* 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 dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃; for 16 h;
Step 1. To a stirred solution of compound 39-1 (1 g, 4 mmol), compound 39-2 (459 mg, 4 mmol) in THF (20 mL) was added DCC (908 mg, 4.4 mmol) at 0°C. The reaction mixture was stirred at r.t. for 16 h. The mixture was filtered and the filtrate was concentrated to give compound 39-3 (Yield: 90 percent).
85.5 g
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 5℃; for 20.75 h;
2-(((benzyloxy)carbonyl)amino)-3-methylbutanoic acid (65g, 259mMol), tetrahydrofuran (450ml) were charged to a flask. N-hydroxy succinimide (33.3g 285mMol) was added to the reaction mass. Reaction mass was stirred for lOmins. Dimethyl amino pyridine (DMAP, lg) was added to the reaction mass. Reaction mass was stirred and temperature of reaction mass was decreased to 5°C. Solution of DCC in THF (42.5percent, 200ml) was added dropwise to the reaction mass over a period of 45 minutes at 5°C. Reaction mass was stirred for 20 hours. Obtained solid was filtered; solvent was stripped off under reduced pressure. Solid was washed with heptane (3x250ml ), to get crude material (2,5- dioxopyrrolidin-l-yl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate) with sufficient purity. Yield 85.5 g. (0091) JH NMR (DMSO-D6, 400 MHz): δ 1.02(d,6H), 2.24(m,lH), 2.82(s,4H), 4.37(q,lH), 5.09 (s,2H), 7.34-7.44 (m,5H), 8.09 (d,lH). (0092) 13C NMR (DMSO D6, 100MHz): δ 18.3, 19.3, 25.4, 30.1, 58.1, 65.9, 127.7, 128.4,136.7, 156.3, 168.0, 170.0, 172.8 (0093) FTIR (KBr): 3327, 2933, 2117, 1816, 1784, 1741, 1527, 1204, 893 cm"1. (0094) MS (EI): Q7H20N2O6 Exact mass: 348.35, observed mass: 366.2 (+ H20).
Reference：
[1] Chemical Communications, 2015, vol. 51, # 67, p. 13213 - 13216
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 28, p. 7736 - 7749
[3] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 133
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 989 - 1000
[5] Journal of the American Chemical Society, 2003, vol. 125, # 22, p. 6677 - 6686
[6] RSC Advances, 2015, vol. 5, # 89, p. 72579 - 72589
[7] Tetrahedron, 1998, vol. 54, # 14, p. 3489 - 3494
[8] Journal of Pharmaceutical Sciences, 1993, vol. 82, # 1, p. 1 - 10
[9] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1981, vol. 30, # 5, p. 806 - 812[10] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1981, # 5, p. 1045 - 1051
[11] Journal of Medicinal Chemistry, 1994, vol. 37, # 18, p. 2841 - 2845
[12] Bioorganic & Medicinal Chemistry Letters, 1998, vol. 8, # 23, p. 3343 - 3346
[13] Organic and Biomolecular Chemistry, 2006, vol. 4, # 5, p. 853 - 859
[14] Chemistry - A European Journal, 2004, vol. 10, # 16, p. 3879 - 3890
[15] Synlett, 2005, # 18, p. 2802 - 2804
[16] Chemical Communications, 2002, # 7, p. 738 - 739
[17] Tetrahedron, 2007, vol. 63, # 38, p. 9493 - 9501
[18] Tetrahedron, 2008, vol. 64, # 41, p. 9717 - 9724
[19] Tetrahedron Letters, 2008, vol. 49, # 48, p. 6885 - 6888
[20] Inorganic Chemistry, 2010, vol. 49, # 17, p. 7841 - 7852
[21] European Journal of Organic Chemistry, 2010, # 31, p. 5967 - 5979
[22] Patent: US2011/224455, 2011, A1, . Location in patent: Page/Page column 11
[23] Tetrahedron, 2013, vol. 69, # 2, p. 551 - 558
[24] Chemistry - A European Journal, 2013, vol. 19, # 48, p. 16256 - 16262
[25] Organic and Biomolecular Chemistry, 2014, vol. 12, # 5, p. 823 - 831
[26] Chemical and Pharmaceutical Bulletin, 2016, vol. 64, # 8, p. 1181 - 1189
[27] Organic and Biomolecular Chemistry, 2016, vol. 14, # 47, p. 11125 - 11136
[28] Organic and Biomolecular Chemistry, 2017, vol. 15, # 14, p. 3013 - 3024
[29] Patent: WO2017/134548, 2017, A1, . Location in patent: Page/Page column 15-16
Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: With ammonium chloride In N,N-dimethyl-formamide at 23℃; for 16 h;
[0197] To a stuffed solution of compound I (10 g, 39.84 mmol, 1 eq) in DMF (100 mL) was added DIPEA (19.7 mL, 119.5 mmol, 3 eq) and HATU (18.17 g, 47.8 mmol, 1.2 eq) at 0°C and the resulting mixture was stuffed for 15 mm. To the mixture was added ammonium chloride (10.7 g, 199.2 mmol, 5 eq) and the resulting mixture was allowed to stir at 23°C for another 16 h. The mixture was poured into ice cold water (500 mL), the organic components were extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was recrystallized from ethanol to obtain the title compound (9.8 g, 98percent) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ö 7.35 (m, 6H), 7.12 (d, 1H, J = 9 Hz), 7.01 (s, 1H), 5.03 (s, 2H), 3.80 (t, 1H, J = 8 Hz), 1.95 (m, 1H), 0.85 (m, 6H). LCMS: mlz = 251.2 [M+Hj , RT = 2.81 minutes, (Program P1, Column Y).
93%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5 h; Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5 h;
General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N at 0°C. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86percent yield) of Cbz-L-Phe-NH2 4a. 4.3.7 Cbz-l-Val-NH2 4d 117 mg (93percent); >99percent ee; coloress solid; mp: 172-175 °C; [α]D25 = +17.8 (c 0.99, DMSO); 1H NMR (400 MHz, DMSO-d6): δ 0.83 (d, J = 6.8 Hz, 3H, CH3), 0.86 (d, J = 6.8 Hz, 3H, CH3), 1.94 (ddd, J = 6.7, 6.8, 6.8 Hz, 1H, CH(CH3)2), 3.80 (dd, J = 6.7, 8.8 Hz, 1H, CHCO), 5.03 (s, 2H, OCH2C6H5), 7.03 (br, 1H, CONHA), 7.16 (d, J = 8.8 Hz, 1H, NHCH), 7.29-7.39 (m, 6H, CONHB, C6H5); 13C NMR (100 MHz, DMSO-d6): δ 18.0, 19.3, 30.1, 60.0, 65.3, 127.6, 127.7, 128.3, 137.1, 156.1, 173.2; IR (KBr, vmax/cm-1): 3381 (CONH), 3319 (CONH), 3203 (CONH), 1654 (CON); HRMS (ESI-TOF): Calcd for C13H18N2O3Na (M+Na)+: 273.1210, found: 273.1193; The enantiomeric ratio was determined by HPLC (Chiralcel AD: hexane/2-propanol = 90/10): Tr 11.5 min.
63.8%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -78℃; for 1 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 2 h;
Step 1. To a solution of 27-1 (8 g, 31.8 mmol) and Et3N (6.43 g, 63.6 mmol) in dry THF (100 mL) at -78°C was added dropwise a solution of ethyl chloro formate (3.45 g, 31.8 mmol) in THF (10 mL). After the reaction was stirred at -78°C for 1 h, NH3.H20 (5 mL) was added. The reaction was warmed to r.t. over 2 h. White solid was collected by filtration and dried to give 27-2 (5.1 g, 63.8percent).
53.15%
With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 0 - 20℃;
To a solution of (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (10.0 g, 39.84 mmol) in 1,4-dioxane (50 mL) was added di-tert-butyl dicarbonate (11.95 g, 51.79mmol) in portions at 0°C. Then pyridine (2 mL, 25.76 mmol) was added drop-wise at 0°C, followed by ammonium bicarbonate (3.94 g, 50.43 mmol) in portions. The reaction was stirred at room temperature overnight. The mixture was poured into ice water and filtered. The filter cake was washed with water and dried under vacuum. The filter cake was then re-crystallized from dioxane/water (80 mL, 9: 1, v/v) to give (S)-benzyl (1-amino-3-methyl-1-oxobutan-2-yl)carbamate(5.3 g, 53.15percent yield) as a white solid. LC-MS (ESI) found: 251 [M+Hf’, ee>99percent, (CHIRALPAK AS-H, 15percent ethanol/ hexane)
Reference：
[1] Patent: WO2015/95128, 2015, A1, . Location in patent: Paragraph 0195; 0196; 0197
[2] Tetrahedron Asymmetry, 2017, vol. 28, # 12, p. 1690 - 1699
[3] Chemische Berichte, 1983, vol. 116, # 5, p. 2037 - 2040
[4] Tetrahedron Letters, 1995, vol. 36, # 39, p. 7115 - 7118
[5] Chemical Communications, 2017, vol. 53, # 75, p. 10362 - 10365
[6] Journal of Organic Chemistry, 2009, vol. 74, # 11, p. 4177 - 4187
[7] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 120
[8] Patent: WO2018/31877, 2018, A1, . Location in patent: Paragraph 00158
[9] Chemische Berichte, 1964, vol. 97, p. 1197 - 1206
[10] Journal of Organic Chemistry, 1999, vol. 64, # 2-5, p. 1657 - 1666
[11] Organic and Biomolecular Chemistry, 2006, vol. 4, # 1, p. 38 - 40
[12] Organic Letters, 2007, vol. 9, # 13, p. 2521 - 2524
[13] Chemistry - A European Journal, 2006, vol. 12, # 20, p. 5383 - 5397
[14] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[15] Organic and Biomolecular Chemistry, 2012, vol. 10, # 48, p. 9660 - 9663
[16] Chemistry Letters, 2013, vol. 42, # 6, p. 580 - 582
6
[ 64-17-5 ]
[ 1149-26-4 ]
[ 67436-18-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1978, vol. 51, # 6, p. 1897 - 1898
[2] Pharmazie, 1997, vol. 52, # 3, p. 203 - 206
[3] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
7
[ 64-17-5 ]
[ 1149-26-4 ]
[ 1685-33-2 ]
[ 67436-18-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1987, vol. 22, p. 347 - 358
[2] Synthetic Communications, 1988, vol. 18, # 4, p. 441 - 444
8
[ 1149-26-4 ]
[ 541-41-3 ]
[ 67436-18-4 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 5, p. 560 - 565
9
[ 1149-26-4 ]
[ 128625-52-5 ]
[ 6415-07-2 ]
[ 126814-51-5 ]
Reference：
[1] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2437 - 2446
With Sodium hydrogenocarbonate In water monomer Inert atmosphere;
100%
With sodium hydroxide In water monomer at 0 - 20℃;
99%
With potassium carbonate In water monomer at 0 - 2℃;
4 Example 4
Weigh 46.8 g (0.4 mol) of L-valine in 250 mL of water, and slowly add benzyl chloroformate and saturated potassium carbonate solution at a temperature of 0 to 2 °C.The molar ratio of proline to benzyl chloroformate is from 1:1.0 to 1.05.Control pH 1.5~2.0 until the reaction is completed, after the reaction is over,Extract the reaction solution three times directly with dichloromethane, using 300 ml each time.After the extraction, the dichloromethane was combined and washed with 50 ml of saturated brine.It is dried over anhydrous sodium sulfate, and the dried dichloromethane is concentrated.After drying, ethyl acetate and petroleum ether crystallize.The product is dried to 99.4g.The yield was 99%, and the purity was 99.5% (purity was determined by high performance liquid phase).
96%
Stage #1: L-valine; benzyl chloroformate With sodium hydroxide In water monomer at 20℃;
Stage #2: With hydrogenchloride In water monomer Cooling with ice;
95%
With sodium hydroxide In tetrahydrofuran at 65℃; for 0.166667h; microwave irradiation;
93.7%
With anhydrous sodium carbonate; sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 8h; Large scale;
1 Example 1 Synthesis of N-Benzyloxycarbonyl-L-valine
Take L-valine 1.17Kg (10mol),2mol/L sodium hydroxide solution 5L,1.06Kg (10mol) sodium carbonate was added to the 20L reaction kettle.Turn on the agitation,After the L-valine is completely dissolved,The temperature of the solution was lowered to below 0 ° C, and 5 L of 1,4-dioxane solution containing 2.05 Kg (12 mol) of benzyl chloroformate was added dropwise, and the temperature of the dropwise addition process solution was kept below 20 ° C, and the reaction was carried out at room temperature. 8h. After completion of the reaction, the reaction solution was extracted with 2.5 L of dichloromethane, the organic phase was discarded, the aqueous phase was cooled to below 10 ° C, concentrated hydrochloric acid was added dropwise until pH = 2, and then stirred at 10 ° C for 30 min to precipitate a large amount of white solid. The filter residue was washed with water, and the white solid was dried in a vacuum oven to obtain white N-benzyloxycarbonyl-L-proline 2.35 Kg, yield 93.7%, purity 99.6% (HPLC),
92%
With anhydrous sodium carbonate In water monomer at 28℃; for 16h;
70.1 Step 1
Step 1. To a mixture of compound 70-1 (3.0 g, 25.61 mmol) in water (20 mL) was added Na2C03 (2.71 g, 25.61 mmol). CbzCl (4.81 g, 28.17 mmol) was added and the reaction mixture was stirred at 28°C for 16 h. The mixture was filtered and extracted with EtOAc (15 mL x 2). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to give compound 70-2 (5.9 g, 92%). NMR (400 MHz, CDC13) δ 8.21-7.30 (m, 5 H), 5.86 (br, 1 H), 5.15 (s, 2 H), 4.37-4.34 (m, 1 H), 2.28-2.21 (m, 1 H), 1.01-0.84 (m, 6 H)
91%
With sodium hydroxide In tetrahydrofuran; water monomer Inert atmosphere;
90%
With anhydrous sodium carbonate In water monomer at 0 - 20℃; for 24h;
85%
With water monomer; Sodium hydrogenocarbonate; anhydrous sodium carbonate In acetone at 15 - 20℃;
3
General procedure: The (S)-amino acid (10.0 g) was dissolved in H2O (300 ml) and Na2CO3 (2.0 equiv) and NaHCO3 (1.0 equiv) were added at rt, with stirring, to give a clear solution. Acetone (4.0 vol, with respect to the amino acid) was added and the slightly turbid solution was cooled in an ice water bath to 15-20 °C. Cbz-Cl (1.25 equiv) was added slowly, with stirring, and the reaction mixture allowed to warm to rt. After stirring for an additional 3 h at rt the mixture was extracted with Et2O (50 ml). To the aqueous phase was slowly added aqueous HCl to give a pH of 2. The resulting oil was extracted into EtOAc (150 ml) and this was washed with H2O (100 ml) and then concentrated in vacuo to give the N-Cbz amino acid as a white solid, see Table 1.
65%
61%
Stage #1: L-valine With sodium hydroxide In water monomer at 0℃; for 0.0833333h;
Stage #2: benzyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h;
5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1
General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification.
61%
Stage #1: L-valine With sodium hydroxide In water monomer at 0℃; for 0.0833333h;
Stage #2: benzyl chloroformate In 1,4-dioxane; water monomer at 25 - 30℃; for 24h;
5.1.2 Procedure for the synthesis of amino acids carbamate (caps) which are shown in Scheme 1
General procedure: In a round-bottomed flask, the required amino acid (24mmol) was dissolved in an aqueous solution of NaOH (75mL, 1M) and left to cool in an ice bath at 0°C for 5min. Then, the respective chloroformate (33mmol) in 1,4-dioxane (30mL) was added portionwise to the above solution and stirred overnight at 25-30°C. Then, the reaction mixture was extracted twice using diethyl ether and the aqueous layer was acidified using HCl until the pH=2. The respective carbamates were isolated from the aqueous layer by extraction with diethyl ether (twice). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to give the product. The product was used without further purification.
58%
With sodium hydroxide at 0℃; for 3h;
57%
In ethyl acetate Heating;
54.3%
With sodium hydroxide In acetone for 12h; Ambient temperature;
With sodium hydroxide
With sodium hydroxide In 1,4-dioxane for 16h; Ambient temperature;
With pyridine; HOBT bound to the polystyrene-divinylbenzene copolymer resin 1.) DMF, H2O, 25 deg C, 2.) DMF, H2O, 25 deg C; Yield given. Multistep reaction;
18 g
With Sodium hydrogenocarbonate In water monomer at 20℃; for 20h;
With Sodium hydrogenocarbonate In water monomer
With sodium hydroxide; Sodium hydrogenocarbonate In water monomer at 0 - 20℃;
In potassium hydroxide
1.a a)
a) Preparation of N-benzyloxycarbonyl-L-valine 10 g of L-valine (85 mmol) are dissolved in 4 M KOH (40 ml) and the mixture is cooled in ice. 21.9 g of benzyloxycarbonyl chloride (128 mmol) are added thereto over 5 minutes and a white solid forms. The mixture is stirred at 0° C. for one hour, the temperature is then allowed to rise and stirring is continued for another hour at room temperature. The reaction mixture is then diluted with 4 M KOH (200 ml) and is extracted with ether (2*100 ml). The aqueous phase is then brought to an acidic pH<1 with concentrated hydrochloric acid and is then extracted with ethyl acetate (3*200 ml). The extracts are combined and dried (Na2SO4) and the solvent is evaporated off. A clear oil is obtained. 1H-NMR (200 MHz, CDCl3, ppm): 7.42-7.52 (1H, d, NH); 7.24-7.36 (5H, m, Ph); 5.00 (2H, s, Ph-CH2); 3.78-3.88 (1H, m, α-CH acid); 1.98-2.08 (1H, m, β-CH acid); 0.80-0.88 (6H, m, 2*CH3).
With anhydrous sodium carbonate In water monomer
1
Example 1Formation of (s)-N-cbz-Valine L-Valine (150 g) was suspended in 1000 mL of water and the mixture was treated with Na2CO3 (136 g). CbzCl (240 g) was added and the reaction mixture was stirred overnight. The mix-ture was filtered and extracted with 500 mL AcOEt. The aqueous layer was adjusted to pH 2 and extracted with 2×500 mL AcOEt. The combined organic layers were dried over Na2SO4 and concentra-ted under reduced pressure to give 350 g (100%) of crude product as a colorless oil.
With sodium hydroxide
Stage #1: L-valine With sodium hydroxide In water monomer; toluene at 10 - 15℃; Large scale reaction;
Stage #2: benzyl chloroformate In water monomer; toluene at 15 - 30℃; Large scale reaction;
Stage #3: With sulfuric acid In water monomer Large scale reaction;
With sodium hydroxide In tetrahydrofuran; water monomer at 0 - 20℃;
2.1.2 4.2. General procedure for the synthesis of N-benzyloxycarbonylprotected amino acids 1
General procedure: N-Benzyloxycarbonyl α-amino acids 1a-f were prepared followingthe method described by Shi et al.19b After usually workup,all products were using direct in the next step without furtherpurification.
With sodium hydroxide In water monomer at 0 - 20℃; for 2h;
With sodium hydroxide at 0℃; for 1.5h;
With Sodium hydrogenocarbonate In diethyl ether; water monomer at 20℃; for 4h; Cooling with ice;
4.b
B: amino acid intermediates preparation: in 500 ml in the reaction bottle, by adding 3.6g sodium bicarbonate, 250 ml water, added under stirring and ice 2.8g of the L-valine, will 3.8g benzyl chloroformate dissolved in 40 ml in ether, then drip, is added to the amino acid in the reaction bottle, is omitted to stirring the mixture at room temperature slowly 4h, is poured into the ice water, regulating pH=1.5 with hydrochloric acid, stirring the mixture at room temperature for 15 min, add 400 ml ethyl acetate extraction three times, ethyl acetate layer with a saturated salt water washing 3 times, the organic layer is dried with anhydrous sodium sulfate, filtration, column chromatography to obtain N-benzyloxycarbonyl valine (Cbz valine) product.
With anhydrous sodium carbonate In water monomer at 20℃; for 12h;
Stage #1: L-valine With sodium hydroxide In water monomer at 0℃; Cooling with ice;
Stage #2: benzyl chloroformate In 1,4-dioxane; water monomer at 20℃;
With sodium hydroxide In water monomer at 0 - 20℃; for 3.5h;
With lithium hydroxide monohydrate In water monomer; toluene at 0 - 20℃; for 15h;
[0197] To a stuffed solution of compound I (10 g, 39.84 mmol, 1 eq) in DMF (100 mL) was added DIPEA (19.7 mL, 119.5 mmol, 3 eq) and HATU (18.17 g, 47.8 mmol, 1.2 eq) at 0C and the resulting mixture was stuffed for 15 mm. To the mixture was added ammonium chloride (10.7 g, 199.2 mmol, 5 eq) and the resulting mixture was allowed to stir at 23C for another 16 h. The mixture was poured into ice cold water (500 mL), the organic components were extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was recrystallized from ethanol to obtain the title compound (9.8 g, 98%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) oe 7.35 (m, 6H), 7.12 (d, 1H, J = 9 Hz), 7.01 (s, 1H), 5.03 (s, 2H), 3.80 (t, 1H, J = 8 Hz), 1.95 (m, 1H), 0.85 (m, 6H). LCMS: mlz = 251.2 [M+Hj , RT = 2.81 minutes, (Program P1, Column Y).
93%
General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67muL (0.70mmol, 1.4equiv) of ClCO2Et and 209muL (1.5mmol, 3.0equiv) of Et3N at 0C. After stirring for 30min at 0C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0C to the colorless suspension. The mixture was stirred for 30min at 0C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86% yield) of Cbz-L-Phe-NH2 4a. 4.3.7 Cbz-l-Val-NH2 4d 117?mg (93%); >99% ee; coloress solid; mp: 172-175?C; [alpha]D25?=?+17.8 (c 0.99, DMSO); 1H NMR (400?MHz, DMSO-d6): delta 0.83 (d, J?=?6.8?Hz, 3H, CH3), 0.86 (d, J?=?6.8?Hz, 3H, CH3), 1.94 (ddd, J?=?6.7, 6.8, 6.8?Hz, 1H, CH(CH3)2), 3.80 (dd, J?=?6.7, 8.8?Hz, 1H, CHCO), 5.03 (s, 2H, OCH2C6H5), 7.03 (br, 1H, CONHA), 7.16 (d, J?=?8.8?Hz, 1H, NHCH), 7.29-7.39 (m, 6H, CONHB, C6H5); 13C NMR (100?MHz, DMSO-d6): delta 18.0, 19.3, 30.1, 60.0, 65.3, 127.6, 127.7, 128.3, 137.1, 156.1, 173.2; IR (KBr, vmax/cm-1): 3381 (CONH), 3319 (CONH), 3203 (CONH), 1654 (CON); HRMS (ESI-TOF): Calcd for C13H18N2O3Na (M+Na)+: 273.1210, found: 273.1193; The enantiomeric ratio was determined by HPLC (Chiralcel AD: hexane/2-propanol?=?90/10): Tr 11.5?min.
63.8%
Step 1. To a solution of 27-1 (8 g, 31.8 mmol) and Et3N (6.43 g, 63.6 mmol) in dry THF (100 mL) at -78C was added dropwise a solution of ethyl chloro formate (3.45 g, 31.8 mmol) in THF (10 mL). After the reaction was stirred at -78C for 1 h, NH3.H20 (5 mL) was added. The reaction was warmed to r.t. over 2 h. White solid was collected by filtration and dried to give 27-2 (5.1 g, 63.8%).
53.15%
With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 0 - 20℃;
To a solution of (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (10.0 g, 39.84 mmol) in 1,4-dioxane (50 mL) was added di-tert-butyl dicarbonate (11.95 g, 51.79mmol) in portions at 0C. Then pyridine (2 mL, 25.76 mmol) was added drop-wise at 0C, followed by ammonium bicarbonate (3.94 g, 50.43 mmol) in portions. The reaction was stirred at room temperature overnight. The mixture was poured into ice water and filtered. The filter cake was washed with water and dried under vacuum. The filter cake was then re-crystallized from dioxane/water (80 mL, 9: 1, v/v) to give (S)-benzyl (1-amino-3-methyl-1-oxobutan-2-yl)carbamate(5.3 g, 53.15% yield) as a white solid. LC-MS (ESI) found: 251 [M+Hf?, ee>99%, (CHIRALPAK AS-H, 15% ethanol/ hexane)
General procedure: The appropriate N-protected amino/peptide acid (1.0 mmol) was dissolved in THF, to which NMM (1.5 mmol) and ECF (1.5 mmol) were added at -15 C, followed by the addition of NH4HCO3 (1.5 mmol) to obtain the corresponding amide. The reaction mixture was stirred until the completion of the reaction and the progress of the reaction was checked by TLC. After the removal of THF, the product was extracted into ethyl acetate (15 mL) and the organic layer was washed with dilute HCl solution (10 mL) or citric acid solution (10 mL) in the case of the Boc-protected compounds, then with Na2CO3 solution (15 mL x 2), water (15 mL) and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The amide thus formed was then treated with P2S5 (0.5 mmol) to form the thioamide under ultrasonic conditions for 2-3 hrs. The resulting thioamide in dry THF was reacted with chloroacetaldehyde (1.0 mmol) under reflux conditions for 2 hrs. N-Protected thiazoles were obtained in good yield after simple acid-base work up and purified through column chromatography using EtOAc:hexane (3:7) as an eluent.
With Amberlite XAD-8 In ethyl acetate at 37℃; for 12h; pH=5.0;
82%
With dmap; dicyclohexyl-carbodiimide In dichloromethane
72%
With tert.-butylnitrite at 60℃; for 48h; Green chemistry;
64%
With ethenetetracarbonitrile at 60℃; for 48h;
With boron trifluoride diethyl etherate Heating;
With triethylamine; isobutyl chloroformate In tetrahydrofuran for 16h; Ambient temperature;
With sulfuric acid
2
Example 2 Formation of (S)-N-cbz-Valine Ethyl EsterThe (S)-N-CBZ-valine from Example 1 (150 g) was mixed with 1200 mL methanol and H2SO4 (15 g) was added. The mixture was stirred overnight and distilled under reduced pressure. The residue was treated with 1000 mL AcOEt and washed with 500 mL water, followed by washing with 400 mL saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 151 g of product.
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃; for 16h;
Step 1. To a stirred solution of compound 39-1 (1 g, 4 mmol), compound 39-2 (459 mg, 4 mmol) in THF (20 mL) was added DCC (908 mg, 4.4 mmol) at 0C. The reaction mixture was stirred at r.t. for 16 h. The mixture was filtered and the filtrate was concentrated to give compound 39-3 (Yield: 90 %).
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 0 - 5℃; for 24h;
A first solution is prepared by dissolving N-alpha-Benzyloxycarbonyl-L-valine (17.60 grams, 70 mmol) and N-hydroxysuccinimide (8.79 g, 77 mmol) in dry THF at 0 C. Once a clear solution is obtained, 17.45 grams of N,N'-Dicyclohhexylcarbodiimide (84.6 mmol) in anhydrous THF is slowly added to the first solution and the resulting mixture is stirred at 0-5 C. in ice-bath for 24 h. The intermediate formed (white solid, 90% yield) is filtered off (filtering plate no 3) and the filtrate was concentrated to dryness. The crude product was recrystallized from 2-propanol to furnish the pure product.
General procedure: The N-Cbz-L-amino acid (1 mmol) and N-hydroxysuccinimide(1 mmol) were dissolved in dry THF at 0 C. Once a clear solutionhad been obtained, DCC (1 mmol) in anhydrous THF was added inseveral aliquots and the resulting solution was stirred at 0e5 C for3 h. The dicyclohexylurea formed was filtered off and the filtratewas concentrated to dryness. The crude product was recrystallizedfrom 2-propanol to furnish the pure product
85.5 g
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 5℃; for 20.75h;
2-(((benzyloxy)carbonyl)amino)-3-methylbutanoic acid (65g, 259mMol), tetrahydrofuran (450ml) were charged to a flask. N-hydroxy succinimide (33.3g 285mMol) was added to the reaction mass. Reaction mass was stirred for lOmins. Dimethyl amino pyridine (DMAP, lg) was added to the reaction mass. Reaction mass was stirred and temperature of reaction mass was decreased to 5C. Solution of DCC in THF (42.5%, 200ml) was added dropwise to the reaction mass over a period of 45 minutes at 5C. Reaction mass was stirred for 20 hours. Obtained solid was filtered; solvent was stripped off under reduced pressure. Solid was washed with heptane (3x250ml ), to get crude material (2,5- dioxopyrrolidin-l-yl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate) with sufficient purity. Yield 85.5 g. (0091) JH NMR (DMSO-D6, 400 MHz): delta 1.02(d,6H), 2.24(m,lH), 2.82(s,4H), 4.37(q,lH), 5.09 (s,2H), 7.34-7.44 (m,5H), 8.09 (d,lH). (0092) 13C NMR (DMSO D6, 100MHz): delta 18.3, 19.3, 25.4, 30.1, 58.1, 65.9, 127.7, 128.4,136.7, 156.3, 168.0, 170.0, 172.8 (0093) FTIR (KBr): 3327, 2933, 2117, 1816, 1784, 1741, 1527, 1204, 893 cm"1 . (0094) MS (EI): Q7H20N2O6 Exact mass: 348.35, observed mass: 366.2 (+ H20).
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In tetrahydrofuran; water; at 20℃; for 18h;
108.0 g (429.8 mmol) of ((benzyloxy)carbonyl)-L-valine and 139.8 g (472.4 mmol / 1 .1 eq.) of fe/ -butyl <strong>[120205-48-3](3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate hydrochloride</strong> was provided in a reaction mixture comprising 1 .5 eq. 4-(4,6-dimethoxy- 1 ,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 2.0 eq. NMM in 1080 ml (10 V) 2% TPGS-750-M in water and 216 ml (2V) THF. The reaction mixture formed a stable emulsion and the reaction was allowed to proceed for 18 h at room temperature under stirring. The product [fe/ -butyl (3R,4S,5S)-4-((S)-2- (((benzyloxy)carbonyl)amino)-N,3-dimethylbutanamido)-3-methoxy-5- methylheptanoate] was obtained with a yield of 88%. The absence of co-solvent such as THF resulted in the formation of oil balls and the yield was reduced to 66%.
58%
(2S)-2-[[(benzyloxy)carbonyl] amino]-3-methylbutanoic acid (15 g, 0.40 mmo 1,1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3 g). The solution was agitated 30 minutes at ambient temperature before adding compound iS (15.99g,0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (C18) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of compound iT in the form of a colourless oil.
58%
(2S)-2-[[(benzyloxy)carbonyl] amino]-3-methylbutanoic acid (15 g, 0.40 mmo 1,1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3 g). The solution was agitated 30 minutes at ambient temperature before adding compound iS (15.99g,0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (C18) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of compound iT in the form of a colourless oil.
58%
(2S)-2-[[(benzyloxy)carbonyl] amino]-3-methylbutanoic acid (15 g, 0.40 mmo 1,1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3 g). The solution was agitated 30 minutes at ambient temperature before adding compound iS (15.99g,0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (C18) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of compound iT in the form of a colourless oil.
58%
Compound IT: tert-butyl (3R,4S,5S)-4-[(2S)-2- [[(benzyloxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-mthoxy-5- meth lheptanoate (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoic acid (15 g, 0.40 mmol, 1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3g). The solution was agitated 30 minutes at ambient temperature before adding compound IS (15.99g, 0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (CI 8) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of compound IT in the form of a colourless oil.
58%
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoic acid (15 g, 0.40 mmol, 1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3g). The solution was agitated 30 minutes at ambient temperature before adding compound IS (15.99g, 0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (CI 8) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58 %) of compound IT in the form of a colourless oil
58%
Compound 1T: tert-butyl (3R,4S,5S)-4-[(2S)-2-[[(benzyloxy)carbonyl]amino]-N,3-dimethylbutanamido]-3-mthoxy-5-methylheptanoate (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoic acid (15 g, 0.40 mmol, 1.00 equiv) was dissolved in 300 mL of DCM in the presence of DIEA (38.3 mL) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP, 32.3 g). The solution was agitated 30 minutes at ambient temperature before adding compound 1S (15.99 g, 0.42 mmol, 1.07 equiv). The reaction medium was agitated 2 hours and then concentrated. The residue was purified in reverse phase (C18) with a mixture of acetonitrile (ACN) and water (30:70 to 100:0 in 40 minutes) to yield 17 g (58%) of compound 1T in the form of a colourless oil.
Stage #1: (S)-N-(benzyloxycarbonyl)valine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.25h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at -15℃; for 1h;
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃;
Multi-step reaction with 2 steps
1: DCC / ethyl acetate / 20 h / 20 °C
2: NaBH4; AcOH / methanol; dioxane
Multi-step reaction with 2 steps
1: PTSA / benzene / 1 h / Heating
2: 93 percent / NaBH4 / methanol / 3 h / 0 deg C -> r.t.
Multi-step reaction with 2 steps
1: 81 percent / PPh3, PPh3*HClO4 / CH2Cl2 / -30 °C / electrolysis, 2.8 F of electricity, graphite plates as anode and cathode
2: NaBH4 / ethanol / 0 °C
Stage #1: (S)-N-(benzyloxycarbonyl)valine With isobutyl chloroformate
Stage #2: With sodium tetrahydroborate In water
Multi-step reaction with 2 steps
1: 4-methyl-morpholine / 1,2-dimethoxyethane / 20 °C
2: sodium tetrahydroborate; water / -15 °C
Multi-step reaction with 2 steps
1: dicyclohexyl-carbodiimide / tetrahydrofuran / 1 h / 0 °C
2: sodium tetrahydroborate / water; tetrahydrofuran / 0.08 h / 0 °C
Multi-step reaction with 2 steps
1: 4-methyl-morpholine / tetrahydrofuran / -15 °C
2: sodium tetrahydroborate
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.5h; Irradiation;
With 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate; 3-hydroxy-3,4-dihydrobenzotriazine-4-one In dichloromethane at 25℃; for 1h;
(S)-2-Benzyloxycarbonylamino-3-methyl-butyric acid 4-(2-amino-6-oxo-1,6-dihydro-purin-9-yl)-2-((S)-2-benzyloxycarbonylamino-3-methyl-butyryloxymethyl)-butyl ester[ No CAS ]
EXAMPLE 1 Preparation of 2-[(2-AMINO-1,6-DIHYDRO-6-OXO-9H-PURIN-9YL)METHOXY] ETHYL N-[(BENZYLOXY)CARBONYL] L-VALINATE (Formula IV) 50 g of N-[(benzyloxy)carbonyl] L-valine (CBZ-L-valine) of Formula III and 500 ml of dimethyl formamide (DMF) were charged into a round bottom flask followed by stirring with simultaneous cooling to 15 C. over a period of 10 minutes. To the obtained clear solution 68.6 g of dicyclohexyl carbodiimide dissolved in 100 ml of dimethyl formamide was slowly added over a period of 45 minutes followed by stirring for 15 minutes at 15 C. 50 g of 9-((2-hyroxyethoxy)methyl)-2-amino-1H-purin-6(9H)-one (acyclovir) of Formula II and 4.066 g of dimethylaminopyridine were charged into the reaction mass and subjected to stirring for about 6 hours at 15 C. After completion of the reaction, the reaction mass was filtered and the solids washed with 100 ml of dimethyl formamide. The resultant filtrate was subjected to distillation under vacuum at 80 C. until 80% of the volume was distilled. The resultant filtrate was transferred into another flask and 300 ml of water was added at 30 C. followed by heating to 70 C. for a period of 30 minutes. The mixture was cooled to 20 C. and the separated solid was filtered, followed by washing the solid with 100 ml of water. The solid material was subjected to suction drying to afford the 256 g of wet solid title compound. 256 g of the above-obtained wet material was taken into a round bottom flask along with 750 ml of methanol and 225 ml of water, followed by heating to 80 C. with simultaneous stirring for 4 hours. The obtained mass was cooled to a temperature of 35 C. with simultaneous stirring. The solid obtained was filtered and washed with a mixture of 338 ml methanol and 178 ml water. Finally the obtained solid material was subjected to suction drying followed by drying under vacuum at 55 C. to afford 88.7 g (87.2%) of the title compound. Purity: 99.3 weight % by HPLC.
EXAMPLE 2 To a 250 mL reaction flask, as described in Example 1, was charged under nitrogen 13.8 grams of Z-valine, 11.3 grams of dry acyclovir and 50 mL of DMF. (The acyclovir was dried in a vacuum oven at 80-85 C. and at less than 5 Torr vacuum for 4 hours.) The mixture in the reaction flask was stirred and cooled to approximately 0-2 C. Benzene sulfonyl chloride (12.4 grams) was added all at once to the cooled mixture and the reaction mixture stirred for 10 minutes. 1-methyl imidazole (12.6 grams) was added drop wise to the reaction mixture over a period of 1 hour and the mixture stirred at 0-5 C. for 4 hours, and then overnight at room temperature. HPLC analysis of the reaction mixture indicated that the esterification reaction was incomplete. Additional 2.2 grams of benzene sulfonyl chloride was added drop wise to the reaction mixture with stirring. The reaction mixture was stirred at 18-20 C. for 2.5 hours. HPLC analysis of the reaction mixture indicated that approximately 2% of the acyclovir remained unreacted. An additional 1 gram of benzene sulfonyl chloride was added all at once to the reaction mixture, which was stirred for 1 additional hour. Water (75 mL) was added to the reaction mixture and the slurry obtained was heated to 80-85 C. whereat a substantial portion of the solids in the reaction mixture dissolved. The solution was cooled gradually to room temperature. The crystals obtained were recovered by filtration and washed twice with approximately 50 mL portions of water. The wet cake was stirred in 60 mL of 95% ethanol and heated to reflux. The mixture in the flask was cooled with stirring overnight to room temperature. The solids that formed were recovered by filtration and washed with 50 mL ethanol and dried in vacuo. The dried product was slurried in a mixture of 50 mL water and 50 mL methanol at 60-65 C., cooled to room temperature, filtered, washed with methanol and dried in vacuo. The product yield was 19.0 grams. HPLC analysis of the recovered product revealed it to be 98.5% Z-valacyclovir (area percent).
With 1-methyl-1H-imidazole; p-toluenesulfonyl chloride; In N,N-dimethyl-formamide; at 10 - 20℃;Product distribution / selectivity;
EXAMPLE 4 A 250 mL reaction flask, as described in Example 1, was charged with 11.3 grams of dry acyclovir, 13.8 grams of Z-valine, 30 mL of DMF and 13.8 grams of 1-methyl imidazole. The mixture was cooled to temperatures of 10-12 C., and a solution of 14.3 grams of p-toluene sulfonyl chloride in 20 mL of DMF was added drop wise over one hour while the mixture was at a temperature of 10-15 C. The mixture was stirred at 10-15 C. for 2 hours and then overnight at room temperature. Water (50 mL) was then added to the reaction flask and the reaction mixture heated to 90-95 C. The resultant solution was cooled over 4 hours to room temperature and the solid crystalline product that formed was recovered by filtration. The crystals were washed three times with 100 mL portions of water, followed by washing two times with 50 mL portions of ethanol. The washed crystals were dried in a vacuum oven at 95-100 C. and 20-25 Torr. 18.2 grams of solid Z-valine acyclovir product were obtained, which by HPLC analysis was found to be greater than 97% pure.
With 4-methyl-morpholine; 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 5 - 10℃; for 5h;Product distribution / selectivity;
EXAMPLE 6 A mixture of 11.8 grams of dry acyclovir, 13.8 grams of Z-valine and 50 mL of DMF was cooled in a reaction flask to 5 C. and 13.4 grams of benzene sulfonyl chloride was added to the cooled mixture. Over a period of 1 hour, a mixture of 10.2 grams of N-methyl morpholine and 4.7 grams of 1-methyl imidazole was added to the contents of the reaction flask, while maintaining the contents at 5-10 C. The contents of the reaction flask were stirred for 4 hours at that temperature. HPLC analysis of the reaction mixture showed that 10% of acyclovir remained unreacted. Additional benzene sulfonyl chloride (3.4 grams) and 1-methyl imidazole (5 grams) were added to the reaction flask and the contents stirred overnight at room temperature. Water (50 mL) was added to the reaction mixture and the mixture heated to 90 C. Thereafter, the contents of the reaction flask were cooled to room temperature and crystals that formed were recovered by filtration. The recovered crystals were washed three times with 50 mL portions of water. The wet cake was mixed with 100 mL of 95% ethanol and heated to reflux. The resulting mixture was cooled to room temperature and the crystals that formed were recovered by filtration. The filtered solids were washed twice with 95% ethanol and dried in a vacuum oven at 60-65 C. and 20-25 Torr. 19.5 grams of Z-valacyclovir product were recovered. HPLC analysis of the product showed it to have a purity of 97.3%.
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 10 - 15℃; for 1.75h;Product distribution / selectivity;
EXAMPLE 3 To a 250 mL reaction flask, as described in Example 1, was charged 11.9 grams of acyclovir containing approximately 5% water, 13.8 grams of Z-valine, 13.8 grams of 1-methyl imidazole and 50 mL of DMF. The mixture was cooled to 10 C. with stirring under nitrogen and 13.4 grams of benzene sulfonyl chloride was added drop wise over 1 hour and 45 minutes while maintaining the temperature of the reaction mixture at 10-15 C. Thereafter, the reaction mixture was stirred for an additional 30 minutes at 10-15 C. and then allowed to warm to room temperature. HPLC analysis did not show the presence of any acyclovir. Water (40mL) was added to the reaction flask and the contents of the flask heated to 85-90 C. to dissolve the precipitate that had formed. The solution was cooled gradually over approximately 2 hours to ambient (room) temperature. The solids that formed were recovered by filtration, and washed three times with 100 mL portions of water. The product was dried in a vacuum oven at approximately 100 C. and 20-25 Torr. The dried product (20.1 grams) was analyzed by HPLC and found to be greater than 99% Z-valacyclovir.
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In N,N-dimethyl-formamide; at 10℃; for 5.5h;Product distribution / selectivity;
EXAMPLE 12 A 500 mL automated reactor flask equipped with a thermocouple, agitator, nitrogen inlet, bubbler and addition lines was charged with 150 mL DMF, 34.8 grams of acyclovir (4.4% water) and 41.4 grams of Z-valine. The slurry in the reactor was cooled to 10 C. and the addition of 44.3 grams of 1-methyl imidazole (NMI) to the reactor at a rate of 0.738 g/min was begun. After 3 minutes, the addition of 47.6 grams of benzene sulfonyl chloride (BSC) was begun at a rate of 1.06 g/min. The total addition time for NMI was 60 minutes, and the total addition time for BSC was 45 minutes. The temperature within the reactor was maintained at 10 C. during the addition of the NMI and BSC. Progress of the reaction was monitored by HPLC. After 5.5 hours, 150 mL of water was added all at once to the yellow homogeneous reaction mixture, which resulted in the formation of a slurry of white granules. The slurry was heated to 85 C., held at that temperature for 10 minutes, and then cooled to room temperature (about 20 C.) at a rate of 1.0 C./minute. The resulting crude reaction slurry was stirred overnight at room temperature. The crude reaction slurry was filtered and the crystals recovered were washed two times with 150 mL of water. The wet cake was charged to a 500 mL 3-necked flask equipped with agitator, nitrogen inlet/bubbler and thermocouple. Water (150 mL) was added to the flask and the resultant slurry heated to 80 C. for one hour. The slurry was allowed to cool to room temperature, and the crystals in the slurry filtered. The filter cake was washed two times with 150 mL of water and one time with 150 mL of 95% ethanol. The washed filter cake was allowed to dry in air for approximately 2 hours, and was returned to the 3-necked flask. Isopropanol (300 mL) was added to the flask, and the resultant slurry heated to 74 C. for 0.5 hours before allowing it to cool to room temperature. The crystals were filtered and washed two times with 150 mL of isopropanol. The wet cake product was dried at 70-75 C. at 20-25 Torr for 3 hours to obtain a yield of 58.15 grams. HPLC analyses showed the product to be 98.2% (area percent normalized) Z-valacyclovir.
With 1-methyl-1H-imidazole; benzenesulfonyl chloride; In acetonitrile; at 10 - 20℃; for 3.25h;Product distribution / selectivity;
EXAMPLE 5 A 100 mL reaction flask equipped with mechanical stirrer and thermometer was charged with 5.65 grams of dry acyclovir, 6.9 grams of Z-valine, 6.9 grams of 1-methyl imidazole and 25 mL of acetonitrile. The mixture was stirred magnetically and cooled with stirring to 10 C. Benzene sulfonyl chloride (6.7 grams) was added drop wise over 15 minutes to the reaction mixture, which was then stirred for 1 hour at 10-15 C., followed by stirring for 2 hours at room temperature. HPLC analysis indicated that the esterification reaction was incomplete. Additional 1-methyl imidazole (0.43 grams) and benzene sulfonyl chloride (0.67 grams) was added to the reaction flask and the contents stirred for 2 hours at room temperature. HPLC analysis of the reaction mixture indicated that the reaction was substantially complete. Water (25 mL) was added to the reaction mixture, which was warmed to approximately 40 C. and stirred at that temperature for 30 minutes. The mixture was cooled to room temperature and the crystals that formed were recovered by filtration. The crystals were washed with water and then with ethanol, and then dried under vacuum (20-25 Torr) to obtain 9.8 grams of product, which by HPLC analysis was 98.5% Z-valacyclovir.
EXAMPLE 7 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 13.4 grams of N-benzyloxycarbonyl-L-valine (Z-valine), 0.55 grams of dimethylamino pyridine (DMAP) and 40 mL of DMF. Triethyl amine (22.4 grams) was added to the slurry at room temperature over 25 minutes. The resulting slurry was cooled to 0-5 C. Diethyl chlorophosphate (DECP, 15.3 grams) was added drop wise to the cooled slurry over 25 minutes, while maintaining the slurry at approximately 0-10 C. The reaction mixture was stirred for 2 hours at 5-10 C. and then overnight at room temperature. HPLC analysis showed that approximately 2% of the added-acyclovir remained unreacted. DECP (1.53 grams) was added to the reaction flask at room temperature and the contents stirred for an additional 2.5 hours. Water (100 mL) was then added slowly to the reaction mixture. A white solid precipitated. The resulting white slurry was heated to 100 C. and maintained at that temperature for approximately 20 minutes. The reaction mixture was then cooled to room temperature and stirred overnight. Precipitated solids in the reaction mixture were isolated by filtration and washed once with 40 mL of water and two times with 40 mL of methanol. The washed solids were dried over 4 hours in a vacuum oven at 65 C. and 20 Torr. 20.9 grams of product were recovered, which HPLC analysis showed to be 99% pure Z-valacyclovir by area percent. EXAMPLE 9 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams of N,N-dimethylamino pyridine (DMAP) and 40 mL of DMF. Triethylamine (15.7 grams) was added to the contents of the reaction flask at room temperature and over 6 minutes. The resultant slurry was cooled to 3 C., and 11.5 grams of diethyl chlorophosphate (DECP) added drop wise to the cooled slurry over 1-hour while maintaining the slurry at 0-10 C. The reaction mixture was stirred for 3 hours at 5-10 C. and then overnight at room temperature. Additional DECP (1.5 grams) was added to the reaction mixture at room temperature, which was then stirred for 22 hours at room temperature. Water (100 mL) was added to the reaction mixture and the resulting white slurry heated to 97 C. and kept at that temperature for 5 minutes. The reaction mixture was then cooled to room temperature and solids in the mixture isolated by filtration. The recovered solids were washed once with water (40 mL) and then twice with 40 mL portions of methanol. The washed white solids were vacuum dried at 65 C. and 25 Torr for 6 hours. 18.2 grams of dried product were recovered. HPLC analysis of the dried product showed it to be 99.2% pure Z-valacyclovir by area percent.
EXAMPLE 11 A 250 mL reaction flask was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams-of DMAP and 40 mL of DMF. N,N-diisopropyl ethylamine (20.1 grams) was added to the-reaction flask at room temperature over 8 minutes. The resulting slurry was cooled to 3 C. and 13.1 grams of DECP added drop wise to the cooled slurry over 23 minutes while maintaining the slurry within the range of 3-7 C. The reaction mixture was stirred for 1.75 hours at 4-5 C. and then for 4 days at room temperature. Water (80 mL) was added to the reaction mixture and the resulting white slurry heated to 100 C. and maintained at that temperature for 20 minutes. The resulting solution was cooled to room temperature, and solids that formed were isolated by filtration. The recovered solids were washed once with water (40 mL) and twice with 40 mL portions of 95% ethanol. The washed white solid was vacuum dried at 65 C. and 25 Torr for 6 hours. The dried solid product (22.0 grams) was analyzed by HPLC and found to be 98.2% pure Z-valacyclovir by area percent.
EXAMPLE 10 A 250 mL reaction flask was charged with 10.6 grams of acyclovir (5.6% water), 12.3 grams of Z-valine, 0.55 grams of DMAP and 40 mL of DMF. N-methyl morpholine (NMM, 15.7 grams) was added to the reactions flask at room temperature over 10 minutes. The resulting slurry was cooled to 2 C., and diethyl chlorophosphate (DECP, 11.5 grams) was added drop wise to the cooled slurry over 15 minutes while maintaining the slurry at 1-10 C. The reaction mixture was stirred for 3 hours at 3 C., and then overnight at room temperature. Additional DECP (3.83 grams) was added to the reaction mixture at room temperature. The reaction mixture was then stirred for 6 hours followed by the addition of 4.5 grams of NMM at room temperature. After 17 hours additional stirring, more DECP (1.5 grams) was added at room temperature. The reaction mixture was then stirred for 4.25 hours at room temperature, and thereafter 100 mL of water was added to the mixture. The resulting white slurry was heated to 95 C. and kept at that temperature for 15 minutes. The resulting solution was cooled to room temperature and solids that formed were isolated by filtration. The recovered solids were washed once with water (40 mL) and twice with 40 mL of methanol. The washed white solids were vacuum dried at 65 C. and 25 Torr. HPLC analysis of the product (19.6 grams) showed it to be 98% pure Z-valacyclovir by area percent.
EXAMPLE 13 A 250 mL reaction flask equipped with mechanical stirrer and thermometer was charged with 10.5 grams of acyclovir (5.6% water), 13.4 grams of Z-valine, and 40 mL of DMF. The resulting slurry was cooled to 3 C. and 6.2 grams of N-methyl imidazole (NMI) was added drop wise to the cooled slurry over 5 minutes while maintaining the slurry at 3 C. The reaction mixture was cooled to -2 C., followed by the addition of 8.65 grams of methane sulfonyl chloride (MSC) over approximately 1.5 hours, while maintaining the temperature of the reaction mixture at 0-1 C. Additional NMI (6.2 grams) was then added to the reaction mixture over 1.5 hours at 1-5 C. The reaction mixture was stirred for 1 hour 50 minutes, and an additional 1.1 grams of NMI was added to the mixture at 5 C. The reaction mixture was stirred for 1 hour 35 minutes at 4-7 C., and 0.36 grams of additional NMI was added to the mixture. The reaction mixture was stirred for 16 hours and 35 minutes in an ice-bath (1-5 C.). Water (40 mL) was added to the reaction mixture and the resulting slurry was then heated to 103 C., thereby to form a light yellow solution. A white solid was observed in the solution after it was cooled to room temperature. The solid was recovered by filtration and washed once with water (50 mL) and two times with 50 mL of a water/ethanol mixture (1:1, v/v). The wet cake was placed in a 250 mL flask containing 100 mL of a water/ethanol mixture (15/85, v/v). The resulting slurry was heated to 79 C. and kept at that temperature for 5 minutes. The resulting solution was cooled to 30 C. The solids that formed upon cooling were recovered by filtration and washed two times with 50 mL of an ethanol/water mixture (3/1, v/v). The white solid was air-dried overnight and then vacuum dried at 65 C. and 25 Torr for 6 hours. The dried solid product (17.8 grams) was analyzed by HPLC and found to be 97.2% pure Z-valacyclovir by area percent.
EXAMPLE 8 A 250 mL reaction flask equipped with a mechanical stirrer and thermometer was charged with 10.6 grams of acyclovir (5.6% water), 13.4 grams of Z-valine and 40 mL of DMF. 1-methyl imidazole (18.6 grams) was added to the reaction flask at room temperature over 10 minutes. The resulting slurry was cooled to 0-5 C. and diethyl chlorophosphate (15.3 grams) was added drop wise to the slurry over 30 minutes while maintaining the slurry at 0-10 C. The reaction mixture was stirred for 5 hours at 10 C. and then overnight at room temperature. Water (100 mL) was added to the reaction mixture and the resulting white slurry was heated to approximately 100 C. The resulting solution was cooled to room temperature and the solids that formed were isolated by filtration. Recovered solids were washed with water (40 mL) and twice with 40 mL portions of methanol. The washed solids were vacuum dried at 65 C. and 25 Torr for 6 hours. The dried product (20.2 grams) was analyzed by HPLC and found to be 99.4% Z-valacyclovir by area percent).
With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 48h;
The starting material of the process, N-[(benzyloxy)carbonyl]-L-valine-2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, (the compound of formula II) is a known compound and can be prepared by a person skilled in the art by following the processes disclosed in the literature. For example, the compound of formula II may be prepared by following the process disclosed in the U.S. Pat. No. 4,957,924, which is incorporated herein by reference. The process involves addition of N-(benzyloxy)carbonyl-L-valine (CBZ-L-valine), dimethylformamide (DMF), 4-dimethylaminopyridine (DMAP) and dicyclohexylcarbodimide (DCC) to the warm solution of acyclovir in DMF to obtain a faint yellow solution. The resulting faint yellow solution was allowed to cool to room temperature and stirred overnight to obtain white precipitate. The reaction mixture was again recharged with the same amounts of CBZ-L-valine, DMAP and DCC, the cloudy suspension obtained is stirred at room temperature for 2 days. The suspension is filtered to remove the solid and the filtrate is concentrated to obtain a light yellow oil. The oil is purified by flash chromatography on silica gel to yield the compound of formula II.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 2.66h;
To a solution of (N-benzyloxycarbonyl)valine (2.10 g, 8.36 mmol) in CH2Cl2(20 mL) at 0 C. (ice bath) under nitrogen is added hydroxybenzotriazole hydrate (1.74 g) followed by 1-ethyl-3-(3',3'-dimethyl-1'-aminopropyl)carbodiimide hydrochloride (2.40 g, 12.5 mmol). After stirring at 0 C. for 10 min, the mixture is treated with aspartic acid, beta-tert-butyl, alpha-methyl ester hydrochloride (2.00 g, 8.34 mmol) and N-methylmorpholine 1.1 mL, 10 mmol), and the reaction allowed to warm to room temperature. After stirring at room temperature for 2.5 hrs, the mixture is concentrated and the residue partitioned between EtOAc-water. The organic phase is washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to give the title compound.
dmap; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 18 - 30℃; for 1 - 1.16667h;Product distribution / selectivity;
To a solution of CBZ-L-valine (88. 4 g) in dimethylsulphoxide (350 ml) at 18-20C was added dicyclohexylcarbidiimide (105 g), followed by the addition of 4-dimethylamino pyridine (2. 8 g). The reaction mixer was stirred for 10 minutes and was added to a solution of anhydrous ganciclovir (100 g) in dimethylsulphoxide (650 ml) in one lot at 20- 25C. The reaction mass was stirred at 20-25C for 60 minutes and then quenched by adding water (400 ml) slowly at 20-30C. The reaction mixture was stirred at 20-25C for 3 0 minutes. The separated solids were filtered and washed with a solution of dimethylsulphoxide (60 ml) in water (40 ml). Analysis of the filtrate showed: Desired product-CBZ-protected mono-L-valyl ester of ganciclovir about 50% Unreacted ganciclovir about 35%; and CBZ-protected Bis L-valyl ester of ganciclovir about 15%.EXAMPLE 10: REACTION OF CBZ-L-VALINE WITH GANCICLOVIR To a solution of anhydrous ganciclovir (100 g) in dimethylsulphoxide (900 ml) (obtained by heating to 60-65C) was added CBZ-L-valine (88.4 g), dicyclohexylcarbodiimide (98 g), followed by the addition of 4-dimethylaminopyridine (1.0 g) at 24-25C. The reaction was stirred at 25-30C for 60 minutes and then quenched by adding water (400 ml) slowly at 25-30C. The reaction mixture was stirred at 25-30 C for 1 hr. The separated solid dicyclohexylurea is filtered and washed with a solution of dimethylsulphoxide (100 ml) in water (40 ml). Analysis of the filtrate showed Desired product-CBZ-protected mono-L-valyl ester of ganciclovir about 30%; Unreacted ganciclovir about 55%; and CBZ-protected Bis L-valyl ester of ganciclovir about 12%.
methyl (2,3-dihydroindole)-L-2-carboxylate[ No CAS ]
[ 1149-26-4 ]
[ 68641-49-6 ]
2-Methyl [(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydroindole-indole]carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.85 g (87%)
With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; N,N-dimethyl-formamide;
b. 2-Methyl [(S)-1-(N-[benzyloxycarbonyl]-L-valyl)-2,3-dihydroindole-indole]carboxylate. To a solution containing 3.00 g (14.0 mmol) of methyl (2,3-dihydroindole)-L-2-carboxylate in 60 mL of anhydrous dichloromethane, under a nitrogen atmosphere at 0 C., 7.15 g (28.8 mmol) of BOPCl and 7.72 mL (70.2 mmol) of DIEA was added a solution of 7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous dichloromethane and 3 mL of DMF. After stirring for 3 days at 5 C. the mixture was diluted with ethyl acetate and washed with 1N HCl (2*) and brine. The mixture was filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 9:1 to 1:1 hexane/ethyl acetate to afford 4.85 g (87%) of the title compound as a white foam.
With hydrogenchloride; triethylamine; In dichloromethane;
b. Benzyloxycarbonyl-L-valyl-N-cyclopentylglycine t-butyl ester To a solution of N-benzyloxycarbonyl-L-valine (50.0 g) and N-cyclopentylglycine t-butyl ester (39.8 g) in dichloromethane (1.3 liter), stirred under nitrogen and cooled in an ice bath to 0-5 C., was added triethylamine (44.5 g) then bis(2-oxo-3-oxazolidinyl)phosphinic chloride (56.0 g) at 0 C. The stirred mixture was allowed to warm to room temperature overnight before it was evaporated. After the residue was partitioned between water (1 liter) and ethyl acetate (1 liter), the ethyl acetate solution was washed (1N hydrochloric acid (twice), water, saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluding with ethyl acetate:dichloromethane (0:100, 5:95, 10:90 and 25:75, successively). A first, mixed fraction was rechromatographed and the product obtained combined with the product obtained from the first chromatography to afford the ester (73.4 g, 85%); TLC, Rf =0.30, ethyl acetate:dichloromethane (5:95); MS, m/e=433 (M+1), 377, 325, 269, 234, 286, 162, 144 91(base).
85%
With hydrogenchloride; triethylamine; In dichloromethane;
e. Benzyloxycarbonyl-L-valyl-N-cyclopentylglycine t-butyl ester (Formula XIV). To a solution of N-benzyloxycarbonyl-L-valine (50.0 g) and N-cyclopentylglycine t-butyl ester (39.8 g) in dichloromethane (1.3 liter), stirred under nitrogen and cooled in an ice bath to 0-5 C., was added triethylamine (44.5 g) then bis(2-oxo-3-oxazolidinyl)phosphinic chloride (56.0 g) at 0 C. The stirred mixture was allowed to warm to room temperature overnight before it was evaporated. After the residue was partioned between water (1 liter) and ethyl acetate (1 liter), the ethyl acetate solution was washed (1N hydrochloric acid (twice), water, saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluding with ethyl acetate:dichloromethane (0:100, 5:95, 10:90 and 25:75, successively). A first, mixed fraction was rechromatographed and the product obtained combined with the product obtained from the first chromatography to afford the ester (73.4 g; 85%); TLC, Rf =0.30, ethyl acetate:dichloromethane (5:95); MS, m/e=433 (M+1), 377, 325, 269, 234, 206, 162, 144 91(base).
N-Benzyloxycarbonyl-L-valyl-γ-t-butyl-L-glutamic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
168.5 g (78%)
With 4-methyl-morpholine; In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide;
(a) N-Benzyloxycarbonyl-L-valyl-gamma-t-butyl-L-glutamic acid methyl ester N-Benzyloxycarbonyl-L-valine (144 g, 0.58 mol, 1.2 eq) was dissolved in 400 ml freshly distilled THF and stirred mechanically in a 3-l 3-neck round bottom flask fitted with a thermometer and dropping funnel and immersed in a dry ice-alcohol bath at -15. While stirring at -15, N-methylmorpholine (55 ml, 0.58 mol, 1.2 eq) was added dropwise. The temperature was maintained at -15 and isobutylchloroformate (66.2 ml, 0.58 mol, 1.2 eq) was added dropwise over a 2 min period. The reaction mixture stirred for an additional 2 min at -15 and a precooled (-20) solution of L-glutamic acid alpha-methyl ester gamma-t-butyl ester.HCL (120.8 g, 0.48 mol) dissolved in 300 ml THF and 150 ml DMF was added dropwise with simultaneous addition of N-methylmorpholine (46 ml, 0.48 mol). [The addition took 6 min while maintaining the temperature below -15.] The reaction mixture was stirred for 30 min at -15, and for 3 h at 25, evaporated in vacuo and the residue dissolved in EtOAc (900 ml) and washed with 10% NaHCO3 (3*200 ml), 1M citric acid (3*200 ml) and satd. NaCl solution (1*200 ml). The aqueous washes were backwashed with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated to ~200 ml and pet. ether (1 l) added. The solid was collected and dried in vacuo(*) and the combined crops were recrystallized from CCl4 (400 ml) pet. ether (1.2 l) to yield 168.5 g (78%) of white crystalline product; mp 66.5-68; Rf 0.74 (n-BuOH:AcOH:EtOAc:H2 O; 1-1-1-1),Rf 0.73 (CHCl3:CH3 OH:AcOH; 80-5-1); [alpha]D25 -28.91, (c 1, MeOH). Anal. calc. for C23 H24 N2 O7 (450.5): C, 61.32; H, 7.61; N, 6.22. Found: C, 61.23; H, 7.58; N, 6.01.
4 N-Benzyloxycarbonyl-L-valine methyl ester
EXAMPLE 4 N-Benzyloxycarbonyl-L-valine methyl ester A mixture of 2.51 g. of N-benzyloxycarbonyl-L-valine, 2.62 g. of triphenyl phosphine, 1.40 g. of benzenesulfenic acid methyl ester, 1.10 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is stirred at room temperature for 5 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 2.30 g. of the desired product. Melting point: 56°C. [α]d17 -15.8° (c = 1, ethanol)
Reference Example 2 Preparation of N-(3-phenylsalicylidene)-(S)-valine piperizide The desired product was prepared in the same manner as Reference Example 1. That is, carbobenzoxy-(S)-valine (3.77 g, 15 mmol) was coupled with piperidine (1.49 ml, 15 mmol) to obtain crude carbobenzoxy-(S)-valine piperizide as a viscous liquid (4.46 g, 93%). This product (0.32 g, 1 mmol) was hydrogenated and then condensed with 3-phenylsalicylaldehyde (0.20 g, 1 mmol) to obtain 0.30 g (68%) of the desired N-(3-phenylsalicylidene)-(S)-valine piperizide, which was further recrystallized from ether. m.p. 140.1-141.0C. [alpha]26D+ 90.1 (c 0.99, CHCl3).
Step (b) Preparation of 2-(2-amino 1,6 dihydro-6oxo-purine-9-yl)-methoxy-3 acetoxy-1-propyl-N-(benzyloxy carbonyl)-Lvalinate. N-CBZ-L-valine(170 gms), dicyclohexyl carbodiimide (130gms) were stirred in dichloromethane (2 litres). Product from step (a) (70 gms) was added to the reaction mass and stirred for 3 - 4 hours. Dimethyl formamide (140 ml) and dimethyl amino pyridine (0.82gms) were added to the reaction mass and stirred at 25 C for 12 hours. Reaction mass was filtered, typically using a diatomaceous earth filter. (for example: Hyflo). Clear filtrate was concentrated under vacuum to remove DMF. Oily residue was dissolved in isopropyl alcohol (180ml) and hexane (700 ml) was added and stirred for 30 minutes and allowed to settle. The upper hexane layer was decanted. Oily layer was further stirred in a mixture of isopropyl alcohol and hexane for 1 hour, resulting solid was filtered and washed with hexane and dried under vacuum at 50 C to get 34gms of the titled compound.
Step (b) Preparation of 2-(2-amino 1,6 dihydro-6oxo-purine-9-yl)-methoxy-3 acetoxy-1-propyl-N-benzyloxy carbonyl)-Lvalinate N-CBZ-L-valine(170 gms), dicyclohexyl carbodiimide (130 gms) were stirred in dichloromethane (2 litres). Product from step (a) (70 gms) was added to the reaction mass and stirred for 3-4 hours. Dimethyl formamide (140 ml) and dimethyl amino pyridine (0.82 gms) were added to the reaction mass and stirred at 25 C. for 12 hours. Reaction mass was filtered, typically using a diatomaceous earth filter. (for example: Hyflo). Clear filtrate was concentrated under vacuum to remove DMF. Oily residue was dissolved in isopropyl alcohol (180 ml) and hexane (700 ml) was added and stirred for 30 minutes and allowed to settle. The upper hexane layer was decanted. Oily layer was further stirred in a mixture of isopropyl alcohol and hexane for 1 hour, resulting solid was filtered and washed with hexane and dried under vacuum at 50 C. to get 34 gms of the titled compound.
With dmap; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 18 - 28℃; for 6.5h;Product distribution / selectivity;
Example 8 PREPARATION OF BIS-(Cbz-L-VALYL)-ESTER OF <strong>[82410-32-0]GANCICLOVIR</strong> (FORMULA IX). Dicyclohexylcarbodiimide (DCC) (64.6 g) solution (DCC (64.6 kg) in DMSO (40 mL) is slowly added to a reaction mixture containing 9-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl) guanine (20 g), Cbz-L-valine (69 g), 4-(dimethylamino)-pyridine (DMAP) (0.8 g), and DMSO (140 mL) at 18-25 C. and the reaction mixture maintained at 18-25 C. for 30 minutes. The reaction mixture temperature is increased to 28 C. and stirred for 6 hours. The mass is filtered and the collected solid washed with DMSO (40 mL). The filtrate is added to a mixture of 5% sodium bicarbonate solution (500 mL) and ethyl acetate (140 mL) at 25-30 C. and stirred for 15 minutes. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (60 mL). The combined organic layer is washed with 20% sodium chloride solution (2×200 mL). Cyclohexane (460 mL) is added to the organic layer at 25-35 C. and the mixture is maintained for 17 hours at 25-35 C. Reaction mixture is further cooled to 10-15 C. and maintained at 16 C. for 15 minutes. The separated solid is collected by filtration, washed with a pre-cooled (10-15 C.) cyclohexane (100 mL) and ethyl acetate (30 mL) mixture, and dried at 48 C. for 4 hours, under reduced pressure. Charged the dried compound and water (400 mL) into round bottom flask and stirred at 28 C. for 1 hour 30 minutes. Reaction mixture is filtered, the collected solid is washed with water (80 mL), and dried at 48 C. for 22 hours under reduced pressure to afford 47.8 g of the title compound. Purity by HPLC: 99.8%.
Example 30: (2S)-4-(2-((S)-2-(Benzyloxycarbonylamino)-3- methylbutanamido)-3-oxopropyl)phenyl 2-(benzyloxycarbonylamino)-3- methylbutanoate [00221] Step 1 . A mixture of <strong>[87745-27-5](S)-tyrosinol hydrochloride</strong> (1 .60 g, 7.86 mmol), (S)-Cbz-Val-OH (2.34 g, 9.31 mmol), 1 -hydroxybenzotriazole hydrate (1 .50 g, 9.79 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 .88 g, 9.81 mmol) and 4-methylmorpholine (2.2 mL, 20.0 mmol) in 100 mL of CH2CI2 was stirred at room temperature under N2 overnight. The sample was concentrated then partitioned between EtOAc and sat. NaHC03 solution. The organic extract was washed with sat.KH2P04 and sat. NaCI solutions, dried (MgS04), filtered and concentrated to give an inseparable mixture of benzyl (2S)-1 -(1 -hydroxy-3-(4- hydroxyphenyl)propan-2-ylamino)-3-methyl-1 -oxobutan-2-ylcarbamate and (2S)-4-(2-((S)-2-(benzyloxycarbonylamino)-3-methylbutanamido)-3- hydroxypropyl)phenyl 2-(benzyloxycarbonylamino)-3-methylbutanoate as a white foamy solid. MS (APCI) m/z 634 (80%), 590 (20%), 401 (78%) and 357 (100%). The sample was used in the next reaction without purification.[00222] Step 2. A solution of the above mixture (Example 30, Step 1 ) in 25 mL of DMSO was treated with 2-iodoxybenzoic acid (IBX, 7.83 g, 27.96 mmol). The sample was stirred at room temperature under N2 for 4 h then carefully partitioned between EtOAc and sat. NaHCC>3 solution (250 mL of each). The organic extract was washed with sat. KH2P04 and sat. NaCI solutions, dried (MgS04), filtered and concentrated. The sample was chromatographed (silica gel, 50% EtOAc in hexanes) to give (2S)-4-(2-((S)- 2-(benzyloxycarbonylamino)-3-methylbutanamido)-3-oxopropyl)phenyl 2- (benzyloxycarbonylamino)-3-methylbutanoate as an off-white solid. MS (APCI) m/z 632 (M+1 , 100%).
Step 1 . To a stirring solution at 0 C under N2 of (S)-Cbz-Val- OH (1 .50 g, 5.97 mmol) in 10 mL of DMF was added solid 1 - hydroxybenzotriazole hydrate (0.96 g, 6.29 mmol) followed by solid N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1 .20 g, 6.26 mmol). The sample was stirred at 0 C for 30 min, room temperature for 30 min, recooled to 0 C then treated with solid <strong>[87745-27-5](S)-tyrosinol hydrochloride</strong> (1 .22 g, 5.99 mmol) followed by 4-methylmorpholine (0.66 mL, 6.00 mmol). The sample was allowed to slowly warm to room temperature overnight. The sample was partitioned between EtOAc and sat. NaHC03 solution (-100 mL of each). The organic extract was washed with sat. KH2P04 and sat. NaCI solutions, dried (MgS04), filtered and concentrated to give mainly benzyl (2S)-1 -(1 -hydroxy-3-(4-hydroxyphenyl)propan-2-ylamino)-3-methyl-1 - oxobutan-2-ylcarbamate as a gelatinous white solid. The sample was used without purification.
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
tert-butyl (3R,4S,5S)-4-[{N-[(benzyloxy)carbonyl]-L-valyl}(methyl)amino]-3-methoxy-5-methylheptanoate 10.65 g (41.058 mmol) of tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate (starting compound 2b) were taken up in 250 ml of dichloromethane and the solution was cooled to -10 C. Then, while stirring, 10.317 g (41.058 mmol) of N-[(benzyloxy)carbonyl]-L-valine, 16.866 g (61.586 mmol) of <strong>[878-23-9]2-bromo-1-ethylpyridinium tetrafluoroborate</strong> (BEP) and 28.6 ml of N,N-diisopropylethylamine were added, and the mixture was subsequently stirred at RT for 20 h. The reaction mixture was then diluted with dichloromethane and shaken twice with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel with 4:1 petroleum ether/ethyl acetate as the eluent. The corresponding fractions were concentrated and the residue was dried under high vacuum overnight. 10.22 g (51% of theory) of the title compound were obtained as a yellowish oil.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
tert-Butyl (3R,4S,5S)-4-[{N-[(benzyloxy)carbonyl]-L-valyl}(methyl)amino]-3-methoxy-5-methyl-heptanoate 425 mg (1.7 mmol) of N-[(benzyloxy)carbonyl]-L-valine were dissolved in 50 ml of DMF, and 500 mg (1.7 mmol) of <strong>[120205-48-3]tert-butyl <strong>[120205-48-3](3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate hydrochloride</strong></strong> (Starting Material 2), 356 mg (1.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 285 mg (1.9 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 655 mg (5.1 mmol) of N,N-diisopropylethylamine were added in succession. The mixture was stirred at RT for 20 h. Another 142 mg (0.5 mmol) of N-[(benzyloxy)carbonyl]-L-valine, 119 mg (0.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 95 mg (0.6 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 218 mg (1.7 mmol) of N,N-diisopropylethylamine were added, and the mixture was treated with ultrasound for 90 min. The mixture was then poured into a mixture of semisaturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was separated off, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. The residue was purified by preparative HPLC. This gave 329 mg (40% of theory) of the title compound as a colourless oil.
(S)-benzyl 1-(2-(4-bromophenyl)-2-oxoethylamino)-3-methyl-1-oxobutan-2-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 16h;
EXAMPLE N-1 Step a [0386] [0387] To a suspension of 2-amino-1-(4-bromophenyl)ethanone, HCl (1 g, 3.99 mmol) in DCM was added (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (1.003 g, 3.99 mmol), DIPEA (1.534 mL, 8.78 mmol) and HATU (1.518 g, 3.99 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3, water and sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated to yield the product (S)-benzyl 1-(2-(4-bromophenyl)-2-oxoethylamino)-3-methyl-1-oxobutan-2-ylcarbamate as a pale yellow solid. The product was used without further purification. LC/MS (Cond. N-1): [M+H]+ 447.12, Rt=3.766 min.
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 dichloromethane; at 20℃; for 16h;
To a suspension of 2-amino- 1 -(4-bromophenyl)ethanone, HC1 (1 g, 3.99 mmol) in DCM was added (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (1.003 g, 3.99 mmol), DIPEA (1.534 mL, 8.78 mmol) and HATU (1.518 g, 3.99 mmol). The reaction mixture was stirred at rt for 16 hrs. The reaction mixture was diluted with EtOAc, washed with sat. aHC03, water and sat. NaCl, dried over anhydrous Na2S04, filtered and concentrated to yield the product (S)-benzyl l-(2-(4- bromophenyl)-2-oxoethylamino)-3 -methyl- 1 -oxobutan-2-ylcarbamate as a pale yellow solid. The product was used without further purification. LC/MS (Cond. N-1): [M+H]+447.12, = 3.766 min. -1
(S)-2-(4'-(2-bromoacetyl)biphenyl-4-yl)-2-oxoethyl 2-(benzyloxycarbonylamino)-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.6 g
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 8.33333h;
To a solution of 1,1?-(biphenyl-4,4?-diyl)bis(2-bromoethanone) (2.207 g, 5.57 mmol) and (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (1.4 g, 5.57 mmol) in MeCN (20 mL) and DMF (60 mL) was added DIPEA (1.022 mL, 5.85 mmol) dropwise over 20 min. The reaction mixture was stirred at rt for 20 h and diluted with EtOAc and washed with ice cold citric acid (2×), water, brine, dried (MgSO4), and the residue was purified on a 80 g silica gel column (EtOAc/hex: 0 to 100%) to afford the product as a white solid (1.6 g). LC-MS: retention time: 2.988 min (method YT-1); m/z 590.01 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.09-8.15 (2H, m), 8.03 (2H, d, J=8.28 Hz), 7.72-7.82 (4H, m), 7.31-7.41 (5H, m), 5.56 (1H, d, J=16.31 Hz), 5.34 (1H, d, J=16.06 Hz), 5.15 (2H, s), 4.50 (2H, s), 4.46-4.57 (1H, m), 2.32-2.48 (1H, m, J=11.39, 6.79, 6.79, 6.65 Hz), 1.10 (3H, d, J=6.78 Hz), 1.05 (3H, d, J=7.03 Hz).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 20h;
To a solution of 1,1?-(biphenyl-4,4?-diyl)bis(2-bromoethanone) (2.207 g, 5.57 mmol) and (S)-2-(benzyloxycarbonylamino)-3-methylbutanoic acid (1.4 g, 5.57mmol) in MeCN (20 mL) and DMF (60 mL) was added DIPEA (1.022 mL, 5.85 mmol) dropwise over 20 mm. The reaction mixture was stirred at rt for 20 h and diluted with EtOAc and washed with ice cold citric acid (2 x), water, brine, dried (Mg504), and the residue was purified on a 80 g silca gel column (EtOAc/hex: 0 to 100%) to afford the product as a white solid (1.6 g). LC-MS: retention time: 2.988mm (method YT-1); m/z 590.01 (M+H7. 1H NMR (400 MHz, CHLOROFORM-d)ppm 8.09 - 8.15 (2 H, m), 8.03 (2 H, d, J= 8.28 Hz), 7.72 - 7.82 (4 H, m), 7.31 -7.41 (5 H, m), 5.56(1 H, d, J= 16.31 Hz), 5.34(1 H, d, J= 16.06 Hz), 5.15 (2 H, s),4.50 (2 H, s), 4.46 - 4.57 (1 H, m), 2.32 - 2.48 (1 H, m, J= 11.39, 6.79, 6.79, 6.65Hz), 1.10 (3 H, d, J= 6.78 Hz), 1.05 (3 H, d, J 7.03 Hz).
(S)-2-(2-(4'-(2-((S)-2-(benzyloxycarbonylamino)-3-methylbutanoyloxy)acetyl)biphenyl-4-yl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate[ No CAS ]
The Cbz-Val-OH (251mg, 1mmol) in 2ml N, N- dimethylformamide (DMF) was dissolved, cooled to -5 deg. C, then added with stirring DIC (63.1mg, 0.5mmol), the reaction was carried out at room temperature for 30min, continued to cool to -5 deg C , followed by adding S1 (265mg, 0.5mmol)then in 2ml DMF solution, triethylamine (60.7mg, 0.6mmol), a catalytic amount of 4-dimethylaminopyridine (DMAP), were added at room temperature for 4h. the reaction was poured into 10ml water ended, extracted three times with 10ml of ethyl acetate, the combined organic layers , dried over anhydrous sodium sulfate, the solvent spin dried to give a yellow solid, separated by silica gel column chromatography to give an off-white powder (M3) 193mg, 50.6% yield.
benzyl N6-((benzyloxy)carbonyl)-N2-(((benzyloxy)carbonyl)-L-valyl)-L-lysinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
0245] A solution/suspension of H-Lys(Z)-OBzl hydrochloride (7.0 g, 17.2 mmol) and Z-(L)-Val-OH (4.32 g, 17.2 mmol) in anhydrous dichloromethane (50 mL) under nitrogen was cooled on ice and treated with HOBT hydrate (3.49 g, 25.8 mmol) and triethylamine (7.22 mL, 52.0 mmol) and the clear solution was stirred for 15 min. EDC hydrochloride (4.12 g, 21.5 mmol) was added and the stirred mixture was allowed to warm to room temperature and stirred 20 h. The product mixture was diluted to 200 mL total volume with dichloromethane, then washed successively with 5% citric acid, water, saturated aqueous sodium bicarbonate and brine (100 mL each) and dried (Na2SO4). The solution was concentrated by half, added directly to a silica gel column and eluted with dichloromethane, then 2:1 dichloromethane/ethyl acetate to afford 9.2 g (89%) of subject material as a light yellow solid.
2-((tert-butoxycarbonyl)amino)ethyl ((benzyloxy)carbonyl)-L-valinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16h;
57.1 2-((tert-butoxycarbonyl)amino)ethyl ((benzyloxy)carbonyl)-L-valinate
Tert-butyl (2-hydroxyethyl)carbamate (1.0 eq), DMAP (0.2 eq) and ((benzyloxy)carbonyl)-L-valine (1.0 eq) were dissolved in DCM (0.4 M) and the solution was cooled to 0°C. EDC HCl (1.2 eq) was added, and the temperature was raised to 20 °C and stirring was continued for 16 h. The resulting mixture was filtered on a pad of silica eluting with DCM/ EtOAc and the seolvent evaporated. The crude was dissolved in DCM and washed with 5% aqueous citric acid solution, saturated aqueous solution of NaHC03, water, and brine, dried over Na2S04, and the solvent evaporated to afford the title compound (85%) as a pale yellow oil, which was used directly in the subsequent reaction step. 1H-NMR (400 MHz, OMSO-d6, 300 K) δ 7.64 (d, J = 8.3 Hz, 1H), 7.40 (m, 5H), 6.89 (t, J = 4.8 Hz, 1H), 5.05 (s, 2H), 4.10-3.95 (m, 3H), 3.17-3.15 (m, 2H), 2.11-2.03 (m, 1H), 1.38 (s, 9H), 0.88 (d, J = 3.1 Hz, 3H), 0.86 (d, J = 3.07 Hz, 3H).
N-[(Benzyloxy)carbonyl]-L-valyl-L-alanine This intermediate was prepared proceeding from N-[(benzyloxy)carbonyl]-L-valine and tert-butyl L-alaninate hydrochloride (1:1) by conventional methods of peptide chemistry. LC-MS (Method 12): Rt=1.34 min; MS (ESIpos): m/z=323.16 (M+H)+.
5,7-dihydroxy-4-oxo-2-phenyl-4H-chromen-6-yl 2-[(benzyloxy)carbonyl]amino}-3-methylbutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.6%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 12h;Inert atmosphere;
General procedure: The compound baicalein (1 equivalent (equiv.)) was dissolved in dry DCM (25 mL) and DMAP(0.5 equiv.), and the protected amino acid (1.2 equiv.) was added. After addition of EDCI (1.5 equiv.),the mixture was stirred at 25 C for 12 h, protected by nitrogen. After completion of the reaction(as monitored by TLC), the solution was evaporated and washed with a saturated sodium carbonatesolution (20 mL). The aqueous layer was extracted withDCM(25 mL), and the combined organic extractswere washed with brine (20 mL), dried over sodium sulfate, filtrated and evaporated. Purification wasperformed by flash chromatography.
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