Home Cart 0 Sign in  

[ CAS No. 109431-87-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 109431-87-0
Chemical Structure| 109431-87-0
Structure of 109431-87-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 109431-87-0 ]

Related Doc. of [ 109431-87-0 ]

Alternatived Products of [ 109431-87-0 ]

Product Details of [ 109431-87-0 ]

CAS No. :109431-87-0 MDL No. :MFCD01317838
Formula : C9H17NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :APCBTRDHCDOPNY-SSDOTTSWSA-N
M.W : 187.24 Pubchem ID :6544479
Synonyms :

Calculated chemistry of [ 109431-87-0 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.89
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 52.95
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.0 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.31
Log Po/w (XLOGP3) : 0.62
Log Po/w (WLOGP) : 0.61
Log Po/w (MLOGP) : 0.56
Log Po/w (SILICOS-IT) : 0.28
Consensus Log Po/w : 0.88

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.19
Solubility : 12.0 mg/ml ; 0.0641 mol/l
Class : Very soluble
Log S (Ali) : -1.24
Solubility : 10.8 mg/ml ; 0.0576 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.42
Solubility : 71.0 mg/ml ; 0.379 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.66

Safety of [ 109431-87-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 109431-87-0 ]

* 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.

  • Downstream synthetic route of [ 109431-87-0 ]

[ 109431-87-0 ] Synthesis Path-Downstream   1~85

  • 1
  • [ 24424-99-5 ]
  • (3R)-3-Hydroxypyrrolidium hydrogen maleate [ No CAS ]
  • [ 109431-87-0 ]
YieldReaction ConditionsOperation in experiment
77% With sodium hydrogencarbonate; In water; at 20℃; [00240] (3i?)-pyrrolidin-3-ol maleate (67.6 g, 333 mmol) was slowly poured in a stirred mixture of sodium bicarbonate (139 g, 1.65 mol) in water (600 ml). Subsequently, di- ter^-butyl dicarbonate (110 g, 504 mmol) was added, and the resulting mixture was stirred overnight at room temperature. Ethyl acetate (600 ml) was added, and the mixture was filtered in order to remove undissolved salts. The layers were separated and the aqueous layer was extracted with ethyl acetate (300 ml). The combined organic layers were washed with saturated aqueous NaCl solution (400 ml), dried over sodium sulfate, filtered, and evaporated to dryness. Yield: 85.7 g (q) of a dark oil that was recrystallized from 150 ml heptanes, yielding 62.2 g (77%) of a white solid identified as xii by 1H-NMR.
With sodium hydrogencarbonate; In water; ethyl acetate; B. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-hydroxypyrrolidine (2) A 10 gallon glass-lined vessel was charged with water (29 l) and sodium bicarbonate (7.42 kg, 88.3 Mol). To the resultant stirred slurry, at 20 C., was added a solution of (3R)-3-hydroxypyrrolidine hydrogen maleate (1) (3.60 kg, 17.7 Mol) in water (10.8 l), over 15 min (effervescence). On complete addition, di-tertbutyldicarbonate (Fluka, 4.64 kg, 21.3 Mol) was added in one portion (no exotherm noted). The slurry was vigorously stirred over the weekend (i.e. total ~ 65 h). Ethyl acetate (10 l) was added and the mixture filtered to remove suspended solids. The aqueous layer was separated and re-extracted with ethyl acetate (10 l). The combined organics were dried (Na2 SO4) and evaporated under reduced pressure to give a colourless oil.
With sodium hydrogencarbonate; In water; ethyl acetate; B. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-hydroxypyrrolidine (2) A 10 gallon glass-lined vessel was charged with water (29 l) and sodium bicarbonate (7.42 kg, 88.3 Mol). To the resultant stirred slurry, at 20 C., was added a solution of (3R)-3-hydroxypyrrolidine hydrogen maleate (1) (3.60 kg, 17.7 Mol) in Water (10.8 l), over 15 min (effervescence). On complete addition, di-tertbutyldicarbonate (Fluka, 4.64 kg, 21.3 Mol) was added in one portion (no exotherm noted) The slurry was vigorously stirred over the weekend (i.e. total -65 h) Ethyl acetate (10 1) was added and the mixture filtered to remove suspended solids The aqueous layer was separated and re-extracted with ethyl acetate (10 l). The combined organics were dried (Na2 SO4) and evaporated under reduced pressure to give a colourless oil.
  • 2
  • [ 109431-87-0 ]
  • [ 124-63-0 ]
  • [ 127423-61-4 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine; In dichloromethane; at 20℃;Cooling with ice; Example 20. N-(4-(4-amino-l-((S)-pyrrolidin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-3- yl)phenyl)-3-(trifluoromethyl)benzamide (AD070); Step 1; [0200] (i?)-l-(ter£-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate. A solution of (R)- tert-bntyl 3-hydroxypyrrolidine-l-carboxylate (1.0 g, 5.3 mmol) and triethylamine (2.77 mL, 20 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (1.15 mL, 15 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3x 50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (R)-I- (te/t-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate (1.53 g, brown oil, 100% yield).
100% With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; (R)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (5.0 g, 26.7 mmol) and Et3N (8.0 g, 80.2 mmol) were dissolved in dichloromethane (50 mL). The mixture was stirred at 0C for 30 minutes, then methanesulfonyl chloride (4.5 g, 40.1 mmol) was added dropwise. It was stirred at room temperature for 2 h and concentrated under reduced pressure. DCM (50 mL) and water (50 mL) were added. The organic phase was washed with saturated NaHC03 (30 mL) and H20 (2 x 30 mL), and concentrated to afford the title compound as oil (6 g, 100%).
100% With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; To a solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.00 g, 5.35 mmol) and TEA (1.62 mg, 16.1 mmol) in DCM (15 mL)was added MsCI (0.920 g, 8.03 mmol) at 0Cunder N2. The mixture was warmed to room temperature and stirred for another 1 h. The mixture was diluted with H20 (40 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with sat.NaHCO3 aq. brine, dried over Na2SO4 and concentrated in vacuum to give the desired product (1.4 g, yield 100%) as yellow oil.1H NMR (300 MHz, CDCI3): 65.29-5.24 (m, 1H), 3.72-3.43 (m, 4H), 305 (s, 3H), 2.35-2.08(m, 2H), 1.47 (s, 9H).LC-MS: [mobile phase: from 90% water (0.02% NH4OAc) and 10% CH3CN to 5% water (0.02% NH4OAc) and 95% CH3CN in 4 mm], Rt = 2.152 mm MS Calcd.: 265, MS Found: 210 [M-56+H].
100% A solution of N-tert-Butoxycarbonyl-(R)-(-)-3-pyrrolidinol (2.0 g, 10.7 mmol) in DCM (28 mL) was treated with TEA (2.9 mL, 21.4 mmol). The solution was cooled to 0C for 30 minutes. Then methanesulfonyl chloride (868 iL, 1 1.2 mmol) was added. The reaction was stirred at 0C for 30 minutes. The reaction was diluted with DCM and washed with saturated NaHCCb(aq). The organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (5-95% EtOAc in Hexanes as the gradient eluent) to afford the title compound (2.83 g, 100% yield). MR (400 MHz, DMSO-d6) δ 5.24 (s, 1H), 3.55-3.38 (m, 3H), 3.31-3.27 (m, 1H), 3.23 (s, 3H), 2.18- 2.08 (m, 2H), 1.40 (s, 9H).
100% With triethylamine; In dichloromethane; at 0 - 20℃; for 7h; (R)-(-)-N-Boc-3-pyrrolidinol (3-I-1; 3.0 g, 16.0 mmol) was dissolved in anhydrous dichloromethane and then mesyl chloride (MsCl; 1.5 mL, 19.2 mmol) and Triethyl amine (TEA; 2.9 ml, 20.8 mmol) was added slowly at 0 C. to react.After raising the temperature to room temperature, it was reacted for 7 hours.After completion of the reaction, the mixture was extracted three times with saturated aqueous NaCl solution and dichloromethane, dried over anhydrous magnesium sulfate, dried and filtered. The filtrate was concentrated under reduced pressure to obtain 4.3 g (100% yield) of the title compound (3-I-2) through a column chromatography.
99% With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; Methanesulfonyl chloride (19.7 g, 172 mmol) was added to a solution of (R)-tertbutyl 3-hydroxypyrrolidine-1-carboxylate (25 g, 133 mmol) and triethylamine (20.1 g, 199 mmol) in DCM (500 mL) at 0 C. After stirring at room temperature for 6 h, the reaction mixture was washed with 1 M HC1 (50 mL) and the aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (35 g, 99%) as a yellow oil1H NMR (400 MHz, CDC13) (ppm): 5.28-5.23 (m, 1H), 3.70-3.40 (m, 4H), 3.04 (s, 3H), 2.34-2.07 (m, 2H), 1.46 (s, 9H).
98% With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; To a mixture of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.00 g, 5.34 mmol, 1.00 eq) and triethylamine (1.62 g, 16.0 mmol, 2.23 mL, 3.00 eq) in dichloromethane (15.0 mL) was added methanesulfonyl chloride (917 mg, 8.01 mmol, 620 uL, 1.50 eq) dropwise at 0 C under nitrogen. The mixture was stirred at 20 C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with saturated sodium bicarbonate (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine -1-carboxylate (1.40 g, 5.28 mmol, 98% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 5.27 (br s, 1H), 3.74 - 3.42 (m, 4H), 3.09 - 3.02 (m, 3H), 2.36 - 2.21 (m, 1H), 2.14 (br d, J = 3.5 Hz, 1H), 2.20 - 2.07 (m, 1H), 1.47 (s, 9H).
92% With triethylamine; In toluene; at -30 - 20℃;Product distribution / selectivity; Example 2. Synthesis of tert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (2); Procedure A:; To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 ml_) at -20 to -30 C was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20 0C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ~600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCI3, 400 MHz) δ 5.27 (m, 1 H), 3.44 - 3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1 H), 2.15 (m, 1 H), 1.47 (s, 9H).
92% With triethylamine; In toluene; at -30 - 20℃;Product distribution / selectivity; Example 2. Synthesis of fert-butyl (R)-3-(methylsulfonyloxy)pyrrolidine-1- carboxylate (2) Procedure A: To a solution of te/t-butyl (R)-3-hydroxypyrrolidine-1- carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at -20 to -30 C was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20 0C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ~600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCI3, 400 MHz) δ 5.27 (m, 1 H), 3.44 - 3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1 H), 2.15 (m, 1 H), 1.47 (s, 9H).
60.2% With triethylamine; In dichloromethane; at 0 - 20℃; Example 14. fert-Butyl (3S)-3-[4-(2-oxo-2,3-dihydro-1W-benzimidazoI-1- yl)piperidin-1-yl]pyrrolidine-1-carboxylate; Step A. The preparation of terf-butyl (3R)-3-[(methylsulfonyl)oxy]pyrrolidine-1- carboxylate <n="55"/>To (R)-N-Boc-3-pyrrolidiϖol (5g, 26.7mmol) in CH2CI2 (10ml) at O0C was added Et3N (4.12g, 40.7mmol), followed by methylsulfonyl chloride (3.81g, 33.25 mmol) in 1ml of CH2CI2 slowly. The reaction mixture was warmed to RT and stirred overnight. The crude was washed with sat. NaHCO3 solution (1X ), extracted with CH2CI2 (3X ), and dried over MgSO4. After filtration and evaporation, the residue was purified by chromatography on silica gel with 30% EtOAc/hexane to afford the mesylate tert- butyl (3R)-3-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (4.26g, 60.2%).
With triethylamine; In dichloromethane; water; PREPARATION 10-2) To a solution of (R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine (32 g) in dichloromethane (300 ml) were added triethylamine (28.6 ml) and then methanesulfonyl chloride (14.6 ml) under nitrogen at -10 C. After stirring at 0 C. for 30 minutes, the solution was washed in turn with water, 1N-hydrochloric acid solution, saturated sodium bicarbonate, and brine. The dried solution was evaporated to give (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (45 g). IR (CH2 Cl2): 1690 cm-1. NMR (CDCl3, δ): 1.47 (9H, s), 2.9-2.42 (2H, m), 3.00 (3H, s), 3.35-3.75 (5H, m).
With sodium chloride; triethylamine; In tetrahydrofuran; 5-(1) (3R)-1-t-Butoxycarbonyl-3-methanesulfonyloxypyrrolidine 16.91 ml of triethylamine and 9.36 ml of methanesulfonyl chloride were added, in that order, whilst ice-cooling, to a solution of 25 g of (3R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and the mixture was stirred at 0 to 5 C. for 30 minutes and then at 15 C. for 30 minutes. At the end of this time, the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.10 g of the title compound as a colorless oil. Nuclear Magnetic Resonance Spectrum (CDCl3, 60 MHz) δ ppm: 1.48 (9H. singlet); 1.91-2.45 (2H, multiplet); 3.04 (3H, singlet); 3.26-3.82 (4H, multiplet); 6.1-6.44 (1H, multiplet).
With triethylamine; In water; ethyl acetate; C. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-methanesulphonyloxypyrrolidine (3) A dry 10 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5 C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 l, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5-2 C. On complete addition, the slurry was aged at -5 C. for 30 min. Water (20 1) was added over 10 min and the phases well mixed The aqueous layer was separated and the organics washed with 1M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 1) and dried (Na2 SO4). Solvent evaporation gave the product as a pale yellow oil.
With triethylamine; In water; ethyl acetate; C. Preparation of (3R)-N-(t-Butoxycarbonyl)-3-methanesulphonyloxypyrrolidine (3) A dry I0 gallon glass-lined vessel was charged with the alcohol (2) (3.39 kg d.b., 18.1 Mol) and ethyl acetate (50 l) under nitrogen. The solution was cooled to -5 C. and triethylamine (Lancaster B/N 076337, 5.1 l) was added in one portion. Methanesulphonyl chloride (Lancaster B/N 79561, 1.68 1, 21.7 Mol) was added dropwise over 1 h, maintaining the reaction temperature at -5-2 C. On complete addition, the slurry was aged at -5 C. for 30 min. Water (20 l) was added over 10 min and the phases well mixed. The aqueous layer was separated and the organics washed with 1 M aqueous hydrochloric acid (10 l), saturated sodium bicarbonate (10 l) and dried (Na2 SO4). Solvent evaporation gave the product as a pale yellow oil.
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10.6g, 56. 7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250mL) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated IN VACUO TO give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 4h; Step 1 : A mixture of f?-1-BOC-3-hydroxy-pyrrolidine (1.0 g, 5.34 mmol) and triethylamine (0.89 ml, 6.41 mmol) in THF (20 ml) was cooled in an ice bath. To this was added methane sulfonyl chloride (0.46 ml, 5.87 mmol). The reaction was then warmed to ambient temperature and allowed to stir for 4 hours. The reaction was quenched with the addition of water, and extracted with ethyl acetate (2x). The organic extracts were combined, washed with saturated NaCI solution, dried over anhydrous MgSO4, filtered and concentrated to provide 1.42 g of a clear oil which was used without further purification. 1H NMR δ (ppm) (CDCI3) 1.48 (9 H, s), 2.05-2.30 (2 H, m), 3.05 (3 H, s), 3.40-3.75 (4 H, m), 5.27 (1 H, br).
With triethylamine; In dichloromethane; at -10 - 0℃; for 0h; Methanesulfonyl chloride (5.26mL, 68MMOL) was added dropwise over 5 minutes to a stirred solution OF 1, 1-DIMETHYLETHYL (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10.6g, 56.7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250ML) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil.
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1,1-dimethylethyl (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (10. 6g, 56. 7MMOL) and triethylamine (11. 8ML, 85MMOL) in dichloromethane (250mL) AT-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (25: 75 to 50: 50), to give the title compound as an oil.
With triethylamine; In dichloromethane; at -10 - 0℃; for 1.08333h; Methanesulfonyl chloride (5.26mL, 68mmol) was added dropwise over 5 minutes to a stirred solution of 1, 1-dimethylethyl (3R)-3-hydroxypyrrolidine-1-carboxylate (10.6g, 56. 7mmol) and triethylamine (11. 8mL, 85mmol) in dichloromethane (250mL) at-10C. After stirring for 1 hour at 0C, the reaction was quenched by addition of water. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (25: 75 to 50: 50), to give the title compound as an oil.
With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 1h; STEP B(S)-tert-butyl 3-(acetylthio)pyrrolidine- 1-carboxylate. [Chem.98][0460] To a solution of (R)-tert-butyl 3-hydroxypyrrolidine- 1-carboxylate (STEP A, 2.25 g, 12.0 mmol) and triethylamine (2.53 mL, 18.0 mmol) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.12 mL, 14.4 mmol) in tetrahydrofuran (5 mL) at 0 C. After stirring at room temperature for 1 h, the precipitate was filtered off and the filtrate was concentrated in vacuo.
With triethylamine; In ethyl acetate; at -10 - 20℃; for 0.5h; A mixture of xiv (20.0 g, 107 mol) and triethylamine (31 ml, 214 mmol) in ethyl acetate (200 ml) was cooled to -10 - -5 C with an ice/salt bath. To this mixture was slowly added mesylchloride (9.9 ml, 128 mmol) via a syringe. Immediately, a white precipitate started forming, stirring was continued for half an hour at room temperature. Then, water (100 ml) was added and the organic layer was separated and washed with 1 N aq. HCl solution (100 ml), 5% aq. NaHCO3 solution (100 ml), and finally with saturated aqueous NaCl solution (100 ml). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness, yielding 28.9 g (107 mmol) of a oil identified as xvii by 1H-NMR. This oil was dissolved in DMF (250 ml) and potassium thioacetate (16.2 g, 142 mmol) was added. The resulting mixture was stirred under a nitrogen atmosphere overnight at about 60 C. After 15 minutes, as solid started forming. The mixture was cooled to room temperature, and water (250 ml) plus TBME (250 ml) were added to the solidified mixture. The resulting mixture was stirred for 10 minutes and subsequently, the layers were separated. The aqueous layer was extracted with 250 ml TBME, and the combined TBME layers were washed with water (3 x 200 ml), saturated aqueous NaCl solution (200 ml), dried over sodium sulfate, filtered, and evaporated to dryness to yield 23.5 g (90%) of an orange oil identified as xix by 1H-NMR.
With triethylamine; In dichloromethane; at 0℃; To (R)-fert-butyl 3-hydroxypyrrolidine-l-carboxylate (87 mg, 0.465 mmol) in DCM (2 mL) at 0 C was added methanesulfonyl chloride (58.5 mg, 0.51 1 mmol) and triethylamine (56.4 mg, 0.558 mmol). The cold bath was removed and the reaction was stirred for 30 minutes. The reaction was diluted with 5 mL DCM, washed with water and brine, dried (Na2S04) and concentrated to give final product (131 mg).
With triethylamine; In dichloromethane; at 0℃; for 2h;Inert atmosphere; Step 1:(R)-Pyrrolidinol (43.56 g, 0.5 mol) was dissolved in dry CH2C12 (1 L) and cooled with ice- bath to 0 C. To the solution was added Et3 (139.4 mL, 1.0 mol), followed by dropwise addition of (Boc)20 (130.95 g, 0.6 mol) in CH2C12 (160 mL), and keep stirring at 0 C for 2h. To the reaction mixture of Boc-protection was added more of Ets (139.4 mL, 1.0 mol), and followed by dropwise addition of MsCI (42.74 mL, 0.55 mol). After 2 h at 0 C, it was treated with H20 (500 mL) for 10 min, separated, and the aqueous phase was extracted with CH2C12 (300 mL x 2). The combined organic layers was washed with brine (500mL), concentrated and purified by silica column chromatography to give N-Boc prortected mesylate 20 as an oily product (123g, 93%)1H NMR (CDC13, 400 MHz): δ 5.29 - 5.23 (m, 1H), 3.74 - 3.40 (m, 4H), 3.05 (s, 3H), 2.36 - 2.20 (m, 1H), 2.20 - 2.05 (m, 1H), 1.46 (s, 9H).
With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; (R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z[M+H]+ 266.1
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; Step 1) (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl methanesulfonate [0199] To a mixture of (R)-l-(tert-butoxycarbonyl)pyrrolidin-3-ol (lg, 5.3mmol) and Et3N(1.2mL) in DCM (15mL) was added MsCl(0.62mL) dropwise at 0C. The reaction was stirred at rt for 2h, then concentrated in vacuo. The residue was diluted with H20(35mL)and extracted with EtOAc (25mL x 3). The combined organic phases were washed with 1M KHSO4(20 mL) followed by H20 (20mL), dried over anhydrous Na2S04, and concentrated in vacuo to give the crude compound as yellow oil (1.4 g), which was used for the next step without further purification.
With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; R)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate 7b (375 mg, 2 mmol) was dissolved in 10 mL of dichloromethane in an ice bath, followed by addition of triethylamine (404 mg, 4 mmol) and methanesulfonyl chloride (274 mg, 2.40 mmol). The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was added with 5 mL of water and extracted with dichloromethane (20 mLx3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 7c (530 mg) as a yellow oil, which was directly used in the next step without further purification.
With triethylamine; In dichloromethane; at 20 - 30℃; for 3h;Cooling with ice; Inert atmosphere; (R)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate 7b (375 mg, 2 mmol) was dissolved in 10 mL of dichloromethane in an ice bath, followed by addition of triethylamine (404 mg, 4 mmol) and methanesulfonyl chloride (274 mg, 2.40 mmol). The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was mixed with 5 mL of water and extracted with dichloromethane (20 mL×3). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate 7c (530 mg) as a yellow oil, which was directly used in the next step without further purification.
1.1 g With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; (R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0 C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z[M+H]+ 266.1
1.1 g With triethylamine; In chloroform; at 0 - 20℃; for 1.5h; (R)-N-Boc-3-pyrrolidinol (935 mg) was dissolved in chloroform (15 ml), and triethylamine (1.04 ml) and methanesulfonyl chloride (467 μl) were added thereto at 0 C. After stirring at room temperature for 1.5 hours, ethyl acetate and water were added thereto to separate the organic layer. After being washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous ammonium chloride solution and water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a colorless, oily compound (1.1 g). Physical properties: m/z [M+H]+ 266.1
With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; (R)-3-hydroxypyrrolidin-1-carboxylic acid tert-butyl ester (1 g, 5.34 mmol) was dissolved in 18 mL of MC. Et3N(2.22 ml, 16.02 mmol) was added thereto at 0C, and MsCl (0.62 ml, 8.01 mmol) was then added thereto. The mixturewas stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with MC. Theorganic layer was dried with anhydrous magnesiumsulfate and purified by column chromatography to obtain (R)-3-methanesulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester. At another flask, diethyl malonate (1.7 ml, 11.3 mmol)was dissolved in 10 ml of ethanol. NaOEt (21%wt, 4.2 ml, 11.3 mmol) was added thereto, and the mixture was stirredat 40C for 1 hour. The obtained (R)-3-methanesulfonyloxypyrrolidin-1-carboxylic acid tert-butyl ester (1.5 g, 5.65 mmol)was dissolved in 8 ml of ethanol and added thereto. The mixture was stirred at 80C for 16 hours. The reaction solutionwas adjusted to pH 2 by the use of 6N HCl aqueous solution and extracted with ether. The organic layer was dried withanhydrous magnesiumsulfate and purified by column chromatography to obtain the title compound (0.785 g, 44 %).1H-NMR (CDCl3) δ 4.21 (4H, m), 3.63 (1H, m), 3.47 (1H, m), 3.25 (2H, m), 3.01 (1H, m), 2.80 (1H, m), 2.06 (1H, m),1.62 (1H, m), 1.42 (9H, s), 1.26 (6H, m).
82.2 g With triethylamine; In dichloromethane; for 2h;Inert atmosphere; a.The reactor was purged with nitrogen, and after stirring 380 g of dichloromethane and 38 g of triethylamine from the feed port for a few minutes, 58 g of the compound 1 was added from the feed port, and then 39 g of methylsulfonyl chloride was slowly added dropwise. The reaction was kept for 2 hours, washed with water and concentrated to obtain Compound 2, and the yield was 82.2 g.

Reference: [1]Patent: WO2010/45542,2010,A2 .Location in patent: Page/Page column 73
[2]Patent: WO2012/62783,2012,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2017/12576,2017,A1 .Location in patent: Page/Page column 187
[4]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001372; 001373; 001374
[5]Journal of Enzyme Inhibition and Medicinal Chemistry,2018,vol. 33,p. 1460 - 1471
[6]Patent: KR2020/22710,2020,A .Location in patent: Paragraph 0379-0382
[7]Patent: WO2020/114487,2020,A1 .Location in patent: Paragraph 00537
[8]Patent: WO2020/114494,2020,A1 .Location in patent: Paragraph 00230; 00666; 00672
[9]Patent: WO2018/102419,2018,A1 .Location in patent: Paragraph 0366; 0367; 0368; 0369
[10]Journal of the Chemical Society. Perkin transactions I,1993,p. 1421 - 1424
[11]Patent: WO2021/127397,2021,A1 .Location in patent: Paragraph 1808; 1922
[12]Journal of Medicinal Chemistry,2020,vol. 63,p. 9020 - 9044
[13]Patent: WO2010/65447,2010,A2 .Location in patent: Page/Page column 30
[14]Patent: WO2010/65443,2010,A1 .Location in patent: Page/Page column 33
[15]Tetrahedron,2006,vol. 62,p. 5763 - 5774
[16]Patent: WO2007/142585,2007,A1 .Location in patent: Page/Page column 53-54
[17]Chemische Berichte,1997,vol. 130,p. 989 - 1006
[18]Journal of Medicinal Chemistry,1997,vol. 40,p. 3497 - 3500
[19]Journal of Antibiotics,1998,vol. 51,p. 757 - 770
[20]Journal of Medicinal Chemistry,1999,vol. 42,p. 677 - 690
[21]Nucleosides, nucleotides and nucleic acids,2005,vol. 24,p. 805 - 808
[22]Patent: US5102877,1992,A
[23]Patent: US5104867,1992,A
[24]Patent: US5124460,1992,A
[25]Patent: US5106853,1992,A
[26]Patent: WO2005/811,2005,A1 .Location in patent: Page/Page column 61
[27]Patent: WO2009/19566,2009,A1 .Location in patent: Page/Page column 19
[28]Journal of Medicinal Chemistry,2008,vol. 51,p. 4601 - 4608
[29]Patent: WO2005/20975,2005,A2 .Location in patent: Page/Page column 221
[30]Patent: WO2005/20976,2005,A2 .Location in patent: Page/Page column 224
[31]Patent: WO2005/60949,2005,A2 .Location in patent: Page/Page column 223
[32]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2742 - 2746
[33]Patent: WO2010/84767,2010,A1 .Location in patent: Page/Page column 86-87
[34]European Journal of Medicinal Chemistry,2010,vol. 45,p. 4594 - 4600
[35]Patent: WO2007/50522,2007,A1 .Location in patent: Page/Page column 59
[36]Patent: WO2011/79076,2011,A1 .Location in patent: Page/Page column 97
[37]Patent: WO2011/160020,2011,A2 .Location in patent: Page/Page column 65
[38]Patent: EP2657233,2013,A1 .Location in patent: Paragraph 0196
[39]Patent: WO2013/138210,2013,A1 .Location in patent: Paragraph 0199
[40]Patent: EP2803664,2014,A1 .Location in patent: Paragraph 0136; 0138
[41]Patent: US2015/5282,2015,A1 .Location in patent: Paragraph 0194; 0196; 0197
[42]Patent: US2016/136168,2016,A1 .Location in patent: Paragraph 0287
[43]Patent: US2016/193210,2016,A1 .Location in patent: Paragraph 0289
[44]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5836 - 5841
[45]Patent: EP3239143,2017,A2 .Location in patent: Paragraph 0547
[46]Patent: CN109851542,2019,A .Location in patent: Paragraph 0026-0028; 0032-0034; 0038-0040
[47]Patent: WO2021/247971,2021,A1 .Location in patent: Paragraph 00758
  • 3
  • [ 24424-99-5 ]
  • (3R)-pyrrolidinol [ No CAS ]
  • [ 109431-87-0 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine; In 1,4-dioxane; As is seen in FIG. 3k, synthesis of compound 16 is a four reaction process. First, compound16b was obtained as a colorless oil (1 .3 g, 100 %) from (R)-3- Pyrrolidinol (539 mg, 6.19 mmol). Spectral data were in agreement with the proposed structures and matched those reported in the literature. (See Kucznierz, R. et. al., J. Med. Chem. 1998, 41 , 4983-4994.) Compound 16c was obtained as a colorless oil from compound 16b. Compound 16e was obtained as a colorless oil over two steps from compound 16c. Finally, compound 16 was obtained as a yellow oil from compound 16e.
94% With triethylamine; In dichloromethane; at 18 - 25℃; for 1h; Example 21[0455] CSVN.N-dimethyl-2-('5-a-methylpyrrolidin-3-ylsulfonylV2-neopentyl-lH-benzordli midazol- l-yPethanamine dihydrochloride. [Chem.96][0456] STEP A(RVtert-butyl 3-hydroxypyrrolidine- 1-carboxylate. [Chem.97][0457] To a solution of (R)-3-pyrrolidinol (4.96 g, 57.0 mmol) in dichloromethane (130 mL) was added triethylamine (10.9 mL, 78.0 mmol) and di-tert-butyl dicarbonate (11.3 g mL, 51.8 mmol) in dichloromethane (20 mL) at room temperature. After 1 h, the mixture was washed with 1 mol/L hydrochloric acid (100 mL) and brine, dried over sodium sulfate and concentrated to give the title compound (9.07 g, 94%) as a colorless oil.[0458] 1H-NMR (300 MHz, CDCI3) δ: 4.49-4.42 (m, IH), 3.55-3.26 (m, 4H), 2.06-1.85 (m, 3H), 1.46 (s, 9H)..
92% With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; Di-tert-butyl dicarbonate (14. 0 g, 63.1 mmol) is added to a stirred solution of 3-R-hydroxypyrrolidine (5.0 g, 57.4 mol) and triethylamine (16 mL, 114.8 mmol) dissolved in dichloromethane (58 mi) at 0 C. The resulting solution is allowed to warm to room temperature and stirred for 4 hours. The solution is then diluted with dichloromethane (50 mL), washed twice with 1 N HCI and twice with aq. NaHC03 solution. The organic layer is then dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (9.9 g, 92 %) as a white solid which is sufficiently pure for use without further purification.
90.3% With triethylamine; In dichloromethane; at 0 - 20℃; for 17.5h; To a dry 5L round bottom flask, (3R)-hydroxypyrrolidine (241 g, 2.77 mol) was added in sequence.Dichloromethane (1100 ml) and triethylamine (477 ml, 3.44 mol),After cooling to 0C to 5C, a solution of (Boc)2O (748 g, 3.43 mol) in dichloromethane (320 ml) was slowly added dropwise.After completion of the dropwise addition, the reaction was maintained at 0 C. to 5 C. for 1.5 h, and then reacted at room temperature for 16 h.TLC identified the endpoint of the reaction [developer: ethyl acetate (v): petroleum ether (v) = 1:5],After the reaction is complete, add saturated citric acid solution (about 2500 ml) to adjust the pH to 5 and stand still.The methylene chloride layer was separated and the organic layer was washed successively with 1600 ml each of water and saturated sodium chloride solution.Anhydrous Na2SO4 was dried, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.A yellow oil (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine 468 g was obtained in a yield of 90.3% and GC (normalized) 97.6%, and used directly in the next step.
87% In methanol; at 0 - 20℃; for 1h; Next, in a four-neck flask of 500 ml equipped with a thermometer and a dropping funnel, 65.1 g (0.75 moles) of the R-HP obtained above was charged, and 130.3 g of methanol was added thereto and ice-cooled. To this solution, 171.4 g (0.79 moles) of di-tert-butyl dicarbonate was added dropwise while maintaining the liquid temperature at 20C or less. After completion of dropping, the resulting mixture was aged for 1 hour, concentrated, and about 200 g was distilled away. To this concentrated liquid, 250 g of n-heptane was added and stirred, and cooled at a temperature in the range from 15 to 20C, followed by stirring overnight. Slurry was subjected to solid-liquid separation, 152. 9 g of crystal was collected by filtration, and dried in vacuum, thereby to obtain R-BocHP of 122.5 g (isolation yield: 87%).
53.4% With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; R)-Pyrrolidin-3-ol 7a (348 mg, 4 mmol) and triethylamine (808 mg, 8 mmol) were dissolved in 20 mL of dichloromethane, followed by addition of di-tert-butyl methyldicarbonate (959 mg, 4.40 mmol) in an ice bath. The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was added with 50 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL*3), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7b (400 mg, yield 53.4%) as a colorless oil.
53.4% With triethylamine; In dichloromethane; at 20 - 30℃; for 3h;Cooling with ice; Inert atmosphere; (R)-Pyrrolidin-3-ol 7a (348 mg, 4 mmol) and triethylamine (808 mg, 8 mmol) were dissolved in 20 mL of dichloromethane, followed by addition of di-tert-butyl dicarbonate (959 mg, 4.40 mmol) in an ice bath. The reaction solution was warmed up to room temperature and stirred for 3 hours. The resulting solution was mixed with 50 mL of dichloromethane, washed with saturated sodium chloride solution (5 mL×3), dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate 7b (400 mg, yield 53.4%) as a colorless oil.
In dichloromethane; for 16h; a) 1,1-DimethylethyI (3/?)-3-hydroxy-1-pyrrolidinecarboxylateTo a solution of (ft)-3-hydroxypyrrolidine (5 g) dissolved in DCM (50 ml_) was added bis(1 ,1-dimethylethyl) dicarbonate (12.5 g). After stirring for 16 h the mixture was quenched with water (50 mL) and the organic layer separated, dried and evaporated to yield a colourless gum. Crystallisation from hexane gave the title compound as a white solid (4.4 g); [α]D (c=1 , CHCI3) -21.8, δH (400 MHz; CDCI3) 1.46 (9H, s), 2.02 -1.84 (2H, m), 2.31 - 2.25 (1 H, m), 3.51 - 3.31 (4H, m), 4.45 - 4.42 (1 H, m).
With sodium hydrogencarbonate; In tetrahydrofuran; (3R)-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine Under a nitrogen atmosphere, di-tert-butyl dicarbonate (12.53 g, 57.39 mmol) was slowly added in portions to a cold (0-5 C.), stirring solution of (R)-(+)-3-pyrrolidinol (5.00 g, 57.39 mmol) in tetrahydrofuran (30 mL). The light yellow solution was allowed to stir and warm to ambient temperature over several hours. The solution was concentrated (rotary evaporation and high vacuum) to give a yellow oil. The oil was treated with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (3*75 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and vacuum dried to give a yellow oil containing colorless crystals. The product was recrystallized from EtOAc-cyclohexane (~1:1-1:2). The mixture was cooled at 5 C. for 16 h. The off-white crystals were filtered, washed with cyclohexane (2*5 mL) and vacuum dried at 40 C. for 16 h affording 7.36 g (68.5%) of off-white, slightly yellow crystals, mp 62.5-65.5 C., literature mp 62-65 C. (P. G. Houghton et al., J. Chem. Soc. Perkin Trans 1 (Issue 13): 1421-1424 (1993), [α]20.5D-25.0 (c 1.0, CH2Cl2), literature [α]D-22.7 (c 1.0, CH2Cl2). The crystallization liquors were concentrated, and the syrup was cooled at 5 C. The resulting yellow crystals were filtered, washed with cyclohexane and vacuum dried at 40 C. producing an additional 2.98 g of a yellow powder, mp 60.5-62.5 C. bringing the total yield to 10.34 g (96.2%).
With sodium hydrogencarbonate; In tetrahydrofuran; (3R)-N-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine Under a nitrogen atmosphere, di-tert-butyl dicarbonate (12.53 g, 57.39 mmol) was slowly added in portions to a cold (0-5 C.), stirring solution of (R)-(+)-3-pyrrolidinol (5.00 g, 57.39 mmol) in tetrahydrofuran (30 mL). The light yellow solution was allowed to stir and warm to ambient temperature over several hours. The solution was concentrated (rotary evaporation and high vacuum) to give a yellow oil. The oil was treated with saturated NaHCO3 solution (100 mL) and extracted with EtOAc (3*75 mL). The combined EtOAc extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and vacuum dried to give a yellow oil containing colorless crystals. The product was recrystallized from EtOAc-cyclohexane (~1:1-1:2). The mixture was cooled at 5 C. for 16 h. The off-white crystals were filtered, washed with cyclohexane (2*5 mL) and vacuum dried at 40 C. for 16 h affording 7.36 g (68.5%) of off-white, slightly yellow crystals, mp 62.5-65.5 C., literature mp 62-65 C. (P. G. Houghton et al., J. Chem. Soc. Perkin Trans 1 (Issue 13): 1421-1424 (1993), [α]20.5D-25.0 (c 1.0, CH2Cl2), literature [α]D-22.7 (c 1.0, CH2Cl2). The crystallization liquors were concentrated, and the syrup was cooled at 5 C. The resulting yellow crystals were filtered, washed with cyclohexane and vacuum dried at 40 C. producing an additional 2.98 g of a yellow powder, mp 60.5-62.5 C. bringing the total yield to 10.34 g (96.2%).
With triethylamine; In tetrahydrofuran; at 20℃; for 18.1667h; A solution of di-tert-bvtyl dicarbonate (7.5 g, 34.40 mmol) in THF (50 ml) was added (10 min) to a stirred solution of (R)- (+)-3-pyrrolidinol (2.5 g, 28.70 mmol) and triethylamine (6.0 g, 57.40 mmol) in THF (60 ml) at room temperature. The reaction mixture was stirred for another 18 h at room temperature. The solvent was evaporated under reduced pressure and the residue was diluted with EtOAc (200 ml) and washed with water (2 x 100 ml) and brine (100 ml). The EtOAc extract was dried (Na2SO4) and evaporated under reduced pressure to give 4.0 g of the product as a white solid; IR (neat) 3422, 2977, 1676, 1420, 1167 cm4; 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.93-2.08 (m, 2H), 3.34-3.49 (m, 4H), 4.43-4.48 (m, IH).
With triethylamine; In dichloromethane; at 0℃; for 2h; Step 1:(R)-Pyrrolidinol (43.56 g, 0.5 mol) was dissolved in dry CH2C12 (1 L) and cooled with ice- bath to 0 C. To the solution was added Et3 (139.4 mL, 1.0 mol), followed by dropwise addition of (Boc)20 (130.95 g, 0.6 mol) in CH2C12 (160 mL), and keep stirring at 0 C for 2h. To the reaction mixture of Boc-protection was added more of Ets (139.4 mL, 1.0 mol), and followed by dropwise addition of MsCI (42.74 mL, 0.55 mol). After 2 h at 0 C, it was treated with H20 (500 mL) for 10 min, separated, and the aqueous phase was extracted with CH2C12 (300 mL x 2). The combined organic layers was washed with brine (500mL), concentrated and purified by silica column chromatography to give N-Boc prortected mesylate 20 as an oily product (123g, 93%)1H NMR (CDC13, 400 MHz): δ 5.29 - 5.23 (m, 1H), 3.74 - 3.40 (m, 4H), 3.05 (s, 3H), 2.36 - 2.20 (m, 1H), 2.20 - 2.05 (m, 1H), 1.46 (s, 9H).
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2h;pH 11.0; (R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0C. The pH value of the mixture was determined with a pH test paper and was found to be 11. The mixture was then stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml), and a trituated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added little by little thereto at room temperature. The mixture was stirred at room temperature for 18 hr. Water (200 ml) was then added to the reaction solution to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was loaded on a silica gel column and developed with chloroform, followed by development with chloroform only to give an intermediate (11.25 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0C, sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH = 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product in methylene chloride was loaded on a silica gel column and developed with hexane. The development was first carried out with hexane only, subsequently with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.70 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.46 (s, 9H), 1.75 - 1.94 (m, 1H), 2.02 - 2.10 (m, 1 H), 3.35 - 3.55 (m, 31 H), 3.75 - 3.86 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.705 - 4.90 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.42 (d, J = 6.4 Hz, 1 H), 9.20 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 314 (M++1)
In dichloromethane; at 20℃; for 2.5h; Commercial alcohol 55 (775 mg, 9 mmol), BoC2O (2.33 g,10.6 mmol), in CH2Cl2 (40 mL), were allowed to stirr for 2 hours 30 minutes at room temperature. Then the reaction mixture was diluted with diluted with CH2Cl2 (20 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 N-Boc pyrrolidnol as an oil.

Reference: [1]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 969 - 973
[2]Patent: WO2015/9731,2015,A2 .Location in patent: Paragraph 00106
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 4983 - 4994
[4]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5812 - 5832
[5]Patent: WO2010/84767,2010,A1 .Location in patent: Page/Page column 86
[6]Patent: WO2004/37797,2004,A2 .Location in patent: Page 176
[7]ChemMedChem,2014,vol. 9,p. 1476 - 1487
[8]Patent: CN105153133,2018,B .Location in patent: Paragraph 0022; 0023; 0024; 0027; 0028
[9]Patent: EP1950198,2008,A1 .Location in patent: Page/Page column 14
[10]Journal of the American Chemical Society,2002,vol. 124,p. 15267 - 15279
[11]Angewandte Chemie - International Edition,2018,vol. 57,p. 12102 - 12105
    Angew. Chem.,2018,vol. 130,p. 12278 - 12281,4
[12]Patent: EP2803664,2014,A1 .Location in patent: Paragraph 0136; 0137
[13]Patent: US2015/5282,2015,A1 .Location in patent: Paragraph 0194; 0195
[14]Chemische Berichte,1997,vol. 130,p. 385 - 397
[15]Patent: WO2006/50940,2006,A1 .Location in patent: Page/Page column 56
[16]Patent: US2001/14691,2001,A1
[17]Patent: US2001/31771,2001,A1
[18]Patent: WO2006/40625,2006,A1 .Location in patent: Page/Page column 47
[19]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 170 - 174
[20]Journal of Medicinal Chemistry,2008,vol. 51,p. 4601 - 4608
[21]Patent: WO2011/160020,2011,A2 .Location in patent: Page/Page column 65
[22]Patent: EP1550660,2005,A1 .Location in patent: Page/Page column 9
[23]Patent: WO2008/133734,2008,A2 .Location in patent: Page/Page column 39-40
  • 4
  • [ 109431-87-0 ]
  • [ 98-59-9 ]
  • [ 139986-03-1 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine;dmap; In dichloromethane; at 20℃; for 8h; The above alcohol (7.3 g, 39 mmol), p-TsCl (8.2 g, 43 mmol), Et3N (9.8 g, 97 mmol), DMAP (240 mg) in CH2Cl2 (100 mL) were allowed to stirr for 8 hours at room temperature. Then the reaction mixture was washed with brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated. Purification of the resulting crude by flash silica gel chromatography provided the ester in quantitative yield
94% With dmap; triethylamine; In dichloromethane; at 20℃; for 12h; Compound (R) -3-hydroxypyrrolidine-1-carboxylic acid third butyl ester 1a (3.5g, 18.7mmol), triethylamine (5.25mL, 37.9mmol), 4-dimethylaminopyridine (0.35g, 2.87mmol) were dissolved in dichloromethane (50mL), and p-toluenesulfonyl chloride (5.4 g, 28.1 mmol), and the reaction mixture was stirred at room temperature for 12 hours.Dilute with water (50 mL) and extract with ethyl acetate (100 mL x 3).The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product (R)- 3- (Toluenesulfonyloxo) pyrrolidine-1-carboxylic acid third butyl ester 1b (6.0 g, yellow oil), yield: 94%.
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (ix); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)- (-)-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from O0C to rt. TLC (5 % MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3. 1H NMR (CDCl3, 300MHz): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (v); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(- )-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich, 10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight at a temperature from about 0 C to rt. TLC (5% MeOH in DCM for SM and DCM for product) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred for 30 min. and 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by <n="27"/>NaHCθ3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3.1H NMR (CDCl3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
82.8% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; Intermediate (ix); 3-(3R)-(Toluene-4-sulfonyloxy)-pyrrolidine-l-carboxylic acid tert-butyl ester; A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)- (-)-N-BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from O0C to rt. TLC (5 % MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (IM, 2 x 5OmL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8 %). MS: 363 (M+Na+); TLC (DCM) Rf= 0.3. 1H NMR (CDCl3, 300MHz): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, IH), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (iii) (R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a250ml addition funnel was added p-tosyl chloride (58g, 305mmol, 1.5eq) and 600ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65ml) and DMAP (2.65g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38g, 203 mmol, 1.0eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 75Og silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%). MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice-water bath; Intermediate (ix)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (v)(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester To a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 ml addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 ml of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65 g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 eq) in 200 ml of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic layer was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 mL), and brine (200 mL). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52 g, 75%).MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i) (R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCIs, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With triethylamine;dmap; In dichloromethane; at 20℃;cooling with ice-water; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
75% With dmap; triethylamine; In dichloromethane; at 20℃;Cooling with ice; Intermediate (i)(R)-3-(Toluene-4-sulfon loxy)-pyrrolidine-1 -carboxylic acid tert-butyl esterTo a 2L round-bottom flask equipped with a mechanical stirring rod and a 250 mL addition funnel was added p-tosyl chloride (58 g, 305 mmol, 1 .5 eq) and 600 mL of anhydrous DCM. The solution was cooled with ice-water bath. Et3N (65 ml) and DMAP (2.65g) were added. A solution of (3R)-(-)-N-Boc-hydroxy pyrrolidine (38 g, 203 mmol, 1 .0 eq) in 200 mL of DCM was added slowly. The reaction mixture was allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rf value of 0.3 in DCM. The reaction was cooled by ice-water bath. Polymer-supported trisamine (32 g) was added and stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 ml of DCM. The organic solution was washed with 200 mL of H3PO4 (1 M) solution twice, followed by saturated NaHCO3 solution (200 ml), and brine (200 ml). The organic phase was dried over K2CO3. After concentration, the crude product was purified by a 750 g silica gel cartridge (DCM to 5% MeOH in DCM) to afford 52 g (75% yield) of the title compound as a beige oil.MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.1 H NMR (CDCI3, 300MHz), δ (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1 .43 (s, 9H).
74% With pyridine; at 20℃; for 16h; To a stirred solution of R-(-)-N-Boc-3-pyrrolidinol (5.03 g, 26.9 mmol) in pyridine (30.0 mL) was added p-TsCl (5.63 g, 30.0 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200.0 mL) and 1.0 N hydrochloric acid (200.0 mL) and separated. The organic layer was washed with water (2 * 100 mL), saturated sodium chloride (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 80:20 to 50:50 heptane/ethyl acetate) to provide tert-butyl 3-(tosyloxy)pyrrolidine-1-carboxylate (6.79 g, 74%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 5.05 (br s, 1H), 3.48-3.38 (m, 4H), 2.46 (s, 3H), 2.17-1.91 (m, 1H), 1.91-1.71 (m, 1H), 1.46 (s, 9H).
25% With dmap; triethylamine; In dichloromethane; at 20℃; for 10h;Inert atmosphere; A mixture of (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) , p-methyl benzene sulfonic chloride (1.5 g, 8.0 mmol) , triethylamine (1.1 g, 11 mmol) and N, N-dimethylaminopyridine (65 mg, 0.53 mmol) in DCM (10 mL) was stirred at rt for 10 h and diluted with water (20 mL) . The resulting mixture was extracted with DCM (10 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 5/1 to give (R) -tert-butyl 3- (tosyloxy) pyrrolidine-1-carboxylate as colorless liquid (460 mg, 25) .1H NMR (400 MHz, CDCl3) : δ ppm 7.79 (d, J 8.0 Hz, 2H) , 7.35 (d, J 7.7 Hz, 2H) , 5.04 (s, 1H) , 3.38-3.50 (m, 4H) , 2.45 (s, 3H) , 1.97-2.15 (m, 2H) , 1.43 (m, 9H) and MS-ESI: m/z 286.20 [M-55] +.

  • 5
  • [ 24424-99-5 ]
  • (R)-N-benzyl-3-hydroxypyrrolidine [ No CAS ]
  • [ 109431-87-0 ]
YieldReaction ConditionsOperation in experiment
86% In methanol; water; a (3R)-N-tert-Butyloxycarbonylpyrrolidin-3-ol A mixture of (3R)-N-benzylpyrrolidin-3-ol (Aldrich; 5.00 g, 28.2 mmol), di-tert-butyldicarbonate (7.39 g, 33.8 mmol), Pearlmans catalyst (0.55 g), methanol (200 ml) and water (20 ml) were hydrogenated at 40 psi in a Parr apparatus for 2 h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. The crude product was chromatographed on silica gel eluding with ethyl acetate/hexane (1:1) to give the title-pyrrolidinol (4.55 g, 86%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.03 (2H, m, CH2),2.07 (1H, s, OH), 3.33-3.50 (4H, m, 2 of CH2), 4.42-4.48 (1H, m,CH--OH).
  • 6
  • [ 100-39-0 ]
  • [ 109431-87-0 ]
  • [ 177947-67-0 ]
YieldReaction ConditionsOperation in experiment
96.5% In a 10L dry reactor,Add 60% sodium hydride (133g, 0.55mol) and dry THF (5400ml),Cool to 0 C ~ 5 C, at this temperature,A solution of (R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (467 g, 2.5 mol) in anhydrous THF (1800 ml) was added dropwise, and the mixture was stirred for 1 h, and the absence of benzyl bromide (500 g, 2.9 mol) was added. Water THF (360 ml) solutionTetrabutylammonium bromide (90 g, 0.29 mol) was stirred at room temperature for 20 h. TLC was used to identify the end point of the reaction [developer:Ethyl acetate (v):methanol (v):dichloromethane (v)=5:2:5]. After completion of the reaction, water (2800 ml) was added, stirred for 10 min, and extracted with ethyl acetate (2200 ml×3). The organic layer was successively watered (1500 mL x 3)Wash with saturated sodium chloride solution (1500mL x 3),Anhydrous Na2SO4 is dried, filtered, and the filtrate is concentrated under reduced pressure.A yellow oil (R)-N-tert-butoxycarbonyl-3-benzyloxypyrrolidine 663 g, 96.5%,The HPLC normalized content was 95.8% and was directly used in the next step reaction.
76% In tetrahydrofuran; water; b (3R)-N-tert-Butyloxycarbonyl-3-benzyloxypyrrolidine A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.25 g, 12.0 mmol), in anhydrous THF (10 ml) was added portionwise to a slurry of sodium hydride (60% dispersion in oil, 0.63 g, 13.8 mmol) in THF (35 ml) and the mixture stirred for 0.3 h at 0 C. A solution of benzyl bromide (2.37 g, 13.8 mmol) in dry THF (2 ml) was added and the mixture warmed to room temperature and stirred for 18 h. Water (70 ml) was added and the mixture extracted with ethyl acetate (3*100 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluding with CH2 Cl2 /MeOH (100:0→97:3) to give the desired product (2.53 g, 76%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2), 3.42-3.50 (4H, m, 2 of CH2), 4.10-4.16 (1H, m, CH--OBn), 4.53 (2H, s, OCH2 Ar), 7.26-7.39 (5H, m, Ar).
68% To the stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 3 g, 16.04 mmol, 1.0 eq) in DMF (30 mL), then the reaction mixture was cooled at 0 C and added NaH (1.9 g, 80.2 mmol, 5.0 eq) followed by benzyl bromide (3.13 mL, 19.24 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for about 3 hours. The reaction mixture was diluted with water and extracted with CH2C12. The combined organic extracts were dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% ethylacetate and hexane as an eluent to afford the desired product (3.0 g, yield: 68.0%) as a white solid.
55.9% With sodium ethanolate; In tetrahydrofuran; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
32.8% With sodium methylate; In tetrahydrofuran; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
5.6% With sodium hydroxide; In tetrahydrofuran; water; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; To a solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (3.2 mmol) in dimethyl formamide (10 mL) was added sodium hydride (3.2 mmol) and benzyl bromide (3.2 mmol) at 0 C. and the resulting mixture was stirred at room temperature. After stirring overnight, distilled water (50 mL) was added and the resulting precipitate was collected by filtration to afford D1.

  • 7
  • [ 108-24-7 ]
  • [ 109431-87-0 ]
  • [ 101408-94-0 ]
YieldReaction ConditionsOperation in experiment
0.87 g With pyridine; dmap; In dichloromethane; at 20℃; for 4h; Crude tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate, prepared from (R)-3-hydroxylpyrrolidine hydrochloride (R)-2a·HCl (0.50 g, 4.1 mmol) by the above-described procedure, was dissolved in anhydrous CH2Cl2 (20 mL). Pyridine (0.98 mL, 12.1 mmol), Ac2O (0.77 mL, 8.1 mmol) and DMAP (25 mg, 0.20 mmol) were added, and the reaction mixture was stirred at rt for 4 h before being quenched with water. The layers were separated, and the aqueous layer was extracted three times with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 3:1) to give 0.87 g of tert-butyl (R)-3-acetoxypyrrolidine-1-carboxylate [93% from (R)-2a·HCl]. A colorless oil, -16.1 (c=0.90, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 1.44 (9H, s), 1.94-2.05 (5H, m), 3.33-3.56 (4H, m), 5.24 (1H, br). 13C NMR (125 MHz, CDCl3) δ: 21.1, 28.4, 30.7, 31.5, 43.6, 43.9, 51.4, 51.8, 72.9, 73.8, 79.5, 154.3, 154.4, 170.5, 170.6. IR (CHCl3): 1735, 1689, 1685 cm-1. HRMS Calcd for C11H19NNaO4 [(M+Na)+] m/z: 252.1206, found: 252.1183.Similarly to the preparation of (R)-1d, 230 mg of (R)-1e (74%, 99% ee) and 76 mg of (R)-4-acetoxy-1-pyrroline N-oxide (R)-4e (24%) were obtained from tert-butyl (R)-3-acetoxypyrrolidine-1-carboxylate (500 mg, 2.2 mmol). The optical purity of (R)-1e was determined by Daicel CHIRALCEL OZ-3 [hexane-iPrOH, 80:20, 2.0 mL/min; retention times 34.5 (R), 41.4 min (S)].(R)-1e. A pale yellow oil, +215 (c=0.42, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.08 (3H, s), 2.25 (1H, dddd, J=2.0, 4.0, 8.0, 14.5 Hz), 2.64-2.73 (1H, m), 3.93 (1H, dddd, J=2.0, 4.0, 9.0, 14.0 Hz), 4.15-4.24 (1H, m), 5.72-5.77 (1H, m), 6.99 (1H, q, J=2.0 Hz). 13C NMR (125 MHz, CDCl3) δ: 20.8, 26.8, 61.3, 73.8, 132.2, 170.4. IR (CHCl3): 1744, 1582, 1242 cm-1. HRMS Calcd for C6H9NNaO3 [(M+Na)+] m/z: 166.0475, found: 166.0493.(R)-4-Acetoxy-1-pyrroline N-oxide [(R)-4e]. A pale yellow oil, -23.7 (c=0.35, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.08 (3H, s), 2.78 (1H, d, J=22.0 Hz), 3.17 (1H, ddd, J=1.5, 7.0, 22.0 Hz), 3.92 (1H, d, J=15.0 Hz), 4.30 (1H, ddd, J=1.5, 7.0, 15.0 Hz), 5.42 (1H, t, J=7.0 Hz), 6.87 (1H, t, J=1.5 Hz). 13C NMR (125 MHz, CDCl3) δ: 20.8, 36.3, 67.4, 67.6, 134.2, 170.2. IR (CHCl3): 1743, 1595, 1238 cm-1. HRMS Calcd for C6H9NNaO3 [(M+Na)+] m/z: 166.0475, found: 166.0480.
  • 8
  • [ 101385-93-7 ]
  • [ 109431-87-0 ]
YieldReaction ConditionsOperation in experiment
92% With recombinant Chryseobacterium sp. CA 49 ketoreductase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 40℃; for 10h;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.
  • 9
  • [ 109431-87-0 ]
  • [ 569660-89-5 ]
YieldReaction ConditionsOperation in experiment
100% With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 5℃; for 0.0833333h; To a 100 mL round bottom flask was added (R)-(-)-N-Boc-3-pyrrolidinol (1.5 g) under an argon atmosphere. CBr4 (1.5 g) was then added followed by dry THF (50 mL) and the mixture was cooled to 5 C. PPh3 was then added over 5 min and the progress was followed by TLC. The solid was removed by filtration and washed with ether. The filtrate was concentrated and purified by column chromatography eluting with 1:3 EtOAc:Hx. Yield: 2.3 g (>100%, used without further purification). 1H-NMR (CDCl3) δ 4.48 (br s, 1H), 3.82-3.65 (m, 2H), 3.62-3.46 (m, 2H), 2.38-2-18 (m, 2H), 1.46 (s, 9H).
90% With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 60℃; for 1h; Example 8; (R)-N-(2-methoxybenzyl)-1-(1-(2-(methylamino)ethyl)pyrrolidin-3-yl)-3-(trifluoromethyl)-1 H- pyrazole-5-carboxamide (78); <n="77"/>Step 1 (S)-tert-butyl 3-bromopyrrolidine-i-carboxylate (72); [0251] To a stirred solution of N-Boc-(R)-3-hydroxypyrrolidine (0 936 g, 5 mmol) in THF (25 ml_) was added carbon tetrabromide (2 487 g, 7 50 mmol) followed by triphenylphosphine(1 967 g, 7 50 mmol) The resulting suspension was allowed to stir at 60 0C for 1 h Insoluble material was filtered, and concentrated The residue was purified by silica gel column chromatography with a gradient of EtOAc (5-30%) in hexanes to afford 72 (1 12 g, 90%) as a colorless oil LRMS (ESI) calc 249 0, found 271 9 (MNa)+
  • 10
  • [ 109431-87-0 ]
  • [ 98-74-8 ]
  • [ 612501-59-4 ]
YieldReaction ConditionsOperation in experiment
59% With pyridine; In dichloromethane; at 10 - 20℃; The 4- (3-chloro-2-fluoroanilino)-6- [ (3S)-1-tert-butoxycarbonylpyrrolidin-3-yloxy]-7- methoxyquinazoline starting material was prepared as follows: A solution of 4-nitrobezenesulfonyl chloride (4.44 g) in methylene chloride (50 ml) was added to a stirred solution of tert-butyl 3-(R)-hydroxypyrrolidine-l-carboxylate (3.75g) and pyridine (2.5 ml) in methylene chloride (30 ml) at 10C and the mixture allowed to warm to ambient temperature with stirring. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum to give tert-butyl3- (R)- [ (4- nitrophenyl) sulfonyloxy] pyrrolidine-l-carboxylate as a yellow crystalline solid. (4.37g, 59%); H NMR Spectrum: (CDC13) 1.43 (s, 9H), 1.80-2. 40 (m, 2H), 3.30-3. 65 (m, 4H), 5.20 (bs, 1H), 8. 10 (d, 2H), 8. 42 (d, 2H).
  • 11
  • [ 109431-87-0 ]
  • [ 752242-26-5 ]
  • [ 1001420-31-0 ]
YieldReaction ConditionsOperation in experiment
92% With 4,4-(dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium; In dichloromethane; toluene; at 20℃; for 3h; To a solution of Example 101 Part A compound (300 mg, 1.427 mmol) and (R) tert-butyl-3-hydroxypyrrolidine-carboxylate (534 m g, 2.85 mmol) in toluene (2 mL) was added a suspension of Example 97 Part B compound (1.17 g, 2.85 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 3 h, then was concentrated in vacuo. The residue was chromatographed (SiO2; continuous gradient 10% EtOAc/Hex to 60% EtOAc/Hexane) to give Part A compound (500 mg, 92%) as a white solid. [M+H]+=402; 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J=6.15 Hz, 6 H), 1.39 (d, J=7.47 Hz, 9 H), 1.95-2.22 (m, 2 H), 3.25-3.46 (m, 4 H), 3.47-3.58 (m, 1 H), 3.82 (s, 3 H), 4.61-4.73 (m, 1 H), 5.07 (s, 1 H), 6.76 (t, J=2.42 Hz, 1 H), 7.00 (s, 1 H), 7.03 (s, 1 H).
  • 12
  • [ 109431-87-0 ]
  • [ 474023-54-6 ]
YieldReaction ConditionsOperation in experiment
70% Step A: f2S.4RVl-Boc-2-allyl-4-hydroxypyrroridine; [460] (3R)-l-BOC-3-hydroxypyrrolidine (1 g, 5.34 mmol) was dissolved in diethylether (50ml), and filled with nitrogen. The reaction mixture was cooled to -78C, N,N,N',N'-tetramethylethylenediamine (620 mg, 5.34 mmol) was added, and sec- butyllithium (1.4M cyclohexane solution 4.45 ml, 6.23 mmol) was slowly added. After being stirred for 30 min at the same temperature, dimethylsulfate (1.44 g, 10.68 mmol) was dissolved in diethylether (10 ml). The reaction solution was slowly heated to rt, diluted with water (12 ml), and extracted with diethylether. The organic extracts were dried over MgSO 4 , and the residue was purified by column chromatography (eluent,EtOAc/Hex = 1/4) to give the title compound (840 mg, 70 %).[461] MS[M+H] = 228(M+1)
  • 13
  • [ 524-38-9 ]
  • [ 109431-87-0 ]
  • [ 952747-25-0 ]
YieldReaction ConditionsOperation in experiment
59% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18.1667h; (R)-3 -Hydroxy-pyrrolidine- 1-carboxylic acid tert-butyl ester (1.37 g, 7.31 mmol) was dissolved in THF (20 mL), 2-hydroxy-isoindole-l,3-dione (1.19 g, 7.31 mmol) and triphenyl phosphine (1.92 g, 7.31 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (1.33 mL, 8.04 mmol) over 10 minutes. The reaction mixture was allowed to stir at ambient temperature for 18 hours then the solvent was evaporated. The residue was purified by flash column chromatography (Si-SPE, DCM: EtOAc, gradient 100:0 to 80:20) to provide the title compound as a colourless oil (1.43 g, 59%). IH NMR (CDCl3, 400MHz) 7.86 (m, 2H), 7.77 (m , 2H), 4.94-5.02 (m, IH), 3.66-3.84 (m, 2H), 3.50-3.65 (m, 2H), 2.24-2.32 (m, IH), 1.93-2.05 (m, IH), 1.49 (s, 9H).
59% Step 3: Preparation of (5)-3-[(l,3-dihydro-l,3-dioxo-isoindol-2-yl)oxy]pyrrolidine-l- carbox lic acid tert- butyl ester (X): To a stirred solution of di-isopropyl azodicarboxylate (97.17 g, 0.481 mol) in tetrahydrofuran (1200 ml), a solution triphenyl phosphine (125.9 g, 0.481 mol) in tetrahydrofuran (300 ml) was added at temperature below -10C. The resulting reaction mixture was stirred for further 45 minute at the same condition and a solution of (3i?)-l- (ieri-butoxycarbonyl)-3-hydroxypyrrolidine (IX) (60 g, 0.3204 mol) in tetrahydrofuran (300 ml) was added over a period of 15 minute. After another 45 minute of stirring, N- hydroxy phthalimide (52.4 g, 0.3204mol) was added in one portion to the reaction mass. The reaction mixture was allowed to warm to room temperature and stirred for 16 hour. The completion of the reaction was monitored by thin layer chromatography. After completion of reaction, the solvent was evaporated under reduced pressure. The residue thus obtained was stirred with di-isopropyl ether (600 ml). The precipitate formed was filtered under suction. The filtrate was concentrated under reduced pressure and the residual mass was purified by silica gel (60-120 mesh) column chromatography using 1-5 % mixtures of acetone: hexane as an eluent. The solvent from the combined fractions was evaporated to obtain 63 g of (5)-3-[(l,3-dihydro-l,3-dioxo-isoindol-2-yl)oxy]pyrrolidine- 1-carboxylic acid tert-buty ester (X), as a white solid, in 59% yield. Analysis: Melting point: 112-115C; Mass: 333.2 (M+l); for Molecular Weight of 332.36 and Molecular Formula of 1H NMR (400 MHz, CDC13): 57.86-7.83 (m, 2H), 7.78-7.75 (m, 2H), 4.99 - 4.94 (d, 1H), 3.80 - 3.68 (m, 2H), 3.60 - 3.53 (m, 2H), 2.28-2.25 (m, 1H), 2.02 (m, 1H), 1.48 (s, 9H).
41% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; Diethyl azodicarboxylate (17.4 g, 100 mmol) was added to a solution of (R)-tert-butyl 3- hydroxypyrrolidin-1-carboxylate (9.40 g, 50.0 mmol), 2-hydro xyisoindoline-l,3-dione (8.16 g, 50.0 mmol) and triphenylphosphine (26.2 g, 100 mmol) in tetrahydrofuran (100 ml) at 0C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl <n="65"/>acetate/petroleum ether: 5/95 to 12.5/87.5) to give (S)-tert-butyl 3~(l,3-dioxoisoindoline-2- yl oxy)pyrrolidin-l-carboxylate (6.74 g, 41%) as a white solid: LCMS: 277 [M-55]+
35% With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 0 - 20℃; for 27h; To a solution of (λ)-iV-«ert-butoxycarbonyl-3-pyrrolidinol (4.00 g), triphenylphosphine (11.80 g) and N-hydroxyphthalimide (7.40 g) in THF (280 ml) at 0C, l,l'-(azodicarbonyl)dipiperidine (12.6 g) was added. After stirring at RT for 27 h, the solvent was evaporated and the crude product was purified by flash chromatography (SiC^, DCM/«-hexane/acetone 5/4/1) to give (S)-I- tert-butoxycarbonyl-3-O-phthalimidoxypyrrolidine (2.50 g, 35%).1H-NMR (300 MHz, DMSOd6, ppm from TMS): δ 7.86 (m, 4H), 4.89 (IH, m), 3.64-3.30 (m, 4H), 2.20-1.90 (m, 2H), 1.41 (s, 9H).

  • 14
  • [ 83220-73-9 ]
  • [ 81107-97-3 ]
  • 3-(2-piperazin-1-yl-trifluoromethyl-phenoxy)-S-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
The title compound was prepared by using Mitsunobu followed by Buchwald condition from <strong>[81107-97-3]2-bromo-4-trifluoromethyl phenol</strong> and N-boc-R-3-pyrrolidinol. MS 416.3 (M+1)
  • 15
  • [ 109431-87-0 ]
  • [ 479253-00-4 ]
YieldReaction ConditionsOperation in experiment
26% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 1.25h; 1) (3S)-3-Fluoropyrrolidine-1-carboxylic acid tert-butyl ester Diethylaminosulfur trifluoride (2.22 mL) was added to a solution of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g) in dichloromethane (50 mL) at - 78C, and the resultant mixture was stirred for 75 minutes at room temperature. The reaction solution was poured into ice water and partitioned. The organic layer was dried over anhydrous magnesium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain (3S)-3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (676 mg, 26%) as an oily product. 1H-NMR(400MHz, CDCl3)δ: 1.45(9H, s), 2.17-2.26(1H, m), 3.52-3.68(5H, m), 5.20(1H, dt, J=52.7, 3.4Hz).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at -78 - 20℃; Slowly add [bis(2-methoxyethyl)amino]sulfur trifluoride (2.40 mL, 13.03 mmol) to a solution of iV-Boc-(i?)-(-)-3-pyrrolidinol (2.00 g, 10.86 mmol) in anhydrous dichloromethane (10 mL), at -78 C and under nitrogen. Allow the reaction mixture to warm to room temperature and stir overnight. Carefully add an aqueous solution of sodium hydrogen carbonate (saturated, 20 mL) and extract with dichloromethane. Concentrate the combined organic extracts under vacuum then purify using automated flash chromatography (ISCO System, 120 g Redisep Si02 column; 0 - 40% ethyl acetate in cyclohexane gradient elution over 30 minutes at 85 mL/min) to give the title compound as a pale yellow liquid (1.67 g): MS (m/e): 212 (M+23).
With diethylamino-sulfur trifluoride; In 1,2-dichloro-ethane; at -30 - 20℃; for 15h; To a well stirred and cooled (-30 C) solution of Step 1 intermediate (1.5 g, 8.01 mmol) in dichloroethane (50 ml) was added diethylaminosulphur trifluoride (1.94 mg, 12.01 mmol) under nitrogen and the reaction mixture was maintained at this temperature for 1 h. The reaction mixture was EPO <DP n="49"/>gradually allowed to warm to room temperature and stirring was continued for another 14 h. The reaction mixture was poured onto a mixture of ice and solid NaHCO3 and stirred till no effervescence was seen. The mixture was diluted with water and extracted with dichloromethane (3 x 100 ml). The combined organic extracts were washed with water, brine and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography (25 % ethyl acetate in petroleum ether) to give 840 mg of the desired compound as yellow oil; IR (neat) 3500, 2978, 1698, 1407 cm"1; 1H NMR (CDCl3, 300 MHz) δ 1.44 (s, 9H), 1.89-2.28 (m, 2H), 3.44-3.77 (m, 4H), 5.11-5.31 (m, IH).
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 0 - 20℃; for 1h; To a solution OF 3- (R)-HYDROXY-PYRROLIDINE-1-CARBOXYLIC acid ter-butyl ester (200mg) in CH2CI2 (10ML) is added [bis (2-methoxyethyl) AMINO] SULFER TRIFLUORIDE (236uL) at 0C, and stirred for 1HR at room temperature. The reaction mixture is poured in aqueous NaHC03 and extracted with Et20. The organic layer is successively washed with H20 and aqueous NACI, dried over MgS04, and concentrated in vacuo. The residue is purified by column chromatography to give a colorless oil.

  • 16
  • [ 24424-99-5 ]
  • [ 104706-47-0 ]
  • [ 109431-87-0 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine; In dichloromethane; at 0 - 20℃; for 0.12h; To a stirred solution of (R)-pyrrolidin-3-ol hydro chloride (3.0 g, 24.2 mmol) in DCM (30 ml), were added N(Et)3(10.2 ml, 72.8 mmol) and (Boc)20 (6 ml, 26.7 mmol) at 0 C. The reaction mixture was allowed to stir at room temperature for about 12 hours. After 12 hours of stirring, saturated NH4C1 was added. The solution was extracted with EtOAc (2x60 mL). The combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by flash chromatography with EtOAc-hexane (4: 6) as an eluent to afford the desired product (4.5 g, yield: 99%) as an oil.
99% To the stirred solution of ( ?)-pyrrolidin-3-ol hydrochloride (10 g, 81 mmol) in dichloromethane (80 ml):methanol (20 ml) mixture at 0 C, triethylamine (22.6 ml, 160 mmol) was added and stirred for 10 min. Boc-anhydride (22.5 ml, 97 mmol) was added drop wise at 0 C. The reaction mixture heated to 25 C and stirred for 16 h. Upon completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure. The residue was diluted with water (50 ml) and the product was extracted thrice with ethyl acetate (150 mL). The combined ethyl acetate layer was washed once with water (20 mL). The ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain tert- butyl (R)-3-hydroxypyrrolidine-l-carboxylate (15 g, 80 mmol, 99 % yield).
96% With potassium carbonate; In tetrahydrofuran; water; (Example 1) N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine 124 g of (R)-3-hydroxypyrrolidine hydrochloride was dissolved in 187 g of distilled water and neutralized by adding 217g of aqueous solution of potassium carbonate (containing 72 g of potassium carbonate). 431 g of THF solution of di-tert-butyl dicarbonate (containing 214 g of di-tert-butyl dicarbonate) was dropped into the solution. After stirring for a while, an extraction was carried out with 565 g of toluene, and the mixture was concentrated, thereby obtaining 180 g of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine (yield of 96 %). 1H-NMR(CDCl3):δ(ppm)1.48 (s,9H),1.86-2.04(m,3H),3.26-3.56(m, 4H),4.45(m,1H).
71% With dmap; triethylamine; In dichloromethane; at 0 - 5℃; for 2h; Step 2: Preparation of (3R)-l-(tert-butoxycarbonyl)-3-hydroxypyrrolidine (IX): To a stirred suspension of 3-(i?)-hydroxypyrrolidine hydrochloride (VIII) (110 g, 0.9 mol) in dichloromethane (1100 ml), triethylamine (273 g, 2.7 mol) was added at 0- 5C. After 5 minute of stirring di-feri-butyldicarbonate [(Boc)20] (245 g, 1.125 mol) was added to the reaction mixture in small portions, followed by 4-dimethylaminopyridine (10.99 g, 0.09 mol). The reaction mixture was stirred for 2 hour and then poured in to water (1100 ml). The organic layer was separated and washed with saturated ammonium chloride solution (1x1100 ml) and water (1100 ml). The organic layer was dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure. The residue was purified by silica gel (60-120 mesh) column chromatography using 1-5% mixtures of acetone: hexane as an eluent. The combined fractions were evaporated, to obtain the 118 g of (3i?)-l-(ieri-butoxycarbonyl)-3-hydroxypyrrolidine (IX), as a white solid, in 71 % yield. Analysis: Melting point: 55 - 58C; Mass: 188 (M+l); for Molecular Weight of 187.24 and Molecular Formula of C9H17N03; and 1H NMR (400MHz, CDC13): 54.428 - 4.424 (s, 1H), 3.46 - 3.43 (m, 2H), 3.37 - 3.28 (m, 2H), 2.36 - 2.30 (d, 1H), 2.00 - 1.86 (m, 2H), 1.44 (s, 9H).
70% With triethylamine; In methanol; at 0 - 20℃; Di-tert-butyl dicarbonate (1.6 g, 7.3 mmol) was added to a solution of (R)-3-pyrrolidinol hydrochloride (1.0 g, 8.1 mmol) in MeOH (20 mL) and triethylamine (3.4 mL, 24.3 mmol) at 0 C. The reaction was stirred overnight while warming to rt. Solvent was removed in vacuo. The residue was diluted with EtOAc (50 mL), washed with water (40 mL*3), washed with brine (50 mL), dried (Na2SO4), and concentrated to give 950 mg (70%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.37 (9H, s), 1.60-1.90 (2H, m), 3.00-3.30 (4H, m), 4.19 (1H, m), 4.87 (1H, d, J=2.8 Hz).
With dmap; triethylamine; In dichloromethane; at 20℃; for 2.25h; Solid di-tert-butyldicarbonate (38.8g, 178mmol) was added in portions over 15 minutes to a stirred solution of (3R)-pyrrolidin-3-ol hydrochloride (20g, 162mmol), triethylamine (24.8mL, 178MMOL) and 4- (DIMETHYLAMINO)-PYRIDINE (DMAP) (20mg) in dry dichloromethane (300mL). After stirring for 2 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 60: 40), to give the title compound as a solid
With dmap; In dichloromethane; at 20℃; for 2h; Solid ditert-butyldicarbonate (38. 8G, 178mmol) was added in portions over 15 minutes to a stirred solution of (3R)-pyrrolidin-3-ol hydrochloride (20g, 162MMOL), triethylamine (24. 8mL, 178mmol) and 4- (dimethylamino)-pyridine (20mg) in dry dichloromethane (300mL). After stirring for 2 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 60: 40), to give the title compound as a solid.
With dmap; triethylamine; In dichloromethane; at 20℃; for 2.25h; Solid ditert-butyldicarbonate (38.8g, 178mmol) was added in portions over 15 minutes to a stirred solution of (3R)-pynolidin-3-ol hydrochloride (20g, 162mmol), triethylamine (24.8mL, 178mmol) and 4- (DIMETHYLAMINO)-PYRIDINE (20mg) in dry dichloromethane (300mL). After stirring for 2 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MGS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 60: 40), to give the title compound as a solid.
With dmap; triethylamine; In dichloromethane; at 20℃; for 2.25h; Solid ditert-butyldicarbonate (38.8g, 178mmol) was added in portions over 15 minutes to a stirred solution of (3R)-pyrrolidin-3-ol hydrochloride (20g, 162mmol), triethylamine (24. 8mL, 178mmol) and 4- (dimethylamino)-pyridine (20mg) in dry dichloromethane (300mL). After stirring for 2 hours at room temperature, the mixture was washed with aqueous citric acid, then brine. The organic extracts were dried (MgS04), filtered and evaporated in vacuo to give an oil. This was purified by flash chromatography on silica, eluting with ethyl acetate/cyclohexane (20: 80 to 60: 40), to give the title compound as a solid.
With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 1.5h; Boc2O (1.02 mL, 4.5 mmol) was added to a solution of (R)-3-hydroxylpyrrolidine hydrochloride (R)-2a·HCl (0.50 g, 4.1 mmol) in THF-satd NaHCO3 (1:1, 20 mL), and the reaction mixture was stirred at rt for 1.5 h. EtOAc was added, and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate, which was used for the following reaction without further purification.The above-described tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate was dissolved in anhydrous DMF (20 mL), to which was added NaH (55% oil suspension, 0.71 g, 16.2 mmol) at 0 C. The ice-cold reaction mixture was stirred for 30 min, and Me2SO4 (0.77 mL, 8.1 mmol) was then added. The reaction mixture was stirred overnight at 50 C before being quenched with water. Hexane-EtOAc (1:1) was added, the layers were separated, and the aqueous layer was extracted three times with hexane-EtOAc (1:1). The combined organic layer was washed two times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 2:1) to afford 0.69 g of tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate [85% from (R)-2a·HCl]. A colorless oil, -8.4 (c=0.52, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 1.44 (9H, s), 1.84-2.02 (2H, m), 3.31 (3H, s), 3.34-3.49 (4H, m), 3.91 (1H, brs). 13C NMR (125 MHz, CDCl3) δ: 28.5, 30.0, 31.1, 43.5, 43.9, 50.3, 51.1, 56.5, 79.09, 79.14, 79.9, 154.5, 154.6. IR (CHCl3): 1686, 1416 cm-1. HRMS Calcd for C10H19NNaO3 [(M+Na)+] m/z: 224.1257, found: 224.1248.Under a nitrogen atmosphere, 4 M HCl in EtOAc (1.2 mL) was added to tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate (50 mg, 0.25 mmol) at 0 C. The solution was stirred at rt for 30 min and concentrated in vacuo. The residue was dissolved in MeCN-water (10:1, 2.5 mL). Aqueous NH3 (30% w/w, 35 μL, 0.62 mmol) and 3 (162 mg, 0.62 mmol) were added to the solution at 0 C. The reaction mixture was stirred at rt for 30 min and concentrated in vacuo, and the residue was purified by flash column chromatography (CH2Cl2-MeOH, 15:1→10:1) to give 21 mg of (R)-1d (75%, 99% ee) and 7.1 mg of (R)-4-methoxy-1-pyrroline N-oxide (R)-4d (25%). The optical purity of (R)-1d was determined by Daicel CHIRALPAK AD-3 [hexane-iPrOH, 95:5, 2.0 mL/min; retention times 20.3 (R), 24.6 min (S)].(R)-1d. Pale yellow oil, +113 (c=0.85, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.17 (1H, dddd, J=3.5, 5.0, 9.0, 14.5 Hz), 2.48-2.57 (1H, m), 3.35 (3H, s), 3.87 (1H, dddd, J=1.0, 6.5, 9.0, 15.5 Hz), 4.10-4.19 (1H, m), 4.56-4.61 (1H, m), 7.02 (1H, q, J=1.5 Hz). 13C NMR (125 MHz, CDCl3) δ: 27.0, 56.5, 61.4, 80.0, 133.3. IR (CHCl3): 1584, 1269, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0534.(R)-4-Methoxy-1-pyrroline N-oxide [(R)-4d]. A pale yellow oil, -22.5 (c=0.66, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.75 (1H, d, J=19.5 Hz), 2.94-3.03 (1H, m), 3.33 (3H, s), 3.94 (1H, d, J=15.0 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, m), 6.84-6.87 (1H, m). 13C NMR (125 MHz, CDCl3) δ: 36.1, 56.5, 67.3, 74.3, 133.1. IR (CHCl3): 1595, 1275, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0533.
1.89 g With triethylamine; In methanol; at 20℃;Cooling with ice; To a solution of (R)-pyrrolidin-3-ol HC1 salt (1.23 g, 10.0 mmol) and Et3N (2.20 g, 20.0 mmol) in MeOH (20 mL) was added (Boc)20(2.20 g, 10.1 mmol) at ice bath. The mixture was stirred at rt overnight. The solvent was removed and the residue was extracted with DCM. The organic layers were washed with brine (20 mL x 2), dried over Na2SO4 and concentrated to give the title product (1.89 g) as a colorless oil which was used directly in the next step.

  • 17
  • [ 109431-87-0 ]
  • [ 101385-93-7 ]
YieldReaction ConditionsOperation in experiment
77.3% With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 0.2h;Inert atmosphere; To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (Intermediate 8-step 1, 4.5 g, 24.1 mmol) in DCM (60 ml) under N2atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0 C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1 : 1 mixture of saturated NaHC03and saturated Na2S203solution. The reaction mixture was extracted with DCM (2x100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3%) as an oil. 1H NMR (300 MHz, CDC13): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H)
77.3% With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; To a stirred solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (4.5 g, 24.1 mmol) in DCM (60 ml) under N2 atmosphere, was added DMP (20.45 g, 48.12 mmol) at 0 C. The reaction mixture was allowed to room temperature and stirred for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1:1 mixture of saturated NaHCO3 and saturated Na2S2O3 solution. The reaction mixture was extracted with DCM (2*100 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give the residue. Purification by column chromatography with EtOAc and hexane (15:85) to afford the desired compound (3.44 g, yield: 77.3%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.80-3.75 (m, 4H), 2.61-2.56 (m, 2H), 1.48 (s, 9H).
34% With pyridine-SO3 complex; triethylamine; In dimethyl sulfoxide; at 20℃; 1) N-tert-Butoxycarbonyl-3-pyrrolidinone Pyridine-sulfur trioxide (4.12 g) was added to a solution of (3R)-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (2.47 g) and triethylamine (9.19 mL) in dimethylsulfoxide (30 mL) at room temperature, and the resultant mixture was stirred overnight. The reaction solution was poured onto water and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain N-tert-butoxycarbonyl-3-pyrrolidinone (855 mg, 34%) as an oily product. 1H-NMR (400MHz, CDCl3)δ: 1.47(9H, d, J=9.3Hz), 2.59(2H, t, J=7.8Hz), 3.75-3.80(4H, t, J=7.9Hz).
With sulfur trioxide trimethylamine complex; triethylamine; In dimethyl sulfoxide; at 20℃; for 18h; (R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0C. The pH value of the mixture was determined with a pH test paper and was found to be 11. The mixture was then stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml), and a trituated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added little by little thereto at room temperature. The mixture was stirred at room temperature for 18 hr. Water (200 ml) was then added to the reaction solution to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was loaded on a silica gel column and developed with chloroform, followed by development with chloroform only to give an intermediate (11.25 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0C, sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH = 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product in methylene chloride was loaded on a silica gel column and developed with hexane. The development was first carried out with hexane only, subsequently with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.70 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.46 (s, 9H), 1.75 - 1.94 (m, 1H), 2.02 - 2.10 (m, 1 H), 3.35 - 3.55 (m, 31 H), 3.75 - 3.86 (m, 1 H), 4.17 - 4.24 (m, 1 H), 4.705 - 4.90 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1 H), 7.58 (t, J = 7.9 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 8.42 (d, J = 6.4 Hz, 1 H), 9.20 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 314 (M++1)

  • 18
  • [ 109431-87-0 ]
  • [ 99-76-3 ]
  • tert-butyl (S)-3-(4-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With diisopropyl (E)-azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 24h; To a solution of methyl 4-hydroxybenzoate (3 g, 19.72 mmol) in THF (75 ml), were added (R)-1 -N-boc-3-hydroxypyrrolidine (4.43 g, 23.66 mmol), diisopropyl(E)-diazene-1 ,2- dicarboxylate (4.78 g, 23.66 mmol) and triphenylphosphine (6.21 g, 23.66 mmol). The reaction mixture was heated at 60C for 24 hours. Water and EtOAc were added. After decantation, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in cyclohexane (0 to 15% ; V/V) to give 6.18 g (98%) of tert-butyl (S)-3-(4-(methoxycarbonyl)phenoxy)pyrrolidine-1 -carboxylate (IVa). LC/MS (m/z, MH+): 322
76% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 0 - 20℃; for 20h; Methyl 4-hydroxybenzoate (1.01 g), (3R)-1-tert-butoxycarbonyl-3-pyrrolidinol (1.36 g) and triphenylphosphine (1.73 g) were dissolved in tetrahydrofuran (50 ml). Under ice cooling, a 40% toluene solution (2.87 ml) of diethylazodicarboxylate was added dropwise and the resulting mixture was stirred at room temperature for 20 hours. Ethyl acetate and a 10% aqueous solution of potassium carbonate were added to the reaction mixture. The organic layer thus separated was washed with a 10% aqueous solution of potassium carbonate and water, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography (hexane:ethyl acetate = 2:1) on a silica gel column, whereby the title compound (1.60 g, 76%) was obtained.1H-NMR (CDCl3) δ: 1.46(9H,s), 2.00-2.20(2H,m), 3.40-3.70(4H,m), 3.89(3H,s), 4.96(1H,br s), 6.88(2H,d,J=8.8Hz), 7.90-8.00(2H,m).
  • 19
  • [ 109431-87-0 ]
  • [ 108-95-2 ]
  • [ 931409-70-0 ]
YieldReaction ConditionsOperation in experiment
75% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h; Di-isopropylazodicarboxylate (5JmL, 29.38mmol) was added to an ice-cooled solution of (R)-(-)-N-boc-3-pyrrolidinol (5g, 26.7ImITIoI)1 phenol (2.51g, 26.71mmol) and triphenyl phosphine (7.71 g, 29.38mmol) in tetrahydrofuran (7OmL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was twice triturated with diethyl ether and filtered. The filtrate was washed with 1N sodium hydroxide solution (2OmL), dried over sodium sulfate and concentrated in vacuo.Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 90:10 to 83:17, afforded the title compound as a colourless oil in 75% yield, 5.27g.1HNMR(400MHz, CD3OD) δ: 1.45(m, 9H), 2.10-2.16(m, 2H), 3.40-3.59(m, 4H), 4.95-4.97(m, 1H), 6.88-6.95(m, 3H), 7.24-7.28(m, 2H)
  • 20
  • [ 109431-87-0 ]
  • [ 64-19-7 ]
  • [ 101385-91-5 ]
YieldReaction ConditionsOperation in experiment
70% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; 00241] Compound xii (25 g, 134 mmol) and triphenylphosphine (42.9 g, 147 mmol) were dissolved in dry THF (200 ml) under a nitrogen atmosphere and were cooled to 0 C on an ice/water bath. Diisopropyl azodicarboxylate (DIAD) (30.5 ml, 154 mmol) was added drop wise followed by the addition of acetic acid (8.1 ml, 141 mmol). The resulting mixture was left warming to room temperature overnight and was evaporated to dryness. Heptanes (240 <n="58"/>ml) and ethyl acetate (10 ml) were added to the residual oil and the mixture was stirred at 50 C for one hour and than at room temperature for 1 additional hour. The solids were removed by filtration and the filtrate was evaporated to dryness to give 51.3 g of an oil. The oil was purified by column chromatography over silica gel with ethyl acetate/heptanes (20:80-40:60) to give xiii (21.6 g, 94 mmol, 70%) identified by 1H-NMR, some residual DIAD fragments were still present.
  • 21
  • [ 109431-87-0 ]
  • [ 105-36-2 ]
  • [ 1024038-25-2 ]
YieldReaction ConditionsOperation in experiment
28% the tert-butyl (3R)-3-(ethoxycarbonylmethoxy)pyrrolidine-1-carboxylate used as starting material was prepared as described below A solution of sodium bis(trimethylsilyl)amide in THF (58.7 mL, 58.75 mmol) was added dropwise to a stirred solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (10 g, 53.41 mmol) in DMF (100 mL) over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 10 minutes. Ethyl bromoacetate (8.92 g, 53.41 mmol) was added dropwise over 10 minutes (exotherm. Temperature kept below 30 C. using a cold water bath) and the reaction was stirred at ambient temperature for 20 hours.The reaction mixture was evaporated, EtOAc (200 mL) added and washed sequentially with water (4×50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product (14 g) as an orange oil.The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the product (4.0 g, 28%) as a pale yellow oil.1H NMR (400.13 MHz, DMSO-d6) δ 1.21 (3H, t), 1.41 (9H, s), 1.83-2.01 (2H, m), 3.2-3.32 (4H, m), 4.12 (2H, s), 4.1-4.2 (5H, m)
6.6 g With sodium hydroxide; In tetrahydrofuran;Cooling with ice; A solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (7.0 g) in THF (30 mL) was added to a suspension of 60% sodium hydroxide (2.3 g) in THF (40 mL) under ice-cooling. At the same temperature, a THF (30 mL) solution of ethyl bromoacetate (13 mL) was added to the mixture, and the mixture was stirred overnight. After water and EtOAc were added to the reaction mixture, extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc = 99:1 to 70:30), whereby tert-butyl (3R)-3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate (6.6 g) was obtained as an oil.
  • 22
  • [ 927892-95-3 ]
  • [ 109431-87-0 ]
  • [ 927892-96-4 ]
YieldReaction ConditionsOperation in experiment
43% (3) Production of tert-butyl 3-({4-[4-[(4-fluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]benzyl}oxy)pyrrolidine-1-carboxylate; Sodium hydride (60 % oily, 40 mg, 0.833 mmol) was added to a DMF (2 mL) solution of the compound obtained in Example 42-(2) (110 mg, 0.587 mmol), and stirred at room temperature for 30 minutes. Tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (79 mg, 0.196 mmol) was added, and stirred at room temperature for 1 hour. Water was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (C-200, methanol:chloroform = 1:99 to 3:97) to obtain the entitled compound (42 mg, 43 %).
  • 23
  • [ 524-38-9 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-((1,3-dioxoisoindolin-2-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18.1667h; (R)-3 -Hydroxy-pyrrolidine- 1-carboxylic acid tert-butyi ester (1.37 g, 7.31 mmol) was dissolved in THF (20 mL) then 2-hydroxy-isoindole-l,3-dione (1.19 g, 7.31 mmol) and triphenyl phosphine (1.92 g, 7.31 mmol) were added. Diisopropyl azodicarboxylate (1.33 mL, 8.04 mmol) was added dropwise over 10 minutes. The reaction mixture was allowed to stir at ambient temperature for 18 hours then the solvent was evaporated. The resultant residue was purified by flash column chromatography (Si- PPC, DCM: EtOAc, gradient 100:0 to 80:20) to provide the title compound as a colourless oil (1.43 g, 59%). IH NMR (CDCl3, <n="100"/>400MHz) 7.86 (m, 2H), 7.77 (m, 2H), 4.94-5.02 (m, IH), 3.66-3.84 (m, 2H), 3.50-3.65 (m, 2H), 2.24-2.32 (m, IH), 1.93-2.05 (m, IH), 1.49 (s, 9H).
  • 24
  • [ 109431-87-0 ]
  • [ 100-44-7 ]
  • [ 177947-67-0 ]
YieldReaction ConditionsOperation in experiment
98% (Example 26) N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine Dimethyl sulfoxide (50 g) was added to about 60 % toluene solution of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine (20 g) which had been obtained separately, and potassium iodide (5.32 g) and a solid of 85 % potassium hydroxide (14.1 g) were added thereto.
96 - 97.7% With sodium hydroxide; In dimethyl sulfoxide; at 30 - 70℃; for 7h;Product distribution / selectivity; Examples 2 to 4 (Form of NaOH) In Example 1, the used amount of each component was set to the following and the form of sodium hydroxide was changed variously for doing studies and the results are shown in Table 1. In the table, the used amount of solvent represents times by weight based on R-BocHP.From the above table, it is known that sodium hydroxide may be used either in the form of aqueous solution or solid.
92 - 97% With sodium hydroxide; tetrabutylammomium bromide;potassium iodide; In water; toluene; at 50 - 72℃;Product distribution / selectivity; 180 g of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine was dissolved into 725 g of toluene, followed by adding 31 g of tetra-n-butyl ammonium bromide and 16g of potassium iodide as a catalyst. Further, after 1924g of 10 % aqueous solution of sodium hydroxide was added and the mixture was heated to 50 C, 158g of benzyl chloride was dropped. After the reaction finished, the mixture was cooled to 25 C and an organic layer was washed with water. The resultant organic layer was concentrated, thereby obtaining 244 g of N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine (yield of 92 %). A residual quantity of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine with respect to N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine was 1.1 wt %.
88.9% With sodium hydroxide; In water; N,N-dimethyl-formamide; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
86.7 - 100% With sodium hydroxide; In water; dimethyl sulfoxide; at 30 - 70℃; for 7h;Product distribution / selectivity; In a four-neck flask of 1 L equipped with a thermometer and a dropping funnel, 182. 0 g of dimethylsulfoxide was charged, 121. 3 g (0. 65 moles) of R-BocHP obtained above was added thereto and stirred to dissolve. Next, 48% sodium hydroxide of 162.0 g (1.94 moles) (3.0 equivalent amount to R-BocHP) was added, and while stirring, benzyl chloride of 106.6 g (0.84 moles) (1.3 equivalent amount to R-BocHP) was added dropwise for the inner temperature to be from 30 to 40C in a water bath. After aging of 7 hours, the reaction liquid was quantitatively analyzed using the above-described HPLC analysis method, as a result, the production amount of R-BocBHP was 171 g (reaction yield: 95%). Examples 2 to 4 (Form of NaOH) In Example 1, the used amount of each component was set to the following and the form of sodium hydroxide was changed variously for doing studies and the results are shown in Table 1. In the table, the used amount of solvent represents times by weight based on R-BocHP. From the above table, it is known that sodium hydroxide may be used either in the form of aqueous solution or solid.Examples 5 to 7 (Used amount of NaOH) In Example 1, the used amount of 48% sodium hydroxide aqueous solution (hereinafter, sometimes abbreviated as "48% NaOH") was variously changed for doing studies and the results are shown in Table 2.From the above table, to progress the reaction efficiently, the more the used amount of base is, the better.Examples 8 to 10 (Used amount of benzyl chloride) In Example 1, the used amount of benzyl chloride was variously changed for doing studies and the results are shown in Table 3. From the above table, to progress the reaction efficiently, the more the used amount of benzyl chloride is, the better. In the table, being quantitatively means that the calculated result based on analytical results by a predetermined HPLC analysis was 99% or more.Examples 11 to 14 (Used amount of DMSO) In Example 1, the used amount of solvent was changed for doing studies of benzylation reaction and the results are shown in Table 4. From the above table, to progress the reaction efficiently, it is particularly good that the used amount of dimethylsulfoxide (DMSO) is 1.3 times by weight or more based on R-BocHP.Examples 15 to 18 (Reaction temperature) In Example 1, the reaction temperature was changed for doing studies of benzylation reaction and the results are shown in Table 5. From the above table, to progress the reaction efficiently, it is particularly good that the reaction temperature is from 30 to 70C.
47.2% With sodium hydroxide; In water; acetonitrile; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
10.2% With potassium hydroxide; In ethanol; at 30 - 70℃; for 7h;Product distribution / selectivity; Comparative examples 1 to 8 In Example 1, the solvent was variously changed for doing studies and the results are shown in Table 6. Additionally, there were used pellet for KOH and powder for sodium methylate.
With sodium hydroxide; tetrabutylammomium bromide; sodium iodide; In water; toluene; at 25 - 50℃; (Example 25) N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine 187 mg of N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine prepared separately was dissolved in 748 mg of toluene followed by adding 16 mg of tetra-n-butyl ammonium bromide and 9 mg of sodium iodide. Further, after 666 mg of 30 % aqueous solution of sodium hydroxide was added and the mixture was heated to 50 C, 164 mg of benzyl chloride was dropped. A reaction temperature was cooled to 25 C to stop the reaction at the stage where a remaining N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine became 6.4 wt % with respect to N-tert-butoxycarbonyl-(R)-3-benzyloxypyrrolidine.
98.6 - 99.1%Chromat. With sodium hydroxide;tetrabutylammonium sulfate; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; To a mixed liquid of R-BocHP of 1.02 g (5.45 mmol), tetrahydrofuran of 1.50 g, tetra-n-butylammonium sulfate of 92.1 mg (0.27 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.39 g (16.68 mmol, 3.06 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.28 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 98.6% on the basis of R-BocHP standard. Example 24 To a mixed liquid of R-BocHP, of 15.13 g (81.77 mmol), tetrahydrofuran of 22.60 g, tetra-n-butylammonium sulfate of 1.40 g (4.12 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 20.00 g (240. 00 mmol, 2.94 equivalent amount to R-BocHP), benzyl chloride of 13.76 g (108.71 mmol, 1.33 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 99.1% on the basis of R-BocHP standard. While maintaining the obtained reaction liquid at a temperature in the range from 25C to 35C, 35% HCl was added dropwise thereto. After completion of dropping, while maintaining 50C, it was heated for 7 hours. As a result of analysis of the resulting reaction liquid by liquid chromatography, the yield of R-3BHP was 93.8% on the basis of R-BocHP standard.
81.1%Chromat. With sodium hydroxide;tetrabutyl-ammonium chloride; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; To a mixed liquid of R-BocHP of 1.00 g (5.34 mmol), tetrahydrofuran of 1.50 g, tri-n-butylbenzylammonium chloride of 84.5 mg (0.27 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.38 g (16.56 mmol, 3.10 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.30 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 81.1% on the basis of R-BocHP standard.
98%Chromat. With sodium hydroxide;trimethyldodecylammonium chloride; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; To a mixed liquid of R-BocHP of 1.02 g (5.45 mmol), tetrahydrofuran of 1.50 g, n-dodecyltrimethylammonium chloride of 77.5 mg (0.29 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.37 g (16.44 mmol, 3.02 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.28 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 98.0% on the basis of R-BocHP standard.
100%Chromat. With sodium hydroxide;tetrabutylammomium bromide; In tetrahydrofuran; water; at 50℃; for 7h;Product distribution / selectivity; In a 50 mL flask equipped with a thermometer and a dropping funnel, to a mixed liquid of R-BocHP of 1.01 g (5.39 mmol), tetrahydrofuran of 1.50 g, tetra-n-butylammonium bromide of 90.3 mg (0.28 mmol, 0.05 equivalent amount to R-BocHP) and 48% sodium hydroxide aqueous solution of 1.37 g (16.44 mmol, 3.05 equivalent amount to R-BocHP), benzyl chloride of 0.88 g (6.95 mmol, 1.29 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 7 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 100% on the basis of R-BocHP standard.
5.6%Chromat. With sodium hydroxide; In tetrahydrofuran; water; at 50℃; for 8h;Product distribution / selectivity; To a mixed liquid of R-BocHP (3.06 g, 16.34 mmol), tetrahydrofuran (18.89 g) and 48% sodium hydroxide aqueous solution (1. 62 g, 19. 44 mmol, 3.05 equivalent amount to R-BocHP), benzyl chloride (3.16 g, 18.47 mmol, 1.13 equivalent amount to R-BocHP) was added and stirred, raised to 50C and heated for 8 hours. As a result of analysis by liquid chromatography, the yield of R-BocBHP was 5.6% on the basis of R-BocHP standard.

  • 25
  • [ 109431-87-0 ]
  • [ 177947-67-0 ]
YieldReaction ConditionsOperation in experiment
98% In toluene; at 80℃; for 72h; (Examples 27 to 28) A similar reaction operation was carried out except that toluene and dimethyl sulfoxide which were solvents of Example 26 were replaced by a single solvent described below and that a reaction temperature and a reaction time were changed. Results are shown in Table 4.
93% In acetonitrile; at 70℃; for 42h; (Examples 27 to 28) A similar reaction operation was carried out except that toluene and dimethyl sulfoxide which were solvents of Example 26 were replaced by a single solvent described below and that a reaction temperature and a reaction time were changed. Results are shown in Table 4.
  • 26
  • [ 109431-87-0 ]
  • [ 104706-47-0 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1h; (R)-tert-Butyl 3-hydroxypyrrolidine-1 -carboxylate (250 mg, 1.34 mmol) was dissolved inHCI/dioxane (4 M, 5 mL) and stirred at rt for 1 h. The reaction mixture was concentrated to give the title compound (150 mg, yield 90%) as a white solid.1H NMR (300 MHz, DMSO-d6): 6 9.47 (br s, I H), 9.24 (br 5, 1 H), 4.38 (s, 1 H), 3.57-2.96 (m, 4H), 1.95-1.79 (m, 2H).
63% With hydrogenchloride; In methanol; water; at 20℃; N-(Tert-butoxycarbonyl)-(R)-3-pyrrolidinol (5g; 26.70 mmol) was diluted in 15 ml of methanol and 5 ml of HCl37% were added. The reaction mixture was stirred at room temperature overnight, then it was concentrated in vacuo.2.1 g (17.07 mmol; 63%) of the desired product were obtained as hydrochloride.
With hydrogenchloride; In ethyl acetate; at 0 - 20℃; Hydrogen chloride gas was added at 0C to a solution of (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol (3 g, 16.0 mmol) in ethyl acetate (100 ml). The reaction mixture was stirred at room temperature overnight and then filtered. The resulting white solid was dried in vacuo to give 1.3 g of the titled compound.[731] 1H-NMR(400MHz, CD3OD) δ 4.55(m, 1H), 3.41-3.36(m, 2H), 3.22(m, 2H), 2.06-2.04(m, 2H)
  • 27
  • [ 109431-87-0 ]
  • [ 1694-92-4 ]
  • [ 1092366-92-1 ]
YieldReaction ConditionsOperation in experiment
73% With dmap; triethylamine; In dichloromethane; at 0 - 20℃; To an ice-cold solution of te/t-butyl (3ft)-3-hydroxypyrrolidine-1 -carboxylate (1 .0 g, 5.34 mmol), 2-nitrobenzenesulfonyl chloride (1 .42 g, 6.41 mmol) and 4- (dimethylamino)pyridine (0.032 g) in anhydrous methylene chloride (6.44 ml_) was added dropwise over 20 minutes triethylamine (1 .86 ml_, 13.35 mmol). The solution was then left to warm to room temperature and was stirred overnight. The precipitate was filtered, washed with CH2CI2 and the filtrate concentrated. The residue was taken up in EtOAc/H2O and extracted with EtOAc. The organic extracts were washed with saturated NaHCO3 (3x), dried over anhydrous MgSO4, filtered and concentrated to generate the crude product. The residue was chromatographed on silica Merck-60 using (1 :1 ) hexane/EtOAc to provide pure title compound as a thick yellow oil (1 .46 g, 73% yield). 1 H NMR/DMSO-d6 was found to be consistent for the desired product.
With trimethylamine hydrochloride; triethylamine; In toluene; acetonitrile; at 5 - 7℃; for 2h; Compound 1 (25.0 g), trimethylamine hydrochloride (2.33 g), acetonitrile (81.0 g) and triethylamine (17.2 g) were mixed together, and the mixture was cooled to 5 C. To the mixture, a 25% toluene solution (125 g) of 2-nitrobenzenesulfonyl chloride was added dropwise, and the remaining toluene solution was added by washing with acetonitrile (8.53 g). The reaction solution was reacted at 7 C. for 2 hours. After the reaction, water (27.0 g) was added. Thereafter, a mixture of water (43.5 g) and concentrated hydrochloric acid (5.05 g) was added dropwise. The solution was raised to room temperature and was separated. Water (80.8 g) was added to the organic phase and the mixture was separated. The same operation was performed again. The organic phase was concentrated to give a toluene solution (108 ml) of Compound 2. The solution was subjected to the next step without isolating the compound.
  • 28
  • [ 109431-87-0 ]
  • [ 64471-45-0 ]
  • [ 1128092-42-1 ]
YieldReaction ConditionsOperation in experiment
With di-isopropyl azodicarboxylate;triphenylphosphine; In tetrahydrofuran; at 20℃; Preparation 3 (R)-3-((R)-2-Cyclopentyl-2-hydroxy-2-phenylacetoxy)pyrrolidine-1-carboxylic acid t-butyl ester At room temperature, diisopropyl azodicarboxylate (980 μl, 5 mmol) was slowly added to a mixture of (R)-cyclopentylhydroxyphenylacetic acid (1.1 g, 5 mmol), (R)-3-hydroxypyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5.5 mmol), and triphenylphosphine (1.3 g, 5 mmol) in 10 ml of THF. The reaction mixture was then stirred at room temperature overnight. The solvent was removed and 100 ml of EtOAc was added. The organic layer was washed with a sodium bicarbonate solution (50 ml*3), then saturated aqueous NaCl, and dried over sodium sulfate. The solvent was removed, providing 4 g of crude product, which was purified by flash chromatography (EtOAc/hexane) to yield the title compound (1.5 g, 99% purity).
  • 29
  • [ 1188908-02-2 ]
  • [ 109431-87-0 ]
  • [ 1188908-06-6 ]
YieldReaction ConditionsOperation in experiment
51% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 15h; Example 96; Preparation of (S)-1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3- yloxyl-quinazolin-4-yloxyl-phenvU-urea fSI-tert-butyl 3-(4-(3-(3-(5-tert- butylisoxazol-3-yl)ureido)phenoxyV6-metlioxyquinazolin-7-yloxy)pyrrolidine-1- carboxylate; [00882] Example 96A: A solution of l-(5-tert-butylisoxazol-3-yl)-3-(3-(7- hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)urea from Example 95B (50 mg, 0.11 1 mmol), (R)-3 -hydroxy- 1 -tert-butoxycarbonylpyrrolidine (31 mg, 0.167 mmol), triphenylphosphine (44 mg, 0.167 mmol) and diisopropylazodicarboxylate (34 mg, 0.167 mmol) in dry tetrahydrofuran (1 mL) was stirred at room temperature for 15 h. The reaction mixture was partitioned between aqueous IM sodium hydroxide solution (20 mL) and 10% methanol in dichloromethane (50 mL) and the organic layer was separated and washed with brine (50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 100% dichloromethane to 10% methanol in dichloromethane to afford (S)-tert-butyl 3 -(4-(3 -(3 -(5-tert-butylisoxazol-3 -yl)ureido)phenoxy)-6-methoxyquinazolin-7- yloxy)pyrrolidine-l -carboxylate as a colorless oil (35 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 9.30 (brs, 1H), 8.62 (s, 1H), 8.30 (brs, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.26- 7.39 (m, 2H), 7.00 (m, 1H), 5.95 (s, 1H), 5.12 (s, 1H), 4.02 (s, 3H), 3.50-3.80 (m, 5H), 2.20-2.40 (m, 2H), 1.50 (s, 9H), 1.30 (s, 9H); LC-MS (ESI) m/z 619 (M + H)+.
  • 30
  • [ 109431-87-0 ]
  • [ 106-95-6 ]
  • [ 474023-54-6 ]
YieldReaction ConditionsOperation in experiment
56% A solution of N-Boc-3-Rhydroxypyrrolidine (3.0 g, 16.0 mmol), and TMEDA (6.4 mL, 40. 1 mmol) is dissolved in THF (50 mL) and cooled to-78 C. To this reaction mixture is added a solution of 1.3 M sec-butyl lithium (50 mL) in cyclohexanes with stirring. The resulting orange-colored mixture is allowed to warm to -40 C and stirred for 2.75 hours. The mixture is again cooled to-78 C and allyl bromide (3.1 mL, 35.3 mmol) is added. This mixture is slowly warmed to room temperature with stirring over 4.5 hours. The reaction is quenched with aq. NH4CI solution and extracted with ethyl acetate (150 mL). The organic layer is then dried over Na2SO4, filtered and concentrated in vacuo. The oily residue is purified over silica gel (CH2CI2/acetone, 3: 1) to afford the desired product (2.0 g, 56%) as a clear oil.
  • 31
  • [ 1221748-96-4 ]
  • [ 109431-87-0 ]
  • [ 1222544-97-9 ]
YieldReaction ConditionsOperation in experiment
83% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; To a solution of 1'-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3'-indol]- 2'(1'/-/)-one (0.45 g, 1.07 mol), tert-butyl (3R)-3-hydroxypyrrolidine-1 -carboxylate (0.60 g, 3.22 mmol) and triphenylphosphine (0.70 g, 2.68 mmol) in tetrahydrofuran (50 ml.) was added diethyl azodicarboxylate (0.42 ml_, 2.68 mmol) slowly at 0 C. The mixture was stirred fo 16 h at ambient temperature, then concentrated in vaccuo. The residue was purified by column chromatography (ethyl acetate/hexanes - 1 :2) to afford tert- butyl (3S)-3-[1'-(diphenylmethyl)-2'-oxo-1',2'-dihydrospiro[1 -benzofuran-3,3'-indol]-6- yl]oxy}pyrrolidine-1-carboxylate as an oil (0.52 g, 83%): 1H NMR (300 MHz, CDCI3) S 7.43-7.25 (m, 10H), 7.16-7.06 (m, 1 H), 7.07-6.91 (m, 3H), 6.58-6.43 (m, 3H), 6.38-6.25 (m, 1 H), 5.00 (d, J = 9.0 Hz, 1 H), 4.80 (s, 1 H), 4.73 (d, J = 9.0 Hz, 1 H), 3.65-3.36 (m, 4H), 2.22-1.95 (m, 2H), 1.45 (s, 9H); MS (ES+) m/z 611.3 (M + 23).
  • 32
  • [ 109431-87-0 ]
  • [ 5451-40-1 ]
  • [ 1222105-90-9 ]
YieldReaction ConditionsOperation in experiment
92% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1.5h;Cooling with ice; Reflux; Tetrahydrofuran (200 ml) was added to 2,6-dichloropurine (6 g, 31.8 mmol), tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (5.94 g, 31.8 mmol), and triphenylphosphine (9.2 g, 34.9 mmol) and the resulting mixture was made uniform. Diisopropyl azodicarboxylate (6.9 ml, 35 mmol) was added with ice cooling and the resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3 to 6:4 to 5:5 to 4:6) to give the title compound (10.5 g, 92%) as a white solid.
  • 33
  • [ 383-50-6 ]
  • [ 109431-87-0 ]
  • [ 864758-06-5 ]
YieldReaction ConditionsOperation in experiment
41% Sodium hydride (55% oiliness,140 mg, 3.2 mmols) was added to DMF (5 mL) solution oftert-butyl (3R)-3-hydroxypyrrolidine-1- carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25 + M, ethyl acetate : hexane =1:10 → 2:8) to provide the title compound (253 mg, 41 %).
NaH 60% dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification.
  • 34
  • [ 83220-73-9 ]
  • [ 76469-41-5 ]
  • [ 1257521-67-7 ]
YieldReaction ConditionsOperation in experiment
47% With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; mineral oil; at 40℃; EXAMPLE 1(R)-(trans-(1-carbamoyl-4-adamantyl)) 3-(3,5-difluoropyridin-2-yloxy)pyrrolidine-1- carboxylateStep 1; To a stirred solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate(1.1O g, 5.89 mmol) and <strong>[76469-41-5]2,3,5-trifluoropyridine</strong> (0.86 g, 6.48 mmol) in dry THF (20 ml.) and dry DMF (4 ml_), at rt was added 60% NaH in oil (0.35 g, 8.84 mmol). The mixture was stirred in a 40 0C oil bath overnight, cooled to rt, diluted with ether (175 ml_), washed with water (25 mL) and brine (25 ml_), and dried over Na2SO4.Removal of the solvent left a dark oil (1.94 g) which was purified by chromatography on a 40-g silica cartridge eluted with a 0 - 100% EtOAc in hexanes gradient to afford (R)-tert-butyl 3-(3,5-difluoropyridin-2-yloxy)pyrrolidine-1- carboxylate (0.83 g, 47%). LC-MS Method 1 tR = 1.85 min, m/z = 301.
  • 35
  • [ 109431-87-0 ]
  • [ 6482-24-2 ]
  • [ 1212413-55-2 ]
YieldReaction ConditionsOperation in experiment
51% To a stirred solution of NaH (3.8 g, 95 mmol, 60% in mineral oil w/w) in THF (20 ml) under N2atmosphere at 0 C, was added tert-butyl (R)-3-hydroxypyrrolidine-l- carboxylate (step 1, 4.5 g, 24 mmol) in THF (40 ml). After 30 minutes l-bromo-2- methoxyethane (3.4 ml, 36 mmol) was added, the reaction mixture was slowly allowed to attain to room temperature and stirred for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of saturated NH4C1 solution at 0 C. The solution was extracted with EtOAc (2x100 mL), the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by flash chromatography with EtOAc-hexane (2: 8) as an eluent to afford the desired product (3.0 g, yield: 51%) as an oil. 1H MR (300 MHz, CDC13): δ 4.10-4.05 (m, 1H), 3.60-3.52 (m, 4H), 3.45-3.36 (m, 4H), 3.38 (s, 3H), 2.02-1.93 (m, 2H), 1.45 (s, 9H).
  • 36
  • [ 109431-87-0 ]
  • [ 121-51-7 ]
  • [ 1374675-75-8 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine; In dichloromethane; at 0 - 25℃; (R)-(-)-N-Boc-3-pyrrolidinol (25 g, 134 mmol) was dissolved in CH2C12 (250 niL) and Nos-Cl (31.36 g, 142 mmol) was added. The solution was cooled down to 0 C and TEA (55.5 mL, 401 mmol) was slowly and carefully added through a dropping funnel. The icebath was removed and the reaction mixture was stirred at 25C for 18 h. The reaction mixture was extracted with aqueous 10% Na2C03 solution and 0.1 N aqueous HC1 solution. The organic layers were dried over Na2S04, filtered and evaporated to dryness to yield a dark brown oil (39.8 g, 80 %). MS: m/z = 373.1 [M+H]+.
With triethylamine; In dichloromethane; at 0 - 25℃; (R)-(-)-N-Boc-3-pyrrolidinol (25 g, 134 mmol) was dissolved in CH2Cl2 (250 mL) and Nos-Cl (31.36 g, 142 mmol) was added. The solution was cooled down to 0 C. and TEA (55.5 mL, 401 mmol) was slowly and carefully added through a dropping funnel. The icebath was removed and the reaction mixture was stirred at 25 C. for 18 h. The reaction mixture was extracted with aqueous 10% Na2CO3 solution and 0.1 N aqueous HCl solution. The organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield a dark brown oil (39.8 g, 80%). MS: m/z=373.1 [M+H]+.
  • 37
  • [ 109431-87-0 ]
  • [ 34617-65-7 ]
  • [ 1184843-10-4 ]
YieldReaction ConditionsOperation in experiment
43% Stage #1: (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate With sodium hydride In 1,4-dioxane; mineral oil for 0.5h; Inert atmosphere; Stage #2: 5-amino-3-chloro-pyrazine-2-carbonitrile In 1,4-dioxane; mineral oil at 90℃; for 14h; Inert atmosphere;
  • 38
  • [ 1446001-99-5 ]
  • [ 109431-87-0 ]
  • [ 1446002-00-1 ]
YieldReaction ConditionsOperation in experiment
74% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 60℃; for 19h; d) (S)-3-(5-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of triphenylphosphine (1.5 g, 5.7 mmol) in THF (20 ml) was treated at 0 C. with DEAD (0.900 ml, 5.69). The orange solution was stirred over 10 min at rt, then 5-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-ol (740 mg, 4.37 mmol) and <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1065 mg, 5.69 mmol) were added. The reaction mixture was stirred for 19 h at 60 C. and then concentrated under reduced pressure. The title compound was obtained after flash chromatography on silica gel (Hexane/EtOAc, 100:0 to 70:30) as a colourless oil (1.1 g, 74% yield). UPLC RtM1=1.07 min; ESIMS: 339 [(M+H)+] 1H NMR (400 MHz, DMSO-d6): δ 6.45 (d, 1H), 6.00 (t, 1H), 5.42 (br.s, 1H), 4.25-4.41 (m, 1H), 4.19 (t, 2H), 3.38-3.66 (m, 6H), 2.00-2.18 (m, 2H), 1.46 (d, 9H)
  • 39
  • [ 1446002-26-1 ]
  • [ 109431-87-0 ]
  • [ 1446002-27-2 ]
YieldReaction ConditionsOperation in experiment
58% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 70℃; for 18h; f) (1,1-Dioxo-hexahydro-1lambda*6*-thiopyran-4-yl)-{(S)-3-[4-(6-methoxy-5-methyl-pyridin-3-yl)-5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-pyrrolidin-1-yl}-methanone A solution of triphenylphosphine (55 mg, 0.21 mmol) in THF (2.5 ml) was treated with DEAD (0.03 ml, 0.21 mmol), followed by (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS registry 127423-61-4) (33 mg, 0.18 mmol) and 4-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ol (50 mg, 0.15 mmol). The resulting red/brown solution was stirred at 70 C. for 18 h. The reaction mixture was cooled down to rt, diluted with EtOAc and washed with sat. aq. NaHCO3 soln. The organic layer was dried over MgSO4. concentrated and purified by flash chromatography on silica gel (cyclohexane/EtOAc 90:10 to 40:60) to afford the title compound as an orange solid (44 mg, 58% yield) HPLC RtM1=1.16 min; ESIMS: 504 [(M+H)+].
  • 40
  • [ 1445651-46-6 ]
  • [ 109431-87-0 ]
  • (S)-3-(4-chloro-5-fluoroquinolin-6-yloxy)pyrrolidin-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 70℃; for 2h; At rt, DEAD (CAS registry 1972-28-7) (1.43 ml, 9.07 mmol) followed by (R)-3-hydroxy- pyrrolidine-1-carboxylic acid tert-butyl ester (CAS registry 109431 -87-0) (1 .82 g, 9.72 mmol) and 4-chloro-5-fluoro-quinolin-6-ol (1 .6 g, 6.48 mmol) were added to a solution of triphenylphosphine (CAS registry 603-35-0) (2.38 g, 9.07 mmol) in THF (20 ml) . The mixture was stirred at 70C for 2 h. The mixture was diluted with EtOAc and washed with sat.aq. NaHC03 soln.. The organic layer was dried over MgS04, concentrated and purified by flash chromatography on silica gel (cyclohexane / EtOAc 100:0 to 70:30), to afford the title compound as a white solid (2.2 g, 93% yield). HPLC RtMOi =1.19 min; ESIMS: 367, 369 [(M+H)+]. 1 H NMR (400 MHz, DMSO-d6): δ 8.72 (d, 1 H), 7.93 (d, 1 H), 7.73 (d, 1 H), 7.62 (d, 1 H), 5.37 (m, 1 H), 3.71 -3.32 (m, 4H), 2.29-2.10 (m, 2H), 1 .38 (s, 9H).
  • 41
  • 4-bromoquinolin-6-ol [ No CAS ]
  • [ 109431-87-0 ]
  • [ 1445651-35-3 ]
YieldReaction ConditionsOperation in experiment
78% With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 70℃; for 18h; At rt, DEAD (CAS registry 1972-28-7) (4.45 ml, 28.1 mmol) followed by (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (CAS registry 109431-87-0) (5.64 g, 30.1 mmol) and 4-bromo-quinolin-6-ol (4.5 g, 20.1 mmol) were added to a solution of triphenylphosphine (CAS registry 603-35-0) (7.37 g, 28.1 mmol) in THF (15 ml) . The mixture was stirred at 70C for 18 h. The mixture was diluted with EtOAc and washed with sat.aq. NaHC03 soln. The organic layer was dried over MgS04, concentrated and purified by flash chromatography on silica gel (cyclohexane / EtOAc 80:20 to 30:70), then with KP-amino column (cyclohexane / EtOAc 100:00 to 60:40) to afford the title compound as a white solid (6.52 g, 78% yield). HPLC RtM02 =1.18 min; ESIMS: 393, 395 [(M+H)+]. 1 H NMR (400 MHz, DMSO): 8.58 (d, 1 H), 8.01 (d, 1 H), 7.90 (d, 1 H), 7.53 (dd, 1 H), 7.39 (d, 1 H), 5.26 (m, 1 H), 3.70-3.61 (m, 1 H), 3.55-3.44 (m, 2H), 3.44-3.34 (m, 1 H), 2.17 (br. s., 2 H), 1 .40 (d, 9 H )
  • 42
  • [ 93-35-6 ]
  • [ 109431-87-0 ]
  • (S)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; Step A: Diisopropyl azodicarboxylate (5.5 mL, 28 mmol) was added dropwise to a mixture of 7-hydroxycoumarin (4.6 g, 28 mmol), (R)-tert-butyl 3-hydroxypyrrolidine-l- carboxylate (6.0 g, 31 mmol), triphenylphosphine (7.4 g, 28 mmol) and triethylamine (3.9 mL, 28 mmol) in THF (28 mL) at 0 C. The mixture was stirred at room temperature overnight. The solids were removed by filtration and washed with cold THF. The solid was dissolved in EtOAc. The solution was washed with aqueous HC1 (0.5 N), dried over NaS04, then filtered and concentrated to give (S)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-l-carboxylate (4.85 g, 52%) as a pale yellow solid. MS m/z 232.2 [M-Boc+H]+.
  • 43
  • [ 123148-78-7 ]
  • [ 109431-87-0 ]
  • tert-butyl (S)-3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -10 - 25℃;Inert atmosphere; To a stirred solution of 11a (10.11 g, 36.18 mmol), (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate (13.55 g, 72.35mmol) and PPh3 (17.08 g, 65.12 mmol) in anhydrous THF (200 mL) was slowly added DIAD (10.97 g, 54.26 mmol) over 1 h at -10 C and under N2 atmosphere. The resulting reaction mixture was subsequently warmed up to rt and stirred overnight. The solvent was evaporated and the residue was purified by a flash column to give the product 13a as white solid (9.87 g, 60% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.39 (s, 1H), 5.47 (br. s, 1H), 3.90 (dd, J 11.5, 6.8 Hz,1H), 3.62-3.58 (m, 3H), 2.45 (td, J 13.9, 7.4 Hz, 1H), 2.25 (td,J 13.0, 6.4 Hz, 1H), 1.50 (s, 9H). HRMS-ESI: calcd for C15H19N4O2Cl[M+H]+ 449.0241, found: 449.0244. Intermediate 13b -k was synthesized by the corresponding chiral alcohol compounds and 11a following the procedure of preparation 13a.
60% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -10 - 20℃;Inert atmosphere; To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.1 g, 36.2 mmol), (R)- tert-butyl3-hydroxypyrrolidine-1-carboxylate (13.6 g, 72.4 mmol) and PPh3 (17.1 g, 65.1 mmol) in anhydrous THF (200 mL) was slowly added DIAD (10.9 g, 54.2 mmol) over 1h at -10 C and under nitrogen atmosphere. The resulting reaction mixture was subsequently warmed up to room temperature and stirred overnight. The solvent was evaporated and the residue was purified by a flash (PE/EA = 5/1) to give (S)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyrrolidine-1-carboxylate (9.9 g, 60%) as a white solid. [M+H] Calcd.: 449.0, found: 449.0
60% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -10 - 20℃;Inert atmosphere; To a stirred solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (10.1 g, 36.2 mmol), (R)- tert-butyl3-hydroxypyrrolidine-1-carboxylate (13.6 g, 72.4 mmol) and PPh3 (17.1 g, 65.1 mmol) in anhydrous THF (200 mL) was slowly added DIAD (10.9 g, 54.2 mmol) over 1h at -10 C and under nitrogen atmosphere. The resulting reaction mixture was subsequently warmed up to room temperature and stirred overnight. The solvent was evaporated and the residue was purified by a flash (PE/EA = 5/1) to give (S)-tert-butyl 3-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7- yl)pyrrolidine-1-carboxylate (9.9 g, 60%) as a white solid. [M+H] Calcd.: 449.0, found: 449.0
1.04 g With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1h; DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)-N-Boc-3-pyrrolidinol (1.01 g), and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z[M+H]+ 448.9
1.04 g With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1h; DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)-N-Boc-3-pyrrolidinol (1.01 g), and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z[M+H]+ 448.9
1.04 g With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1h; DIAD (1.41 ml) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.00 g), (R)-N-Boc-3-pyrrolidinol (1.01 g), and triphenylphosphine (1.88 g) in tetrahydrofuran (40 ml), and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated and washed with ethyl acetate to obtain the title compound as a white solid (1.04 g). Physical properties: m/z [M+H]+ 448.9

  • 44
  • [ 109431-87-0 ]
  • [ 1175273-55-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 °C 2.2: 6 h / 70 °C 3.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / dimethyl sulfoxide / 2 h / 80 °C / Inert atmosphere
  • 45
  • 3-((1r,4r)-4-(piperidin-4-yloxy)cyclohexyloxy)pyrazine-2-carbonitrile hydrochloride [ No CAS ]
  • [ 109431-87-0 ]
  • (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl 4-((1r,4r)-4-(3-cyanopyrazin-2-yloxy)cyclohexyloxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74.2% (R)-tert-Butyl 3-hydroxypyrrolidine-1-carboxylate (0.150 g, 0.799 mmol) and 1,1’- carbonyldiimidazole (0.130 g, 0.799 mmol) in THF (3 mL) was stirred for 1 hat rt, then 3- ((1 r,4r)-4-(piperidin-4-yloxy)cyclohexyloxy)pyrazine-2-carbonitrile hydrochloride (0.1 g, 0.295 mmol) was added, followed by triethylamine (0.223 mL, 1.599 mmol). The reaction mixture was stirred at reflux overnight, diluted with water and extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography with 85% ethyl acetate/hexanes to give the title compound (102 mg, 0.198 mmol, 74.2% yield) as oil. Exact mass calculated for C26H37N506: 515.2, found LC/MS m/z = 516.4 (M+Hj.
  • 46
  • [ 109431-87-0 ]
  • [ 106-95-6 ]
  • [ 1478194-96-5 ]
YieldReaction ConditionsOperation in experiment
97% A solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (195 mg, 1.04 mmol) in DMF (2 ml) was cooled to 0C, sodium hydride (>50% oil, 75.0 mg, 1.56 mmol) was added, and the mixture was remained at 0C and stirred for 10 minutes. Allyl bromide (0.176 ml, 2.08 mmol) was added, and the mixture was stirred at room temperature for two hours. Water was added to the reaction mixture, then extraction with a mixed solvent of ethyl acetate and hexane was carried out. The organic layer was washed with brine twice and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, then concentration under reduced pressure was carried out. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give tert-butyl (3R)-3-prop-2-enoxypyrrolidine-1-carboxylate (230 mg, 97%) as a colorless oily substance. 1H-NMR (400 MHz, CDCl3) δ: 5.83-5.98 (1H, m), 5.23-5.33 (1H, m), 5.14-5.22 (1H, m), 4.04-4.14 (1H, m), 3.93-4.03 (2H, m), 3.32-3.53 (4H, m), 1.87-2.07 (2H, m), 1.46 (9H, s).
  • 47
  • [ 109431-87-0 ]
  • [ 952747-27-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 1 h / -10 °C 1.2: 16 h / -10 - 20 °C 2.1: hydrazine hydrate / dichloromethane / 2.5 h / 25 °C
  • 48
  • [ 2075-46-9 ]
  • [ 109431-87-0 ]
  • tert-butyl (S)-3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; To a solution of 4-nitro-IH-pyrazole (1 g, 8.84 mmol), triphenylphosphine (2.78 g, 10.61 mmol) and <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.656 g, 8.84 mmol) in THF (50 mL) was added dropwise DIAD (2.264 mL, 11.50 mmol) at 0 C under nitrogen. The mixture was then slowly warmed to room temperature and stirred overnight. Solvent was evaporated and the crude product was directly purified by column chromatography on silica gel (PE:EA2: 1) to give the title compound D132 (2.23 g, 7.90 mmol, 89 % yield) as yellow oil.LCMS: 227 [M-t-Bu+H]. tR =2.295 mins. (LCMS condition 1)1H NMR (400 MHz, CHLOROFORM-cl): 68.20 (s, 1H), 8.10 (s, 1H), 3.50-3.94(m, 5H), 2.43(d, J=6.36 Hz, 2H), 1.49 (s, 9H).
  • 49
  • 3-iodo-1-(4-methoxybenzyl)-N-(4-phenoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-4-amine [ No CAS ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(1-(4-methoxybenzyl)-4-(4-phenoxyphenylamino)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
62% With copper(l) iodide; 1,10-Phenanthroline; potassium fluoride on basic alumina; In toluene; at 120℃;Inert atmosphere; A mixture of 3-iodo-l -(4-methoxybenzyl)-N-(4-phenoxyphenyl)- lH-pyrazolo[3,4-Z?]pyri din-4- amine (26) (550 mg, 1.0 mmol), (R)-tert-butyl 3-hydroxypyrrolidine-l- carboxylate (3.7 g, 20 mmol), Cul (190 mg, 1.0 mmol), phenanthroline (180 mg, 1.0 mmol) and KF/A1203 (46% wt. 884 mg, 7.0 mmol) in toluene (20 mL) was heated to 120C under N2 atmosphere overnight. After cooling to r.t., the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 0 to 35% EA in PE) to afford (R)-teri-butyl 3-(l-(4-methoxybenzyl)-4-(4- phenoxyphenylamino)- lH-pyrazolo[3,4-Z7]pyridin-3-yloxy)pyrrolidine- l -carboxylate (27) (376 mg, 62 % yield) as a white solid. LC-MS (ESI): m/z (M+l) 607.2
  • 50
  • [ 75-15-0 ]
  • [ 109431-87-0 ]
  • [ 74-88-4 ]
  • tert-butyl (3R)-3-[(methylsulfanyl)methanethioyl]oxy}pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% General procedure: A solution of desired N-Boc-protected cyclic alcohol 10(1 equiv) in THF was treated with NaH (60% suspension in mineraloil, 1.2 equiv). The mixture was stirred at rt for approximately20 min. Followed addition of CS2 (1.5 equiv) and then approximately5 min later addition of MeI (1.2 equiv). The mixture wasstirred until consumption of the limiting reagent was observedand then partitioned between CH2Cl2 or EtOAc and water. Thewater layer was extracted with CH2Cl2 or EtOAc (2) and the combinedorganic layer was dried over Na2SO4, filtered and concentratedto a residue that was chromatographed on a silica gelcolumn with an EtOAc in hexanes gradient to afford the product.
94% To a stirred solution of ie/t-butyl (R)-3-hydroxypyrrolidine- 1-carboxylate (1.10 g, 5.85 mmol) in anhydrous THF (20 ml) under nitrogen was added NaH (668 mg, 3.46 mmol) portion- wise. The mixture was stirred for 20 minutes and then treated with CS2 (0.53 ml, 8.77 mmol). 5 min later followed dropwise addition of Mel (0.44 ml, 7.02 mmol). The mixture was stirred at room temperature until TLC indicated consumption of the starting material and then partitioned between CH2C12 and water. The water layer was extracted twice more with CH2CI2 and the combined organic layer was dried over Na2S04 filtered and evaporated to a residue that was chromatographed with a 0-20% ethyl acetate in hexanes gradient to yield the product, iert-butyl (3R)-3- { [(methylsulfanyl)methanethioyl]oxy} pyrrolidine- 1-carboxylate, as a yellowish oil (1.43 g, 94% yield). 1HNMR (600 MHz CDCI3) δ = 1.46 (s, 9H) 2.11-2.21 (m, lH), 2.22-2.28 (m, 1H), 2.56 (s, 3H), 3.40-3.51 (m,lH), 3.52-3.73 (m, 3H), 5.96 (apparent s, 1H). LC-MS (ESI) m/z C11H19NO3S2 calculated: 277.08, observed [M+Na] : 300.
  • 51
  • [ 381247-99-0 ]
  • [ 109431-87-0 ]
  • methyl (S)-5-bromo-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)nicotinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere; To a solution of 36 (0.626 g, 2.70 mmol) in dry THF (35 mL) under anhydrous conditions was added (R)-tent-butyl 3-hydroxypyrrolidine-1-carboxylate (0.505 g, 2.70 mmol) and triphenyl phosphine (1.43 g, 5.39 mmol). The reaction mixture was then cooled in an ice bath, and DIAD (1.12 g, 5.56 mmol) dissolved in THF (10 mL) was added dropwise. The reaction mixture was stirred for 1 h at room temperature under argon. Upon completion the reaction was diluted with ethyl acetate (100 mL). The organic layer was washed with water (2×50 ml), brine (50 mL), dried over MgSO4, solids filtered, and the solvent removed under reduced pressure. The residue was then purified by column chromatography (silica gel, hexanes:EtOAc=7:1) to yield 37 (0.837 g, 77% yield) as white solid. 1H NMR (500 MHz, CDCl3): δ ppm 8.70 (d, 1H, J=2.0 Hz), 8.38 (d, 1H, J=2.1 Hz), 5.64-5.62 (m, 1H), 3.91 (s, 3H), 3.72-3.69 (m, 1H), 3.59-3.52 (m, 3H), 2.21-2.17 (m, 2H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3): δ ppm 164.65, 161.64, 154.51, 147.88, 142.55, 121.08, 107.19, 79.47, 72.19, 52.30, 51.65, 44.02, 28.49.
  • 52
  • [ 1072004-32-0 ]
  • [ 109431-87-0 ]
  • [ 1895004-04-2 ]
YieldReaction ConditionsOperation in experiment
30% With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere;
  • 53
  • methyl 3-hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate [ No CAS ]
  • [ 109431-87-0 ]
  • tert-butyl (3S)-3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 72.083h; To a solution of Intermediate 3 (250 mg, 1.0 mmol), tert-butyl (3R)-3- hydroxypyrrolidine-1 -carboxylate (375 mg, 2 mmol) and triphenylphosphine (1 .05 g, 4 mmol) in THF (5 mL) cooled to 0 C was added DIAD (394 pL, 2 mmol) dropwise.The solution was stirred at 0 C for 5 mm then allowed to warm to RT and stirred for a further 72 h. The reaction mixture was then concentrated under reduced pressure and the crude material was purified by Biotage Isolera chromatography (silica gel, eluting with heptane-EtOAc, 20:1 to 2:3) to give 745 mg (88% yield, 50 % purity) of the title compound as a colourless gum.1H NMR (500MHz, Chloroform-d) 6 [ppm] 8.11 (d, J = 7.2 Hz, 1H), 7.68 (5, 1H), 7.56 (5, 1H), 7.53 (5, 1H), 5.04 (5, 1H), 3.94 (5, 3H), 3.68 (5, 3H), 3.30 (5, 1H), 2.53 (5, 3H), 2.26-2.09 (m, 2H), 1.27 (5, 9H).LCMS (Analytical Method A) Rt = 1.37 min, MS (ESIpos): m/z = 419.1 (M+H)+.
  • 54
  • [ 109431-87-0 ]
  • [ 591-27-5 ]
  • (R)-tert-butyl 3-(3-nitrophenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 70℃; for 8h; Weighed (R)-tert-butyl-3-hydroxy-pyrrolidine-1-carboxylate(6a) (7. 49g, 40mmol), placed in 250mL round bottom flask, lOOmL of tetrahydrofuran was added to the reaction flask and stirred uniform. To the reaction flask were sequentially added m-aminophenol (4.36g, 40mmol), triphenylphosphine (15.7g, 60mmol), isopropyl azodicarboxylate (12g, 60mmol). The reaction was raised stirred for 8 hours at 70 C. Tetrahydrofuran was removed under reduced pressure, column chromatography (petroleum ether / ethyl acetate (ν / ν) = 4: 1) to give a yellow oily liquid (R)-tert-butyl-3-(3-nitrophenoxy)pyrrolidine-1-carboxylate(6b) (10. lg, yield: 82%)
  • 55
  • [ 109431-87-0 ]
  • [ 24241-18-7 ]
  • (R)-3-(3-amino-6-bromopyrazin-2-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% (R) -3- (3- amino-6-bromo-pyrazin-2-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester: 0.105 g of sodium hydride / mineral oil (2.62 mmol) with n-hexane washed twice, and pooled into 2.0 ml of tetrahydrofuran, was added 0.350 g (R) -1- tert-butoxycarbonyl-3-hydroxypyrrolidine (1.87 mmol), the reaction mixture was stirred at room temperature for 5 minutes, the gelable reaction, followed by addition of 2.0 ml containing 0.235 g of 2-amino-3,5-dibromo-pyrazine (1.87 mmol) in tetrahydrofuran, the reaction mixture was heated to 50 deg.] C for 2.5 hours, the reaction mixture was cooled to and saturated sodium bicarbonate was added at room temperature, the whole solution was diluted with ethyl acetate and washing with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo, the crude product with 0-70% ethyl acetate in hexane as solvent red extract was purified by flash column isolated 160 mg (48% yield) of product. (Rf = 0.48 in 1: 1 hexane / ethyl acetate).
  • 56
  • [ 112052-11-6 ]
  • [ 109431-87-0 ]
  • tert-butyl (R)-3-(((R)-tetrahydrofuran-3-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
28.1% Stage #1: (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: toluene-4-sulfonic acid (S)-(tetrahydrofuran-3-yl)ester In N,N-dimethyl-formamide; mineral oil at 20℃; 1 Synthesis of tert-butyl (R)-3-(((R)-tetrahydrofuran-3-yl)oxy)pyrrolidine-l- carboxylate: To a stirred solution of NaH (1.38 g, 36.3 mmol, 60% in mineral oil w/w) in DMF (10 ml) under N2atmosphere at 0 °C, was added tert-butyl (R)-3-hydroxypyrrolidine- l- carboxylate (Intermediate 8-step 1, 3.4 g, 18.0 mmol) in DMF (40 ml). After 30 minutes (S)- tetrahydrofuran-3-yl 4-methylbenzenesulfonate (4.84 g, 21.8 mmol) was added and the reaction mixture was slowly allowed to attain to room temperature and stirred for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by addition of saturated NH4C1 solution at 0 °C. The solution was extracted with EtOAc (2x100 mL) and the combined organic phases were washed with brine, dried over Na2S04and concentrated under reduced pressure to give the crude product. Purification by column chromatography with EtOAc:hexane (30:70) as an eluent to afford the desired product (0.9 g, yield: 28.1%) as an oil. 1H MR (300 MHz, DMSO-d6): δ 4.22-4.17 (m, 1H), 4.08-4.06 (m, 1H), 3.72-3.56 (m, 4H), 3.28-3.17 (m, 4H), 1.91 -1.82 (m, 4H), 1.39 (s, 9H)
  • 57
  • [ 109431-87-0 ]
  • [ 195447-25-7 ]
  • 58
  • [ 19438-10-9 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(3-(methoxycarbonyl)phenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
78.4% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; A solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (0.140 g, 0.75mmol), methyl 3-hydroxybenzoate (125 mg, 0.822 mmol) and triphenylphosphine (235mg, 0.897 mmol) in THF (1.5 mL) was treated dropwise with DIAD (0.174 mL, 0.897 mmol) with stirring under argon at 0 C. The reaction mixture was stirred at rt overnight. The reaction was concentrated, and the product isolated by silica gel chromatography to give 239A as a colorless oil, (189 mg, 78.4%). MS(ESI) 266.1 (M+H-tBu).
  • 59
  • [ 109431-87-0 ]
  • [ 151266-23-8 ]
  • [ 1422827-96-0 ]
YieldReaction ConditionsOperation in experiment
84% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; A solution of 4-amino-3-iodo-lH-pyrazolo [3,4-D] pyrimidine (10 g, 38 mmol)(R) -1-Boc-3-hydroxypyrrole (16 g, 85 mmol)Triphenylphosphine (20 g, 76 mmol) was added to a three-necked flask,THF (120 ml) was added,Cooling to 0 ,A mixture of diisopropyl azodicarboxylate (DIAD) (15.2 g, 76 mmol) and THF (30 ml)About 1h drops finished,Slowly warmed to room temperature overnight.The reaction solution was spin-dried,Extracted with water, extracted with ethyl acetate, dried and concentrated to give the product (13.8 g, yield 84%) by column chromatography.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h; General procedure: Toa stirred solution of 3-Iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 10 (10 mmol) and triphenylphosphine (20 mmol) in THF (25 mL) wasadded 11a-11e (20 mmol) and DIAD (20mmol) at 0,it was stirred at room temperature for 12h. Then the mixture was concentratedto a residue and purified via column chromatography (0% ethyl acetate indichloromethane to 80%) to provide the desired compound 12a-12e (Yield: 39%-55%).
  • 60
  • [ 5750-76-5 ]
  • [ 109431-87-0 ]
  • C13H17Cl2N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With caesium carbonate; In acetonitrile; at 80℃; for 3h; compound 1a (3 g, 16.36 mmol), tert-butyl (R)-3-hydroxypyrrolidine-1-formate (3.1 g, 16.56 mmol) and cesium carbonate (8 g, 24.55 mmol) were added into 30 ml of acetonitrile. The reaction mixture was stirred at 80 C. for 3 hours. The reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated to obtain a crude product which was purified by combiflash (PE:EA=95:5-80:20) to obtain compound 14a-1 (3.31 g, yield 60.0%). MS m/z(ESI): 278 [M-56+H]+.
  • 61
  • [ 93-35-6 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% With di-isopropyl azodicarboxylate; triethylamine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h; Step A: Diisopropyl azodicarboxylate (5.5 mL, 28 mmol) was added dropwise to a mixture of 7-hydroxycoumarin (4.6 g, 28 mmol), <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (6.0 g, 31 mmol), triphenylphosphine (7.4 g, 28 mmol) and triethylamine (3.9 mL, 28 mmol) in THF (28 mL) at 0 C. The mixture was stirred at room temperature overnight. The solids were removed by filtration and washed with cold THF. The solid was dissolved in EtOAc. The solution was washed with aqueous HCl (0.5 N), dried over NaSO4, then filtered and concentrated to give (S)-tert-butyl 3-(2-oxo-2H-chromen-7-yloxy)pyrrolidine-1-carboxylate (4.85 g, 52%) as a pale yellow solid. MS m/z 232.2 [M-Boc+H]+.
  • 62
  • 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran [ No CAS ]
  • [ 109431-87-0 ]
  • tert-butyl (R)-3-((2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20℃; for 1h; A mixture of 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (50 mg, 0.22 mmol) and tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (82 mg, 0.44 mmol) in DMSO (1.7 ml) was treated with sodium hydride (60% in oil, 18 mg, 0.44 mmol) at room temperature for 1h. The reaction mixture was diluted with saturated sodium bicarbonate solution, brine, and isopropyl acetate. The layers were separated and the aqueous phase extracted into isopropyl acetate (3x). The combined organic layers were dried over sodium sulfate, filtered and absorbed under reduced pressure onto celite. The crude product was purified by silica gel chromatography (eluting gradient 0-100% isopropyl acetate in heptanes) to afford tert-butyl (R)-3-((2,2-dimethyl-5-nitro-2,3- dihydrobenzofuran-6-yl)oxy)pyrrolidine-1-carboxylate (64 mg, 0.17 mmol, 77% yield) as a solid.
  • 63
  • N-[5-(4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methoxypyridin-3-yl]methanesulfonamide [ No CAS ]
  • [ 109431-87-0 ]
  • tert-butyl (3R)-3-[(6-{6-methoxy-5-[(methylsulfonyl)amino]pyridin-3-yl}-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)oxy]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydride; In 1-methyl-pyrrolidin-2-one; at 80℃; for 0.5h; Sodium hydride (55% purity including mineral oil, 1.44 g, 33.0 mmol) was added to the mixture of 11 (4.0 g, 10.9 mmol) and tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.5 g, 13.2 mmol) in NMP (40 mL) at 0 C, and the mixture was stirred at 80 C for 30 min. The reaction mixture was cooled to 0 C and quenched with sat. NH4Cl solution at the same temperature. The aqueous layer was extracted with AcOEt. The combined organic layer was washed with water (x2) and brine, dried over MgSO4 and concentrated at reduced pressure. The residue was purified by amino silica gel column chromatography (CHCl3/MeOH) to give the desired compound as a yellow solid (5.60 g, 99%). 1H-NMR (DMSO-d6) δ 1.39 (9H, s), 2.11-2.39 (2H, m), 3.08 (3H, s), 3.35-3.57 (3H, m), 3.65-3.78 (1H, m), 4.01 (3H, s), 4.05 (3H, s), 5.52-5.63 (1H, m), 7.30 (1H, s), 8.10 (1H, s), 8.44 (1H, d, J = 2.2 Hz), 8.86 (1H, d, J = 2.2 Hz), 9.38 (1H, s); ESI-MS m/z 519.3 [(M+H)+].
  • 64
  • [ 109431-87-0 ]
  • [ 151266-23-8 ]
  • tert-butyl (S)-3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3.5h;Inert atmosphere; Intermediate 2 (2.09g, 8mmol) was dissolved in 150mL of tetrahydrofuran,Add compound 3 (1.8g, 9.6mmol), triphenylphosphine (4.2g, 16mmol), protected by N2, stir at 0, then add diisopropyl azodicarboxylate (3.1mL, 16mmol) dropwise, add dropwise After half an hour, it was transferred to room temperature and reacted for 3 hours, followed by TLC monitoring. After the completion of the reaction, the reaction solution was concentrated, washed with water 3 times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the intermediate 4 (light yellow solid, 70%) was obtained by column chromatography.
70% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3.5h;Inert atmosphere; Intermediate 2 (2.09g, 8mmol) was dissolved in 150mL of tetrahydrofuran, and compound 3 (1.8g, 9.6mmol) was added,Triphenylphosphine (4.2g, 16mmol), protected by N2, stirred at 0C, and then diisopropyl azodicarboxylate (3.1mL, 16mmol) was added dropwise,After the addition was completed, it was transferred to room temperature after half an hour and reacted for 3 hours, followed by TLC monitoring.After the completion of the reaction, the reaction solution was concentrated, washed with water 3 times, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography gave Intermediate 4 (light yellow solid, 70%)
32% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 12h;Inert atmosphere; Procedure: 3-Iodo-4-amino-1H-pyrazolo[3,4-d]pyrimidine (5.1 g, 19.5 mmol), (R)-1-Boc-3-hydroxytetrahydropyrrole (7.3 g, 39mmol), triphenylphosphine PPh3 (7.7g, 29.3mmol) was placed in a 250mL round-bottomed flask, magnets were placed, 100mL of THF was added, and stirred under nitrogen atmosphere at room temperature; diisopropyl azodicarboxylate was taken. DIAD (5.9 g, 29.3 mmol) was dissolved in about 25 mL of THF and slowly added dropwise to the reaction system. After the addition was complete, the reaction was continued for about 12 hours. According to TLC results, the reaction was stopped, and the filtrate was concentrated under reduced pressure using silica gel column chromatography. Purified with petroleum ether-ethyl acetate as eluent to obtain a white solid 2b with a yield of 32%
32% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; 3-iodo-4-amino-1H-pyrazolo [3,4-d] pyrimidine (5.1g, 19.5mmol), (R) -1-Boc-3-hydroxytetrahydropyrrole (7.3g, 39mmol), triphenylphosphine PPh3 (7.7g, 29.3mmol) was placed in a 250mL round-bottomed flask, placed in a magnet, 100mL of THF was added, and stirred at room temperature under the protection of nitrogen; diisopropyl azodicarboxylate was taken DIAD (5.9 g, 29.3 mmol) was dissolved in about 25 mL of THF, and slowly added dropwise to the reaction system. After the dropwise addition was completed, the reaction was continued for about 12 hours. According to the results of TLC, the reaction was stopped, concentrated under reduced pressure, and silica gel column chromatography was used. Purification with petroleum ether-ethyl acetate as eluent gave 2b as a white solid, yield 32%

  • 65
  • 4-(2-bromo-7-methoxy-3,4-dihydronaphthalen-1-yl)phenol [ No CAS ]
  • [ 109431-87-0 ]
  • (S)-tert-butyl 3-(4-(2-bromo-7-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With diamide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h; To a solution of 4-(2-bromo-7-methoxy-3,4-dihydronaphthalen-1 -yl)phenol (Id1 ) (1.01 g, 3.06 mmol) in THF(19 ml), were added (R)-tert-butyl 3-hydroxypyrrolidine-1 -carboxylate (635 mg, 3.39 mmol), (E)-N1 ,N1 ,N2,N2-tetramethyldiazene-1 ,2-dicarboxamide (975 mg, 5.66 mmol) and triphenylphosphine (1 .48 g, 5.64 mmol). The reaction mixture was stirred for 24 hours at room temperature. Water and EtOAc were added. After decantation, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in EtOAc (100/0 to 70/30; v/v) to give 1 .46 g (95%) of (S)-tert-butyl 3- (4-(2-bromo-7-methoxy-3,4-dihydronaphthalen-1 -yl)phenoxy)pyrrolidine-1 -carboxylate (Ie1 ). LC/MS (m/z, MH+): 500
  • 66
  • 2-iodopyrimidin-5-ol [ No CAS ]
  • [ 109431-87-0 ]
  • (S)-tert-butyl 3-((2-iodopyrimidin-5-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With diamide; triphenylphosphine; In tetrahydrofuran; at 0℃; for 24h; To a solution of 2-iodopyrimidin-5-ol (200 mg, 900.97 μηιοΙ) in THF (3 ml), were added (R)-1 -N-Boc-3-hydroxypyrrolidine (208.69 mg, 1 .08 mmol) and triphenylphosphine (283.57 g, 1 .08 mmol). After cooling at 0C, (E)-N1 ,N1 ,N2,N2-tetramethyldiazene-1 ,2- dicarboxamide (0.2 ml, 1.08 mmol) was added dropwise and the reaction mixture is stirred for 24 hours. Water and EtOAc were added. After decantation, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (0 to 100% ; V/V) to give 340 mg (96%) of (S)-tert-butyl 3-((2-iodopyrimidin-5- yl)oxy)pyrrolidine-1 -carboxylate. LC/MS (m/z, MH+): 392
  • 67
  • [ 540-38-5 ]
  • [ 109431-87-0 ]
  • (S)-tert-butyl 3-(4-iodophenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% With diamide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h; To a solution of 4-iodophenol (2 g, 9.09 mmol) in THF (20 ml), were added (R)-1 -N-boc-3- hydroxypyrrolidine (2.1 1 g, 10.91 mmol), (E)-N1 ,N1 ,N2,N2-tetramethyldiazene-1 ,2- dicarboxamide (2.47 g, 13.64 mmol) and triphenylphosphine (3.58 g, 13.64 mmol). The reaction mixture was stirred for 24 hours at room temperature. Water and EtOAc were added. After decantation, the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of EtOAc in heptane (0 to 15% ; V/V) to give 2.29 g (65%) of (S)-tert-butyl 3-(4-iodophenoxy)pyrrolidine-1 -carboxylate. LC/MS (m/z, MH+): 390
  • 68
  • [ 109431-87-0 ]
  • [ 182347-24-6 ]
  • tert-butyl (3R)-3-(2-(2-azidoethoxy)ethoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 40℃; To a 100-mL round-bottom flask was added fert-bulyl (3R)-3- hydrox p rrolidine-l-carboxylate (700 mg, 3.74 mmol, 1 equiv), DMF (30 mL), and tosylate INT-Y2 (900 mg, 3.15 mmol, 0.84 equiv). This was followed by the addition of sodium hydride (300 mg, 12.50 mmol, 3.34 equiv) in several portions at 0 C. The resulting slurry was stirred overnight at 40 C. The resulting mixture was diluted with 50 mL of ethyl acetate and quenched by the addition of 50 mL of water. The resulting solution was extracted with 2 x 150 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 150 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum This resulted in 940 mg (84%) of terf-butyl (3R)-3-[2-(2- azidoethoxy)ethoxy]pyrrolidine-l-carboxylate (INT-Y3) as alight brown solid.
  • 69
  • [ 20210-14-4 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 6h; A mixture of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.09 g, 5.41 mmol), 2-(4-bromobutyl)-2-methyl-1,3-dioxolane (1.2 g, 5.41 mmol) and sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at 100 C. for 6 h. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether:EtOAc 10:1) to give the desired product (R)-tert-butyl 3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil (380 mg). Yield 21% (ESI 330.2 (M+H)+).
21% With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 6h; A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (1.09 g, 5.41 mmol), 2- (4-bromobutyl)-2-methyl-l,3-dioxolane (1.2 g, 5.41 mmol) and sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at 100 C for 6h. Solvent was removed in vacuo , and the residue was purified by silica gel column (pet ether: EtOAc 10: 1) to give the desired product (R)-tert-butyl 3-(4-(2-methyl-l,3-dioxolan-2-yl)butoxy)pyrrolidine-l- carboxylate as a colorless oil (380 mg). Yield 21% (ESI 330.2 (M+H) +).
21% With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 6h; [0076] A mixture of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (1.09 g, 5.41 mmol), 2-(4-bromobutyl)-2-methyl-1,3-dioxolane (1.2 g, 5.41 mmol) and sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at 100 C for 6h. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product (R)-tert-butyl 3-(4-(2-methyl-1,3-dioxolan-2-yl)butoxy)pyrrolidine-1-carboxylate as a colorless oil (380 mg). Yield 21% (ESI 330.2 (M+H)+).
21% With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 6h; A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-l-carboxylate (1.09 g, 5.41 mmol), 2- (4-bromobutyl)-2-methyl-l,3-dioxolane (1.2 g, 5.41 mmol) and sodium hydride (260 mg, 10.82 mmol) in DMF (5 mL) was stirred at 100 C for 6h. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet ether: EtOAc 10: 1) to give the desired product (R)-tert-butyl 3-(4-(2-methyl-l,3-dioxolan-2-yl)butoxy)pyrrolidine-l- carboxylate as a colorless oil (380 mg). Yield 21% (ESI 330.2 (M+H) +).

  • 70
  • [ 109431-87-0 ]
  • 3-iodo-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 3h;Cooling with ice; Iodine (7.45g, 29.37 mmol) was added portionwise to a solution of (R)-(-)-N-Boc-3- pyrrolidinol (CAS: 103057-44-9; 5 g, 26.70 mmol), imidazole (2.73 g, 40.06 mmol) and triphenylphosphine (7.70 g, 29.37 mmol) in THF (50 mL) at 0 C (ice bath). The mixture was stirred at rt for 3 h. The excess of iodine was quenched with Na2S203 (10%, aq. soltn.). The mixture was extracted with EtOAc. The organic layer was separated, dried (Na2S04), filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography (silica, EtOAc in DCM from 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo affording intermediate 32 as a colourless oil (7.21 g, 91%).
  • 71
  • [ 109431-87-0 ]
  • [ 98-59-9 ]
  • (R)-3-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
94% With dmap; triethylamine; In dichloromethane; at 20℃; for 12h; The compound (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 1a (3.5 g, 18.7 mmol), triethylamine (5.25 mL, 37.9 mmol), 4-dimethylaminopyridine (0.35 g, 2.87 mmol) were dissolved in dichloromethane (50 mL), and then p-toluenesulfonyl chloride (5.4 g, 28.1 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours, next water (50 mL) was added for dilution, and ethyl acetate (100 mL*3) was used next for extraction, the resulting organic phases were combined and then dried with anhydrous sodium sulfate, next the desiccant was removed by filtration, and the solvent was evaporated off under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1), such that the title product (R)-3-(toluenesulfonyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester 1b (6.0 g, yellow colored oily matter) was obtained, and the yield was 94%. MS m/z (ESI): 364[M+23]
  • 72
  • [ 109431-87-0 ]
  • [ 106-96-7 ]
  • [ 887261-89-4 ]
YieldReaction ConditionsOperation in experiment
99% To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5.00 g, 26.7 mmol, CAS109431-87-0) and TBAI (493 mg, 1.34 mmol) in THF (50 mL) was added sodium hydride (1.28 g, 32.0 mmol, 60% oil dispersion) in portions at 0 C. After 0.5 hour, 3-bromoprop-1-yne (6.35 g, 53.4 mmol) was added to the mixture. The reaction mixture was stirred at 0-25 C. for 12.5 hours. On completion, the reaction was quenched with water (1.0 mL). The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel to give the title compound (6.00 g, 99% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.28 (s, 1H), 4.24-4.06 (m, 2H), 3.55-3.32 (m, 4H), 2.44 (t, J=2.4 Hz, 1H), 2.13-1.88 (m, 2H), 1.46 (s, 9H).
99% To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5.00 g, 26.7 mmol, CAS 109431-87-0) and TBAI (493 mg, 1.34 mmol) in THF (50 mL) was added sodium hydride (1.28 g, 32.0 mmol, 60% oil dispersion) in portions at 0 C. After 0.5 hour, 3-bromoprop- 1-yne (6.35 g, 53.4 mmol) was added to the mixture. The reaction mixture was stirred at 0 - 25 C for 12.5 hours. On completion, the reaction was quenched with water (1.0 mL). The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel to give the title compound (6.00 g, 99% yield) as yellow oil.1H NMR (400 MHz, CDCl3) d 4.28 (s, 1H), 4.24 - 4.06 (m, 2H), 3.55 - 3.32 (m, 4H), 2.44 (t, J = 2.4 Hz, 1H), 2.13 - 1.88 (m, 2H), 1.46 (s, 9H).
  • 73
  • [ 3512-75-2 ]
  • [ 109431-87-0 ]
  • C16H24N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 60℃; (R)-tert- Butyl 3-hydroxypyrrolidine-l-carboxylate (CAS: 109431-87-0; 1.50 g, 8.01 mmol) was stirred in DMF (3.2 mL) at room temperature. NaH (60% dispersion in mineral oil, 320 mg, 8.01 mmol) was added. A solution of 4-chloro-2,6-lutidine (CAS: 3512-75-2; 1.02 mL, 8.01 mmol) in DMF (3.22 mL) was added dropwise. The reaction mixture was stirred overnight at 60 C. The mixture was evaporated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was dried (Na2S04), filtered and evaporated in vacuo. The crude mixture was purified by flash column chromatography (Si02, EtOAc in heptane, gradient from 0/100 to 90/10) to afford intermediate 43 (1.20 g, 51%).
Sodium hydride (341.8 mg, 8.55 mmol) was added to a stirred solution of (3S)-l-Boc- 3-hydroxypyrrolidine (CAS: 109431-87-0, 1600 mg, 8.55 mmol) in DMF (4.12 mL) at 0 C and the mixture was stirred for 30 min. Then the mixture was allowed to warm to rt and a solution of 4-chloro-2,6-dimethylpyridine (CAS: 3512-75-2, 1.09 mL, 8.55 mmol) in DMF (2.78 mL) was added dropwise. The mixture was stirred at rt for 16 h and then at 60 C for 6 h. After cooling to rt, water was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, EtOAc in heptane: 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 44 (1670 mg, 67%) as a colorless oil.; Intermediate 45 was prepared following an analogous procedure to the one described for the synthesis of intermediate 44 using (3R)-l-Boc-3-hydroxypyrrolidine (CAS: 109431-87-0) and 4-chloro-2,6-dimethylpyridine (CAS: 3512-75-2) as starting materials.
  • 74
  • [ 3678-63-5 ]
  • [ 109431-87-0 ]
  • C15H22N2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With 15-crown-5; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 60℃; for 20h;Inert atmosphere; To a solution of (7?)-(-)-N-Boc-3-pyrrolidinol (CAS: 103057-44-9; 150 mg, 0.80 mmol) in anhydrous DMF (2.02 mL) were added NaH (60% dispersion in minerall oil, 38.5 mg, 0.96 mmol) and l5-crown-5 (0.2 mL, 0.96 mmol) at 0 C under N2 atmosphere. 4- Chloro-2-methylpyridine (CAS: 3678-62-4; 97.8 uL, 0.88 mmol) was added and the reaction mixture was stirred at 60 C for 16 h. Additional amount of NaH (60% dispersion in mineral oil, 1 eq) was added and the reaction mixture was stirred overnight at 60 C. Again NaH (60% dispersion in mineral oil, 1 eq) was added and the reaction mixture was stirred for another 4 h at 60 C. Water was added at 0 C and the mixture was extracted with EtOAc. The organic layer was dried (Na2S04), filtered and the solvents were evaporated in vacuo. The crude mixture was purified by flash column chromatography (silica, EtOAC in heptane, gradient from 0/100 to 80/20). The desired fractions were collected and the solvents were evaporated in vacuo to give intermediate 135 (178.9 mg, 80%) as a yellow oil.
  • 75
  • [ 109431-87-0 ]
  • [ 2695-47-8 ]
  • tert-butyl (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; To a suspension of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (12.8 g, 68.4 mmol), tetrabutyl ammonium bromide (1.102 g, 3.42 mmol) and 6-bromo-l -hexene (13.71 mL, 103 mmol) in heptane (256 mL) was added sodium hydroxide (128 mL, 68.4 mmol, 50 wt% solution in water). The mixture was vigourously stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water and extracted with heptane and twice with diethyl ether/heptane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (600 g silica, 5 -> 14% ethyl acetate in heptane) afforded the desired product tert-butyl (R)-3- (hex-5-en-l-yloxy)pyrrolidine-l-carboxylate (14.93 g). Yield 81%. 'H NMR (400 MHz, Chloroform -if) d 5.87 - 5.74 (m, 1H), 5.05 - 4.91 (m, 2H), 4.04 - 3.95 (m, 1H), 3.48 - 3.27 (m, 6H), 2.07 (q, J = 7.2 Hz, 2H), 2.02 - 1.84 (m, 2H), 1.60 - 1.51 (m, 2H), 1.51 - 1.38 (m, 11H).
81% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; [0144] To a suspension of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (12.8 g, 68.4 mmol), tetrabutylammonium bromide (1.102 g, 3.42 mmol) and 6-bromo-1-hexene (13.71 mL, 103 mmol) in heptane (256 mL) was added sodium hydroxide (128 mL, 68.4 mmol, 50 wt% solution in water). The mixture was vigourously stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water and extracted with heptane and twice with diethyl ether/heptane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (600 g silica, 5 -> 14% ethyl acetate in heptane) afforded the desired product tert-butyl (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate (14.93 g). Yield 81%. 1H NMR (400 MHz, Chloroform-d) δ 5.87 - 5.74 (m, 1H), 5.05 - 4.91 (m, 2H), 4.04 - 3.95 (m, 1H), 3.48 - 3.27 (m, 6H), 2.07 (q, J = 7.2 Hz, 2H), 2.02 - 1.84 (m, 2H), 1.60 - 1.51 (m, 2H), 1.51 - 1.38 (m, 11H).
81% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; To a suspension of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (12.8 g, 68.4 mmol), tetrabutyl ammonium bromide (1.102 g, 3.42 mmol) and 6-bromo-l -hexene (13.71 mL, 103 mmol) in heptane (256 mL) was added sodium hydroxide (128 mL, 68.4 mmol, 50 wt% solution in water). The mixture was vigourously stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water and extracted with heptane and twice with diethyl ether/heptane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (600 g silica, 5 -> 14% ethyl acetate in heptane) afforded the desired product tert-butyl (R)-3- (hex-5-en-l-yloxy)pyrrolidine-l-carboxylate (14.93 g). Yield 81%. 'H NMR (400 MHz, Chloroform -if) d 5.87 - 5.74 (m, 1H), 5.05 - 4.91 (m, 2H), 4.04 - 3.95 (m, 1H), 3.48 - 3.27 (m, 6H), 2.07 (q, J = 7.2 Hz, 2H), 2.02 - 1.84 (m, 2H), 1.60 - 1.51 (m, 2H), 1.51 - 1.38 (m, 11H).
  • 76
  • [ 37865-98-8 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
57% [0122] To a solution of <strong>[109431-87-0](R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate</strong> (3.5 g, 18.7 mmol) in DMF (25 mL) was added NaH (830 mg, 20.6 mmol) in portions at 0 C. The reaction mixture was stirred at 0 C for 1 h. 2-(5-bromopentyl)-2-methyl-1,3-dioxolane (4.9 g, 20.6 mmol) was added and the reaction mixture was stirred at 100C for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (150 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4. The organic phase was concentrated, and the residue was chromatographed on silica gel (20% EtOAc in pet. Ether) to give the product (R)-tert-butyl 3-(5-(2-methyl-1,3-dioxolan-2-yl)pentyloxy)pyrrolidine-1-carboxylate as yellow oil (3.7 g, 57%); (ESI 344.3 (M+H)+).
  • 77
  • [ 110-52-1 ]
  • [ 109431-87-0 ]
  • (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; To a solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (500 mg, 2.67 mmol) in n-Heptane (10 mL) was added sodium hydroxide 50% solution in water (5 mL, 31.2 mmol), tetrabutyl ammonium bromide (43.0 mg, 0.13 mmol) and l,4-dibromobutane (1.595 mL, 13.35 mmol). The mixture was stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with diethyl ether (3x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc=4: l) to give the desired product (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-l-carboxylate as a colorless oil (686 mg). Yield 80% (ESI 314 (M+H-Boc) +).
80% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; [0084] To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in n-Heptane (10 mL) was added sodium hydroxide 50% solution in water (5 mL, 31.2 mmol), tetrabutylammonium bromide (43.0 mg, 0.13 mmol) and 1,4-dibromobutane (1.595 mL, 13.35 mmol). The mixture was stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with diethyl ether (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc=4:1) to give the desired product (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-1-carboxylate as a colorless oil (686 mg). Yield 80% (ESI 314 (M+H-Boc)+).
80% With tetrabutylammomium bromide; sodium hydroxide; In n-heptane; water; at 80℃; for 2h; To a solution of tert-butyl (R)-3-hydroxypyrrolidine-l-carboxylate (500 mg, 2.67 mmol) in n-Heptane (10 mL) was added sodium hydroxide 50% solution in water (5 mL, 31.2 mmol), tetrabutyl ammonium bromide (43.0 mg, 0.13 mmol) and l,4-dibromobutane (1.595 mL, 13.35 mmol). The mixture was stirred at 80 C for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with diethyl ether (3x 10 mL). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc=4: l) to give the desired product (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-l-carboxylate as a colorless oil (686 mg). Yield 80% (ESI 314 (M+H-Boc) +).
  • 78
  • [ 109431-87-0 ]
  • [ 139585-70-9 ]
  • tert-butyl (R)-3-((5-cyanopyridin-2-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% To the stirred solution of tert- butyl (7?)-3-hydroxypyrrolidine-l-carboxylate (15 g, 80 mmol) in toluene (160 ml), 6-bromonicotinonitrile (17.6 g, 96 mmol), 2,2'-bis(diphenyiphosphino) T,T· binaphthyl (7.5 g, 12 mmol) and cesium carbonate (52 g, 160 mmol) was added at 25 C under nitrogen atmosphere. The reaction mixture was degassed with nitrogen for 10 min and added palladium (II) acetate (1.35 g, 6 mmol). The reaction mixture was further degassed with nitrogen gas for 10 min and heated to 100 C in a sealed tube for 18 h. Upon completionof the reaction, the reaction mixture was diluted with water (100 mL) and product was extracted thrice by ethyl acetate (150 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude compound was purified by flash column chromatography on silica gel using 60% ethyl acetate in hexane as an eluent to obtain tert- butyl (R)-3-((5-cyanopyridin-2- yl)oxy)pyrrolidine-l-carboxylate (17.25 g, 60 mmol, 74% yield).
  • 79
  • [ 36801-01-1 ]
  • [ 109431-87-0 ]
  • tert-butyl (R)-3-((4-cyanophenyl)thio)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
61.3% To the stirred solution of 4-mercaptobenzonitrile (7.4 g, 49 mmol) and tert- butyl (S)-3- hydroxypyrrolidine-l-carboxylate (9.2 g, 49 mmol) in tetrahydrofuran (70 mL), triphenylphosphine (19.4 g, 74 mmol) was added. The reaction mixture was degassed with nitrogen for 10 min and cooled to 0 C. Diisopropyl azodicarboxylate (14 mL, 74 mmol) was added to reaction mixture at 0 C drop wise. The reaction mixture was stirred at 25 C for 16 h. Upon completion of the reaction, the reaction mixture was diluted with water (100 mL) and product was extracted twice by dichloromethane (100 mL). The combined dichloromethane layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by flash column chromatography using 20% ethyl acetate in hexane as an eluent to obtain tert- butyl (R)-3-((4- cyanophenyl)thio)pyrrolidine-l-carboxylate (9.2 g, 30.2 mmol, 61.3 % yield) as colorless oil.
  • 80
  • 3-bromo-N-(2,6-dimethoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine [ No CAS ]
  • [ 109431-87-0 ]
  • tert-butyl (S)-3-(3-bromo-4-((2,6-dimethoxybenzyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.8% After tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (386.6 mg, 1.5 eq) was dissolved in tetrahydrofuran (10.0 mL), triphenylphosphine (541.6 mg, 1.5 eq) was added at room temperature and diisopropyl azodicarboxylate (400.0 uL, 1.5 eq) was added at 0 C. The reaction mixture was allowed to react at room temperature for 10 minutes and then 3-bromo-N-(2,6-dimethoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-4-amine (500.0 mg, 1.0 eq) obtained in step 41-1 was added thereto. The reaction mixture was allowed to react at room temperature for 1 day, then water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:hexane=1:1) to obtain 651.0 mg (yield: 88.8%) of the title compound.
  • 81
  • [ 2713-34-0 ]
  • [ 109431-87-0 ]
  • tert-butyl (3S)-3-(3,5-difluorophenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 48h; To an ice-cooled solution of 3,5-difluorophenol (0.250 g, 1.92 mmol), tert-butyl (3R)-3- hydroxypyrrolidine-1-carboxylate (359 mg, 1.92 mmol) and triphenylphosphine (553 mg, 2.11 mmol) in tetrahydrofuran (4.80 mL) at 60 C was added diisopropyl azodicarboxylate (414 µL, 2.11 mmol) dropwise. The reaction mixture was stirred at 60 C for 48 h. The reaction mixture was then concentrated under reduced pressure. The crude oil was diluted with diethyl ether (10 mL) and 1 M aqueous sodium hydroxide (10 mL) was added. The aqueous layer was extracted with diethyl ether (10 mL x 2). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via column chromatography (ISCO, 24 g, 0-20% ethyl acetate in hexanes) to give tert-butyl (3S)-3-(3,5-difluorophenoxy)pyrrolidine-1-carboxylate (409 mg, 1.36 mmol, 71%) as a clear oil.1H NMR (300 MHz, Chloroform-d) d 6.51- 6.31 (m, 3H), 4.83 (p, J = 2.6 Hz, 1H), 3.73- 3.38 (m, 4H), 2.26- 2.01 (m, 2H), 1.48 (s, 9H).
  • 82
  • [ 2713-33-9 ]
  • [ 109431-87-0 ]
  • tert-butyl (3S)-3-(3,4-difluorophenoxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 60℃; for 48h; To an ice-cooled solution of 3,4-difluorophenol (0.250 g, 1.92 mmol), tert-butyl (3R)-3- hydroxypyrrolidine-1-carboxylate (359 mg, 1.92 mmol) and triphenylphosphine (553 mg, 2.11 mmol) in tetrahydrofuran (4.80 mL) at 25 C was added diisopropyl azodicarboxylate (414 µL, 2.11 mmol) dropwise. The reaction mixture was stirred at 60 C for 48 h, then concentrated under reduced pressure. The crude oil was diluted with diethyl ether (10 mL) and then 1 M aqueous sodium hydroxide (10 mL) was added. The aqueous layer was extracted with diethyl ether (10 mL x 2). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified via column chromatography (ISCO, 24 g silica gel, 0-20% ethyl acetate in hexanes over 20 min gradient) to give tert-butyl (3S)-3-(3,4-difluorophenoxy)pyrrolidine-1-carboxylate (400 mg, 1.33 mmol, 70%) as a yellow solid.1H NMR (300 MHz, Chloroform-d) d 7.08 (dt, J = 10.2, 9.1 Hz, 1H), 6.71 (ddd, J = 11.9, 6.6, 3.0 Hz, 1H), 6.58 (dtd, J = 9.2, 3.2, 1.8 Hz, 1H), 4.80 (dq, J = 6.1, 2.5 Hz, 1H), 3.68- 3.41 (m, 4H), 2.12 (dtd, J = 18.1, 13.4, 9.8 Hz, 2H), 1.48 (s, 9H).
  • 83
  • [ 2075-45-8 ]
  • [ 109431-87-0 ]
  • [ 1357384-35-0 ]
YieldReaction ConditionsOperation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 16h; Intermediate P19 [001375] tert-butyl (S)-3-(4-bromo-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [001376] A solution of N-tert-butoxycarbonyl-(R)-(-)-3-pyrrolidinol (5.1 g, 27 mmol) in THF (275 mL) was treated sequentially with 4-bromopyrazole (4.4 g, 30 mmol) and PPfi3 (11 g, 41 mmol), then cooled to 0 °C. The resulting mixture was treated with DIAD (8.0 mL, 41 mmol), then stirred for 16 h at ambient temperature. The reaction mixture then was concentrated in vacuo. The resulting residue was purified twice by silica chromatography (using 5-95% DCM-EtOAc then 5-95% Hexanes-acetone as gradient eluent) to afford the title compound (8.61 g, quantitative yield assumed). MS (apci) m/z = 318.2 (M+H).
  • 84
  • N,1-dimethyl-5-((4-(3-methyl-4-((2-nitrophenyl)sulfonamido)-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-1H-indazole-3-carboxamide [ No CAS ]
  • [ 109431-87-0 ]
  • C33H37N11O7S [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% With cyanomethylenetributyl-phosphorane; In toluene; at 100℃; for 1h;Inert atmosphere; Microwave irradiation; To a solution of N,1-dimethyl-5-((4-(3-methyl-4-((2-nitrophenyl)sulfonamido)-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-1H-indazole-3-carboxamide 43 (100 mg, 0.18 mmol) in toluene (1.0 mL) was added tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (67 mg, 0.36 mmol) followed by the addition of (tributylphosphoranylidene)acetonitrile (0.093 mL, 0.36 mmol). The reaction mixture was stirred under microwave irradiation at 100 C for 1 hr. The reaction mixture was diluted with EtOAc (20 mL), washed with water (15 mL), saturated NaHCO3 solution (15 mL) and brine (15 mL), dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash silica chromatography, elution gradient 0-100% EtOAc in heptane. Product containing fractions were combined and concentrated to afford tert-butyl (S)-3-((N-(3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-2-nitrophenyl)sulfonamido)pyrrolidine-1-carboxylate (89 mg, 68 %) as a beige solid. To a solution of tert-butyl (S)-3-((N-(3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-2-nitrophenyl)sulfonamido)pyrrolidine-1-carboxylate (89 mg, 0.12 mmol) in methanol (1 mL) and DMF (0.3 mL) was added 2-mercaptoacetic acid (0.021 mL, 0.30 mmol) followed by potassium carbonate (84 mg, 0.61 mmol) and the mixture stirred at RT for 16 hrs. The solvent was evaporated and the residue purified by flash silica chromatography, elution gradient 0-100% EtOAc in heptane. Pure fractions were concentrated to afford tert-butyl (S)-3-((3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)amino)pyrrolidine-1-carboxylate (51 mg, 77 %) as a yellowish solid. To a solution of tert-butyl (S)-3-((3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)amino)pyrrolidine-1-carboxylate (51 mg, 0.09 mmol) in DCM (1 mL) was added TFA (1 mL) and the reaction mixture stirred at RT for 60 minutes. The reaction mixture was concentrated and co-evaporated with toluene (x2). The residue was purified by filtration on a SCX-2 ion-exchange column. The column was washed with DCM/MeOH (1:1, v/v), eluted with 1M NH3-MeOH in DCM (1:1, v/v) and the filtrate concentrated to a fawn solid. The solid was further purified by flash silica chromatography, elution gradient 0-10% 1M NH3/MeOH in DCM. Pure fractions were combined and concentrated to afford (S)-N,1-dimethyl-5-((4-(3-methyl-4-(pyrrolidin-3-ylamino)-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-1H-indazole-3-carboxamide 17 (29 mg, 70 %) as a cream coloured solid. 1H NMR (500 MHz, DMSO-d6, 27C): 1.67 (1H, dd), 1.95 - 2.04 (1H, m), 2.20 (3H, s), 2.73 - 2.79 (1H, m), 2.82 (4H, d), 2.94 (1H, dd), 3.00 (1H, dt), 3.18 (2H, s), 4.10 (3H, s), 4.65 (1H, d), 7.09 (1H, d), 7.53 (1H, dd), 7.61 - 7.67 (1H, m), 7.99 (1H, s), 8.22 (1H, q), 8.38 (1H, d), 9.09 (1H, s), 9.78 (1H, s). MS (ESI) [MH]+ m/z 447; chiral purity >99% e.e., tR:7.79 min (tR other enantiomer 16: 8.88 min; SFC: column: Chiralpak IC, 3.0 x 150 mm, 3 micron; mobile phase: gradient from 5% to 50% MeOH + 0.1% NH3 / 95% to 50% s.c. CO2 over 5 min then isocratic 50% MeOH + 0.1% NH3 / 50% s.c. CO2; flow rate: 2 mL/min; BPR: 120 bar; column temperature: 40C)
  • 85
  • 5-((4-(4-hydroxy-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-N,1-dimethyl-1H-indazole-3-carboxamide [ No CAS ]
  • [ 109431-87-0 ]
  • tert-butyl (S)-3-((3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With cyanomethylenetributyl-phosphorane; In toluene; at 100℃; for 2h;Inert atmosphere; Microwave irradiation; To a mixture of 5-((4-(4-hydroxy-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-N,1-dimethyl-1H-indazole-3-carboxamide 46 (100 mg, 0.26 mmol) and tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (74 mg, 0.40 mmol) was added (tributylphosphoranylidene)acetonitrile (128 mg, 0.53 mmol) in toluene (3 mL). The reaction mixture was stirred under microwave irradiation at 100 C for 2 hrs, cooled, evaporated to dryness and the residue was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5µ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (S)-3-((3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate (69 mg, 48 %) as a solid. TFA (0.5 mL) was added to a stirred solution of tert-butyl (S)-3-((3-methyl-1-(2-((1-methyl-3-(methylcarbamoyl)-1H-indazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate (69mg, 0.13 mmol) in DCM (2 mL). The resulting solution was stirred at RT for 2 hrs. The reaction mixture was evaporated to dryness, redissolved in MeOH (1 mL) and purified by ion exchange chromatography, using an SCX2 column. The desired product was eluted from the column using 1M NH3/MeOH and pure fractions were evaporated to dryness to afford (S)-N,1-dimethyl-5-((4-(3-methyl-4-(pyrrolidin-3-yloxy)-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-1H-indazole-3-carboxamide 22 (54 mg, 96 %) as a white solid. 1H NMR (500 MHz, DMSO-d6, 27C): 1.83 - 1.93 (1H, m), 1.94 - 2.04 (1H, m), 2.19 (3H, s), 2.76 - 2.85 (4H, m), 2.93 - 3.05 (3H, m), 4.10 (3H, s), 5.27 (1H, s), 7.16 (1H, d), 7.50 (1H, dd), 7.66 (1H, d), 8.27 (1H, q), 8.46 (2H, d), 9.24 (1H, s), 9.93 (1H, s), 1 exchangeable proton not observed; MS (ESI) [MH]+ m/z 448; chiral purity >99% e.e., tR: 8.02 min (tR other enantiomer: 7.22 min; column: Chiralpak IC, 3.0 x 150 mm, 3 micron; mobile phase: gradient from 5% to 50% MeOH + 0.1% NH3 / 95% to 50% s.c. CO2 over 5 min then isocratic 50% MeOH + 0.1% NH3 / 50% s.c. CO2; flow rate: 2 mL/min; BPR: 120 bar; column temperature: 40C)
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 109431-87-0 ]

Alcohols

Chemical Structure| 2856018-37-4

[ 2856018-37-4 ]

(3R,4S)-tert-Butyl 3,4-dihydroxypyrrolidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 885102-33-0

[ 885102-33-0 ]

(3R,4S)-rel-tert-Butyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 348165-62-8

[ 348165-62-8 ]

(2R,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 114676-61-8

[ 114676-61-8 ]

(2S,4R)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 849935-87-1

[ 849935-87-1 ]

(3S,4S)-tert-Butyl 3-hydroxy-4-(hydroxymethyl)pyrrolidine-1-carboxylate

Similarity: 0.91

Amides

Chemical Structure| 2856018-37-4

[ 2856018-37-4 ]

(3R,4S)-tert-Butyl 3,4-dihydroxypyrrolidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 885102-33-0

[ 885102-33-0 ]

(3R,4S)-rel-tert-Butyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 1175835-99-0

[ 1175835-99-0 ]

tert-Butyl 3-propoxypyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 348165-62-8

[ 348165-62-8 ]

(2R,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 114676-61-8

[ 114676-61-8 ]

(2S,4R)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Related Parent Nucleus of
[ 109431-87-0 ]

Aliphatic Heterocycles

Chemical Structure| 2856018-37-4

[ 2856018-37-4 ]

(3R,4S)-tert-Butyl 3,4-dihydroxypyrrolidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 885102-33-0

[ 885102-33-0 ]

(3R,4S)-rel-tert-Butyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 1175835-99-0

[ 1175835-99-0 ]

tert-Butyl 3-propoxypyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 114214-49-2

[ 114214-49-2 ]

tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

Similarity: 0.92

Chemical Structure| 348165-62-8

[ 348165-62-8 ]

(2R,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Pyrrolidines

Chemical Structure| 2856018-37-4

[ 2856018-37-4 ]

(3R,4S)-tert-Butyl 3,4-dihydroxypyrrolidine-1-carboxylate

Similarity: 0.98

Chemical Structure| 885102-33-0

[ 885102-33-0 ]

(3R,4S)-rel-tert-Butyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 1175835-99-0

[ 1175835-99-0 ]

tert-Butyl 3-propoxypyrrolidine-1-carboxylate

Similarity: 0.94

Chemical Structure| 348165-62-8

[ 348165-62-8 ]

(2R,4S)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 114676-61-8

[ 114676-61-8 ]

(2S,4R)-tert-Butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate

Similarity: 0.92