* 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.
Stage #1: With potassium carbonate In diethyl ether; water at 20℃; for 4 h; Stage #2: With hydrogenchloride In water
30.5 g (207 mmol) of (S)-2-amino-4-methoxy-4-oxobutanoic acid obtained in Step 1-2(1) was dissolved in 726 mL of distilled water, and 260 mL of diethyl ether was added thereto. 40.15 g (290 mmol) of potassium carbonate was added and dissolved, and then 41.5 mL (290 mmol) of benzyl chloroformate was added thereto. The mixture was stirred at room temperature for 4 hours. After phase-separation, the organic layer was discarded. The aqueous layer was washed with diethyl ether several times, and was adjusted to pH 1 with 1 N hydrochloric acid. The aqueous layer was extracted with diethyl ether several times, dried over magnesium sulfate, and concentrated under vacuum to give 55 g of the title compound (yield: 94percent). 1H NMR(300MHz, CDCl3)δ8.23(s, 1H), 7.35(m, 5H), 5.87(d, 1H), 5.12(s, 2H), 4.69(m, 1H), 3.68(s, 3H), 2.97(dd, 2H)
Reference：
[1] European Journal of Organic Chemistry, 2003, # 17, p. 3387 - 3397
[2] Patent: WO2012/148246, 2012, A2, . Location in patent: Page/Page column 16
[3] Tetrahedron Letters, 2003, vol. 44, # 28, p. 5251 - 5253
[4] Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4177 - 4187
[5] Tetrahedron Asymmetry, 2011, vol. 22, # 20-22, p. 1849 - 1854
2
[ 501-53-1 ]
[ 3160-47-2 ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium carbonate In 1,4-dioxane; water at 0 - 20℃;
This is a known compound. Goodman, Murray; Boardman, Franklin; J. Amer. Chem. Soc. 1963, 85, 2483-90. The crude compound 4-9 (9.8 g, 53 mmol) was dissolved in water (115 mL) and dioxane (53 mL), and cooled to 0 °C. Na2CO3 (5.6 g, 53 mmol) was added, followed by benzyl chloroformate (9.1 g, 53.4 mmol) in dioxane (63 mL) dropwise over 3 h. The reaction mixturewas stirred at ambient temperature overnight. The solution was washed with ethyl acetate (3 x 50 mL). The aqueous layer was acidified to pH 2 with 6 M HC1. The product was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2 SO4 and the solvent was evaporated under reduced pressure. The crude compound was passed through a short pad of silica gel using ethyl acetate and concentrated to providecompound 4-10 as a semi-solid (78percent).
Stage #1: With potassium carbonate In diethyl ether; water at 20℃; for 4 h; Stage #2: With hydrogenchloride In water
L-Aspartic acid (10.0 g, 75.1 mmol) was added to MeOH (50 mL) and cooled to -30 °C. SOCl2 (7.5 mL) was added dropwise to the mixture, the cooling bath was removed and the solution was slowly warmed to room temperature. After stirring for 25 min, Et2O (1.0 mL) was added to the mixture and upon cooling and shaking, the product was precipitated as a colorless solid which was filtered immediately, washed with ice cold diethyl ether and collected. The amine hydrochloride was obtained as a colorless solid, and was used to the next reaction without further purification. To the amine hydrochloride dissolved in H2O (310 mL) was added Et2O (120 mL), K2CO3 (14.5 g, 105.1 mmol) and CbzCl (15 mL, 105.1 mmol). The solution was stirred at room temperature for 4 h, the layers were separated, the aqueous layer was washed with Et2O and acidified to pH 1 with 1 N HCl. The resulting solution was extracted with Et2O. The combined organic phases were dried over Na2SO4 and the solvents evaporated. Purification on silica gel column chromatography (CH2Cl2/MeOH = 10:1) yielded the product 16 as a colorless solid (16.0 g, 57.0 mmol, 76percent (2 steps)); IR (neat, cm-1) 2945, 1690, 1538, 1264, 1179, 1035, 873, 747, 636; 1H NMR (300 MHz, CD3OD) δ 7.36-7.28 (5H, m, Bn), 5.10 (2H, s, Bn), 4.54 (1H, dd, J = 7.2, 5.2 Hz, H20), 3.67 (3H, s, Me), 2.94-2.75 (2H, m, H19); 13C NMR (75 MHz, CDCl3) δ 174.9, 171.6, 156.3, 136.4, 128.6, 128.3, 128.2, 67.4, 52.3, 50.2, 36.4; ESI-HRMS (m/z) calcd for C13H15NNaO6 [M+Na]+ 304.0797, found 304.0772.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1989, p. 833 - 834
[2] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 17, p. 2022 - 2034
[3] Journal of the American Chemical Society, 1963, vol. 85, p. 2483 - 2490
[4] Bulletin of the Chemical Society of Japan, 1974, vol. 47, # 1, p. 151 - 155
[5] Tetrahedron, 2017, vol. 73, # 27-28, p. 3838 - 3847
L-Aspartic acid (10.0 g, 75.1 mmol) was added to MeOH (50 mL) and cooled to -30 C. SOCl2 (7.5 mL) was added dropwise to the mixture, the cooling bath was removed and the solution was slowly warmed to room temperature. After stirring for 25 min, Et2O (1.0 mL) was added to the mixture and upon cooling and shaking, the product was precipitated as a colorless solid which was filtered immediately, washed with ice cold diethyl ether and collected. The amine hydrochloride was obtained as a colorless solid, and was used to the next reaction without further purification. To the amine hydrochloride dissolved in H2O (310 mL) was added Et2O (120 mL), K2CO3 (14.5 g, 105.1 mmol) and CbzCl (15 mL, 105.1 mmol). The solution was stirred at room temperature for 4 h, the layers were separated, the aqueous layer was washed with Et2O and acidified to pH 1 with 1 N HCl. The resulting solution was extracted with Et2O. The combined organic phases were dried over Na2SO4 and the solvents evaporated. Purification on silica gel column chromatography (CH2Cl2/MeOH = 10:1) yielded the product 16 as a colorless solid (16.0 g, 57.0 mmol, 76% (2 steps)); IR (neat, cm-1) 2945, 1690, 1538, 1264, 1179, 1035, 873, 747, 636; 1H NMR (300 MHz, CD3OD) delta 7.36-7.28 (5H, m, Bn), 5.10 (2H, s, Bn), 4.54 (1H, dd, J = 7.2, 5.2 Hz, H20), 3.67 (3H, s, Me), 2.94-2.75 (2H, m, H19); 13C NMR (75 MHz, CDCl3) delta 174.9, 171.6, 156.3, 136.4, 128.6, 128.3, 128.2, 67.4, 52.3, 50.2, 36.4; ESI-HRMS (m/z) calcd for C13H15NNaO6 [M+Na]+ 304.0797, found 304.0772.
Stage 1 - Synthesis of 1-tert-butyl 4-methyl lambda/-[(benzyloxy)carbonyl]-L-aspartate ; <n="26"/>A solution of (2S)-2-[(benzyloxy)carbonyl]amino}-4-methoxy-4-oxobutanoic acid (9g, 32.0mmol) in DCM (180ml) was cooled to -50 0C and sulphuric acid (1.028ml, 18.50mmol) added. Condensed methylpropylene (80ml, 32.0mmol) was added to the stirred solution in a single portion, the reaction was then allowed to stand and allowed to warm to RT over 1 h. After standing overnight, the reaction was neutralized with sat. NaHCO3, the layers separated and the organic layer washed with water and brine. The organic phase was dried over MgSO4, filtered and evaporated, and the residue purified by column chromatography eluting with 10 to 20% EtOAc in hexanes to give product as a colourless oil (10.2g, 94%). m/z 338 [M+H]+.
4-(4-<i>tert</i>-butoxycarbonylmethyl-2-methoxycarbonylmethyl-3-oxo-piperazin-1-yl)-3-(4-carbamimidoyl-benzoylamino)-4-oxo-butyric acid methyl ester[ No CAS ]
4-(3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propyl)-2-methoxycarbonylmethyl-3-oxo-2,3,4,5-tetrahydro-1<i>H</i>-benzo[<i>e</i>][1,4]diazepine-7-carboxylic acid[ No CAS ]
3-[(2-amino-3-methoxycarbonyl-propionyl)-(3-{2-[2-(3-<i>tert</i>-butoxycarbonylamino-propoxy)-ethoxy]-ethoxy}-propyl)-amino]-methyl}-4-fluoro-benzoic acid <i>tert</i>-butyl ester[ No CAS ]
[7-[(1<i>H</i>-benzoimidazol-2-ylmethyl)-methyl-amino]-hydroxy-methyl}-4-(3-{2-[2-(3-<i>tert</i>-butoxycarbonylamino-propoxy)-ethoxy]-ethoxy}-propyl)-3-oxo-2,3,4,5-tetrahydro-1<i>H</i>-benzo[<i>e</i>][1,4]diazepin-2-yl]-acetic acid methyl ester[ No CAS ]
[(S)-1-(Methylcarbamoylmethyl-carbamoyl)-3-((1S,5S,8S)-5,9,9-trimethyl-2,4-dioxa-3-bora-tricyclo[6.1.1.01,5]dec-3-yl)-propyl]-carbamic acid benzyl ester[ No CAS ]
[(S)-1-Benzenesulfonylaminocarbonyl-3-((1S,5S,8S)-5,9,9-trimethyl-2,4-dioxa-3-bora-tricyclo[6.1.1.01,5]dec-3-yl)-propyl]-carbamic acid benzyl ester[ No CAS ]
[(S)-1-Trifluoromethanesulfonylaminocarbonyl-3-((1S,5S,8S)-5,9,9-trimethyl-2,4-dioxa-3-bora-tricyclo[6.1.1.01,5]dec-3-yl)-propyl]-carbamic acid benzyl ester[ No CAS ]
[(S)-1-(4-Amino-benzenesulfonylaminocarbonyl)-3-((1S,5S,8S)-5,9,9-trimethyl-2,4-dioxa-3-bora-tricyclo[6.1.1.01,5]dec-3-yl)-propyl]-carbamic acid benzyl ester[ No CAS ]
((S)-1-{2-[4-(2-Benzyloxycarbonylamino-ethyl)-benzoylamino]-acetyl}-4-tert-butoxycarbonylmethyl-3-oxo-piperazin-2-yl)-acetic acid methyl ester[ No CAS ]
methyl (S)-13-(((benzyloxy)carbonyl)amino)-2,2-dimethyl-4,12-dioxo-3,8-dioxa-5,11-diazapentadecan-15-oate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Compound 4-10 (7.9 g, 28 mmol) was dissolved in anhydrous THF (60 mL) and thesolution was cooled to -20 C under nitrogen. N-methyl morpholine (NMM, 3.4 mL, 31 mmol)was added and the solution was then stirred for 10 mi iso-Butyl chloroformate (3.7 mL, 29mmol) was added to the cold solution via syringe slowly and the solution was stirred at -10 Cfor 45 mm. The mixture was cooled to -40 C and a solution of Boc-5L10-amine HC1 salt (compound 2-4, 6.9 g, 29 mmol) and NIVIM (3.2 mL) in DMF (40 mL) was added dropwise via a Teflon tube. The mixture was stirred at -40 C for 20 mm and then allowed to warm to room temperature slowly, and stirred for another 8 hr. The reaction mixture was then evaporated to dryness, and dissolved in DCM (50 mL), and washed with aqueous 10% citric acid (2 x 30 mL)and 5% KHCO3 solution (2 x 30 mL) successively. The organic phase was applied to a flash silica column and purified by gradient elution using methanol in DCM to provide compound 4- 11 as a semisolid material (10.5 g, 81%).
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