.1 mmol) and potassiumcarbonate (0.91 g, 6.6 mmol) in DMF (12 mL) cooled on an ice bath was added a solution of iodomethane (0.80mL, 12.8 mmol) in DMF (6 mL). After stirring for 30 min on an ice bath, the mixture was stirred for 4 h at rt.Precipitates were filtered off, and the filtrate was added with water and extracted with EtOAc. The organiclayer was washed with water and brine, dried over MgSO4, and evaporated. The obtained colorless oil waspurified by silica gel column chromatography (hexane:EtOAc = 1:1) to give 5 as a colorless oil (1.24 g, 93percent).The spectral data of 5 were identical to the literature,25 and the purity was confirmed by 1H NMR. |
87.4% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.25 h; Cooling with ice Stage #2: for 24 h; |
Under ice cooling, 18.7 g of N-Boc-L-serine was dissolved in 200 ml of DMF and 13.25 g of solid K2CO3 was added and for 15 minutes, and then 41.6 g (3.2 eq) of Mel was added, followed by stirring for 24 hours. After the reaction, the reaction solution was filtered through celite and concentrated. The residue was extracted by liquid separation using 400 ml of water and 150 ml x 4 of ethyl acetate and dried over sodium sulfate. The ethyl acetate layer was concentrated and subjected to silica gel column chromatography to obtain 17.1 g (87.4percent) of an N-Boc-L-serine methyl ester as a transparent oily product. |
5.3 g | With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 1.5 h; | To an ice-cold solution of L-serine (3.2 g, 30 mmol) in 1 M sodium hydroxide (60 mL) was added di-tert-butyl dicarbonate [(Boc)2O] (7.8 g, 36 mmol) in dioxane (25 mL). The mixture was stirred at 5 °C for 30 min, then allowed to warm to room temperature over 3.5 h. The reaction mixture was concentrated to half its original volume, quenched with 1 M potassium bisulfate (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (2 x 30 mL) and water (30 mL), dried over Na2SO4 and concentrated in vacuo. The crude product (5.8 g) was used to the next step. To an ice-cold solution of N-Boc-L-serine (5.8 g, 28 mmol) in DMF (40 mL) solid potassium carbonate (4.3 g, 31 mmol) was added. After stirring for 10 min methyl iodide (3.5 mL, 56 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. The reaction was allowed to reach room temperature and stirred for an additional hour. Then the reaction mixture was filtered to remove inorganic material, water (20 mL) was added and the filtrate was extracted with diethyl ether (3 x 20 mL). The combined extracts were washed with brine (2 x 20 mL) and water (10 mL), dried over Na2SO4. After concentration in vacuo 5.3 g (86percent yield) of N-Boc-L-serine methyl ester was obtained as a colorless oil. The product was sufficiently pure to be used in the next step without further purification. 1H and 13C NMR spectra were consistent with literature data.2 IR (ATR, cm-1) ν: 3433, 2978, 1743, 1710, 1368, 1163; 1H NMR (400 MHz, CDCl3) δ: 5.67 (br s, 1H, NH), 4.25 (br s, 1H, CH-N), 3.85-3.74 (m, 2H, CH2-O), 3.63 (s, 3H, OCH3), 1.35 (s, 9H, Boc); 13C NMR (400 MHz, CDCl3) δ: 171.4, 155.7, 79.9, 62.7, 55.5, 52.3, 28.0; MS (ESI) m/z: [M+Na]+ 242. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dimethyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; acetonitrile at -55℃; for 2 h; Inert atmosphere | Example 2; Standard Procedure for the Synthesis of Boc-Imidazol-1-yl-Ala (AA2); Step 2-1. Boc-Serine-β-lactone (AA2-1).; This procedure is based on that found in the literature (Vederas, J. C.; et al. J. Am. Chem. Soc. 1987, 109, 4649-4659). Into a dry 250 mL 3-neck flask equipped with a mechanical stirrer under a nitrogen atmosphere was added triphenylphosphine (4.5 g, 17.1 mmol, 1.1 eq), followed by 100 mL of an anhydrous THF:CH3CN (1:9) mixture. The mixture was stirred until a solution was obtained, then cooled to -55° C. (bath temperature) and dimethylazodicarboxylate (DMAD, 1.9 mL, 17.1 mmol, 1.1 eq) added dropwise over 10 min. After the addition, the mixture was stirred for 20 min and a solution of Boc-Ser-OH (3.18 g, 15.5 mmol, 1.0 eq.) in 50 mL of anhydrous THF:CH3CN (1:9) was added dropwise over 30 min. The mixture was stirred at -55° C. for 1.5 h, then the bath was removed and the solution allowed to warm slowly to room temperature. Once the mixture reached room temperature, the solvent was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography [gradient, hexanes:EtOAc, (80:20) to (60:40)] to give 2.10 g of AA2-1 as a white solid in 72percent yield. Purification of the crude material is best performed on the same day as the reaction to avoid decomposition. DCM can be added to help dissolve the crude residue.TLC (Hex/EtOAc, 60/40): Rf=0.55 (CMA) |
53% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at -78 - 20℃; for 2.83333 h; Inert atmosphere | Anhydrous tetrahydrofuran (THF) (100 mL) was added dropwise to triphenylphosphine (Ph3P) (6.3 g, 24.00 mmol), stirred at -78 ° C under argon for more than 10 min. A solution of diethyl azodicarboxylate (DEAD) was added dropwise and the resulting solution was stirred for 10 min. The above tetrahydrofuran mixed solution was added dropwise to a solution of N- (tert-butoxycarbonyl 1) -L-serine (5 g, 24.36 mmol) and stirred for more than 20 min. The resulting solution was stirred at -78 ° C for 20 min and then further stirred at room temperature for 2.5 h. The solvent was removed from tetrahydrofuran and the crude product was purified by chromatography on a column (3: 1 by volume ethane / ethyl acetate). And finally purified by recrystallization from ethyl acetate / n-hexane to give white solid compound 2 (2.4 g, yield 53percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5 h; | To an ice-cold solution of D-serine (5.0 g, 47.6 mmol) and NaOH (2.11 g, 52.9 mmol) in a mixture of water (110mL) and t-BuOH (110 mL) was added di-tert-butyl dicarbonate(11.38 g, 52.1 mmol) with stirring. After 1 h at 0 °C, the mixture was warmed to room temperature and stirred for 13h. The mixture was concentrated to one third its original volume using reduced pressure and water (110 mL) was added.The aqueous layer was extracted with hexanes (3 X 100 mL)and acidified to pH 1-2 by slow addition of cold 1 M KHSO4(55 mL). The resulting mixture was extracted with EtOAc (4X 150 mL). The combined organic layers were washed with water (150 mL), dried over Na2SO4, filtered and concentrated to give the crude product 3 as colorless oil (9.6 g, 98percentyield) which was used without further purification.To a white suspension of 3 (9.6 g, 46.8 mmol) and potassium carbonate (7.19 g, 52 mmol) in anhydrous DMF (50mL) was added methyl iodide (6.01 mL, 96.5 mmol). The mixture was stirred at room temperature for 1.5 h. To the resulting solution was added water (100 mL). The aqueouslayer was extracted with EtOAc (4 X 100 mL). The combined organic layers were washed with brine (2 X 175 mL),dried over Na2SO4, filtered and concentrated to give 4 as colorless oil (8.2 g, 80percent yield): []D21 +17.2 (c 5.0, MeOH),lit: []D +18.9 (c 5.0, MeOH) [15]; IR v 3388, 2978, 2936,2886, 1740, 1691, 1456, 1437 cm-1; 1H NMR (200 MHz,acetone-d6) (ppm): 6.00 (bs, 1H, NHCO), 4.3-3.76 (m, 4H,CH2OH, OH, CHNH), 3.69 (s, 3H, OCH3), 1.41 (s, 9H,C(CH3)3); 13C NMR (50 MHz, acetone-d6) (ppm): 171.70(COOCH3), 155.89 (NHC=O), 79.05 (C(CH3)3), 62.65(CH2OH), 56.53 (CHNH), 51.84 (COOCH3), 28.08(C(CH3)3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With caesium carbonate In N,N-dimethyl-formamide for 0.5 h; Stage #2: for 12 h; |
To a stirring solution of N-Boc- (L) -Serine (4.87 mmol) in DMF (100 mL) was added cesium carbonate (5.11 mmol) and stirring was continued 30 minutes. Benzyl bromide (5.84 mmol) was then added and the resulting solution was stirred 12 hours. The reaction mixture was then diluted with ethyl acetate (25 mL), washed with lithium bromide (3 x 15 mL), sodium bicarbonate (2 x 15 mL), and brine (2 x 15mL). The organic layer was dried over sodium sulfate. The solvent was then removed under reduced pressure and the resulting tan oil was purified by flash chromatography, using 1: 1 petroleum ether/diethyl ether, to afford the product (100percent) as a white solid. Rf= 0. 26 (1: 1 petroleum ether/diethyl ether).; To a stirring solution of N-Boc- (L) -Serine (2.44 mmol) in DMF (50 mL) was added cesium carbonate (2. 56 mmol) and stirring was continued 30 minutes. Benzyl bromide (2. 92 mmol) was then added and the resulting solution was stirred 12 hours. The reaction mixture was then diluted with ethyl acetate (15 mL), washed with lithium bromide (3 x 10 mL), sodium bicarbonate (2 x 10 mL), and brine (2 x 10 mL). The organic layer was dried over sodium sulfate. The solvent was then removed under reduced pressure and the resulting tan oil was purified by flash chromatography, using 1: 1 petroleum ether/diethyl ether, to afford the product (100percent) as a white solid. Rf= 0.26 (1: 1 petroleum ether/diethyl ether). |
100% | Stage #1: With caesium carbonate In N,N-dimethyl-formamide for 0.5 h; Stage #2: for 12 h; |
To a stirring solution of N-Boc- (L) -Serine (4.87 mmol) in DMF (100 mL) was added cesium carbonate (5.11 mmol) and stirring was continued 30 minutes. Benzyl bromide (5.84 mmol) was then added and the resulting solution was stirred 12 hours. The reaction mixture was then diluted with ethyl acetate (25 mL), washed with lithium bromide (3 x 15 mL), sodium bicarbonate (2 x 15 mL), and brine (2 x 15mL). The organic layer was dried over sodium sulfate. The solvent was then removed under reduced pressure and the resulting tan oil was purified by flash chromatography, using 1: 1 petroleum ether/diethyl ether, to afford the product (100percent) as a white solid. Rf= 0. 26 (1: 1 petroleum ether/diethyl ether).; To a stirring solution of N-Boc- (L) -Serine (2.44 mmol) in DMF (50 mL) was added cesium carbonate (2. 56 mmol) and stirring was continued 30 minutes. Benzyl bromide (2. 92 mmol) was then added and the resulting solution was stirred 12 hours. The reaction mixture was then diluted with ethyl acetate (15 mL), washed with lithium bromide (3 x 10 mL), sodium bicarbonate (2 x 10 mL), and brine (2 x 10 mL). The organic layer was dried over sodium sulfate. The solvent was then removed under reduced pressure and the resulting tan oil was purified by flash chromatography, using 1: 1 petroleum ether/diethyl ether, to afford the product (100percent) as a white solid. Rf= 0.26 (1: 1 petroleum ether/diethyl ether). |
91% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In benzene at 20℃; | Some tBOC-L-serine (commercially available) 41 (30 mmol, 6.16 g) was dissolved in dry benzene (100 mL), to which some 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (36 mmol, 5.5 mL) and some benzyl bromide 42 (36 mmol, 4.4 mL) was then added. The solution was agitated overnight at ambient temperature under nitrogen, and the solvent was later eliminated under low pressure to give an off-white liquid residue. Some ethyl acetate (200 mL) was added, and the contents of the flask were ultrasound-treated, then washed with a 1M solution of HCl (2×50 mL), a 10percent weight/volume aqueous solution of K2CO3 (2×50 mL) and brine (2×50 mL). The organic layer was dried on MgSO4, filtered, concentrated under vacuum and purified by column chromatography [petrol/ethyl acetate (1:1)] to give the product 43 in the form a white solid (8.05 g, 27.3 mmol, 91percent); m.p. 61-66° C. (lit. m.p. [10] 59-60° C.); [α]21D−18.5° (c 1.0, CH3OH); νmax/cm−1 3419 (NH), 3361 (OH), 2978 (CH), 1758 (C═O), 1668 (C═O), 1524 (NH bend), 1155 (C—O), 1068 (C—O); 1H NMR (300 MHz, DMSO) δH 1.38 (9H, s, C(CH3)3), 3.68 (2H, t, J=6.0 Hz, CH2OH), 4.10-4.16 (1H, m, CH-2), 4.91 (1H, t, J=6.0 Hz, OH), 5.10 (1H, d, J=12.0 Hz, OCH2aAr), 5.17 (1H, d, J=12.0 Hz, OCH2bAr), 6.97 (1H, d, J=9.0 Hz, NH), 7.32-7.38 (SH, m, 5×CHAr); 13C NMR (75 MHz, DMSO) δC 28.6 (C(CH3)3), 57.0 (CH-2), 61.8 (CH2-3), 66.2 (OCH2Ar), 78.8 (C(CH3)3), 128.0 (CHAr), 128.4 (CHAr), 128.8 (CHAr), 136.5 (CHAr quat), 155.8 (C-4, quat), 171.4 (C-1, quat). |
82% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; | Cs2CO3 (217 g, 0.67 mol) was added portionwise to a solution of N-Boc-serine (119 g, 0.58 mol) in DMF (1.5 L) under stirring at r.t. Then benzyl bromide (76 mL, 0.64 mol) was added and the mixture was stirred at r.t. overnight. The resulting mixture was poured into water (2.0 L) and extracted with MTBE (3 * 1.0 L), combined organic layers were washed with water (3 * 500 mL) and brine (500 mL), dried with MgSO4 and concentrated under reduced pressure giving pure N-Boc serine benzyl ester, which was used for the next step without purification. Yield: 141 g, (82percent). Colorless solid. Mp 66-68 °C (lit. 69-71) [ 33 ]. NMR spectra coincide with the literature data [ 33 ]. To a solution of N-Boc serine benzyl ester (141 g, 0.48 mol) in CH3CN (2.0 L) DMAP (5.83 g, 47 mmol) and Boc-anhydride (229 g, 1.05 mol) were consecutively added. The mixture was stirred under reflux overnight. Then the mixture was cooled to r.t., concentrated under reduced pressure, dissolved in MTBE (2.0 L) and washed with water (0.5 L) and 1percent HCl solution (0.5 L), dried with MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc/cHex, 1:2, Rf = 0.65) giving pure compound 4. Yield: 150 g (83percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Stage #1: With methanol; sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1 h; Stage #2: at 20℃; for 38 h; Stage #3: With citric acid In water |
A. (S)-2-(tert-Butoxycarbonylamino)-3-methoxypropanoic acid A sodium methanolate (NaOMe) solution was prepared by slowly adding MeOH (50 mL) to a suspension of sodium hydride (60percent in mineral oil, 28 g, 0.71 mol) in dry THF (1.2 L) at 0° C. The resulting mixture was stirred at RT for 2 h. A portion of the NaOMe solution (320 mL) was added to (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (36 g, 175 mmol) in dry THF (1.6 L), and the mixture was stirred at RT for 1 h. Methyl iodine (16 mL) was then added and the mixture was stirred at RT for 1 h. Another aliquot of NaOMe solution (540 mL) was added and the reaction mixture stirred at RT for 1 h. Additional methyl iodine (38 mL) in THF (200 mL) was added and the reaction mixture was stirred at RT for 36 h. Following reaction, the mixture was concentrated and the residue was dissolved in water and washed with diethyl ether (2.x.100 mL). The aqueous layer was acidified to pH 2 by the addition of solid citric acid and was extracted with EtOAc (3.x.200 mL) and dried over Na2SO4. The organic phase was concentrated, and the residue was dissolved in water and extracted with DCM (4.x.150 mL). The organic layers were combined and concentrated to give the title compound as an oil, which was used without further purification (10.9 g, 28percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240.3 kg | at 10℃; for 44 h; Large scale | Example 2 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-methoxypropanoic acid (0033) (0034) 45percent 4 NaOH (746.3 kg; 8.40 kmoles) and DMS (1053.8 kg; 8.36 kmoles) were added to the reaction mixture below 10° C. over 38 h and for an additional 6 h to complete the reaction. 20percent 9 NH4OH (20.0 kg) was added to quench the reaction in the reaction mixture. The pH value was adjusted by 10 citric acid monohydrate (55.8 kg) and 32percent 11 HCl (180 kg) to around 3. The 12 product was extracted by toluene (1165 L) twice, and the organic layer was washed by 1percent NaOH (40 L) and H2O (39 L×2). The organic layer was concentrated, and stripped by IPA as oil residue (240.3 kg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -10 - 5℃; for 1 h; Stage #2: at 0 - 5℃; for 9 h; |
A solution of N-Boc-D-serine (22g, 0.107 mol) in dry tetrahydrofuran (352ml) was cooled to <-10°C under a nitrogen atmosphere. To this was added via a dry addition funnel 15percent w/w n-butyllithium in hexanes (134ml, 0.216mol) keeping the temperature <10°C. The resultant slurry was aged for 1 hour at 0- 5°C. Dimethyl sulphate (12.1ml, 0.128mol) was added keeping the temperature at 0-5°C and the reaction mixture aged at 0-5°C for 9 hours. The reaction was quenched by the addition of water (110ml), basified to pH 10-13 with 30percent sodium hydroxide (3ml) and the tetrahydrofuran/hexane evaporated in vacuo. The residue was washed with toluene (44ml) and then acidified to a pH of <3.5 with 50percent citric acid. The acidified aqueous phase was extracted with methylene chloride (2x91 ml, 1x66ml) and the combined C936 extracts dried by azeotropic distillation. Yield on evaporation 23.7g, 100percent. HPLC purity 90.0percent, Chiral purity 100percent. |
100% | Stage #1: With sodium hydroxide In water; toluene at 10℃; for 0.5 h; Stage #2: at 10℃; for 1 h; |
A suspension of N-Boc-D-serine (22g, 0.107 mol) and tetrabutylammonium bromide (1.3g, 0.004mol) in toluene (110ml) was cooled to <10°C. To this was added 20percent sodium hydroxide (17.6ml, 0.107mol) keeping the temperature <10°C and the resultant mixture was aged for 30 minutes at <10°C. Dimethyl sulphate (40.6ml, 0.429mol) and 50percent sodium hydroxide (25.4ml, 0.485mol) were added keeping the temperature <10°C and the reaction mixture aged at 10°C for 1 hour. Water (66ml) was added to the mixture and the phases separated. The aqueous layer was acidified to a pH of <3.5 with 50percent citric acid, extracted with methylene chloride (2x91 ml, 1x66ml) and the combined C936 extracts dried by azeotropic distillation. (Yield on evaporation 27.5g, 100percent, HPLC purity 96.3percent, Chiral purity 98.1percent). |
100% | With sodium hydroxide In water at 0 - 10℃; for 6 h; | The above prepared compound of formula I (20.5g, 0 . 100mol) cooling the aqueous solution to 0-10°C. Maintain 0-10°C, at the same time by adding drops of sulfuric acid dimethyl ester (50.5g, 0 . 400mol) and 50percent sodium hydroxide (36.0g, 0 . 450mol), reaction mixture in 0-10 °C reaction 6 hours. After the reaction, the reaction liquid maintain 0-10°C, with 50percent citric acid dyeworks to pH= 2-3, then with dichloromethane (1×123 ml, 2×82 ml) to extract and after drying with anhydrous sodium sulfate is distilled under reduced pressure to dry obtains the type compound II 21.9g (yield 100percent, HPLC purity 92.9percent, chiral purity 98.0percent). |
83% | Stage #1: With tetrabutylammomium bromide; sodium hydroxide In toluene for 0.5 h; Cooling with ice Stage #2: With sodium hydroxide In toluene at 10℃; for 3 h; Stage #3: With citric acid In water |
Synthesis of (R)-2-N-Boc-amino-3-methoxypropanoic acid[0155] A suspension of N-Boc-D-serine (17.6 g, 86 mmol) and tetrabutylammonium bromide (1.04 g, 3.23 mmol) in toluene (90 mL) was cooled with an ice-bath with stirring. To the reaction mixture was added 20percent sodium hydroxide (14 mL, 86 mmol) and the resulting mixture was stirred for thirty minutes. Dimethyl sulphate (43.3 g, 343 mmol) and 50percent sodium hydroxide (20.3 mL, 388 mmol) were added and the reaction mixture was stirred at < 10 °C for 3 hours. Water (60 ml) was then added to the mixture and the resulting two phases were separated. The aqueous phase was washed with dichloromethane (100 mL x 2). The aqueous phase was then acidified to a pH of <3.5 with 50percent citric acid and extracted with methylene chloride (100 mL χ 3). The organic phases were combined, dried over sodium sulfate, filtered, and solvent removed under reduced pressure to afford a colorless oil (15.6 g, yield: 83percent, purity >95percent). 1H NMR (500 MHz, CDC13) δ 1.45 (s, 9H), 3.37 (s, 3H), 3.62 (m, 1H), 3.85 (m, 1H), 4.43 (m, 1H), 5.42 (d, 1H). LC-MS (m/z) calculated 219.1 , found 242.0 [M + Naf. |
87 g | With sodium hydroxide In water at 0 - 5℃; | Into a 2 L, four-necked RB flask was charged 90 ml of water and 40 g of sodium hydroxide. D-Serine is added to the solution at 20-25° C. Boc anhydride (150 g) is slowly added to the reaction mass keeping the temperature below 20° C. The reaction mass was allowed to reach 25-30° C. and maintained for 16 h. TLC of the reaction mass showed the presence of D-serine content at <1.0percent level. The reaction mass is cooled to 0-5° C. and started the simultaneous addition of aqueous sodium hydroxide (104 g of sodium hydroxide dissolved in 100 ml of water) and dimethyl sulphate (300 g) through addition funnels keeping the temperature below 5° C. The reaction mass was maintained at same temperature till the completion of reaction. The reaction mass is diluted with water and extracted the product into diisopropyl ether. Aqueous layer is neutralized with citric acid to get <3.5 pH. The reaction mass is extracted with diisopropyl ether and distilled of solvent to get 87 g of title compound as an oil. |
34.5 g | With sodium hydroxide In water at 5 - 10℃; for 14 h; | To a stirred aqueous solution of sodium hydroxide (23.1 g of NaOH in 150 ml of water) was added D-serine (30 g) lot wise at 2G-25°C and BOC anhydride (74.7 g) at 10-15°C. The traction mixture was stirred at 20-25 0C for 10 hours. Sodium hydroxide pellets (11.4g) was added to the reaction mixture at 5-10°C and stirred for another 30 mins. To the resulting reaction mixture was slowly added dimethylsulphate (340 ml) and aqueous solution of sodium hydroxide (91.0 g NaOH in 1 10 mL of water) at 5-10°C over 4 hours and then stirred for 10 hrs. The reaction mixture was acidified to pH -1 -2 with 2percent hydrochloric acid solution at 0-5°C and extracted with methylene chloride (300 ml). Separating organic layer, aqueous layer was extracted with methylene chloride (100 mL). The combined organic layer was concentrated under vacuum. The obtained residue was dissolved in methyl tert-butyl ether (83.25 mL) at 60-65°C. To the resulting solution was added H-hexane (466.2 mL) at 20-25°C and mixture was stirred for 10-12h. The solid was filtered and dried to provide the title compound as white solid. Weight: 34.5 g Yield: 55.29percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With potassium hydroxide In toluene at 0 - 5℃; for 0.5 h; Stage #2: With tetrabutylammomium bromide In toluene at 0 - 5℃; for 8 h; |
In a 1000 mL three-necked flask,400 mL of toluene and 40 g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine)The stirring temperature was lowered to 0-5 ° C,36.5 g of 30percent potassium hydroxide solution was added dropwise.After stirring for 30 minutes,Then 72.65 g of methyl p-toluenesulfonate was added,Tetrabutylammonium bromide 4g,Then 43.68 g of 50percent potassium hydroxide solution was added dropwise.After reaction at 0-5 ° C for 8 hours,Add water 200mL and layered,The aqueous layer was washed with 100 mL of toluene,Discard the organic layer.The combined aqueous layers were then cooled to below 15 [deg.] C and acidified with 50percent phosphoric acid to pH = 2-3.5,Extraction with dichloromethane (200 mL * 3)The combined organic layers were added 30g of anhydrous sodium sulfate and stirred overnight.The next day filterThe filtrate was concentrated to dryness under reduced pressure,42.9 g of light yellow oil,Yield: 100percent, HPLC purity: 98.0percent, Chiral purity: 99.4percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydroxide In water at 0 - 10℃; for 6 h; | The above prepared compound of formula I (20.5g, 0 . 100mol) cooling the aqueous solution to 0-10°C, maintain 0-10°C, drop at the same time add iodomethane (28.4g, 0 . 20mol) and 50percent sodium hydroxide (36.0g, 0 . 450mol), reaction mixture in 0-10 °C reaction 6 hours, after the reaction, the reaction liquid maintain 0-10°C, with 50percent citric acid dyeworks to pH= 2-3, then with dichloromethane (1×123 ml, 2×82 ml) extraction and drying with anhydrous sodium sulfate, then distilled under reduced pressure to dry obtains the type compound II 21.9g (yield 100percent, chiral purity 98.5percent). |
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