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Chemical Structure| 15761-39-4
Chemical Structure| 15761-39-4
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Product Details of [ 15761-39-4 ]

CAS No. :15761-39-4 MDL No. :MFCD00037324
Formula : C10H17NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :ZQEBQGAAWMOMAI-ZETCQYMHSA-N
M.W : 215.25 Pubchem ID :85083
Synonyms :
NSC 164660;1-tert-butyloxycarbonyl-L-Proline;N-Boc-L-Proline

Calculated chemistry of [ 15761-39-4 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 4
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 58.36
TPSA : 66.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.18
Log Po/w (XLOGP3) : 1.47
Log Po/w (WLOGP) : 1.09
Log Po/w (MLOGP) : 0.74
Log Po/w (SILICOS-IT) : 0.22
Consensus Log Po/w : 1.14

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.84
Solubility : 3.14 mg/ml ; 0.0146 mol/l
Class : Very soluble
Log S (Ali) : -2.48
Solubility : 0.712 mg/ml ; 0.00331 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.38
Solubility : 90.6 mg/ml ; 0.421 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.62

Safety of [ 15761-39-4 ]

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 [ 15761-39-4 ]

* 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.

  • Upstream synthesis route of [ 15761-39-4 ]
  • Downstream synthetic route of [ 15761-39-4 ]

[ 15761-39-4 ] Synthesis Path-Upstream   1~49

  • 1
  • [ 15761-39-4 ]
  • [ 34381-71-0 ]
Reference: [1] Tetrahedron Letters, 1983, vol. 24, # 33, p. 3513 - 3516
  • 2
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  • [ 56502-01-3 ]
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 20, p. 3609 - 3610
[2] RSC Advances, 2014, vol. 4, # 70, p. 37419 - 37422
  • 3
  • [ 186581-53-3 ]
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  • [ 56502-01-3 ]
Reference: [1] Organic Syntheses, 2002, vol. 79, p. 154 - 154
  • 4
  • [ 15761-39-4 ]
  • [ 170491-63-1 ]
Reference: [1] Patent: WO2004/58705, 2004, A2, . Location in patent: Page 38;39
[2] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 6793 - 6805
[3] Organic and Biomolecular Chemistry, 2015, vol. 13, # 42, p. 10456 - 10460
[4] Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 10294 - 10298
  • 5
  • [ 15761-39-4 ]
  • [ 170491-63-1 ]
Reference: [1] Patent: US3976660, 1976, A,
  • 6
  • [ 15761-39-4 ]
  • [ 51207-66-0 ]
Reference: [1] Journal of the American Chemical Society, 1987, vol. 109, p. 2040
  • 7
  • [ 15761-39-4 ]
  • [ 91229-91-3 ]
Reference: [1] Chemical & Pharmaceutical Bulletin, 1986, vol. 34, # 9, p. 3873 - 3878
  • 8
  • [ 15761-39-4 ]
  • [ 91229-91-3 ]
Reference: [1] Tetrahedron, 1989, vol. 45, # 23, p. 7459 - 7468
  • 9
  • [ 15761-39-4 ]
  • [ 53267-93-9 ]
  • [ 37169-36-1 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 74, p. 60354 - 60364
  • 10
  • [ 67-56-1 ]
  • [ 15761-39-4 ]
  • [ 2133-40-6 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 70℃; for 7.5 h; Inert atmosphere; Cooling with ice
Stage #2: With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 0.0833333 h; Inert atmosphere
To a solution of (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.50 g, 6.97 mmol) in methanol (20 mL) was added sulfoxide chloride (0.51 mL, 6.97 mmol) dropwise in an ice-bath. The mixture was stirred in the ice-bath for 30 min, and then stirred at 70 for 7 h. The reaction mixture was concentrated, and DCM (8 mL) and a HCl in EtOAc solution (4 M, 6 mL) were added. The resulting mixture was stirred at rt for 5 min, and then concentrated to give the title compound as white thick oil (800 mg, 88) .1H NMR (400 MHz, CD3OD) : δ ppm 4.47 (t, J 7.8 Hz, 1H) , 3.88 (s, 3H) , 3.37-3.45 (m, 2H) , 2.41-2.50 (m, 1H) , 2.07-2.21 (m, 3H) .
88%
Stage #1: at 70℃; for 7.5 h; Cooling with ice
Stage #2: With hydrogenchloride In dichloromethane; ethyl acetate at 20℃; for 0.0833333 h;
To Boc-L- proline (1.50g, 6.97mmol) in methanol (20 mL) was added dropwise thionyl chloride (0.51 mL underice-cooling, 6.97mmol), The reaction under ice 30min, 70 ° C 7H reaction, the solvent is removed,dichloromethane (8mL) and HCl in ethyl acetate Solution (4M, 6mL), stirred at rt for 5min, the solvent wasremoved to give 800mg of white viscous material, yield: 88percent.
Reference: [1] Patent: WO2016/34134, 2016, A1, . Location in patent: Paragraph 00324
[2] Patent: CN105399698, 2016, A, . Location in patent: Paragraph 0707-0709
  • 11
  • [ 15761-39-4 ]
  • [ 16652-71-4 ]
Reference: [1] Patent: WO2012/30160, 2012, A2,
  • 12
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  • [ 13734-41-3 ]
  • [ 13139-16-7 ]
  • [ 13836-37-8 ]
  • [ 73821-95-1 ]
  • [ 47689-67-8 ]
  • [ 35899-43-5 ]
  • [ 4474-91-3 ]
Reference: [1] Bioorganic Chemistry, 2011, vol. 39, # 2, p. 101 - 109
  • 13
  • [ 110-89-4 ]
  • [ 15761-39-4 ]
  • [ 84466-85-3 ]
Reference: [1] Tetrahedron, 1984, vol. 40, # 8, p. 1381 - 1390
[2] Chemistry Letters, 1983, p. 297 - 298
  • 14
  • [ 15761-39-4 ]
  • [ 15401-08-8 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1998, vol. 37, # 4, p. 370 - 375
[2] Bulletin of the Chemical Society of Japan, 1984, vol. 57, # 1, p. 97 - 102
[3] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 3, p. 766 - 769
[4] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 4, p. 1028 - 1033
[5] Liebigs Annalen der Chemie, 1983, vol. NO. 9, p. 1524 - 1532
[6] Tetrahedron Asymmetry, 2011, vol. 22, # 1, p. 22 - 25
[7] Synlett, 2011, # 4, p. 499 - 502
[8] Patent: US8710008, 2014, B2,
[9] Organic Letters, 2016, vol. 18, # 7, p. 1662 - 1665
[10] European Journal of Organic Chemistry, 2018, vol. 2018, # 19, p. 2204 - 2207
  • 15
  • [ 15761-39-4 ]
  • [ 2577-90-4 ]
  • [ 52071-65-5 ]
Reference: [1] Tetrahedron, 2009, vol. 65, # 7, p. 1444 - 1449
  • 16
  • [ 15761-39-4 ]
  • [ 52071-65-5 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1992, vol. 26, # 11/12, p. 803 - 807[2] Khimiko-Farmatsevticheskii Zhurnal, 1992, vol. 26, # 11-12, p. 16 - 18
[3] Tetrahedron, 2013, vol. 69, # 25, p. 5136 - 5143
[4] Synthetic Communications, 2017, vol. 47, # 1, p. 78 - 85
  • 17
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  • [ 63-91-2 ]
  • [ 52071-65-5 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1988, vol. 22, # 2, p. 106 - 110[2] Khimiko-Farmatsevticheskii Zhurnal, 1988, vol. 22, # 2, p. 155 - 158
  • 18
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  • [ 86953-79-9 ]
Reference: [1] Chemical Communications, 2007, # 48, p. 5244 - 5246
  • 19
  • [ 15761-39-4 ]
  • [ 74-88-4 ]
  • [ 145681-01-2 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h; K2CO3 (1.1 kg, 8.0 mol) and CH3I (659 g, 4.65 mol) was added to a solution of 1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (500 g, 2.32 mol) in DMF (2.5 L) at r.t. and the mixture was stirred for 12h, then filtered. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (2 L) and washed with water (2 x 1 L), brine (1 L), dried (MgSO4) and concentrated in vacuo to give the title compound (417.8 g, 96percent) as yellow oil; 1H NMR: (CDCl3) 1.37 (9H, m), 1.72-1.84 (3H, m), 2.15 (1H, m), 3.26-3.51 (2H, m), 3.65 (3H, s), 4.17 (1H, m).
95% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16.1667 h; To a stirred solution of (tert-butoxycarbonyl)proline (6.5 g, 30.2 mmol) in DMF was added potassium carbonate (12.5 g, 90.6 mmol) at room temperature and the reaction was stirred for 10 min. Methyl iodide (6.43 g, 45.3 mmol) was added at 0 °C, then the reaction was allowed to warm to ambient temperature and stirred for 16 h. Completion of the reaction was confirmed by TLC. The product was isolated and purified via standard methods to afford 1-(tert-butyl) 2-methyl pyrrolidine-1,2-dicarboxylate (6.6 g, 95 percent) as yellow oil.
93.91% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 24 h; A: Pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester To a stirred solution of pyrrolidine- 1 ,2-dicarboxylic acid 1-tert-butyl ester (5.0 g, 23.25 mmol) and methyl iodide (6.0 mL, 93.02 mmol) in DMF (25 mL) was added NaH (60percent w/w, 2.3 g, 57.09 mmol) portion-wise at 0°C. The resulting mixture was allowed to stir at rt for 24 hours. The reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was washed with water and brine. Drying over Na2S04, filtering and concentration provided crude compound 2d. Yield: 5.0 g (93.91percent); 1H-NMR (400 MHz, DMSO-<): δ 4.18-4.13 (m, 1 H), 3.65 (s, 3 H), 3.38-3.32 (m, 2 H), 2.22-2.18 (m, 1 H), 1.87-1.78 (m, 3 H), 1.32 (s, 9 H); LCMS [M+H] = 230.2, RT = 3.28 minutes (Program P 1 , Column Z).
90% With caesium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16 h; Example 141 - Preparation of Intermediate 44 The synthesis of Intermediate 44 followed the procedure of General Procedure 13 following: Intermediate 44 To a cooled solution (0°C) of 1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20 g, 92.9 mmol) in dry dimethylformamide (DMF, 100 mL) was added cesium carbonate (Cs2CO3, 103 g, 316 mmol) followed by iodomethane (MeI, 12 mL, 186 mmol). After stirring at room temperature for 16 hours, water (100 mL) was added and extracted into EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 10- 15percent EtOAc/n-hexanes, to obtain 1-tert-butyl-2-methyl pyrrolidine-1,2-dicarboxylate (Intermediate 44, 19 g, yield: 90percent) as a pale yellow liquid; TLC System: 20percent ethyl acetate in hexane Rf-0.5.

Reference: [1] Patent: WO2013/14448, 2013, A1, . Location in patent: Page/Page column 103
[2] Patent: WO2016/89977, 2016, A1, . Location in patent: Paragraph 00137
[3] Patent: WO2014/28675, 2014, A1, . Location in patent: Page/Page column 118
[4] Patent: WO2016/138532, 2016, A1, . Location in patent: Paragraph 0376
[5] Tetrahedron Asymmetry, 2003, vol. 14, # 10, p. 1323 - 1333
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4453 - 4459
[7] Patent: US2012/214809, 2012, A1, . Location in patent: Page/Page column 68-69
  • 20
  • [ 145681-01-2 ]
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  • [ 73323-65-6 ]
Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 10, p. 1323 - 1333
  • 21
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  • [ 73323-65-6 ]
Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 10, p. 1323 - 1333
  • 22
  • [ 15761-39-4 ]
  • [ 91550-08-2 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 1998, vol. 46, # 2, p. 616 - 619
[2] Journal of the American Chemical Society, 1993, vol. 115, # 24, p. 11393 - 11409
[3] Journal of the American Chemical Society, 1984, vol. 106, # 18, p. 5360 - 5361
[4] Journal of the American Chemical Society, 1989, vol. 111, # 13, p. 4988 - 4990
[5] Journal of Organic Chemistry, 1992, vol. 57, # 4, p. 1179 - 1190
[6] Tetrahedron Letters, 2011, vol. 52, # 38, p. 4878 - 4881
[7] Organic Letters, 2013, vol. 15, # 4, p. 824 - 827
[8] Patent: WO2006/127550, 2006, A1,
  • 23
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  • [ 676-58-4 ]
  • [ 91550-08-2 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 48, p. 7119 - 7122
  • 24
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  • [ 35150-07-3 ]
YieldReaction ConditionsOperation in experiment
85% With pyridine; ammonium bicarbonate In 1,4-dioxane at 20℃; for 6 h; General procedure: A mixture of compound 1 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) in dioxane (20 mL) was stirred at room temperature for 6 h. the product was extracted with CH2Cl2, washed with 1 M HCl and saturated NaCl, dried, filtrated, and concentrated. n-Hexane (100 mL) was added and the product 2 (0.85 g, 85percent) began to precipitate using the ultrasound as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.37–4.34 (m, 1H), 3.47–3.36 (m, 2H), 2.07–1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215 [M+H]+.
85% With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃; for 6 h; A mixture of compound 8 (1.00 g, 4.65 mmol), (Boc)2O (1.52 g, 6.97 mmol), NH4HCO3 (0.55 g, 6.97 mmol) and pyridine (1.0 mL) indioxane (20 mL) was stirred at room temperature for 6 h. the product wasextracted with CH2Cl2, washed with 1M HCl and saturated NaCl, dried, filtrated,and concentrated. n-hexane (100 mL) was added and the product 9 (0.85 g, 85percent) began to precipitate using the ultrasoundas a white solid . 1H NMR (CDCl3, 300 MHz):δ4.37-4.34(m, 1H), 3.47-3.36 (m, 2H), 2.07-1.85 (m, 4H), 1.49 (s, 9H). MS (ESI) m/z 215[M+H]+.
76%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.583333 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; for 4 h;
General procedure: The solution of Boc-L-proline 1 g, 4.6 mmol,) in THF (12 mL) at 0 °C was charged with N-Methylmorpholine (0.54 g, 5.38 mmol). Then isobutyl chloroformate (0.75 g, 5.52 mmol) was added dropwise over 5 minutes. After 30 minutes of stirring the reaction was treated with the 25percent aqueous solution of ammonia (0.53 g, 15.18 mmol). The mixture was allowed to warm to room temperature and stirred for 4 h. Then, the mixture was concentrated under reduced pressure. Product was crystallized from hexane to yield 0.76 g (76percent) of product 1 as colorless crystals.
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[3] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[4] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 228 - 247
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[15] Patent: US2011/136799, 2011, A1, . Location in patent: Page/Page column 43
[16] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
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YieldReaction ConditionsOperation in experiment
43%
Stage #1: With benzotriazol-1-ol; 1,2-dichloro-ethane In tetrahydrofuran at 20℃; for 6 h;
71f[0529] (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (71a): To a solution of 1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.2 g, 0.93 mmol) in THE (13 mL), HOBT (142 mg, 0.93 mmol) was added followed by EDC (205 mg, 1.07 mmol). After stirring at r.t. for 6 hours, concentrated ammonium hydroxide (0.3 mL, 6.50 mmol) was added and the reaction mixture was stirred for 16-60 hours. Once reaction showed by TLC to be at completion, the organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to afford final product 71a (87 mg, 43percent) as an oil. 1H NMR (500 MHz, CDCI3) 64.17 (d, i=62.9 Hz, 1H), 3.35 (d, i=67.9 Hz, 2H), 2.26-1.98 (m, 2H), 1.92-1.75 (m, 2H), 1.39 (s, 9H); 13C NMR (126 MHz, CDCI3) 6175.15, 154.61, 80.33, 59.67, 47.15, 31.12, 28.37, 24.52. HRMS (ESI+): Calcd for C10H19N203 [M+H]: 215.1395, Eound:215.1389.
Reference: [1] Patent: WO2013/119946, 2013, A1, . Location in patent: Paragraph 0529
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Reference: [1] Patent: WO2006/116764, 2006, A1,
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  • [ 142253-50-7 ]
Reference: [1] Patent: WO2006/116764, 2006, A1,
  • 37
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  • [ 228244-04-0 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With triethylamine; isobutyl chloroformate In dichloromethane at -25℃; for 0.75 h;
Stage #2: With ammonia In methanol; dichloromethane at 20℃; for 16 h;
Stage #3: With triethylamine; trifluoroacetic anhydride In tetrahydrofuran
To a flame dried flask was added 2 grams (9.3 mmols) of N-Boc proline followed by 93 ml, of dichloromethane and 4.24 grams (41.85 mmols) of triethylamine. The reaction mixture was then cooled to -25° C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring for 45 minutes at this low temperature, 0.83 grams (49 mmol) of ammonia was added to the reaction mixture as a 7N solution in methanol. The flask was allowed to warm to ambient temperature and stir for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was then immediately dehydrated to the nitrile according to general procedure E using 1.9 grams (18.88 mmols) of triethylamine and 2.34 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After standard work-up and purification techniques (column chromatography, 25percent EtOAc in hexanes), 0.91 grams (4.65 mmols, 50percent) of the title product was recovered as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.53 (d, J=5.5 Hz, 0.5H), 4.48-4.38 (m, 0.5H), 3.57-3.41 (m, 1H), 3.41-3.22 (m, 1H), 2.31-1.92 (m, 4H), 1.47 (d, J=9.4 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ 153.25, 119.38, 81.64, 47.39, 45.93, 31.86, 31.01, 28.52, 24.88, 24.04.
Reference: [1] Patent: US2012/214858, 2012, A1, . Location in patent: Page/Page column 27-28
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
[3] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[4] European Journal of Organic Chemistry, 2013, # 26, p. 5886 - 5892
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[6] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
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  • [ 15761-39-4 ]
  • [ 119020-01-8 ]
Reference: [1] Synthetic Communications, 2011, vol. 41, # 17, p. 2517 - 2523
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 48, p. 11382 - 11385
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 4, p. 509 - 511
[4] Synthesis (Germany), 2013, vol. 45, # 17, p. 2458 - 2468
  • 40
  • [ 15761-39-4 ]
  • [ 207557-35-5 ]
Reference: [1] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
  • 41
  • [ 15761-39-4 ]
  • [ 74-89-5 ]
  • [ 783325-25-7 ]
Reference: [1] Patent: WO2004/92170, 2004, A2, . Location in patent: Page 32; 33
  • 42
  • [ 15761-39-4 ]
  • [ 54503-10-5 ]
YieldReaction ConditionsOperation in experiment
62% With ammonium carbonate; triethylamine; 1,1'-carbonyldiimidazole In acetonitrile at 20℃; for 24 h; General procedure: To a solution of 20 g (93 mmol) of Boc-proline 5a in 150 mL of anhydrous acetonitrile were added successively 19.5 g (120 mmol) of 1,1'-carbonyldiimidazole, 21.0 mL (150 mmol) of trimethylamine, and 19.2 g (200 mmol) of ammonium carbonate. The reaction mixture was stirred at room temperature for 24 h. After the reaction completion the mixture was poured into a saturated solution of potassium carbonate (250 mL) and extracted with dichloromethane (3 × 250 mL). The combined organic extracts were washed with water (2 × 150 mL) and dried with sodium sulfate. After removal of the solvent the reaction product was purified by flash chromatography on silica gel using hexane–ethyl acetate (100 : 0 → 1 : 1). Yield 12.3 g (62percent). Mass spectrum, m/z (Irel, percent): 215.1 (100) [M + H]+.
Reference: [1] Russian Journal of General Chemistry, 2017, vol. 87, # 4, p. 717 - 730[2] Zh. Obshch. Khim., 2017, vol. 87, # 4, p. 584 - 596,13
[3] Synthetic Communications, 2007, vol. 37, # 21, p. 3793 - 3799
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 9, p. 2225 - 2239
[5] Tetrahedron, 2008, vol. 64, # 12, p. 2801 - 2815
  • 43
  • [ 15761-39-4 ]
  • [ 4072-67-7 ]
  • [ 1007882-23-6 ]
YieldReaction ConditionsOperation in experiment
60.0 g
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 15 - 25℃;
Stage #2: With ammonium acetate In toluene at 95 - 105℃;
4,4’-Bis(2-bromoacetyl)biphenyl bOg was added to methylene dichloride (l000ml) andstirred to get solution. Boc-L-Proline (120g) was added to it. Diisopropylethylamine68.5g was added to the reaction mass at 15-25°C. The reaction mass was stirred for about4 to 5h. The reaction mass was quenched by adding water. The aqueous layer was separated and organic layer was washed with aqueous acetic acid solution (Conc HC1 also can be used instead of acetic acid) till pH of aqueous layer was between 4-6. Theorganic layer was washed with water and distilled under vacuum to get a residue. The residue was dissolved in toluene and toluene solution was used further. Ammonium acetate 390g was added to the toluene solution and the reaction mass was stirred. The reaction mass heated to 95-105°C and maintained till completion of reaction. After completion of the reaction, the reaction mass was cooled to 50-60°C, methanol wasadded and the reaction mass cooled to 20-30°C and stirred for 2 to 3 hours. The solid was filtered and washed with toluene. Purity of crude:- 93.92percent.Crude wet cake was stirred in mixture of toluene, methanol and acetic acid and the reaction mass was heated to 60- 70°C, water was added to reaction mass at 60-70°C and the reaction mass cooled to 20-30°C and stirred. The solid obtained was filtered and washed with toluene and then withwater. Wet solid was dried. Purity - 97.04percent. The above purification was repeated to obtain 60.Og of the title compound in a purity of 98.97percent.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4864 - 4868
[2] Patent: WO2018/15847, 2018, A1, . Location in patent: Paragraph 0132
  • 44
  • [ 15761-39-4 ]
  • [ 1007882-23-6 ]
Reference: [1] Patent: US2008/44379, 2008, A1,
[2] Patent: US2008/50336, 2008, A1,
[3] Patent: US2008/44379, 2008, A1,
[4] Patent: US2008/50336, 2008, A1,
[5] Patent: WO2009/102318, 2009, A1,
[6] Patent: WO2009/102318, 2009, A1,
  • 45
  • [ 15761-39-4 ]
  • [ 745017-94-1 ]
Reference: [1] Tetrahedron, 2017, vol. 73, # 16, p. 2255 - 2266
  • 46
  • [ 15761-39-4 ]
  • [ 1007882-58-7 ]
YieldReaction ConditionsOperation in experiment
82% With ammonium hydroxide; Glyoxal In methanol; dichloromethane; water at 20℃; Example 38
{(2S,5S)-2-[5-(2'-Cyano-4'-{2-[(S)-1-((8)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl}-carbamic acid methyl ester
To a solution of N-Boc-L-proline (10 g, 50.2 mmol) in MeOH (100 ml), glyoxal (40percent w/w in water, 25 g, 170.6 mmol) and NH4OH (5N aq. solution 191 ml, 954 mmol) were added.
The reaction mixture was stirred at RT overnight.
The reaction mixture was partitioned between dichloromethane and water.
The aqueous phase was extracted twice more with dichloromethane.
The combined organic phases were evaporated under vacuum and the residue was purified by silica gel flash column (MeOH/dichloromethane 0 to 3percent gradient, then 3percent) to afford 9.87 g (82percent yield) of (S)-2-(1H-Imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester as off-white solid.
ESI-LCMS m/e calcd. for C12H19N3O2 237.1 [M+], found 237.9 [M+H+].
Reference: [1] Patent: US2012/230951, 2012, A1, . Location in patent: Page/Page column 101
[2] Patent: WO2011/15657, 2011, A1,
[3] Patent: WO2011/54834, 2011, A1,
[4] Patent: US2012/136027, 2012, A1,
[5] Patent: WO2014/19344, 2014, A1,
[6] Patent: WO2014/82380, 2014, A1,
[7] Patent: WO2014/82379, 2014, A1,
[8] Patent: EP2730572, 2014, A1,
[9] Patent: WO2014/131315, 2014, A1,
[10] Patent: US2015/79028, 2015, A1,
[11] ChemMedChem, 2014, vol. 9, # 7, p. 1378 - 1386
[12] Patent: CN103880823, 2017, B,
[13] Patent: EP2730572, 2015, B1,
  • 47
  • [ 15761-39-4 ]
  • [ 131543-46-9 ]
  • [ 1007882-58-7 ]
Reference: [1] Patent: WO2012/122716, 2012, A1, . Location in patent: Page/Page column 54-55
  • 48
  • [ 15761-39-4 ]
  • [ 7644-04-4 ]
  • [ 1007881-98-2 ]
YieldReaction ConditionsOperation in experiment
62% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 5℃; for 1.5 h; Preparation of intermediate 1-11N,N-Diisopropylethylamine (80.0 g, 0.62 mol) was added dropwise, over 30 minutes, to a mixture of 2-amino-l-(4-bromo-phenyl)-ethanone (50 g, 0.2 mol),2-( 1 H-7-azabenzotriazo 1- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyl uranium hexafluorophosphate methanaminium (HATU; 53 g, 0.21 mol), JV-Boc-L-Proline (43.0 g, 0.2 mol ) in DMF (600 mL). The reaction mixture was stirred at 5°C for 1 hour. Most of the volatile components were removed in vacuo, and the resulting residue was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic layer was washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over MgSO4, the solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 3:1 to 1 :1) to obtain a pale yellow solid, 60 g (62percent) o f intermediate I- 11.1H NMR: CDCl3 400 MHzδ 7.85 (d, J = 8.4 Hz ,2H), 7.66 (d, J = 8.4 Hz ,2H), 4.67-4.80 (m, 2H), 4.33-4.41 (m, IH), 3.42-3.53 (m, 2H), 2.19- 2.31 (m, 2H), 1.90- 2.00 (m, 2H), 1.50 (s, 9H) 1.10
62% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 5℃; for 1 h; 1.3 preparation of intermediate Villa (PG= Boc X= Br ; A= ^O"^Step 1N,N-Diisopropylethylamine (80.0 g, 0.62 mol) was added dropwise, over 30 minutes, to a mixture of aminomethyl-(4-bromo-phenyl)-ketone (50 g, 0.2 mol),2-( 1 H-7-azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU; 53 g, 0.21 mol), N-Boc-L-Proline (43.0 g, 0.2 mol ) in DMF (600 mL). The reaction mixture was stirred at 5°C for 1 hour. Most of the volatile components were removed in vacuum, and the resulting residue was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic layer was washed with saturated aqueous NaHC03 (500 mL) and brine (500 mL), dried over MgS04, the solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 3: 1 to 1 : 1) to obtain a pale yellow solid, 60 g (62percent) of intermediate XXIII.1H NMR: (CDCls 400 MHz): δ 7.85 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 4.67- 4.80 (m, 2H), 4.33-4.41 (m, 1H), 3.42-3.53 (m, 2H), 2.19- 2.31 (m, 2H), 1.90- 2.00 (m, 2H), 1.50 (s, 9H)
62% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 5℃; for 1.5 h; 1.9 Preparation of Intermediate I-11; N,N-Diisopropylethylamine (80.0 g, 0.62 mol) was added dropwise, over 30 minutes, to a mixture of 2-amino-1-(4-bromo-phenyl)-ethanone (50 g, 0.2 mol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU; 53 g, 0.21 mol), N-Boc-L-Proline (43.0 g, 0.2 mol) in DMF (600 mL). The reaction mixture was stirred at 5° C. for 1 hour. Most of the volatile components were removed in vacuo, and the resulting residue was partitioned between ethyl acetate (600 mL) and water (300 mL). The organic layer was washed with saturated aqueous NaHCO3 (500 mL) and brine (500 mL), dried over MgSO4, the solids were removed via filtration and the solvents of the filtrate were removed under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 3:1 to 1:1) to obtain a pale yellow solid, 60 g (62percent) of intermediate I-11.1H NMR: CDCl3 400 MHz δ 7.85 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 4.67-4.80 (m, 2H), 4.33-4.41 (m, 1H), 3.42-3.53 (m, 2H), 2.19-2.31 (m, 2H), 1.90-2.00 (m, 2H), 1.50 (s, 9H)
Reference: [1] Patent: WO2011/15657, 2011, A1, . Location in patent: Page/Page column 20
[2] Patent: WO2011/54834, 2011, A1, . Location in patent: Page/Page column 31-32
[3] Patent: US2012/136027, 2012, A1, . Location in patent: Page/Page column 9
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 5, p. 2058 - 2073
  • 49
  • [ 15761-39-4 ]
  • [ 5467-72-1 ]
  • [ 1007881-98-2 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: at 20℃; for 0.5 h;
Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.166667 h;
Example 1
Synthesis of (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (1a)
A solution of N-Boc-L-Proline (5.16 g, 24.0 mmol) and HOBt.H2O (3.67 g, 24.0 mmol) was stirred at room temperature for 10 min and then treated with N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 4.60 g, 24.0 mmol).
The resulting mixture was stirred at room temperature for 30 min and then treated with a yellow solution formed by stirring 2-amino-4'-bromoacetophenone hydrochloride (5.0 g, 20.0 mmol) and N,N-diisopropylethylamine (DIPEA, 2.58 g, 20 mmol) in dichloromethane (DCM, 150 ml) at room temperature for 10 min.
The resulting mixture was stirred at room temperature overnight and then filtered through Celite.(R). to remove the precipitate.
The filtrate was extracted with DCM and H2O.
The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated.
The residue was purified with column chromatography (ethyl acetate:hexanes=2:5) to yield pure product 1a as a yellow gel (7.39 g, 90percent).
83% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16 h; 2-Amino-4-bromoacetophenone hydrochloride salt (26.38 mmol) and N-Boc-L-proline (26.91 mmol) were dissolved inanhydrous dimethylformamide. HATU (28.49 mmol) was added, followed by DIPEA (83.89 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was then concentrated under vacuum, diluted with EtOAc (250mL) and water (180 mL). The organic layer was separated, washed sequentially with water (180 mL) and brine (180mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc)to give compound 4 as a beige compound in 83 percent yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 1.32 (s, 9H), 1.80 (m,3H), 2.09 (m, 1H), 3.35 (m, 1H), 4.14 (m, 1H), 4.55 (m, 2H), 7.74 (d, J = 7.90 Hz, 2H), 7.91 (d, J = 7.90 Hz, 2H), 8.20 (brs, 1H).
76% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2 h; Ν,Ν-Diisopropyethylamine (3.2 g, 24.7 mmol) was added dropwise at room temperature to a heterogeneous mixture of 2-amino-l-(4-bromophenyl)ethanone hydrochloride (2.0 g, 7.98 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.72 g, 7.98 mmol), HATU (3.04 g, 7.98 mmol) and DMF (20 mL). After the addition was complete the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, IN hydrochloric acid, a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (0percent to 100percent ethyl acetate/hexane) to afford, (S)-tert-butyl 2-(2-(4-bromophenyl)- 2-oxoethylcarbamoyl)pyrrolidine-l-carboxylate as a white solid, (2.50 g, 76percent): ESI-LRMS m/e calcd for [M+] 410, found 411 [M+H+].
61%
Stage #1: With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.166667 h;
Intermediate 7: 1 ,1-dimethylethyl(2S)-2-([2-(4-bromophenyl)-2-A mixture of 1-[(1 ,1-dimethylethyl)oxy]carbonyl}-L-proline (50 g, 0.233mol), HATU (106 g, 0.279 mol) and DIEA (150 mL) in DMF (400mL) was stirred at ambient temperature for 10 min. 2-Amino-1-(4-bromophenyl)ethanone hydrochloride (Intermediate 4) (70g, 0.279 mol) in DMF (500 mL) was added and the resulting mixture was stirred overnight before diluted with EtOAc (4L). The solution was washed with 1 N HCI (500 mL χ 4) and brine, dried over Na2S04, concentrated. The crude product was recrystallized from a mixture of petroleum ether / ethyl acetate (2/1 ) to give 1 ,1-dimethylethyl(2S)-2-([2-(4-bromophenyl)-2- oxoethyl]amino}carbonyl)-1 -pyrrolidinecarboxylate (Intermediate 7) (58.4g, yield: 61 percent) as yellow solid. 1H NMR (300 MHz, DMSO) δ ppm 8.22 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 4.46-4.51 (m, 2H), 4.15-4.21 (m, 1 H), 3.28-3.40 (m, 2H),1.78-1.90 (m, 4H), 1.29-1.41 (m, 9H). ES LC-MS m/z = 411.1 , 4113.1 (M+H)+ .
56% With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one In N,N-dimethyl-formamide for 2 h; To a solution of 2-amino- 1 -(4-bromophenyl)ethanone hydrochloride salt (1.10 g, 4.39 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.02 g, 4.73 mmol), and diisopropylethylamine (3.10 mL, 17.4 mmol) in DMF (20 mL) was added 3-(diethoxyphosphoryloxy)-(l,2,3)-benzotriazin-4(3H)-one (DEPBT, 2.0 g, 6.68 mmol) and the solution was allowed to stir for 2 hours. The mixture was poured into H2O-ethyl acetate and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O x 2, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (1 : 1 hexanes: ethyl acetate) to provide (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-l- carboxylate (1.02 g, 56percent) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 8.16 - 8.21 (m, IH), 7.90 - 7.92 (m, 2H), 7.73 - 7.75 (m, 2H), 4.59 (dd, J = 5.7, 18.4 Hz, IH), 4.51 (dd, J = 5.7, 18.4 Hz, IH), 4.13 - 4.19 (m, IH), 3.24 - 3.27 (m, 2H, partially obscured by H2O), 2.05 - 2.12 (m, IH), 1.74 - 1.81 (m, 3H), 1.39 (s, 3H), 1.33 (3, 6H); LCMS: Anal. Calcd. for Ci8H23BrN2O4: 410; found: 411 (M+H)+.

Reference: [1] Patent: US2011/136799, 2011, A1, . Location in patent: Page/Page column 42
[2] Patent: EP2513113, 2018, B1, . Location in patent: Paragraph 0240; 0241; 0242
[3] Patent: WO2013/53657, 2013, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2011/28596, 2011, A1, . Location in patent: Page/Page column 11-12
[5] Patent: WO2008/144380, 2008, A1, . Location in patent: Page/Page column 41
[6] Patent: US2009/233925, 2009, A1, . Location in patent: Page/Page column 62
[7] Patent: WO2012/18325, 2012, A1, . Location in patent: Page/Page column 149
[8] Patent: WO2013/25975, 2013, A1, . Location in patent: Page/Page column 82
[9] Patent: US2008/44379, 2008, A1, . Location in patent: Page/Page column 64-65
[10] Patent: US2008/44380, 2008, A1, . Location in patent: Page/Page column 67-68
[11] Patent: US2008/50336, 2008, A1, . Location in patent: Page/Page column 62-63
[12] Patent: WO2008/144380, 2008, A1, . Location in patent: Page/Page column 39
[13] Patent: WO2009/102318, 2009, A1, . Location in patent: Page/Page column 108
[14] Patent: WO2010/117635, 2010, A1, . Location in patent: Page/Page column 76-77
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