* 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 sodium hydroxide In 1,4-dioxane; water Stage #2: at 20℃;
Example 2. Compound 1 (Boc-Asp) (0203) In a 500 mL one-neck round bottom flask, aspartic acid (Asp, 4 g, 30 mmol), 1,4-Dioxane (120 mL) and H2O (60 mL) were mixed yielding a heterogeneous solution. An aqueous solution of NaOH (1 M) was added to the mixture with constant stirring until the solution became homogeneous and clear indicating that the aspartic acid was completely dissolved. The solution was cooled using an ice-bath, then di-tert-butyl dicarbonate (Boc2O, 7.2 g, 33 mmol) dissolved in 1,4-Dioxane (20 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. Once the reaction was complete, the solvent was partially evaporated, using a rotary evaporator, to a final volume of 30 mL. Then, EtOAc (20 mL) was added and the water layer was acidified under ice-cold conditions using an aqueous solution of KHSO4 to pH2. The solution mixture was transferred to a separatory funnel and the product was extracted using EtOAc (volume, 3 times). The organic layers were combined and dried over Na2SO4. The solvent was evaporated using rotary evaporator, and further vacuum drying was applied overnight to yield the compound as white solid (6 g; reaction yield85percent). (0204) 1H NMR (600 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.51-2.55 (m, 1H), 2.65-2.69 (m, 1H), 4.24-4.28 (m, 1H), 7.05-7.07 (d, 1H, J=12 Hz), 12.5 (s, 2H).
76.5%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 5 h;
L-aspartic acid (10 g, 0.075 mol) and sodium hydroxide (6.0 g, 0.15 mol) are dissolved in distilled water (100 mL). The solution is cooled in ice bath to 0°C and dioxane (100 mL) was added. (Boc)2O (18.0 g, 0.083 mol) is added dropwise during 1 h. Reaction mixture is stirred in ice bath for 2 hours and then another 2 h at room temperature. Reaction mixture is concentrated on vacuum evaporator. The unreacted (Boc)2O is removed by extraction into the diethyl ether. The aqueous layer is separated, acidified to pH=2 with saturated solution of sodium hydrogen sulfate and the product is extracted into the ethyl acetate. Organic phase is separated, dried with sodium sulfate and concentrated on vacuum evaporator. Boc-L-Asp-OH was crystallized from mixture ethyl acetate/hexane. Yield: 13.4 g (76.5percent), m.p. 116-118°C.
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 51, p. 16084 - 16097
[2] Patent: US2017/168042, 2017, A1, . Location in patent: Paragraph 0203-0204
[3] Asian Journal of Chemistry, 2014, vol. 26, # 15, p. 4716 - 4722
[4] Patent: EP1647283, 2006, A1, . Location in patent: Page/Page column 5
[5] Chemistry Letters, 1988, # 10, p. 1643 - 1646
[6] Tetrahedron Letters, 2001, vol. 42, # 43, p. 7599 - 7603
[7] Tetrahedron, 2007, vol. 63, # 29, p. 6932 - 6937
[8] Synthesis, 2010, # 15, p. 2512 - 2514
[9] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 7, p. 2011 - 2015
2
[ 56-84-8 ]
[ 13726-67-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium hydroxide In water; acetonitrile at 25℃; for 15 h;
General procedure: L-Phenylalanine (1.0 g, 6.05 mmol) and sodium carbonate (0.71 g, 6.70 mmol) in water (10 mL) was reacted with a solution of 2 (1.89 g, 6.36 mmol) in acetone (10 mL). The reaction mixture was stirred at room temperature till the reaction completes, as monitored by TLC. The resulting solution was concentrated, to the residue was added water (10 mL) and ethyl acetate (10 mL), pH adjusted to 6.0 with 10percent KHSO4 and stirred for 5 minutes. The organic layer was removed and the aqueous layer was acidified to pH 2.0 with 10percent KHSO4 at 0-5°C and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 5percent NaHCO3 solution, water, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was concentrated and the residue was crystallized from EtOAc/ n-hexane (2:8) mixture to give the product as a white solid (1.53g, 95percent yield).
Reference：
[1] Tetrahedron Letters, 2002, vol. 43, # 2, p. 311 - 313
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 8, p. 2597 - 2601
[3] Journal of Organic Chemistry, 1979, vol. 44, p. 3442 - 3444
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2002, vol. 41, # 5, p. 1064 - 1067
[5] Tetrahedron Letters, 2007, vol. 48, # 46, p. 8230 - 8233
[6] Tetrahedron Letters, 1993, vol. 34, # 44, p. 7031 - 7034
4
[ 56-84-8 ]
[ 98015-52-2 ]
[ 13726-67-5 ]
Yield
Reaction Conditions
Operation in experiment
60%
With triethylamine In 1,4-dioxane; water
EXAMPLE 28 Synthesis of tert-butyloxycarbonyl-L-aspartic acid To a solution of 1.33 g (10 mmol) of L-aspartic acid in a dioxane/water (1:1) mixture (30 ml), 4.2 ml (30 mmol) of triethylamine are added, and the mixture is stirred until solution is complete (approximately 10 min). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate are then added and the mixture is stirred for 6 hours at 20° C. 50 ml of water are then added and the mixture is extracted with 2*20 ml of ethyl acetate. The aqueous phase is acidified (pH 2-3) with NHCl, and then extracted with 3*30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over MgSO4 and evaporated. The product obtained is crystallized in ethyl acetate and petroleum ether. 1.4 g (60percent yield) of the expected acid is obtained. STR60
Reference：
[1] Synthesis, 1986, # 8, p. 627 - 632
[2] Journal of Organic Chemistry, 1985, vol. 50, # 20, p. 3951 - 3953
[3] Patent: US4725680, 1988, A,
5
[ 116596-40-8 ]
[ 13726-67-5 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 22, p. 5386 - 5389
Reference：
[1] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 10, p. 3103 - 3108
[2] Synthetic Communications, 2017, vol. 47, # 22, p. 2127 - 2132
14
[ 56-84-8 ]
[ 58632-95-4 ]
[ 13726-67-5 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1977, vol. 50, p. 718 - 721
With hydrogen; In ethanol; at 20℃; under 760.051 Torr; for 3h;
General procedure: A mixture of substrate (0.2 mmol) and Pd/Al2O3Si (6.4 mg, 1 mol%) in ethanol (2 mL) was stirred under hydrogen atmosphere (H2 balloon pressure) at room temperature. The progress of reaction was monitored by TLC analysis or GC-MS. After the reaction was completed, the reaction mixture was filtered, and the catalyst was washed with ethanol. The solvent in filtrate was removed by vacuum to give the crude product. The purified product was obtained by column chromatography or recrystallization. After each cycle, the palladium residue in the reaction mixture solvent was determined by ICP-OES.
Example 2. Compound 1 (Boc-Asp) (0203) In a 500 mL one-neck round bottom flask, aspartic acid (Asp, 4 g, 30 mmol), 1,4-Dioxane (120 mL) and H2O (60 mL) were mixed yielding a heterogeneous solution. An aqueous solution of NaOH (1 M) was added to the mixture with constant stirring until the solution became homogeneous and clear indicating that the aspartic acid was completely dissolved. The solution was cooled using an ice-bath, then di-tert-butyl dicarbonate (Boc2O, 7.2 g, 33 mmol) dissolved in 1,4-Dioxane (20 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. Once the reaction was complete, the solvent was partially evaporated, using a rotary evaporator, to a final volume of 30 mL. Then, EtOAc (20 mL) was added and the water layer was acidified under ice-cold conditions using an aqueous solution of KHSO4 to pH2. The solution mixture was transferred to a separatory funnel and the product was extracted using EtOAc (volume, 3 times). The organic layers were combined and dried over Na2SO4. The solvent was evaporated using rotary evaporator, and further vacuum drying was applied overnight to yield the compound as white solid (6 g; reaction yield85%). (0204) 1H NMR (600 MHz, DMSO-d6): delta 1.38 (s, 9H), 2.51-2.55 (m, 1H), 2.65-2.69 (m, 1H), 4.24-4.28 (m, 1H), 7.05-7.07 (d, 1H, J=12 Hz), 12.5 (s, 2H).
76.5%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 5h;
L-aspartic acid (10 g, 0.075 mol) and sodium hydroxide (6.0 g, 0.15 mol) are dissolved in distilled water (100 mL). The solution is cooled in ice bath to 0C and dioxane (100 mL) was added. (Boc)2O (18.0 g, 0.083 mol) is added dropwise during 1 h. Reaction mixture is stirred in ice bath for 2 hours and then another 2 h at room temperature. Reaction mixture is concentrated on vacuum evaporator. The unreacted (Boc)2O is removed by extraction into the diethyl ether. The aqueous layer is separated, acidified to pH=2 with saturated solution of sodium hydrogen sulfate and the product is extracted into the ethyl acetate. Organic phase is separated, dried with sodium sulfate and concentrated on vacuum evaporator. Boc-L-Asp-OH was crystallized from mixture ethyl acetate/hexane. Yield: 13.4 g (76.5%), m.p. 116-118C.
To a solution of L-aspartic acid (1.0 g, 7.51 mmol) in dioxane/H2O(1:1, 40 mL) NaOH was added (1.2 g, 4 eq). The reaction mixture was stirred at room temperature for 0.5 h, and then cooled to 0 C (ice bath). To the cooled reaction mixture (Boc)2O (2.5 g, 1.5 eq) was added and allowed to warm up to room temperature and further stirred for 18 h. After completion of the reaction, the mixture was diluted with water (200 mL) and titrated to pH 3-4 with 1 N HCl. The aqueous solution was extracted with EtOAc (100 mL× 3) and the EtOAc layers were all combined. The organic layer was washed with brine (100 mL × 2), water (100 mL × 2),and then evaporated in vacuo. The given BocNH-Asp-OH as colorless syrup was directly used in the next step.
EXAMPLE 28 Synthesis of tert-butyloxycarbonyl-L-aspartic acid To a solution of 1.33 g (10 mmol) of L-aspartic acid in a dioxane/water (1:1) mixture (30 ml), 4.2 ml (30 mmol) of triethylamine are added, and the mixture is stirred until solution is complete (approximately 10 min). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate are then added and the mixture is stirred for 6 hours at 20 C. 50 ml of water are then added and the mixture is extracted with 2*20 ml of ethyl acetate. The aqueous phase is acidified (pH 2-3) with NHCl, and then extracted with 3*30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over MgSO4 and evaporated. The product obtained is crystallized in ethyl acetate and petroleum ether. 1.4 g (60% yield) of the expected acid is obtained. STR60
di-(3-estradiol)aspartate (Boc protected)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
0.233 g (1.00 mmol) of Boc-Asp was dissolved in dry DMF under ice-cooling and 0.270 g (2.00 mmol) of 1-hydroxybenzotriazole (HOBt) and 0.495 g (2.40 mmol) of dicyclohexylcarbodiethylene were added. The amine (DCC) was stirred for 0.5 h to give an activating solution.0.653 g (2.40 mmol) of estradiol was dissolved in dry tetrahydrofuran, adjusted to pH 8 with N-methylmorpholine (NMM) and added to the activation solution, followed by N-methylmorpholine (NMM) Adjust the pH to 8, remove the ice bath, and react at room temperature for 8 h. TLC (petroleum ether/ethyl acetate, 1/1) showed disappearance of Boc-Asp. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate and filtered. The filtrate was washed with 5% sodium bicarbonate solution three times, saturated sodium chloride solution three times, and 5% potassium hydrogensulfate solution three times. The solution was washed 3 times with saturated sodium chloride solution, 3 times with 5% sodium bicarbonate solution and 3 times with saturated sodium chloride solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol, 50/1) to give 501 mg (68%) of the title compound as colorless. solid.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;dmap; In chloroform; at 20℃; for 20.25h;
To a 1 litre 3-neck round-bottom flask fitted with a magnetic stirrer under nitrogen was charged N-(tert-butoxycarbonyl)aspartic acid (9.44 g; 0.04 mol), and chloroform (440 ml) with stirring. EDCI (27.60 g, 0.14 mol), and triethylamine (17.88 ml) were added and stirred for 15 minutes. Estradiol (20.00 g; 0.07 mol) was charged followed by DMAP (2.24 g, 0.018 mol). The solution was stirred for 20 hours at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with chloroform (400 ml), and washed successively with a 2M hydrochloric acid solution (2×400 ml) then brine (400 ml) and finally saturated sodium bicarbonate solution (2×400 ml). The organic layer was dried over magnesium sulphate filtered and concentrated to afford a white solid. The crude material was purified by dry column on silica using a gradient elution of Hexane:Ethyl acetate 70:30 to 60:40. Fractions containing product were combined and concentrated to afford a white solid.
With hydrogenchloride; lithium borohydride; sodium chloride; potassium hydrogencarbonate; In tetrahydrofuran; methanol; water;
Reference Example 1-54 Synthesis of (4S)-2,2-dimethyl-3-(t-butoxycarbonyl)-4-(2-hydroxyethyl)-1,3-oxazolidine (Reference Compound No. 1-54): 40.1 g (0.4 mol) of potassium hydrogencarbonate was added to an anhydrous N,N'-dimethylformamide solution containing 23.4 g (0.1 mol) of t-butoxycarbonyl-L-aspartic acid. The above mixture was stirred at room temperature for one hour. Furthermore, the reaction mixture was stirred overnight at room temperature after the dropwise addition of 31.1 ml (0.5 mol) of methyl iodide. Water was then added to the reaction mixture, followed by the extraction with ethyl acetate. The resultant organic extract layer was successively washed with 1 N hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 25.8 g of a dimethyl ester was obtained in a yield of 99%. A tetrahydrofuran solution containing 25.7 g (98.4 mmol) of the above prepared dimethyl ester was added to a tetrahydrofuran solution containing 4.3 g (196.8 mmol) of lithium borohydride. To this reaction mixture, 50 ml of methanol was further added dropwise. After stirring for two hours, water was added to the reaction mixture and the solvent was distilled away therefrom under reduced pressure. To the residue thus obtained, 1 N hydrochloric acid was added. The mixture was extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 18.5 g of a diol was obtained in a yield of 92%.
<strong>[13726-67-5]Boc-Asp-OH</strong> (1.475 g, 6.33 mmol), HCl.Asp-(OMe)2 (2.5 g, 12.66 mmol) and Et3N (1.77 mL, 6.33 mmol) are mixed in 50 mL of tetrahydrofurane (THF) and suspension is cooled to -10C. The DCC (3.12 g, 15.1 mmol) is dissolved in 20 mL THF and the solution is cooled to -10C. Cool solution of DCC in THF is added to the suspension and the reaction mixture is left one hour at -10C and then overnight at 5C without mixing. Reaction mixture is warmed up to room temperature, acetic acid (0.1 mL) is added and a mixture is stirred for 30 min at room temperature. Precipitated N,N'-dicyclohexylurea (DCU) and triethylamine hydrochloride (Et3N.HC1) are filtered off, and a filtrate is concentrated on vacuum evaporator. Oily residue is diluted with ethyl acetate (100 mL) and gradually extracted with 2 wt% aqueous sodium hydrogen carbonate (50 mL), 0.5 wt% citric acid (50 mL) and water (50 mL) in a last step. Organic layer is dried with sodium sulfate and product is crystallized from a mixture ethyl acetate/hexane. Yield: 2.1g (64.5%), m.p. 115-116C, TLC: (silica gel, ethyl acetate, Rf = 0.54). Elemental analysis: Calcd/found C = 48.55/48.85, H = 6.40/6.50, N = 8.09/8.05. The Boc protection group is removed by trifluoroacetic acid (TFA). Boc-Asp-[Asp-(OMe)2]2 (2.0 g) is dissolved in TFA (8.0 mL) and stirred for 30 min at room temperature. The excess of TFA is evaporated, the mixture was tree times diluted with dry methanol and the solvent evaporated again. The oilly residue is triturated with diethyl ether to form crystals of TFA.Asp-[Asp-(OMe)2]2. Yield 1.6 g (77.9%)
(S)-3-(tert-butoxycarbonylamino)-4-((R)-1-carboxy-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)ethylamino)-4-oxobutanoic acid[ No CAS ]
(R)-3-(tert-butoxycarbonylamino)-4-((R)-1-carboxy-2-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)ethylamino)-4-oxobutanoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a 100 mL round bottom flask, N-Boc-L-glutamic acid (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (136 mg, 17%) to yield a 1 :1 ratio mixture of R-R and S-R isomers of Compound N- 64, similar to Compound C racemate in Examples 5 and 5a. 1H-NMR (500 MHz, CDCl3): delta 1.36 (s, 9H), 1.53 (s, 6H), 1.59 (s, 3H), 1.61 (s, 3H), 1.88-2.03 (m, 10H), 2.77-2.86 (m, IH), 2.94-2.97 (m, IH), 3.11-3.17 (m, 2H), 4.45 (m, IH), 4.63 (m, IH), 5.01-5.03 (m, 2H), 5.12- 5.15 (m, IH), 5.89-5.90 (m, IH), 7.33 (m, IH), 8.70 (broad, 2H). 13C-NMR (125 MHz, CDCl3): delta 15.00, 15.13, 16.68, 24.71, 25.43, 25.67, 27.29, 28.70, 28.79, 28.85, 31.43, 36.68, 38.62, 38.67, 49.38, 51.36, 79.65, 79.85, 118.23, 118.33, 122.69, 123.27, 130.33, 134.31, 134.34, 134.37, 139.32, 154.89, 170.77, 172.68, 172.79; ES-MS: mass calcd for Chemical Formula: C27H44N2O7S 540.71. Found (M+Na) m/z 563.4.
With pyridine; ammonium bicarbonate; In tetrahydrofuran; at 20℃; for 12h;
Example 19 Synthesis of (2S)-2-tert-butoxycarbonylamino-butanedioic acid diamide (compound 29b) To a solution of N-Boc-L-aspartic acid (29.5 g, 126.5 mmol) in THF (348 mL) was added pyridine (11.7 g, 147.9 mmol), Boc2O (70.5 g, 323.0 mmol), and ammonium bicarbonate (24.3 g, 307.4 mmol) with stirring. The reaction mixture was stirred for 12 hours at room temperature and then evaporated. The residue was diluted with ethyl acetate (250 mL) and washed with water (50 mL) with stirring. The organic layer was evaporated to give compound 29b (20.1 g, 69%). MP: 190-192 C. (MeOH); 1H NMR (4d-MeOH, 300 MHz): delta1.44 (s, 9H), 2.64, 2.59 (ABq, J=5.4 Hz, 2H), 4.37-4.45 (m, 1H); MS: m/e 254.1 (M++23).
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