* 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] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1773 - 1778
2
[ 130312-02-6 ]
[ 100858-32-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide In aq. phosphate buffer; isopropyl alcohol at 50℃; for 21 h; Enzymatic reaction
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5percent (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 °C. For ChKRED20, 40percent (v/v) 2-propanol and a reaction temperature of 40 °C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
Reference：
[1] Process Biochemistry, 2017, vol. 56, p. 90 - 97
3
[ 501-53-1 ]
[ 100243-39-8 ]
[ 100858-32-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine In dichloromethane at 5 - 20℃; for 48 h;
Step 1: preparation of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate. A solution of (3S)-pyrrolidin-3-ol (10.0 g, 0.12 mol) in dichloromethane (130 mL) was cooled to 5°C. Triethylamine (16.9 mL, 0.12 mol) was added, followed by drop wise addition ofbenzyl chloroformate (13.9 mL, 0.10 mol), ensuring that the temperature did not exceed5°C. The reaction mixture was then allowed to stir at ambient temperature for 48h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane. The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography (50percent ether hexanes followed by ether) to afford the title compound as a clear oil (14 g, 92percent).
Reference：
[1] Patent: WO2014/68527, 2014, A1, . Location in patent: Page/Page column 81; 82
[2] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1773 - 1778
4
[ 100858-33-1 ]
[ 100858-32-0 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With sodium 2,2,2-trifluoroacetate; 2,2-difluoro-1,3-dimethyl-imidazolidine In toluene at 0 - 50℃; for 4 h; Stage #2: With water; sodium hydrogencarbonate In toluene at 15 - 20℃; for 0.5 h;
Sodium trifluoroacetate (32.6 g) was suspended in toluene (213 g), and DFI (32.6 g) was added dropwise thereto at 0°C. The mixture was stirred at 0°C for 1 hour, and then R-CHP (44.2 g) was added thereto. The reaction solution was stirred at 0°C for 1 hour, and then at 50°C for 2 hours. The reaction solution was kept at 15°C or lower, a 5 wtpercent aqueous sodium hydrogen carbonate solution (480 g) was added dropwise to the reaction solution, which was stirred at room temperature for 30 min. Subsequently, the toluene layer was separated. The toluene layer was washed three times with water (100 g), and then concentrated under reduced pressure. To the obtained residue were added toluene (40 g) and hexane (80 g), and the mixture was crystallized at 0°C. The obtained crystal was collected by filtration, and dried at 40°C for 12 hours under reduced pressure to obtain a target compound. Amount 39.3 g Yield 89percent Stereoisomer ratio S-CHP:R-CHP=99.9:0.1 1H-NMR (toluene-d8, 400 MHz) δ 7.23-7.20 (m, 2H), 7.13-6.98 (m, 3H), 5.11-4.99 (m, 2H), 3.93 (bs, 1H), 3.46-3.12 (m, 4H), 1.65-1.45 (m, 1H), 1,45-1.30 (m, 1H) The stereoselectivity in the reaction was determined by using the concentrated residue before crystallization and using the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition 6. S-CHP:R-CHP=99.8:0.2
85%
Stage #1: With hexafluoropropene-diethylamine adduct; sodium 2,2,2-trifluoroacetate In toluene at 0 - 50℃; for 4 h; Stage #2: With water; sodium hydrogencarbonate In toluene at 15 - 20℃; for 0.5 h;
Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and PPDA (3.35 g) was added dropwise thereto at 0°C. The mixture was stirred at 0°C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0°C for 1 hour, and then at 50°C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15°C or lower, and added dropwise to an ice-cooled, 5 wtpercent aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.94 g Yield 85percent The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=96:4 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.
78%
Stage #1: With 1,1-difluoro-N,N,N',N'-tetramethylmethanediamine; sodium 2,2,2-trifluoroacetate In toluene at 0 - 50℃; for 4 h; Stage #2: With water; sodium hydrogencarbonate In toluene at 15 - 20℃; for 0.5 h;
Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and BDDF (2.07 g) was added dropwise thereto at 0°C. The mixture was stirred at 0°C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0°C for 1 hour, and then at 50°C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15°C or lower, and added dropwise to an ice-cooled, 5 wtpercent aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.87 g Yield 78percent The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=94:6 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 10, p. 1764 - 1773
17
[ 501-53-1 ]
[ 122536-94-1 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Patent: US5977381, 1999, A,
18
[ 95656-88-5 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 3, p. 509 - 512
19
[ 31970-04-4 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Journal of the American Chemical Society, 1986, vol. 108, # 8, p. 2049 - 2054
20
[ 108-22-5 ]
[ 95656-88-5 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 13, p. 2321 - 2327
21
[ 25070-74-0 ]
[ 100858-32-0 ]
[ 100858-33-1 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 18, p. 3380 - 3390
22
[ 100858-32-0 ]
[ 122536-75-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 10, p. 1764 - 1773
23
[ 100858-32-0 ]
[ 130312-02-6 ]
Yield
Reaction Conditions
Operation in experiment
88%
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In dichloromethane for 2 h; Molecular sieve; Inert atmosphere
Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution ofbenzyl (3S)-3-hydroxypyrrolidine-1-carboxylate (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88percent).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h;
Example M48: (R)-l-methylcyclopropyl 4-((5-(4-(pyrrolidin-3- ylsulfonyl)piperazin-l-yl)pyrazin-2-yloxy)methyl)piperidine-l-carboxylateCl M48a M48b M48c M48dStep E r M48e: R=Cbz^ Example M48: R=H <n="129"/>Step A: A solution of M48a (10 g, 45.2 mmol) in dichloromethane (200 mL) is cooled in an ice/water bath and treated with diisopropylethylamine (9.4 mL, 54.3 mmol) followed by dropwise addition of methanesulfonyl chloride (3.8 mL, 50 mmol). The resulting solution is stirred at 0 0C for 1 hour, concentrated and purified on silica gel using a linear gradient of 0-100% ethyl acetate in hexane to afford M48b; ESIMS m/z for (M+H)+ C13H18NO5S calcd: 300.1, found: 300.0.
With triethylamine; In dichloromethane; at 5 - 20℃; for 48h;
Step 1: preparation of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate. A solution of (3S)-pyrrolidin-3-ol (10.0 g, 0.12 mol) in dichloromethane (130 mL) was cooled to 5C. Triethylamine (16.9 mL, 0.12 mol) was added, followed by drop wise addition ofbenzyl chloroformate (13.9 mL, 0.10 mol), ensuring that the temperature did not exceed5C. The reaction mixture was then allowed to stir at ambient temperature for 48h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane. The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography (50% ether hexanes followed by ether) to afford the title compound as a clear oil (14 g, 92%).
With potassium hydroxide; water; In ethanol; for 0.25h;
To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3-ACETOXYPYRROLIDINE-1-CARBOXYLATE was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 ML of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
With potassium hydroxide; ethanol; water; for 0.25h;
Step B: Benzyl (3S)-3-hydroxypyrrolidine-l-carboxylate; To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3- acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
With potassium hydroxide; ethanol; water; for 0.25h;
To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3- acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.
Sodium trifluoroacetate (32.6 g) was suspended in toluene (213 g), and DFI (32.6 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (44.2 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. The reaction solution was kept at 15C or lower, a 5 wt% aqueous sodium hydrogen carbonate solution (480 g) was added dropwise to the reaction solution, which was stirred at room temperature for 30 min. Subsequently, the toluene layer was separated. The toluene layer was washed three times with water (100 g), and then concentrated under reduced pressure. To the obtained residue were added toluene (40 g) and hexane (80 g), and the mixture was crystallized at 0C. The obtained crystal was collected by filtration, and dried at 40C for 12 hours under reduced pressure to obtain a target compound. Amount 39.3 g Yield 89% Stereoisomer ratio S-CHP:R-CHP=99.9:0.1 1H-NMR (toluene-d8, 400 MHz) delta 7.23-7.20 (m, 2H), 7.13-6.98 (m, 3H), 5.11-4.99 (m, 2H), 3.93 (bs, 1H), 3.46-3.12 (m, 4H), 1.65-1.45 (m, 1H), 1,45-1.30 (m, 1H) The stereoselectivity in the reaction was determined by using the concentrated residue before crystallization and using the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition 6. S-CHP:R-CHP=99.8:0.2
85%
Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and PPDA (3.35 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15C or lower, and added dropwise to an ice-cooled, 5 wt% aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.94 g Yield 85% The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=96:4 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.
78%
Sodium trifluoroacetate (2.04 g) was suspended in toluene (10 g), and BDDF (2.07 g) was added dropwise thereto at 0C. The mixture was stirred at 0C for 1 hour, and then R-CHP (1.11 g) was added thereto. The reaction solution was stirred at 0C for 1 hour, and then at 50C for 2 hours. To the reaction solution was added toluene (20 g), and the mixture was kept at 15C or lower, and added dropwise to an ice-cooled, 5 wt% aqueous sodium hydrogen carbonate solution (30 g). The reaction solution was stirred at room temperature for 30 min, and then the toluene layer was separated. The toluene layer was washed three times with water (20 g), and then concentrated under reduced pressure to obtain a residue as a pale brown solid containing a target compound. Amount 0.87 g Yield 78% The stereoselectivity in this reaction was determined from the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition-6. Stereoisomer ratio S-CHP:R-CHP=94:6 1H-NMR (toluene-d8, 400 MHz) was consistent with that in Example 29.
a) Preparation of benzyl (S)-3-hydroxy-pyrrolidine-1-carboxylate The pH of a solution of 6.18 g of (S)-3-hydroxy-pyrrolidine hydrochloride in 175 ml of water was adjusted to 10 with 10% sodium hydroxide solution and cooled to 0-5 C. 7.1 ml of benzyl chloroformate were added dropwise within 30 minutes under argon, with the pH of the solution being held between 9.5 and 11.5 by the dropwise addition of 10% sodium hydroxide solution. After completion of the addition the suspension was stirred at room temperature for 16 hours. The suspension was extracted with ethyl acetate, the organic phase was washed with water, dried over Na2 SO4, filtered and the filtrate was concentrated. Purification of the crude product over a silica gel column gave 7.33 g of benzyl (R)-3-hydroxy-pyrrolidine-1-carboxylate as a beige liquid.
With sodium hydroxide; water; In toluene; at 20℃; for 0.5h;Product distribution / selectivity;
The stereoselectivity in the reaction was determined by dissolving the obtained compound in toluene (10 ml), and stirring it in a 1 N-aqueous NaOH solution (20 ml) at room temperature for 30 min to derive a corresponding (S)-N-benzyloxycarbonyl-3-hydroxypyrrolidine (hereinafter abbreviated as S-CHP), and using the peak area ratio of S-CHP and R-CHP under an HPLC analysis condition 6. S-CTFAP:R-CTFAP=97:3 HPLC analysis condition 6 Chiral column used DAICEL CHIRALPACK AD-H Eluent hexane/2-propanol=95/5 Flow rate 1 ml/min Detection wavelength UV 210 nm Column temperature 35C
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; for 2h;Molecular sieve; Inert atmosphere;
Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution of<strong>[100858-32-0]benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate</strong> (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88%).
(S)-3-methoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.3%
To a stirred solution of cbz-(S)-pyrrolidin-3-ol (5.4 g, 24 mmol, 1 eq) in anhydrous tetrahydrofuran (100 mL) at 0 C, sodium hydride (60% in oil, 2.4 g, 60 mmol, 2.5 eq) was added and the solution was stirred at room temperature for thirty minutes. Methyl bromoacetate (7.3g, 4.4 mL, 48 mmol, 2 eq) was added to the solution and then further stirred at room temperature for three hours, by which time LC-MS analysis revealed the formation of a new product. Saturated aqueous ammonium chloride solution (10 mL) was added to the mixture and the mixture was extracted with ether (3 x 30 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of solvents, hexane: ethyl acetate from 5-50% ethyl acetate to give the desired product (6.6 g, 94.3 %) as light brown oil. LC-MS (ESI, MH+): 294.1 . NMR (250 MHz, CDC13) delta 7.6-7.1 (5H, m), 5.15 (2H, s), 4.25-4.05 (3H, m), 3.85-3.4 (7H, m), 2.2-1.7 (4 H, m).
(S)-3-{2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy}pyrrolidine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.6%
To a solution of (S)-3-hydroxy-pyrrolidine- l -carboxylic acid benzyl ester (3.5 g, 15 mmol, 1.2 eq) in 60 mL of anhydrous tetrahydrofuran, NaH (60% in oil, 800 mg, 20 mmol) was added and the solution was stirred at room temperature for thirty minutes. Toluene-4-sulfonic acid 2-[2-benzyolxy-ethoxy)-ethoxy] ethyl ester (5 g, 13 mmol leq) was then added. The mixture was heated at 50 C overnight. LC-MS analysis revealed the formation of a new product. Saturated aqueous ammonium chloride solution ( 10 mL) was added to the mixture and the aqueous layer was extracted with ether (4 x 15 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (4 x10 mL), brine (4 x 10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate (10-60 % ethyl acetate) to give (S)-3-{2-[2-(2-Benzyloxy-ethoxy)-ethoxy]-ethoxy}- pyrrolidine-l -carboxylic acid benzyl ester (4 g, 69.6%) as light brown oil.
With recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 50℃; for 21h;pH 7.0;Enzymatic reaction;
General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry.
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