* 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] Journal of Organic Chemistry, 1988, vol. 53, # 3, p. 487 - 499
[2] Journal of Natural Products, 2003, vol. 66, # 2, p. 183 - 199
2
[ 24424-99-5 ]
[ 13515-93-0 ]
[ 42492-57-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine In dichloromethane at 0 - 20℃; for 48 h; Inert atmosphere
To a suspension of sarcosine (35.64 g, 0.40 mol) in 350 mL MeOH was added thionyl chloride (29.02 mL, 0.40 mol) dropwise at 0 °C. After complete addition the cooling bath was removed and the reaction mixture was stirred for 30 min at r.t. and refluxed for further 6 h. The resulting solution was concentrated in vacuum and the residue was dried in high vacuum over night at r.t. to afford sarcosine methyl ester.HCl as a white powder which was used in the next step without further purification; yield: 56.14 g (quant.); mp. 102 °C. 1H-NMR (300 MHz, CDCl3): δ = 9.76 (s, 2 H, NH2), 3.88 (t, J = 5.6 Hz, 2 H, H-2), 3.82 (s, 3 H, H-4)), 2.83 (t, J = 5.2 Hz, 3 H, H-3). 13C-NMR(75 MHz, CDCl3): δ = 166.7 (C-1), 53.3 (C-2), 48.9 (C-3), 33.4 (C-4).1 To a suspension of sarcosine methylester.HCl (59.80 g, 0.43 mol) and (Boc)2O (138.01 mL, 0.65 mol) in 1.0 L CH2Cl2 TEA (119.09 mL, 0.86 mol) was added dropwise at 0 °C. After complete addition the cooling bath was removed and the reaction mixture was stirred for two days at r.t. Aq. HCl (1 M) was added until the aqueous layer showed pH = 6. The resulting two layers were separated and the organic layer was washed with dist. H2O, dried (Na2SO4), concentrated in vacuum and volatile impurities were removed in high vacuum over night at r.t. to afford a clear oil; yield: 78.65 g (90 percent)
Boc-N-sarcosine methyl ester (18) was prepared by treating a solution of Boc-Sar- OH (1.0 g, 5.3 mmol) in 1 : 1 DCM/MeOH (25 mL) cooled to 0° C portionwise with diazomethane (2M solution, excess) until the reaction mixture turned slight yellow. The reaction was kept at 0° C for 30 min and then HOAc (2 drops) was added. The organic solvents were removed to afford 1.0 g (90percent) of 18.
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water for 18 h; Stage #2: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5 h; Stage #3: at 20℃; for 48 h;
Glycine methyl ester hydrochloride (50.0 g, 0.398 mol, 1 eq.) was added to a 1 L flask containing water (300 mL) and THF (200 mL). Sodium bicarbonate (37.8 g, 0.438 mol) was added portionwise, followed by di-tert-butyl dicarbonate (83.4 g, 0.382 mol). The reaction was stirred for 18 h, and then the separated organic phase was concentrated. The mixture was redissolved in EtOAC, washed with brine, dried over Na2SO4, and evaporated to give an oily product (72 g, 95percent). The oily product was dissolved in DMF (500 mL) and cooled to 0° C. To the mixture was added NaH (60percent, 18.3 g, 0.457 mol) portionwise. The mixture was then stirred for 30 min and MeI (81.1 g, 0.571 mol) was added at such a rate as to maintain a reaction temperature below 20° C. The mixture was stirred at RT for 48 h. The mixture was poured into ice water (1.5 L), extracted with MTBE (300 mL×2). The combined organics were washed with brine, dried over Na2SO4, and evaporated. Silica gel chromatography (PE:EtOAc 7:1) gave N-Boc-N-methyl glycine methyl ester (21 g, 27percent).
With hydrogenchloride In 1,4-dioxane; dichloromethane at 0 - 20℃; for 1 h;
General procedure: A solution of HCl (3.3 M) in dioxane (5 mL) was added to a stirred solution of Nα-Boc-protected peptide (1 mmol) in DCM (2 mL) at 0 °C. The temperature was risen to 20 °C and the solution maintained for 1 h. The solvents were removed under vacuum and the residue stirred in dry ether to produce a crystalline product. In case of the poorly crystallizing or highly hygroscopic compounds the residual material was dissolved in dry chloroform, the solution evaporated and the product dried in a vacuum desiccator over P4O10 or KOH. Some products were purified by chromatography using silica gel and eluent mixture B, or by gel filtration on biogel P2 or fractogel TCK HW 40 with subsequent lyophilization.
With triethylamine; In dichloromethane; at 0 - 20℃; for 48h;Inert atmosphere;
To a suspension of sarcosine (35.64 g, 0.40 mol) in 350 mL MeOH was added thionyl chloride (29.02 mL, 0.40 mol) dropwise at 0 C. After complete addition the cooling bath was removed and the reaction mixture was stirred for 30 min at r.t. and refluxed for further 6 h. The resulting solution was concentrated in vacuum and the residue was dried in high vacuum over night at r.t. to afford sarcosine methyl ester.HCl as a white powder which was used in the next step without further purification; yield: 56.14 g (quant.); mp. 102 C. 1H-NMR (300 MHz, CDCl3): delta = 9.76 (s, 2 H, NH2), 3.88 (t, J = 5.6 Hz, 2 H, H-2), 3.82 (s, 3 H, H-4)), 2.83 (t, J = 5.2 Hz, 3 H, H-3). 13C-NMR(75 MHz, CDCl3): delta = 166.7 (C-1), 53.3 (C-2), 48.9 (C-3), 33.4 (C-4).1 To a suspension of sarcosine methylester.HCl (59.80 g, 0.43 mol) and (Boc)2O (138.01 mL, 0.65 mol) in 1.0 L CH2Cl2 TEA (119.09 mL, 0.86 mol) was added dropwise at 0 C. After complete addition the cooling bath was removed and the reaction mixture was stirred for two days at r.t. Aq. HCl (1 M) was added until the aqueous layer showed pH = 6. The resulting two layers were separated and the organic layer was washed with dist. H2O, dried (Na2SO4), concentrated in vacuum and volatile impurities were removed in high vacuum over night at r.t. to afford a clear oil; yield: 78.65 g (90 %)
Step 1: Treat a solution of 3,4-dichlorophenylacetic acid (25 g) with N-t-BOC-sarcosine methyl ester (24.3 g) (prepared from sarcosine methyl ester HCl and di-t-butyldicarbonate) according to a procedure similar to Example 11, Step 2, to give the desired product (36 g).
Step 4: Treat the product from Step 3 (28 g) with O-allylhydroxylamine HCl (17 g) according to a procedure similar to Example 1, to give the title compound (24.5 g).
Separately, the compound(0.35 g, 1.72 mmole) prepared in Preparation 7 was dissolved in dichloromethane(2 ml) and cooled down to -10 C. Trifluoroacetic acid(2 ml) was added thereto and the mixture was stirred for 5 minutes, slowly warmed to room temperature, stirred again for 30 minutes and then distilled under reduced pressure to remove the volatile substance. The resulting compound thus prepared and N-methylmorpholine(1 ml) were added to the solution as obtained above, and then the reaction solution was slowly warmed to room temperature and stirred for 3.5 hours. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile substance. The residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated.
Separately, the compound(0.35g, 1.72 mmole) prepared in Preparation 7 was dissolved in dichloromethane(2ml) and cooled down to -10C. Trifluoroacetic acid(2ml) was added thereto and the mixture was stirred for 5 minutes, slowly warmed to room temperature, stirred again for 30 minutes and then distilled under reduced pressure to remove the volatile substance. The resulting compound thus prepared and N-methylmorpholine(1ml) were added to the solution as obtained above, and then the reaction solution was slowly warmed to room temperature and stirred for 3.5 hours. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove the volatile substance. The residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated.
25
[ 42492-57-9 ]
[ 870-63-3 ]
2-(N-(tert-butoxycarbonyl)-N-methylamino)-5-methylhex-4-enoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
A solution of 2 (30.49 g, 0.15 mol) in 250 mL THF/DME (1:1) was added to NaHMDS (75 mL, 0.15 mol, 2.0 M in THF) dropwise at -78 C. The reaction mixture was stirred for 1 h before prenyl bromide (44.71 g, 0.30 mol) was added dropwise. Stirring was continued overnight, while the reaction was allowed to warm to r.t. Work-up started by quenching with some drops of sat. aq NH4Cl. All solvents were removed in vacuum and the residue was partitioned between EtOAc (300 mL) and dist. H2O (50 mL). The aqueous layer was removed and the organic layer was washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuum. The residue was purified by column chromatography (10 -> 50 % EtOAc in petroleum ether) to afford 3a as a clear oil; yield: 19.32 g (58 %)
22.1 g (63.7%)
With ammonium chloride; diisopropylamine; In tetrahydrofuran; hexane; ethyl acetate;
(b) A 2 M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0. 1279 tool) in 40 ml of dry THF at -78 C. under nitrogen and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4 -bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78 C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with a saturated ammonium chloride solution at -78 C, and then water was added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7 %) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl) sarcosine methyl ester as an oil.
22.1 g (63.7%)
With ammonium chloride; diisopropylamine; In tetrahydrofuran; hexane; water; ethyl acetate;
(b) A 2M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) in 40 ml of dry THF at -78 C. under nitrogen and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78 C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78 C., 20 ml of water was added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7%) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl ester as an oil.
22.1 g (63.7%)
With ammonium chloride; diisopropylamine; In tetrahydrofuran; hexane; water; ethyl acetate;
(a) A 2 M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) in 40 ml of dry THF at -78 C. under nitrogen and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78 C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78 C., 20 ml of water added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7 %) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl ester as an oil.
2-(3-methyl-3-chlorobutyl)-sarcosine methyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15.69 g (61.5%)
With ammonium chloride; diisopropylamine; In tetrahydrofuran; ethereal HCl; hexane; water; ethyl acetate;
(b) A 2 M solution of LDA (67.61 ml, 0. 135 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (24.96 g, 0.1279 mol) in 40 ml of dry THF at -78 C. under nitrogen, and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (19.23 g, 0.129 mol) with stirring at -78 C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78 C., 20 ml of water added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was partially purified by silica gel column chromatography (20% ethyl acetate in hexane). The product was then dissolved in 400 ml of ethereal HCl and stirred for 24 hours. The solid product was filtered, the residue washed with ether, and dried in vacuo to afford 15.69 g (61.5 %) of 2-(3-methyl-3-chlorobutyl)-sarcosine methyl ester hydrochloride (Formula XIII: R=CH3; R1 =H; R2 =(CH2)2 C(Cl)(CH3)2; R3 =CH3; X- =Cl-) as a solid.
(a) To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring, cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
46.38 g (86.4%)
In benzene;
(a) To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution added 74.94 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, a saturated sodium bicarbonate solution, and then brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
46.38 g (86.4%)
In benzene;
(a) To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0. 528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4 %) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
46.38 g (86.4%)
In benzene;
(a) To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo [5.4.0]-undec-7-ene (DBU; 40.19 g, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4 %) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
46.38 g (86.4%)
In benzene;
(a) To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml of benzene was added 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU; 40.19, 0.264 mol) in one portion. To the above clear solution was added 74.84 g (0.528 mol) of methyl iodide in one portion and the resulting clear solution was allowed to reflux for 7 hours. After adding additional methyl iodide (16 ml), the reaction mixture was refluxed with stirring and then cooled to room temperature, and stirred overnight. The reaction mixture was filtered, the residue washed with ether, and the combined filtrate was washed with water, saturated sodium bicarbonate solution, and brine. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil.
N-t-butoxycarbonyl-2-(3-methyl-2-buten)yl-sarcosine methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.1 g (63.7%)
With ammonium chloride; diisopropylamine; In tetrahydrofuran; hexane; water; ethyl acetate;
(b) A 2M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) in 40 ml of dry THF at -78 C. under nitrogen, and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78 C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78 C., 20 ml of water was added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7 %) of N-t-butoxycarbonyl-2-(3-methyl-2-buten)yl-sarcosine methyl ester as an oil.
With sodium hydroxide; In dimethylformamide(DMF, 10 ml); hexane; water; ethyl acetate;
PREPARATION 7 Synthesis of N-t-butoxycarbonyl-N-methylaminoacetic acid methyl ester Glycine methyl ester hydrochloride(1.0 g, 8.2 mmole) was dissolved in water(12 ml) and 1N aqueous sodium hydroxide solution (8.2 ml), and then 1,4-dioxane(20 ml) was added thereto. To this mixture was added di-t-butyldicarbonate(2.2 g, 9.8 mmole) at 0 C., and the mixture was warmed to room temperature and stirred for 2 hours. The volatile substance was removed from the reaction mixture under reduced pressure and the residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting product was dissolved in dimethylformamide(DMF, 10 ml). To this solution was slowly added 60% sodium hydride(NaH, 0.25 g, 6.4 mmole) at 0 C. and then added dropwise iodomethane(CH3, 1.1 ml). The mixture was slowly warmed to room temperature and stirred for 3 hours at the same temperature. The mixture was filtered through a Celite bed and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by column chromatography using ethyl acetate/hexane (6/4, by volume) as an eluent to obtain the purified title compound(1.0 g, Yield: 65%). 1 H NMR(CDCl3, ppm) delta: 1.45(d, 9H), 2.95(s, 3H), 3.78(s, 3H), 3.92(s, 1H), 4.00(s, 1H) Mass(FAB, m/e): 204(M+1)
With sodium hydroxide; In dimethylformamide(DMF, 10ml); hexane; water; ethyl acetate;
Preparation 7 Synthesis of N-t-butoxycarbonyl-N-methylaminoacetic acid methyl ester Glycine methyl ester hydrochloride(1.0g, 8.2 mmole) was dissolved in water(12ml) and 1N aqueous sodium hydroxide solution(8.2ml), and then 1,4-dioxane(20ml) was added thereto. To this mixture was added di-t-butyldicarbonate(2.2g, 9.8 mmole) at 0C, and the mixture was warmed to room temperature and stirred for 2 hours. The volatile substance was removed from the reaction mixture under reduced pressure and the residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting product was dissolved in dimethylformamide(DMF, 10ml). To this solution was slowly added 60% sodium hydride(NaH, 0.25g, 6.4 mmole) at 0C and then added dropwise iodomethane(CH3I, 1.1ml). The mixture was slowly warmed to room temperature and stirred for 3 hours at the same temperature. The mixture was filtered through a Celite bed and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified by column chromatography using ethyl acetate/hexane (6/4, by volume) as an eluent to obtain the purified title compound(1.0g, Yield: 65%).
Boc-N-sarcosine methyl ester (18) was prepared by treating a solution of Boc-Sar- OH (1.0 g, 5.3 mmol) in 1 : 1 DCM/MeOH (25 mL) cooled to 0 C portionwise with diazomethane (2M solution, excess) until the reaction mixture turned slight yellow. The reaction was kept at 0 C for 30 min and then HOAc (2 drops) was added. The organic solvents were removed to afford 1.0 g (90%) of 18.
A solution of di-isopropylamine (0.14 mL, 1.2 eq) in THF was cooled to - 78 C and then n-butyllithium (1 equiv) was added. The reaction mixture was warmed to 0 C then stirred for 15 min. To the resulting solution was added 18 (0.2 g, 1.2 eq) and the resulting solution stirred for 30 min. The enolate solution was cooled to -78 C and a THF solution of D-Ia (Ar = 3-chloro-5-cyano-phenyl, R4 = Br, 0.3 5g, 0.833 mmol) was added. The reaction was warmed up to RT and stirred for 4 h. The reaction mixture was poured into aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with H2O, then dried (Na2SO4) and purified by SiO2 chromatography to afford 0.2 g (44%) of D-Ib (Ar = 3-chloro-5-cyano-phenyl, R4 = Br).
Step 1: Treat a solution of 3,4-dichlorophenylacetic acid (25 g) with N-t-BOC-sarcosine methyl ester (24.3 g) (prepared from sarcosine methyl ester HCl and di-t-butyldicarbonate) according to a procedure similar to Example 11, Step 2, to give the desired product (36 g).Step 2 : Treat 2-bromoethanol (107 g) in CH2Cl2 (2 L) at 0 C with t-butyldimethylsilyichloride (143 g), NEt3 (130 g) and DMAP (11 g), allow the reaction mixture to warm to 23 C and stir for 18 h. Wash the mixture with H2O (250 mL), 20% HCl (250 mL), 20% NH4OH (250 mL), dry (MgSO4) and concentrate to give 2-(t-butyldimethylsilyloxy)-ethylbromide (197 g).Step 3 : Treat the product of Step 1 (57 g) in DMF (500 mL) at -10 C with NaH (8.6 g, 60% disp. in oil) and stir for 1 h. Add 2-(t-butyldimethylsilyloxy)ethylbromide (51.3 g) and Nal (6.4 g) and stir for 18 h. Add EtOAc (400 mL) and saturated NaCl solution (300 mL). Separate the organic portion, dry (MgSO4), filter and concentrate. Purify the crude oil by silica gel chromatography eluting with EtOAc/hexane mixtures to give product (60.1 g).Step 4 : Treat the product from Step 3 (28 g) with O-allylhydroxylamine HCl (17 g) according to a procedure similar to Example 1, to give the title compound (24.5 g).
General procedure: A suspension of NaH in mineral oil (40 mmol) was added to a stirred solution of Nalpha-Boc-Nalpha-alkylamino acid (10 mmol) in anhydrous THF (30 mL), and the mixture was stirred at 20 C for 10 min. Then alkyl iodide (100 mmol) was added, and the mixture was stirred at 60 C for 10 h, and maintained at rt overnight. The solvent was removed under vacuum, the residue partitioned in a mixture of ethyl acetate (100 mL) and water (25 mL), and acidified with citric acid to pH 3. The organic phase was separated, washed with saturated aqueous NaCl, containing 1% of Na2S2O3, and dried over anhydrous MgSO4. After evaporation of ethyl acetate, the residue was loaded on Al2O3 (30 g), and eluted consecutively with heptane (to remove mineral oil), eluent A (for Boc-Xaa-OAlk), and finally, with eluent L (for Boc-Xaa-OH). The fractions were evaporated under vacuum. The traces of acetic acid from eluent L were removed by the azeotrope distillation with toluene under reduced pressure. The products were dried in a desiccator under the residual pressure of 0.13-0.26 kPa.
With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 0 - 20℃; for 1h;
General procedure: A solution of HCl (3.3 M) in dioxane (5 mL) was added to a stirred solution of Nalpha-Boc-protected peptide (1 mmol) in DCM (2 mL) at 0 C. The temperature was risen to 20 C and the solution maintained for 1 h. The solvents were removed under vacuum and the residue stirred in dry ether to produce a crystalline product. In case of the poorly crystallizing or highly hygroscopic compounds the residual material was dissolved in dry chloroform, the solution evaporated and the product dried in a vacuum desiccator over P4O10 or KOH. Some products were purified by chromatography using silica gel and eluent mixture B, or by gel filtration on biogel P2 or fractogel TCK HW 40 with subsequent lyophilization.
With hydrogenchloride; In 1,4-dioxane; methanol; at 20 - 25℃;
To a solution of Compound 6a.1 (500 mg, 2.644 mmol) in methanol (10 mL) was added hydrochloric acid/1,4-dioxane (2.6 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated and used directly in the next reaction.
With n-butyllithium; In tetrahydrofuran; hexane; at -10 - 20℃; for 0.166667h;
A solution of B-16 (10.0 g, 51.5 mmol) in THF (15 mL) was cooled to -10 C., and then n-BuLi (1.8 M in hexanes, 30 mL) was added dropwise. The mixture was transferred dropwise to a solution of <strong>[42492-57-9]N-Boc-N-methyl glycine methyl ester</strong> (5.75 g, 28.3 mmol) in THF (20 mL) while maintaining the temperature below 20 C. The reaction was stirred for 10 min. and then a sat. NH4Cl solution was added. The organic layer was separated, dried over Na2SO4 and concentrated. Silica gel chromatography (PE:EA 10:1) afforded B-17 (5 g, 66%) as a yellow oil.
amino-acetic acid methyl ester hydrochloride salt[ No CAS ]
[ 74-88-4 ]
[ 42492-57-9 ]
Yield
Reaction Conditions
Operation in experiment
27%
Glycine methyl ester hydrochloride (50.0 g, 0.398 mol, 1 eq.) was added to a 1 L flask containing water (300 mL) and THF (200 mL). Sodium bicarbonate (37.8 g, 0.438 mol) was added portionwise, followed by di-tert-butyl dicarbonate (83.4 g, 0.382 mol). The reaction was stirred for 18 h, and then the separated organic phase was concentrated. The mixture was redissolved in EtOAC, washed with brine, dried over Na2SO4, and evaporated to give an oily product (72 g, 95%). The oily product was dissolved in DMF (500 mL) and cooled to 0 C. To the mixture was added NaH (60%, 18.3 g, 0.457 mol) portionwise. The mixture was then stirred for 30 min and MeI (81.1 g, 0.571 mol) was added at such a rate as to maintain a reaction temperature below 20 C. The mixture was stirred at RT for 48 h. The mixture was poured into ice water (1.5 L), extracted with MTBE (300 mL×2). The combined organics were washed with brine, dried over Na2SO4, and evaporated. Silica gel chromatography (PE:EtOAc 7:1) gave N-Boc-N-methyl glycine methyl ester (21 g, 27%).
General procedure: A solution of 2 (30.49 g, 0.15 mol) in 250 mL THF/DME (1:1) was added to NaHMDS (75 mL, 0.15 mol, 2.0 M in THF) dropwise at -78 C. The reaction mixture was stirred for 1 h before prenyl bromide (44.71 g, 0.30 mol) was added dropwise. Stirring was continued overnight, while the reaction was allowed to warm to r.t. Work-up started by quenching with some drops of sat. aq NH4Cl. All solvents were removed in vacuum and the residue was partitioned between EtOAc (300 mL) and dist. H2O (50 mL). The aqueous layer was removed and the organic layer was washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuum. The residue was purified by column chromatography (10 -> 50 % EtOAc in petroleum ether) to afford 3a as a clear oil; yield: 19.32 g (58 %)
General procedure: A 1.9 M of sodium bis(trimethylsilyl) amide in tetrahydrofuran(68 mL, 88.6 mmol) was added to a solution of acetonitrile(4.6 mL, 88.6 mmol) in tetrahydrofuran (75 mL) at-78C. After stirring at -50C for 20 min, methyl N-(tertbutoxycarbonyl)-N-methyl-L-alaninate (6.0 g, 29.5 mmol) intetrahydrofuran (45 mL) at -78C was added to the mixture.After stirring at -50C for 1 h, acetic acid (5.2 mL, 91.5 mmol)at -78C was added to the mixture. The mixture was pouredinto sat. ammonium chloride aq. and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and concentrated under reducedpressure to obtain tert-butyl (S)-(4-cyano-3-oxobutan-2-yl)-methylcarbamate (7.2 g, crude) as a brown oil, which was usedfor the next reaction without further purification
In methanol; diethyl ether; toluene; at 0 - 20℃; for 1h;
General procedure: To a solution of N-(tert-butoxycarbonyl)-Nmethyl-L-alanine (6.0 g, 29.3 mmol) in toluene (18 mL)-methanol(12 mL) was added 2.0 M of trimethylsilyl diazomethanein diethyl ether (22.0 mL, 43.9 mmol) at 0C, and the mixturewas stirred for 1 h at room temperature. Acetic acid was addedto the reaction solution until the solution became clear. Thereaction mixture was basified with sat. sodium bicarbonate aq.and extracted with chloroform. The organic layer was driedover anhydrous magnesium sulfate and concentrated underreduced pressure to obtain methyl N-(tert-butoxycarbonyl)-Nmethyl-L-alaninate (6.5 g, quant.) as a colorless oil, which wasused for the next reaction without further purification
methyl N-(tert-butyloxycarbonyl)-2-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)sarcosinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate With n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical With ferrocenium hexafluorophosphate In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;