* 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.
Reference：
[1] European Journal of Organic Chemistry, 2001, # 10, p. 1821 - 1829
2
[ 2491-20-5 ]
[ 39537-23-0 ]
Reference：
[1] Bioscience, Biotechnology and Biochemistry, 2011, vol. 75, # 11, p. 2087 - 2092
3
[ 67-56-1 ]
[ 56-41-7 ]
[ 2491-20-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: at -15 - 0℃; Stage #2: for 3 h; Reflux
The L-alanine was used as substrate to produce (S)-alanine methyl ester hydrochloride (1a) according to the literature. (Xing et al., 2012). Add 15 mL of absolute methanol to the round bottom flask. Slow-drop 2.16 mL of SOCl2 (0.03 mol) into absolute methanol at −15 °C and maintained at 0 °C for an hour. Take 14 mL of absolute methanol and 1.4 mL (0.019 mol) of SOCl2 to another round bottom flask with the above steps. Then, 1.118 g of L-alanine were put into the solution and heating reflux for 1.5 h. After concentrated the solution under reduced pressure, the initial preparation of the SOCl2 solution was poured into the round bottom flask and continued reflux for 1.5 h to give 1a (yield 100percent). Since the hydrochloric acid produced in this step was not conducive to the next reaction, put NaHCO3 into the round bottom flask when reflux was ended to destroy its acidity until no more bubbles are generated. Finally, the solution was concentrated to afford 1b (yield 100percent).The fusaric acid (4) and 1b together with 15 mL of dichloromethane were put into a round bottom flask and stirred uniformly, then an excessof catalyst dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) were added and reflux for 24 h. Concentrated the solution under reduced pressure and the product was purified by using preparative HPLC (25–45percent CH3CN/H2O, 20 min) to obtain 1c (yield 52percent).
99%
at 20℃; for 2 h;
SOCl2 (21.8mL, 0.3mol) and (S)-alanine ((S)-19, 8.91g, 0.1mol) were added to CH3OH (100mL) and the mixture was stirred at RT for 2h. The solvent was removed in vacuo, the residue was dissolved in methanol (30mL) and the organic solvent was removed in vacuo again. This procedure was repeated twice. Colorless amorphous solid, mp 103°C (Ref. 39 mp 98–99°C), yield 14.3g (>99percent). [α]589=+7.9 (c=0.94, CH3OH) [Ref. 38 [α]589=+7.4 (c=1.76, CH3OH)].
98%
Stage #1: With thionyl chloride In water at -14 - -10℃; for 1 h; Stage #2: for 4 h; Reflux
Take 125mL of methanol and add it to a 250mL three-necked flask (ensure that the environment is anhydrous during the reaction, with a drying device; the reaction will generate HCl and SO2 gas, use a lye absorption device) and cool it in a constant temperature reaction bath to - At 14°C, 10 mL (0.138 mol) of SOCl2 was slowly added dropwise with magnetic stirring. The reaction temperature was controlled to be below -10°C during the dropwise addition, and the reaction was continued for 1 h after the addition was completed. The reaction solution was transferred to a 250 mL round-bottomed flask, and the temperature was naturally raised to room temperature. 12.21 g (0.137 mol) of alanine was added and the reaction was stopped by heating to reflux under magnetic stirring for 4 hours. The product was evaporated and the solvent was distilled off to give alanine methyl ester hydrochloride as a yellow viscous liquid with a yield of 98percent. It can be used directly in the next step without purification.
96.4%
at -5 - 20℃;
General procedure: A suspension of L-amino acid (50mmol) in methanol (50mL) was stirred under ice cold conditions. Thionyl chloride (5mL) was slowly dropped to the solution at−5°C. Then, the mixture was allowed to slowly warm to room temperature while being stirred. The reaction was monitored by TLC (N-butanol: water: acetic acid=4:1:1). When the reaction was completed, the solvent was evaporated under reduced pressure to afford the crude product, which was recrystallized from methanol/ether to give a white solid.
7.7 g
at -20 - 20℃;
To a solution of L-alanine (5.0 g, 56 mmol) in methanol (60 mL) at -20°C was added dropwise thionyl chloride (6.1 mL, 84 mmol) and the mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. The solid residue was washed with diethyl ether, filtered and dried under vacuum to afford the title compound as a white solid (7.7 g). The crude product was used without further purification in subsequent reactions.1 H NMR (500 MHz, d4-MeOH) δ 4.1 1 (q, 1 H), 3.84 (s, 3H), 1.54 (d, 3H).
3.36 g
at 20℃; for 6 h;
Add L-alanine (2.5 g, 27.8 mmol) to a dry flask.Add anhydrous anaerobic methanol (278 mL), stir at 0 ° C for 10 min,Thionyl chloride (0.5 mL) was slowly added thereto, and the reaction was stirred for 6 hours.After the reaction was completed, the solvent was evaporated, diluted with diethyl ether and filtered.L-Alanine methyl ester 13 was obtained as a white solid, 3.36 g.
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4
[ 67-56-1 ]
[ 6003-05-0 ]
[ 2491-20-5 ]
Yield
Reaction Conditions
Operation in experiment
86%
at -10 - 20℃; for 16 h;
General procedure: For the synthesis of compounds 2a, 2c–2g, we used slightly modificated known procedure [1]. To a stirred solution of amino acid (32.2mmol) in dry methanol (100mL) was added drop-wise thionyl chloride (64.4mmol). The temperature was kept between−10 and−5°C. After complete addition, the reaction was stirred at RT overnight. After 16h, the solution was evaporated to dryness. The product was diluted with EtOAc and collected by filtration. The residue was dried under reduced pressure to give an amino acid methyl ester hydrochloride as white crystalline powder. The yields were higher in all experiments than 80percent. Melting point and 1H as well as 13C NMR spectra in D2O were used for characterization of the prepared compounds. The data are in good agreement with literature data [20].
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 253 - 259
[2] Tetrahedron Letters, 1998, vol. 39, # 47, p. 8563 - 8566
5
[ 56-41-7 ]
[ 2491-20-5 ]
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[1] Tetrahedron, 1988, vol. 44, # 6, p. 1685 - 1690
[2] Patent: US5496927, 1996, A,
[3] Patent: US5113009, 1992, A,
[4] Patent: US2006/287500, 2006, A1, . Location in patent: Page/Page column 2; 3
Stage #1: at 20℃; for 20 h; Sealed tube; Large scale Stage #2: With hydrogenchloride In waterLarge scale
500g of methanol, L-Alanine of 100g were placed in a 1000ml of three necked flask, then 90ml of Thionyl chloride was added dropswise (T≤35°C). After the addition was completed, the three-necked flask was transferred to a water bath and the temperature was raised to reflux (T≤35°C),and fully removed SO2. In the ice bath(T≤20°C), ammonolysis was performed on 0.56 kg of ammonia, and seal in a water bath at room temperature overnight (20 hours). The water bath was warmed to Τ=55°C to remove ammonia cocentration, the final concentration volume was 300 ml and removal of ammonia concentration was complete. The excess ammonium chloride was filtered, rinsed with 100 ml of methanol, rinsed liquid combined with the mother liquor and transferred to a 1000 ml beaker. 34.5 ml of hydrochloric acid (10percent concentration) was slowly added dropwise to adjust the pH to 1.55 and the acid adjustment was completed. After being sealed in a refrigerator and refrigerating for 12 hours, after taking out, 400 ml of acetone was added, and crystals were precipitated. After suction filtration, rinsing, and drying at 45° C for 12 hours, 85 g of white crystals were obtained (yield was 85percent).See the test results [a] =+11.4°
Reference：
[1] Journal fur Praktische Chemie - Chemiker - Zeitung, 1996, vol. 338, # 3, p. 251 - 256
[2] Patent: CN108069867, 2018, A, . Location in patent: Paragraph 0015-0017
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[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 36, p. 11683 - 11687[2] Angew. Chem., 2018, vol. 130, # 36, p. 11857 - 11861,5
[3] Organic Syntheses, 2011, vol. 88, p. 42 - 53
[4] Organic and Biomolecular Chemistry, 2017, vol. 15, # 6, p. 1355 - 1362
29
[ 28920-43-6 ]
[ 2491-20-5 ]
[ 146346-88-5 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 4008 - 4017
[2] Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3359 - 3362
500g of methanol, L-Alanine of 100g were placed in a 1000ml of three necked flask, then 90ml of Thionyl chloride was added dropswise (T?35C). After the addition was completed, the three-necked flask was transferred to a water bath and the temperature was raised to reflux (T?35C),and fully removed SO2. In the ice bath(T?20C), ammonolysis was performed on 0.56 kg of ammonia, and seal in a water bath at room temperature overnight (20 hours). The water bath was warmed to Tau=55C to remove ammonia cocentration, the final concentration volume was 300 ml and removal of ammonia concentration was complete. The excess ammonium chloride was filtered, rinsed with 100 ml of methanol, rinsed liquid combined with the mother liquor and transferred to a 1000 ml beaker. 34.5 ml of hydrochloric acid (10% concentration) was slowly added dropwise to adjust the pH to 1.55 and the acid adjustment was completed. After being sealed in a refrigerator and refrigerating for 12 hours, after taking out, 400 ml of acetone was added, and crystals were precipitated. After suction filtration, rinsing, and drying at 45 C for 12 hours, 85 g of white crystals were obtained (yield was 85%).See the test results [a] =+11.4
N-t-butoxycarbonyl-glycyl-L-valyl-L-alanine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 1h;
N-t-Butoxycarbonyl-glycyl-L-valine is dissolved in dry tetrahydrofuran (THF; Aldrich; Cat. No. 401757) and treated with diisopropylcarbodiimide (DIC; Fluka Cat. No.38370) dissolved in anhydrous THF. Immediately thereafter, L-alanine methyl ester hydrochloride (Aldrich Cat. No. 330639) which has been treated with one equivalent of diisopropylethylamine (DIEA; Aldrich Cat. No. D125806) in anhydrous TUF is added to the stirring suspension. The reaction is allowed to proceed for one hour at room temperature (r.t.), filtered to remove solid diisopropylurea and diisopropylethylamine hydrochloride andthe solvent is removed by rotary evaporation to yield N-t-BOC-glycyl-L-valyl-L-alanine methyl ester (BOC-GVA(OMe)) as a low-melting solid.
General procedure: L-amino acids hydrochlorides 4a-e (0.05 mol) in dry methanol 50 mL were converted into the corresponding methyl esters 5a-e in quantitative yields by slowly adding fresh thionyl chloride (0.1 mol) at 0C and then the mixture was stirred for 4 h. After completion of the reaction, the solvent was evaporated and the product was crystallized from dry diethyl ether. (S)-Methyl 2-aminopropanoate hydrochloride (5a): white solid, yield 96%, m.p.: 107-109C (lit. 109-111C).34 [alpha](25/D)+ 8.3 (c 1.5, CH3OH) [lit. [alpha](20/D)+ 7.0 (c 1.6, CH3OH)].34
86%
With thionyl chloride; at -10 - 20℃; for 16h;
General procedure: For the synthesis of compounds 2a, 2c-2g, we used slightly modificated known procedure [1]. To a stirred solution of amino acid (32.2mmol) in dry methanol (100mL) was added drop-wise thionyl chloride (64.4mmol). The temperature was kept between-10 and-5C. After complete addition, the reaction was stirred at RT overnight. After 16h, the solution was evaporated to dryness. The product was diluted with EtOAc and collected by filtration. The residue was dried under reduced pressure to give an amino acid methyl ester hydrochloride as white crystalline powder. The yields were higher in all experiments than 80%. Melting point and 1H as well as 13C NMR spectra in D2O were used for characterization of the prepared compounds. The data are in good agreement with literature data [20].
With sodium hydrogencarbonate; In water; ethyl acetate; at 0 - 20℃; for 18.33h;
To alanine methyl ester hydrochloride (9.73g, 69.71 mmol) in a stirred mixture of ethyl acetate (175ml) and saturated aqueous sodium bicarbonate (175ml), cooled to 0-50C (ice bath), was added benzyl chloroformate (10.9ml, 76.37mmol) dropwise over ca. 20min. Stirring was continued for 18hr as the temperature rose to 200C then the layers were separated. The aqueous phase was further extracted with ethyl acetate (100ml) then the combined extracts were washed with 1 M HCI (150ml), dried (sodium sulphate) and evaporated in vacuo. The residue was evaporated from DCM to obtain a colourless liquid (16.07g, 97.2%).1H NMR (400 MHz, CHLOROFORM-d) deltappm 7.31 - 7.41 (m, 5H) 5.32 (br. s., 1 H) 5.13 (s, 2H) 4.35 - 4.45 (m, 1 H) 3.74 (s, 3H) 1.42 (d, 3H).
95%
With sodium carbonate; In chloroform; at 0 - 20℃; for 2h;
The crude compound 2 (3.378 g, 24.2 mmol) was dissolved in 40 ml of chloroform and cooled to 0 C. To this was added 40 ml of 20% sodium carbonate, and stirred for an additional 15 min to complete the neutralization. The solution was cooled to 0 C., 8 ml (27.8 mmol) of 50% benzyl chloroformate was added slowly, and the reaction stirred for 2 h at room temperature. The layers were separated, and the chloroform layer was washed with 20 ml of 1N hydrochloric acid and dried over magnesium sulfate. The solvent was removed to give 5.45 g (95%) of the desired product as clear oil. 1H NMR (500 MHz, CDCl3): delta 7.36-7.30 (m, 5H), 5.34 (br, 1H), 5.11 (s, 2H), 4.39 (q, J=7.0 Hz, 1H), 3.74 (s, 3H), 1.41 (d, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): delta 173.61, 155.70, 136.34, 128.66, 128.31, 128.25, 67.05, 52.61, 49.69, 18.82.
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
To a stirred solution of 3, 5-<strong>[105184-38-1]difluorophenylacetic acid</strong> (6.02 g, 34.97 [MMOL),] L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at [0C] was added NMM (8.84g, 87.39 mmol) and EDAC-HCl (7.38 g, [38.] 49 [MMOL).] The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, IN aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1 : [1] [(V/V)] hexanes: ethyl acetate to afford [N [ (3,] 5- difluorophenyl) acetyl] -L-alanine methyl ester (7.91 g, 88% yield) as a white [SOLID. LH NMR] (300 MHz, [CDC13)] [6] 1.39 (d, 3H, [J= 7.] 0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br [1H),] 6.67-6. 87 (m, 3H). MS APCI, m/z = 258 (M+1). LC/MS: 1.68 min. Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N [ (3, 5-difluorophenyl) acetyl] -L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with IN aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white [SOLID. LH] NMR (300 MHz, d6-DMSO) 5 1.28 (d, 3H, J= 7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7. 12 (m, 3H), 8.44 (d, 1H, J= 7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
88%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 25℃; for 12h;
e. JV-r(3,5-DifluorophenvI)acetyl1-L-aIanine (Ie)To a stirred solution of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in DCM (200 mL) under nitrogen at 0 0C was added NMM (8.84g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm to 25 0C and to stir for -12 h. The reaction was diluted with EtOAc and extracted sequentially with aqueous sodium bicarbonate, IN aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes-EtOAc to afford N- [(3,5- difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) ? 1.39 (d, 3H, J= 7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, IH), 6.02 (br IH), 6.67-6.87 (m, 3H). MS APCI, m/z = 258 (M+l). LC/MS: 1.68 min.
82%
With dmap; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 14h;Inert atmosphere;
General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of 4-hydroxyphenylglycine (12 g, 71.860 mmol) in a 1:1 mixture of acetone and water was addeddi-tert-butyldicarbonate (16.5 mL, 71.8 mmol, 1 eq) andsodium bicarbonate (6.03 g, 0.11 mol, 1.5 eq). The solutionwas allowed to stir overnight, and then was quenched with theaddition of citric acid (pH 3) to pH 4. The aqueous layer was65 then extracted 2x with EtOAc and the combined organiclayers were washed with brine, dried over Na2S04 and concentratedto a white foam. The crude material (18.43 g, 69mmol (assumed)) was used without further purification bydissolving it in anhydrous DMF and treating sequentiallywith triethylamine (12.6 mL, 75.9 mmol, 1.3 eq), HOBT(9.32 g, 69 mmol, 1 eq) andAla-OMe HCl (9.63 g, 69 mmol,1 eq). The solution was then cooled to oo C. and EDC (19.55 5g, 0.1 mol, 1.5 eq) was added in one portion. The reaction wasallowed to warm to room temperature and stirred overnight.Water and EtOAc were added, the aqueous layer wasextracted 3x, and the combined organic layers were washedwith brine, dried over Na2S04 and concentrated. The residue 10was purified by flash chromatography (6% MeOH, 0.6%AcOH in DCM) to give a clear residue (17.82 g, 71% yield).Rf=0.39 (7% MeOH in DCM). 1H NMR (CDC13 , 600 MHz)o (ppm) 7.11 (d, 1=8.4 Hz, 2H), 6.64 (d, 1=8.4 Hz, 2H), 6.51 15(brd, 1=6.6 Hz, lH), 5.71 (brs, lH), 5.07 (brs, lH), 4.57-4.52(m, 1H),3.69(s,3H), 1.42-1.40(m, 12H). 13CNMR(CDC13 ,600 MHz) o (ppm) 173.2, 170.5, 156.6, 155.4, 129.0, 128.7(2C), 116.1 (2C), 80.5, 58.2, 52.7, 48.5, 28.4 (3C), 18.4. IR(film)vmax=1655, 1512,1450,1365,1215,1157,1049 cm-1. 20ESI HRMS calcd for [(M+NatJ C17H24N20 6 : 375.1526.found: 375.1532.
With methanol; sodium cyanoborohydride; magnesium sulfate; In tert-butyl methyl ether; at 0℃;
A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester; To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were added at 0 C. dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the title compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+.
80%
With methanol; sodium cyanoborohydride; magnesium sulfate; In tert-butyl methyl ether; at 0℃; for 16h;
Intermediate 1 (S)-2-[Benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in MeOH (100 mL) were added at 0C <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (5.50 g, 80%>). Light yellow liquid, MS (ISP) = 192.2 (M+H)+.
80%
To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in MeOH (100 mL) were added at 0 C. <strong>[51673-84-8]dimethoxyacetaldehyde</strong> (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+.
80%
With sodium cyanoborohydride; magnesium sulfate; In methanol; tert-butyl methyl ether; at 0℃; for 16h;
To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were aded at 0C dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful adition of sat. aq. sodium hydrogencarbonate solution at 0C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgS04), filtered, and evaporated to afford the titled compound (5.50 g, 80%). Light yellow liquid, MS (ISP) = 192.2 (M+H)+.
80%
With sodium cyanoborohydride; magnesium sulfate; In methanol; tert-butyl methyl ether; at 0℃; for 16h;
A) (S)-2-(2,2-Dimethoxy-ethylamino)-propionic acid methyl ester To a solution of L-alanine methyl ester hydrochloride (5.00 g, 35.8 mmol) in methanol (100 mL) were added at 0 C. dimethoxyaldehyde (45% solution in tert-butyl methyl ether, 12.0 mL, 47 mmol) magnesium sulfate (38.8 g, 322 mmol), and sodium cyanoborohydride (3.08 g, 46.6 mmol). The ice bath was removed, then after 16 h the excess reagent was destroyed by careful addition of sat. aq. sodium hydrogencarbonate solution at 0 C. The reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to afford the titled compound (5.50 g, 80%). Light yellow liquid, MS (ISP)=192.2 (M+H)+.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;
L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN (20 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (2.0 g, 6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIEA (1.3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed with dilute aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 79%).(S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 4.8 mmol) was taken up in THF (8 mL) along with 5M aqueous NaOH (5 mL) and stirred vigorously at room temperature for 3 h. The reaction mixture was diluted with water and concentrated under reduced pressure. Enough 6N HCl was then added to adjust the pH to 2. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoic acid. This was taken up in CH3CN (15 mL) along with N-Boc-L-threonine methyl ester (1.11 g, 4.78 mmol), HATU (2.0 g, 5.3 mmol) and DIEA (1.2 mL). The resulting reaction mixture was stirred at room temperature for 6 h and diluted with EtOAc. The organic layer was washed with NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded (2S,3R)-methyl 2-(tert-butoxycarbonyl)-3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate (1.0 g).(2S,3R)-methyl 2-(tert-butoxycarbonyl)-3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docodsa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate (300 mg, 0.488 mmol) was taken up in 4M HCl in dioxane (2 mL) and allowed to stand at room temperature for 10 min. The reaction mixture was then diluted with EtOAc and concentrated under reduced pressure to afford the HCl salt of (2S,3R)-methyl 2-amino-3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)butanoate. This material was taken up in CH3CN (5 mL) along with nicotinic acid (60 mg, 0.488 mmol), HATU (204 mg, 0.54 mmol) and DIEA (0.25 mL, 1.46 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting oily residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford (2S,3R)-methyl 3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoyloxy)-2-(nicotinamido)butanoate (120 mg, 40%). MS calculated for C36H49N3O6: 619.36; found: [M+H]+620.
79%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;
[0247j L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN(20 mL) along with (4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)-docosa-4,7, 10,13,16,1 9-hexaenoic acid (2.0 g,6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIEA (1.3 mL). The resulting reaction mixture wasstirred at room temperature for 2 h. It was then diluted with EtOAc and washed with diluteaqueous NaHCO3 and brine. The organic layer was dried over Na2504, filtered and concentrated under reduced pressure to afford (5)-methyl 2-((4Z,7Z, 1 OZ, 1 3Z, 1 6Z, 1 9Z)- docosa-4,7, 10,13,16,1 9-hexaenamido)propanoate (2.0 g, 79%).
79%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;
Example 11 Preparation of (2S,3R)-methyl 3-((S)-2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13, 16,19-hexaenamido)propanoyloxy)-2-(nicotinamido)butanoate (1-9) [0335] L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN (20 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (2.0 g, 6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIE A (1.3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed with dilute aqueous NaHC03 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure to afford (5)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 79%).
methyl (S)-2-(2,3-dihydro-1H-indan-2-ylamino)propanoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With 4-methyl-morpholine; palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 3000.3 Torr; for 12h;Inert atmosphere;
General procedure: Under Ar, 10% Pd-C (500 mg) was added to a solution of alpha-amino acid ester hydrochloride 1a-e,g,h (10 mmol) in a mixture of methanol (30 mL), symmetrical ketone (10 mmol)§ or propionaldehyde (0.87 mL, 12 mmol), and 4-methylmorpholine (4 drops). The hydrogenation vessel was flushed five times with hydrogen, and the mixture was hydrogenated (4 bar of H2, rt) for 12 h. The catalyst was removed by filtration through a fritted funnel and washed with methanol (10 mL). The combined filtrate was evaporated in vacuo to give crude 2a,b,d-h,j-p in quantitative yields. The oily compound 2f was used for further transformations without purification. The solid compounds 2a,b,d,e,g,h,j-p were suspended in ethyl acetate (50 mL), the suspensions were stirred at rt for 1 h, and the precipitate was collected by filtration to give purified compounds 2a,b,d,e,g,h,j-p.The following compounds were prepared in this manner.
(S)-2-amino-1,1-di(4-methoxy-3,5-di-tert-butylphenyl)-3-methyl-1-butanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Production Example 7 of Optically Active AminoalcoholA 300 mL round-bottom four-neck flask equipped with a Dimroth condenser with a nitrogen introducing tube attached thereto, a thermometer, a magnetic rotator and a dropping funnel was heated under reduced pressure, nitrogen was then introduced into the flask, pressure in the flask was returned to normal pressure, and the flask was cooled to room temperature. After 1.99 g of magnesium and a minor amount of iodine were added to the flask, a small amount of a solution obtained by mixing 25.30 g of 4-methoxy-3,5-di-tert-butylbromobenzene and 119.0 mL of dehydrated tetrahydrofuran was added dropwise. The flask was heated, and it was confirmed that the Grignard reaction was initiated. Thereafter, the remaining solution was added dropwise over 30 minutes. The resulting mixture was refluxed for 1.5 hours. After the resulting reaction mixture was cooled to -10 C., 1.45 g of L-alanine methyl ester hydrochloride was added. The temperature of the resulting mixture was raised to room temperature, and the mixture was further refluxed for 3 hours. The resulting reaction mixture was cooled to 0 to 5 C. To the reaction mixture were added dropwise 70.0 mL of an aqueous saturated ammonium chloride solution, and further 20.0 mL of water. The resulting mixture was stirred at 20 C. for 12 minutes. The resulting mixture was extracted with 70.0 mL of diethyl ether three times. The resulting organic layers were mixed, and dried with anhydrous sodium sulfate. After sodium sulfate was removed by filtration, the resulting filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/9830/70) to obtain 3.32 g of a pale yellow solid of (S)-2-amino-1,1-di(4-methoxy-3,5-di-tert-butylphenyl)-3-methyl-1-butanol.1H-NMR (300 MHz, CDCl3, TMS standard)delta (ppm): 7.49 (2H, s), 7.34 (2H, s), 4.01 (1H, m), 3.86 (1H, brs), 3.67 (3H, s), 3.66 (3H, s), 1.44 (18H, s), 1.42 (18H, s), 1.22 (2H, br.s), 0.94 (3H, d)13C-NMR (75 MHz, CDCl3, TMS standard)delta (ppm): 158.58, 158.29, 143.46, 142.94, 141.10, 139.19, 124.95, 124.84, 79.58, 64.76, 53, 42, 36.58, 36.50, 32.91, 21.75, 18.07
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In tetrahydrofuran;
N-(5-hexynyl) L-alanine methyl ester In a flame-baked, two neck 100 mL round bottom flask, 20 mmol of L-alanine methyl ester hydrochloride (2.8 g), 40 mmol of K2CO3 (5.53 g), and 20 mmol of tetrabutylammonium iodide (TBAI, 7.39 g) were charged under a stream of dry N2 gas. 35 mL of tetrahydrofuran (THF) was slowly added and the mixture was stirred for 15 min at room temperature. 2.6 mL of 6-iodo-hex-1-yne was added dropwise while the mixture was stirred. The reaction mixture was refluxed at ~70 C. for 15-18 h with TLC check. After consumption of the starting material, the mixture was cooled to room temperature, diluted by diethylether, and filtered. The filtrate was further diluted by diethylether and filtered again. The solvent was removed by rotavap and the crude product was purified by flash chromatography on silica gel (1:2=Hexane/EtOAc, 1% triethylamine) to give N-(5-hexynyl) L-alanine methyl ester (2.044 g, 11.2 mmol) as a yellow oil. Yield: 56%. Rf=0.27 (1:1=Hexane/EtOAc); ESI-MS [M+H]+=184.1 m/z; 1H NMR (300 MHz, CDCl3): delta 3.70 (s, 3H), 3.32 (q, J=7.0 Hz, 1H), 2.53 (m, 2H), 2.18 (m, 2H), 1.92 (t, J=2.6 Hz, 1H), 1.56 (m, 5H), 1.27 (d, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): delta 176.29, 84.21, 68.41, 56.61, 51.74, 47.41, 29.20, 26.01, 19.11, 18.23.
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; at 20℃;Inert atmosphere;
General procedure: To a solution of trifluorocrotonic acid (1.0 equiv) in DMF, was added the amino acid methyl ester hydrochloride (1.2 equiv), DIPEA (4.0 equiv), HBTU (1.2 equiv) and HOBt (1.2 equiv) in this order. The mixture was stirred overnight at room temperature under argon atmosphere. The solvent was evaporated under vacuum and the residue dissolved in ethyl acetate. The organic layer was washed with 10% citric acid aqueous solution (two times), water, 10% K2CO3aqueous solution (two times) and brine, dried over Na2SO4, filtrated and evaporated. The crude product was purified by column chromatography (EtOAc/cyclohexane: 3/7) to afford the corresponding alkene.
methyl (2S)-2-[[(2S)-4-amino-2-(tert-butoxycarbonylamino)-4-oxo-butanoyl]amino]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 12.25h;
To a mixture of (2S)-4-amino-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid (998 mg, 4.30 mmol,1 .2 equiv.), methyl (2S)-2-aminopropanoate (500 mg, 3.58 mmol, 1 equiv., HCI), HOBt (532 mg, 3.94 mmol,1 .1 equiv.) and TEA (797 mg, 7.88 mmol, 1 .10 mL, 2.2 equiv.) in DMF (5 was added EDCI (755 mg, 3.94 mmol, 1 .1 equiv.) at 0 aC. The reaction mixture was stirred at 0 aC for 15 min and was then warmed to 25 C for 12 hr. The reaction mixture was filtered and filtrate was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um ; mobile phase: [water (0.1 %TFA)-ACN];B%: 10%-40%, 20min). Methyl (2S)-2-[[(2S)-4- amino-2-(tert-butoxycarbonylamino)-4-oxo-butanoyl]amino] propanoate (750 mg, 66%) was obtained as a white solid.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50.0℃;
Scheme 4 A B (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) and (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B): To a mixture of <strong>[98136-42-6]2,6-dichloropyrimidine-4-carboxamide</strong> (4.800 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.565 g, 25.54 mmol) and iPr2NEt (9.60 mL, 55.1 1 mmol). The mixture was heated at 50C overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 20-60% acetone in hexanes. Two isomers were obtained from the chromatography. The first isomer to elute was (S)-methyl 2-((6- carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) and the second to elute was (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B). Separately, the appropriate product fractions were evaporated in vacuo to give (S)- methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) as a pale tan powder (5.133 g, 19.84 mmol, 79% yield). LC/MS: m/z= 259.2 [M+H]+ and (S)- methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B) as a tan powder (0.652 g, 2.52 mmol, 10% yield). LC/MS: m/z= 259.2 [M+H]+.
79%; 10%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50.0℃;
To a mixture of <strong>[98136-42-6]2,6-dichloropyrimidine-4-carboxamide</strong> (4.800 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.565 g, 25.54 mmol) and iPr2NEt (9.60 mL, 55.1 1 mmol). The mixture was heated at 50C overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 20-60% acetone in hexanes. Two isomers were obtained from the chromatography. The first isomer to elute was (S)-methyl 2-((6-carbamoyl-2- chloropyrimidin-4-yl)amino)propanoate (A) and the second to elute was (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B). Separately, the appropriate product fractions were evaporated in vacuo to give (S)-methyl 2-((6- carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) as a pale tan powder (5.133 g, 19.84 mmol, 79% yield). LC/MS: m/z= 259.2 [M+H]+ and (S)-methyl 2-((4- carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B) as a tan powder (0.652 g, 2.52 mmol, 10% yield). LC/MS: m/z= 259.2 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃;
EXAMPLE 8 Preparation of (S)-6-((l -amino- 1 -oxopropan-2-yl)amino)-2-(4-(4- (trifluoromethyl)phenoxy)phenyl)pyrimidine-4-carboxamide (Cpd No. 14) Scheme 17 (S)-methyl 2-chloro-6-((l -methoxy- 1 -oxopropan-2-yl)amino)pyrimidine-4- carboxylate: To a mixture of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (5.175 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.497 g, 25.05 mmol) and iPr2NEt (9.6 mL, 55.1 mmol). The mixture was heated at 50C overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 30-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-methyl 2-chloro-6-((l-methoxy-l - oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a thick yellow-orange oil (4.194 g, 15.33 mmol, 61% yield). LC/MS: m/z= 274.2 [M+H]+.
61%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 50℃;
To a mixture of <strong>[6299-85-0]methyl 2,6-dichloropyrimidine-4-carboxylate</strong> (5.175 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.497 g, 25.05 mmol) and iPr2NEt (9.6 mL, 55.1 mmol). The mixture was heated at 50C overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 30-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-methyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a thick yellow-orange oil (4.194 g, 15.33 mmol, 61% yield). LC/MS: m/z= 274.2 [M+H]+.
To a mixture of (S)-methyl 2-aminopropanoate hydrochloride ( 1 .397 g, 10.01 mmol) in DCM (80 mL) was added iPr2NEt (4.35 mL, 24.97 mmol). The mixture was stirred for a few minutes and a solution of the 2,6-dichloropyrimidine-4- carbonyl chloride (2.107 g, 9.97 mmol) in DCM (20 mL) was added over a period of 1 minute. After stirring overnight, the reaction was concentrated in vacuo to a residue. The residue was chromatographed over silica gel using 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2,6- dichloropyrimidine-4-carboxamido)propanoate as a yellow oil (0.921 g, 3.31 mmol, 33% yield). LC/MS: m/z= 278.1 [M+H]+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 50h;
General procedure: Mycophenolic acid 1 (0.156 mmol), methyl ester amino acid hydrochloride 9 (0.178 mmol) and DMAP (0.178 mmol) was dissolved in dry DMF (3 mL). A reaction mixture was cooled to 0 C in an ice bath and with stirring was added EDCI (0.17053 mmol). The solution was stirred at 0 C for 2 h and after that time left at room temperature for 48 h. Progress of the reaction controlled by TLC plates. After completion of the reaction solution was poured into water (15 mL), extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude products were purified by chromatography (SiO2). Structures of synthesized derivatives 10 were established by spectroscopic methods (1H NMR, 13C NMR, MS, HPLC-MS, optical rotation and melting point). Ester hydrolysis: the methyl ester 10 was dissolved in MeOH (30 mL/g), and a solution of LiOH*H2O (3 mol equiv - 2-fold more for 10d and 10e) in an equal volume of water was added. When hydrolysis was complete (48 h), the solution was added to water and washed with ether. The aqueous phase was acidified with 2 N HCl and extracted with EtOAC. The extract was dried with MgSO4 and evaporated, and the residue was recrystallized [17].
To a solution of 4-hydroxyphenylglycine (12 g, 71.8 mmol) in a 1 :1 mixture of acetone and water was added di-ieri-butyldicarbonate (16.5 mL, 71.8 mmol, 1 eq) and sodium bicarbonate (6.03 g, 0.11 mol, 1.5 eq). The solution was allowed to stir overnight, and then was quenched with the addition of citric acid (pH 3) to pH 4. The aqueous layer was then extracted 2x with EtOAc and the combined organic layers were washed with brine, dried over Na2S04 and concentrated to a white foam. The crude material (18.43 g, 69 mmol (assumed)) was used without further purification by dissolving it in anhydrous DMF and treating sequentially with triethylamine (12.6 mL, 75.9 mmol, 1.3 eq), HOBT (9.32 g, 69 mmol, 1 eq) and Ala-OMe HCl (9.63 g, 69 mmol, 1 eq). The solution was then cooled to 0 C and EDC (19.55 g, 0.1 mol, 1.5 eq) was added in one portion. The reaction was allowed to warm to room temperature and stirred overnight. Water and EtOAc were added, the aqueous layer was extracted 3x, and the combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by flash chromatography (6% MeOH, 0.6% AcOH in DCM) to give a clear residue (17.82 g, 71 % yield).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 1.9 - 20℃; for 4h;Inert atmosphere;
(S)-2-(4--{5-[Bis-(2-chloro-ethyl)-amino]-l-methyl-lH-benzoimidazol-2-yl}-butyrylam propionic acid methyl ester: A 250 mL three neck round bottom flask equipped with a stir bar, thermocouple, cooling bath, addition funnel and nitrogen in/outlet was charged with 10 g (25.3 mmol) of <strong>[3543-75-7]<strong>[3543-75-7]bendamustine</strong> hydrochloride</strong>, 10.6 g (27.8 mmol) of HATU and 100 mL of DMF. The batch was cooled to 1.9C where 8.8 mL (6.54 g, 50.6 mmol) of DIPEA was added over 2 minutes. The reaction exothermed to 9C and became orange. A solution of 3.57 g (25.6 mmol) of L-alanine methyl ester hydrochloride and 6.2 mL (4.57 g, 35.4 mmol) of DIPEA in 20 mL of DMF was added drop-wise over 10 minutes at 4.9-5.7C. The reaction was slowly warmed to RT over one hour and stirred for three hours at which time an in process assay indicated the reaction was complete. The batch was quenched onto 400 mL of 1 : 1 ethyl acetate/DI water. The layers were separated, the organic was washed with 10% sodium hydrogen phosphate (I X 200 mL), 8% sodium bicarbonate 91 X 200 mL) and brine (1 X 200 mL), before drying over sodium sulfate, filtering and evaporating to dryness in vacuo. The residue was purified by chromatography using lOOg of silica gel 60, 230-400 mesh, eluting with 1%> MeOH/MDC (3 L), 2.5 % MeOH/MDC (1L) and 5% MeOH/MDC (500 mL) collecting -100 mL fractions. The product containing fractions were combined and concentrated to dryness in vacuo to yield 7.1 g (16.0 mmol, 63.3%) of the desired product as a white solid with an HPLC purity of 97.4A%. XH NMR (400 MHz, DMSO-d6) delta 8.25 (d, J= 6.92 Hz), 1H), 7.40 (d, J= 8.84 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.86 (dd, J= 2.32, 8.88 Hz), 4.25 (q, 1H), 3.72 (s, 8H), 3.71 (s, 3H), 3.62 (s, 3H), 2.87 (t, J= 7.48 Hz, 2H), 2.25 (t, J= 7.52 Hz, 2H), 1.99 (m, 2H), 1.26 (d, J= 7.32 Hz, 3H).
General procedure: To a stirred suspension of theophyline-7-acetic acid (200 mg, 1 eq) and L-aminoacid methyl ester.HCl (1.05 eq) in CH2Cl2 (20 ml) was added N-ethyldiisopropylamine (1.1 eq). After 10 min the reaction became a clear solution and EDC (1.1 eq), and HOBt (1.1 eq) were added. The mixture was stirred overnight at r.t., then washed with water (2 x 20 ml) and sat. aq. NaHCO3 (20 ml). For hygroscopic compounds (2a-b, 2e, 2h), was done a back-extraction of the combined aqueous layers with CH2Cl2:MeOH = 10:1. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The product was purified by filtration through a pad of silica gel (EtOAc/MeOH = 4:1).
N-(2,5-dibromothiophene-3-carbonyl)-L-alanine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 20℃;
L-Alanine methyl ester hydrochloride (1.74 g, 12.5 mmol) and 2,5-dibromo-3-thenoic acid (2.95 g, 10.3 mmol) and TRIAZIMOCH (6.49 g, 23.5 mmol) were dissolved in MeOH (19 mL). Then triethylamine (8.00 mL, 57.4 mmol) was added to the solution, and the resulting mixture was stirred at room temperature overnight. It was concentrated on a rotary evaporator, and subsequently washed with saturated NaHCO3 aq. and saturated NaCl aq. The organic layer was dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The residual mass was purified by silica gel column chromatography eluted with hexane/CH2Cl2 = 7:3 (v/v) to obtain 1a as a white solid in 90% yield.
General procedure: To a solution of alanine methyl ester hydrochloride (3.00 g, 21.6 mmol) in CH2Cl2(120 mL) was added NMM (6.19 mL, 45.5 mmol) and methanesulphonyl chloride (1.67mL, 21.6 mmol). The reaction was stirred at room temperature for 20h. Thereaction was quenched upon addition of 1 N HCl (120 mL) and extracted with CH2Cl2(2 x 100 mL). The combined organic extracts were dried over Na2SO4and concentrated under vacuum. The residue was dissolved in DMF (100 mL) andadded K2CO3 (5.94 g, 44.0 mmol) and 4-bromobenzyl bromide(6.00 g, 24.0 mmol). The reaction was stirred at 40 C for 6h. The reaction wascooled to room temperature, diluted with water (400 mL) and extracted withEtOAc (2 x 200 mL). The combined organic extracts were washed with 5% LiCl (aq.Solution., 2 x 300 mL) and brine (300 mL), dried over Na2SO4and concentrated under vacuum. The residue was purified by columnchromatography (silica gel) using 0 to 70% EtOAc/hexanes to afford 2 a clear yellow oil (5.56 g, 73%); 1H-NMR(400 MHz, CDCl3) delta 7.45 (dt, J= 8.5, 2.0 Hz, 2H), 7.29 (dt, J =8.5, 2.0 Hz, 2H), 4.68 (q, J = 8.0Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 4.25 (d, J= 16.0 Hz, 1H), 3.73 (s, 3H), 2.95 (s, 3H), 1.32 (d, J = 8.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3) delta 172.1,136.8, 131.6, 129.5, 121.6, 56.2, 52.5, 48.8, 39.8, 17.5.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 4h;Ionic liquid; Green chemistry;
General procedure: In a 50 mL round bottom flask, a mixture of N-benzoylglycine (1 mmol, 0.179 g), glycine methyl ester hydrochloride(1.5 mmol, 0.188 g), EDC.HCl (1 equiv.) in [C4-DABCO][N(CN)2] (3 mL) was added and stirred at roomtemperature for 4 h. After completion of the reaction (by TLCmonitoring), the reaction mixture was extracted with diethylether (3 × 10 mL) and the organic layer was washed withdistilled water (20 mL), dried over anhydrous Na2SO4 andthe organic layer was evaporated in vacuum. The residue waspurified by column chromatography on silica gel using ethylacetate/hexanes (1:1) as eluent to get the corresponding peptide.
61%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ethylene glycol; at 20℃; for 4h;Green chemistry;
General procedure: In a 50 ml round bottomflask, a mixture of benzoyl protected glycine (1 mmol, 0.179 g), glycine methylester hydrochloride (1.5 mmol, 0.188 g), EDCHCl (1 mmol, 0.192 g) in WEB(3 mL) and 0.2 ml ethylene glycol was added and stirred at room temperaturefor 4 h. After completion of the reaction (by TLC monitoring); the reactionmixture was extracted with diethyl ether (3 10 ml) and the organic layer waswashed with distilled water (20 mL), dried over Na2SO4, and organic layer isevaporated in vacuo. The residue was purified by column chromatographyon silica gel using ethyl acetate/hexanes (1:1) as eluent to give thecorresponding peptide. The products were characterized by 1H NMR andESI-MS spectrometry.
(S)-methyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanamido)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.3 g
(S)-methyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanamido)propanoate To a solution of <strong>[5545-54-0](S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(tert-butoxy)phenyl)propanoic acid</strong> (2.24 g, 6.03 mmol) and (S)-methyl 2-aminopropanoate hydrochloride (0.850 g, 6.09 mmol) in DCM (30.2 ml) at 0 C. was added solid HATU (2.408 g, 6.33 mmol). After 15 mins N-methylmorpholine (1.326 ml, 12.06 mmol) was added and the mixture was allowed to warm to RT, overnight. Added 1 N HCl 30 ml and extracted 3* with dichloromethane (30 mL), combined organics were dried over Na2SO4, filtered, and stripped to a wax. The residue was purified via normal phase chromatography, ISCO 80 grams silica, hexanes to ethyl acetate gradient, produced 1.3 grams. LCMS Condition E: retention time=0.97 mins 457.5 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) delta 7.40-7.31 (m, 5H), 7.14-7.05 (m, J=8.1 Hz, 2H), 6.97-6.84 (m, 2H), 5.31 (s, 1H), 5.11 (s, 2H), 4.49 (s, 1H), 3.72 (s, 3H), 1.57 (br. s., 2H), 1.38-1.29 (m, 12H).
methyl (2S)-2-[[(2R)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoyl]amino]propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 12.25h;
A mixture of <strong>[61348-28-5](2R)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid</strong> (1 .06 g, 4.30 mmol, 1 .2 equiv.), methyl (2S)-2-aminopropanoate hydrochloride (500 mg, 3.58 mmol, 1 equiv.), HOBt (532 mg, 3.94 mmol, 1 .1 equiv.) and TEA (797 mg, 7.88 mmol, 1 .10 ml_, 2.2 equiv.) in DMF (5 ml_) was cooled to 0 C and EDCI (755 mg, 3.94 mmol, 1 .1 equiv.) was added to the mixture. The reaction mixture was stirred at 0 SC for 15 min and at 25 C for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um ; mobile phase: [water(0.1 %TFA)-ACN];B%: 10%-40%,20min). Methyl (2S)-2-[[(2R)-5- amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoyl]amino] propanoate (660 mg, 56%) was obtained as a white solid.
10%Spectr.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 25℃;
(0247) To an oven-dried round bottom flask equipped with a stir bar was added a Boc-protected amino acid or carboxylic acid (1.0 equiv), the HC1-salt of the methyl ester-protected amino acid (1.0 equiv) and dry DMF (0.1-0.3 M). The starting materials were dissolved at room temperature and HOBt (Sigma Aldrich, 1.2 equiv) and PyBOP (Chem-Impex International, Inc) were added. The flask was then cooled to 0 C. and DIPEA (2.1 equiv) was added dropwise. The reaction mixture was warmed to room temperature overnight. The reaction mixture was then diluted with 5 reaction volumes of EtOAc or DCM and quenched by the addition of 1 reaction volume of aqueous 1 M HCl. The aqueous and organic layers were separated and the aqueous layer was extracted 2 more times with the same solvent (EtOAc or DCM). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and then concentrated in vacuo. The crude product was either used directly in the subsequent step or was purified as described for the individual compounds listed below.
benzyl (3R)-3-(tert-butoxycarbonylamino)-4-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-4-oxo-butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 12.25h;
A mixture of <strong>[51186-58-4](2R)-4-benzyloxy-2-(tert-butoxycarbonylamino)-4-oxo-butanoic acid</strong> (1 .39 g, 4.30 mmol, 1 .2 equiv.), methyl (2S)-2-aminopropanoate hydrochloride (500 mg, 3.58 mmol, 1 equiv.), HOBt (532 mg, 3.94 mmol, 1 .1 equiv.) and TEA (797 mg, 7.88 mmol, 1 .10 mL, 2.2 equiv.) in DMF (10 ml_) was cooled to 0 C. EDCI (755 mg, 3.94 mmol, 1 .1 equiv.) was added to the mixture. The reaction mixture was stirred at 0 C for 15 min and at 25 C for 12 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um;mobile phase: [water(0.1 %TFA)-ACN];B%: 25%-55%,20min). Benzyl (3R)- 3-(tert-butoxycarbonylamino)-4-[[(1 S)-2- methoxy-1 -methyl-2-oxo-ethyl]amino]-4-oxo-butanoate (1 .2 g, 82%) was obtained as a yellow oil.
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