* 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.
With triethylamine In DMF (N,N-dimethyl-formamide); dichloromethane at 20℃; for 2 h;
To a solution of 9.82 g (0.041 m) of (L)-tyrosine, tert-butyl ester in 150 ml of methylene chloride and 20 ml of DMF was added 5.2 g (0.04 m) of triethyl amine followed by 9.03 g (0.04 m) of ditertbutyldicarbonate. The reaction mixture was stirred for 2 hours at room temperature and was then washed with 1 N HCl (3.x.50 ml), NaHCO3 solution (1.x.50 ml) and brine (1.x.50 ml) and was dried over MgSO4. The mixture was filtered and concentrated in vacuo to give 13.59 g (98percent yield) of a white solid. 300 MHz 1H NMR (CDCl3): 1.42 (s, 18H); 2.95 (d, 2H); 4.39 (dd, 1H); 5.01 (d, 1H); 6.15 (s, 1H); 6.70 (d, 2H); 7.00 d, 2H).
96%
With triethylamine In 1,4-dioxane; water at 21℃; Inert atmosphere
To a stirred solution of Tyr-OBut (4) (5.0 g, 21.0 mmol) in dioxane and water (42 ml, 0.5 M, dioxane/water = 1/1) were added Et3N (3.27 g, 4.5 mL, 32.3 mmol, 1.54 equiv) and (Boc)2O (5.56 g, 24.4 mmol, 1.14 equiv). The reaction mixture was stirred at rt overnight. After confirming the completion of the reaction by TLC, the reaction mixture was acidified to pH 3 by adding 10percent aqueous KHSO4, and extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4) and evaporated. Column chromatography on silica gel (petroleum ether/EtOAc = 20/1 then 2/1) to yield N-Boc-Tyr(OH)-OBut (5) (6.82 g, 96percent) as a white solid, mp 106-107°C (lit.12 112.8-113.0 °C (nhexane/CH2Cl2)). The spectroscopic data of compound 5 were identical to those reported in the literature.
95%
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
Example 1 (0506) This example details the synthesis of the carbonyl-containing amino acid presented in FIG. 4. The carbonyl-containing non-natural amino acid was produced as described in FIG. 4.
94%
With sodium carbonate In water; acetone for 18 h;
To a stirring solution of sodium bicarbonate (37.4 g, 445 mmol) in water (1 L) was added (S)-tert-b\ity\ 2-amino-3-(4-hydroxyphenyl)propanoate (96 g, 405 mmol) and acetone (850 mL). A solution of di-tert-butyl dicarbonate (97 g, 445 mmol) in acetone (220 mL) was then added slowly over 2 h. After a further 16 h, the mixture was treated with water (1.7 L) then treated with a solution of AcOH (30 mL) in water (300 mL) added slowly. The mixture was extracted with EA (1 L) and the organics dried over Na2SO4 and partially concentrated. The residue was re-slurried with iso- hexanes (1 L). The precipitate was collected by filtration, washing with iso-hexanes (100 mL) to afford 128.4 g (94percent) of tert-butyl (ri-butoxycarbonyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for Ci8H27NO5: 337.2; found 360.2 [M+Na]+, tR = 5.93 min (Method 10).
85%
With triethylamine In 1,4-dioxane; water at 20℃;
To a solution of commercially available L-tyrosine ieri-butyl ester (700 mg, 2.95 mmol) in 50 mL of Dioxane-H20 (5: 1), NEt3 (1.23 ml, 8.85 mmol) and (Boc)20 (966 mg, 4.42 mmol) were added, and the reaction mixture was stirred at room temperature. When TLC indicated the consumption of L- tyrosine ieri-butyl ester, the reaction mixture was concentrated under reduced pressure to remove dioxane, and then the resulting solution was diluted with water and extracted with EtOAc (2 χ 50 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel with MeOH:CH2CI2 (1 :20) afforded the title compound as a white solid (846 mg, 85percent). For more details and analytical data, see: Wang, L; Qu, W.; Lieberman, B. P.; Plossl, K.; Kung, H. F. Nucl. Med. Biol. 201 1, 38, 53-62)
77%
With triethylamine In dichloromethane at 0 - 20℃; for 18 h;
Step 1. 2-Methyl-2-propanyl N-[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate To a solution of L-tyrosine tert-butyl ester (1.43 g, 2.64 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.320 mL, 2.31 mmol) and di-tert-butyldicarbonate (0.303 g, 1.39 mmol) at 0° C. After the solution was stirred at room temperature for 18 h, the solution was diluted with CH2Cl2 and washed with 2 N HCl(aq). The organic layer was dried over MgSO4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30percent ethyl acetate in n-hexane) to give 2-methyl-2-propanyl N-[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (299 mg, 77percent) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.02 (d, 2H), 6.73 (d, 2H), 5.59 (br s, 1H), 5.00 (br d, 1H), 4.39 (q, 1H), 3.01-2.92 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H).
Reference：
[1] Patent: US6353099, 2002, B1, . Location in patent: Page column 28
[2] Arkivoc, 2014, vol. 2014, # 3, p. 228 - 238
[3] Patent: EP1828224, 2016, B1, . Location in patent: Page/Page column 197
[4] Patent: WO2016/15014, 2016, A1, . Location in patent: Paragraph 0384
[5] Amino Acids, 2014, vol. 46, # 8, p. 1947 - 1959
[6] Patent: WO2017/68070, 2017, A1, . Location in patent: Page/Page column 44
[7] Patent: US2017/253569, 2017, A1, . Location in patent: Paragraph 0708-0709
[8] Patent: WO2010/39474, 2010, A1, . Location in patent: Page/Page column 9
[9] Organic and Biomolecular Chemistry, 2014, vol. 12, # 26, p. 4708 - 4715
[10] Organic Process Research and Development, 2018, vol. 22, # 2, p. 236 - 240
2
[ 24424-99-5 ]
[ 18938-60-8 ]
Yield
Reaction Conditions
Operation in experiment
88.5%
With sodium hydrogencarbonate In water; acetone at 20 - 25℃; for 2 h; Large scale
A 100L stirred reactor was charged with water (52.5 kg), sodium bicarbonate (4.0 kg, 46.0 moles), L-tyrosine-t-butyl ester HC1 (1) (10.0 kg, 42.2 moles) and acetone (36 kg). The mixture was stirred at 20-25°C. In a separate vessel, di-tert-butyl dicarbonate (10.0 kg, 45.8 moles) and acetone (10 kg) were charged and the mixture stirred until a solution is formed. The Boc2O/acetone solution was charged to the reactor over a period of lh while controlling the addition so that the temperature did not exceed 25°C. The mixture was stirred for 2 h at 20-25°C then sampled for completion by HPLC analysis. Upon completion, the reaction mixture was concentrated under ambient pressure to remove approximately 80percent of volume (40L). The resulting mixture was cooled to 20-25°C. MTBE (37 kg) and acetic acid (2 kg) were charged to the reactor and the mixture stirred for 10-20 minutes after which stirring was stopped and the phasesallowed to separate. The organic layer was collected and the aqueous layer returned to the reactor. MTBE (38 kg) was charged to the reactor and the mixture stirred for 10-20 minutes. Stirring was stopped and the phases allowed to separate. The aqueous layer was drained form the reactor and the first organic extract recharged to the reactor. Water (71 kg) was charged to the reactor and the mixture stirred for 10-20 minutes.Stirring was stopped to allow the phases to separate. The aqueous phase was drained from the reactor. The remaining organic phase was concentrated under ambient pressure to remove approximately 90percent of volume. The mixture was cooled to 0-5°C over a period of 2-3 h. Petroleum ether (32 kg) was added and the mixture stirred for 3h at 0-5°C. The resulting slurry was filtered then dried in an oven under reducedpressure at 3 5-40°C for 16h to obtain N-tert-butoxycarbonyl-L-tyrosine-t-butyl ester (2) (12.6 kg, 37.3 moles, 88.5percent yield, HPLC purity: 99percent).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;
To an anhydrous N,N-dimethylformamide solution (2.0 mL) of N-t-butoxycarbonyl-L-tyrosine-t-butyl ester (338 mg, 1.0 mM), potassium carbonate (173 mg, 1.25 mM) and 1-bromo-2-butyne (147 mg, 1.1 mM) were added, followed by stirring at room temperature for 15 hours. Ethyl acetate (30 mL) was added to the reaction solution, followed by washing three times with water (20 mL) and with brine (20 mL) sequentially. The ethyl acetate layer was dehydrated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Subsequently, the resulting oily substance was purified by silica gel column chromatography. From n-hexane/ethyl acetate (5:1) eluted fraction, Compound 48 (370 mg, 95%) was obtained as a colorless oily substance. Physicochemical property of Compound 48 Molecular weight: 389 FAB-MS (positive mode, matrix m-NBA) 390 (M+H+) 1H-NMR Chemical shift value delta (in deuterated chloroform): 1.41 (9H, s), 1.42 (9H, s), 1.86 (3H, t, J=2.5Hz), 3.00 (2H, d, J=6.0Hz), 4.41 (1H, dd, J=7.5, 6.0Hz), 4.62 (2H, q, J=2.5Hz), 4.97 (1H, d, J=7.5Hz), 6.88 (2H, d, J=8.5Hz), 7.08 (2H, d, J=8.5Hz)
2-<i>tert</i>-butoxycarbonylamino-3-(4-{4-[1-(3-<i>tert</i>-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-(3-hydroxy-2-methyl-benzoylamino)-3-phenylsulfanyl-propoxycarbonylamino]-butoxy}-phenyl)-propionic acid <i>tert</i>-butyl ester[ No CAS ]
5-[4-(2-<i>tert</i>-butoxycarbonyl-2-<i>tert</i>-butoxycarbonylamino-ethyl)-phenoxy]-pentanoic acid 1-(3-<i>tert</i>-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-{3-carbamoyl-2-[(quinoline-2-carbonyl)-amino]-propionylamino}-3-phenyl-propyl ester[ No CAS ]
2-<i>tert</i>-butoxycarbonylamino-3-{4-[4-(1-(3-<i>tert</i>-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-{3-carbamoyl-2-[(quinoline-2-carbonyl)-amino]-propionylamino}-3-phenyl-propoxycarbonylamino)-butoxy]-phenyl}-propionic acid <i>tert</i>-butyl ester[ No CAS ]
(S)-2-Amino-3-(4-{(1S,2R)-1-[(2R,4S)-2-benzyl-5-((S)-2-tert-butylcarbamoyl-4-pyridin-3-ylmethyl-piperazin-1-yl)-4-hydroxy-pentanoylamino]-indan-2-yloxycarbonylmethoxy}-phenyl)-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-{4-[(1S,3R)-1-((S)-2-tert-butylcarbamoyl-4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-3-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-4-phenyl-butoxycarbonylmethoxy]-phenyl}-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-(4-{4-[(1R,2R)-1-((3S,8aS)-3-tert-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-(3-hydroxy-2-methyl-benzoylamino)-3-phenylsulfanyl-propoxycarbonylamino]-butoxy}-phenyl)-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-(4-{4-[(1S,3R)-1-((S)-2-tert-butylcarbamoyl-4-pyridin-3-ylmethyl-piperazin-1-ylmethyl)-3-((1S,2R)-2-hydroxy-indan-1-ylcarbamoyl)-4-phenyl-butoxycarbonylamino]-butoxy}-phenyl)-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
5-[4-((S)-2-Amino-2-carboxy-ethyl)-phenoxy]-pentanoic acid (1R,2S)-1-((3S,8aS)-3-tert-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-{(S)-3-carbamoyl-2-[(quinoline-2-carbonyl)-amino]-propionylamino}-3-phenyl-propyl ester; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-{4-[4-((1R,2S)-1-((3S,8aS)-3-tert-butylcarbamoyl-octahydro-isoquinolin-2-ylmethyl)-2-{(S)-3-carbamoyl-2-[(quinoline-2-carbonyl)-amino]-propionylamino}-3-phenyl-propoxycarbonylamino)-butoxy]-phenyl}-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-(4-{(1S,2R)-1-[(2R,4S)-4-{2-[4-((S)-2-amino-2-carboxy-ethyl)-phenoxy]-acetoxy}-2-benzyl-5-((S)-2-tert-butylcarbamoyl-4-pyridin-3-ylmethyl-piperazin-1-yl)-pentanoylamino]-indan-2-yloxycarbonylmethoxy}-phenyl)-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
(S)-2-Amino-3-(4-[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-tetrahydro-furan-2-ylmethoxy]-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphoryloxy}-phenyl)-propionic acid; compound with trifluoro-acetic acid[ No CAS ]
With triethylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; at 20℃; for 2h;
To a solution of 9.82 g (0.041 m) of (L)-tyrosine, tert-butyl ester in 150 ml of methylene chloride and 20 ml of DMF was added 5.2 g (0.04 m) of triethyl amine followed by 9.03 g (0.04 m) of ditertbutyldicarbonate. The reaction mixture was stirred for 2 hours at room temperature and was then washed with 1 N HCl (3×50 ml), NaHCO3 solution (1×50 ml) and brine (1×50 ml) and was dried over MgSO4. The mixture was filtered and concentrated in vacuo to give 13.59 g (98% yield) of a white solid. 300 MHz 1H NMR (CDCl3): 1.42 (s, 18H); 2.95 (d, 2H); 4.39 (dd, 1H); 5.01 (d, 1H); 6.15 (s, 1H); 6.70 (d, 2H); 7.00 d, 2H).
96%
With triethylamine; In 1,4-dioxane; water; at 21℃;Inert atmosphere;
To a stirred solution of Tyr-OBut (4) (5.0 g, 21.0 mmol) in dioxane and water (42 ml, 0.5 M, dioxane/water = 1/1) were added Et3N (3.27 g, 4.5 mL, 32.3 mmol, 1.54 equiv) and (Boc)2O (5.56 g, 24.4 mmol, 1.14 equiv). The reaction mixture was stirred at rt overnight. After confirming the completion of the reaction by TLC, the reaction mixture was acidified to pH 3 by adding 10% aqueous KHSO4, and extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4) and evaporated. Column chromatography on silica gel (petroleum ether/EtOAc = 20/1 then 2/1) to yield N-Boc-Tyr(OH)-OBut (5) (6.82 g, 96%) as a white solid, mp 106-107C (lit.12 112.8-113.0 C (nhexane/CH2Cl2)). The spectroscopic data of compound 5 were identical to those reported in the literature.
95%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
Example 1 (0506) This example details the synthesis of the carbonyl-containing amino acid presented in FIG. 4. The carbonyl-containing non-natural amino acid was produced as described in FIG. 4.
94%
With sodium carbonate; In water; acetone; for 18h;
To a stirring solution of sodium bicarbonate (37.4 g, 445 mmol) in water (1 L) was added (S)-tert-bity 2-amino-3-(4-hydroxyphenyl)propanoate (96 g, 405 mmol) and acetone (850 mL). A solution of di-tert-butyl dicarbonate (97 g, 445 mmol) in acetone (220 mL) was then added slowly over 2 h. After a further 16 h, the mixture was treated with water (1.7 L) then treated with a solution of AcOH (30 mL) in water (300 mL) added slowly. The mixture was extracted with EA (1 L) and the organics dried over Na2SO4 and partially concentrated. The residue was re-slurried with iso- hexanes (1 L). The precipitate was collected by filtration, washing with iso-hexanes (100 mL) to afford 128.4 g (94%) of tert-butyl (ri-butoxycarbonyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for Ci8H27NO5: 337.2; found 360.2 [M+Na]+, tR = 5.93 min (Method 10).
85%
With triethylamine; In 1,4-dioxane; water; at 20℃;
To a solution of commercially available L-tyrosine ieri-butyl ester (700 mg, 2.95 mmol) in 50 mL of Dioxane-H20 (5: 1), NEt3 (1.23 ml, 8.85 mmol) and (Boc)20 (966 mg, 4.42 mmol) were added, and the reaction mixture was stirred at room temperature. When TLC indicated the consumption of L- tyrosine ieri-butyl ester, the reaction mixture was concentrated under reduced pressure to remove dioxane, and then the resulting solution was diluted with water and extracted with EtOAc (2 chi 50 mL). The combined organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to give the crude product. Purification by flash chromatography on silica gel with MeOH:CH2CI2 (1 :20) afforded the title compound as a white solid (846 mg, 85%). For more details and analytical data, see: Wang, L; Qu, W.; Lieberman, B. P.; Plossl, K.; Kung, H. F. Nucl. Med. Biol. 201 1, 38, 53-62)
77%
With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;
Step 1. 2-Methyl-2-propanyl N-[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate To a solution of L-tyrosine tert-butyl ester (1.43 g, 2.64 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.320 mL, 2.31 mmol) and di-tert-butyldicarbonate (0.303 g, 1.39 mmol) at 0 C. After the solution was stirred at room temperature for 18 h, the solution was diluted with CH2Cl2 and washed with 2 N HCl(aq). The organic layer was dried over MgSO4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl N-[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (299 mg, 77%) as a white solid. 1H NMR (CDCl3, 400 MHz) delta 7.02 (d, 2H), 6.73 (d, 2H), 5.59 (br s, 1H), 5.00 (br d, 1H), 4.39 (q, 1H), 3.01-2.92 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H).
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
INTERMEDIATE 4fert-Butyl (2^)-2-r(fer?-butoxycarbonyl)amino]-3-(4-hvdroxyphenyl)propanoate; A solution of di-fert-butyl dicarbonate (6.81 g, 31.2 mmol) in dry CH2Cl2 (15 mL) was added dropwise via cannula to a stirred solution of L-tyrosine tert-butyl ester (6.17 g, 26.0 mmol) and triethylamine (5.26 g, 7.25 mL, 52.0 mmol) al 0 0C under N2. The reaction was stirred at room temperature overnight. Water (30 mL) was added and the mixture was stirred for 30 min. The organic layer was washed with water (20 mL), 0.05 M HCl (20 mL), water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 65i, Si, ~70 mL/min, 100% hexanes for 450 mL, gradient to 25% EtOAc in hexanes over 4446 mL, gradient to 40% EtOAc in hexanes over 2448 mL) to afford tert-bxxty (2S)-2-[(ferr-butoxycarbonyl)amino]-3-(4- hydroxyrhohenyl)propanoate. R/ = 0.28 (20% EtOAc/hexanes). LCMS calc, = 360.2; found = 359,9 (M+Na)+. 1H NMR (500 MHz, CDCl3): delta 7.02 (d, J= 8.1 Hz, 2 H); 6.73 (d, J = 8.1 Hz, 2 H); 5.41 (s, I H); 4.99 (d, J= 7.9 Hz, 1 H); 4.40 (q, J- 6.6 Hz, 1 H); 3.01-2.93 (m, 2 H); 1.42 (s, 9 H); 1.41 (s, 9 H).
With sodium hexamethyldisilazane; In tetrahydrofuran; at 0 - 20℃; for 48h;
To a solution of 8.18 g (0.024 m) of the product of Step A in a clean, dry flask dissolved in 100 ml of THF under a dry nitrogen atmosphere was added at 0 C. 25.5 ml (0.025 m) of a 1M solution of sodium hexamethyldisilazide in THF. The solution was stirred for 20 minutes. A solution of 3.2 g (0.024 m) of pyrrolidine carbamoyl chloride in 10 ml of THF was added. The reaction mixture was allowed to warm to room temperature and was stirred for 48 hours. The solution was diluted with 100 ml of ethyl acetate and was washed with 1N HCl (3×75 ml), saturated NaHCO3 (1×75 ml), 1N NaOH (2×75 ml) and brine (1×75 ml) and was dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was recrystalized from ethyl acetate/hexanes to give 8.6 g of a white solid.300 MHz 1H NMR (CDCl3): delta1.40 (s, 9H); 1.41 (s, 9H); 1.92 (m, 4H); 3.02 (d, 2H); 3.45 (t, 2H); 3.55 (t, 2H); 4.42 (dd, 1H); 4.99 (d, 1H); 7.05 (d, 2H); 7.15 (d, 2H).
(S)-3-{4-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2-yloxy]-phenyl}-2-tert-butoxycarbonylamino-propionic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With potassium carbonate; In isopropyl alcohol;Heating / reflux;
To a 250 ml flask, R-(+)-1-(2-naphthyl)ethylamine (400 mg, 2.424 mmol), 2-amino-4,6-dichloro triazine (373 mg, 2.181 mmol), anhydrous 1,4-dioxane (40 ml), and N,N-diisopropylethylamine (1 ml, 5.732 mmol) were added and heated to mild reflux for about 4 hours. The reaction was monitored carefully in order to avoid the formation of the disubstituted product. (It was observed that the longer the reaction, the more disubstituted product is formed). After 4 hours, the reaction mixture was cooled and the solvent was removed under reduced pressure. Water was added to the residue, and the solution was sonicated for 2-3 minutes. The solvent was then filtered, washed with water and dried to give 540 mg (83% crude yield) of the mono-chloride, 6-chloro-N-(1-naphthalen-2-yl-ethyl)-[1,3,5]triazine-2,2-diamine, which was used for the next step reaction without further purification. A mixture of 6-chloro-N-(1-naphthalen-2-yl-ethyl)-[1,3,5]triazine-2,2-diamine (90 mg, 0.300 mmol), 2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid tert-butyl ester (102 mg, 0.303 mmol) and potassium carbonate (82 mg, 0.594 mmol) in isopropanol (8 ml) was refluxed over night. The solvent was removed under reduced pressure and the residue was suspended in ethyl acetate. The solid was filtered and washed with ethyl acetate. The filtrate was concentrated and then redissolved in a mixture of methanol/water (90:10) and purified by a preparative-LC using a Sunfire C18 OBD 100×30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were combined and concentrated to give 50 mg of pure product, 3-{4-[4-amino-6-(1-naphthalen-2-yl-ethylamino)-[1,3,5]triazin-2yloxy]-phenyl}2-tert-butoxycarbonylamino-propionic acid tert-butyl ester, (28% yield). The above product (50 mg, 0.083 mmol) was dissolved in trifluoro acetic acid/dichloromethane (8 ml/2 ml) and stirred at room temperature over night. The solvent was removed under reduced pressure. The residue was then redissolved in a mixture of methanol/water (90:10) and purified by a preparative-LC using a Sunfire C18 OBD 100×30 mm ID column (MeOH/H2O/TFA solvent system). The pure fractions were combined and concentrated under reduced pressure to afford about 4 ml, which was frozen and lyophilized to give 4 mg of the title compound as a TFA salt (11% yield). 1H NMR (CD3OD) delta 7.37-7.81 (m, 8H), 7.19 (m, 2H), 6.98 (m, 1H), 5.37 (m, 1H), 4.19 (m, 1H), 3.17-3.38 (m, 2H), 1.56 (m, 3H). M+1=445.
With acetic acid; In water; at 160℃; for 0.0833333h;Microwave irradiation;
General procedure: A mixture of 3 (0.8 g, 1.94 mmol) in acetic acid (0.2 M, 9.7 mL) and water (0.2 M; 9.7 mL) was heated to 160 C in a Biotage Initiator microwave for 5 min. After cooled to rt, the reaction mixture was concentrated in vacuo. Water was added and removed in vacuo (twice) to remove the residual acetic acid. The residual was washed with iPrOH to afford 2 (0.44 g, 98%) as a white solid after drying.
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