* 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] Nucleosides, Nucleotides and Nucleic Acids, 2005, vol. 24, # 5-7, p. 805 - 808
[2] Tetrahedron, 2006, vol. 62, # 24, p. 5763 - 5774
4
[ 773837-37-9 ]
[ 132945-75-6 ]
[ 132945-76-7 ]
Yield
Reaction Conditions
Operation in experiment
67%
at 100℃; for 18 h; Inert atmosphere
b) 1,1-Dimethylethyl (3R)-3-cyano-l-pyrrolidinecarboxylateA mixture of 1,1-dimethylethyl (35)-3-[(methylsulfonyl)oxy]-l-pyrrolidinecarboxylate (211 mmol) and sodium cyanide (633 mmol) in N,N-dimethylformamide (300 mL) was vigorously stirred with a mechanical stirrer while heating at 100 °C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 mL). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo.Purification of the residue by flash chromatography (0-50percent ethyl acetate/hexanes) gave the title product (141 mmol, 67 percent yield). 1H NMR (400 MHz, CDC13) δ ppm 1.48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=11.05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
67%
at 100℃; for 18 h; Inert atmosphere
A mixture of 1 , 1 -dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-l- pyrrolidinecarboxylate (211 mmol) and sodium cyanide (633 mmol) in N,N- dimethylformamide (300 mL) was vigorously stirred with a mechanical stirrer while heating at 100 °C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 mL). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (0-50percent ethyl acetate/hexanes) gave the title product (141 mmol, 67 percent yield). .H NMR (400 MHz, CDC13) δ ppm 1.48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=l 1.05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
67%
at 100℃; for 18 h; Inert atmosphere
A mixture of 1 , 1 -dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate (21 1 mmol) and sodium cyanide (633 mmol) in A/JV-dimethylformamide (300 ml.) was vigorously stirred with a mechanical stirrer while heating at 100 °C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 ml_). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (0-50percent ethyl acetate/hexanes) gave the title product (141 mmol, 67 percent yield). 1H NMR (400 MHz, CDCI3) δ ppm 1 .48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=1 1 .05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
36%
at 100℃; Inert atmosphere
b) 1,1 -dimethylethyl (3i?)-3 -cyano- 1 -pyrrolidmecarboxylateTo a solution of 1,1 -dimethylethyl (35)-3-[(methylsulfonyl)oxy]-l- pyrrolidmecarboxylate (24 g, 90 mmol) in DMF (150 mL) was added NaCN (13.30 g, 271 mmol). The reaction mixture was stirred at 100 °C under nitrogen overnight, at which point analysis by TLC and NMR indicated the reaction was complete. The mixture was diluted with Et20 (600 mL), stirred briefly, and filtered. The Et20 filtrate was washed with 1 : 1 watenbrine (7x), and the organic layer was dried over Na2S04, filtered, andconcentrated in vacuo. Purification of the residue by flash chromatography (5-50percentEtOAc/hexanes) provided the title compound (6.4 g, 36percent). MS(ES)+ m/e 266.0 [M+H]+.
Powdered sodium cyanide (550 mg, 1.3 mmol) was added to a solution of TERT- butyl (3S)-3-[(METHYLSULFONYL) oxy] pyrrolidine-1-carboxylate (2.0 g, 7.54 mmol) in DMSO (10 ml) and the reaction mixture heated at 80°C for 4 hours. The resulting yellow mixture was cooled and brine (4 ml) and water (4.5 ml) were added. The mixture was extracted with diethyl ether (x3), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by flash chromatography on SI02 eluting with diethylether/isohexane (50/50) to give TERT-BUTYL (3R)-3-cyanopyrrolidine-1- CARBOXYLATE AS A COLOURLESS OIL (579MG, 39percent) ; 1H NMR SPECTRUM: (DMSOD6) 1.39 (S, 9H); 2.08 (m, 1H); 2. 18 (m, 1H); 3. 34 (m, 4H); 3.53 (m, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 21, p. 2417 - 2419
8
[ 132945-75-6 ]
[ 147081-49-0 ]
Yield
Reaction Conditions
Operation in experiment
64%
With ammonia In water at 80 - 90℃; for 10 - 19 h;
Step 5-1: Production of (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; To 5.56 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 36.4 g of a 28percent by weight aqueous ammonia solution, and the mixture was stirred at 90°C for 19 hrs (internal pressure: about 4 barr). After cooling, ammonia was removed by distillation, and thereto were added 10 ml of water and 3.21 g of a 30percent by weight aqueous sodium hydroxide solution. After the aqueous solution was concentrated under reduced pressure, 10 ml of a saturated brine was added thereto, and the target substance was extracted with 20 ml of ethyl acetate three times. Thus obtained organic layer was washed with 3 ml of a saturated brine, followed by concentration under reduced pressure to give the title compound as 3.20 g of a yellow liquid (chemical purity: 63.5 areapercent,, optical purity: 100percent e.e., yield: 64percent). It was ascertained that 41.4percent of the optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) was contaminated with respect to the HPLC area value of the title compound, while 7.8percent of 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was contaminated with respect to the HPLC area value of the title compound.; Step 6-1: Production of (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; To 11.2 g of a solution in toluene including 7.83 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 62.7 g of a 40percent by weight aqueous ammonia solution, and the mixture was stirred at 80°C for 10 hrs (internal pressure: about 8 barr). After cooling, the reaction mixture was concentrated under reduced pressure, to which 31.3 g of a saturated brine, 19.6 g of toluene, and 4.13 g of a 30percent by weight aqueous sodium hydroxide solution were added. Thus obtained organic layer was concentrated under reduced pressure to give the title compound as 5.09 g of a yellow liquid (chemical purity: 74.5 areapercent, yield: 74percent, optical purity: 99.4percent ee). It was ascertained that 18.1percent of the optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) was contaminated with respect to the HPLC area value of the title compound, while 4.1percent of 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was contaminated with respect to the HPLC area value of the title compound.
To a suspension of KOH powder (4.86 g) in DMSO (250 mL) under vig- orous stirring, benzophenone oxime (7.86 g) was added. After stirring <n="96"/>at room temperature for 30 min, a solution of N-tert-butoxycarbonyl- (S)-3-pyrrolidinyl methansulfonate (10 g) in DMSO (70 mL) was added. After 18 h at room temperature the reaction was poured into iced water (900 mL) and extracted with Et2theta. The combined organic layers were washed with water, brine, dried and the solvent evaporated. Ben- zophenone O-[(R)-3-pyrrolidinyl]oxime was obtained (13.0 g, 96%) as a white solid and used without purification in the next step. 1H-NMR (300 MHz, DMSO-de, ppm from TMS): delta 7.50-7.20 (1OH, m), 4.84 (IH, m), 3.50-3.00 (4H, m), 2.01 (2H, m), 1.38 (9H, s).
96%
To a suspension of KOH powder (4.86 g) in DMSO (250 mL) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at room temperature for 30 min, a solution of N-tert-butoxycarbonyl-(S)-3- <n="80"/>pyrrolidinyl methansulfonate (10 g) in DMSO (70 niL) was added. After 18 h at room temperature the reaction was poured into iced water (900 niL) and extracted with Et2theta. The combined organic layers were washed with water, brine, dried and the solvent evaporated. Benzophenone O-[(R)-3- pyrrolidinyl] oxime was obtained (13.0 g, 96%) as a white solid and used without purification in the next step. 1H-NMR (300 MHz, DMSO"d6, ppm from TMS): delta 7.50-7.20 (lOH, m), 4.84 (IH, m), 3.50-3.00 (4H, m), 2.01 (2H, m), 1.38 (9H, s).
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
To a solution of N-tert-butoxycarbonyl-(S)-pyrrolidinol (10.0 g) and triethylamine (8.2 mL) in CH2CI2 (150 niL) at 0 C, methanesulfonyl chloride (4.34 mL) was added. After stirring at room temperature for 3 h, the reaction mixture was poured into ice/water and extracted with CH2CI2. The organic phase was washed with 5% aqueous NaHCO3, water, brine, dried and evaporated to dryness to give an oil which solidified after standing overnight in the refrigerator. The solid was triturated with Et2theta to give N- tert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (13.0 g, 92%) as a light yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): delta 5.23 (IH, m), 3.60-3.10 (4H, m), 3.23 (3H, s), 2.11 (2H, m), 1.39 (9H, s).
Powdered sodium cyanide (550 mg, 1.3 mmol) was added to a solution of TERT- butyl (3S)-3-[(METHYLSULFONYL) oxy] pyrrolidine-1-carboxylate (2.0 g, 7.54 mmol) in DMSO (10 ml) and the reaction mixture heated at 80C for 4 hours. The resulting yellow mixture was cooled and brine (4 ml) and water (4.5 ml) were added. The mixture was extracted with diethyl ether (x3), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residues were purified by flash chromatography on SI02 eluting with diethylether/isohexane (50/50) to give TERT-BUTYL (3R)-3-cyanopyrrolidine-1- CARBOXYLATE AS A COLOURLESS OIL (579MG, 39%) ; 1H NMR SPECTRUM: (DMSOD6) 1.39 (S, 9H); 2.08 (m, 1H); 2. 18 (m, 1H); 3. 34 (m, 4H); 3.53 (m, 1H).
b (S)-3-Methanesulphonyloxypyrrolidine-1-carboxylic acid tert-butyl ester Methanesulphonyl chloride (900 mul, 11.6 mmol) was added dropwise to a stirred solution of the alcohol from above (2.0 g, 10.7 mmol) and triethylamine (3.2 ml, 23 mmol) in dry THF (30 ml) at 0 C. under nitrogen. After 15 minutes at 0 C. the ice bath was removed and the reaction was stirred at room temperature for 11/2 hours. The reaction was quenched with saturated aqueous sodium hydrogen carbonate. The aqueous was extracted with dichloromethane (*3). The combined extracts were dried (Na2 SO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluding with 2% MeOH/CH2 Cl2 to afford the title mesylate (3 g, ~100%) as a thick oil. delta (360 MHz, CDCl3), 1.47 (9H, s, t Bu), 2.08-2.38 (2H, br m), 3.05 (3H, s, CH3), 3.44-3.74 (4H, m, CH2 N), 5.26 (1H, m, CHOMs).
18
[ 103-67-3 ]
[ 132945-75-6 ]
[ 199336-82-8 ]
Yield
Reaction Conditions
Operation in experiment
61%
a (R)-3-(N-Benzyl-N-methylamino)pyrrolidine-1-carboxylic acid tert-butyl ester A mixture of (S)-3-methanesulphonyloxypyrrolidine-1-carboxylic acid tert-butyl ester (Example 14) (2.43 g, 9.2 mmol) and N-benzyl-N-methylamine (3.5 g, 27 mmol) was stirred and heated at 100 C. for 3 hours, under nitrogen. The N-benzyl-N-methylamine was removed in vacuo, and the residue was partitioned between dichloromethane/water. The aqueous was further extracted with dichloromethane (*1). The combined extracts were washed with brine (*2), dried (Na2 SO4) filtered and evaporated. The residue was purified by chromatography on silica gel, eluding with 20% ethyl acetate/hexane to afford the title amine (1.64 g, 61%) as an oil; delta (250 MHz, CDCl3) 1.46 (9H, s, t Bu), 1.80-2.05 (2H, m), 2.10 (3H, s, NCH3), 2.95-3.80 (7H, m), 7.24-7.34 (5H, m, ArH).
PREPARATION 10-5) (S)-1-t-Butoxycarbonyl-3-methanesulfonyloxypyrrolidine was obtained in 88.4% yield in substantially the same manner as that of Preparation 10-2). IR (Neat): 1690 cm-1. NMR (CDCl3, delta): 1.47 (9H, s), 2.01-2.42 (2H, m), 3.04 (3H, s), 3.55-3.75 (5H, m).
20
[ 24424-99-5 ]
[ 40499-83-0 ]
[ 124-63-0 ]
[ 132945-75-6 ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Preparation 78 tert -Butyl (3 S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate Triethylamine (8.7ml, 62.4mmol) was added to a solution of (3R)-3-pyrrolidinol (5.16g, 41.7mmol) in dichloromethane (30ml), and the solution stirred for 10 mins. Di-tert-butyl dicarbonate (9.11g, 41.7mmol) was added and the reaction stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with 1N citric acid, water, and brine, then dried over MgSO4, and evaporated under reduced pressure to give a pale yellow oil, 7.14g. This intermediate alcohol was dissolved in dichloromethane (100ml), triethylamine (6.4ml, 45.9mmol) added and the solution cooled in an ice-bath. Methanesulphonyl chloride (3.25ml, 41.9mmol) was added slowly, and the reaction stirred for 2 hrs. The reaction mixture was washed with 1N citric acid, saturated NaHCO3solution, brine, the dried over Na2SO4and evaporated under reduced pressure to afford the title compound as an oil, (9.36g, 85%). 1H NMR (CDCl3, 300MHz) delta: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1H). LRMS: m/z = 283 (M+18)+
With triethylamine; In dichloromethane;
Preparation 78 tert-Butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate Triethylamine (8.7 ml, 62.4 mmol) was added to a solution of (3R)-3-pyrrolidinol (5.16 g, 41.7 mmol) in dichloromethane (30 ml), and the solution stirred for 10 mins. Di-tert-butyl dicarbonate (9.11 g, 41.7 mmol) was added and the reaction stirred at room temperature for 20 hrs. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with 1N citric acid, water, and brine, then dried over MgSO4, and evaporated under reduced pressure to give a pale yellow oil, 7.14 g. This intermediate alcohol was dissolved in dichloromethane (100 ml), triethylamine (6.4 ml, 45.9 mmol) added and the solution cooled in an ice-bath. Methanesulphonyl chloride (3.25 ml, 41.9 mmol) was added slowly, and the reaction stirred for 2 hrs. The reaction mixture was washed with 1N citric acid, saturated NaHCO3 solution, brine, the dried over Na2SO4 and evaporated under reduced pressure to afford the title compound as an oil, (9.36 g, 85%). 1H NMR (CDCl3, 300 MHz) delta: 1.40 (s, 9H), 2.03-2.28 (m, 2H), 2.99 (s, 3H), 3.36-3.60 (m, 4H), 5.18 (m, 1H). LRMS: m/z=283 (M+18)+.
Preparation 79 tert -Butyl (3R)-3-cyano-1-pyrrolidinecarboxylate Potassium cyanide (5.80g, 89.0mmol) was added to a solution of tert-butyl (3S)-3-[(methylsulphonyl)oxy]-1-pyrrolidinecarboxylate (preparation 78) (9.35g, 35.3mmol) in dimethylsulphoxide (100ml), and the reaction stired at room temperature for 18 hrs, and then at 100C for a further 24 hrs. The cooled mixture was poured into water and extracted well with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as eluant to give the title compound as an oil, (4.28g, 62%). 1H NMR (CDCl3, 300MHz) d: 1.46 (s, 9H), 2.21 (m, 2H), 3.10 (m, 1H), 3.39-3.78 (m, 4H). LRMS: m/z = 214 (M+18)+
[00243] To a cooled (-5 to-10C, ice/salt bath) solution of pyrrolidinol (xiv) (18.2 g, 98 mmol) and triethylamine (28 ml, 196 mmol) in ethylacetate (150 ml) was slowly added methanesulfonyl chloride (9.1 ml, 118 mmol) via a syringe. After completion of addition, the mixture was left stirring at room temperature for one hour. Water (100 ml) was added, and the layers were separated. The organic layer was washed with 1 N aq. HCl solution (100 ml), 5% aq. sodium bicarbonate solution (100 ml), and with saturated aqueous NaCl solution (100 ml). Then, the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure, yielding 24.3 g (92 mmol, 94%) of a yellow oil. This oil was dissolved in 150 <n="59"/>ml dry DMF, and potassium thioacetate (13.5 g, 119 mmol) was added. The resulting mixture was heated to 65 0C overnight under a nitrogen atmosphere, the solution started to solidify after about half an hour. After the mixture was cooled to room temperature, water (250 ml) and TBME (200 ml) were added. The layers were separated, and the aqueous layer was extracted with another portion of TBME (250 ml). The combined organic layers were washed with water (3x250 ml), and with brine (200 ml), dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. Yield: 20.8 g (92%) of a yellow oil, identified as xvi by 1H- NMR.
In N,N-dimethyl-formamide; at 20 - 80℃; for 16h;Inert atmosphere;
Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of argon, were placed a solution of ()-tert-butyl 3- ((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (4.0 g, 11.3 mmol) in DMF (40 ml). This was followed by the addition of potassium ethanethioate (5.17 g, 45.2 mmol) at ambient temperature. The resulting mixture was stirred under argon atmosphere at 80C for 16 hr. The reaction was allowed to cool to 20C and quenched with ice water (150 ml) and extracted with EtOAc (3 x 150 ml).The combined organic layers were washed with brine (2 x 200 ml),dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography, eluting with EtOAc in Pet. ether (35%) to afford the title compound: LCMS (ESI) calc?d forC,,H,9N035[2M + H]:491, found49l.1 ; ?H NMR (300 MHz, CD3C1) : oe 3.99- 3.95 (m, 1H), 3.79-3.73 (m, 1H), 3.45-3.40 (m, 2H), 3.28-3.18 (m, 1H), 2.34 (s, 3H), 2.32-2.27 (m, 1H), 1.90-1.86 (m, 1H), 1.47 (s, 9H).
9 g
In acetone; for 20h;Reflux;
To a solution of the crude methylate in acetone (380 mL) was added potassium thioacetate (7.8 g, 68.3 mmol). The reaction mixture was refluxed for 20 h, cooled to rt, filtered, and the filtrate was concentrated. To the residue was added diethyl ether, washed with water, brine, dried over Na2S04, concentrated in vacuo, and purified by flash chromatography on silica gel (hexane -EtO Ac, 20: 1-2: 1) to afford the product, 9 g.
(i?)-3-Benzylaminqpvrrolidine'l"carboxylic acid ferfrbutvl ester; A solution of (^-S-methanesulfonyloxypyrrolidine-l-carboxylic acid £er£-butyl ester (16.9 g, 57 mmol) and benzylamine (18.3 g, 171 mmol) was stirred for 4hours at 95 C. The remaining benzylamine was evaporated off under reduced pressure and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford (^3-benzylaminopyrrolidine-l-carboxylic acid tertbutyl ester (15.3 g, 97%) as pale yellow oil.
With sodium azide; In N,N-dimethyl-formamide; at 60℃; for 6h;
The above mesolate (2.9 g, 11 mmol), NaN3 (1 g, 16 mmol), in DMF (20 mL) were allowed to stirr for 6 hours at 60oC. Then the reaction mixture was diluted with diluted with ethyl acetate (50 mL) and the organic layer washed with brine (2x20 mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the title azide 32 (1.87 g, 81%) as an oil. 1H-NMR (CDC13,4OO MHz):delta 4.12 (m, IH), 3.4 (m, 4H), 2 (m, 2H), 1.45 (s, 9H)
S-BMSP (2.65 g) was dissolved in N,N-dimethyl formamide (30 g), and phthalimidepotassium (2.22 g) was added thereto. The reaction solution was heated to 85C, and stirred for 5 hours. The obtained reaction solution was used as a sample for measurement of the optical purity. Further, a part of the sample was isolated to confirm its structure. 1H-NMR (CDCl3, 270 MHz) delta 7.89-7.83 (m, 2H), 7.78-7.72 (m, 2H), 4.86 (dddd, 1H, J=8.0 Hz), 3.74-3.62 (m, 3H), 3.46-3.36 (m, 1H), 2.68-2.56 (m, 1H), 2.17-2.05 (m, 1H), 1.47 (s, 9H) HPLC analysis condition 5 Chiral column used DAICEL CHIRALCEL OJ Eluent hexane/2-propanol=90/10 Flow rate 1 ml/min Detection wavelength UV 210 nm Column temperature 25C
In acetonitrile; at 60 - 65℃; for 7h;Product distribution / selectivity;
Sodium methanesulfonate (2.28 g) was suspended in acetonitrile (15 g) under a nitrogen atmosphere, and DFI (2. 62 g) was added dropwise thereto at a temperature in a range of 20 to 30C. The reaction solution was stirred at 20 to 30C for 3 hours to obtain a solution of FMSI in acetonitrile. Subsequently, (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (2.41 g) was added to the solution, and the mixture was stirred at 60 to 65 C for 7 hours. The reaction solution was added dropwise to a solution obtained separately by suspending sodium hydrogen carbonate (4.05 g) in water (40 g). The mixture was then extracted with toluene (50 g), washed with water (40 g), and subsequently, the obtained toluene layer was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was separated by filtration, and the toluene solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 60 g, hexane:ethyl acetate=3:1?2:1) to obtain a target compound (S-BMSP) as a colorless clear syrup. The results of 1H-NMR, and derivatization and analysis of optically active HPLC columns in accordance with Reference Example 12 were the same as in S-BMSP obtained in Reference Example 9. Amount 2.74 g Yield 80% 1H-NMR (CD3CN, 400 MHz) delta 5.28-5.24 (m, 1H), 3.68-3.46 (m, 4H), 3.05 (s, 3H), 2.28-2.12 (m, 2H), 1.47 (s, 9H) The stereoselectivity in the reaction was determined by derivation of (R)-3-phthalimide-N-tert-butoxycarbonylpyrrolidine (hereinafter abbreviated as R-BPP) as in Reference Example 12, and using the peak area ratio of R-BPP and (S)-3-phthalimide-N-tert-butoxycarbonylpyrrolidine (hereinafter abbreviated as S-BPP) under an HPLC analysis condition-5. S-BMSP:R-BMSP=99.5:0.5
In acetonitrile; at 75 - 80℃; for 8h;Product distribution / selectivity;
Sodium methanesulfonate (1.41 g) was suspended in acetonitrile (15 g) under a nitrogen atmosphere, and BDDF (1.65 g) was added dropwise thereto at a temperature in a range of 20 to 30C. The reaction solution was stirred at 20 to 30C for 3 hours to obtain a solution of BDDFMS in acetonitrile. Subsequently, (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (1.49 g) was added to the solution, and the mixture was stirred at 75 to 80C for 8 hours. The reaction solution was added dropwise to a solution obtained separately by suspending sodium hydrogen carbonate (2.50 g) in water (25 g). The mixture was then extracted with toluene (30 g), washed with water (20 g), and subsequently, the obtained toluene layer was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was separated by filtration, and the toluene solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 50 g, hexane:ethyl acetate=3:1?2:1) to obtain a target compound (S-BMSP) as a colorless clear syrup. 1H-NMR was consistent with that of the S-BMSP obtained in Example 19. Amount 1.37 g Yield 65% The stereoselectivity in the reaction was determined by derivation as in Reference Example 12, and using the peak area ratio of R-BPP and S-BPP under an HPLC analysis condition-5. S-BMSP:R-BMSP=99.5:0.5
In acetonitrile; at 20 - 30℃; for 8h;Product distribution / selectivity;
Sodium methanesulfonate (1.18 g) was suspended in acetonitrile (12 g) under a nitrogen atmosphere, and PPDA (2.22 g) was added dropwise thereto at a temperature in a range of 0 to 5C. The reaction solution was stirred at 20 to 30C for 3 hours to obtain a solution of PPDAMS in acetonitrile. Subsequently, (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (1.25 g) was added to the solution, and the mixture was stirred at 20 to 30C for 8 hours. The reaction solution was added dropwise to a solution obtained separately by suspending sodium hydrogen carbonate (2.10 g) in water (25 g). The mixture was then extracted with toluene (30 g), washed with water (20 g), and subsequently, the obtained toluene layer was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was separated by filtration, and the toluene solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 50 g, hexane:ethyl acetate=3:1?2:1) to obtain a target compound (S-BMSP) as a colorless clear syrup. 1H-NMR was consistent with that of the S-BMSP obtained in Example 19. Amount 1.36 g Yield 77% The stereoselectivity in the reaction was determined by derivation as in Reference Example 12, and using the peak area ratio of R-BPP and S-BPP under an HPLC analysis condition-5. S-BMSP:R-BMSP=99.5:0.5
Step 9-1: Production of (R)-1-(tert-butoxycarbonyl)-3-dimethylaminopyrrolidine hydrochloric acid salt; To 7.58 g of a solution in toluene including 5.31 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 90.2 g of a 50% by weight aqueous dimethylamine solution, and the mixture was stirred at 80C for 18 hrs (internal pressure: about 2 barr). After cooling, the reaction mixture was concentrated under reduced pressure, to which 21.2 g of a saturated brine, 13.3 g of toluene, and 2.80 g of a 30% by weight aqueous sodium hydroxide solution were added. Thus obtained organic layer was concentrated under reduced pressure to give the title compound as 5.43 g of a yellow liquid. Thereto were added 40 mL of isopropanol, and 1.86 g of conc. hydrochloric acid (0.89 equivalent), and then the mixture was concentrated under reduced pressure. When 53.9 g of ethyl acetate was added to the residue, a crystal was precipitated. After the mixture was stirred at 22C for 1 hour, and further stirred at 4C for 1 hour, the crystal was filtrated under reduced pressure. The crystal was washed with 15 mL of cooled ethyl acetate, and thereafter vacuum drying was carried out to give the title compound as 3.83 g of a white solid (chemical purity: 99.9 area%, yield: 75%). The optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) was ascertained to be undetected on HPLC (4.6% before the crystallization). Moreover, the 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was ascertained to be undetected on HPLC (3.9% before the crystallization). 1H-NMR (CDCl3): d (ppm) 1.46 (s, 9H), 1.89 (m, 1H), 2.35 (m, 1H), 2.84 (s, 6H), 3.38 (m, 1H), 3.51-3.91 (m, 4H)
5%-palladium/activated carbon; In methanol; at 24℃; for 3h;Product distribution / selectivity;
Production Example 1: Production of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine; (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Reference Example 1, in an amount of 1.39 g, was dissolved in 10 ml of methanol, and thereto were added 1.13 g of di t-butyl dicarbonate and 127 mg of 5% by weight palladium-carbon. Then the mixture was stirred in a hydrogen atmosphere under an ordinary pressure at 24C for 3 hrs. After palladium was filtrated under reduced pressure, washing obtained using 30 ml of methanol was included. Thus obtained filtrate was concentrated under reduced pressure to give 1.37 g of the title compound as a pale yellow oily material (chemical purity: 90.9 area%, yield: 96%). The title compound could be obtained at an extremely high yield as compared with the case of Comparative Production Example 1.
89%
palladium 10% on activated carbon; In methanol; at 22℃; for 7h;Product distribution / selectivity;
Production Example 2: Production of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine; To 627 g of a solution in toluene of 180 g of (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Reference Example 1 were added 159 g of di t-butyl dicarbonate and 27 g of 10% palladium carbon. Then the mixture was stirred in a hydrogen atmosphere under an ordinary pressure at 22C for 7 hrs. After palladium was filtrated under reduced pressure, washing obtained using 270 g of toluene was included. Thus obtained filtrate was concentrated under reduced pressure to give 238 g of a solution in toluene of 167 g of the title compound (yield: 89%, chemical purity: 93.0 area%, optical purity: 100% e.e.).
86%
Comparative Production Example 1: Production of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine; (S)-1-benzyl-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Reference Example 1, in an amount of 1.39 g, was dissolved in 10 ml of methanol, and thereto were added 678 mg of conc. hydrochloric acid, and 128 mg of 5% by weight palladium-carbon. Then the mixture was stirred in a hydrogen atmosphere under an ordinary pressure at 40C, for 18 hrs. After palladium was filtrated under reduced pressure, washing obtained using 10 ml of methanol was included. Thus obtained filtrate was concentrated under reduced pressure to obtain a concentrate. Thereto were added 10 ml of water and 10 ml of ethyl acetate, and then added 660 mg of triethylamine, and 1.13 g of di tert-butyl dicarbonate under cooling on ice, followed by stirring for 30 min. After conducting liquid separation, the organic layer was washed with 10 ml of water, and the resulting organic layer was concentrated under reduced pressure to give 1.23 g of the title compound as a colorless and transparent oily material (chemical purity: 97.6 area%, yield: 86%). 1H-NMR (CDCl3): d (ppm) 1.47 (s, 9H), 2.15 (m, 1H), 2.27 (m, 1H), 3.05 (s, 3H), 3.42-3.78 (m, 4H), 5.26 (m, 1H)
Step 7-1: Production of (S)-1-(tert-butoxycarbonyl)-3-methylaminopyrrolidine hydrochloric acid salt; To 7.58 g of a solution in toluene including 5.31 g of (R)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 77.7 g of a 40% by weight aqueous methylamine solution, and the mixture was stirred at 80C for 18 hrs (internal pressure: about 2 barr). After cooling, the reaction mixture was concentrated under reduced pressure, to which 21.2 g of a saturated brine, 13.3 g of toluene, and 2.81 g of a 30% by weight aqueous sodium hydroxide solution were added. Thus obtained organic layer was concentrated under reduced pressure to give the title compound as 4.61 g of a yellow liquid. Thereto were added 40 mL of isopropanol, and 1.72 g of conc. hydrochloric acid (0.83 equivalent), and then the mixture was concentrated under reduced pressure. When 53.9 g of ethyl acetate was added to the residue, a crystal was precipitated. After the mixture was stirred at 22C for 1 hour, and further stirred at 4C for 1 hour, the crystal was filtrated under reduced pressure. The crystal was washed with 15 mL of cooled ethyl acetate, and thereafter vacuum drying was carried out to give the title compound as 3.45 g of a white solid (chemical purity: 100.0 area%, yield: 73%, optical purity: 99.5% ee). The optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) decreased to 0.03% with respect to the HPLC area value of the title compound (6.4% before the crystallization). It was ascertained that the 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was not detected on HPLC (1.6% before the crystallization). 1H-NMR (CDCl3): d (ppm) 1.47 (s, 9H), 2.36 (m, 2H), 2.72 (s, 3H), 3.39 (m, 1H), 3.60-3.70 (m, 3H), 3.81 (m, 1H), 9.91 (m, 1H)
Example 2 Production of (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine acetic acid salt In an autoclave were charged 11.2 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine (29.5 mmol), and 62.7 g of 40% by weight aqueous ammonia (50 equivalent), which was heated to 80C whereby an internal pressure of 8 barr was observed. After allowing the reaction for 10 hrs, the reaction mixture was cooled to room temperature, followed by concentration under reduced pressure. To the residue were added 4.13 g of a 30% by weight aqueous sodium hydroxide solution, 31.3 g of a saturated brine, and 19.6 g of toluene to execute extraction. By concentrating under reduced pressure, 5.09 g of a yellow oily material was obtained. When 53.8 g of toluene, and 1.43 g of acetic acid (0.8 equivalent) were added sequentially thereto, a crystal was precipitated. After stirring at 20C for 13 hrs, the crystal was filtrated under reduced pressure, which was washed with 16.2 mL of toluene, and thereafter vacuum drying was carried out to give a white crystal of 4.81 g (yield: 67%, purity: 100% by weight, optical purity: 99.9% e.e.) 1H-NMR (CDCl3, 400 MHz): d (ppm) 1.45 (s, 9H), 1.88 (m, 1H), 1.97 (s, 3H), 2.13 (m, 1H), 3.16-3.32 (m, 1H), 3.40 (m, 1H), 3.46-3.62 (m, 2H), 3.66 (m, 1H), 6.63 (m, 2H)
Step 8-1: Production of (R)-1-(tert-butoxycarbonyl)-3-ethylaminopyrrolidine hydrochloric acid salt; To 7.58 g of a solution in toluene including 5.31 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 64.4 g of a 70% by weight aqueous ethylamine solution, and the mixture was stirred at 80C for 18 hrs (internal pressure: about 2 barr). After cooling, the reaction mixture was concentrated under reduced pressure, to which 21.2 g of a saturated brine, 13.3 g of toluene, and 2.80 g of a 30% by weight aqueous sodium hydroxide solution were added. Thus obtained organic layer was concentrated under reduced pressure to give the title compound as 5.61 g of a yellow liquid. Thereto were added 40 mL of isopropanol, and 1.89 g of conc. hydrochloric acid (0.91 equivalent), and then the mixture was concentrated under reduced pressure. When 53.9 g of ethyl acetate was added to the residue, a crystal was precipitated. After the mixture was stirred at 22C for 1 hour, and further stirred at 4C for 1 hour, the crystal was filtrated under reduced pressure. The crystal was washed with 15 mL of cooled ethyl acetate, and thereafter vacuum drying was carried out to give the title compound as 3.91 g of a white solid (chemical purity: 99.7 area%, yield: 78%). The optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) decreased to 0.03% with respect to the HPLC area value of the title compound (6.1% before the crystallization). The 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was decreased to 0.02% with respect to the HPLC area value of the title compound (20.1% before the crystallization). 1H-NMR (CDCl3): d (ppm) 1.45 (s, 9H), 1.53 (t, 3H), 2.27-2.49 (m, 2H), 3.07 (m, 2H), 3.35 (m, 1H), 3.66 (m, 3H), 3.86 (m, 1H), 9.97 (m, 1H)
With ammonia; In water; at 80 - 90℃; under 3000.3 - 6000.6 Torr; for 10 - 19h;Product distribution / selectivity;
Step 5-1: Production of (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; To 5.56 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 36.4 g of a 28% by weight aqueous ammonia solution, and the mixture was stirred at 90C for 19 hrs (internal pressure: about 4 barr). After cooling, ammonia was removed by distillation, and thereto were added 10 ml of water and 3.21 g of a 30% by weight aqueous sodium hydroxide solution. After the aqueous solution was concentrated under reduced pressure, 10 ml of a saturated brine was added thereto, and the target substance was extracted with 20 ml of ethyl acetate three times. Thus obtained organic layer was washed with 3 ml of a saturated brine, followed by concentration under reduced pressure to give the title compound as 3.20 g of a yellow liquid (chemical purity: 63.5 area%,, optical purity: 100% e.e., yield: 64%). It was ascertained that 41.4% of the optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) was contaminated with respect to the HPLC area value of the title compound, while 7.8% of 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was contaminated with respect to the HPLC area value of the title compound.; Step 6-1: Production of (R)-1-(tert-butoxycarbonyl)-3-aminopyrrolidine; To 11.2 g of a solution in toluene including 7.83 g of (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine produced by the method described in Production Example 2 was added 62.7 g of a 40% by weight aqueous ammonia solution, and the mixture was stirred at 80C for 10 hrs (internal pressure: about 8 barr). After cooling, the reaction mixture was concentrated under reduced pressure, to which 31.3 g of a saturated brine, 19.6 g of toluene, and 4.13 g of a 30% by weight aqueous sodium hydroxide solution were added. Thus obtained organic layer was concentrated under reduced pressure to give the title compound as 5.09 g of a yellow liquid (chemical purity: 74.5 area%, yield: 74%, optical purity: 99.4% ee). It was ascertained that 18.1% of the optically active 1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine represented by the above formula (3) was contaminated with respect to the HPLC area value of the title compound, while 4.1% of 1-(tert-butoxycarbonyl)-3,4-dehydropyrrolidine represented by the above formula (4) was contaminated with respect to the HPLC area value of the title compound.
benzophenone O-[(R)-3-pyrrolidinyl]oxime[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
To a suspension of KOH powder (4.86 g) in DMSO (250 ml) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at RT for 30 min, a solution of N-tert-butoxy-carbonyl-3-(S)-pyrrolidinyl methanesulfonate (10.0 g) in DMSO (70 ml) was added. After 18 h at RT the reaction was poured into iced water (900 ml) and extracted with Et2theta. The combined organic layers were washed with water, brine, dried and the solvent was evaporated. Benzophenone O-[(R)-3-pyrrolidinyl]oxime was obtained (13.0 g, 96%) as a white solid and used without any further purification in the next step. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): delta 7.50-7.20 (1OH, m), 4.84 (IH, m), 3.50-3.00 (4H, m), 2.01 (2H, m), 1.38 (9H, s).
With caesium carbonate; In acetonitrile; at 120℃; for 1h;
Intermediate 117 :(S)-tert-butyl 3-(3-carbamoyl-4-chlorophenoxy)pyrrolidine-l- carboxylate; To a stirred solution of 2-chloro-5-hydroxybenzamide (343 mg, 2.00 mmol) and (S)-tert-butyl 3 -(methylsulfonyloxy pyrrolidine- 1 -carboxylate (557 mg, 2.10 mmol) in acetonitrile (10.0 mL) in a 20 mL microwave vial was added cesium carbonate (1.95 g, 6.00 mmol). The mixture was heated at 120 0C in microwave for 1 hour, cooled to ambient temperature and pressure, evaporated in vacuo to a residue which was taken up in ethyl acetate (25 mL), the ethyl acetate layer was washed with brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica with ethyl acetate as eluant to give (S)-tert-butyl 3 -(3 -carbamoyl-4-chlorophenoxy pyrrolidine- 1 -carboxylate (510 mg, 74.9 %). 1H NMR (CDCl3): 1.4 (s, 9H), 2.0 - 2.1 (m, 2H), 3.4 - 3.6 (m, 4H), 4.8 (br s, IH), 5.9 (s, IH), 6.4 (s, IH), 6.8 (d, IH) and 7.2 - 7.3 (m, 2H).
To a suspension of KOH powder (4.86 g) in DMSO (250 mL) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at room temperature for 30 min, a solution of N-tert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (10 g) (Compound A) in DMSO (70 mL) was added. After 18 h at room temperature the reaction was poured into iced water (900 mL) and extracted with Et20. The combined organic layers were washed with water, brine, dried and the solvent evaporated. Benzophenone 0-[(R)-3-pyrrolidinyl] oxime (Compound B) was obtained (13.0 g, 96%) as a white solid and used without purification in the next step. 1 H-NMR (300 MHz, DMSO-d6, ppm from TMS): delta 7.50-7.20 (10H, m), 4.84 (1H, m), 3.50-3.00 (4H, m), 2.01 (2H, m), 1.38 (9H, s).
To a suspension of KOH powder (4.86 g) in DMSO (250 mL) under vigorous stirring, benzophenone oxime (7.86 g) was added. After stirring at room temperature for 30 min, a solution of N-tert-butoxycarbonyl-(S)-3-pyrrolidinyl methansulfonate (10 g) (Compound B) in DMSO (70 mL) was added. After 18 h at room temperature, the reaction was poured into iced water (900 mL) and extracted with Et20. The combined organic layers were washed with water and brine, dried and the solvent evaporated. Benzophenone 0-[(R)-3-pyrrolidinyl]oxime (Compound C) was obtained (13.0 g, 96%) as a white solid, which was used in the next step without further purification. 1 H- MR (300 MHz, DMSO-de, ppm from TMS): delta 7.50-7.20 (10H, m), 4.84 (IH, m), 3.50-3.00 (4H, m), 2.01 (2H, m), 1.38 (9H, s).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;Inert atmosphere;
Step 2; [0206] (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-lH-pyrazolo[3,4-rf]pyrimidin-l- yl)pyrrolidine-l-carboxylate. A solution of 3 -(4-nitrophenyl)-lH-pyrazolo [3,4- d]pyrimidin-4-amine (0.5 g, 1.95 mmol), K2CO3 (1.08 g, 7.8 mmol), and (S)--(tert- butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (0.62 g, 2.34 mmol) in DMF (20 mL) was brought to 80 0C under an argon atmosphere. The reaction mixture was left stirring for 2 hours, then cooled and filtered. The filtrate was concentrated in vacuo, but not to dryness. 20 mL of 0.1 sodium citrate was added causing a solid to form, which was collected by filtration to afford (R)-tert-bvLambday 3-(4-amino-3-(4-nitrophenyl)-lH-pyrazolo[3,4-
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;
Example 90: (R)-3-(2-Benzyloxy-4-chloro-phenoxy)-pyrrolidine.; Step A: Preparation of 3-(4-chloro-2-formyl-phenoxy)-pyrrolidine-1 - carboxylic acid tert-butyl ester.; To (SJ-S-hydroxy-pyrrolidine-i-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH2CI2 (50 ml_) at 0 0C was added Et3N (1.4 g, 1.9 ml_, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 ml_, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH2CI2 (2X). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1 - carboxylic acid tert-butyl ester that was used without further purification.To this compound in DMF (50 ml_) was added 5-chloro-2-hydroxy- benzaldehyde (1.9 g, 12.1 mmol) and K2CO3 (1.8 g, 13.1 mmol). The reaction was heated at 90 0C for 2h, then cooled to rt and H2O was added. The mixture was extracted with EtOAc (2X). The combined organics were washed with brine and dried. Silica gel chromatography (10-50% EtOAc in hexanes) gave 1.85 g (52%) of the title compound. 1H NMR (CDCI3): 10.36 (s, 1 H), 7.81 (s, 1 H), 7.50 (s, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 5.00 (s, 1 H), 3.72-3.50 (m, 4H), 2.26-2.18 (m, 2H), 1.47 (s, 9H).
With potassium tert-butylate; In tetrahydrofuran; toluene;Reflux;
Example 3: Production of (S)-1-(tert-butoxycarbonyl)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine The toluene solution (2.23 g) containing (S)-1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)pyrrolidine (1.56 g) was concentrated under reduced pressure. To the concentrate, tetrahydrofuran (1.51 g) and potassium tert-butoxide (0.79g) were added. To the mixture, the solution consisting of diphenylacetonitrile (1.37 g) and tetrahydrofuran (1.63 g) was added dropwise over 1 hour under reflux condition. The mixture was stirred for 21 hours. After the mixture was cooled to room temperature, distilledwater (2.8 ml) and toluene (5 ml) were added thereto in order to extract the target compound into the organic layer. The obtained organic layer was washed with distilled water (2.5 ml) twice. The organic layer was concentrated under reduced pressure and dried in vacuo to obtain 2.47 g of the target compound as an orange oil (content amount: 77.7wt%, yield: 90%). The obtained target compound was purified with column chromatography (packing material: silica gel, eluent: ethyl acetate / hexane = 1 / 2), and the obtained fraction was concentrated under reduced pressure and dried in vacuo to obtain 1.57 g of the target compound as a white solid (content amount: 97.4wt%, optical purity: 100%ee, yield: 72%). 1H-NMR (CDCl3): delta (ppm) 1.44(s, 9H), 1.78-2.14(m, 2H), 3.25-3.40(m, 3H), 3.42-3.68(m, 2H), 7.24-7.42(m, 6H), 7.42-7.60(m, 4H)
A solution of E1 (0.75 mmol) and an amine (3.75 mmol) was stirred at 100 C. After stirring overnight, the residue was dissolved in methylene chloride (30 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (1:1 hexanes/ethyl acetate) to give E2.
With potassium carbonate; In N,N-dimethyl-formamide; at 70 - 80℃;
V.2. 4-[2-((R)-1 - e/t-Butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro- phenylamino1-5-methyl-thieno[2,3-c lpyhmidine-6-carboxylic acid methyl ester4-(4-Fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-c/]pyhmidine-6-carboxylic acid methyl ester carboxylate (445.0 mg), (S)-1 Boc-3-methansulfonyloxy-pyrrolidine (708.0 mg) and potassium carbonate (368.0 mg) were dissolved in DMF (7.0 ml). The reaction mixture was heated at 70C overnight and at 80C for further 4h. EtOAc and H2O were added and the resultant suspension was fitlered. The solid was washed with water and EtOAc and dried under vacuo over P2O5. The residue was dissolved in dichloromethane, passed through an hydrophobic frit and the solvent was evapoerated. The residue triturated with diethylether.Yield: 482.0 mg
With potassium carbonate; In N,N-dimethyl-formamide; at 70 - 80℃;Product distribution / selectivity;
V.2. 4-[2-((R)-1-tert-Butoxycarbonyl-pyrrolidin-3-yloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester 4-(4-Fluoro-2-hydroxy-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester carboxylate (445.0 mg), (S)-1 Boc-3-methansulfonyloxy-pyrrolidine (708.0 mg) and potassium carbonate (368.0 mg) were dissolved in DMF (7.0 ml). The reaction mixture was heated at 70 C. overnight and at 80 C. for further 4 h. EtOAc and H2O were added and the resultant suspension was fitlered. The solid was washed with water and EtOAc and dried under vacuo over P2O5. The residue was dissolved in dichloromethane, passed through an hydrophobic frit and the solvent was evapoerated. The residue triturated with diethylether. Yield: 482.0 mg
In N,N-dimethyl-formamide; at 100.0℃; for 18h;Inert atmosphere;
b) 1,1-Dimethylethyl (3R)-3-cyano-l-pyrrolidinecarboxylateA mixture of 1,1-dimethylethyl (35)-3-[(methylsulfonyl)oxy]-l-pyrrolidinecarboxylate (211 mmol) and sodium cyanide (633 mmol) in N,N-dimethylformamide (300 mL) was vigorously stirred with a mechanical stirrer while heating at 100 C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 mL). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo.Purification of the residue by flash chromatography (0-50% ethyl acetate/hexanes) gave the title product (141 mmol, 67 % yield). 1H NMR (400 MHz, CDC13) delta ppm 1.48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=11.05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
67%
In N,N-dimethyl-formamide; at 100.0℃; for 18h;Inert atmosphere;
A mixture of 1 , 1 -dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-l- pyrrolidinecarboxylate (211 mmol) and sodium cyanide (633 mmol) in N,N- dimethylformamide (300 mL) was vigorously stirred with a mechanical stirrer while heating at 100 C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 mL). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (0-50% ethyl acetate/hexanes) gave the title product (141 mmol, 67 % yield). .H NMR (400 MHz, CDC13) delta ppm 1.48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=l 1.05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
67%
In N,N-dimethyl-formamide; at 100.0℃; for 18h;Inert atmosphere;
A mixture of 1 , 1 -dimethylethyl (3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate (21 1 mmol) and sodium cyanide (633 mmol) in A/JV-dimethylformamide (300 ml.) was vigorously stirred with a mechanical stirrer while heating at 100 C under a nitrogen atmosphere for 18 h. The mixture was allowed to cool to ambient temperature, filtered, and washed thoroughly with diethyl ether. The filtrate was diluted with dilute brine and extracted with diethyl ether (4 x 700 ml_). The combined organic extracts were washed with dilute brine, filtered through a pad of sodium sulfate, and concentrated in vacuo. Purification of the residue by flash chromatography (0-50% ethyl acetate/hexanes) gave the title product (141 mmol, 67 % yield). 1H NMR (400 MHz, CDCI3) delta ppm 1 .48 (s, 9 H) 2.14 - 2.37 (m, 2 H) 3.00 - 3.20 (m, 1 H) 3.45 (dt, J=1 1 .05, 6.98 Hz, 1 H) 3.53 - 3.66 (m, 2 H) 3.65 - 3.76 (m, 1 H).
36%
In N,N-dimethyl-formamide; at 100.0℃;Inert atmosphere;
b) 1,1 -dimethylethyl (3i?)-3 -cyano- 1 -pyrrolidmecarboxylateTo a solution of 1,1 -dimethylethyl (35)-3-[(methylsulfonyl)oxy]-l- pyrrolidmecarboxylate (24 g, 90 mmol) in DMF (150 mL) was added NaCN (13.30 g, 271 mmol). The reaction mixture was stirred at 100 C under nitrogen overnight, at which point analysis by TLC and NMR indicated the reaction was complete. The mixture was diluted with Et20 (600 mL), stirred briefly, and filtered. The Et20 filtrate was washed with 1 : 1 watenbrine (7x), and the organic layer was dried over Na2S04, filtered, andconcentrated in vacuo. Purification of the residue by flash chromatography (5-50%EtOAc/hexanes) provided the title compound (6.4 g, 36%). MS(ES)+ m/e 266.0 [M+H]+.
6-[4-(4-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1-([2-(trimethylsilyl)ethyl]oxy}methyl)-1H-pyrrolo[3,2-b]pyridine[ No CAS ]
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
