* 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.
The product N-pyrazineformyl-L-phenylalanine methyl ester (1.0g, 3.51mmol) in Preparation example 2 was dissolved with 10ml of acetone, 2N NaOH was added dropwise slowly until a pH value of 12∼13 was obtained, and the solution was kept reacting under the condition of ice water bath, the reaction was monitored by TLC and completed after 2h. Hydrochloric acid was add dropwise under the condition of ice water bath until a pH value of 2∼3 was obtained, a large amount of white solid was produced, the generated precipitate was filtered, washed with water and diethyl ether followed by airing to dry and gave 0.89g of white product with a yield of 93.6percent, m.p.: 166-169°C. 1H-NMR (DMSO-d6, 300MHz): δ 3.23 (-CH2, m, 2H), 4.74 (-CH, m, 1H), 7.16∼7.25 (-Ph, m, 5H), 8.74 (-CONH, t, 1H), 8.86∼8.89 (-Pyz, t, 2H), 9.14 (-Pyz, d, 1H), 13.06 (-COOH, s, 1H).
93%
With lithium hydroxide In tetrahydrofuran; water at 0℃; for 1 h;
The product 6a (1mmol) was dissolved in 10mL THF and was added 3N LiOH dropwise at 0°C until TLC showed methyl ester 6a was disappeared completely (1h). The reaction solution was acidified to pH 2. The precipitate was filtered and washed with water until pH value reached 6–7. After dryness, the acid 7a was obtained with high yield and used exactly without further purification, 93percent yield; mp: 166–169°C. 1H NMR (400MHz, CDCl3) δ 9.37 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=8.1Hz, 1H), 7.25 (dt, J=16.6, 7.2Hz, 5H), 5.12 (dd, J=13.8, 6.2Hz, 1H), 3.31 (dd, J=20.6, 14.1, 6.0Hz, 2H)
1.22 g
With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h;
To a solution of 8a (1.44 g, 5.05 mmol) in THF (5 mL) were added 1 M aq LiOH(6 mL) dropwise with the aid of ice-water bath followed by stirring to r.t. over 2 h.The reaction mixture were diluted with water (20 mL) and extracted with EtOAc (3×5mL). The alkaline water layer were acidized to pH = 2-3 with 1 M aq HCl to give awhite suspension, which were filtrated, washed to pH = 6-7 by water, and dried togive the title compound 9a (1.22 g, 89percent) as a white solid;
Reference：
[1] Patent: EP2444411, 2016, B1, . Location in patent: Paragraph 0038
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 4031 - 4044
[3] Organic and Biomolecular Chemistry, 2007, vol. 5, # 9, p. 1416 - 1426
[4] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 19, p. 6851 - 6861
[5] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4192 - 4199
[6] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 37-38
[7] Patent: WO2009/36281, 2009, A2, . Location in patent: Page/Page column 39
[8] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4365 - 4377
[9] Patent: WO2012/48745, 2012, A1, . Location in patent: Page/Page column 14-15
[10] Synthesis (Germany), 2013, vol. 45, # 20, p. 2843 - 2852
[11] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 8, p. 1958 - 1962
2
[ 19847-10-0 ]
[ 63-91-2 ]
[ 114457-94-2 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: With sodium carbonate In water; toluene at 10 - 25℃; for 3 h; Stage #2: With hydrogenchloride In methanol; water at 15 - 20℃;
Step B. Preparation of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino] -propionic acid (i.e., acid of Formula II, wherein R]is 2-pyrazinyl and R2 is benzyl). A second 500 ml three neck round bottomed flask was equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/outlet and ice/water cooling bath. L- Phenylalanine, 20.2 g (0.122 mol) was added, followed by 28.2 g (0.266 mol) of sodium carbonate and 225 mL of deionized water. The aqueous solution was cooled to 10.0 °C. During this time the addition funnel was charged with the acid chloride/toluene solution prepared in Step A (-125 mL). This toluene solution was added dropwise to the aqueous reaction over approximately 10 minutes at -10 °C. Once the addition was complete, the reaction was warmed to room temperature (-22-25 °C) and vigorously stirred for 3 h. The reaction mixture was then transferred to a separatory funnel and the two layers were separated. The lower aqueous phase was then recharged to the reaction flask. Methanol (125 mL) was then added to the red solution followed by pH adjustment (target pH=l-2) with 3.0 M HC1 (-175 mL), keeping the temperature at 15-20 °C. Some off-gassing occurred at - pH=5, followed by precipitation of the product at pH=3. The slurry was allowed to stir at room temperature for 30 minutes at ambient temperature post pH adjustment. The resulting pink solid precipitate was collected by vacuum filtration,(mother liquor losses <2 mg/mL), washed with deionized water (1X50 ml) then dried in a vacuum oven at 40 °C with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol, 36percent) of the title compound with an HPLC purity of 99Apercent. 1H NMR (d6- DMSO, 400MHz) δ 13.04 (s, IH), 9.14 (d, IH, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, IH, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, IH), 4.75 (dt, IH, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
36%
With sodium carbonate In water; toluene at 10 - 25℃;
A second 500 ml three neck round bottomed flask is equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/ outlet and ice/water cooling bath. E-Phenylalanine, 20.2 g (0.122 mol) is added, followed by 28.2 g (0.266 mol) ofsodium carbonate and 225 mE of deionized watet The aqueous solution is cooled to 10.0°C. During this time the addition flannel is charged with the acid chloride/toluene solution prepared in Step A (.-125 mE). This toluene solution is added dropwise to the aqueous reaction over approximately 10 mm-utes at .—10° C. Once the addition is complete, the reaction is warmed to room temperature (.-22-25° C.) and vigorously stirred for 3 h. The reaction mixture is then transferred to a reparatory flannel and the two layers are separated. The lower aqueous phase is then recharged to the reaction flask. Metha40 nol (125 mE) is then added to the red solution followed by pHadjustment (target pH=1 -2) with 3.0 M HC1 (.-175 mE), keeping the temperature at 15-20° C. Some off-gassing occurs at .-pH=5, followed by precipitation of the product at pH=3. The slurry is allowed to stir at room temperature for 30 minutes atambient temperature post pH adjustment. The resulting pink solid precipitate is collected by vacuum filtration, (mother liquor losses <2 mg/mE), washed with deionized water (1 x50 ml) then dried in a vacuum oven at 40° C. with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol,36percent) of the title compound with an HPEC purity of 99 A percent. ‘HNMR(d6-DMSO, 400 MHz)ö 13.04(s, 1H), 9.14(d, 1H, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, 1H, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, 1H), 4.75 (dt, 1H, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
N,O-Bis(trimethylsilyl)acetamide (BSA, 2.49 mL, 10.05 mmol) was added to a solution of L-phenylalanine (0.83 g, 5.02 mmol) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 16 h. In another 100 mL reaction flask, 1,1'-carbonyldiimidazole (1.7 g, 10.48 mmol) was added to a solution of pyrazinecarboxylic acid (1 g, 8.06 mmol) and dichloromethane (17 mL). After stirring at room temperature for 16 h, the reaction mixture was cooled in a −40 °C bath and the above solution of L-phenylalanine-BSA was added dropwise over 30 min. The reaction mixture was stirred at room temperature for another 16 h, citric acid(aq) (0.78 M, 17 mL) was added, and extracted with dichloromethane (10 mL × 3). The organic layers were separated, combined, dried over anhydrous Na2SO4 and concentrated. The crude product was recrystallized in dichloromethane/hexanes to give N-(2-pyrazinylcarbonyl)-L-phenylalanine (8, R = benzyl; R' = pyrazinyl, 0.96 g, 3.54 mmol, 70percent) as a colorless solid.
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In dichloromethane; acetonitrile at -15 - 25℃; for 1.5 h;
Example 3: Compound of formula (4)Mix the (S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid (10.85 g,40.0 mmol) with the trifluoroacetate salt of the compound of formula (2) (16.27g, 40.0 mmol) in 215 ml of anhydrous dichloromethane at 20-25°C. Cool the formed white suspension under stirring to -15°C and add N-methylmorpholine (17.7 ml, 160 mmol) while keeping the internal temperature at -10°C. Add the T3P reagent (2,4,6-triprop-l-yl-l,3,5-trioxa-2,4,6- triphosphinane-2,4,6-trioxide, 38.2 g of 50percent solution in acetonitrile, 60 mmol)at the same temperature. Stir the reaction mixture at -10 to -15°C for 1.5 hours.Warm the reaction mixture to 20-25°C and add 215 ml of water. Separate the layers and was the organic layer with 210 ml of brine. Dry the organic extract with anhydrous sodium sulphate and evaporate the volatiles (5 mbar, 40°C) to an oily residue. Transfer the residue to silic gel pad (54.3 g, Silica gel 60 Merck, 40-63 μιη, 230-400 Mesh) and elute crude product with a mixture of n-heptane/MTBE (460 ml). Evaporate volatiles (5mbar, 40°C) and yield 18.12 g of a yellow residue (86percent).HPLC: Chemical purity 98.69percent (IN), Chiral purity 99.7percent.
With sodium hydroxide; In acetone;pH 12 - Ca. 13;Cooling with ice;
The product N-pyrazineformyl-L-phenylalanine methyl ester (1.0g, 3.51mmol) in Preparation example 2 was dissolved with 10ml of acetone, 2N NaOH was added dropwise slowly until a pH value of 12?13 was obtained, and the solution was kept reacting under the condition of ice water bath, the reaction was monitored by TLC and completed after 2h. Hydrochloric acid was add dropwise under the condition of ice water bath until a pH value of 2?3 was obtained, a large amount of white solid was produced, the generated precipitate was filtered, washed with water and diethyl ether followed by airing to dry and gave 0.89g of white product with a yield of 93.6%, m.p.: 166-169C. 1H-NMR (DMSO-d6, 300MHz): delta 3.23 (-CH2, m, 2H), 4.74 (-CH, m, 1H), 7.16?7.25 (-Ph, m, 5H), 8.74 (-CONH, t, 1H), 8.86?8.89 (-Pyz, t, 2H), 9.14 (-Pyz, d, 1H), 13.06 (-COOH, s, 1H).
93%
With lithium hydroxide; In tetrahydrofuran; water; at 0℃; for 1h;
The product 6a (1mmol) was dissolved in 10mL THF and was added 3N LiOH dropwise at 0C until TLC showed methyl ester 6a was disappeared completely (1h). The reaction solution was acidified to pH 2. The precipitate was filtered and washed with water until pH value reached 6-7. After dryness, the acid 7a was obtained with high yield and used exactly without further purification, 93% yield; mp: 166-169C. 1H NMR (400MHz, CDCl3) delta 9.37 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=8.1Hz, 1H), 7.25 (dt, J=16.6, 7.2Hz, 5H), 5.12 (dd, J=13.8, 6.2Hz, 1H), 3.31 (dd, J=20.6, 14.1, 6.0Hz, 2H)
Step-g) Preparation of N-(pyrazinylcarbonyl)-L-Phenylalanine (Formula VIII):; <n="39"/>To a stirred mixture of Formula VII (100 g) in acetone (500 ml) at 25-300C, was charged NaOH solution (obtained by dissolving 15.4 g of NaOH in 500 ml of water) and maintained at the same temperature for 30-50 minutes. Adjusted the pH of the reaction mass to 2 by using 1 N HCI and cooled the reaction mass to 0-50C. Maintained the reaction mass at 0-5 0C under stirring for 1 -2 hours, filtered under vacuum and dried the material obtained at 45-500C for 4-5 hours to give 84.4 g of the title compound (Formula VIII). Purity by HPLC: 99.94 % by weight. Chiral purity by HPLC: 100 %
Pyrazine-2-carbonylphenylalanine methyl ester (5 g) was dissolved in acetone (25 ml) and stirred for about 5 minutes. Sodium hydroxide solution (701 mg of sodium hydroxide in 25 ml of water) was added to the reaction solution and stirred for about 3 hours at a temperature of about 25C, and the pH was then adjusted withi N hydrochloric acid (11 ml) to a pH of about 2. The reaction mixture was cooled to a temperature of about 00C to about 5C and stirred for about 1 hour. The suspension was filtered and suck dried to afford 4.0 g of pyrazine-2- carbonylphenylalanine.Chiral purity by chiral HPLC: 100% Chemical purity by HPLC: 99.88%.
Example 2: (S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid = Compound of formula (6) [R1 is hydrogen]Dissolve (S)-Methyl 3-phenyl-2-(pyrazine-2-carboxamido)propanoate (57.65 g) in 572 ml of acetonitrile and add 1 1.7 ml water and 84 ml of triethylamine. Cool the reaction mixture to 0C on ice bath and add 175.0 g of LiBr in several portions at vigorous stirring. After 10 minutes of stirring, increase the temperature to ambient temperature. (NB. A HPLC sample showed 99.97% conversion with 98.78% content of the desired product).After 5 hours of stirring, dilute the reaction mixture with 572 ml of water and adjust pH of the solution to 3-4 (pH-paper) at 0-2 C with approx. 56 ml of 36% HC1. Extract the solution with 3x250 ml of ethyl acetate. Dry the combined organic layers with MgSC^ and concentrate them at 50C to 170 ml volume. Cool the formed suspension to ambient temperature and dilute with 170 ml of n-heptane. Allow to stand overnight at -10C. Isolate crude product by filtration and wash with 2x40 ml of ethyl acetate-n-heptane mixture 1 : 1 (v/v).Yield: 56.85 g of the title product as off-white crystals. HPLC: Chemical purity 98.98% (IN), Chiral purity 99.51% (GammaNu)
1.22 g
With water; lithium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a solution of 8a (1.44 g, 5.05 mmol) in THF (5 mL) were added 1 M aq LiOH(6 mL) dropwise with the aid of ice-water bath followed by stirring to r.t. over 2 h.The reaction mixture were diluted with water (20 mL) and extracted with EtOAc (3×5mL). The alkaline water layer were acidized to pH = 2-3 with 1 M aq HCl to give awhite suspension, which were filtrated, washed to pH = 6-7 by water, and dried togive the title compound 9a (1.22 g, 89%) as a white solid;
With lithium hydroxide monohydrate; In methanol; at 20℃; for 14h;
General procedure: The prepared methyl esters2a-2g(3.13 mmol) was dissolved in 8 mL of CH3OH and 2.4 mL of water, LiOHH2O (9.39 mmol) was added. After completion of reaction as determined by TLC analysis, CH3OH was evaporated under vacuum. The reaction system was acidified with 1M HCl until the pH value was 2. The product was extracted with ethyl acetate and dried over anhydrous Na2SO4, filtered and evaporated to give3a-3g, yields 74%-95%.
(a) Using ethylchloroformate according to the process as described below:; A mixture of acetone (40 ml), pyrazine carboxylic acid (5 g) and thethylamine(6.77 ml) was cooled to about -5C to about 00C and ethylchloroformate (4.76 ml) was charged. The reaction mass was stirred for about 30 minutes. The reaction suspension was allowed to reach the temperature of about 25C to about 300C and maintained for about 3 hours. The reaction suspension was cooled to about 00C to about 5C. In the second flask the aqueous sodium hydroxide (1.68 g in 70 ml water) solution was cooled to about 00C to about 5C and to that acetone (30 ml) and L-phenyl alanine (6.6 g) were added and the mixture was stirred for about 1 hour at that temperature. The reaction mass of the second flask was added to the reaction mass of the first flask at a temperature of about 00C to about 5C and then stirred for about 2 hours followed by raising the temperature to about 25C to about 300C. The reaction mass was further stirred for about 16 hours at a temperature of about 25C to about 300C. Ethyl acetate (150 ml) was charged to the reaction solution and stirred for about 30 minutes. The layers were separated and 1 N hydrochloric acid (35 ml) was added to the separated aqueous layer. The reaction solution was cooled to about 00C to about 5C and stirred for about 2 hours. The obtained suspension was filtered and the solid was washed with water (10 ml). The <n="40"/>solid was then dried at a temperature of about 500C for about 4 hours to afford 2.6 g of title compound. Purity by HPLC: 99.2% by weight. Chiral purity by HPLC: 100%
(aR,3aS,4S,6S,7aR)-hexahydro-3a,8,8-trimethyl-α-(2-methylpropyl)-4,6-methano-1,3,2-benzodioxaborole-2-methanamine 2,2,2-trifluoroacetate[ No CAS ]
[ 114457-94-2 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; acetonitrile; at -15 - 25℃; for 1.5h;
Example 3: Compound of formula (4)Mix the <strong>[114457-94-2](S)-3-phenyl-2-(pyrazine-2-carboxamido)propanoic acid</strong> (10.85 g,40.0 mmol) with the trifluoroacetate salt of the compound of formula (2) (16.27g, 40.0 mmol) in 215 ml of anhydrous dichloromethane at 20-25C. Cool the formed white suspension under stirring to -15C and add N-methylmorpholine (17.7 ml, 160 mmol) while keeping the internal temperature at -10C. Add the T3P reagent (2,4,6-triprop-l-yl-l,3,5-trioxa-2,4,6- triphosphinane-2,4,6-trioxide, 38.2 g of 50% solution in acetonitrile, 60 mmol)at the same temperature. Stir the reaction mixture at -10 to -15C for 1.5 hours.Warm the reaction mixture to 20-25C and add 215 ml of water. Separate the layers and was the organic layer with 210 ml of brine. Dry the organic extract with anhydrous sodium sulphate and evaporate the volatiles (5 mbar, 40C) to an oily residue. Transfer the residue to silic gel pad (54.3 g, Silica gel 60 Merck, 40-63 muiotaeta, 230-400 Mesh) and elute crude product with a mixture of n-heptane/MTBE (460 ml). Evaporate volatiles (5mbar, 40C) and yield 18.12 g of a yellow residue (86%).HPLC: Chemical purity 98.69% (IN), Chiral purity 99.7%.
Step-h) Preparation of Formula IX:; <n="41"/>To a stirred mixture of compound of Formula VIII (28.6 g) in dichloromethane (400 ml) at 25-300C under nitrogen atmosphere, were charged N-hydroxysuccinimide (13.3 g) and DCC (23.9 g) and stirred for 10-20 minutes. Charged compound of Formula-V (40 g) to the reaction mass was and stirred for 15-20 minutes.Charged diisopropylethylamine (DIPEA) (27 ml) and maintained the reaction mass at 25-300C for 2-3 hours. The reaction mass was filtered and the solid was washed with dichloromethane (80 ml). The filtrate obtained was washed with 1 N HCI, followed by washing with sodium bicarbonate solution. Concentrated the organic layer up to 2 volumes with respect to Formula-V. Charged methanol (200 ml) and concentrated up to 2 volumes with respect to Formula-V. The concentrated mass obtained is the title compound (Formula IX).
Alternately, compound of Formula IX may also be prepared by using EDCHCI, and Hydroxybenzotriazole by a process as described below: N-(2-pyrazinecarbonyl)-L-phenylalanine (500 mg) was suspended in dichloromethane (10 ml) and cooled to about -5C to about 00C. Hydroxybenzotriazole (HOBt:310 mg) was charged in to the reaction mass followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCI, 385 mg) and stirred for 15 minutes. (1 R)-(S)-pinanediol 1 -ammonium trifluoroacetate-3-methylbutane-i -boronate (695 mg) was added to the reaction mixture and stirred for about 10 minutes at a temperature of about 5C Diisopropyl ethyl amine (0.6 ml) was charged to the reaction mixture and stirred for about 30 minutes at a temperature of about 5C The reaction mixture was allowed to warm to a temperature of about 25C to about 300C and stirred for about 1 hour followed by the addition of 1 N hydrochloric acid (30 ml). The layers were separated and the organic layer was washed with 1 N hydrochloric acid (15 ml) and saturated sodium bicarbonate solution (2x30 ml). The organic layer was concentrated completely to afford title compound. <n="42"/>Purity by HPLC: 84.98% Note that it is believed that 9.01 % measured by HPLC is Bortezomib that is formed prior to the final Bortezomib step. Thus, overall purity should be 84.98% + 9.0% or 93.99% as measured by HPLC.
N,O-Bis(trimethylsilyl)acetamide (BSA, 2.49 mL, 10.05 mmol) was added to a solution of L-phenylalanine (0.83 g, 5.02 mmol) and dichloromethane (8 mL), and the reaction mixture was stirred at room temperature for 16 h. In another 100 mL reaction flask, 1,1'-carbonyldiimidazole (1.7 g, 10.48 mmol) was added to a solution of pyrazinecarboxylic acid (1 g, 8.06 mmol) and dichloromethane (17 mL). After stirring at room temperature for 16 h, the reaction mixture was cooled in a -40 C bath and the above solution of L-phenylalanine-BSA was added dropwise over 30 min. The reaction mixture was stirred at room temperature for another 16 h, citric acid(aq) (0.78 M, 17 mL) was added, and extracted with dichloromethane (10 mL × 3). The organic layers were separated, combined, dried over anhydrous Na2SO4 and concentrated. The crude product was recrystallized in dichloromethane/hexanes to give N-(2-pyrazinylcarbonyl)-L-phenylalanine (8, R = benzyl; R' = pyrazinyl, 0.96 g, 3.54 mmol, 70%) as a colorless solid.
With 4-methyl-morpholine; hydrogenchloride; benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0℃; for 2h;pH 12 - Ca. 13;
Preparation example 4 N-pyrazineformyl-L-phenylalanyl-L-phenylalanine methyl ester L-phenylalanine methyl ester hydrochloride (0.8g, 3.69mmol) was dissolved with 20ml of THF, then the hydrochloric acid was neutralized with NMM (0.49ml, 4.43 mmol), cooled with an ice bath for later use. N-Pyrazineformyl-L-phenylalanine (1.0g, 3.69mmol) of Preparation example 3 was added to another reaction flask, dissolved with 20ml of THF, and cooled with an ice water bath, dicyclohexylcarbodiimide (DCC) (0.76g, 3.69mmol), HOBt (0.60g, 4.42mmol) were added at 0C and reacted for 40min at 0C, then the solution of L-phenylalanine methyl ester hydrochloride in THF prepared, cooled and neutralized according to the above was added, the reaction was monitored by TLC and completed after 2h, insoluble DCU was removed by filtration, to the filtrate was added 80ml of ethyl acetate, washed with 5% sodium bicarbonate solution, 10% citric acid solution, 5% sodium bicarbonate solution, saturated salt solution (2*20ml) successively. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and evaporated the solvent under reduced pressure, 1.52g of white solid was obtained with a yield of 95.6%, m.p.: 111?113C. 1H-NMR (CDCl3, 300MHz): delta 3.04 (-CH2, m, 2H), 3.18 (-CH2, d, 2H), 3.69 (-CH3, s, 3H), 4.82 (-CH, m, 2H), 6.36 (-CONH, d, 1H), 6.92?7.30 (-Ph, m, 10H), 8.26 (-CONH, d, 1H), 8.54 (-Pyz, d, 1H), 8.76 (-Pyz, d, 1H), 9.33 (-Pyz, s, 1H).
81%
General procedure: To pyrazine-2-carboxylic acid (1mmol) in absolute THF (30mL) at 0C was added DCC (1mmol) and HOBt (1.2mmol), and the mixture was reacted for 40min. Then methyl l-phenylalaninate hydrochloride (1mmol) and 4-Methylmorpholine (NMM) were added and the react was performed until TLC showed the starting materials disappeared (12h). After the reaction finished, the resulting solid was filtered and the solvent was removed under vacuum. The white solid was dissolved in 50mL ethyl acetate and washed with 5% NaHCO3, 10% citric acid, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and evaporated to provide methyl ester 6a as colorless oil 0.28g (98% yield); mp: 152-155C. 1H NMR (CDCl3, 400MHz) 3.26 (m, 2H), 3.75 (s, 3H), 5.09 (m, 1H), 7.15-7.32 (m, 5H), 8.23 (d, 1H), 8.52 (d, 1H), 8.74 (d, 1H), 9.37 (s, 1H).
General procedure: To pyrazine-2-carboxylic acid (1mmol) in absolute THF (30mL) at 0C was added DCC (1mmol) and HOBt (1.2mmol), and the mixture was reacted for 40min. Then methyl l-phenylalaninate hydrochloride (1mmol) and 4-Methylmorpholine (NMM) were added and the react was performed until TLC showed the starting materials disappeared (12h). After the reaction finished, the resulting solid was filtered and the solvent was removed under vacuum. The white solid was dissolved in 50mL ethyl acetate and washed with 5% NaHCO3, 10% citric acid, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and evaporated to provide methyl ester 6a as colorless oil 0.28g (98% yield); mp: 152-155C. 1H NMR (CDCl3, 400MHz) 3.26 (m, 2H), 3.75 (s, 3H), 5.09 (m, 1H), 7.15-7.32 (m, 5H), 8.23 (d, 1H), 8.52 (d, 1H), 8.74 (d, 1H), 9.37 (s, 1H).
N-[(1S)-1-[[[(1S)-1-[(3aR,4R,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-2-phenyl]-2-pyrazinecarboxamide[ No CAS ]
(aR,3aS,4S,6S,7aR)-hexahydro-3a,8,8-trimethyl-α-(2-methylpropyl)-4,6-methano-1,3,2-benzodioxaborole-2-methanamine 2,2,2-trifluoroacetate[ No CAS ]
[ 114457-94-2 ]
(1S,2S,3R,5S)-pinanediol N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.5%
A solution of (1R)-(S)-Pinanediol 1-ammonium trifluoroacetate-3- methylbutane-1-boronate (13.97 g) and N-hydroxysuccinimide (6.23 g) of in 66 mL of DMF was cooled to-5 C, followed by the addition of dicyclohexylcarbodiimide (10.83 g). The resulting suspension was stirred for one hour at a temperature of-5 to 0 C. To a solution of N- (2-pyrazinecarbonyl)-L-phenylalanine (19.52 g; prepared by coupling the preformed succinimide ester of pyrazinecarboxylic acid with L-phenylalanine in dioxane-water) in 62 mL of DMF was added N-methylmorpholine (5.7 mL) at a temperature of 0 C, and the resulting solution was added to the suspension. The suspension was adjusted to pH 7 by the addition of another 5.7 mL of N-methylmorpholine and stirred overnight, raising the temperature slowly to 21 C. After filtration, the filtercake was washed twice with MTBE and the combined filtrates were diluted with 950 mL of MTBE. The organic layer was washed with 20% aqueous citric acid (3 x 150 mL), 20% aqueous NaHC03 (3 x 150 mL), and brine (2x). The organic layer was dried over Na(at)SO(at), filtered, and concentrated, yielding 25.5 g (95.5 %) of the title compound as a foam. As indicated by tlc this material contained some minor impurities, including approximately 2% of cyclohexyl urea.
Step B. Preparation of (S)-3-Phenyl-2-[(pyrazine-2-carbonyl)-amino] -propionic acid (i.e., acid of Formula II, wherein R]is 2-pyrazinyl and R2 is benzyl). A second 500 ml three neck round bottomed flask was equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/outlet and ice/water cooling bath. L- Phenylalanine, 20.2 g (0.122 mol) was added, followed by 28.2 g (0.266 mol) of sodium carbonate and 225 mL of deionized water. The aqueous solution was cooled to 10.0 C. During this time the addition funnel was charged with the acid chloride/toluene solution prepared in Step A (-125 mL). This toluene solution was added dropwise to the aqueous reaction over approximately 10 minutes at -10 C. Once the addition was complete, the reaction was warmed to room temperature (-22-25 C) and vigorously stirred for 3 h. The reaction mixture was then transferred to a separatory funnel and the two layers were separated. The lower aqueous phase was then recharged to the reaction flask. Methanol (125 mL) was then added to the red solution followed by pH adjustment (target pH=l-2) with 3.0 M HC1 (-175 mL), keeping the temperature at 15-20 C. Some off-gassing occurred at - pH=5, followed by precipitation of the product at pH=3. The slurry was allowed to stir at room temperature for 30 minutes at ambient temperature post pH adjustment. The resulting pink solid precipitate was collected by vacuum filtration,(mother liquor losses <2 mg/mL), washed with deionized water (1X50 ml) then dried in a vacuum oven at 40 C with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol, 36%) of the title compound with an HPLC purity of 99A%. 1H NMR (d6- DMSO, 400MHz) delta 13.04 (s, IH), 9.14 (d, IH, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, IH, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, IH), 4.75 (dt, IH, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
36%
With sodium carbonate; In water; toluene; at 10 - 25℃;
A second 500 ml three neck round bottomed flask is equipped with a stir bar, thermocouple, pressure equalizing dropping funnel, nitrogen inlet/ outlet and ice/water cooling bath. E-Phenylalanine, 20.2 g (0.122 mol) is added, followed by 28.2 g (0.266 mol) ofsodium carbonate and 225 mE of deionized watet The aqueous solution is cooled to 10.0C. During this time the addition flannel is charged with the acid chloride/toluene solution prepared in Step A (.-125 mE). This toluene solution is added dropwise to the aqueous reaction over approximately 10 mm-utes at .-10 C. Once the addition is complete, the reaction is warmed to room temperature (.-22-25 C.) and vigorously stirred for 3 h. The reaction mixture is then transferred to a reparatory flannel and the two layers are separated. The lower aqueous phase is then recharged to the reaction flask. Metha40 nol (125 mE) is then added to the red solution followed by pHadjustment (target pH=1 -2) with 3.0 M HC1 (.-175 mE), keeping the temperature at 15-20 C. Some off-gassing occurs at .-pH=5, followed by precipitation of the product at pH=3. The slurry is allowed to stir at room temperature for 30 minutes atambient temperature post pH adjustment. The resulting pink solid precipitate is collected by vacuum filtration, (mother liquor losses <2 mg/mE), washed with deionized water (1 x50 ml) then dried in a vacuum oven at 40 C. with a nitrogen sweep to a constant weight to provide 11.92 g (0.43.9 mmol,36%) of the title compound with an HPEC purity of 99 A %. ?HNMR(d6-DMSO, 400 MHz)oe 13.04(s, 1H), 9.14(d, 1H, J=1.44 Hz), 8.88 (dd, 2H, J=2.48, 6.16 Hz), 8.75 (dd, 1H, J=1.52, 2.4 Hz), 7.25 (m, 4H), 7.18 (m, 1H), 4.75 (dt, 1H, J=5.48, 8.08 Hz), 3.2 (dd, 2H, J=1.79, 5.32 Hz).
(S)-N-{1-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-6-yl)amino]-1-oxo-3-phenylpropan-2-yl}pyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With 4-methyl-morpholine; In tetrahydrofuran; at 20℃; for 0.166667h;
General procedure: To a soln of 9 (or 16) in THF (0.2 M) was added NMM dropwise atr.t. and the mixture was stirred for 10 min. After cooling to -20 Cfor 10 min, IBCF was added dropwise and the mixture was stirredfor a further 20 min. Then, 6 in THF (0.3 M) was added dropwise atthe same temperature and then the mixture was stirred and the temperaturewas allowed to rise gradually to r.t. over 5 h. The mixturewas diluted with EtOAc (20 mL), washed with brine (3 × 5 mL),dried (anhyd Na2SO4), and the solvent evaporated in vacuo to givethe crude product.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;
N-[(1S)-1-[[[(1R)-1-[(3aS,4S,6S,7aR)-Hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl]-amino]carbonyl]-2-phenyl]-2-pyrazincarboxamide (1). Diethylisopropylamine(0.2 mL, 0.15 g, 1.19 mmol) was added to the solution of <strong>[114457-94-2]N-(2-pyrazinylcarbonyl)-L-phenylalanine</strong> (75 mg, 0.26 mmol), (R)-BoroLeu-(+)-Pinanediol (100 mg, 0.28 mmol) and HBTU (110 mg, 0.29 mmol) in DMF (2 mL) at 0 C. The reaction mixture was stirred at room temperature for 16 h, the water (30 mL) was added, and it was extracted with EtOAc (10 mL × 3). The organic layers were combined, washed with citric acid(aq) (0.1 N, 30 mL), NaHCO3(aq) (0.1 N, 30 mL), sat. NaCl(aq) (30 mL), dried over Na2SO4, filtered and conventrated. The crude product was purified by column chromatography (SiO2, EtOAc/hexanes, 1:1; Rf 0.40) to give 1 [11] (100 mg, 0.19 mmol, 73%) as a colorless solid.
(R)-boroleu-(+)-pinanediol trifluoroacetic acid[ No CAS ]
[ 114457-94-2 ]
N-((2S)-1-((3-methyl-1-((3aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage-1: Preparation of N-((2S)-1-((3-methyl-1-((3aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)amino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (Intermediate, which is used without isolation for the next stage) Take 98 ml MDC under nitrogen and add 7 gm of (S)-3-phenyl-2-(pyrazine-2carboxamido) propanoic acid, 3.3 gm of N-Hydroxy succinimide and 6.0 gm of N,N-Diyclohexylcarbodiimide. Stir the reaction solution for 20 min at room temperature and under continuous N2 purging. (0080) Charge (R) Boroleu pinanediol trifluoro acetic acid 9.8 gm and 7.0 ml triethylamine and continue stirring for about 4 hrs at room temperature and under continuous N2 purging. Filter the mass and wash the cake with 20 ml methylene dichloride (MDC). Collect MDC layer and wash with IN HCl 200 ml followed by 200 ml of saturated solution of sodium bicarbonate. (0081) Dry the MDC layer with dried sodium sulphate. Distill out MDC under vacuum below 40 deg C and add 98 ml methanol and redistill. Again add 98 ml methanol and redistill under vacuum at 45 deg C to get Stage 1-Intermediate material as residue.
General procedure: t -10,3a-3g(0.13 mmol) was dissolved in 2 mL of anhydrous CH2Cl2. Then 1-hydroxybenzotriazole (HOBt) (0.14 mmol) was added, and after 10 min, EDCI (0.14 mmol) was added. The reaction was performed for 15 min. And then DIPEA (0.39 mmol) and10a-10d(0.13 mmol) was added all at once. After completion of reaction as determined by TLC analysis, the resulted mixture was washed with 5% NaHCO3, 1M HCl, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and evaporated to provide crude products. Concentration and flash chromatography over silica gel (EtOAC:petroleum 1:2) produced11a-11k, yields were listed in Table 1.
General procedure: t -10,3a-3g(0.13 mmol) was dissolved in 2 mL of anhydrous CH2Cl2. Then 1-hydroxybenzotriazole (HOBt) (0.14 mmol) was added, and after 10 min, EDCI (0.14 mmol) was added. The reaction was performed for 15 min. And then DIPEA (0.39 mmol) and10a-10d(0.13 mmol) was added all at once. After completion of reaction as determined by TLC analysis, the resulted mixture was washed with 5% NaHCO3, 1M HCl, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and evaporated to provide crude products. Concentration and flash chromatography over silica gel (EtOAC:petroleum 1:2) produced11a-11k, yields were listed in Table 1.
General procedure: t -10,3a-3g(0.13 mmol) was dissolved in 2 mL of anhydrous CH2Cl2. Then 1-hydroxybenzotriazole (HOBt) (0.14 mmol) was added, and after 10 min, EDCI (0.14 mmol) was added. The reaction was performed for 15 min. And then DIPEA (0.39 mmol) and10a-10d(0.13 mmol) was added all at once. After completion of reaction as determined by TLC analysis, the resulted mixture was washed with 5% NaHCO3, 1M HCl, 5% NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and evaporated to provide crude products. Concentration and flash chromatography over silica gel (EtOAC:petroleum 1:2) produced11a-11k, yields were listed in Table 1.
(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamine hydrochloride[ No CAS ]
[ 114457-94-2 ]
[ 205393-22-2 ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at -40 - -11℃;
A 500 ml three neck round bottomed flask equipped with a stir bar, addition funnel, ther60 mocouple, nitrogen inlet/outlet and cooling bath is chargedwith 11 g (99.9 mmol) of(S)-3-phenyl-2-[(pyrazine-2-carbo- nyl)-amino]-propionic acid, 15.5.0 g (40.6 mmol) of o-(7- azabenzotriazol- 1 -yl)-N,N,N?N?-tetramethyluroniumhexafluorophosphate (HATU), 12.2 g (40.6 mmol) of (1R)-1 -[(3a5,45,65,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1 ,3,2-benzodioxaborol-2-yl]-3-methylbutylaminehydrochloride salt (87:13 mixture of isobutyl diastereomers (R:S)) and 165 mE of N,N-dimethylformamide (DMF). The pale yellow reaction solution is cooled to -35 C. where 12.6 g (17 mE, 97.3 mmol) of N,N-di-isopropyl ethyl amine is added dropwise over six minutes at -34 C. to -35 C. The resulting solution is then stirred overnight at -40 to -11 C. The reaction mixture is quenched onto 600 ml of a 1:1 cold water/ethyl acetate mixture. Afier transferring into a reparatory funnel the layers are separated. The organic phase is then washed successively with 10% aqueous sodium hydrogen phosphate (1 x200 mE), 8% aqueous sodium bicarbonate(2x200 mE) and saturated sodium chloride (1 x200 mE). The product solution is dried over magnesium sulfate then filtered. The filtrate is evaporated to dryness in vacuo to give 19.57 g (37.7 mmol, 93%) of the title compound as a light brown foam with an HPEC purity of 92 A %. ?H NMR (d6-DMSO, 400 MHz) oe 9.15 (d, 1H, J=1 .44 Hz), 8.87 (d, 1H, J=2.48 Hz), 8.7 (m, 3H), 7.25 (m, 4H), 7.18 (m, 1H), 4.89 (q, 1H, J=6.88, 15.4 Hz), 4.13 (dd, 1H, J=1.8, 8.56 Hz), 3.15 (d, 2H, J=6.88 Hz), 2.7 (m, b, 1H), 2.22 (m, b, 1H), 2.05 (m, b, 1H), 1.87 (t, 1H, J=5.40 Hz), 1.81 (s, b, 1H), 1.67 (d, b, 1H),1.52 (m, b, 1H), 1.13-1.33 (m, 9H), 0.83 (dd, 6H, J=2.48, 6.56 Hz), 0.80 (s, 3H).
(1S,2S,3R,5S)-pinanediol L-proline boronate hydrochloride[ No CAS ]
[ 114457-94-2 ]
N-((S)-1-oxo-3-phenyl-1-((R)-2-((3aS,4S,6S,7aR)-3a,5,5,7a-tetramethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)pyrrolidin-1-yl)propan-2-yl)pyrazine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 24h;
To a stirred suspension of 7a (1.0mmol) in CH2Cl2 (15mL) were added 1-(3 (dimethyl amino) propyl)-3-ethylcarbodiimide hydrochloride (EDCI, 1.2mmol) and 1-hydroxybenzotriazole monohydrate (HOBt, 1.1mmol). Pinanediol proline boronate hydrochloride 3 (1.0mmol, prepared according to the literature24) and DIPEA (0.36mL, 2.4mmol) were then added. The mixture was stirred at room temperature for 24h and solvent was removed under vacuum. The residue was dissolved in 20mL of ethyl acetate and was successively washed with 10% citric acid, 5% NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and then was evaporated to give crude product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether=1:3) to give product 8a as colorless oil, 71% yield. 1H NMR (400MHz, CDCl3) delta 9.37 (d, J=1.3Hz, 1H), 8.75 (d, J=2.3Hz, 1H), 8.57 (s, 2H), 5.05 (td, J=9.3, 5.5Hz, 1H), 4.37-4.14 (m, 1H), 3.30 (dd, J=16.2, 9.2Hz, 1H), 3.18 (dd, J=12.8, 5.5Hz, 1H), 3.13-3.06 (m, 1H), 3.05-2.97 (m, 1H), 2.60-2.47 (m, 1H), 2.36-2.24 (m, 1H), 2.06 (ddd, J=18.3, 9.2, 4.0Hz, 1H), 1.88 (ddd, J=20.1, 14.2, 8.0Hz, 7H), 1.72-1.55 (m, 1H), 1.39 (s, 4H), 1.24 (s, 3H), 0.82 (d, J=4.8Hz, 3H). 13C NMR (101MHz, CDCl3) delta 167.6, 161.4, 146.3, 143.7, 143.5, 141.8, 135.5, 128.7, 127.6, 126.2, 85.0, 77.0, 51.4, 50.3, 45.4, 39.3, 38.7, 37.4, 34.6, 27.7, 26.3, 26.0, 25.2, 23.2, 0.1.
With trifluoroacetic acid; In dichloromethane; at 20℃; for 2h;
The compound 1 (398.4 mg, 1.22 mmol) was charged into an eggplant flask, and 5 mL of dichloromethane was then added. This was stirred at room temperature for 5 minutes, and then 7 mL of TFA was added, and stirred atroom temperature for 2 hours. After evaporating the solvent under reduced pressure, vacuum drying was performed toobtain a compound 2 (318.8 mg, 96%) .
The compound 2 (271.3 mg, 1.00 mmol, 1 eq) and H-Leu-OtBu-HCl (223.8 mg, 1.00 mmol, 1 eq, Code No.14G110356, Watanabe Chemical Industries, Ltd.) were charged into an eggplant flask, and 10 mL of dehydrate DMFwas then added. After stirred at room temperature for 5 minutes, 2 mL of DIEA was added to neutralize the solution.After stirred for 5 minutes at room temperature, DMT-MM (553.4 mg, 2.00 mmol, 2 eq, Code No. 329-53751, Wako PureChemical Industries, Ltd.) was directly added to the reaction solution, and stirred at room temperature for 3 hours. Undercooling conditions, 20 mL of 10 mass% brine/0.1 N aqueous hydrochloric acid was added, and extracted with ethylacetate for 3 times. This was washed with 0.5 N aqueous hydrochloric acid and then brine, and then dried over anhydroussodium sulfate. After evaporating the solvent under reduced pressure, separation and purification treatment was performedby silica gel chromatography (Code No. 30511-35, Nacalai Tesque, Inc.) (hexane/chloroform = 1/1 to 0/1, gradient)to obtain a compound 3 (168.1 mg, 0.38 mmol, 38%)
(R)-1-amino-3-methylbutane-1-boronic acid-1-(neopentyl glycol) ester hydrochloride[ No CAS ]
[ 114457-94-2 ]
C24H33BN4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; tert-butyl methyl ether; at 0 - 20℃; for 12h;Large scale;
20 liter reactor pre-joined3-methyl-alpha-aminobutylboronic acid neopentyl glycol ester hydrochloride1.18 kg (5.0 mol),(S)-3-phenyl-2-(piperazin-2-carboxamido)propionic acid (VII)1.36 kg (5.0 mol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate quaternary ammonium salt(TATU) 1.93 kg (6.0 mol),Then add 4 liters of tert-butyl methyl ether.Stir and mix well as a suspension,Then, a solution of diisopropylethylamine (DIPEA) was slowly added dropwise thereto at 0 C.1.6 liters of dichloromethane solution 3 liters,The dripping time must not be less than two hours.After the addition is completed,Slowly warm to room temperature for 12 hours.TLC monitors the progress of the reaction,After the reaction is completed, 5 liters of water is added to the reaction vessel for washing.Then washed three times with 3% potassium carbonate,Wash three times with water, then with 3% citric acid, and finally with saturated brine for several times.The organic phase was separated and dried over anhydrous sodium sulfate.Finally, the organic phase is concentrated under reduced pressure to give a compound(2R,5S)-N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucoboronic acid neopentyl glycol ester
(R)-1-amino-3-methylbutane-1-boronic acid-1-(2-methyl-2,4-pentanediol) ester hydrochloride[ No CAS ]
[ 114457-94-2 ]
C25H35BN4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 24h;Large scale;
20 liter reactor pre-joined3-methyl-alpha-aminobutyric acid (2-methyl-2,4-pentanediol) hydrochloride 1.26 kg (5.4 mol),(S)-3-phenyl-2-(piperazin-2-carboxamido)propionic acid (VII)1.46 kg (5.4 mol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate quaternary ammonium salt (HBTU) 2.25 kg (6.0 mol), Then add 4 liters of dichloromethane,Stir and mix well as a suspension,Then, 3 liters of a solution of 1.8 liters of diisopropylethylamine (DIPEA) in dichloromethane was slowly added dropwise thereto at 0 C.The dripping time must not be less than two hours.After the addition is completed,Keep the reaction at 0 C for 24 hours.The progress of the reaction was monitored by TLC. After the reaction was completed, 5 liters of water was added to the reaction vessel for washing.Then washed three times with 3% potassium carbonate and three times with water.Wash with 3% citric acid,Finally, it is washed several times with saturated brine and the organic phase is separated.Dry with anhydrous sodium sulfate,Finally, the organic phase is concentrated under reduced pressure to give a compound(2R,5S)N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic acid (2-methyl-2,4-pentanediol) ester(2.37 kg, 94%).
(R)-1-amino-3-methylbutane-1-boronic acid-1-(2,4-dimethyl-2,4-pentanediol) hydrochloride[ No CAS ]
[ 114457-94-2 ]
C26H37BN4O4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; at 0 - 20℃; for 12h;Large scale;
A 20 liter reactor was previously charged with 1.32 kg (5.0 mol) of 3-methyl-alpha-aminobutyrate (2,4-dimethyl-2,4-pentanediol) hydrochloride.(S)-3-phenyl-2-(piperazin-2-carboxamido)propionic acid (VII) 1.36 kg (5.0 mol),1-ethyl-3-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDCI)1.15 kg (6.0 mol) and 1-hydroxybenzotriazole(HOBt) 810 g (6.0 mol),Then add 4 liters of n-hexane,Stir and mix well as a suspension,Then slowly add dropwise to the solution of diisopropylethylamine (DIPEA) at 0 C.1.6 liters of dichloromethane solution 3 liters,The dropping time should not be less than two hours. After the addition is completed,Slowly warm to room temperature for 12 hours.The progress of the reaction was monitored by TLC. After the reaction was completed, 5 liters of water was added to the reaction vessel for washing.Then washed three times with 3% potassium carbonate,Wash three times with water and then wash with 3% citric acid.Finally, it was washed several times with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate.Finally, the organic phase is concentrated under reduced pressure to give a compound.(2R,5S)-N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic acid (2,4-dimethyl-2,4-pentanediol) ester(2.23 kg, yield 93%).
(R)-3-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-1-amine hydrochloride[ No CAS ]
[ 114457-94-2 ]
[ 1029701-48-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
With 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 12h;Large scale;
20-liter reactor was pre-added with 3-methyl-alpha-aminoboric acid pinacol ester hydrochloride1.36 kg (5.5 mol), (S)-3-phenyl-2-(piperazin-2-carboxamido)propionic acid (VII) 1.49 kg (5.5 mol) and TATU 1.95 kg (6.05 mol),Then add 4 liters of ethyl acetate.Stir and mix well as a suspension,Then, 3 liters of a dichloromethane solution containing 1.9 liters of triethylamine (TEA) was slowly added dropwise thereto at 0 C.The dropping time should not be less than two hours. After the addition is completed,Slowly warm to room temperature for 12 hours.The progress of the reaction was monitored by TLC. After the reaction was completed, 5 liters of water was added to the reaction vessel for washing.It was then washed three times with 3% potassium carbonate, three times with water, and then with 3% citric acid.The mixture was washed several times with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate.Finally, the organic phase is concentrated under reduced pressure to give a compound(2R,5S)-N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic acid pinacol ester
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; toluene; at 0 - 80℃; for 8h;Large scale;
20 liter reactor pre-joined3-methyl-alpha-aminobutylboronic acid neopentyl glycol ester trifluoroacetate 1.60 kg (4.9 mol),(S)-3-phenyl-2-(piperazin-2-carboxamido)propionic acid (VII) 1.33 kg (4.9 mol)And 1-ethyl-3-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDCI)1.02 kg (5.4 mol)And 661 g of 1-hydroxybenzotriazole (4.9 mol), then added 4 liters of toluene,Stir well and mix as a suspension.Then, 3 liters of a solution of 1.7 liters of DIPEA in dichloromethane was slowly added dropwise at 0 C.The dripping time must not be less than two hours.After the addition was completed, the temperature was slowly raised at 80 C for 8 hours.TLC monitors the progress of the reaction,After the reaction is completed, 5 liters of water is added to the reaction vessel for washing.Then washed three times with 3% potassium carbonate,Wash three times with water,Wash with 3% citric acid, and finally wash with saturated brine several times.Minute Out of the organic phase,Dry with anhydrous sodium sulfate,Finally, the organic phase was concentrated under reduced pressure to give Compound (2R,5S)-N-(2-pyrazinecarbonyl)-L-phenylalanine-L- leucine boronic acid ester (1.96 kg, yield 86%).
Pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.3%
(S) -3-phenyl-2-[(pyrazine-2-carbonyl) amino] propionic acid (Compound 1) (5.0 g, 18.4 mmol, 1.0 eq) was dissolved in N, N-dimethylformamide (200 mL), triethylamine (5.60 g, 55.3 mmol, 3.0 eq) and HATU (10.5 g, 27.7 mmol, 1.5 eq) were added, followed by stirring at room temperature for 30 min, and then ammonium chloride (1.48 g, 27.7 mmol, 1.5 eq) and react at room temperature for 12 hours. After that, the reaction solution was washed with saturated brine (100 mL × 3), and then dried over anhydrous Na 2 SO 4, and the solvent was removed by rotary evaporation under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 4.40 g of a yellow solid (Compound 2) with a yield of 88.3%.
N-((S)-1-(((S)-1-(((S)-1-(furan-2-yl)-4-methyl-1-oxopentan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide[ No CAS ]
Chemistry
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