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[ CAS No. 364750-81-2 ] {[proInfo.proName]}

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Chemical Structure| 364750-81-2
Chemical Structure| 364750-81-2
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Product Details of [ 364750-81-2 ]

CAS No. :364750-81-2 MDL No. :MFCD07784043
Formula : C11H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :MXKSXPYZNXUHEZ-YUMQZZPRSA-N
M.W : 229.27 Pubchem ID :26596883
Synonyms :
Chemical Name :(2S,4S)-1-(tert-Butoxycarbonyl)-4-methylpyrrolidine-2-carboxylic acid

Calculated chemistry of [ 364750-81-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 16
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.82
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 63.17
TPSA : 66.84 ?2

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) : -6.51 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.19
Log Po/w (XLOGP3) : 1.67
Log Po/w (WLOGP) : 1.34
Log Po/w (MLOGP) : 1.03
Log Po/w (SILICOS-IT) : 0.32
Consensus Log Po/w : 1.31

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.05
Solubility : 2.05 mg/ml ; 0.00892 mol/l
Class : Soluble
Log S (Ali) : -2.69
Solubility : 0.47 mg/ml ; 0.00205 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.53
Solubility : 67.2 mg/ml ; 0.293 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.99

Safety of [ 364750-81-2 ]

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

Application In Synthesis of [ 364750-81-2 ]

* 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 [ 364750-81-2 ]

[ 364750-81-2 ] Synthesis Path-Downstream   1~16

  • 1
  • [ 364750-81-2 ]
  • [ 67-56-1 ]
  • [ 14770-40-2 ]
  • N-(2-13CH3-acetyl)-(2S,4S)-4-methylproline methyl ester [ No CAS ]
  • 2
  • [ 61-90-5 ]
  • [ 24424-99-5 ]
  • [ 364750-81-2 ]
  • (2S)-2-(ter-butoxycarbonylamino)-4,4-dimethyl-4-butanolide [ No CAS ]
  • [ 364750-80-1 ]
  • 3
  • [ 364750-81-2 ]
  • [ 1738-76-7 ]
  • [ 901139-29-5 ]
YieldReaction ConditionsOperation in experiment
84% With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 27h; Compound 9 (1.6 g, 7.0 mmol), glycine benzyl ester tosylate (3.07 g, 9.1 mmol), and PyBOP (3.64 g, 7.0 mmol) were dissolved in anhydrous CH2Cl2 (80 mL). DIEA (2.26 g, 17.5 mmol) was added, and the resulting solution was stirred for 27 h under Ar(g). The reaction mixture was washed with 10percent w/v aqueous citric acid (3.x.50 mL), NaHCO3 (3.x.50 mL), water (50 mL), and brine (50 mL), dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The crude oil was purified by flash chromatography (1:1 EtOAc:hexane) to afford 11 (2.13 g, 5.9 mmol, 84percent) as a colorless, sticky liquid. 1H NMR delta: 1.03 and 1.04 (d, J=3.2, 3H), 1.44 (bs, 9H), 1.55-2.50 (m, 4H), 2.90 (t, J=9.8, 1H), 3.65-3.94 (m, 1H), 4.01-4.34 (m, 3H), 5.18 (s, 2H), 7.36 (bs, 5H); HRMS-ESI (m/z): [M+Na]+ calcd for C20H28N2O5Na, 399.1896; found, 399.1897.
  • 4
  • [ 540501-56-2 ]
  • [ 364750-81-2 ]
YieldReaction ConditionsOperation in experiment
94% With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium chlorite; sodium dihydrogenphosphate; In water; acetonitrile; at 40 - 45℃; for 19h;pH 6.6; Following the method of Del Valle and Goodman, three solutions were prepared prior to the oxidation. The first solution consisted of NaClO2 (1.33 g, 14.7 mmol) in water (7.4 mL). The second solution consisted of bleach (436 muL) in water (7.4 mL). The third solution consisted of compound 8 (1.60 g, 7.4 mmol) dissolved in 100 mL of 3:2 CH3CN:NaH2PO4 buffer (pH 6.6, 0.67 M). The solution containing 8 was heated to 45° C., and TEMPO (193 mg, 0.7 mmol) was added. The two oxidant solutions were added simultaneously in 618 muL portions over 1 h, and the resulting solution was stirred at 40° C. for 18 h. After cooling to room temperature, the reaction was quenched by dropwise addition of saturated aqueous Na2SO3 until the solution became colorless. The acetonitrile was removed under reduced pressure, and the resulting aqueous solution basified to pH 10 with 1 M NaOH. The basic solution was washed with ether (5*125 mL) and then acidified to pH 2 with 2 M HCl. The acidic solution was extracted with ether (4*200 mL), and the organic layer was dried over anhydrous MgSO4(s) and concentrated under reduced pressure to afford 9 (1.60 g, 7.0 mmol, 94percent) as a white solid. 1H NMR delta: 1.09 (d, J=6.0, 3H), 1.44 and 1.50 (s, 9H), 1.58-1.70 and 1.88-2.00 (m, 1H), 2.21-2.31 (m, 1H), 2.31-2.52 (m, 1H), 2.89-3.04 (m, 1H), 3.67-3.82 (m, 1H), 4.20-4.38 (2m, 1H); 13C NMR delta: 16.9, 17.2, 28.2, 28.3, 32.7, 36.4, 38.8, 53.3, 54.1, 59.4, 59.5, 80.4, 81.6, 159.4, 162.1, 174.9, 179.6; ESI-MS (m/z): [M-H]- calcd for C11H18NO4, 228.1; found, 228.4.
  • 5
  • [ 364750-81-2 ]
  • [ 67-56-1 ]
  • C7H13NO2*ClH [ No CAS ]
YieldReaction ConditionsOperation in experiment
With acetyl chloride; at 0 - 20℃; for 10h; Following the method of Nudelman et al., compound 9 (100 mg, 0.44 mmol) was dissolved in anhydrous MeOH (10 mL), and the resulting solution was cooled to 0° C. Acetyl chloride (11.80 g, 150 mmol) was added dropwise and the reaction mixture was allowed to warm slowly to room temperature and stirred for 10 h. The resulting solution was concentrated under reduced pressure and the residue dissolved in anhydrous CH2Cl2 (15 mL). N,N-4-Dimethylaminopyridine (450 mg, 3.7 mmol) was added, followed by the dropwise addition of H313CC(O)Cl (99 mg, 1.2 mmol). The reaction mixture was stirred for 9 h. Additional unlabeled acetyl chloride was added to ensure complete reaction, followed by MeOH (10 mL) to quench the reaction. The resulting solution was concentrated under reduced pressure, and the residue was dissolved in 10percent w/v aqueous citric acid, extracted with CH2Cl2 (2.x.40 mL), dried over anhydrous MgSO4(s), and concentrated under reduced pressure. The crude product was purified by flash chromatography (50percent v/v EtOAc in hexane to elute byproducts followed by 6percent v/v MeOH in EtOAc) to afford 10 (40 mg, 0.21 mmol, 52percent) as a yellow oil. 1H NMR delta: 1.06 and 1.10 (2 d, J=6.4, 3H), 1.56 (q, J=10.5, 1H), 2.09 (d, JC-H=128, 3H), 2.28-2.46 (m, 2H), 3.18 (t, J=9.8, 1H), 3.69 (m, 1H), 3.74 and 3.78 (2 s, 3H), 4.36 (t, J=8.4, 1H); 13C NMR delta: 17.0, 21.8, 22.4, 33.9, 37.6, 52.3, 55.1, 59.3, 168.9, 169.4, 173.1, 173.2; HRMS-ESI (m/z): [M+Na]+ calcd for C813CH15NO3Na, 209.0983; found, 209.0980.
  • 6
  • [ 364750-81-2 ]
  • (2S,4S)-4-methylprolyl-glycine benzyl ester [ No CAS ]
  • 7
  • [ 364750-81-2 ]
  • [ 901139-44-4 ]
  • 8
  • [ 364750-81-2 ]
  • [ 901139-69-3 ]
  • 9
  • [ 364750-81-2 ]
  • [ 901139-37-5 ]
  • 10
  • [ 364750-81-2 ]
  • [ 901139-63-7 ]
  • 11
  • (S)-2-tert-butyldimethylsilyloxymethyl-N-tert-butyloxycarbonyl-4-methylenepyrrolidine [ No CAS ]
  • [ 364750-81-2 ]
  • 12
  • [ 364750-81-2 ]
  • [ 99-56-9 ]
  • [ 1233365-43-9 ]
  • 13
  • [ 138512-73-9 ]
  • [ 364750-81-2 ]
YieldReaction ConditionsOperation in experiment
With water; lithium hydroxide; In ethanol; at 20℃; for 5h; Exam le Ml 2.2, Step cTo a solution of ester M12.2b (1.69 g, 6.95 mmol) in ethanol (10 mL) was added solution of LiOH (0.250 g, 10.42 mmol) in water (5.00 mL), and the reaction mixture was stirred at room temperature for 5 hr. The organic solvent was evaporated in vacuo and the residue was diluted with water (10 mL) and washed with ether (10 mL). It was chilled in ice-water bath, and acidified to a pH range of ~2 with IN HCl. It was then extracted with EtOAc (20 mL, 3x). The organic layer was dried with Na2S04 and concentrated in vacuo to afford acid M12.2c as a colorless oil, which became a white solid upon extended exposure to high vacuum (1.38g). XH NMR (CDC13, delta = 7.24 ppm, 400 MHz): 4.39-4.22 (m, 1H), 3.80-3.69 (m, 0.91H), 3.59-3.35 (m, 0.18H), 3.03-2.89 (m, 0.91H), 2.51-2.22 (m, 2H), 1.98-1.91 (m, 0.71H), 1.68-1.60 (0.29H), 1.50/1.44 (two 's', 9H), 1.09 (app m, 3H).
Example M 12.2, Step c; To a solution of ester M12.2b (1.69 g, 6.95 mmol) in ethanol (10 mL) was added solution of LiOH (0.250 g, 10.42 mmol) in water (5.00 mL), and the reaction mixture was stirred at room temperature for 5 hr. The organic solvent was evaporated in vacuo and the residue was diluted with water (10 mL) and washed with ether ( 10 mL) . It was chilled in ice- water bath, and acidified to a pH range of ~2 with IN HCl. It was then extracted with EtOAc (20 mL, 3x). The organic layer was dried with Na2SO4 and concentrated in vacuo to afford acid M 12,2c as a colorless oil, which became a white solid upon extended exposure to high vacuum (1.38g). 1H NMR (CDCl3, delta - 7.24 ppm, 400 MHz): 4.39-4.22 (m, IH), 3.80-3.69 (m, 0.91H), 3.59-3.35 (m, 0.18H), 3.03-2.89 (m, 0.91H), 2.51-2.22 (m, 2H), 1.98-1.91 (m, 0.71H), 1.68-1.60 (0.29H), 1.50/1.44 (two 's\\ 9H), 1.09 (app m, 3H).
  • 14
  • [ 364750-81-2 ]
  • [ 99-73-0 ]
  • [ 1250939-42-4 ]
YieldReaction ConditionsOperation in experiment
94% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; To a solution of compound M-1 (2 g, 7.2 mmol) and M-2 (1.5 g, 6.55 mmol) in MeCN (50 mL) was added DIPEA (1.3 mL) at 0 °C. At the end of the addition, the mixture was stirred at rt and the reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with ice water (10 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound M-3 (2.55 g, 94percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.78 (m, 2H), 7.65 (m, 2H), 5.54-5.15 (m, 2H), 4.39 (m, 1H), 3.76 (m, 1H), 3.03 (m, 1H), 2.53 (m, 1H), 2.27 (m, 1H), 1.84 (m, 1H), 1.43 (m, 9H), 1.24 (m, 1H), 1.09 (m, 3H). [0524] A mixture of compound M-3 (2.55 g, 6.2 mmol) and ammonium acetate (4.6 g, 59.7 mmol) in xylene (100 mL) in a sealed tube was stirred at 130 °C for 5 hours, cooled to rt and washed with water. The organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound M-4 (1.63 g, 64.7percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.78 (m, 2H), 7.65 (m, 2H), 4.39 (m, 1H), 3.76 (m, 1H), 3.03 (m, 1H), 2.53 (m, 1H), 2.27 (m, 1H), 1.84 (m, 1H), 1.43 (m, 9H), 1.24 (m, 1H), 1.09 (m, 3H). [0525] To a mixture of compound M-4 (1.63 g, 4 mmol), bis(pinacolato)diboron (1.12 g, 4.4 mmol), Pd(dppf)Cl2·CH2Cl2 (71 mg, 0.09 mmol) and KOAc (0.98 g, 10 mmol) was added DME (20 mL) under N2 via syringe. The resulting mixture was stirred at 90 °C for 5 hours in an oil bath and concentrated in vacuo. To the residue was added a small amount of water, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 2/1) to give the title compound 28-1 as a pale yellow solid (1.77 g, 97.6percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.78 (m, 2H), 7.65 (m, 2H), 4.39 (m, 1H), 3.76 (m, 1H), 3.03 (m, 1H), 2.53 (m, 1H), 2.27 (m, 1H), 1.84 (m, 1H), 1.43 (m, 9H), 1.24 (m, 1H), 1.09 (m, 3H).
62.9% With triethylamine; In dichloromethane; at 0 - 20℃; To a solution of compound 2-3-0 (3.63 g, 13.1 mmol) and compound 10-1 (3.0 g, 13.1 mmol) in DCM (40 mL) at 0 °C was added TEA (3.9 mL, 26.3 mmol) dropwise slowly. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the reaction was quenched with water (50 mL) and the aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound (3.27 g, 62.9percent) without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 399.3 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 5h; To a solution of M12.2c (1.38 g, 6.02 mmol) and 2-bromo-l-(4- bromophenyl)ethanone (1.673 g, 6.02 mmol) in acetonitrile (35 mL) was added DIEA (1.051 mL, 6.02 mmol). It was stirred at room temperature for 5 hrs. The solvent was evaporated in vacuo and water (50 mL) and EtOAc (70 mL) were added, organic layer was separated and washed by sat. aHC03 (30 mL), dried with Na2S04, evaporated in vacuo to give crude M12.2d as a red oil (2.71 g), which was used in the next step without further purification. XH NMR (DMSO-d6, delta = 2.5 ppm, 400 MHz): 7.91 (m, 2H), 7.78 (d, J = 8.5 Hz, 2H), 5.60-4.90 (m, 2H), 4.29 (app t, 1H), 3.61 (m, 1H), 2.85 (m, 1H), 2.35-1.80 (m, 2H), 1.65 (m, 1H), 1.40-1.32 (two s, 9H), 1.02 (d, J = 6.5 Hz, 3H). LC/MS: Anal. Calcd. for [M+Na Ci9H24 81BrNNa05: 450.07; found: 450.11.
With N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl acetamide; at 35℃; for 3h;Inert atmosphere; (a) (S)-Pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester To a mixture of p-bromophenacyl bromide (242 mg, 0.87 mmol) in DCM (1.5 mL) and DMA (1.5 mL), under nitrogen, was added <strong>[364750-81-2](2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester</strong> (200 mg, 0.87 mmol) and N,N-diisopropylethylamine (531.8 muL, 3.05 mmol) and the resulting mixture was stirred at 35° C. for 3 h, concentrated under vacuum, dissolved in DCM (30 mL), and washed with water (2*5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title intermediate.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; To a solution of compound 20-1 (3.0 g. 13.1 mmol) and compound 1 -6-2 (3.63 g. 13.1 mmol) in DCM (40 mL) at 0 °C was added Et3N (2.73 mL, 19.65 mmol) dropwie, and the mixture was stirred at rt for 2 hrs. After the reaction was completed, the reaction was quenched with water (50 mL). The resulting mixture was extracted with DCM (50 mL x 3), and the combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound (3.27 g). which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 399.29 [M+H] +.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; Sealed tube; To a solution of compound 14-1 (3.0 g, 13.1 mmol) and compound 1-12-2 (3.63 g, 13.1 mmol) in DCM (40 mL) was added Et3N (3.9 mL, 26.3 mmol) dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL). The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the crude product (3.27 g), which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 499.5 [M+H]+.
With triethylamine; In dichloromethane; at 0 - 25℃; for 2h; [001911 To a cooled 0 °C solution of compound 2-1 (3.0 g, 13.1 mmol) and compound 1-6-2 (3.63 g, 13.1 mmol) in 40 mL of DCM was added TEA (3.9 mL, 26.3 mol) dropwise. After the addition, the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was quenched with water (50 mL). The resulting mixture was extracted with DCM (50 mLx3), The combined organic phases were dried over anhydrous Na2504 and concentrated in vacuo to give the crude product (3.27 g) which was used directly for the next step. The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 426.1[M+Hfb.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2.16667h; A mixture of /?-bromophenacyl bromide (7.8 g, 28 mmol), (25',45 -4-methyl- pyrrolidine-l,2-dicarboxylic acid 1-fert-butyl ester (7.0 g, 30 mmol) and acetonitrile (100 mL) was stirred at RT for 10 min and and NN-diisopropylethylamine (5.8 mL, 33 mmol) was added dropwise. The resulting mixture was stirred at RT for 2 h, concentrated by rotary evaporation to about 30 mL, dissolved in ethyl acetate (100 mL), and washed with water (2 x 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to provide the crude title intermediate as an oil.
3.27 g With triethylamine; In dichloromethane; at 0 - 25℃; for 2h; Step 1) the Preparation of Compound 4-1 (0309) To a cooled 0° C. solution of compound 2-1 (3.0 g, 13.1 mmol) and compound 1-6-2 (3.63 g, 13.1 mmol) in 40 mL of DCM was added TEA (3.9 mL, 26.3 mol) dropwise. After the addition, the mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the mixture was quenched with water (50 mL). The resulting mixture was extracted with DCM (50 mL×3), The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product (3.27 g) which was used directly for the next step. The compound was characterized by the following spectroscopic data: (0310) MS (ESI, pos. ion) m/z: 426.1 [M+H]+.
With triethylamine; In dichloromethane; at 20℃; for 2h; Compound 8-1 (3.0 g, 13.1 mmol) and compound 3-1-0 (3.63 g, 13.1 mmol) weredissolved in DCM (40 mL) and TEA (3.9 mL, 26.3 mmol) Complete, the reaction at roomtemperature 2.0 hours. After the reaction was completed, the reaction was quenched bythe addition of water (50 mL) and the aqueous layer was extracted with DCM (50 mL × 3).The organic phases were combined, washed with saturated brine and dried over anhydrousNa 2SO 4Drying, concentration gave 3.27 g of crude product, yield: 62.9percent. Directly usedfor the next reaction.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 5h; Example Ml 2.2, step d; To a solution of M12.2c (1.38 g, 6.02 mmol) and 2-bromo-l-(4- bromophenyl)ethanone (1.673 g, 6.02 mmol) in acetonitrile (35 mL) was added DIEA (1.051 mL, 6.02 mmol). It was stirred at room temperature for 5 hrs. The solvent was evaporated in vacuo and water (50 niL) and EtOAc (70 mL) were added, organic layer was separated and washed by sat. NaHCO3 (30 mL), dried with Na2SO4, evaporated in vacuo to give crude M12.2d as a red oil (2.71 g), which was used in the next step without further purification. 1H NMR (DMSO-d, delta - 2.5 ppm, 400 MHz): 7.91 (m, 2H)5 7.78 (d, J = 8.5 Hz5 2H), 5.60-4.90 (m, 2H), 4.29 (app t, IH), 3.61 (m, IH), 2.85 (m, IH), 2.35-1.80 (m, 2H), 1.65 (m, IH)9 1.40-1.32 (two s, 9H), 1.02 (d, J = 6.5 Hz, 3H). LC/MS: Anal. Calcd. for [M+Na]+ Ci9H2481BrNNaO5: 450.07; found: 450.11.

  • 15
  • [ 1262320-71-7 ]
  • [ 364750-81-2 ]
YieldReaction ConditionsOperation in experiment
60% With hydrogen;5% Pd(II)/C(eggshell); In water; under 2250.23 Torr; for 8h;Industry scale; Example 49. Synthesis of 4(S)-methyl-L-BOC-proline (2) 2A solution of 1 (100Og, 3.32mol) in water (10L) was charged to a 2OL hydrogenator along with 5percent Palladium on Carbon (56percent wet, 12Og, JM-JR537). The resulting mixture was hydrogenated for 8hrs with rapid agitation under a 3.0 bar hydrogen pressure. The catalyst was removed by filtration through Celite and the resulting light yellow solution was acidified to pH 1.5 with 3N HCl in the presence of isopropyl acetate (16L). The layers were separated and the aqueous layer was re-extracted with isopropyl acetate (8L). The combined organic layers were then washed with water (16L), followed by brine (8L) and then distilled under reduced pressure to dryness. The crude product (695g) was obtained as an off-white solid. Analysis by 1H-NMR indicated that the solid was a diastereomeric mixture of 9:1 cis/trans isomers (ratio of the methine proton alpha to the carbonyl). This mixture was upgraded to 20:1 cis/trans isomers by re-crystallizing twice from a 2:1 isopropyl acetate/heptane solvent mixture to obtain 459g of solid (60percent yield). 1H-NMR(dmsod6): 12.45(s,1 H); 4.03(t,1 H, J=10.5Hz); 3.54(m, 1 H); 2.77(m, 1 H); 2.37(m, 1 H); 2.17(m, 1 H); 1.41 (m, 1 H); 1.38(m, 9H); 0.97(t, 3H, J=8.0Hz).
  • 16
  • [ 364750-81-2 ]
  • [ 38875-53-5 ]
  • [ 1335137-71-7 ]
YieldReaction ConditionsOperation in experiment
91.9% With 2,4,6-trimethyl-pyridine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; To a stirred solution of 5-bromopyridine-2,3-diamine (811.6 mg, 4.18 mmol) and (2S,4S)-1 -tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (800 mg, 3.48mmol) in DMF (12.00 mL) is added 2,4,6-collidine (1.384 ml_, 10.47 mmol). The reaction mixture is cooled to 0°C before the addition of HATU (1.59 g, 4.18 mmol). The reaction mixture is stirred at room temperature overnight, diluted with water and extracted with ethyl acetate. The Combined extracts are washed with brine, dried over Na2SC>4 and concentrated. The residue is purified by flash column chromatography on silica gel using EtOAc in Hexanes Attorney Docket No. 097546-0171as eluent (10 to 100percent) to afford tert-butyl (2S,4S)-2-[(2-amino-5-bromo-3- pyridyl)carbamoyl]-4-methyl-pyrrolidine-1 -carboxylate (1.28 g, 91.9percent) as a pale yellow foam.LC/MS: m/z = 400.7(M+H+)
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