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[ CAS No. 147-85-3 ] {[proInfo.proName]}

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Chemical Structure| 147-85-3
Chemical Structure| 147-85-3
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Product Details of [ 147-85-3 ]

CAS No. :147-85-3 MDL No. :MFCD00064318
Formula : C5H9NO2 Boiling Point : -
Linear Structure Formula :(C4H8N)C(O)OH InChI Key :-
M.W : 115.13 Pubchem ID :-
Synonyms :
(S)-(–)-Proline;NSC 46703;Prolina;HSDB 1210;FEMA No. 3319;CB 1707;Proline;L-(–)-Proline

Calculated chemistry of [ 147-85-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.8
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 32.52
TPSA : 49.33 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) : -8.78 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.84
Log Po/w (XLOGP3) : -2.5
Log Po/w (WLOGP) : -0.56
Log Po/w (MLOGP) : -2.59
Log Po/w (SILICOS-IT) : 0.22
Consensus Log Po/w : -0.92

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 1.09
Solubility : 1410.0 mg/ml ; 12.2 mol/l
Class : Highly soluble
Log S (Ali) : 2.01
Solubility : 11700.0 mg/ml ; 102.0 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.13
Solubility : 85.7 mg/ml ; 0.745 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.54

Safety of [ 147-85-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 147-85-3 ]

* 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 [ 147-85-3 ]
  • Downstream synthetic route of [ 147-85-3 ]

[ 147-85-3 ] Synthesis Path-Upstream   1~109

  • 1
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  • [ 22348-32-9 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 6, p. 1082 - 1096
[2] Organic Preparations and Procedures International, 1996, vol. 28, # 4, p. 487 - 490
[3] Tetrahedron, 1993, vol. 49, # 23, p. 5127 - 5132
[4] Tetrahedron, 1993, vol. 49, # 23, p. 5127 - 5132
[5] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 691 - 704
[6] Molecules, 2012, vol. 17, # 5, p. 5626 - 5650
[7] Organic Syntheses, 1997, vol. 74, p. 50 - 50
  • 2
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  • [ 34381-71-0 ]
YieldReaction ConditionsOperation in experiment
57% With aq. sodium hydroxide; acetic anhydride In tetrahydrofuran; formic acid; water (2)
To a solution of 5.0 g (0.0434 mol) of L-proline in 92 ml of 97percent formic acid maintained at 5°-10° was slowly added 30 ml of acetic anhydride.
The solution was stirred for 2 hr. at room temperature followed by the addition of 35 ml of ice-cold water.
Evaporation of the mixture afforded (S)-(-)-N-formylproline ([α]D2: =-105°, c=2.885, methanol), a clear, viscous, pale-yellow oil utilized directly in the next step.
The (S)-(-)-N-formylproline was reduced by adding a solution of it in 20 ml of tetrahydrofuran to a slurry of 8.23 g (0.217 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran under a nitrogen atmosphere.
The addition was regulated such that a gentle reflux was maintained.
Following addition, the mixture was refluxed for 48 hr.
After cooling, the mixture was carefully treated with 8.3 ml of water, followed by 8.3 ml of 15percent aq. sodium hydroxide, and finally 25 ml of water.
The grey-white mixture was filtered, and the filtrate dried with magnesium sulfate and evaporated to an oil.
Bulb to bulb distillation [oven temp 40°-55° (0.15 torr)] afforded 2.823 g of V (57percent yield based on L-proline).
Reference: [1] Patent: US4321387, 1982, A,
[2] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 19, p. 2891 - 2896
[3] Tetrahedron Letters, 1995, vol. 36, # 43, p. 7885 - 7888
[4] Journal of the American Chemical Society, 1991, vol. 113, # 24, p. 9286 - 9292
[5] Tetrahedron Letters, 1983, vol. 24, # 33, p. 3513 - 3516
  • 3
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  • [ 34381-71-0 ]
Reference: [1] European Journal of Inorganic Chemistry, 2016, vol. 2016, # 28, p. 4573 - 4580
  • 4
  • [ 50-00-0 ]
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  • [ 475-11-6 ]
YieldReaction ConditionsOperation in experiment
92% With palladium 10% on activated carbon; hydrogen In methanol; water General procedure: L-Proline(2.0 g, 17.4 mmol) was dissolved in methanol (20 mL) and40 percent aqueous formaldehyde (1.4 mL, 19.1 mmol) wasadded to this solution. Next, 10 percent Pd/C catalyst (500 mg)was added to the reaction mixture and the resulting slurrywas stirred in hydrogen overnight. The slurry was then filtered through a Celite pad to remove the catalyst. Thepad was washed with methanol and the combined filtrateswere concentrated under reduced pressure. The residue wasdissolved in ethanol/benzene (1:1, 100 mL) and concentratedsecond time to provide a solid that was re-crystallizedin methanol/diethyl ether. In this way Nmethylproline7a was isolated as fine needles (2.1 g, 92 percentyield); mp 109–111°C; 1H NMR (D2O, 300 MHz):δ = 3.95–3.90 (1H, m, CH2 (CH2)2CHNCH3), 3.24–3.15(2H, m, CH2 (CH2)2CHNCH3), 2.97 (3H, s, CH2 (CH2)2CHNCH3), 2.22–2.01 (4H, m, CH2 (CH2)2CHNCH3); ESI–MS (m/z):130.2 [M + H] +(100).
89% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24 h; L-proline (4.0 g, 34.8 mmol)Soluble in methanol (40mL),40percent aqueous formaldehyde solution (2.8 mL, 38.2 mmol) was added in orderAnd 10percent Pd on carbon (1g), addition, hydrogenation,Reaction at room temperature for 24 hours,After the reaction is complete, filterThe mother liquor was concentrated and dried to give 4g of a white solid with a yield of 89percent.That is, N-methyl-L-proline (compound b).
88% With sodium dihydrogenphosphate; zinc In water at 30℃; for 48 h; The vigorously stirred suspension of zinc dust(6.50 g; 100 mmol), L-proline (5.57 g; 50 mmol) and NaH2PO4 (11.90 g; 100 mmol) in water (22 mL) was treated with 35percent aq. formaldehyde (2.10 mL).Stirring was continued for 48 h at 30°C. The suspension was discarded, the filtrate was neutralized with2 M aq. ammonia to pH 8, concentrated under vacuum,the solid residue was dissolved in small amount of water and lyophilized. Dry residue was extracted with hot mixture of benzene-ethanol (1 : 1, v/v).Collected extracts were evaporated to dryness and then recrystallized from the mixture methanol/ether affording L-N-methylproline (1) (5.68 g; yield 88percent)as white crystals m.p. 115-120°C, lit. (12) m.p.115-116°C.
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 7, p. 2652 - 2667
[2] Green Chemistry, 2016, vol. 18, # 16, p. 4374 - 4392
[3] European Journal of Organic Chemistry, 2005, # 5, p. 934 - 938
[4] Tetrahedron Letters, 2007, vol. 48, # 43, p. 7680 - 7682
[5] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[6] Journal of the American Chemical Society, 2012, vol. 134, # 5, p. 2823 - 2834
[7] Patent: CN107963987, 2018, A, . Location in patent: Paragraph 0046-0048
[8] Acta Poloniae Pharmaceutica - Drug Research, 2014, vol. 71, # 6, p. 994 - 1003
[9] Synthesis, 2011, # 3, p. 490 - 496
[10] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 3592 - 3615
[11] Archiv der Pharmazie (Weinheim, Germany), 1976, vol. 309, p. 380,382
[12] Journal of Biological Chemistry, 1953, vol. 202, p. 193,194
[13] Angewandte Chemie, 1995, vol. 107, # 9, p. 1095 - 1098
[14] Analytical Chemistry, 2007, vol. 79, # 22, p. 8631 - 8638
[15] European Journal of Organic Chemistry, 2009, # 22, p. 3790 - 3794
  • 5
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YieldReaction ConditionsOperation in experiment
90% With formaldehyd In methanol 3a.
N-Methyl (L)-proline
To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Arm of H2.
After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum.
The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90% With formaldehyd In methanol 3a.
N-Methyl (L)-proline
To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2.
After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum.
The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1 H-NMR (D2 O) d 1.94-2.23 (m, 4 H); 2.45-2.57 (m, 1 H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
90% With formaldehyd In methanol 3 a. N-Methyl (L)-proline
To 175 mL of methanol containing (L)-proline (33 g, 286.7 mmol) and 37 wt percent of aqueous formaldehyde (24 mL) was added 10percent Pd/C (1.65 g), and the reaction mixture was hydrogenated at 4 Atm of H2.
After the reaction was complete, the catalyst was removed by filtration, the filtrate was concentrated, and the residue was triturated with ether and dried under high vacuum.
The crude product was obtained as a white powder (33.44 g, 90percent). MS (DCl/NH3) m/e 130 (M+H)+, 147 (M+NH4)+; 1H-NMR (D2 O) d 1.94-2.23 (m, 4H); 2.45-2.57 (m, 1H); 2.94 (s, 3 H); 3.16 (m, 1 H); 3.74 (m, 1 H); 3.90 (dd, 1 H).
Reference: [1] Patent: US5424444, 1995, A,
[2] Patent: US5508418, 1996, A,
[3] Patent: US5516912, 1996, A,
  • 6
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Reference: [1] Organic Letters, 2015, vol. 17, # 10, p. 2530 - 2533
  • 7
  • [ 64-17-5 ]
  • [ 147-85-3 ]
  • [ 5817-26-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 14, p. 3798 - 3803
[2] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2254 - 2256
[3] Pharmaceutical Chemistry Journal, 1984, vol. 18, # 12, p. 811 - 815[4] Khimiko-Farmatsevticheskii Zhurnal, 1984, vol. 18, # 12, p. 1445 - 1448
[5] Tetrahedron Asymmetry, 1997, vol. 8, # 8, p. 1187 - 1192
[6] Journal of the Indian Chemical Society, 2003, vol. 80, # 8, p. 765 - 768
[7] Journal of the American Chemical Society, 1949, vol. 71, p. 3100
[8] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 691 - 704
[9] Bioscience, Biotechnology and Biochemistry, 2006, vol. 70, # 1, p. 303 - 306
[10] Australian Journal of Chemistry, 2008, vol. 61, # 7, p. 521 - 525
[11] Organic Letters, 2013, vol. 15, # 13, p. 3378 - 3380
[12] Chemistry - A European Journal, 2014, vol. 20, # 17, p. 4948 - 4955
[13] Patent: CN105198784, 2018, B, . Location in patent: Paragraph 0016-0019
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Reference: [1] RSC Advances, 2017, vol. 7, # 17, p. 10158 - 10174
[2] International Journal of Pharmaceutics, 2018, vol. 546, # 1-2, p. 31 - 38
  • 9
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  • [ 68-95-1 ]
YieldReaction ConditionsOperation in experiment
84.2% With N-ethyl-N,N-diisopropylamine In methanol at 70℃; for 7 h; 115.1 mg (1 mmol) of L-proline,Add the right amount of solvent methanol dissolved,The amount of acetic anhydride syringe 0.3mL (about 3mmol)DIEA0.5mL (about 3mmol) was added to the reaction system,70 reflux reaction 7h. Completed the reaction,The methanol in the reaction solution was removed under reduced pressure and the unreacted acetic anhydride was removed by freeze-drying.Prepared by HPLC (mobile phase methanol: water = 45: 65 with 0.05percent formic acid, UV wavelength 214 nm)Obtained as a white solid in 84.2percent yield.
500 mg at 30℃; To a solution of (S)-pyrrolidine-2-carboxylic acid (1.0 g) in DCM (20 mL) was added acetic anhydride (2.7 g). The resulting mixture was stirred at 30°C overnight and concentrated in vacuo. Cold water (30 mL) was added, and the aqueous layer was extracted with DCM(2x100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give (S)-1-acetylpyrrolidine-2- carboxylic acid (500 mg) as a white solid. MS(ES) mlz 158 (MH).
Reference: [1] Synthetic Communications, 1992, vol. 22, # 2, p. 257 - 264
[2] New Journal of Chemistry, 2016, vol. 40, # 6, p. 5209 - 5220
[3] Patent: CN107082754, 2017, A, . Location in patent: Paragraph 0087; 0091
[4] Journal of Pharmaceutical Sciences, 1995, vol. 84, # 5, p. 640 - 642
[5] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2819 - 2834
[6] Tetrahedron, 2001, vol. 57, # 34, p. 7277 - 7289
[7] Journal of Biological Chemistry, 1932, vol. 99, p. 143,150
[8] Journal of Biological Chemistry, 1932, vol. 98, p. 305
[9] Journal of Biological Chemistry, 1951, vol. 193, p. 81,87
[10] Chemical & Pharmaceutical Bulletin, 1984, vol. 32, # 6, p. 2126 - 2139
[11] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1999, vol. 38, # 9, p. 1123 - 1125
[12] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1437 - 1443
[13] Patent: WO2015/181186, 2015, A1, . Location in patent: Page/Page column 83
[14] Angewandte Chemie - International Edition, 2016, vol. 55, # 31, p. 8944 - 8947[15] Angew. Chem., 2016, vol. 128, # 31, p. 9090 - 9093,4
  • 10
  • [ 75-36-5 ]
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  • [ 68-95-1 ]
YieldReaction ConditionsOperation in experiment
84% for 2 h; Reflux To a suspension of l-proline (4.34 mmol, 500 mg) in tetrahydrofuran was added acetyl chloride (20 mL) at room temperature and the reaction mixture was refluxed for 2 h.
After completion of the reaction, the mixture was cooled to room temperature, diluted with water, and stirred for 20 min.
Saturated brine and ethyl acetate were added and the organic layer was collected.
The aqueous layer was re-extracted with ethyl acetate.
The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under vacuum.
The semisolid residue was stirred in diisopropyl ether for 0.5 h at room temperature and the mixture was then cooled to 0 °C for 1 h.
The precipitated crystalline solid was filtered, washed with cold diisopropyl ether, and dried under vacuum to afford compound (S)-1-acetylpyrrolidine-2-carboxylic acid 1.
White solid (573 mg, 84percent).
Mp 75-77 °C, 1H NMR (300 MHz, CDCl3): δ 11.18 (s, 1H, OH), 3.96 (t, 1H, J = 9.3 Hz, 6.0 Hz), 3.53 (t, 2H, J = 10.1 Hz, 5.8 Hz), 3.05 (q, 2H, J = 11.2 Hz, 6.7 Hz, 4.4 Hz), 2.39 (s, 3H), 2.12-2.26 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 178.32, 172.12, 59.46, 52.09, 26.71, 21.45; GC-MS m/z 157.10 (M+); Elemental Analysis: Calcd C7H11NO3 C, 53.49; H, 7.05; N, 8.91; O, 30.54.
Found C, 53.46; H, 7.03; N, 8.93; O, 30.52.
Reference: [1] Tetrahedron Asymmetry, 2012, vol. 23, # 17, p. 1320 - 1325
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  • [ 68-95-1 ]
Reference: [1] Biochemical Journal, 1938, vol. 32, p. 1455
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  • [ 68-95-1 ]
Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 21, p. 3583 - 3584
  • 13
  • [ 830-03-5 ]
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  • [ 68-95-1 ]
Reference: [1] Russian Journal of General Chemistry, 2018, vol. 88, # 1, p. 80 - 85[2] Zh. Obshch. Khim., 2018, vol. 88, # 1, p. 84 - 89,6
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  • [ 1074-79-9 ]
Reference: [1] Journal of the American Chemical Society, 1952, vol. 74, p. 2859,2862
[2] Archives of Biochemistry, 1950, vol. 26, p. 92,93
[3] Journal of Biological Chemistry, 1949, vol. 178, p. 503,508[4] Journal of Biological Chemistry, 1949, vol. 180, p. 201
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  • [ 34079-31-7 ]
Reference: [1] European Journal of Organic Chemistry, 2005, # 20, p. 4287 - 4295
[2] Tetrahedron Asymmetry, 2004, vol. 15, # 12, p. 1831 - 1834
[3] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842
[4] Carbohydrate Research, 2013, vol. 381, p. 12 - 18
[5] Patent: CN104086475, 2016, B,
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  • [ 1160-54-9 ]
Reference: [1] Tetrahedron Letters, 1995, vol. 36, # 12, p. 2105 - 2108
[2] Journal of Mass Spectrometry, 2010, vol. 45, # 2, p. 178 - 189
[3] Tetrahedron Letters, 1997, vol. 38, # 17, p. 3039 - 3042
[4] Synlett, 2009, # 8, p. 1233 - 1236
  • 17
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Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 9, p. 2632 - 2638
[2] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5794 - 5801
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Reference: [1] Chemistry of Natural Compounds, 1990, vol. 26, # 6, p. 686 - 690[2] Khimiya Prirodnykh Soedinenii, 1990, # 6, p. 805 - 810
[3] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 12, p. 3253 - 3260
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 3, p. 584 - 589
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 12, p. 3253 - 3260
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Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 3, p. 584 - 589
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Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 2, p. 501 - 517
  • 23
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  • [ 1160-54-9 ]
Reference: [1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1932, vol. 212, p. 72,79
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: With sodium hydroxide In water at 20℃; for 1 h;
Stage #2: With hydrogenchloride In waterCooling with ice
L-Prolin (2.5 g, 22 mmol) wird in NaOH (5percent, 25 mL, 31 mMol) in Loesung gebracht und nach Abkuehlen tropfenweise, unter starkem Ruehren, mit 4-Fluorhenzoesaeurechlorid (3.17 g, 20 mMol) versetzt. Die entstehende Suspension wird nochmals mit NAOH (5percent, 15 mL, 19 mmol) versetzt und 1 h bei RT geruehrt. Unter Eiskuehlung wird HCl (20 percentig, 10 mL) zugesetzt und bis zur Bildung eines absaugbaren Kristallisates geruehrt. Das anschliessend abgesaugte Kristallisat wird mit Wasser HCl-frei gewaschen und im Exsiccator ueber P2O5 getrocknet. Nach dem Trocknen verbleiben 4,21 g (88,8 percent d.Th.) Kristallisat. Y: 89 percent (4,21 g), C12H12FNO3, MW = 237.23; Mp: 174.0 °C; IR (NaCl): 1/λ (cm-1) = 1735, 1605, 1585, 1514, 1440, 1230, 1180, 1161, 856, 762, 513;1HNMR (CDCl3): δ (ppm) = 7.64-7.61 (d, 2H, J=5.4Hz), 7.59-7.57 (d, 2H, J=5.4Hz), 7.16-7.07 (t, 2H, J=8.6Hz).
79% With hydrogenchloride In sodium hydroxide; water a
N-(4-Fluorobenzoyl)proline
L-Proline (15.0 g, 130 mmol) is dissolved in NaOH (5percent, 150 ml, 190 mmol) and the solution is cooled in an ice bath (0-5° C.).
4-Fluorobenzoyl chloride (19.0 g, 120 mmol) is added dropwise with vigorous stirring, the cooling is removed and stirring is continued for 1 h.
After acidifying the reaction mixture with HCl (10percent strength, 45 ml) the amide deposits in large lumps, which are comminuted, suspended using water, filtered off with suction and washed with water (50 ml).
The substance is dried over P2O5 in vacuo: 24.41 g.
M.p.: 174.0° C., yield: 79percent; C12H12FNO3; MW=237.23.
IR (KBr): 1/λ (cm-1)=1735, 1605, 1585, 1514, 1440, 1230, 1180, 1161, 856, 762 513;
1H-NMR (CDCl3:) δ[ppm]=7.64-7.57 (m, 2H,); 7.16-7.07 (m, 2H); 4.78-4.71 (m, CH); 3.63-3.57(CH2); 2.36-1.85 (m; 2 CH2).
Reference: [1] Patent: EP1246825, 2003, B1, . Location in patent: Page 32
[2] Patent: US2003/153558, 2003, A1,
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Reference: [1] Tetrahedron, 1990, vol. 46, # 15, p. 5325 - 5332
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  • [ 43041-12-9 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at -5 - 25℃; for 2 h;
Stage #2: With potassium carbonate In water at 0℃;
A solution of L-proline (2.23 g) in dry methanol (15 ml) was cooled to -5° C. and thionyl chloride (4.52 g) was added dropwise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction was continued at 25° C. for 2 h. The solvent was distilled and the residue stored in ice-chest for 12 h. The solid mass was added to aqueous solution of potassium carbonate (50percent, 20 ml) at 0° C. and the separated oily layer was extracted into ether (15 ml.x.3). The ethereal layer was dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine (85percent), [MS (m/z) M+129 (1percent), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. It was taken in dry diethyl ether (15 ml), cooled to 0° C. and t-butylhypochlorite (2.16 g) added dropwise. The reaction was monitored on silica gel thin layer using chloroform as the eluant. After completion of the reaction (15 min.), potassium t-butoxide (2.24 g) was added gradually over 10 min. and the reactants stirred at 25° C. for 5 h. The solution was filtered and the solvent distilled under reduced pressure to afford 2-(carbomethoxy)-1-pyrrroline (2 g), [MS (m/z) M+ 127(1percent), 112(0.5), 97 (15), 69 (100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry ether, iodine (0.01 g) was added followed by dropwise addition of a solution of methyl iodide (3.08 g) in ether (5 ml) at 35° C. The mixture was stirred until the disappearance of magnesium turnings (15 min), then cooled to 0° C. To it, a solution of 2-(carbomethoxy)-1-pyrrroline (2 g) in dry ether (5 ml) was added over 5 min. and the mixture was stirred at room temperature. On completion of the reaction (2 h) the product was worked up by the addition of dilute hydrochloric acid (5percent, 10 ml) and the organic layer separated. The aqueous layer was further extracted with ether (10 ml.x.2) and the combined organic layers dried over anhydrous sodium sulphate and distilled to afford pure 2-acetyl-1-pyrroline [1.3g, 95percent purity, [MS (m/z) M+ 111 (5percent), 96 (0.1), 83 (15), 69(8), 68 (10), 55 (2), 52 (0.2), 43 (100),42 (25), 41 (50)].To a solution of L-proline (2.23 g) in dry methanol (15 ml) cooled to -5° C., thionyl chloride (4.52 g) was added drop wise, while stirring and maintaining the temperature of the reactants below 0° C. The reaction mixture was allowed to attain room temperature (25° C.) and further stirred for 2 h. The solvent was distilled off from it and the residue stored in ice-chest for 12 h. The solid mass that separated was added to an aqueous potassium carbonate solution (50percent, 20 ml) at 0° C. and the separated oily layer extracted into ether (15 ml.x.3). The combined ethereal layers were dried over anhydrous sodium sulfate and distilled to afford 2.3 g of 2-(carbomethoxy)-pyrrolidine [85percent, MS (m/z) M+129 (1percent), 114 (0.5), 70(100), 68(50), 43(80), 41(90)]. To an ice-cooled solution of the compound in dry diethyl ether (15 ml), t-butylhypochlorite (2.16 g) was added drop-wise. The reaction was monitored on thin layer of silica gel using chloroform as the eluant. After 15 min. anhydrous potassium acetate (2.76 g) was added gradually added to it over 10 min., and the mixture stirred at 25° C., while monitoring the reaction by TLC. At the end of the reaction (3 h), the solution was filtered and the solvent distilled under reduced pressure to afford 2-carbomethoxy)-1-pyrrroline [Yield: 1.9 g, MS (m/z) M+ 127(1percent), 112(0.5), 97 (15), 69,(100), 54 (50), 41 (75)]. To a suspension of magnesium turnings (0.43 g) in dry diethylether, iodine (0.01 g) was added followed by a solution of methyl iodide (3.08 g) in ether (5 ml) dropwise at 35° C. The mixture was stirred until the disappearance of magnesium (15 min) and then after cooling to 0° C., a solution of 2-(carbomethoxy)-1-pyrrroline (1.9 g) in dry diethylether (5 ml) was added over 5 min. On completion of the reaction (2 h) as found by GC, the product was worked up by addition of dilute hydrochloric acid (5percent, 10 ml) and separation of the organic layer. The aqueous layer was further extracted with diethylether (10 ml.x.2) and the combined organic layers dried over anhydrous sodium sulphate. Removal of the solvent afforded pure 2-acetyl-1-pyrroline [1.2 g, 95percent purity, MS (m/z) M+ 111 (5percent), 96 (0.1), 83 (15), 69(8), 68 (10), 55(2), 52 (0.2), 43 (100), 42 (25), 41 (50)].
Reference: [1] Patent: US6723856, 2004, B1, . Location in patent: Page column 4-5
  • 27
  • [ 147-85-3 ]
  • [ 43041-12-9 ]
Reference: [1] Patent: US6201006, 2001, B1,
  • 28
  • [ 100-44-7 ]
  • [ 147-85-3 ]
  • [ 31795-93-4 ]
YieldReaction ConditionsOperation in experiment
75% With potassium hydroxide In isopropyl alcohol at 40℃; Compound 2 was prepared by a three step sequence according to Belokon et at (1998), Tetrahedron Asymm. 9:4249-4252. A solution of S-proline (100 g, 0.869 mol) and KOH (172 g, 2.61 mol) in isopropanol (600 ml) was prepared with stirring at 40 C. As soon as the solution became transparent, benzyl chloride (156 ml, 1.34 mol) was added at the same temperature. After the addition was complete (3.5 h), the reaction was stirred overnight at 40 C. The reaction was neutralized with conc. HCl (110 ml) until pH 5, then chloroform (400 ml) was added to the reaction mixture and the mixture was left stirring overnight. The mixture was then filtered and the precipitate washed with CHC1. The CHCL3 solutions were combined and evaporated, the residue was treated with acetone and the precipitate of the crude product filtered and additionally washed with acetone. The benzyl proline product was isolated in 75percent yield.
73%
Stage #1: With potassium hydroxide In isopropyl alcohol at 40℃;
Stage #2: at 40℃; for 15 h;
Stage #3: With hydrogenchloride In water; isopropyl alcohol
A solution of (S)-prolιne 12 (23 01 g, 0 20 mol) and KOH (3360 g, 0 60 mol) in /-PrOH (150 mL) was stirred at 4O0C After the solution became transparent, benzyl chloride (30 24 g, 0 24mol) was added dropwise with stirring at the same temperature for 1h and the stirring was continued for 14 h more The reaction mixture was neutralized with cone HCI until pH 5- 6, then was added to CH2CI2 (200 mL) with stirring The mixture was left for 2h at O0C, then filtered and the precipitate was washed with CH2CI2 The CH2CI2 solution was concentrated, and the residue was treated with acetone (150 mL) and the precipitate was dried to give the desired product as a white solid (30 14 g, 73percent) <n="76"/>1H NMR (300 MHz, DMSO-d6) δ 11 42 (brs, 1 H), 4 18-423 (d, 1 H), 3 92-3 96 (d, 1H), 3 60- 365 (m, 1 H), 3 15-3 22 (m, 1H), 2 76-2 85 (m, 1H), 2 14-226 (m, 1 H), 1 70-1 96 (m, 3H) LC- MS 206 (M + H)*
5.39 g
Stage #1: With potassium hydroxide In isopropyl alcohol at 40℃;
Stage #2: at 40℃; for 6 h;
A solution of L-proline 29 (5.00 g, 43.44 mmol, 1.0 eq.) and potassiumhydroxide (9.78 g, 174.3 mmol, 4 eq.) in iso-propanol(50 ml) was stirred at 40 °C until the solution turned clear, afterwhich benzyl chloride (8.25 g, 7.50 ml, 65.2 mmol, 1.5 eq.) was added and the solutionwas stirred for 6 h at 40 °C. The solution was neutralised with concentrated aqueous hydrochloric acid to pH5-6. Chloroform (30 ml) was added after neutralization and themixture was stirred overnight. The resulting precipitate wasremoved by filtration and washed with chloroform (30 ml). Theorganic fractions were combined and evaporated in vacuo. Theresulting residue was treated with acetone (30 ml) resulting in theprecipitation of crude product whichwas filtered and againwashedwith acetone to afford the product (S)-1-benzylpyrrolidine-2-carboxylic acid 30, as a white solid (5.39 g, 26.26 mmol, 60percent). Rf0.09 (9:1 dichloromethane: methanol); mp 175 °C (literature [47]167 °C); νmax (neat)/cm-1 3041, 2992, 2969, 1634, 1450, 1375,1311, 1190, 753, 704; 1H NMR (300 MHz, D2O); δ 7.53 (s, br, 5 H, Ar-H's), 4.40 (s, 2H, CH2Ph), 4.01 (dd, 1H, J 6.7 & 9.3 Hz, CHCO2H),3.73-3.58 (m, 1H, CH2CH2aN), 3.38e3.21 (m, 1H, m, CH2CH2bN),2.62e2.41 (m, 1H, CH2aCH), 2.27-1.89 (m, 3H, CH2bCH &CH2CH2N); 13C NMR (75 MHz, D2O); δ 173.54, 130.55, 130.05,129.96, 129.25, 68.24, 58.30, 54.61, 28.79, 22.78; HRMS m/z (ESI)206.1215 ([M + H]+ requires 206.1165).
Reference: [1] Organic and biomolecular chemistry, 2003, vol. 1, # 17, p. 3010 - 3014
[2] Tetrahedron Asymmetry, 1998, vol. 9, # 23, p. 4249 - 4252
[3] Advanced Synthesis and Catalysis, 2014, vol. 356, # 10, p. 2203 - 2208
[4] Journal of Organic Chemistry, 2003, vol. 68, # 18, p. 7104 - 7107
[5] Journal of Organic Chemistry, 2011, vol. 76, # 6, p. 1513 - 1520
[6] Patent: US2016/31936, 2016, A1, . Location in patent: Paragraph 0271
[7] Patent: WO2009/46098, 2009, A1, . Location in patent: Page/Page column 73-75
[8] Chemistry - A European Journal, 2018, vol. 24, # 36, p. 9136 - 9147
[9] Organic Letters, 2005, vol. 7, # 15, p. 3151 - 3154
[10] Tetrahedron, 2007, vol. 63, # 36, p. 8735 - 8741
[11] Tetrahedron, 2008, vol. 64, # 8, p. 1888 - 1894
[12] Advanced Synthesis and Catalysis, 2008, vol. 350, # 11-12, p. 1781 - 1784
[13] European Journal of Organic Chemistry, 2009, # 22, p. 3790 - 3794
[14] Patent: WO2011/15658, 2011, A1, . Location in patent: Page/Page column 22
[15] Tetrahedron Asymmetry, 2013, vol. 24, # 15-16, p. 958 - 965
[16] Angewandte Chemie - International Edition, 2014, vol. 53, # 31, p. 8150 - 8153
[17] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 671 - 690
  • 29
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  • [ 147-85-3 ]
  • [ 31795-93-4 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: With potassium hydroxide In isopropyl alcohol at 40℃;
Stage #2: With hydrogenchloride In chloroform; water; isopropyl alcohol at 20℃; for 12 h;
General procedure: To a solution of proline (2.0 g, 17 mmol) and KOH (2.85 g, 51 mmol) in i-PrOH (50 mL),4-substituted benzyl derivative (21 mmol) was added at 40° C. Afterwards, the mixture was stirred for8 h at 40° C and then the reaction mixture was cooled to room temperature. 6 M HCl was added toadjust the pH value of the mixture to 4–5 and then CHCl3 (50 mL) was added. The mixture was stirredfor 12 h, followed by filtration and evaporation in vacuo. The residue was purified by recrystallizationin acetone at 0° C to give 6 (about 90percent yield).
71% With potassium hydroxide In isopropyl alcohol at 40℃; for 7 h; To a stirred solution of (L)-proline (5.0 g, 43.4 mmol)and KOH (7.3 g, 130.3 mmol) in iPrOH (30 mL), BnBr (6.2 mL, 8.9 g, 52.1 mmol) was added dropwiseat 40 °C. After the addition completed (3 h), the stirring was continued overnight at 40 °C. Thereaction mixture was neutralized by adding concentrated aqueous HCl (about 2 mL) to reach pH 5–6,and then CH2Cl2 (15 mL) was added to the reaction mixture with stirring. The mixture was leftovernight without stirring. After filtration of the KCl salt formed and evaporation of the CH2Cl2,acetone (30 mL) was added to the residue obtained. After a slow precipitation, compound 10 was filtered and dried over P2O5 under vacuum and obtained as a white solid (6.31g, 30.8 mmol, 71percent).
Reference: [1] Molecules, 2017, vol. 22, # 10,
[2] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 2842 - 2853
  • 30
  • [ 147-85-3 ]
  • [ 100-51-6 ]
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YieldReaction ConditionsOperation in experiment
68% With 1-hydroxytetraphenylcyclopentadienyl(tetraphenyl-2,4-cyclopentadien-1-one)-μ-hydrotetracarbonyldiruthenium(II) In neat (no solvent) at 90℃; for 18 h; Schlenk technique; Inert atmosphere General procedure: General procedure, 0.2 or 0.5 mmol 1, 1 - 4 ml or 0.6 - 2 mmol 2, neat or 2d/tol as solvent, 1 mol percent Cat 2, 18 - 24 h, 90 °C, isolated yields are shown, unless otherwise specified; "yields are base crude H MNR and mass balance; 6100 °C. For details see Table 4 and 5. After exploring the reactivity of various cc-amino acids with ethanol (2a) and isopropanol (2b), diverse alcohols were tried (Scheme 2, Table 4). As previously shown, MeOH (2c) or CF3CH2OH (2d) did not react with la, probably because they were not prone to be dehydrogenated under the present reaction conditions, which allowed for the possibility of using 2c or 2d as solvent. For other alcohol substrates such as 1-butanol (2e), cyclopropylmethanol (2f) and 2-chloroethanol (2g), employed in the reaction with la, resulted in quantitative yield of 3ea, 55 percent of 3af, and 71 percent of 3ag, respectively (Table 4, entry 3 - 5). Also, benzyl alcohol (3h) and 4- chlorobenzyl alcohol (3i) were successfully applied to benzylate la with good yields of 68 percent and 82 percent (Table 4, entry 6 and 7). Here it needs to be pointed out that, the chloro- group on 3ag and 3ai would allow the further functionalization of the obtained amino acid derivatives. Subsequently, the use of other amino acids such as phenylalanine (Id) and glycine (lg) were examined. Id reacted with 1-butanol (2e) to give 84 percent yield of 3de (Table 4, entry 8). Surprisingly, instead of forming a 6-membered heterocycle, the reaction of Id with 1,5-pentane-diol (2k) gave a 35percent yield of the di-alkylated 3dk as the major product (Table 4, entry 9). The introduced 2-hydroxyl groups on 3dk can not only be exploited for further functionalization, but also dramatically increase the hydrophilicity of the product. Next, the functionalization of lg with various alcohols was further explored. Upon reaction with 3h the di-benzylation product 3gh was obtained in 52 percent yield while when secondary alcohol 2-butanol (21) was employed to alkylate lg, selective formation of mono-alkylated product 3gl was obtained in quantitative yield (Table 4, entry 10 and 12). Table 4: Direct N-alkylation of free amino acid (1) with various alcohols (2). General reaction conditions: General procedure, 0.2 or 0.5 mmol 1, 0.6 - 2 mmol or 2 - 5 ml 2, neat or with solvent (amount shown in the table), 1 mol percent Cat 2, 16 - 24 h, 90 or 100°C, isolated yields in parenthesis; "Conversion and selectivities are based on crude H NMR. After this, the possibility of mono-alkylation with primary alcohols was also investigated. Using 4 eq. of 1-pentanol (lm), lg was successfully di- alkylated giving 90 percent of 3gm. When the amount of lm was decreased to 1.2 eq., 46 percent mono-alkylated product 3gm' was obtained, only giving 29 percent of the di-alkylated product 3gm (Table 4, entry 15 and 16). As 3gm' is more basic than 3g, without enough steric hindrance on the nitrogen atom, the second alkylation step occurred immediately once 3gm' formed. Thus, mono-N- alkylated amino acids can be obtained from primary amino acids and primary alcohols, but with low selectivity. Long-chain N-alkylated amino acids are widely used in surfactants, among which N-alkylated amino acids are not well studied because they are relatively difficult to be synthetized9. Envisioning the possibility of easily synthetizing long-chain N-alkylated amino acids with our methodology, 1- nonanol (2j) was selected to react with Id and lg. Di-alkylated compounds 3dj and 3gj were selectively obtained with good to excellent yields of 75 percent and 91 percent, respectively (Table 4, entry 9 and 13). The reaction also readily proceeded with 1-dodecanol (In) and lg as substrate, obtaining the corresponding product 3gn in an excellent yield of 92 percent (Table 4, entry 17).
Reference: [1] Patent: WO2018/178397, 2018, A1, . Location in patent: Page/Page column 17-19; 26; 28-31; 42; 43
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Reference: [1] Catalysis Science and Technology, 2015, vol. 5, # 2, p. 716 - 723
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Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
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[2] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
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[2] Journal of Mass Spectrometry, 2012, vol. 47, # 1, p. 79 - 88
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[2] Journal of the Chemical Society, 1941, p. 337
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[2] Journal of the Chemical Society - Series Chemical Communications, 1988, # 4, p. 287 - 289
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YieldReaction ConditionsOperation in experiment
100% for 2 h; Inert atmosphere; Reflux Methyl (S)-pyrrolidine-2-carboxylate was prepared29 from (S)-proline (10.2 g, 88.6 mmol) and SOCl2 (11.6 g, 7.10 mL, 97.5 mmol) in refluxing MeOH (60 mL) for 2 h. Subsequent removal of the excess solvent and SOCl2 yielded the proline ester (15.9 g, quant.) as a grey oil.30 The title compound 1 was prepared according to the literature15 from 2-fluoro-1-nitro benzene (6.92 g, 5.18 mL, 49.0 mmol) and methyl (S)-pyrrolidine-2-carboxylate (7.55 g, 45.6 mmol) as bright yellow crystals (12.0 g, quant.) and was used without further purification.
100% at 0 - 80℃; for 1.5 h; To a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOCl2 (12.6 mL, 174 mmol) at 0 °C. The mixture was stirred at 80 °C for 1.5 hours and concentrated in vacuo to afford the title compound 26-1 as a white solid (14.3 g, 100percent). The compound was characterized by the following spectroscopic data: MS-ESI: m/z 130.2 [M+H]+; and1H NMR (400 MHz, CD3OD): δ 4.45 (m, 1H), 3.85 (s, 1H), 3.40 (m, 2H), 2.42 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H).
100% at 0 - 80℃; for 1.5 h; To a solution of L-proline (10 g, 86.9 mmol) in MeOH (100 mL) was added SOCl2 (12.6 mL, 174 mmol) at 0°C. The mixture was stirred at 80 °C for 1.5 hours and concentrated in vacuo to afford the title compound 26-1 as a whitesolid (14.3 g, 100percent). The compound was characterized by the following spectroscopic data:MS-ESI: m/z 130.2 [M+H]+; and1H NMR (400 MHz, CD3OD): δ 4.45 (m, 1H), 3.85 (s, 1H), 3.40 (m, 2H), 2.42 (m, 1H), 2.12 (m, 1H), 2.07 (m, 1H).
100% at 25℃; for 12 h; To the solution L-proline (15.0 g, 130.3 mmol, 1.0 equiv) in MeOH (200 mL) at 0 °C,was added thionyl chloride (12.3 mL, 156.4 mmol, 1.2 equiv) over a period of 10 minutes. Thereaction mixture was slowly warm to room temperature and stirred it for 12 h. The resultedmixture was concentrated under reduced pressure by using KOH trapper attached rotaryevaporator and then the flask was connected with vacuum pump over a period of 1 h to affordcompound (14b) as colorless oil.
99.6%
Stage #1: With pyridine; hydrogenchloride In 1,2-dichloro-ethane at 20℃; for 0.5 h;
Stage #2: With hydrogenchloride In 1,2-dichloro-ethane at 84℃; for 3 h; Reflux
, 11.5 g (0.1 mol) of proline,20 ml of dichloroethane and step 2)The resulting mother liquor (i.e., step 2) was sprinkled with 20 ml of filtrate) into a 250 ml three-necked flask,A hydrogen chloride gas was introduced at a rate of 1.25 ml / s,Reaction at room temperature for 0.5 h,Consumption of HCl 0.1mol., then 4.16 g (0.13 mol) of methanol was put into a three-necked flask,Continue to pass hydrogen chloride gas (0.05ml / s) under reflux conditions,The aqueous dichloroethane was distilled off,And anhydrous dichloroethane was added dropwise to the reaction system at the same rate (using step 2)The dichloroethane obtained after the water treatment) was maintained so that the amount of dichloroethane in the reaction remained substantially unchanged. After 3 hours of reaction,Consumption of HCl 0.024 mol, co-distillation of azeotrope (water-containing dichloroethane) about 140ml.The resulting reaction solution was cooled to room temperature, and then the remaining dichloroethane (solvent) and methanol were removed by vacuum distillation (10 mmHg pressure, 40C). The reaction mixture was recrystallized at -10C to precipitate a solid,Washed with 20 ml of 0 ° C ice dichloroethane and filtered to obtain a filtrate and a filter cake, respectively,The filter cake was dried at 40 ° C for 5 hours to give a yield of 99.6percent of 16.5 g (0.0996 mol) of proline methyl ester hydrochloride.The distilled azeotrope (aqueous dichloroethane) was subjected to water removal to give anhydrous dichloroethane,The anhydrous dichloroethane can be used in the presence of anhydrous dichloroethane in the following cyclic application (thereby enabling recycling).The filtrate was steamed (40 ° C) to 20 ml as the next circulating mother liquor (i.e., as a starting materialIn the middle).The total amount of HCl in step 3) was 0.124 mol.
99% at 0℃; for 2.5 h; Reflux SOCl2 (76 mL, 1.04 mol) was added dropwise to a solution of (S)-proline (28.64 g, 0.25 mol)in MeOH (500 mL) at 0 °C. When the addition was complete, the mixture was refluxed for2.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure.The resultant (S)-1’ was obtained in 99percent yield (42 g, 0.25 mol) as a pale-yellow oil and wasused in the alkylation step without further purification.
98% Cooling with ice Optically active L-proline amino acid was purchased from LOBA Chemie and was commercial grade and used without further purification for thesynthesis of methyl L-prolinate hydrochloride. About1.0 g (6.0379 mmol) of L-proline was treated with methanol in the presence of 0.7183 g (6.0379 mmol)of SOCl2 to form this ester. It was synthetically an effective and well-known acid-catalyzed method for this esterification process.[11] Since the addition ofSOCl2 was an exothermic reaction, the entire reactionsystem was maintained under ice bath for about24 hr in a fume hood chamber. The completion ofthe reaction and purity of the product were checkedduring reasonable intervals using precoated Merckgraded thin layer chromatographic (TLC) plates inthe mixture of the hexane and ethyl acetate solventsystem. Finally, the formed ester was separated usinga Roto Vacuum Evaporator branded from BucheLabortechnike AG with appropriate temperatureand pressure. The percentage of yield was >98percent.The scheme of the reaction is shown in Fig.
96% Inert atmosphere To a solution of proline (5.00 g, 43.5 mmol) in MeOH (250 mL) at 0 °C was added thionyl chloride (10.3 mL, 86.9 mmol) (dropwise). The reaction was warmed to 50 °C and stirred for 20 h. Cooled the reaction to room temperature and concentrated under vacuum to afford methyl ester 6 as a clear yellow oil (6.88 g, 96percent); 1H-NMR (400 MHz, CDCl3) δ 10.57 (br s, 1H), 9.05 (br s, 1H), 4.51 (s, 1H), 3.85 (s, 3H), 3.62-3.52 (m, 2H), 2.47-2.41 (m, 1H), 2.24-2.07 (m, 3H).
143.9 g at 0℃; for 12 h; Reflux To a stirring solution of L-proline (SMI) (100 g, 0.87 mol) in methanol (800 mL) was slowly added thionyl chloride (76.9 mL, 1.04 mol) at 0°C. The reaction mixture was slowly warmed to RT and heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure to afford A (143.9 g, HCl salt). H-NMR: (400 MHz, CDC13): δ 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (m/z): 166 [M++l]
143.9 g at 0℃; Reflux To a stirred solution of L-proline 1 (100 g, 0.87 mol) in methanol (800 mL) was added thionyl chloride (76.9 mL, 1.04 mol) slowly drop wise at 0°C. The reaction mixture was heated to reflux for 12 h. After consumption of the starting material (by TLC), the reaction was concentrated under reduced pressure. The residue was washed with w-hexane to afford 2 (143.9 g, HC1 salt). 1H-NMR: (400 MHz, CDC13): δ 3.89 (s, 3H), 3.68-3.62 (m, 2H), 3.59-3.47 (m, 2H), 2.49-2.37 (m, 1H), 2.27-2.05 (m, 3H). LCMS (m/z): 166 [M++l]

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YieldReaction ConditionsOperation in experiment
93%
Stage #1: at 0℃; Inert atmosphere
Stage #2: at 0 - 20℃; for 50 h; Inert atmosphere
Benzyl alcohol (70 mL, 651 mmol) was cooled to 0 °C under nitrogen and 7.0 mL thionyl chloride (91.2 mmol) was added. l-Proline (5.0 g, 43.4 mmol) was then added and the mixture was stirred at 0 °C under nitrogen for 2 h.
The mixture was warmed to room temperature and stirring continued for 48 h.
The reaction mixture was then poured into 300 mL diethyl ether and stored at -20 °C for 7 days.
The precipitate formed was collected by filtration, washed with diethyl ether, and dried under vacuum to give 8 as white solid (9.88 g, 93percent yield); mp 142.1-144.0 °C; lit: 143-144 °C. 1H NMR (300 MHz, CDCl3): δ 7.41-7.21 (m, 5H), 5.16 (s, 2H), 3.80 (dd, J = 3.83, 5.9 Hz, 1H), 3.15-3.01 (m, 1H), 3.00-2.82 (m, 1H), 2.42-2.21 (m, 1H), 2.13 (dd, J = 12.9 Hz, 7.5 Hz, 1H), 1.92-1.62 (m, 3H).
13C NMR (75 MHz, CDCl3): δ 175.5, 136.0, 128.8, 128.5, 128.3, 66.9, 59.9, 47.2, 30.4, 25.6. Anal. Calcd for C12H16ClNO2: C, 59.63; H, 6.67; N, 5.79. Found: C, 59.50; H, 6.86; N, 5.64.
25
75.3%
Stage #1: With hydrogenchloride; iron(III) chloride In dichloromethane at 20℃; for 0.5 h;
Stage #2: for 3 h; Reflux
Will 11 · 5g (0 · lmol) valine,30ml of dichloroethane and 16.2g (0.1mol) of FeCl3 were put into a 250ml three-necked flask,Hydrogen chloride gas is fed at a rate of 1.25 ml/s (hydrogen chloride gas is always fed at this rate for a reaction time of 0.5 h).Reaction at room temperature for 0.5 h. Pass into HC1 total 2250ml, molar amount 0. lmolThen, 11.66 g (0.108 mol) of benzyl alcohol (proline: benzyl alcohol = 1:1.08) was put into a three-necked flask, and hydrogen chloride was introduced at 0.05 ml/s (hydrogen chloride gas was always fed at this rate for a reaction time of 3 h). , Under reflux conditions, distill off the aqueous dichloroethane (ie, the mixture distilled out during azeotropic distillation), and add anhydrous dichloroethane to the reaction system at the same rate to maintain The amount of dichloroethane in the reaction was essentially constant, and the reaction was completed in 3 hours. A total of 120 mL of azeotrope (ie, mixed liquor, ie, aqueous dichloroethane) was distilled out, and HC1 540 mL (0.024 mol) was introduced in total.The reaction solution was filtered while hot to obtain a filter residue containing a catalyst (Note: The "heat filtration reaction liquid" is for the purpose of removing the metal chloride as a catalyst, which can be used in the subsequent step 2).0032] After the filtered reaction solution was cooled to room temperature, the remaining dichloroethane solvent was removed by vacuum distillation (lOmmHg pressure, 40°C temperature), recrystallized at -10°C, and the precipitated solid was cooled with 20 ml of The solution was washed with iced dichloroethane at 0° C., filtered (retain filtrate), and the filter cake was dried at 40° C. for 5 h to obtain 18.20 g of proline benzyl ester hydrochloride. The yield was 75.3percent.[0033] 120ml of the mixed liquor having been distilled out during the water-retention process is obtained, and after dehydration treatment (water is removed with anhydrous sodium sulfate and 5g of anhydrous sodium sulfate is added per 100ml of dichloromethane), anhydrous dichloroethane (118mL) is obtained. Recycle in step 2.The retained filtrate was rotary evaporated (pressure of 10 mmHg, temperature of 40° C.) to 20 ml as a mother liquor for the next cycle (BP, as a raw material, fed into Step 2)..3percent.See also3/4
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YieldReaction ConditionsOperation in experiment
83.1%
Stage #1: at 0℃; for 2 h; Inert atmosphere
Stage #2: at 0 - 20℃; for 1 h; Inert atmosphere
Stage #3: With hydrogenchloride In water
Me2SiCl2 (148.4 g, 1.15 mol) was added dropwise to a suspension of L-proline (1) (115.1 g, 1.00 mol) in dry pyridine (500 ml) at 0°C under argon atmosphere. The reaction mixture was stirred at 0°C for 2 h and then dry EtNH2 (180.3 g, 4.00 mol) was added at the same temperature. The reaction mixture was subsequently stirred at room temperature for 1 h. The residue precipitated during the process was separated from the solution by filtration, and the solvent was removed under low pressure. The viscous residue was then dissolved in 5percent Na2CO3 solution (300 ml), and the resulting solution was washed with Et2O–hexane (1:1, 400 ml). The water layer was concentrated under low pressure, 17percent HCl (200 ml) was added to the obtained residue of crude L-proline ethylamide, and the resulting mixture was evaporated again in vacuo. MeOH (400 ml) was added to the residue, after which the inorganic salts were filtered off and the solvent was removed under low pressure. After adding Et2O (500 ml) and stirring for 1 h, pure hydrochloride 2 was separated from the solution by filtration. Yield 148.4 g (83.1percent), white crystals, mp 98-100°C (mp 97°C [14]). Purity 99.24percent (HPLC). [α]D27 -52.48 (c 0.3, H2O). IR spectrum, ν, cm-1: 3509, 3453, 2971, 2927, 2593, 2471, 1686, 1577, 1471, 1396, 1290, 1259, 1147, 1055, 816, 565. 1H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, t, J = 7.2, CH2CH3); 1.96-2.11 (3H, m, 3-CHA, 4-CH2); 2.50-2.64 (1H, m, 3-CHB); 3.19-3.35 (2H, m, 5-CH2); 3.43-3.52 (2H, m, CH2CH3); 4.62-4.71 (1H, m, 2-CH); 7.89 (1H, br. s, N+H); 10.46 (1H, br. s, N+H); 8.68 (1H, t, J = 7.1, CONH). 13C NMR spectrum, δ, ppm: 12.9; 23.3; 29.2; 34.3; 46.1; 59.4; 168.4. Mass spectrum, m/z (Irel, percent): 143 [M–Cl]+ (100). Found, percent: C 47.13; H 8.55; N 15.81. C7H15ClN2O. Calculated, percent: C 47.06; H 8.46; N 15.68.
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YieldReaction ConditionsOperation in experiment
69% With triethylamine In methanol; diethyl ether; acetonitrile Example 5
Synthesis of N-Benzyl (S)-Proline Methyl Ester 5
Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL).
After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature.
The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension.
After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4C1 (200 mL) and Et2O (200 mL).
The phases were separated, the aqueous layer was extracted with Et2O (40 mL*2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated.
The residue was purified over silica gel using 5 to 10percent EtOAc/pet ether to give a clear oil (6.37g, 69percent): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4H), 2.32-2.46 (m, 1H), 3.00-3.10 (m, 1H), 3.20-3.30 (m, 1H), 3.56 (d, J=12.7 Hz, 1H), 3.64 (s, 3H), 3.88 (d, J=12.7 Hz, 1H), 7.25-7.35 (m, 5H).
The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442).
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YieldReaction ConditionsOperation in experiment
31%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: at 0 - 20℃;
EΞxample - 1: Preparation of 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1- (2,4,5-trifluoro-benryl)-3-(3-trmuoromethyl-6,6-dihydro-8H-['1.2,4]triazolo[4,3-a]pyra-.in-7- yl)-propyl]-amlde Hydrochloride STEP -1 : Preparation 1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidiπfr-2-carboxylic acidTo a stirred solution of N-Boc L-Valine (Compound of formula 2) [8 gm, 0.037 mole] and tri ethyl amine (5.15 ml. 0.037 mole) in THF (120 ml), ethyl chloro formate (3 52 ml, 0.037 mole) was added dropwise at 0-5 0C. The reaction was stirred at 0 0C for 15 minutes and stirred at room temperature for 1 hour. Then keep the reaction at 0 C and add mixture of tri ethyl amine (10.3 ml, 0.074 mole) and THF (60 ml).Finally L-Proline (4.25 gm, 0-037 mole) was added to above mixture at 0 C. Reaction was stirred at 0 C for 30 minutes and stirred at room temperature for over night After being stirred, THF was concentrated under vacuum and residue was acidified with 1N HCI (till pH - 3). The product layer was extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated to give (B). The resulted product was subjected to column chromatography using EtoAC / Hexane 5/5 as an elυentto give N-Boc Val-Pro (Compound of formula 3). (Yield = 3.Q gm, 31percent)
Reference: [1] Patent: WO2010/29422, 2010, A1, . Location in patent: Page/Page column 8
  • 72
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  • [ 23361-28-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7333 - 7342
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 664 - 674
  • 73
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  • [ 23361-28-6 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 6, p. 1282 - 1287
  • 74
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  • [ 145681-01-2 ]
Reference: [1] Patent: WO2014/120786, 2014, A1,
  • 75
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  • [ 110529-22-1 ]
Reference: [1] Tetrahedron Asymmetry, 1999, vol. 10, # 8, p. 1551 - 1561
  • 76
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  • [ 91550-08-2 ]
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 38, p. 4878 - 4881
[2] Organic Letters, 2013, vol. 15, # 4, p. 824 - 827
  • 77
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  • [ 35150-07-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
[2] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[4] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
  • 78
  • [ 24424-99-5 ]
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  • [ 35150-07-3 ]
Reference: [1] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 27, p. 7698 - 7701[3] Angew. Chem., 2016, vol. 128, p. 7829 - 7832,4
[4] Journal of the American Chemical Society, 2017, vol. 139, # 48, p. 17500 - 17507
  • 79
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  • [ 108963-96-8 ]
Reference: [1] Chemical & Pharmaceutical Bulletin, 1986, vol. 34, # 9, p. 3873 - 3878
  • 80
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  • [ 119020-03-0 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 49, p. 7183 - 7186
  • 81
  • [ 497-19-8 ]
  • [ 147-85-3 ]
  • [ 27957-91-1 ]
YieldReaction ConditionsOperation in experiment
60% With thionyl chloride; trimethyl orthoformate; paraformaldehyde In methanol; dichloromethane 11a.
(S)-1-Methyl-2-pyrrolidinecarboxylic Acid Methyl Ester
L-Proline (46 kg), paraformaldehyde (13.2 kg), palladium on carbon (5percent, 350 g) and methanol (158 kg) were charged into a hydrogenation reactor and hydrogenated at 40 psi for 6 hr.
The mixture was filtered, and the filtrate returned to a reaction vessel.
Trimethyl orthoformate (170 kg) and thionyl chloride (171 kg) were added, and the mixture was heated at reflux for 2 hr.
The volatiles were then removed by distillation under vacuum.
The residue was dissolved in methylene chloride (215 kg), and aqueous sodium carbonate solution (10percent, 360 kg) was added to the mixture.
After vigorous mixing, the methylene chloride layer was separated.
The aqueous layer was extracted with methylene chloride (215 kg), and the extract combined with the first organic extract.
The solvent was dried with sodium sulfate (anhydrous, 40 kg) and filtered.
The volatiles were removed by distillation under vacuum, and the residue was distilled under high vacuum (10 mm Hg) to yield the product (34.5 kg, 60percent yield).
60% With thionyl chloride; trimethyl orthoformate; paraformaldehyde In methanol; dichloromethane 11a.
(S)-1-Methyl-2-pyrrolidinecarboxylic acid methyl ester
L-Proline (46 kg), paraformaldehyde (13.2 kg), palladium on carbon (5percent, 350 g) and methanol (158 kg) were charged into a hydrogenation reactor and hydrogenated at 40 psi for 6 hr.
The mixture was filtered, and the filtrate returned to a reaction vessel.
Trimethyl orthoformate (170 kg) and thionyl chloride (171 kg) were added, and the mixture was heated at reflux for 2 hr.
The volatiles were then removed by distillation under vacuum.
The residue was dissolved in methylene chloride (215 kg), and aqueous sodium carbonate solution (10percent, 360 kg) was added to the mixture.
After vigorous mixing, the methylene chloride layer was separated.
The aqueous layer was extracted with methylene chloride (215 kg), and the extract combined with the first organic extract.
The solvent was dried with sodium sulfate (anhydrous, 40 kg) and filtered.
The volatiles were removed by distillation under vacuum, and the residue was distilled under high vacuum (10 mm Hg) to yield the product (34.5 kg, 60percent yield).
Reference: [1] Patent: US5424444, 1995, A,
[2] Patent: US5516912, 1996, A,
[3] Patent: US5508418, 1996, A,
  • 82
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  • [ 50-00-0 ]
  • [ 147-85-3 ]
  • [ 27957-91-1 ]
  • [ 151490-81-2 ]
YieldReaction ConditionsOperation in experiment
20%
Stage #1: With methanol In diethyl ether; dichloromethane at 0℃; Inert atmosphere
Stage #2: With potassium carbonate In diethyl ether for 1 h; Reflux; Inert atmosphere
Methanol (15 mL) was added to a suspension of proline (5.7 g,0.05 mol) in dichloromethane (50 mL), followed by a dropwiseaddition of a solution of diazomethane (4.2 g, 0.1 mol) in diethylether (150 mL) with stirring and cooling to 0 °C. The mixturewas stirred until evolution of nitrogen stopped and the solution became colorless. The solvent was evaporated, the residue wasdistilled to obtain a mixture of esters 2 and 3 (5 g), the ratio ofwhich according to the 1H NMR data was 3 : 1; b.p. 60—62 °C(7 Torr). Paraformaldehyde (0.7 g, 0.023 mol) was added to thismixture, which was heated to 70 °C. After addition of diethylether (50 mL) and potassium carbonate (10 g), the mixture wasrefluxed for 1 h. A precipitate was filtered off, the ether wasevaporated, the residue was distilled to obtain ester 3, the yieldwas 1.4 g (20percent), b.p. 64 °C (6 Torr). Found (percent): C, 58.49; H, 9.07.C7H13NO2. Calculated (percent): C, 58.72; H, 9.15. 1H NMR(CDCl3), δ: 2.35 (s, 3 H, MeN); 3.53 (dd, 1 H, C(2)H, 3JH,H == 6.0 Hz, 3JH,H = 8.0 Hz); 3.49 (s, 3 H, CH3O). 13C{1H} NMR(CDCl3), δ: 40.52 (s, MeN); 66.99 (s, C(2)); 56.10 (s, C(3));23.59 (s, C(4)); 29.40 (s, C(5)); 50.98 (s, CH3O); 173.40 (s, C(6)).In the highboiling point fraction, aminal 5 was also obtained, the yield was 3.6 g (74percent), b.p. 120 °C (1 Torr) (see below).
Reference: [1] Russian Chemical Bulletin, 2016, vol. 65, # 7, p. 1846 - 1854[2] Izv. Akad. Nauk, Ser. Khim., 2016, vol. 65, # 7, p. 1846 - 1854,9
[3] Russian Journal of General Chemistry, 1993, vol. 63, # 9.1, p. 1410 - 1413[4] Zhurnal Obshchei Khimii, 1993, vol. 63, # 9, p. 2020 - 2025
  • 83
  • [ 584-08-7 ]
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  • [ 27957-91-1 ]
Reference: [1] Patent: US5424444, 1995, A,
[2] Patent: US5508418, 1996, A,
[3] Patent: US5516912, 1996, A,
  • 84
  • [ 186581-53-3 ]
  • [ 67-56-1 ]
  • [ 147-85-3 ]
  • [ 2577-48-2 ]
  • [ 27957-91-1 ]
Reference: [1] Russian Chemical Bulletin, 2016, vol. 65, # 7, p. 1846 - 1854[2] Izv. Akad. Nauk, Ser. Khim., 2016, vol. 65, # 7, p. 1846 - 1854,9
  • 85
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  • [ 50-00-0 ]
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  • [ 27957-91-1 ]
Reference: [1] Heteroatom Chemistry, 2017, vol. 28, # 1,
  • 86
  • [ 186581-53-3 ]
  • [ 147-85-3 ]
  • [ 2577-48-2 ]
  • [ 27957-91-1 ]
Reference: [1] Heteroatom Chemistry, 2017, vol. 28, # 1,
[2] Russian Journal of General Chemistry, 1993, vol. 63, # 9.1, p. 1410 - 1413[3] Zhurnal Obshchei Khimii, 1993, vol. 63, # 9, p. 2020 - 2025
  • 87
  • [ 147-85-3 ]
  • [ 60419-23-0 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
  • 88
  • [ 147-85-3 ]
  • [ 129223-22-9 ]
YieldReaction ConditionsOperation in experiment
91% With triethylamine In tetrahydrofuran at 20℃; for 15 h; General procedure: A mixture of Boc-l-phenyl alanine-ASUDester (Table 1, entry 6) (3.0g, 6.7mmol), l-phenyl alanine methyl ester hydrochloride (1.46g, 6.7mmol), and triethylamine (1.71g, 16.9mmol) in dry THF (15mL) was stirred overnight at room temperature (15h). After completion of the reaction, the reaction mixture was filtered (remove TEA·HCl salt) and washed with THF (5mL). The filtrate was concentrated under vacuum to obtain an oily crude. The oily crude was dissolved in ethyl acetate, washed with 1.0percent NaHCO3 solution and water. The ethyl acetate layer was dried over Na2SO4 and distilled under vacuum to give an oily crude product.
Reference: [1] Tetrahedron Asymmetry, 2016, vol. 27, # 11-12, p. 487 - 491
  • 89
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  • [ 22348-31-8 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 691 - 704
  • 90
  • [ 147-85-3 ]
  • [ 118971-03-2 ]
Reference: [1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 8-9, p. 691 - 704
  • 91
  • [ 147-85-3 ]
  • [ 74-88-4 ]
  • [ 4136-37-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 865 - 868
  • 92
  • [ 147-85-3 ]
  • [ 103336-06-7 ]
Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 22, p. 3777 - 3793
  • 93
  • [ 147-85-3 ]
  • [ 117928-94-6 ]
Reference: [1] Patent: WO2017/136348, 2017, A1,
[2] Patent: WO2017/136348, 2017, A1,
  • 94
  • [ 147-85-3 ]
  • [ 134756-75-5 ]
Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 18, p. 8625 - 8632
  • 95
  • [ 147-85-3 ]
  • [ 157115-85-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 1996, vol. 31, # 2, p. 151 - 157
  • 96
  • [ 147-85-3 ]
  • [ 214398-99-9 ]
Reference: [1] Patent: US2011/34434, 2011, A1,
[2] Patent: WO2011/101861, 2011, A1,
[3] Asian Journal of Chemistry, 2013, vol. 25, # 13, p. 7557 - 7560
[4] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[5] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3489 - 3492
[6] Letters in Organic Chemistry, 2014, vol. 11, # 10, p. 780 - 784
[7] Patent: WO2015/92806, 2015, A1,
[8] Patent: CN105503878, 2016, A,
[9] European Journal of Organic Chemistry, 2016, vol. 2016, # 30, p. 5160 - 5168
[10] Patent: CN104817482, 2017, B,
[11] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4402 - 4409
  • 97
  • [ 147-85-3 ]
  • [ 228244-04-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 10, p. 3524 - 3548
[2] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 35, p. 8544 - 8551
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[4] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
  • 98
  • [ 111398-44-8 ]
  • [ 147-85-3 ]
  • [ 181827-47-4 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water for 0.0833333 h; Cooling with ice
Stage #2: With benzotriazol-1-ol In water for 1 h; Cooling with ice
Stage #3: With sodium hydroxide In water at 0 - 5℃;
100g MOC-L- valine in 2L three-necked reaction flask was added 600mL of water, with mechanical stirring. In an ice bath was added 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride 111.61g, stirred for 5 minutes, to the system was added 1-hydroxybenzotriazole 39.33g, in an ice bath with stirring for about 1h, the system has a viscous white precipitate, the white viscous material as reactive intermediates.
L-proline 69.01g into a conical flask then dissolved with 120mL water, then transferred to a pressure-equalizing dropping funnel, weigh 28.7percent aqueous sodium hydroxide 192g on the other pressure-equalizing dropping funnel. The two solutions were simultaneously added dropwise to the above reaction system. Dropwise addition of about one hour. The temperature of the system was kept at 0-5 degrees. The reaction was continued until the active ester content was less than 0.5percent. After completion of the reaction, white floc precipitates appeared.
After completion of the reaction it was added with 2.4N hydrochloric acid to adjust the pH to 1-2, large amount of solid precipitated was filtered. The filtrate was extracted three times with dichloromethane. The organic phase was concentrated to give the product MOC-L-valinyl-L-proline 150g, 96percent yield.
Reference: [1] Patent: CN105753844, 2016, A, . Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039
  • 99
  • [ 147-85-3 ]
  • [ 181827-47-4 ]
YieldReaction ConditionsOperation in experiment
10.67 g With N-ethyl-N,N-diisopropylamine In water; acetonitrile at 20℃; To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of (S)-2,5-dioxopyrrolidin-l-yl 2- (methoxycarbonylamino)-3-methylbutanoate (lOg, 36.7 mmol) in acetonitrile (20 mL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HC1 (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25percent NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25percent NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give (S)-l-((S)-2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (10.67g) as a white solid.
Reference: [1] Patent: WO2015/171162, 2015, A1, . Location in patent: Paragraph 0022
  • 100
  • [ 112175-14-1 ]
  • [ 147-85-3 ]
  • [ 181827-47-4 ]
Reference: [1] Patent: CN105753844, 2016, A, . Location in patent: Paragraph 0058; 0059
  • 101
  • [ 147-85-3 ]
  • [ 181827-47-4 ]
Reference: [1] Patent: CN107235884, 2017, A,
[2] Patent: CN107235965, 2017, A,
  • 102
  • [ 147-85-3 ]
  • [ 119020-01-8 ]
Reference: [1] Phosphorus, Sulfur and Silicon and the Related Elements, 2013, vol. 188, # 4, p. 509 - 511
[2] Journal of the Korean Chemical Society, 2013, vol. 57, # 5, p. 591 - 598
  • 103
  • [ 147-85-3 ]
  • [ 207557-35-5 ]
Reference: [1] Patent: WO2006/90244, 2006, A1, . Location in patent: Page/Page column 28
[2] Patent: WO2007/99385, 2007, A1, . Location in patent: Page/Page column 26
[3] Patent: WO2011/101861, 2011, A1,
[4] Letters in Organic Chemistry, 2013, vol. 10, # 3, p. 159 - 163
[5] Asian Journal of Chemistry, 2014, vol. 26, # 12, p. 3489 - 3492
[6] Letters in Organic Chemistry, 2014, vol. 11, # 10, p. 780 - 784
[7] Chemical Biology and Drug Design, 2015, vol. 85, # 4, p. 439 - 446
[8] European Journal of Organic Chemistry, 2016, vol. 2016, # 30, p. 5160 - 5168
[9] Patent: CN104817482, 2017, B,
[10] Asian Journal of Chemistry, 2014, vol. 26, # 18, p. 6275 - 6278
[11] Patent: CN107954914, 2018, A,
[12] Patent: CN107954914, 2018, A,
[13] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 15, p. 4402 - 4409
[14] Patent: WO2006/11035, 2006, A1, . Location in patent: Page/Page column 30
  • 104
  • [ 147-85-3 ]
  • [ 207557-35-5 ]
Reference: [1] Patent: WO2005/75426, 2005, A1, . Location in patent: Page/Page column 35
  • 105
  • [ 147-85-3 ]
  • [ 848821-58-9 ]
Reference: [1] Molecules, 2012, vol. 17, # 5, p. 5626 - 5650
  • 106
  • [ 147-85-3 ]
  • [ 848821-76-1 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 7066 - 7069
  • 107
  • [ 147-85-3 ]
  • [ 1007882-58-7 ]
Reference: [1] Patent: EP2730572, 2014, A1,
[2] Patent: EP2730572, 2015, B1,
[3] Patent: EP2730572, 2015, B1,
  • 108
  • [ 761423-87-4 ]
  • [ 147-85-3 ]
  • [ 951382-34-6 ]
YieldReaction ConditionsOperation in experiment
99% at 35℃; for 3 h; In dichloromethane,24.65 g (61.02 mmol) of iglitavir and 7.02 g (61.02 mmol) of L-valine were added. Heat to 35 ° C and stir for 3 hours.After the reaction is over,Cooling the mixture,Filtration of the obtained crude solid product,Recrystallization of methanol,Obtained 31.35 g of Iglipide L-valine salt;Purity 99.8percent; yield 99percent;
83.7% at 100℃; for 0.5 h; A round-bottom flask was charged with compound 6 (20 g, 49.4 mmol), and filled up with ethanol (100 mL), and then L-proline (5.7 g, 1.0 equiv) and water (10 mL) were added. The mixture was stirred at 100 °C for 0.5 h. Thereafter, the reaction solution was cooled to room temperature, and crystallized to get a white solid 21.5 g. Yield 83.7percent; purity (HPLC): 99.92percent; decomposition temperature 203.3–205 °C; [α]D25 = -9.2° (c 1, acetonitrile/H2O 7:3); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz,1H), 7.67 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2.4 Hz, 1H),7.39–7.36 (m, 1H), 7.31–7.23 (m, 2H), 7.10 (t, J = 9.2 Hz, 1H),7.07 (s, 1H), 4.32–4.23 (m, 2H), 4.14 (d, J = 9.2 Hz, 1H),4.00–3.97 (m, 1H), 3.89 (dd, J = 12.0 Hz, 1.6 Hz, 1H), 3.71 (dd,J = 12.0 Hz, 5.2 Hz, 1H), 3.50–3.31 (m, 5H), 3.27–3.20 (m,1H), 2.35–2.26 (m, 1H), 2.17–2.09 (m, 1H), 2.01–1.94 (m, 2H);13C NMR (100 MHz, CDCl3) δ 172.6, 161.6, 159.2, 143.6,139.9, 135.9, 130.4, 127.9, 126.0, 123.8, 123.4, 122.6, 121.5,114.5, 81.5, 80.8, 78.4, 75.1, 70.5, 61.5, 45.6, 29.2, 23.7; MS(ES+) m/z: 427.16 [M + Na]+
Reference: [1] Patent: CN108276396, 2018, A, . Location in patent: Paragraph 0041; 0070; 0085; 0054; 0055
[2] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 1064 - 1070
[3] Patent: EP2009010, 2008, A1, . Location in patent: Page/Page column 7
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  • [ 739363-75-8 ]
  • [ 204387-53-1 ]
Reference: [1] Patent: CN107954914, 2018, A,
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