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CAS No. : | 1676-90-0 | MDL No. : | MFCD00076912 |
Formula : | C13H23NO6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PHJDCONJXLIIPW-QMMMGPOBSA-N |
M.W : | 289.32 | Pubchem ID : | 7010636 |
Synonyms : |
Boc-Asp(OtBu)-OH
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.77 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 72.21 |
TPSA : | 101.93 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) : | -7.09 cm/s |
Log Po/w (iLOGP) : | 2.6 |
Log Po/w (XLOGP3) : | 1.37 |
Log Po/w (WLOGP) : | 1.7 |
Log Po/w (MLOGP) : | 1.08 |
Log Po/w (SILICOS-IT) : | 0.8 |
Consensus Log Po/w : | 1.51 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.9 |
Solubility : | 3.62 mg/ml ; 0.0125 mol/l |
Class : | Very soluble |
Log S (Ali) : | -3.11 |
Solubility : | 0.223 mg/ml ; 0.00077 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.55 |
Solubility : | 8.12 mg/ml ; 0.0281 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.44 |
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 |
---|---|---|
100% | With triethylamine In 1,4-dioxane; water | 2.1. Preparation of Boc-Asp(O-tBu)-NCA (II-a)This method consisted in the cyclization of the free carboxylic acid with a main chain with one of the Bocs protecting the amine function, therefore first of all requiring the preparation of (Boc)2-Asp(O-t-Bu)-OH (VII-a). This was achieved by esterification of the α-carboxylic acid of Boc-Asp(O-t-Bu)-OH (V-a) into the benzyl ester (VI(a)), followed by a reaction with Boc2O in the presence of DMAP in order to give the amino compound protected by two Boc groups (VII-a), and then by deprotection of the benzyl ester group by hydrogenation in order to give (VIII-a). The following step consisted in the cyclization of the amino acid (VIII-a) protected with Vilsmeier's salt. The best results were obtained by forming the salt of DMF and oxalyl chloride in acetonitrile. The compound (II-a) was obtained with 90percent yield. |
97% | Stage #1: at 0℃; for 0.0833333 h; Stage #2: With sodium carbonate In tetrahydrofuran; water at 20℃; for 24 h; |
General procedure: L-Aspartic acid 4-tert-butyl ester 4a (1.89 g, 10 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (12 mL) at 0°C. After stirring for 5 minutes, di-tert-butyl dicarbonate (4.35 g, 2 eq.) was added in small portions followed by sodium carbonate (4.20 g, 4 eq.). The reaction was stirred at room temperature for 24 hours before evaporating the solvents under reduced pressure. The residue was dissolved in 10percent aqueous sodium hydrogen carbonate solution (50 mL), washed with diethyl ether (3 x 20 mL) and citric acid was added until pH 4.0 was reached. The product was extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give pure 4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid 5a as a colourless oil (2.82 g, 97percent). |
96% | With sodium hydroxide In 1,4-dioxane; water | (2S)-2-(tert-Butoxycarbonylamino)-4-tert-butoxy-4-oxo-butanoic acid is commercially available. The compound was prepared from commercial H-L-Asp(OtBu)-OH (5.68 g, 30.0 mmol) and Boc20 (6.55 g, 30.0 mmol) in a mixture of 1,4-dioxane (25 mL) and a freshly prepared 1.0 N aqueous sodium hydroxide (NaOH) solution (33 mL, 33 mmol) (8.33 g, 96percent yield) (Bowers, et al., J. Am. Chem Soc, 2009, 131(8), 2900-2905; and Keller, et al., Org. Synth., 1985, 63, 160). Colorless solid; m.p. : 47-53 °C; 1H NMR (300 MHz, CDCI3): δ 7.2-6.6 (br. s, 1H), 5.52 (d, J= 8.7 Hz, 1H), 4.62-4.50 (m, 1H), 2.94 (dd, J= 16.8, 4.2 Hz, 1H), 2.74 (dd, J= 16.8, 4.8 Hz, 1H), 1.45 (s, 9H, partially superimposed), 1.44 (s, 9H, partially superimposed) ppm; LC/MS: Rt = 1.645 min; ESI (pos.) m/z = 290.20 (M+H+)+, 601.00 (2M+Na+)+; ESI (neg.) m/z = 288.10 (M-H+)", 576.90 (2M-H+)~ The analytical data correspond to the analytical data obtained for the (S)-enantiomer (Example 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 4-methyl-morpholine; sodium tetrahydroborate; chloroformic acid ethyl ester; In tetrahydrofuran; at -10 - 20℃; for 3.5h; | A solution of <strong>[1676-90-0]Boc-Asp(OtBu)-OH</strong> (96) (5.0 g, 1 7.3 mmol) in 50 ml dry THF was cooled to -10 degree C. N-Methylmorpholine (1 .75 g, 17.3 mmol) was added. After 1 min, CIC02Et (1 .65 ml, 17.3 mmol) was added dropwise. The reaction mixture was stirred for an additional 15 min at -5 degree C. The precipitated N-methylmorpholie hydrochloride was filtered off, and the filtrate was added to a solution of NaBH4 (1 .47 g, 38.9 mmol) in 20 m L of water at 5-10 degree C within 10 min. The reaction mixture was stirred at room temperature for 3.5 h and then cooled to 5 degree C. 3M hydrochloric acid was added to give a pH of 2, and the mixture was extracted twice with ethyl acetate. The combined organic phase was washed twice with water and then dried with anhydrous Na2S04. The product is dried in vaccuo and purified via silica gel chromatography using EA: PE (1 :2) as eluent to give 4.0 g product 97 as colorless oil in 85% yield. |
85% | Synthesis compound 97: A solution of <strong>[1676-90-0]Boc-Asp(OtBu)-OH</strong> (96) (5.0 g, 17.3 mmol) in 50 ml dry THF was cooled to -10 degree C. N-Methylmorpholine (1 .75 g, 17.3 mmol) was added. After 1 mi CICO2Et (1 .65 ml, 17.3 mmol) was added dropwise. The reaction mixture was stirred for an additional 15 mm at -5 degree C. The precipitated N-methylmorpholie hydrochloride was filtered off, and the filtrate was added to a solution of NaBH4 (1.47 g, 38.9 mmol) in 20 mL of water at 5-10degree C within 10 mm. The reaction mixture was stirred at room temperature for 3.5 h and then cooled to 5 degree C. 3M hydrochloric acid was added to give a pH of 2, and the mixture was extracted twice with ethyl acetate. The combined organic phase was washed twice with water and then dried with anhydrous Na2504. The product is dried in vaccuo and purified via silica gel chromatography using EA: PE (1:2) as eluent to give 4.0 g product 97 as colorless oil in 85% yield. | |
85% | Synthesis compound 97: A solution of <strong>[1676-90-0]Boc-Asp(OtBu)-OH</strong> (96) (5.0 g, 1 7.3 mmol) in 50 ml THF was cooled to -10 degree C. N-Methylmorpholine (1 .75 g, 17.3 mmol) was added. After 1 n, CIC02Et (1 .65 ml, 17.3 mmol) was added dropwise. The reaction mixture was stirred for an ditional 15 min at -5 degree C. The precipitated N-methylmorpholie hydrochloride was filtered off, d the filtrate was added to a solution of NaBH4 (1 .47 g, 38.9 mmol) in 20 ml_ of water at 5-10 gree C within 1 0 min. The reaction mixture was stirred at room temperature for 3.5 h and then oled to 5 degree C. 3M hydrochloric acid was added to give a pH of 2, and the mixture was racted twice with ethyl acetate. The combined organic phase was washed twice with water and n dried with anhydrous Na2S04. The product is dried in vaccuo and purified via silica gel omatography using EA: PE (1 :2) as eluent to give 4.0 g product 97 as colorless oil in 85% yield. |
85% | Synthesis compound 97: A solution of <strong>[1676-90-0]Boc-Asp(OtBu)-OH</strong> (96) (5.0 g, 17.3 mmol) in 50 ml dry THF was cooled to -10 degree C. N-Methylmorpholine (1.75 g, 17.3 mmol) was added. After 1 min, ClCO2Et (1.65 ml, 17.3 mmol) was added dropwise. The reaction mixture was stirred for an additional 15 min at -5 degree C. The precipitated N-methylmorpholie hydrochloride was filtered off, and the filtrate was added to a solution of NaBH4 (1.47 g, 38.9 mmol) in 20 mL of water at 5-10 degree C within 10 min. The reaction mixture was stirred at room temperature for 3.5 h and then cooled to 5 degree C. 3M hydrochloric acid was added to give a pH of 2, and the mixture was extracted twice with ethyl acetate. The combined organic phase was washed twice with water and then dried with anhydrous Na2SO4. The product is dried in vaccuo and purified via silica gel chromatography using EA: PE (1:2) as eluent to give 4.0 g product 97 as colorless oil in 85% yield. | |
70% | To a solution of compound 1 (S)-enantiomer (15.0 g, 51.8 mmol) in DME (100 mL) was added isobutyl carbonochloridate (7.1 g, 51.8 mmol) and NMM (5.2 g, 51.8 mmol) slowly. After 10 min, stirring continued and the reaction mixture was allowed to 20 C for 30 min, the reaction mixture was filtered to remove precipitated NMM hydrochloride, the filtrate was cooled to -15 C and a solution of NaBH4 (1.9 g, 51.8 mmol) in H2O (10 mL) was added. Then the reaction mixture was stirred at -15 C for 20 min. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc 500mL (250 mL x 2), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue comprising compound 2 (10.0 g, 70% yield) as a white oil. LCMS (conditions A): RT = 1.03 min MS: (M+Na+): 298.0. | |
To a cold solution of Boc-L-Asp(OfBu)-OH (25.0 g, 86.0 mmol) in DME (86 mL) were successively added N-methylmorpholine (10.1 mL, 90.0 mmol) and isobutyl chloroformate (12.2 mL, 91 .0 mmol) at such a rate that the temperature stayed below -10C. After 30 min, the precipitated N-methyl morpholine hydrochloride was removed by filtration, washed with DME (25 mL) and the filtrate and washings were combined in a flask in an ice-salt bath. A solution of NaBH4 (4.14 g, 108 mmol) in water (30 mL) was added slowly, followed by water (70 mL) maintaining the temperature between -15C and -30C. The suspension was filtered and washed thoroughly with water. The filtrate was extracted with EtOAc (4x50 mL) and the combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (heptane: EtOAc 1 :0 to 1 : 1 ) affording the title compound as a thick oil that slowly solidified. M/z = 276.2 [M+H]+, Rt = 3.04 min (U PLC-MS conditions b), Rt = 6.83 min (HPLC conditions g), 1 H NMR (400 MHz, CDCI3) delta = 5.22 (s, br, 1 H), 3.87-4.03 (m, 1 H), 3.68 (d, 2H), 2.39-2.63 (m, 2H), 1 .35-1 .54 (m, 18 H) ppm. | ||
At this rate, Boc-L-Asp (OtBu) -OH (25.0 g, 86.0 mmol)In DME (86 mL)In the cold solution in the continuous additionN-methylmorpholine (10.1 mL, 90.0 mmol)And isobutyl chloroformate (12.2 mL, 91.0 mmol)So that the temperature is kept below -10 C.After 30 minutes,The precipitated N-methylmorpholine hydrochloride was removed by filtration,Washed with DME (25 mL)And the filtrate and the laundry were combined in an ice-salt bath in a flask.NaBH4 (4.14 g, 108 mmol) was slowly added,In water (30 mL)Followed by the addition of water (70 mL)The temperature was maintained between -15 C and -30 C.The suspension was filtered and washed thoroughly with water.The filtrate was extracted with EtOAc (4 x 50 mL)And the combined organic layers were washed with brine,Dried by Na2SO4,And concentrated under reduced pressure.By flash chromatography on silica (heptane:EtOAc 1: 0 to 1: 1) to purify the crude product,To give the title compound as a crude oil,Its slow solidification. | ||
4.76 g | The aspartic acid derivative (5.0 g, 17.28 mmol) was dissolved in anhydrous THF (100 mL)and then the solution was cooled to -15 C. The triethylamine (2.41 mL, 17.28 mmol) was then added slowly dropwise, followed by the ethyl chloroformate (1.65 mL, 17.28 mmol). The reaction mixture was stirred at the same temperature for 15 minutes, and then the sodium borohydride (1.96 g, 51.84 mmol) was added, followed by the slow addition of methanol (100 mL) over a period of 30 minutes at -15 C. The solution was further stirred for 30 minutes and then neutralized with 0.5N HC1 (to pH 7). The organicsolvents were removed under reduced pressure and then the residue was diluted with water (100 mL), extracted with ethyl acetate (3 X 150 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum and gave the desired product 1 as a colorless oil (4.76 g) and used for the next reaction without further purification. 1H NMR(500 IVIFIz, CDCl3) oe 5.47 (bs, 1H), 5.23 (bs, 1H), 3.99-3.93 (m, 1H), 3.68 (d, J 5.0 Hz,2H), 2.57-2.47 (m, 2H), 1.45 (s, 9H), 1.43 (s, 9H). 13C NMR (150 IVIFIz, CDCl3) 171.2,155.9, 81.1, 79.6, 64.3, 49.7, 37.5, 28.4 (3C), 28.0 (3C). HRMS (ESI): Calcd. for C,3H25NNaO5([M+Na]): 298.1625. Found: 298.1611. | |
1.93 g | Reference Example 2-33-1 (3R)-3-Amino-4-(1,6-dihydropyrimidin-2-yl)butan-1-ol dihydrochloride To a solution of (2S)-4-(tert-butoxy)-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoic acid (2 g) in tetrahydrofuran (10 mL) were added N-methylmorpholine (840 mg) and chloroformic acid isobutyl ester (1.04 g) at 0C, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. To a solution of the residue in methanol (10 mL) was added sodium borohydride (525 mg) at 0C, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added hydrochloric acid (1 mol/L), and the crude product was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane) to afford (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoic acid tert-butyl ester (1.93 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 18h; | To a solution of N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N'-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (420 mg, 0.92 mmol) and N-(tert-butoxycarbonyl)-L-aspartic acid beta-t-butyl ester (305 mg, 1.06 mmol) in 1,2-dichloroethane (6 mL) was added N,N-diisopropylethylamine (0.50 mL, 2.88 mmol), 1-hydroxybenzotriazole hydrate (175 mg, 1.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (250 mg, 1.30 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction was worked-up as described above and the crude material was purified by column chromatography on silica gel (CH2Cl2/MeOH, 98:2) to give the desired amide (145 mg, 23%) as a mixture of diastereomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With citric acid; In water; ethyl acetate; | A solution of N-(tert-butoxycarbonyl)-L-aspartic acid beta-t-butyl ester dicyclohexylammonium salt (500 mg, 1.06 mmol) in EtOAc (25 mL) was washed with a 10% aqueous citric acid solution (2×25 mL) and brine (1×25 mL). The organic phase was dried (MgSO4), filtered and concentrated to give the corresponding free acid (305 mg) as a clear oil. | |
Commercially available N-(t-butoxycarbonyl)-L-aspartic acid beta-t-butylester dicyclohexylammonium salt (1.00 g, 2.12 mmol) was subjected to column chromatography using an ion exchange resin (Dowex 50W-8X, Na type preparated using 1N aqueous solution of sodium hydroxide; 5 ml) (eluent; methanol). The collected fractions were concentrated under reduced pressure, and the residue was dissolved in water (50 ml). To the aqueous solution was added a 1N aqueous solution of hydrochloric acid (22 ml) to adjust the pH of the solution to about 4, and the liberated carboxylic acid was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained colorless oil was dissolved in dichloromethane (10 ml), and triethylamine (420 mul, 3.0 mmol) and 2,2,2-trichloroethyl formate (466 mg, 2.20 mmol) were added thereto at room temperature followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, then the obtained residue was dissolved in ethyl acetate, and the organic layer was washed successively with an aqueous solution of sodium hydrogen carbonate, an aqueous solution of ammonium chloride, and an aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (15 g) column (eluent; hexane : ethyl acetate = 2 : 1) to afford the title compound (627 mg, 73% yield) as a colorless oil. NMR spectrum (400 MHz, CDCl3) delta ppm: 1.44 (9H, s), 1.46 (9H, s), 2.79(1H, dd, J=17, 4 Hz), 3.01 (1H, dd, J=17, 5 Hz), 4.68 (1H, m), 4.86 (2H, s), 5.54 (1H, br d, J=9 Hz) IR spectrum nu max CHCl3 cm-1: 3439, 2982, 2934, 1769, 1717, 1498 Mass spectrum m/z (FAB) : 420 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; | To a solution of compound 2.3 (1. 0g ; 1.5 MMOL) and Boc-Asp (OtBu) -OH (0.48g ; 1.7 MMOL) in 30 mi N, N-DIMETHYLFORMAMIDE was added EDCI (0.32g ; 1.7 MMOL) and HOAt (0.02g ; 0.15 MMOL). After overnight stirring at room temperature the reaction mixture was partitioned between ETHYLACETATE and 0. 1 N HCI. The H20- layer was extracted 3 times and the combined organic layer was washed with 0. 1N HCl, H20, saturated NAHCO3 and HAO. After drying over NA2SO4, the solvent was removed and the residue was triturated in diisopropylether. 1. 12G of compound 2.4 was obtained (yield 79%, purity 94% LC-MS) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61%; 23% | With dicyclohexyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 0.75h; | To a solution of 1' (176 mg, 0.249 mmol), N-t-Boc-(L)-aspartic acid beta-t-butyl ester (144 mg, 0.499 mmol), and 4-dimethylamino pyridine (2.0 mg, 0.066 mmol) in 1.0 ml of anhydrous methylene chloride at room temperature was added a solution of 1,3-dicyclohexylcarbodiimide (103 mg, 0.499 mmol) in 200 mul of methylene chloride. After stirring for 45 min, the cloudy white reaction mixture was treated with 88 mg of celite and diluted with ethyl acetate-hexanes (3:1, 2 ml), stirred for 10 min, and filtered through a plug of celite, washing with ethyl acetate:hexanes (3:1). The filtrate and washings were concentrated in vacuo to an off-white oil. Chromatography (30 g of flash silica gel, 2:1 ethyl acetate-hexanes) afforded pure 37' (lower Rf) along with mixed fractions. The mixed fractions were chromatographed (25 g of flash silica gel, 1:1 then 2:1 then 3:1 ethyl acetate-hexanes) affording more pure 37' along with pure 39' (higher Rf). All fractions containing pure 37' were combined to yield 149 mg (61%) as a white foam while all fractions containing pure 39' were combined to yield 56 mg (23%) as a white foam. 500 MHz 1H NMR (CDCl3) data for 37': delta 7.39-7.30 (m, 5H), 7.24 (d, 1H, J=2.0 Hz), 7.24-7.18 (m, 1H), 7.09 (dd, 1H, J=8.4, 2.0 Hz), 6.88 (d, 1H, J=8.4 Hz), 6.76 (ddd, 1H, J=15, 13, 4.3 Hz), 5.75 (d, 1H, 15 Hz), 5.50 (d, 1H, J=7.9 Hz), 5.46 (d, 1H, J=9.2 Hz), 5.01-4.98 (m, 2H), 4.93 (t, 1H, J=9.9 Hz), 4.85 (d, 1H, J=9.2 Hz), 4.78-4.71 (m, 1H), 4.17-4.10 (m, 1H), 3.91 (s, 3H), 3.41 (dd, 1H, J=13, 8.2 Hz), 3.22 (dd, 1H, J=13, 3.9 Hz), 3.17 (dd, 1H, J=14, 5.1 Hz), 3.09 (dd, 1H, J=14, 7.7 Hz), 2.61-2.50 (m, 4H), 2.36-2.28 (m, 1H), 2.02-1.97 (m, 1H), 1.83-1.76 (m, 2H), 1.45 (s, 9H), 1.41 (s, 9H), 1.28 (s, 3H), 1.20 (s, 3H), 1.06-1.01 (m, 6H), 0.99 (d, 3H, J=6.2 Hz). 500 MHz 1H NMR (CDCl3) data for 39': delta 7.39-7.30 (m, 5H), 7.24 (d, 1H, J=2.0 Hz), 7.24-7.18 (m, 1H), 7.09 (dd, 1H, J=8.4, 2.0 Hz), 6.88 (d, 1H, J=8.4 Hz), 6.73 (ddd, 1H, J=15, 13, 4.3 Hz), 5.74 (d, 1H, 15 Hz), 5.47 (d, 1H, J=7.9 Hz), 5.42 (d, 1H, J=9.1 Hz), 5.29 (d, 1H, J=9.0 Hz), 4.98 (dd, 1H, J=10, 3.0 Hz), 4.92 (t, 1H, J=9.6 Hz), 4.85 (d, 1H, J=9.1 Hz), 4.77-4.71 (m, 1H), 4.18-4.12 (m, 1H), 3.91 (s, 3H), 3.39 (dd, 1H, J=13, 8.1 Hz), 3.21 (dd, 1H, J=13, 4.0 Hz), 3.16 (dd, 1H, J=14, 5.2 Hz), 3.07 (dd, 1H, J=14, 7.6 Hz), 2.63-2.52 (m, 2H), 2.45 (dd, 1H, J=17, 5.8 Hz), 2.36-2.26 (m, 1H), 2.22 (dd, 1H, J=17, 4.5 Hz), 1.99-1.90 (m, 1H), 1.86-1.69 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H), 1.25 (s, 3H), 1.19 (s, 3H), 1.11 (d, 3H, J=7.0 Hz), 1.03 (d, 3H, J=6.5 Hz), 0.99 (d, 3H, J=6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 2h; | (2R, 4S)-4- { (5-Aminopyrimidin-2-yl)- [3, 5-bis (trifluoromethyl) benzyl- amino-2-ethyl-6-methoxy-3, 4-dihydro-2H- [1, 5]-naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in N, N-dimethylformamide (4 ml), and thereto are added 4-tert-butyl (S)-2-tert-butoxycarbonylaminosuccinate (123 mg) and 1-hydroxybenzotriazole (68 mg), then added under ice-cooling 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (96 mg) and triethylamine (0.06 ml). The mixture is stirred at room temperature for 2 hours, and partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane : ethyl acetate = 4: 1<3 : 2) to give (2R, 4S)-4- { [3, 5-bis (trifluoromethyl) benwl]-15-((S)-3-tert-butoxycarbonyl-2- tert-butoxycarbonylaminopropionylamino) pyrimidin-2-yl] amino-2-ethyl-6- methoxy-3, 4-dihydro-2H- [1, 5]-naphthyridine-1-carboxylic acid ethyl ester (242 mg). MS (m/z): 870 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 0.5h; | Intermediate 36: tert-Butyl N2 -(tert-butoxvcarbonvl)-N¹-H (5S)-3-(5-{2-fluoro-4-r (5R)-2- oxo-5-(1FI-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-3-yllnhenyl)nyridin-2-yl)-4,5- dihydroisoxazol-5-vllmethvl)-L-a-asparaeinate; (5R)-3-(4-{ 6-[(5S)-5-(Aminomethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl }-3-fluorophenyl)- 5-(1H 1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Reference Example 16, 287 mg, 0.66 mmol), diisopropyl ethyl amine (0.345 ml, 1.98 mmol), N-[(dimethylamino)(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate ( 300 mg, 0.79 mmol), N-tert-butoxycarbonyl-L-aspartic acid 4-tert- butyl ester (190 mg, 0.66 mmol) and DMF (3 ml) were combined and stirred at room temperature for 30 minutes. The reaction mixture was absorbed onto silica gel and was purified by silica gel column (elution with 100% dichloromethane to 10% methanol in dichloromethane). The title product was obtained as a yellow solid after drying at 40 C under vacuum for 24 hours (371 mg). MS (electrospray) : 709 (M+l) for C34H41FN8O8 |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In dichloromethane; at 20℃; for 1h; | Commercially available N-(t-butoxycarbonyl)-L-aspartic acid beta-t-butylester dicyclohexylammonium salt (1.00 g, 2.12 mmol) was subjected to column chromatography using an ion exchange resin (Dowex 50W-8X, Na type preparated using 1N aqueous solution of sodium hydroxide; 5 ml) (eluent; methanol). The collected fractions were concentrated under reduced pressure, and the residue was dissolved in water (50 ml). To the aqueous solution was added a 1N aqueous solution of hydrochloric acid (22 ml) to adjust the pH of the solution to about 4, and the liberated carboxylic acid was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained colorless oil was dissolved in dichloromethane (10 ml), and triethylamine (420 mul, 3.0 mmol) and 2,2,2-trichloroethyl formate (466 mg, 2.20 mmol) were added thereto at room temperature followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, then the obtained residue was dissolved in ethyl acetate, and the organic layer was washed successively with an aqueous solution of sodium hydrogen carbonate, an aqueous solution of ammonium chloride, and an aqueous solution of sodium chloride. The solution was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (15 g) column (eluent; hexane : ethyl acetate = 2 : 1) to afford the title compound (627 mg, 73% yield) as a colorless oil. NMR spectrum (400 MHz, CDCl3) delta ppm: 1.44 (9H, s), 1.46 (9H, s), 2.79(1H, dd, J=17, 4 Hz), 3.01 (1H, dd, J=17, 5 Hz), 4.68 (1H, m), 4.86 (2H, s), 5.54 (1H, br d, J=9 Hz) IR spectrum nu max CHCl3 cm-1: 3439, 2982, 2934, 1769, 1717, 1498 Mass spectrum m/z (FAB) : 420 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 78 (3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoic acid The desired product was prepared by substituting N-(tert-butoxycarbonyl)-L-aspartic acid 4-tert-butyl ester for N-(tert-butoxycarbonyl)-L-valine in Example 70. MS (ESI(+)) m/z 492 (M+H)+; 1H NMR (DMSO-d6): delta8.33 (m, 1H), 7.73 (m, 2H), 7.61 (d, J=3 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 6.40 (s, 2H), 3.95 (m, 1H), 3.88 (s, 3H), 3.76 (s, 6H), 3.74 (s, 3H), 2.75 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | a) 3.78 ml of 4-ethylmorpholine, 4.42 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and a solution of 2.25 g of N-cyclohexylglycine ethyl ester (J. Heterocycl. Chem. 23, 1986, 929-933) in 8 ml of DMF are added to a solution of 2.89 g of N-Boc-L-aspartic acid beta-t-butyl ester in 50 ml of DMF. The reaction mixture is stirred at room temperature, then evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried, evaporated and the residue is chromatographed on silica gel with ethyl acetate/hexane 1:1. There are thus isolated 4.5 g of t-butyl-(S)-3-(1-t-butoxyformamido)-N-cyclohexyl-N-[(ethoxycarbonyl)methyl]succinamate, Fab-MS: 457 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; In dichloromethane; | 2.B)e) 10.6ml of 4-ethylmorpholine, 4.6g of N-(dimethyl- aminopropyl)-N'-ethylcarbodiimide hydrochloride, 244 mg of 4-dimethylaminopyridine and 3.1 g of sarcosine ethyl ester hydrochloride added in succession to a solution of 5.78 g of N-Boc-L-aspartic acid-beta-t-butyl ester in 100 ml of methylene chloride. After stirring the reaction mixture is poured into ice-cold 5% potassium hydrogen sulfate-10% potassium sulfate solution and extracted with ethyl acetate. The organic phase is washed with water, then dried, evaporated and the residue is chromatographed on silica gel with hexane-ethyl acetate (3:1). There are obtained 6.8 g of t-butyl (S)-3-t-butoxycarbonylamino-N-ethoxycarbonylmethyl-N-methylsuccinamate, MS (ion spray): 389.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; | f) A solution of 3.9 g of N-Boc-L-aspartic acid beta-t-butyl ester in 40 ml of methylene chloride is treated with 5.5 ml of 4-ethylmorpholine, 3.1 g of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 0.17 g of 4-dimethylaminopyridine. The material obtained under e), dissolved in 20 ml of methylene chloride, is added to this solution. After stirring, the reaction solution is poured into ice-cold 5% potassium hydrogen sulfate-10% potassium sulfate and extracted with methylene chloride. The organic phase is washed with sodium chloride solution, then dried and evaporated, and the residue is chromatographed on silica gel with hexane-methyl acetate 2:1. There are obtained 3.7 g of t-butyl (S)-N-(2-acetylethyl)-3-t-butoxycarbonylamino-N-cyclopropyl-succinamate, MS (ion spray): 399.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Example 17; (S)-3-amino-4-{4-[5-amino-l-(2,6-difluoro-benzoyl)-lH- [ 1 ,2,4]triazol-3-ylamino]-benzenesulfonylamino } -4-oxo-butyric acid (Cpd 17); EPO <DP n="47"/> 17a; Using the mixed anhydride formation procedure, 3.5 g (88 %) of Compound 17a was generated from N-Boc-O-t-Bu-L-Asp (3.0 g) and pivaloyl chloride (1.4 g). 1H NMR (300 MHz, CDCl3) delta 5.55 (m, IH), 4.60 (m, 1 H), 2.88 (m, 1 H), 2.78 (m, 1 H), 1.40 (s, 18 H), 1.20 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of the peptide is carried out by a regular stepwise Fmoc SPPS procedure starting from 2-Cl-Trt-chloride resin. The first amino acid (Fmoc-Phe) is loaded on the resin as described in previous examples to obtain a loading of about 0.7 mmol/g of amino acid/resin. After washing of the resin and removal of the Fmoc group by treatment with piperidine/DMF, the second amino acid (Fmoc-Asp(tBu)) is introduced to continue sequence elongation. Fmoc protected amino acids are activated in situ using TBTU/HOBt and subsequently coupled to the resin over about 50 minutes. Diisopropylethylamine or collidine is used during coupling as an organic base. Completion of the coupling is indicated by ninhydrin test. After washing of the resin, the Fmoc protecting group on the alpha-amine is removed with 20% piperidine in DMF for 20 min. These steps are repeated each time with another amino acid according to the peptide sequence. All amino acids used are Fmoc-Nalpha protected, except the last amino acid, which is protected with Boc. Trifunctional amino acids are side chain protected as follows: Asp(tBu). Three equivalents of the activated amino acids are used in the coupling reactions. At the end of the synthesis, the peptide-resin is washed with DMF, followed by DCM, and dried under vacuum to obtain dry peptide-resin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 0 - 20℃; for 1.25h; | 3,4-Methylenedioxy-5,4 -dimethoxy-3 -(Op-tert-butyI-iValpha-Boc-L-Asp)-ainido-Z-stilbene (10).To a stirred mixture of amine Ia (0.13 g, 0.43 mmol), O^tert-butyl-iV^-Boc-L-As] (0.22 g, 0.76 mmol, 1.8 eq), and PyBroP (0.35 g, 0.76 mmol, 1.8 eq) in DCM (3 mL) at 0 E< under Ar was added DIPEA (0.21 mL, 1.2 mmol, 2.8 eq). The reaction mixture was stirre for 75 min at rt5 and the solvent was removed in vacuo. The product was obtained by flas column chromatography (1:1, n-hexane:acetone) as an oil (10, 0.22 g, 88%); Rf 0.64 (1:1, EPO <DP n="30"/>hexane-acetone); [alpha]24D -13. OE (c 1.42, CHCl3); 1H-NMR (300 MHz, CDCl3) delta 1.44 (9H, s, tBu), 1.49 (9H5 s, tBu), 2.88 (2H, m, -CH2-), 3.73 (3H, s, OCH3), 3.84 (3H5 s, OCH3), 4.59 (IH3 m, alpha H)5 5.81 (IH, br), 5.92 (2H5 s, -OCH2O-), 6.38 (IH5 d, J = 12.6 Hz, vinyl H)5 6.44 (IH, s, ArH)5 6.46 (IH5 d, J= 12.6 Hz5 vinyl H)5 6.47 (IH5 s5 ArH), 6.70 (IH, d5 J = 8.1 Hz5 ArH)5 6.97 (IH5 dd, J= 8.4, 1.8 Hz, ArH)5 8.28 (IH, d, J = 2.4 Hz, ArH), 8.76 (IH, s); and HRMS calcd for C30H39N2O9 [M+H]+ 571.2655, found 571.2617. Anal, calcd for C30H38N2O9: C5 63.14; H, 6.71; N5 4.91. Found: C5 62.64; H, 7.00; N5 4.89. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With dmap; scandium tris(trifluoromethanesulfonate); diisopropyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 1.83333h; | To an ice cooled suspension of Camptothecin (1) (1.006 g, 2.889 mmol), Boc-D- Asp(OtBu)-OH (2.51g g, 8.67 mmol), (Cf3Sa)3Sc (0.855g, 1.733 mmol) and DMAP (1.061 g, 8.667 mmol) in DCM (20 ml) was added followed by the addition of DIC (9.1 ml, 1.424 mmol). The reaction solution was stirred under a blanket of N2 in a salt-ice bath for 0.5h. After removal from the salt-ice bath, the reaction suspension was stirred and become a clear solution within 20 minutes. After one hour later, TLC (DCM/MeOH, v/v 9/1) analysis showed the reaction was done. The reaction mixture was diluted with DCM and washed successively with 10% citric acid (50 ml x 3), saturated NaHCO3 (50 ml x 3) and brine (50 ml x 3), dried over Na2SO4 and stripped down under vacuum. The crude product (3.19g) was purified by crystallization from 20 ml of MeOH to give pure 1.4642g product. The yield was 82%. The actual molecular weight of the camptothecin-rvD-Asp(OtBu)-NHBoc as determined by MS (electro-spray) was 620, in keeping with calculated molecular weight 619.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate [197] [198] 360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc2O (353.0 g) and ammonium bicarbonate (NH4HCO3, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.[199] | |
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | Example 11 Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]-4-oxobutanoate 360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc2O (353.0 g) and ammonium bicarbonate (NH4HCO3, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; | 2.1. Preparation of Boc-Asp(O-tBu)-NCA (II-a)This method consisted in the cyclization of the free carboxylic acid with a main chain with one of the Bocs protecting the amine function, therefore first of all requiring the preparation of (Boc)2-Asp(O-t-Bu)-OH (VII-a). This was achieved by esterification of the alpha-carboxylic acid of Boc-Asp(O-t-Bu)-OH (V-a) into the benzyl ester (VI(a)), followed by a reaction with Boc2O in the presence of DMAP in order to give the amino compound protected by two Boc groups (VII-a), and then by deprotection of the benzyl ester group by hydrogenation in order to give (VIII-a). The following step consisted in the cyclization of the amino acid (VIII-a) protected with Vilsmeier's salt. The best results were obtained by forming the salt of DMF and oxalyl chloride in acetonitrile. The compound (II-a) was obtained with 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; | To a solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazol-2-ylthio)methyl)-5-fluoroaniline (50 mg, 93.6 mumol) and (S)-4-t- butoxy-2-(t-butoxycarbonylamino)-4-oxobutanoic acid (2.4 equiv, 66 mg, 0.244 mmol) in DCM (3 mL) was added HATU (2.2 equiv, 80 mg, 0.204 mmol) followed by DIPEA (3.0 equiv, 49 mL, 0.281 mmol). The mixture was stirred at room temperature overnight. Purification by column chromatography provided the protected product. Deprotection was performed by stirring with TFA (1 mL) and DCM (1 mL) for 1 h. Purification by HPLC using NH4CO3 as a modifier afforded the title compound as a white solid (11 mg, 18%). 1H NMR (400 MHz, MeOD) delta 7.43 (s, IH), 7.37 (d, J= 11.6 Hz, IH), 7.25 (s, IH), 7.18 (d, J = 8.4 Hz, IH), 6.80 (m, 2H), 6.56 - 6.49 (m, 2H), 6.38 - 6.30 (m, IH), 6.22 (m, IH), 4.19 (t, J = 7.6, IH), 4.00 (dd, J = 13.5, 7.4 Hz, 2H), 3.71 (s, 3H), 2.89 - 2.78 (m, IH), 2.67 (dd, J = 17.0, 8.1 Hz, IH), 1.54 (s, 3H), 1.53 (s, 3H); MS (EI) m/z 649 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | Example 16 (3S)-4-({(1S)-2-[2-([(2Z)-3-butyl[1,3]thiazolo[4,5-c]pyridin-2(3H)-ylidene]amino}carbonyl)-4-(trifluoromethyl)phenoxy]-1-methylethyl}oxy)-3-amino-4-oxobutanoic acid Example 16A (S)-4-tert-butyl 1-((S)-1-(2-((Z)-3-butylthiazolo[4,5-c]pyridin-2(3H)-ylidenecarbamoyl)-4-(trifluoromethyl)phenoxy)propan-2-yl) 2-(tert-butoxycarbonylamino)succinate To a solution of Example 18C (0.380 g, 0.838 mmol), triethylamine (0.584 ml, 4.19 mmol), (S)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxobutanoic acid (0.242 g, 0.838 mmol), DMAP (0.026 g, 0.209 mmol) in DMF (10 mL) added HATU (0.794 g, 2.095 mmol). The mixture was stirred overnight at room temperature then diluted with ice water (50 mL). The solid was collected by filtration to give the title compound (490 mg, 0.676 mmol, 81% yield). 1H NMR (300 MHz, DMSO-d6) delta ppm 0.95 (t, J=7.29 Hz, 3H) 1.23-1.28 (m, 7H) 1.29-1.36 (m, 13H) 1.36-1.46 (m, 4H) 1.76-1.89 (m, 2H) 2.36-2.47 (m, 1H) 2.60-2.73 (m, 1H) 4.18-4.33 (m, 3H) 4.54 (t, J=7.12 Hz, 2H) 5.13-5.23 (m, 1H) 7.37 (d, J=8.81 Hz, 1H) 7.85 (dd, J=8.81, 2.37 Hz, 1H) 7.99 (t, J=4.75 Hz, 1H) 8.31 (d, J=2.71 Hz, 1H) 8.50 (d, J=5.09 Hz, 1H) 9.04 (s, 1H); MS (DCI/NH3) m/z 725 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; HATU; In tetrahydrofuran; at 20℃; for 4h; | Example 11; Compound No.5; 7-{3-[2-((2S)-2-Amino-3-carboxy-propionylamino)-1-fluoro-ethylidene]-piperidin-1-yl}-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid hydrochloride; STEP A: 7-{3-[2-((2S)-3-tert-Butoxycarbonyl-2-tert-butoxycarbonylamino-propionylamino)-1-fluoro-ethylidene]-piperidin-1-yl}-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid Solid HATU (7.3 g, 19.3 mmol) was added to a THF solution (200 mL) of 7-[3-(2-amino-1-fluoro-ethylidene)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (8.0 g, 17.5 mmol), (S)-2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (5.6 g, 19.3 mmol) and Et3N (6.1 mL, 43.7 mmol). After 4 h at room temperature, the resulting mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), concentrated and purified via column chromatography to a white solid. MS m/z 691 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester [179] [180] N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5C, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).[181] 1H NMR (400 MHz, CDCl3) delta: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).[182] Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).[183] | ||
41.7 g | Example 8 Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5 C., to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc:Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol). 1H NMR (400 MHz, CDCl3) delta: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H). Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester [185] [186] L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5C, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).[187] 1H NMR (400 MHz, CDCl3) delta: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).[188] Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).[189] | ||
6.0 g | Example 9 Synthesis of N,N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5 C., to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc:Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol). 1H NMR (400 MHz, CDCl3) delta: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H). Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55). |
[ 77004-75-2 ]
(R)-4-(tert-Butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid
Similarity: 0.98
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P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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