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[ CAS No. 28920-43-6 ] {[proInfo.proName]}

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Chemical Structure| 28920-43-6
Chemical Structure| 28920-43-6
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Product Details of [ 28920-43-6 ]

CAS No. :28920-43-6 MDL No. :MFCD00001138
Formula : C15H11ClO2 Boiling Point : -
Linear Structure Formula :- InChI Key :IRXSLJNXXZKURP-UHFFFAOYSA-N
M.W :258.70 Pubchem ID :34367
Synonyms :

Calculated chemistry of [ 28920-43-6 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.13
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 70.97
TPSA : 26.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -4.67 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.74
Log Po/w (XLOGP3) : 4.52
Log Po/w (WLOGP) : 4.17
Log Po/w (MLOGP) : 3.26
Log Po/w (SILICOS-IT) : 3.92
Consensus Log Po/w : 3.72

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.59
Solubility : 0.0067 mg/ml ; 0.0000259 mol/l
Class : Moderately soluble
Log S (Ali) : -4.79
Solubility : 0.00416 mg/ml ; 0.0000161 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.67
Solubility : 0.000554 mg/ml ; 0.00000214 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.83

Safety of [ 28920-43-6 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 UN#:3261
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 28920-43-6 ]

* 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 [ 28920-43-6 ]
  • Downstream synthetic route of [ 28920-43-6 ]

[ 28920-43-6 ] Synthesis Path-Upstream   1~96

  • 1
  • [ 150-30-1 ]
  • [ 28920-43-6 ]
  • [ 126727-04-6 ]
Reference: [1] Chemical Communications, 2013, vol. 49, # 26, p. 2697 - 2699
  • 2
  • [ 28920-43-6 ]
  • [ 126727-04-6 ]
Reference: [1] Synthesis, 2006, # 12, p. 1931 - 1933
  • 3
  • [ 3182-95-4 ]
  • [ 28920-43-6 ]
  • [ 129397-83-7 ]
YieldReaction ConditionsOperation in experiment
89% at 20℃; for 0.0333333 h; Sonication; Irradiation; Green chemistry General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 404 - 414
[2] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 3, p. 546 - 550
[3] Journal of Organic Chemistry, 1995, vol. 60, # 2, p. 405 - 410
[4] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
  • 4
  • [ 1208119-52-1 ]
  • [ 28920-43-6 ]
  • [ 103478-62-2 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1386 - 1392
  • 5
  • [ 449806-69-3 ]
  • [ 186581-53-3 ]
  • [ 28920-43-6 ]
  • [ 103478-62-2 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
  • 6
  • [ 56-84-8 ]
  • [ 28920-43-6 ]
  • [ 136083-57-3 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6825 - 6831
[2] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 509 - 515
  • 7
  • [ 56-86-0 ]
  • [ 28920-43-6 ]
  • [ 104091-09-0 ]
Reference: [1] Journal of the Chinese Chemical Society, 2011, vol. 58, # 4, p. 509 - 515
[2] Soft Matter, 2011, vol. 7, # 19, p. 8913 - 8922
  • 8
  • [ 28920-43-6 ]
  • [ 104091-09-0 ]
Reference: [1] Synlett, 2011, # 14, p. 2013 - 2016
  • 9
  • [ 5267-64-1 ]
  • [ 28920-43-6 ]
  • [ 130406-30-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 404 - 414
[2] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
  • 10
  • [ 1208119-58-7 ]
  • [ 28920-43-6 ]
  • [ 133373-24-7 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1386 - 1392
  • 11
  • [ 28920-43-6 ]
  • [ 133373-24-7 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 6, p. 1777 - 1789
  • 12
  • [ 186581-53-3 ]
  • [ 941296-83-9 ]
  • [ 28920-43-6 ]
  • [ 133373-24-7 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
  • 13
  • [ 2177-63-1 ]
  • [ 28920-43-6 ]
  • [ 150009-58-8 ]
Reference: [1] Journal of Natural Products, 2017, vol. 80, # 7, p. 2136 - 2140
  • 14
  • [ 28920-43-6 ]
  • [ 104-15-4 ]
  • [ 617-45-8 ]
  • [ 100-51-6 ]
  • [ 150009-58-8 ]
Reference: [1] Chemical communications (Cambridge, England), 2001, # 19, p. 1908 - 1909
  • 15
  • [ 28920-43-6 ]
  • [ 3105-95-1 ]
  • [ 101555-63-9 ]
YieldReaction ConditionsOperation in experiment
1.41 g With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 16 h; To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2C03 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-C1 (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HC1 (10 mL) to pH 2 and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous a2S04, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1111 - 1115
[2] Journal of the American Chemical Society, 2006, vol. 128, # 11, p. 3838 - 3847
[3] Patent: WO2013/148478, 2013, A1, . Location in patent: Page/Page column 23
  • 16
  • [ 28920-43-6 ]
  • [ 15912-30-8 ]
  • [ 101555-63-9 ]
Reference: [1] Journal of Organic Chemistry, 1992, vol. 57, # 16, p. 4394 - 4400
  • 17
  • [ 28920-43-6 ]
  • [ 25691-37-6 ]
  • [ 117106-21-5 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 14, p. 4347 - 4354
  • 18
  • [ 28920-43-6 ]
  • [ 109425-55-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 9, p. 1189 - 1191
  • 19
  • [ 28920-43-6 ]
  • [ 109425-55-0 ]
Reference: [1] Protein and Peptide Letters, 2010, vol. 17, # 7, p. 889 - 898
  • 20
  • [ 28920-43-6 ]
  • [ 135944-07-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 56 - 70
  • 21
  • [ 28920-43-6 ]
  • [ 23239-35-2 ]
  • [ 135944-05-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2353 - 2371
  • 22
  • [ 42417-72-1 ]
  • [ 28920-43-6 ]
  • [ 117106-20-4 ]
Reference: [1] Tetrahedron, 1988, vol. 44, # 6, p. 1773 - 1782
  • 23
  • [ 28920-43-6 ]
  • [ 13030-09-6 ]
  • [ 122350-52-1 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 9, p. 2707 - 2710
  • 24
  • [ 28920-43-6 ]
  • [ 35146-32-8 ]
  • [ 109425-51-6 ]
Reference: [1] Liebigs Annalen der Chemie, 1987, p. 1025 - 1030
  • 25
  • [ 1208119-51-0 ]
  • [ 28920-43-6 ]
  • [ 103478-58-6 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1386 - 1392
  • 26
  • [ 186581-53-3 ]
  • [ 28920-43-6 ]
  • [ 270073-00-2 ]
  • [ 103478-58-6 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
  • 27
  • [ 67-56-1 ]
  • [ 72-18-4 ]
  • [ 28920-43-6 ]
  • [ 103478-58-6 ]
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 42, p. 7307 - 7310
  • 28
  • [ 28920-43-6 ]
  • [ 30845-10-4 ]
  • [ 102971-73-3 ]
YieldReaction ConditionsOperation in experiment
15% With sodium carbonate In tetrahydrofuran The compound 2 (2g, 7.60mmol) was dissolved in 10percent Na2CO3, and the Fmoc-Cl (2.94g, 11.4mmol) was added slowly, which was mixed with THF (7mL). After stirring overnight, 10percent citric acid was added to adjust PH 4 ~ 5. The THF was removed under reduced pressure and the residual solution was extracted by CH2Cl2. After washing successively with saturated NaCl solution, the organic phase was dried over anhydrous Na2SO4 and concentrated, the residue was purified by silica gel column chromatography (550mg, 15percent). 1H NMR (400 MHz, DMSO-d6 ) δ 7.85 (d, J = 7.5 Hz, 2H), 7.77 ~7.61 (m, 3H), 7.37 (t, J = 7.5 Hz, 2H), 7.28 (t, J =7.4 Hz, 2H), 4.32~4.14 (m, 3H), 4.08 (qd, J = 8.8, 4.6 Hz, 1H), 2.86 (dt, J = 24.4, 10.2 Hz, 1H), 2.70(ddd, J = 15.2, 9.6, 5.6 Hz, 1H), 2.55 ~ 2.41 (m, 2H), 2.23 (t, J = 7.3 Hz, 2H), 1.68 (dd, J = 8.4, 6.1 Hz, 2H), 1.33 (s, 9H). 13C-NMR (100 MHz, DMSO-d6 ): δ172.86, 172.31, 156.54, 144.32, 141.26, 141.24, 128.17, 127.59, 125.84, 125.80, 120.64, 80.13, 66.26, 54.58, 47.14, 34.11, 33.05, 33.04, 31.15, 28.24, 25.03.
10% With sodium carbonate In tetrahydrofuran at 20℃; Preparation of Compound 21: Compound 4 (2 g, 7.6 mmol) was dissolved with 10 ml of 10percent Na 2 CO 3 solution, Fmoc-Cl (2.94 g, 11.4 mmol) dissolved in THF was added, reacted overnight at room temperature, and the pH was adjusted with 10percent citric acid. 5, THF was removed under reduced pressure, extracted with CH2Cl2, the organic phase was washed with saturated NaCl solution, and dried under reduced pressure to give a brown yellow oil product 21 (200 mg, yield: 10percent);
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 14, p. 2375 - 2378
[2] Patent: CN107628975, 2018, A, . Location in patent: Paragraph 0142; 0143; 0144; 0145; 0146; 0147
  • 29
  • [ 28920-43-6 ]
  • [ 25840-83-9 ]
  • [ 111061-56-4 ]
Reference: [1] Liebigs Annalen der Chemie, 1987, p. 1025 - 1030
  • 30
  • [ 28920-43-6 ]
  • [ 45125-00-6 ]
  • [ 104091-08-9 ]
Reference: [1] Journal of Organic Chemistry, 1986, vol. 51, # 24, p. 4590 - 4594
  • 31
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  • [ 2491-20-5 ]
  • [ 146346-88-5 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 4008 - 4017
[2] Journal of the American Chemical Society, 2013, vol. 135, # 9, p. 3359 - 3362
  • 32
  • [ 10065-72-2 ]
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  • [ 146346-88-5 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 24, p. 18751 - 18760
[2] Monatshefte fuer Chemie, 1992, vol. 123, p. 1015 - 1022
  • 33
  • [ 16338-48-0 ]
  • [ 28920-43-6 ]
  • [ 146549-21-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2005, vol. 3, # 10, p. 2016 - 2025
[2] Organic Letters, 2005, vol. 7, # 21, p. 4765 - 4767
  • 34
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  • [ 146549-21-5 ]
Reference: [1] Helvetica Chimica Acta, 1992, vol. 75, # 8, p. 2572 - 2582
  • 35
  • [ 28920-43-6 ]
  • [ 106719-44-2 ]
  • [ 115186-31-7 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 27, p. 5427 - 5439
  • 36
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  • [ 52-52-8 ]
  • [ 117322-30-2 ]
Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2001, vol. 40, # 1, p. 70 - 74
  • 37
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  • [ 146803-41-0 ]
Reference: [1] Patent: WO2011/69063, 2011, A2,
[2] Patent: WO2018/127130, 2018, A1,
  • 38
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  • [ 150308-80-8 ]
Reference: [1] Arkivoc, 2016, vol. 2017, # 2, p. 260 - 271
[2] Arkivoc, 2016, vol. 2017, # 2, p. 260 - 271
  • 39
  • [ 28920-43-6 ]
  • [ 141-43-5 ]
  • [ 105496-31-9 ]
YieldReaction ConditionsOperation in experiment
87% at 20℃; for 0.0333333 h; Sonication; Irradiation; Green chemistry General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
Reference: [1] Nucleosides and Nucleotides, 1994, vol. 13, # 1-3, p. 255 - 273
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 871 - 882
[3] Journal of Carbohydrate Chemistry, 2012, vol. 31, # 4-6, p. 384 - 419
[4] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 352 - 356
[5] European Journal of Organic Chemistry, 2008, # 34, p. 5786 - 5797
[6] Green Chemistry, 2011, vol. 13, # 12, p. 3355 - 3359
[7] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 3, p. 546 - 550
[8] Chemical Communications, 2014, vol. 50, # 54, p. 7132 - 7135
[9] Patent: WO2018/149419, 2018, A1, . Location in patent: Paragraph 001283
[10] Tetrahedron Letters, 1993, vol. 34, # 39, p. 6189 - 6192
[11] Tetrahedron Letters, 2002, vol. 43, # 17, p. 3125 - 3128
[12] Patent: US2006/51291, 2006, A1, . Location in patent: Page/Page column 7; 24
[13] Patent: US5599587, 1997, A,
[14] Patent: WO2006/39668, 2006, A2, . Location in patent: Page/Page column 40
[15] Patent: WO2006/105123, 2006, A2, . Location in patent: Page/Page column 50
  • 40
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  • [ 156939-62-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 2, p. 871 - 882
[2] Journal of the American Chemical Society, 2014, vol. 136, # 9, p. 3362 - 3365
[3] Patent: WO2018/149419, 2018, A1,
  • 41
  • [ 28920-43-6 ]
  • [ 141-43-5 ]
  • [ 156939-62-7 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 27, p. 4793 - 4796
  • 42
  • [ 7533-40-6 ]
  • [ 28920-43-6 ]
  • [ 139551-83-0 ]
YieldReaction ConditionsOperation in experiment
87% at 20℃; for 0.0333333 h; Sonication; Irradiation; Green chemistry General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
Reference: [1] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 3, p. 546 - 550
[2] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
  • 43
  • [ 20859-02-3 ]
  • [ 28920-43-6 ]
  • [ 132684-60-7 ]
YieldReaction ConditionsOperation in experiment
96% With sodium carbonate In 1,4-dioxane at 0 - 20℃; Take 500mL of the reaction bottle,Chiral amino acids S-3b (5.1 g, 38.6 mmol) were added to the reaction flask, respectively,Dioxane (40 mL) and10percent sodium carbonate (100 mL),The reaction flask was placed in an ice bath, mechanically stirred,To the dropping funnel was added l-chloroformate-9-fluorenylmethyl ester (10.0 g, 38.6 mmol) andDioxane (100 mL),Slowly drop into the reaction flask and gradually return to room temperature and stir overnight.After completion of the reaction, add water 100mL, extracted with 50mL ether three times, take the water phase into the ice bath to cool, add 1M dilute HCl to PH 1.The aqueous solution was extracted three times with 50 mL of ethyl acetate.The oil phase was combined and dried over magnesium sulfate and filtered to dryness to give intermediate S-4b (14.3 g, 96percent).
Reference: [1] Patent: CN106588987, 2017, A, . Location in patent: Paragraph 0195; 0196; 0197
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 45, p. 11846 - 11851[3] Angew. Chem., 2013, vol. 125, # 45, p. 12062 - 12067,6
[4] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
[5] Patent: WO2018/145021, 2018, A1, . Location in patent: Page/Page column 134
  • 44
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  • [ 139163-43-2 ]
  • [ 132684-60-7 ]
Reference: [1] Angewandte Chemie - International Edition, 2007, vol. 46, # 4, p. 612 - 614
  • 45
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  • [ 133464-46-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 1, p. 165 - 177
  • 46
  • [ 28920-43-6 ]
  • [ 156-87-6 ]
  • [ 157887-82-6 ]
YieldReaction ConditionsOperation in experiment
98% at 20℃; for 1.5 h; Cooling with ice 3-Amino-1-propanol (300 mg, 4 mmol) was dissolved in anhydrous dichloromethane (15 mL) and the reaction was placed in an ice bath. A solution of FmocCl (528 mg, 2 mmol) in dichloromethane The reaction mixture was added dropwise for 30 minutes. Raise temperatureAt room temperature, stirring was continued for 1.5 hours. The mixture was washed three times with 0.5 M HCl solution (5 mL × 3). The organic phases were further washed with saturated brine (5 mL) and finally dried over anhydrous Na 2 SO 4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (50percent ethyl acetate in petroleum ether) to give 15 as a white solid (585 mg, 98percent)
313 g With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; Inert atmosphere Step 1 To a solution of 10percent NaHCO3 (aq., 3 L) was added to a solution of 3-aminopropan-1-ol (75 g, 998 mmol) in 1,4-dioxane at 0° C. Fluorenylmethyloxycarbonyl chloride (Fmoc-Cl; 309.6 g, 1.189 mol) was added dropwise to the reaction mixture. The solution was warmed to room temperature (RT) and stirred overnight. The reaction mixture was diluted with EtOAc (1 L) and H2O (600 mL). The organic phase was separated and washed with H2O (500 mL) and brine (500 mL), followed by drying over Na2SO4. The solution was concentrated in vacuo to give the crude product as a white solid. The crude product was washed with hexane (5*1 L) and dried in vacuo to afford (9H-fluoren-9-yl)methyl(3-hydroxypropyl)carbamate (313 g, 105.5percent) as a white solid, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.5 Hz, 2H), 7.59 (d, J=7.4 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.32 (td, J=8.6, 1.1 Hz, 2H), 5.03 (brs, 1H), 4.44 (d, J=6.7 Hz, 2H), 4.21 (t, J=6.6 Hz, 1H), 3.64 (t, T=5.7 Hz, 2H), 3.30-3.37 (m, 2H), 2.00-2.20 (m, 2H), 1.64-1.73 (m, 2H).
313 g With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; Inert atmosphere Step 1 To a solution of 10percent NaHCO3 (aq., 3 L) was added to a solution of 3-aminopropan-1-ol (75 g, 998 mmol) in 1,4-dioxane at 0° C. Fluorenylmethyloxycarbonyl chloride (Fmoc-Cl; 309.6 g, 1.189 mol) was added dropwise to the reaction mixture. The solution was warmed to room temperature (RT) and stirred overnight. The reaction mixture was diluted with EtOAc (1 L) and H2O (600 mL). The organic phase was separated and washed with H2O (500 mL) and brine (500 mL), followed by drying over Na2SO4. The solution was concentrated in vacuo to give the crude product as a white solid. The crude product was washed with hexane (5*1 L) and dried in vacuo to afford (9H-fluoren-9-yl)methyl(3-hydroxypropyl)carbamate (313 g, 105.5percent) as a white solid, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.76 (d, J=7.5 Hz, 2H), 7.59 (d, J=7.4 Hz, 2H), 7.40 (t, J=7.2 Hz, 2H), 7.32 (td, J=8.6, 1.1 Hz, 2H), 5.03 (brs, 1H), 4.44 (d, J=6.7 Hz, 2H), 4.21 (t, J=6.6 Hz, 1H), 3.64 (t, J=5.7 Hz, 2H), 3.30-3.37 (m, 2H), 2.00-2.20 (m, 2H), 1.64-1.73 (m, 2H).
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[9] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
[10] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 352 - 356
[11] Patent: US2014/323477, 2014, A1, . Location in patent: Paragraph 0184-0186
[12] Patent: US2014/323478, 2014, A1, . Location in patent: Paragraph 0167; 0168
[13] Patent: US2015/31674, 2015, A1, . Location in patent: Paragraph 42.1
  • 47
  • [ 632-20-2 ]
  • [ 28920-43-6 ]
  • [ 157355-81-2 ]
Reference: [1] Tetrahedron Letters, 1994, vol. 35, # 37, p. 6937 - 6940
  • 48
  • [ 2749-11-3 ]
  • [ 28920-43-6 ]
  • [ 161529-13-1 ]
YieldReaction ConditionsOperation in experiment
90% With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; To a mixture of (S)-2-aminopropan-l-ol (2 g, 26.6 mmol) and Na2C03 (5.6 g, 53.2 mmol) in 1,4-dioxane and water (25 mL / 25 mL) at 0 °C was added FmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed to room temperature gradually. After the amine was consumed completely as indicated by TLC, water (25 mL) was added. The mixture was extracted with DCM (3 x 50 mL). The organic phase was washed with brine (50 mL), and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (7.1 g, 90percent).
Reference: [1] Patent: WO2011/69063, 2011, A2, . Location in patent: Page/Page column 82
  • 49
  • [ 28920-43-6 ]
  • [ 79069-13-9 ]
  • [ 161529-13-1 ]
Reference: [1] Patent: WO2018/127130, 2018, A1, . Location in patent: Paragraph 295; 296
  • 50
  • [ 2026-48-4 ]
  • [ 28920-43-6 ]
  • [ 160885-98-3 ]
YieldReaction ConditionsOperation in experiment
86% at 20℃; for 0.0333333 h; Sonication; Irradiation; Green chemistry General procedure: Amine (1 mmol) and Fmoc-Cl (1.1 mmol) were placed in a glass tube under neat conditions and were sonicated for a suitable time (as indicated in Tables 1, 2 and 3). All reactions were performed in a water bath at room temperature. After completion of the reaction (as indicated by TLC), 5 cm3 of diethyl ether was added to the mixture. The N-Fmoc derivatives were crystallized and were obtained in good to excellent yields. Purification of the product was accomplished by recrystallization from diethyl ether.
Reference: [1] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 3, p. 546 - 550
[2] Journal of Organic Chemistry, 1995, vol. 60, # 2, p. 405 - 410
  • 51
  • [ 70-26-8 ]
  • [ 28920-43-6 ]
  • [ 147071-84-9 ]
Reference: [1] Organic Preparations and Procedures International, 1994, vol. 26, # 5, p. 578 - 580
  • 52
  • [ 28920-43-6 ]
  • [ 74536-29-1 ]
  • [ 162558-25-0 ]
Reference: [1] Tetrahedron, 2000, vol. 56, # 16, p. 2513 - 2522
  • 53
  • [ 28920-43-6 ]
  • [ 16874-12-7 ]
  • [ 133852-23-0 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 40, p. 9472 - 9476
  • 54
  • [ 56-89-3 ]
  • [ 28920-43-6 ]
  • [ 135273-01-7 ]
YieldReaction ConditionsOperation in experiment
98% With sodium carbonate In 1,4-dioxane; water at 10 - 20℃; for 2 h; Sodium carbonate (4.6 g, 43.6 mmol) and L-cystine (5.0 g, 20.8 mmol) were dissolved in water (200 mL). The resulting solution was cooled to 10° C. FmocCl (11.85 g, 45.8 mmol) was dissolved in dioxane (80 mL), and the resulting solution was added dropwise to the aqueous solution of L-cystine. The solution was stirred for 2 h at 10° C. and allowed to gradually warm to room temperature. A thick white precipitate was obtained that was filtered onto a sintered glass funnel. The product was triturated with diethyl ether (50 mL) and dried in vacuuo for 2 d. N,N'-Bis(Fmoc)-L-cystine (14.0 g, 98percent yield) was obtained as a white powder.
Reference: [1] Patent: US2007/37963, 2007, A1, . Location in patent: Page/Page column 11-12; Figure 4
  • 55
  • [ 4378-19-2 ]
  • [ 28920-43-6 ]
  • [ 169566-81-8 ]
Reference: [1] Amino Acids, 2012, vol. 43, # 1, p. 207 - 218
[2] Helvetica Chimica Acta, 1995, vol. 78, # 3, p. 563 - 580
  • 56
  • [ 28920-43-6 ]
  • [ 62574-13-4 ]
  • [ 139592-37-3 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 21, p. 8185 - 8192
  • 57
  • [ 28920-43-6 ]
  • [ 116857-07-9 ]
  • [ 172169-88-9 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 22, p. 3843 - 3846
  • 58
  • [ 56-91-7 ]
  • [ 28920-43-6 ]
  • [ 164470-64-8 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6518 - 6524
[2] Tetrahedron, 1998, vol. 54, # 50, p. 15063 - 15086
[3] Organic Letters, 2008, vol. 10, # 10, p. 1881 - 1884
[4] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 873 - 879
[6] Patent: US9422239, 2016, B1, . Location in patent: Page/Page column 89
  • 59
  • [ 28920-43-6 ]
  • [ 56-12-2 ]
  • [ 116821-47-7 ]
Reference: [1] Chemistry - A European Journal, 1998, vol. 4, # 3, p. 425 - 433
[2] Tetrahedron Letters, 1998, vol. 39, # 28, p. 5117 - 5120
[3] Bioorganic Chemistry, 1996, vol. 24, # 1, p. 50 - 58
[4] Tetrahedron Letters, 2004, vol. 45, # 19, p. 3703 - 3706
[5] Patent: US2003/143591, 2003, A1,
[6] Russian Journal of General Chemistry, 2010, vol. 80, # 12, p. 2572 - 2589
  • 60
  • [ 1208119-61-2 ]
  • [ 28920-43-6 ]
  • [ 138775-22-1 ]
Reference: [1] Journal of Organic Chemistry, 2010, vol. 75, # 5, p. 1386 - 1392
  • 61
  • [ 852852-81-4 ]
  • [ 186581-53-3 ]
  • [ 28920-43-6 ]
  • [ 138775-22-1 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
  • 62
  • [ 28920-43-6 ]
  • [ 128421-86-3 ]
  • [ 141743-15-9 ]
Reference: [1] Tetrahedron, 1999, vol. 55, # 7, p. 1937 - 1958
  • 63
  • [ 28920-43-6 ]
  • [ 183673-71-4 ]
  • [ 183673-66-7 ]
YieldReaction ConditionsOperation in experiment
42% With sodium carbonate In tetrahydrofuran at 0 - 25℃; for 12 h; 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1, compound 8) [0225] A solution of 4-amino-1 -(terf-butoxycarbonyl)piperidine-4- carboxylic acid (5 g, 20.5 mmol) in THF (300 mL) and Na2CO3 (6.45 g, 61 .5 mmol, 3.0 eq in 64.5 mL of water) was cooled to 0°C before the dropwise addition of a solution of Fmoc chloride (5.3 g, 30.7 mmol, 1 .5 eq) in THF (30 mL). The resulting mixture was slowly warmed to 25°C and stirred for an additional 12 hours. Upon completion, the reaction contents were carefully acidified with HCI (1 M), and the crude material was extracted with EtOAc (three times). The combined organic layers were dried (Na2SO4), concentrated, and the crude material was purified by combiflash 0 to 10percent MeOH in DCM to provide 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1 -(te/t- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1 , compound 8) (4.02 g, 42percent yield). [0226] 1 H NMR (400 MHz, Ch lore-form -c/) δ 7.75 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.45-7.34 (m, 2H), 7.30 (td, J = 6.9, 6.3, 1 .4 Hz, 2H), 4.68-4.26 (m, 2H), 4.19 (t, J = 6.5 Hz, 1 H), 3.96-3.65 (m, 3H), 3.08 (s, 2H), 1 .91 -1 .77 (m, 2H), 1 .48 (s, 9H). 13C NMR (101 MHz, CDCI3) 177.19, 154.73, 143.67, 141 .32, 127.72, 127.08, 124.95, 1 19.97, 80.06, 67.90, 66.86, 57.49, 47.19, 31 .98, 28.42, 25.57. HRMS (m/z): [M+] cald for C26H30N2O6, 466.53, found 466.2
Reference: [1] Organic Syntheses, 2005, vol. 81, p. 213 - 224
[2] Patent: WO2015/184349, 2015, A2, . Location in patent: Paragraph 0225-0226
  • 64
  • [ 28920-43-6 ]
  • [ 587-33-7 ]
  • [ 178432-48-9 ]
Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 48, p. 16796 - 16797
  • 65
  • [ 28920-43-6 ]
  • [ 190656-01-0 ]
YieldReaction ConditionsOperation in experiment
68% With hydroxylamine hydrochloride; sodium hydrogencarbonate In dichloromethane; water at 0 - 20℃; for 73 h; (9H-Fluoren-9-yl)methyl ((9H-fluoren-9-yl)methoxy)carbonyloxycarbamate (56). Sodium bicarbonate (15.96 g, 190 mmol) is added to a biphasic mixture of hydroxylamine hydrochloride (6.0 g, 86 mmol) in CH2CI2 (250 mL) and water (1 0° mL) at 0 °c- After 1 0 mins, solid FmocCI (21 g, 81 mmol) is added portionwise with vigorous stirring. After 1 h a white precipitate forms and more CH2CI2 (100 mL) is added. The solution is allowed to warm to 20 °C and left to stir for 3 d. The white solid that remains is filtered away, re- dissolved in ethyl acetate (300 mL), washed with brine and dried over MgS04 to yield (9H-fluoren-9-yl)methyl hydroxycarbamate (Mellor, S. L; McGuire, C; Chan, W. C; Tet. Lett., 1997, 38, 3311-3314) as a white solid (15 g, 68percent). Futhermore, the mother- liquor is concentrated and purified by column chromatography (silica gel, ethyl acetate/CH2CI2 1 :1 to 1:0) to yield the title compound (by-product) as a white solid (0.55 g, 1percent). M.p. 160.5 °C (determined by differential scanning calorimetry, sharp onset); 1H NMR (500 MHz; CDCI3) δ 7.95 (s, 1 H), 7.77-7.74 (m, 4H), 7.63-7.57 (m, 4H), 7.43-7.38 (m, 4H), 7.32-7.28 (m, 4H), 4.52 (2 x d, J = 7.1 , 7.5, 4H), 4.31 (t, J = 7.5 Hz, 1 H), 4.26 (t, J = 7.1 Hz, 1 H); 13C NMR (125 MHz; CDCI3) δ 156.29, 155.34, 143.15, 142.73, 141.33, 128.12, 127.96, 127.32, 127.22, 125.17, 125.05, 120.17, 120.09, 71.91 , 68.70, 46.80, 46.52; m/z calcd for C3oH23N05(M+Na)+ 500.1468, found 500.1469.
Reference: [1] Patent: WO2011/159177, 2011, A1, . Location in patent: Page/Page column 76-77
  • 66
  • [ 28920-43-6 ]
  • [ 190656-01-0 ]
YieldReaction ConditionsOperation in experiment
47% With hydroxylamine hydrochloride; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1 h; (9H-Fluoren-9-yl)methyl hydroxycarbamate. (Mellor, S. L; McGuire, C; Chan, W. C; Tet. Lett., 1997, 38, 3311-3314.)To a biphasic mixture of hydroxylamine hydrochloride (3.00 g, 43.2 mmol) in DCM (50 mL) and water (20 mL) at 0 °C is added sodium bicarbonate (7.30 g, 87.0 mmol) portionwise. After 10 min FmocCI (12.0 g, mmol) is added portionwise to the vigorously stirred suspension which is then left to stir for 1 h at room temperature. The white precipitate that formed filtered and washed with DCM and water. The filter cake is then dissolved in ethyl acetate and washed with brine, dried over MgS04 and concentrated to give the title compound (5.20 g, 47percent) as a white solid which does not require any further purification. 1H NMR (500 MHz; DMSO-cfe) δ 9.75 (br s, 1 H), 8.78 (s, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 4.35 (d, J = 7.0 Hz, 2H), 4.24 (t, J = 7.0 Hz, 1 H); 13C NMR (125 MHz; DMSO-cf6) δ 157.5, 143.7, 140.7, 127.6, 127.0, 125.1, 120.0, 65.5, 46.6; HRMS (ES+) m/z calcd for C15H13N03 (M+Na)+ 278.0788, found 278.0793.
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 18, p. 3311 - 3314
[2] Patent: WO2011/159177, 2011, A1, . Location in patent: Page/Page column 43
[3] Journal of Organic Chemistry, 2007, vol. 72, # 21, p. 8123 - 8126
[4] Journal of Organic Chemistry, 2011, vol. 76, # 2, p. 358 - 372
  • 67
  • [ 28920-43-6 ]
  • [ 150-13-0 ]
  • [ 185116-43-2 ]
YieldReaction ConditionsOperation in experiment
94% for 24 h; Inert atmosphere p-­Aminobenzoic acid (10 g, 73 mmol) was dissolved in dry NMP (50 ml) under an inert atmosphere followed by the dropwise addition of Fmoc-­Cl (18.9 g, 73 mmol) in dry NMP (50 ml). After 24 hrs, the reaction mixture was poured slowly into 400 ml water. The colorless precipitate was collected by filtration, washed with water and dried in vacuum at 120 ºC to give N‐Fmoc-­p-­amino benzoic acid (24.8 g, 94percent). mp: 215 ºC (dec.) 1H-­NMR: δ (300 MHz, DMSO-d6) 4.33 (t, 3J = 6.25 Hz, 1 H); 4.54 (d, 3J = 6.25 Hz, 2 H); 7.33-­7.45 (m, 4 H); 7.57 (d, 3J = 7.35 Hz, 2 H); 7.76 (d, 3J = 7.35 Hz, 2 H); 7.89 (m, 4 H), 10.08 (s, 1H); 12.69 (s, 1H). 13C-­NMR and DEPT: δ (300 MHz, DMSO-­d6) 46.61 (+); 65.83 (-­); 117.5 (+); 120.22 (+); 124.48; 125.14 (+); 127.17 (+); 127.74 (+); 130.48 (+); 140.86; 143.31; 143.74; 153.31; 167.03. IR ν (cm-­‐1): 3344, 2970, 2887, 2660, 2544, 1709, 1673, 1610, 1592, 1526, 1511, 1411, 1311, 1282, 1221, 1052, 850, 736. RP-­HPLC (min): 26.6 min. M (FD): m/z (percent) = 359.1 (100); 360.1 (17.4); calc.[C22H17NO4] = 359.1
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 8, p. 753 - 756
[2] Chemical Communications, 2013, vol. 49, # 40, p. 4555 - 4557
[3] Journal of Chemical Research, Miniprint, 1998, # 10, p. 2736 - 2753
[4] Chemical Communications, 2014, vol. 50, # 14, p. 1691 - 1693
  • 68
  • [ 28920-43-6 ]
  • [ 134978-99-7 ]
  • [ 139338-72-0 ]
Reference: [1] Tetrahedron, 1997, vol. 53, # 20, p. 6977 - 6992
  • 69
  • [ 1197-17-7 ]
  • [ 28920-43-6 ]
  • [ 188715-40-4 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With sodium carbonate In 1,4-dioxane; water at 20℃; for 2.5 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Ψt, 2 H, J = 6.2Hz); 4.19 (br.Ψt, 1 H, J = 6.5Hz); 4.42 (br.Ψd, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Ψt, 2 H, J = 7.4Hz); 7.38 (Ψt, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz).
Reference: [1] Patent: EP1577289, 2005, A1, . Location in patent: Page/Page column 23
[2] Organic Letters, 2008, vol. 10, # 10, p. 1881 - 1884
  • 70
  • [ 67-56-1 ]
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  • [ 152548-66-8 ]
Reference: [1] Tetrahedron Letters, 1997, vol. 38, # 42, p. 7307 - 7310
  • 71
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  • [ 177609-12-0 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 14, p. 1673 - 1695
  • 72
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Reference: [1] Angewandte Chemie - International Edition, 2009, vol. 48, # 10, p. 1784 - 1787
  • 73
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  • [ 220498-02-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 13, p. 6580 - 6588
  • 74
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  • [ 112883-41-7 ]
Reference: [1] Patent: US5097013, 1992, A,
  • 75
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  • [ 138775-05-0 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
  • 76
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  • [ 204251-86-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 5, p. 1490 - 1510
  • 77
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  • [ 198544-42-2 ]
Reference: [1] Tetrahedron, 2000, vol. 56, # 16, p. 2513 - 2522
  • 78
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Reference: [1] Chemical communications (Cambridge, England), 2003, # 20, p. 2606 - 2607
  • 79
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Reference: [1] Tetrahedron, 2000, vol. 56, # 16, p. 2513 - 2522
  • 80
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  • [ 23356-96-9 ]
  • [ 148625-77-8 ]
Reference: [1] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
  • 81
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  • [ 210345-89-4 ]
  • [ 1018899-99-4 ]
Reference: [1] Chemical communications (Cambridge, England), 2001, # 22, p. 2330 - 2331
  • 82
  • [ 22059-21-8 ]
  • [ 28920-43-6 ]
  • [ 126705-22-4 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1698 - 1708
  • 83
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  • [ 693-57-2 ]
  • [ 128917-74-8 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 5, p. 1691 - 1698
[2] Chemical Communications, 2013, vol. 49, # 57, p. 6403 - 6405
[3] Chemical Communications, 2008, # 45, p. 5951 - 5953
[4] Macromolecular Bioscience, 2013, vol. 13, # 1, p. 84 - 92
[5] Journal of Lipid Research, 2015, vol. 56, # 1, p. 129 - 141
[6] Journal of Materials Chemistry B, 2014, vol. 2, # 38, p. 6478 - 6486
  • 84
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  • [ 28920-43-6 ]
  • [ 201046-59-5 ]
Reference: [1] Patent: US6455587, 2002, B1,
  • 85
  • [ 28920-43-6 ]
  • [ 2133-34-8 ]
  • [ 136552-06-2 ]
Reference: [1] Patent: US5064814, 1991, A,
  • 86
  • [ 28920-43-6 ]
  • [ 497-19-8 ]
  • [ 2133-34-8 ]
  • [ 136552-06-2 ]
Reference: [1] Patent: US5053392, 1991, A,
  • 87
  • [ 146725-85-1 ]
  • [ 28920-43-6 ]
  • [ 159611-02-6 ]
YieldReaction ConditionsOperation in experiment
53% With LiOH; sodium hydrogencarbonate In 1,4-dioxane c
(S)-2-(9-Fluorenylmethyloxycarbonylamino)-3-(2-furyl)-propionic acid
Methyl (S)-2-amino-3-(2-furyl)propionate (1 g, 6.5 mmol) was mixed with 2M LiOH (3.27 ml, 6.5 mmol) and dioxane (3.27 ml) at 0° C. and stirred overnight under N2.
The next day a TLC control (CHCl3 /MeOH/NH3 aq 1/1/0.1) of the reaction mixture showed no ester present. 1M NaHCO3 (9.75 ml, 9.75 mmol) and 9-fluorenylmethyloxycarbonyl chloride (2.5 g, 9.75 mmol) dissolved in dioxane (10 ml) were added to the above solution and the stirring continued for a further 1 hour.
Dioxane was removed under reduced pressure and the aqueous solution acidified with a 10percent KHSO4 solution to pH 2.
The solution was extracted with CHCl3 (3*20 ml), dried (MgSO4), evaporated and purified by flash chromatography (Hexane/ethyl acetate/acetic acid 10/10/1).
Yield: 1.3 g (53percent), white crystals.
1 H NMR (CDCl3): δ2.95 (dd, 1H, J 9.9, J 15.2 Hz), 3.08 (dd, 1H, J 4.4, J 15.2 Hz), 3.6 (br.s, 1H), 4.16-4.26 (m, 4H), 6.12 (d, 1H, J 2.9 Hz), 6.33 (t, 1H, J 2.3 Hz), 7.29 (t, 2H, J 7.32 Hz), 7.39 (t, 2H, J 7.48 Hz), 7.49 (br.s, 1H), 7.64 (dd, 2H, J 7.17, J 2.14 Hz), 7.85 (d, 2H, J 7.48 Hz).
13 C NMR (CDCl3): δ29.8, 46.98, 66.04, 107.45, 110.85, 120.48, 125.57, 125.63, 127.50, 128.07, 141.06, 142.21, 144.09, 151.84, 156.26, 160.35.
Reference: [1] Patent: US5629293, 1997, A,
  • 88
  • [ 1115-74-8 ]
  • [ 28920-43-6 ]
  • [ 150114-97-9 ]
YieldReaction ConditionsOperation in experiment
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18 h; (a) (R)-2-((R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methylbuta propanoic acid (20b) HO-Ala-Val-H 20a (350 mg, 1.86 mmol) and Na2C03 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 ml.) and the mixture was cooled to 0°C before dioxane (15 ml.) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-CI (504 mg, 1 .95 mmol) in dioxane (15 ml.) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 ml_). The pH was adjusted from 9 to 2 with 1 N HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 ml_). The combined organics were washed with brine (100 ml_), dried with MgS04, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-Val- Fmoc 20b (746 mg, 97percent yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H- NMR (400 MHz, CDCI3) δ 7.79 (d, J=7.77 Hz, 2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1 H), 5.30 (bs, 1 H), 4.71-7.56 (m, 1 H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1 H), 2.21-2.07 (m, 1 H), 1.50 (d, J=l A Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18 h; HO-Ala-Val-H 1 (350 mg, 1.86 mmol) and Na2C03 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15 mL) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-CI (504 mg, 1 .95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with 1 N HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried with MgS04, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-Val- Fmoc 2 (746 mg, 97percent yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDCI3) δ 7.79 (d, J=7.77 Hz, 2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1 H), 5.30 (bs, 1 H), 4.71 -7.56 (m, 1 H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1 H), 2.21 -2.07 (m, 1 H), 1 .50 (d, J=7.1 Hz, 3H), 1 .06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18 h; HO-Ala-Val-H 1 (350 mg, 1 .86 mmol) and Na2C03 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 ml.) and the mixture was cooled to 0°C before dioxane (15 ml.) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-CI (504 mg, 1.95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with 1 N HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried with MgS04, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO- Ala-Val-Fmoc 2 (746 mg, 97percent yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDCI3) δ 7.79 (d, J=7.77 Hz, 2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1 H), 5.30 (bs, 1 H), 4.71-7.56 (m, 1 H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1 H), 2.21-2.07 (m, 1 H), 1 .50 (d, J=1A Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18 h; HO-Ala-Val-H 20a (350 mg, 1.86 mmol) and Na2CO3 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15mL) was added (partial precipitation of the amino acid salt occurred). A solution of FmocCl (504 mg, 1.95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pHwas adjusted from 9 to 2 with iN HC1 and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried with MgSO4, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-Val-Fmoc 20b (746 mg, 97percent yield). LC/MS 2.85 mm (ES+) rn/z (relative intensity) 410.60 ; ‘H-NMR (400 MHz, CDC13) ö 7.79 (d, J7.77 Hz,2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1H),5.30 (bs, 1H), 4.71-7.56 (m, 1H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1H), 2.21-2.07 (m,1H), 1.50 (d,J=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18.16 h; HO-Ala-Val-H 13(350 mg, 1.86 mmol) and Na2CO3 (493 mg, 4.65 mmol) were dissolved indistilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15 mL) was added(partial precipitation of the amino acid salt occurred). A solution of Fmoc-Cl (504 mg, 1 .95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with IN HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). Thecombined organics were washed with brine (100 mL), dried with MgSO4, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-ValFmoc 14 (746 mg, 97percent yield). LC/MS 2.85 mm (ES+) m/z (relative intensity) 410.60 ; NMR (400 MHz, CDCI3) 5 7.79 (d, J7.77 Hz, 2H), 7.60(d, J7.77 Hz, 2H), 7.43(d, J7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, IH), 5.30 (bs, IH), 4.71-7.56 (m, IH), 4.54-4.36 (m,2H), 4.08-3.91 (m, IH), 2.21-2.07 (m, IH), 1.50 (d, J=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18 h; HO-Ala-Val-H 13 (350 mg, 1 .86 mmol) and Na2C03 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 ml.) and the mixture was cooled to 0°C before dioxane (15 ml.) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-CI (504 mg, 1 .95 mmol) in dioxane (15 ml.) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 ml_). The pH was adjusted from 9 to 2 with 1 N HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 ml_). The combined organics were washed with brine (100 ml_), dried with MgS04, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-Val- Fmoc 14 (746 mg, 97percent yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1 H- NMR (400 MHz, CDCI3) δ 7.79 (d, J=7.77 Hz, 2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1 H), 5.30 (bs, 1 H), 4.71 -7.56 (m, 1 H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1 H), 2.21 -2.07 (m, 1 H), 1 .50 (d, J=7.1 Hz, 3H), 1 .06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18.16 h; HO-Ala-Val-H 13(350 mg, 1.86 mmol) and Na2CO3 (493 mg, 4.65 mmol) were dissolved indistilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15 mL) was added(partial precipitation of the amino acid salt occurred). A solution of Fmoc-Cl (504 mg, 1 .95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with IN HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). Thecombined organics were washed with brine (100 mL), dried with MgSO4, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-ValFmoc 14 (746 mg, 97percent yield). LC/MS 2.85 mm (ES+) m/z (relative intensity) 410.60 ; NMR (400 MHz, CDCI3) 5 7.79 (d, J7.77 Hz, 2H), 7.60(d, J7.77 Hz, 2H), 7.43(d, J7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, IH), 5.30 (bs, IH), 4.71-7.56 (m, IH), 4.54-4.36 (m,2H), 4.08-3.91 (m, IH), 2.21-2.07 (m, IH), 1.50 (d, J=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 18.16 h; HO-Ala-Val-H 13(350 mg, 1.86 mmol) and Na2CO3 (493 mg, 4.65 mmol) were dissolved indistilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15 mL) was added(partial precipitation of the amino acid salt occurred). A solution of Fmoc-Cl (504 mg, 1 .95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with IN HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). Thecombined organics were washed with brine (100 mL), dried with MgSO4, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-ValFmoc 14 (746 mg, 97percent yield). LC/MS 2.85 mm (ES+) m/z (relative intensity) 410.60 ; NMR (400 MHz, CDCI3) 5 7.79 (d, J7.77 Hz, 2H), 7.60(d, J7.77 Hz, 2H), 7.43(d, J7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, IH), 5.30 (bs, IH), 4.71-7.56 (m, IH), 4.54-4.36 (m,2H), 4.08-3.91 (m, IH), 2.21-2.07 (m, IH), 1.50 (d, J=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
97%
Stage #1: With sodium carbonate In 1,4-dioxane; water
Stage #2: at 0℃; for 18.2 h;
HO-Ala-Val-H 20a (350 mg, 1.86 mmol) and Na2C03 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 niL) and the mixture was cooled to 0°C before dioxane (15 mL) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-Cl (504 mg, 1.95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with IN HC1 and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried with MgS04, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-Val-Fmoc 20b (746 mg, 97percent yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDC13) δ 7.79 (d, .7=7.77 Hz, 2H), 7.60(d, .7=7.77 Hz, 2H), 7.43(d, .7=7.5 Hz, 2H), 7.34 (d, .7=7.5 Hz, 2H), 6.30 (bs, IH), 5.30 (bs, IH), 4.71-7.56 (m, IH), 4.54-4.36 (m, 2H), 4.08-3.91 (m, IH), 2.21- 2.07 (m, IH), 1.50 (d, .7=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
97% With sodium carbonate In 1,4-dioxane; water at 0℃; for 2.16667 h; (a) (R)-2-((R)-2-((((9H-fluoren-9-yI)methoxy)carbonyl)amino)-3-methylbutanamido) propanoic acid (20b)HO-Ala-Val-H 20a (350 mg, 1.86 mmol) and Na2003 (493 mg, 4.65 mmol) were dissolved in distilled H20 (15 mL) and the mixture was cooled to 0°C before dioxane (15 mL) was added (partial precipitation of the amino acid salt occurred). A solution of Fmoc-Cl (504 mg, 1.95 mmol) in dioxane (15 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and stirring was maintained for 16 hours. The solvent was removed by rotary evaporation under reduced pressure and the residue dissolved in water (150 mL). The pH was adjusted from 9 to 2 with iN HCI and the aqueous layer was subsequently extracted with EtOAc (3x100 mL). The combined organics were washed with brine (100 mL), dried with MgSO4, filtered and the volatiles removed by rotary evaporation under reduced pressure to afford pure HO-Ala-ValFmoc 20b (746 mg, 97percent yield). LC/MS 2.85 mm (ES+) m/z (relative intensity) 410.60; NMR (400 MHz, CDCI3) O 7.79 (d, J=7.77 Hz, 2H), 7.60(d, J=7.77 Hz, 2H), 7.43(d, J=7.5 Hz, 2H), 7.34 (d, J=7.5 Hz, 2H), 6.30 (bs, 1H), 5.30 (bs, 1H), 4.71-7.56 (m, 1H), 4.54-4.36 (m, 2H), 4.08-3.91 (m, 1H), 2.21-2.07 (m, 1H), 1.50 (d, J=7.1 Hz, 3H), 1.06-0.90 (m, 6H).
94% With sodium carbonate In 1,4-dioxane; water at 0 - 20℃; for 18 h; H-Val-Ala-OH 11 (1 .0g, 5.313 mmol, 1.0 eq.) and Na2C03 (1 .42 g, 13.282 mmol, 2.5 eq.) were solubilised in distilled H20 (40 mL) and the mixture was cooled to 0°C before dioxane (40 mL) was added. Partial precipitation of the amino acid salt occurred. A solution of Fmoc-CI (1.44 g, 5.579 mmol, 1 .05 eq.) dissolved in dioxane (40 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0°C for 2 hours before the ice bath was removed and the stirring maintained for 16 hours. The solvent was evaporated under reduced pressure and the solid remaining dissolved in water (450 mL). The pH was adjusted to 2 with 1 N HCI (25 mL) and the aqueous layer was subsequently extracted with EtOAc (3 x 250 mL). The combined organics were washed with brine (100 mL), dried over MgS04, filtered and the volatiles removed under reduced pressure to afford pure HO-Ala-Val-Fmoc 12 as a white solid (2.06 g, 94percent). LC/MS (2.758min (ES+)), m/z: 41 1 .0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1 H), 8.20 (d, 1 H, J = 6.7 Hz), 7.89 (d, 2H, J = 7.5 Hz), 7.75 (t, 2H, J = 6.8 Hz), 7.43 - 7.38 (m, 3H), 7.34 - 7.30 (m, 2H), 4.31 - 4.16 (m, 4H), 3.88 (dd, 1 H, J = 8.8, 7.2 Hz), 1 .98 (m, 1 H), 1 .26 (d, 3H, J = 7.3 Hz), 0.89 (d, 3H, J = 6.8 Hz), 0.86 (d, 3H, J = 6.8 Hz).

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YieldReaction ConditionsOperation in experiment
22.2% With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2 h; Example A73 Preparation of Ar2-acetyl-L-lysyl-L-valyl-A^-carbamoyl-Ar-[4-([(2-[(3i?,51S',7i?,8i?)-8-hydroxy-7- {(l£,3£)-5-[(21S,,35',5i?,6i?)-5-[(2Z,41S)-4-hydroxypent-2-enoyl]amino}-3,6-dimethyltetrahydro- 2H-pyran-2-yl]-3-methylpenta-l,3-dien-l-yl}-l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-L-ornithinamide, acetate salt (B222). B227 Step 1. Synthesis of N2-acetyl-N6-(teri-butoxycarbonyl)-L-lysine (B223). To a mixture of N6- (fert-butoxycarbonyl)-L-lysine (22.5 g, 91.5 mmol, 1 eq.) and K2CO3 (63.1 g, 0.457 mol, 5 eq.) in tetrahydrofuran/water (200 mL/200 mL) at 0 °C was added acetyl chloride (8.62 g, 0.109 mol, 1.2 eq.), and the mixture was stirred at rt for 4 h. The mixture was concentrated in vacuo to remove the tetrahydrofuran, and the aqueous layer was adjusted to pH = 1 with 2 M HCI and extracted with EtOAc (100 mL) three times. The extract was washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to afford B223 (23.1 g, 87.7 percent) as a yellow oil. Step 2. Synthesis of N2-acetyl-L-lysine hydrochloride salt (B224). To a solution of B223 (23.1 g, 0.080 mmol, 1 eq.) in ethyl acetate (400 mL) at 0 °C was added HC1 (g) in ethyl acetate (250 mL) under nitrogen. The mixture was stirred at rt for 4 h and filtered. The solid was washed with ethyl acetate and dried in vacuo to afford B224 (18.5 g, >100 percent) as a white solid which was used without further purification. Step 3. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysine (B225). To a mixture of B224 (8 g, 35.6 mmol, 1 eq.) and NaHC03 (5.99 g, 71.3 mmol, 2 eq.) in acetone/water (80 mL/80 mL) at 0 °C was added a solution of Fmoc-Cl (9.41 g, 36.3 mmol, 1.02 eq.) in acetone (80 mL), and the mixture was stirred at rt for 2 h. The mixture was adjusted to pH = 3-4 with 2 N HC1 and extracted with ethyl acetate (100 mL) three times. The extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give the crude product (7 g) as a yellow oil. To the crude product was added dichloromethane and fert-butylmethyl ether (100 mL), and the suspension was stirred for 30 min and then filtered. The filter cake was dried in vacuo to afford B225 (3.25 g, 22.2 percent) as a white solid. Step 4. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-(hydroxymethyl)phenyl]-L-ornithinamide (B226). To a mixture of B225 (1.04 g, 2.54 mmol, 1 eq.) in NN-dimethylformamide (20 mL) at 0 °C was added N-methylmorpholine (769 mg, 7.61 mmol, 3 eq.), l -ethyl-3-(3-dimethylaminopropyl) carbodiimide-HCl (632 mg, 3.30 mmol, 1.3 eq.), 1 -hydroxybenzotriazole hydrate (445 mg, 3.30 mmol, 1.3 eq.) and L-valyl-N5-carbamoyl-N-[4- (hydroxymethyl)phenyl]-L-ornithinamide (From WO04010957, 1.01 g, 2.66 mmol, 1.05 eq.) under nitrogen, and the mixture was stirred at rt for 2 h. the mixture was poured into teri-butylmethyl ether (300 mL) and filtered. The solid was washed with dichloromethane (50 mL) and water (50 mL) and dried in vacuo to afford B226 (1.87 g, 95.6percent) as a white solid. Step 5. Synthesis of N2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-( [(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-ornithinamide (B227). To a mixture of B226 (1.87 g, 2.43 mmol, 1 eq.) and bis-(4-nitrophenyl)carbonate (2.21 g, 7.28 mmol, 3 eq.) in NN-dimethylformamide (30 mL) at 0 °C was added NN-diisopropylethylamine (313 mg, 2.43 mmol, 1 eq.) under nitrogen, and the mixture was stirred at rt overnight. The mixture was poured into teri-butylmethylether (50 mL) and filtered. The solid (1.95 g) was purified by prep HPLC to give B227 (580 mg, 25.7 percent) as a white solid. lU NMR (400Hz, DMSO-dg): 10.1 (s, 1 H), 8.29 (d, 2 H), 8.00 (d, 1 H), 7.86 (d, 1 H), 7.65 (d, 2 H), 7.64 (d, 1 H), 7.61 (m, 4 H), 7.40 (m, 2 H), 7.38 (m, 4 H), 7.30 (m, 3 H), 6.01 (br, 1 H), 5.21 (s, 2 H), 4.35 (br, 1 H), 4.27-4.15 (m, 5 H), 2.96 (m, 4 H), 1.98 (m, 1 H), 1.82 (s, 3 H), 1.65 (br, 3 H), 1.43-1.24 (m, 7 H), 0.83 (m, 6 H). Step 6. Synthesis ofN2-acetyl-N6-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-lysyl-L-valyl-N5- carbamoyl-N-[4-( [(2-[(3R,5S,7R,8R)-8-hydroxy-7-{(l£',3£')-5-[(2S,3S,5R,6R)-5- [(2Z,4S)-4- hydroxypent-2-enoyl]amino}-3,6-dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l -yl} - 1.6- dioxaspiro [2.5] oct-5-yl] acetyl} hydrazinyl)carbonyl] oxy } methyl)phenyl] -L-ornithinamide (B228) . To a solution of B209 (8.1 mg, 0.016 mmol, 1 eq.) in NN-dimethylformamide (0.4 mL) at rt was added 2,6-lutidine (7.5 \L, 0.064 mmol, 4 eq.), NN-diisopropylethylamine (11.3 \L, 0.064 mmol, 4 eq.) and 4-NN-dimethylamino pyridine (2 mg, 0.016 mmol, 1 eq.) followed by B227 (17.8 mg, 0.019 mmol, 1.2 eq.), and the reaction was stirred for 5 h. The reaction was purified by reverse phase chromatography (Method A) to give B228 as a white solid. Yield: 5.5 mg, 0.004 mmol, 26percent. LCMS (Protocol D): m/z 1306.1 [M+H]+, retention time = 0.81 minutes. Step 7. Synthesis of N2-acetyl-L-lysyl-L-valyl-N5-carbamoyl-N-[4-([(2- [(3R,5S,7R,8R)-8- hydroxy-7-{(l£',3£')-5-[(2S,3S,5R,6R)-5-[(2Z,4S)-4-hydroxypent-2-enoyl]amino}-3,6- dimethyltetrahydro-2H-pyran-2-yl]-3-methylpenta-l,3-dien-l -yl} -l,6-dioxaspiro[2.5]oct-5- yl]acetyl}hydrazinyl)carbonyl]oxy}methyl)phenyl]-L-ornithinamide, acetate salt (B222). The title compound was prepared in 79percent yield from 9.5 mg (0.007 mmol, 1.0 eq.) of B228 and 11.9 mg (0.14 mmol, 20.0 eq.) of piperidine using the procedure described for preparation of compound B47. LCMS (Protocol D): m/z 1084.1 [M+H]+, retention time = 0.58 minutes. lU NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1 H), 8.22-8.12 (m, 1 H), 8.03 (d, J= 7.8 Hz, 1 H), 7.87-7.74 (m, 2 H), 7.64-7.53 (m, 2 H), 7.34-7.18 (m, 2 H), 6.31 (d, J= 15.9 Hz, 1 H), 6.09-6.01 (m, 1 H), 5.98 (d, J= 11.8 Hz, 1 H), 5.86 (dd, J= 11.8 and 7.1 Hz, 1 H), 5.66-5.56 (m, 1 H), 5.55-5.49 (m, 1 H), 5.44 (br s, 1 H), 5.23-4.91 (m, 3 H), 4.43-4.33 (m, 1 H), 4.30-4.21 (m, 2 H), 4.20-4.12 (m, 1 H), 3.69-3.59 (m, 1 H), 3.53-3.45 (m, 1 H), 3.07- 2.88 (m, 2 H), 2.76-2.71 (m, 1 H), 2.61-2.56 (m, 1 H), 2.35-2.14 (m, 4 H), 2.04-1.53 (m, 18 H), 1.52-1.18 (m, 10 H), 1.11 (d, J= 6.4 Hz, 3 H), 1.06 (d, J= 6.4 Hz, 3 H), 0.95 (d, J= 7.3 Hz, 3 H), 0.85 (d, J= 6.9 Hz, 3 H), 0.82 (d, J= 6.9 Hz, 3 H).
Reference: [1] Patent: WO2014/68443, 2014, A1, . Location in patent: Page/Page column 203; 204
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  • [ 201004-29-7 ]
Reference: [1] Journal of the American Chemical Society, 2012, vol. 134, # 35, p. 14310 - 14313
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  • [ 49606-99-7 ]
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YieldReaction ConditionsOperation in experiment
84% With sodium carbonate In 1,4-dioxane; water at 0 - 25℃; for 8.17 h; (5)-2-((((9/ -fluoren-9-yl)methoxy)carbonyl)amino)-2-cyclopropylacetic acid (43a): To a stirred solution of Na2C03 (2.3 g) in water (34 mL) was added (2C12); FT-IR (neat) 2669, 2335, 2159, 2106, 1785, 1689, 1550, 1489, 1463, 1433, 1369, 1296, 1253, 1172, 1128, 1001 cm"1; NMR: (CDCI3, 600 MHz) δ = 7.76 (d, 2 H, J = 7.2 Hz), 7.60-7.59 (m, 2 H), 7.41-7.39 (m, 2 H), 7.32-7.30 (m, 2 H), 5.36 (d, 1 H, J = 6), 4.45-4.39 (m, 2 H), 4.24-4.21 (m, 1 H), 3.83-3.81 (m, 1 H), 1.14-1.13 (m, 1 H), 0.65-0.46 (m, 5 H) ppm. 13C NMR: (CDCI3, 150 MHz) δ = 176.6, 156.2, 143.9, 143.8, 141.4, 127.9, 127.2, 125.2, 125.1, 120.1, 67.3, 57.4, 47.3, 13.9, 3.4 ppm; HRMS calcd for C20H19NO4 [ +Na+] 360.1206 found 360.1193.
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1698 - 1708
[2] Patent: WO2016/138288, 2016, A1, . Location in patent: Page/Page column 124
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Reference: [1] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
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