There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 28920-43-6 * Storage: {[proInfo.prStorage]}
* 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.
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 ]
Yield
Reaction Conditions
Operation 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 ]
Yield
Reaction Conditions
Operation 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
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
[ 28920-43-6 ]
[ 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
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
[ 28920-43-6 ]
[ 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,
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 ]
Yield
Reaction Conditions
Operation 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
[ 28920-43-6 ]
[ 139163-43-2 ]
[ 132684-60-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 4, p. 612 - 614
45
[ 28920-43-6 ]
[ 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 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] Patent: CN107129455, 2017, A, . Location in patent: Paragraph 0118; 0119; 0120; 0121
[2] Journal of Organic Chemistry, 2007, vol. 72, # 19, p. 7222 - 7228
[3] Synthesis, 1998, # 6, p. 859 - 866
[4] Nucleosides, Nucleotides and Nucleic Acids, 2000, vol. 19, # 8, p. 1301 - 1310
[5] Chinese Chemical Letters, 2012, vol. 23, # 8, p. 923 - 926
[6] Antimicrobial Agents and Chemotherapy, 2016, vol. 60, # 5, p. 3076 - 3089
[7] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 9, p. 1463 - 1464
[8] Tetrahedron Letters, 2002, vol. 43, # 17, p. 3125 - 3128
[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
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).
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
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 40, p. 9472 - 9476
54
[ 56-89-3 ]
[ 28920-43-6 ]
[ 135273-01-7 ]
Yield
Reaction Conditions
Operation 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] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 14, p. 1673 - 1695
66
[ 28920-43-6 ]
[ 112883-41-7 ]
Reference：
[1] Patent: US5097013, 1992, A,
67
[ 852852-85-8 ]
[ 186581-53-3 ]
[ 28920-43-6 ]
[ 138775-05-0 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3723 - 3728
68
[ 28920-43-6 ]
[ 23356-96-9 ]
[ 148625-77-8 ]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 12, p. 4023 - 4034
69
[ 28920-43-6 ]
[ 210345-89-4 ]
[ 1018899-99-4 ]
Reference：
[1] Chemical communications (Cambridge, England), 2001, # 22, p. 2330 - 2331
70
[ 22059-21-8 ]
[ 28920-43-6 ]
[ 126705-22-4 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1698 - 1708
71
[ 28920-43-6 ]
[ 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
72
[ 28920-43-6 ]
[ 2133-34-8 ]
[ 136552-06-2 ]
Reference：
[1] Patent: US5064814, 1991, A,
73
[ 28920-43-6 ]
[ 497-19-8 ]
[ 2133-34-8 ]
[ 136552-06-2 ]
Reference：
[1] Patent: US5053392, 1991, A,
74
[ 146725-85-1 ]
[ 28920-43-6 ]
[ 159611-02-6 ]
Yield
Reaction Conditions
Operation 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,
75
[ 1115-74-8 ]
[ 28920-43-6 ]
[ 150114-97-9 ]
Yield
Reaction Conditions
Operation 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).
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 11, p. 3779 - 3792
79
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[ 152593-04-9 ]
[ 148101-51-3 ]
Yield
Reaction Conditions
Operation 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] 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
81
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[ 1172579-62-2 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
With hydrazine hydrate; In water; acetonitrile; at 0 - 20℃; for 14h;
9-H-Fluoren-9-ylmethyl carbazate (1) (0156) To a well-stirred solution of hydrazine hydrate (19 g, 386 mmol) in 150 mL of CH3CN/H2O (1/1, v/v), a solution of FmocCl (10 g, 38.65 mmol) in 600 mL CH3CN was added dropwise at 0 C. over 2 h. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 12 hours, concentrated in vacuo to 150 mL and filtered to yield the title compound as a white solid, which was washed with water and hexane and dried to a constant weight in vacuo (9.74 g, 99%): mp 172-173 C.; 1H NMR (DMSO) ? 4.08 (brs, 2H), 4.21 (t, J=7.2 Hz, 1H), 4.28 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.69 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.4 Hz, 2H), 8.36 (brs, 1H); 13C NMR (DMSO) ?? 47.7, 66.7, 121.1 (2C), 126.3 (2C), 128.1 (2C), 128.7 (2C), 141.7 (2C), 144.9 (2C), 159.2.
99%
With hydrazine; In diethyl ether; at 20℃;Cooling with ice;
Synthesis of compound 7 Synthesis of (9H-fluoren-9-yl)methyl hydrazinecarboxylate (Compound 1): To a round bottom flask containing hydrazine (9.3 g, 0.291 mol) in diethyl ether (anhydrous, 200 mL) at ice bath temperature, was added 9-fluorenylmethyl chloroformate (25 g, 97 mmol) in diethyl ether (anhydrous, 200 mL) dropwise in a two-hour time period. After addition, the reaction was allowed to room temperature and stirred overnight. The reaction was concentrated in vacuo to remove the volatiles. The white solid residue was washed with water (500 mL), filtered and dried to afford compound 1 (24.2 g, 95 mmol, 99 % yield).
98%
With hydrazine hydrate; In diethyl ether; at 0 - 20℃; for 0.5h;
The hydrazine hydrate (48.5 g, 970 mmol) was dissolved in diethyl ether (200 ml).Cooling at 0 C,A cooling solution was obtained, and FMOC-Cl (25 g, 97 mmol) was dissolved in diethyl ether (100 ml).And added dropwise to the cooling solution, stirred for 30 minutes, and then stirred at room temperature overnight.The obtained reaction mixture A was filtered, and the obtained solid was washed with water (3×100ml).The solvent was removed to give A1 (24.1 g, 95 mmol, 98%).
95%
With hydrazine hydrate; In water; acetonitrile; at 0 - 20℃;
At 0 C Fmoc chloride (2 mmol, 517.4 mg) dissolved in acetonitrile (30 mL) is added to hydrazine hydrate (20 mmol, 1 g, 10 equiv) dissolved in 10 mL of a 1/1 mixture water/acetonitrile. The reaction was stirred at 0 C for 2 h (formation of a white precipitate), then allowed to warm up to room temperature and stirred for an additional hour. The mixture was concentrated under vacuo and the precipitate was washed with water, cyclohexane, and then dried under vacuo to afford the pure title compound as a white solid (481 mg, 95%). Mp 174 C (lit. 172-173 C).refPreviewPlaceHolder30Comment1H NMR (DMSO) delta 4.07 (s, 2H), 4.18-4.31 (m, 3H), 7.32 (t, 2H, J=7.4 Hz), 7.41 (t, 2H, J=7.4 Hz), 7.68 (d, 2H, J=7.4 Hz), 7.88 (d, 2H, J=7.4 Hz), 8.34 (s, 1H); 13C NMR (DMSO) delta 46.6, 65.6, 120.1, 125.2, 127.0, 127.6, 140.7, 143.8, 158.2. MS (ESI) m/z: 255.1 [M+H]+.
81%
With hydrazine; In diethyl ether; at 0 - 20℃; for 0.5h;
Fmoc-CI (10 g, 38.7 MMOL) dissolved in diethyl ether (180 mL) was added dropwise to a solution of hydrazine hydrate (3.8 mL, 77 MMOL) in diethyl ether (100 mL) cooled in an ice-bath. White precipitation formed quickly. When all the FMOC-CI was added the resulting white suspension was warmed to rt. and stirred for 30 min. The white solid was isolated by filtration, washed with diethyl ether (x3) and water (x3) and dried in vacuo to give the desired product. Yield : 8 g (81%) ; Rf = 0.2 (PE: EA 1: 1 + a few drops of acetic acid); HPLC: Rt = 4.16 min. (>99%) ; H-NMR (DMSO-D6, 250 MHz) 8 8.34 (br, 1 H), 7.90-7. 88 (d, J = 7.3, 2H), 7.71-7. 68 (d, J = 7.3, 2H), 7.45-7. 29 (m, 4H), 4.30-4. 18 (m, 3H), 4.08 (br, 2H) ; 13C (DMSO-D6, 250 MHz) 8 158.2, 143.8, 140.7, 127.6, 127.0, 125.2, 120.0, 65.6, 46.7 ; ES-MS: mass CALCD for C15H15N202 255.1 (MH+). Found m/z 255.1.
With hydrazine; In diethyl ether; at 0 - 20℃; for 16.5h;
40 Hydrazine (18.0 mL, 213 mmol) was dissolved in 41 diethyl ether (240 mL) at 0 C.A solution of 42 Fmoc chloride (1) (12.0 g, 46.4 mmol) in diethyl ether (240 mL) was added to the hydrazine solution over a 30-minute period. The reaction mixture was stirred at room temperature for 16 h. The solution was evaporated, and 26 water (400 mL) and 15 ethyl acetate (400 mL) were added. The organic phase was washed with water (4×150 mL). The resulting suspension was evaporated. 43 Fmoc-hydrazine (2) was obtained as a white solid (13.92 g, 118%). 1H NMR (300 MHz, CDCl3) delta (ppm) 7.71-7.29 (m, 8H), 6.05 (s, 1H), 4.45 (d, 1H, J=6.8 Hz), 4.23 (t, 1H, J=8.3 Hz), 3.81 (s, 2H). 13C NMR (75.5 MHz, CDCl3) delta (ppm) 143.6, 141.3, 127.8, 127.1, 120.1, 67.3, 47.1 IR (CHCl3) v (cm-1) 1686, 1633, 1506, 1446.
1.92 g
With hydrazine hydrate; In water; acetonitrile; at 20℃; for 12h;
Synthesized according to literature procedures [12,16]. Briefly, a solution of Fmoc-Cl (2.00 g,7.73 mmol) in 120 mL of CH3CN was added dropwise over 2 h at 0 C to a solution of excess hydrazinehydrate (3.8 mL, 78.0 mmol, 10 equiv) in 26 mL of CH3CN/H2O (1:1, v/v). The solution was warmedto room temperature and left stirring for 12 h, prior to being concentrated in vacuo and filtered.The resulting solid was washed with water, followed by hexanes, to give 1.92 g of white solid in 98%yield. The resulting 9H-fluoren-9-ylmethyl hydrazinecarboxylate 3 (1.92 g, 7.55 mmol) was suspendedin acetone (50 mL) and heated at reflux for 2 h. Acetone was evaporated in vacuo and the hydrazoneintermediate was dissolved in THF (50 mL), treated with acetic acid (0.48 mL, 8.39 mmol, 1.1 equiv) andNaBH3CN (521 mg, 8.31 mmol, 1.1 equiv), and stirred for 2 h. The volatiles were removed and the crudewas dissolved in EtOAc (100 mL), washed with 1Maqueous KHSO4 (4 50 mL) and brine (2 50 mL),dried over Na2SO4, and concentrated to give a white solid. The obtained product was dissolved inEtOH and heated for 1 h, followed by evaporation of EtOH to yield N?-isopropyl-fluoren-9-ylmethylcarbazate 4 as a white solid (1.32 g, 59% yield) after column chromatography using a 20-100% gradientof EtOAc in hexanes. NMR (CDCl3) spectra matched literature values [12].
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 25 - 30℃;
Example 2 Synthesis of (2S, 4R)-1-[(9H-fluoren-9-ylmethoxy) carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid To a solution of (2S,4R)-4-hydroxy-L-proline (100 g) in tetrahydrofuran (200 ml) was added sodium bicarbonate (80 g), water (400 ml) and 9-fluorenylmethyloxycarbonyl (Fmoc) chloride (226 g) solution (in 200 ml THF) at 25-30 C. The reaction mixture was stirred at about 25-30 C. for about 10-12 h. After completion of reaction, water was added. Then the aq. reaction mass was washed with diisopropyl ether (DIPE) and acidified with 1N hydrochloric acid. The reaction mixture was stirred for about 2-3 hours. The solid was collected by filtration to give the 150 g of title compound as white solid. 1H NMR (300 MHz, DMSO-d6): delta 1.89-2.24 (m, 2H), 3.34-3.43 (m, 2H), 3:43-3.54 (m, 0.5H), 4.12-4.21 (m, 3H), 4.25 (s, 2H), 4.28-4.42 (m, 0.5H), 5.16 (brs, 1H), 7.29-7.34 (m, 2H), 7.38-7.65 (m, 21-1), 7.63-7.65 (m, 2H), 7.87-7.89 (m, 2H) Melting point:-188-190 C. Mass-(M+H):-354.33
7.83 g
With sodium carbonate; In 1,4-dioxane; water; at 20℃;Cooling with ice;
2.93 g of PRO-6 (L-hydroxyproline, CAS No.: 51-35-4, purchased from Energy Chemical, 22.4 mmol) was dissolved in 22.5 ml of 1, 4-dioxane and added with 34 ml of 10% (w/w) aqueous Na2CO3 solution. 6.954 g of Fmoc-Cl (9-fluorenylmethyl chloroformate, CAS No.: 28920-43-6, purchased from Energy Chemical, 26.8 mmol) was dissolved in 56.5 ml of 1, 4-dioxane, added into the above reaction mixture under an ice bath, and naturally warmed to room temperature for reacting overnight. The reaction liquid was poured into 150 ml of ice water, and extracted three times, each with 100 ml of methyl t-butyl ether, the resulting organic phases were discarded. The aqueous phase remained was adjusted to pH ? 5 with concentrated hydrochloric acid, extracted twice with 100 ml of ethyl acetate, and the obtained organic phases were combined and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 7.83 g of product PRO-7 as a white foamy solid. 1H NMR (400 MHz, DMSO-d6) delta 7.91 (t, J = 7.2 Hz, 2H) , 7.67 (d, J = 7.5 Hz, 2H) , 7.48 -7.39 (m, 2H) , 7.38 -7.27 (m, 2H) , 5.17 (s, 1H) , 4.27 (s, 2H) , 4.23 -4.11 (m, 2H) , 3.55 -3.41 (m, 3H) , 2.31 -2.10 (m, 1H) , 2.08 -1.88 (m, 1H) . HRMS (ESI) m/z calcd for C20H19NO5 [M-H] -352.1190, measured: 352.1033.
L. Cipolla, M. Rescigno, A. Leone, F. Peri, B. The Ferla, F. Nicotra Bioorg. Med. Chem. 2002, 10, 1639-1646 by protection of commercial O-carboxymethyl-hydroxylamine hemihydrochloride ((H2NOCH2COOH)2. HCl) with 9-fluorenylmethyl chloroformate (Fmoc-Cl) in dioxane in the presence of Na2CO3 (77%) followed by reaction of the acid obtained as an intermediate product (FmocNHOCH2COOH) with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide (DCC) in an ethyl acetate/dioxane mixture (yield: 93%). The physical and spectroscopic characteristics of the 2 compounds are described.
With pyridine; In dichloromethane; at 0 - 20℃; for 24h;
Tert-butyl 2-hydroxy-acetate (2.5 g) was dissolved in a mixture of pyridine (15 ml) and dichloromethane (DCM, 30 ml). Then Fmoc-chloride (5 g) in dry DCM (15ml) was added dropwise at 0 C. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the residue was redissolved in DCM (40 ml), washed with 1M sodium bicarbonate solution (20 mL) twice, brine solution (20 ml) twice, dried over anhydrous magnesium sulfate and concentrated. The obtained Fmoc-glycolic acid tert-butyl ester (4 g) was dissolved in trifluoroacetic acid (TFA), triisopropylsilane (TIS) and water (95/2.5/2.5, v/v/v, 15 mL) and stirred for 120 min. The solvent was removed under vacuum and the viscous residue was redissolved in 5% sodium bicarbonate solution (150 ml), washed with diethyl ether (75 ml) 3 times. The aqueous solution was then mixed with ethyl acetate (45 mL) and acidified with 40% phosphoric acid to pH = 2 at 0 C. The organic layer was collected and dried with anhydrous magnesium sulfate. The solvent was removed under vacuum to give the final product Fmoc-glycolic acid (Fmoc-GA).
With pyridine; In dichloromethane; at 0 - 20℃; for 24h;
Tert-butyl 2-hydroxy-acetate (2.5 g) was dissolved in a mixture of pyridine (15 ml) and dichloromethane (DCM, 30 ml). Then Fmoc-chloride (5 g) in dry DCM (15ml) was added dropwise at 0 C. The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum and the residue was redissolved in DCM (40 ml), washed with 1M sodium bicarbonate solution (20 mL) twice, brine solution (20 ml) twice, dried over anhydrous magnesium sulfate and concentrated. The obtained Fmoc-glycolic acid tert-butyl ester (4 g) was dissolved in trifluoroacetic acid (TFA), triisopropylsilane (TIS) and water (95/2.5/2.5, v/v/v, 15 mL) and stirred for 120 min. The solvent was removed under vacuum and the viscous residue was redissolved in 5% sodium bicarbonate solution (150 ml), washed with diethyl ether (75 ml) 3 times. The aqueous solution was then mixed with ethyl acetate (45 mL) and acidified with 40% phosphoric acid to pH = 2 at 0 C. The organic layer was collected and dried with anhydrous magnesium sulfate. The solvent was removed under vacuum to give the final product Fmoc-glycolic acid (Fmoc-GA).
1 -[(9H-fluoren-9-ylmethoxy)carbonyl]-<strong>[5382-49-0]1,2,3,4-tetrahydroquinoline-6-carboxylic acid</strong> EPO <DP n="100"/> To a mixture of I^S^-tetrahydroquinoline-theta-carboxylic acid (1.03g, 5.8mmol) in 1 ,4-dioxane (12ml) and 0.5M aqueous sodium hydroxide solution (12ml) was added 9- fluorenylmethoxycarbonyl chloride (1.68g, 6.5mmol). The mixture was partitioned between 1 M HCI (aq) and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with water then brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1, 2,3,4- tetrahydroquinoline-6-carboxylic acid as a white solid (2.Og; 86%).
86%
With sodium hydroxide; In 1,4-dioxane; water;
.15 1-[(9H-fluoren-9-ylmethoxy)carbonyl1-1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid; To a mixture of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (1.03 g, 5.8 mmol) in 1 ,4-dioxane (12 ml) and 0.5M aqueous sodium hydroxide solution (12 ml) was added 9- fluorenylmethoxycarbonyl chloride (1.68 g, 6.5 mmol). The mixture was partitioned between 1 M HCI (aq) and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with water then brine and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1 , 2,3,4- tetrahydroquinoline-6-carboxylic acid as a white solid (2.Og; 86%).
76%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃;
A mixture of 1 ,2,3,4-tetrahydroquinoline-6-carboxylic acid (5 g, 28.2 mmol) in 1 ,4-dioxane (30 ml.) and 0.5 M aqueous sodium hydroxide solution (30 ml.) was treated with 9-fluorenylmethoxycarbonyl chloride (8.3 g, 31 mmol) and stirred at RT overnight. The mixture was partitioned between 1 M HCI (50 ml.) and dichloromethane (50 ml_). The aqueous layer was extracted with dichloromethane (3 x 20 ml.) and the combined organic layer was washed with water (30 ml.) then brine (30 ml.) and dried over sodium sulfate. The solvent was removed in vacuo and the crude product purified by flash column chromatography on silica to give 1-[(9H-fluoren-9-ylmethoxy)carbonyl]-1 , 2,3,4- tetrahydroquinoline-6-carboxylic acid, 6S-23 (8.57 g, 76% yield) as a white solid. The material was used in the next step without further purification
(a) [(1R)-2-amino-1-methyl-2-oxoethyl]carbamic acid, 9H-fluoren-9-ylmethyl ester A solution of D-Alaninamide hydrochloride (3 g) in 10percent sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24 g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0 g of the subtitle compound. MS (ESI) BP 311 (+H)
To a solution of L-serine (methyl ether) hydrochloride (069) (1.0 g, 6.4 mmol) in water/dioxane (1:1, 80 ml) was added sodium hydroxide (768 mg, 19.2 mmol). After the mixture was stirred at room temperature for 30 minutes, it was cooled to 0 ° C., and a solution of 9-fluorenylmethyl chloroformate (1.65 g, 6.4 mmol) in dioxane (16 mL) was added dropwisely. The reaction mixture was allowed to stir at room temperature for another 4 hours. The solvents were then removed, the residue was diluted with water and the pH was adjusted to 1 with 1N HCl, and the aqueous layer was extracted with ethyl acetate (4.x.100 mL). The organic layers were concentrated under reduced pressure and placed under high vacuum to provide (070) (1.8 g) as confirmed by LC/MS (LCRS (MH) m/z: 342.13) which was used without further purification.
A solution of D-Alaninamide hydrochloride (3g) in 10percent sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0g of the subtitle compound. MS (ESI) BP 311 (+H)
2-Chloroquinoline-4-carboxylic acid (0.15 g, 0.72 mmol), 4-(aminomethylphenyl)boronic acid (0.16g, 0.87 mmol, 1.2 eq.) and Pd(PPh3)4 (42 mg, 0.036 mmol, 0.05 eq.) were added to a mixture of dioxane (2 mL) and a IM aq. solution OfK2CO3 (2 mL). The reaction mixture was degassed, sealed, and heated in the microwave at 140 0C for 15 min. The reaction mixture was cooled to 0 0C and a solution of (9-fiuorenylmethyl)chloro formate (0.46 g, 1.8 mmol) in dioxane (1 mL) was added dropwise. The reaction mixture was warmed to rt and stirred for 36 h. The reaction mixture was filtered and the solid was washed with DMSO, water and MeOH to give 2-[4-([(9H-fluoren-9-ylmeth- oxy)carbonyl]amino}methyl)phenyl]-quinoline-4-carboxylic acid (0.22 g, 60percent over two steps) as a crude solid, which was used directly in the next step without further purification, m/z 501.3 (M+eta)+.The crude 2-[4-([(9H-fluoren-9-ylmethoxy)carbonyl]-amino}methyl)phenyl]quinoline-4- carboxylic acid was reacted with tert-butyl [?ralpha"5f-4-(aminomethyl)cyclohexyl]methyl}- carbamate using essentially the same procedure as described for Example 1 (Method 1) to give the crude 9H-fluoren-9-ylmethyl [4-(4-[(?ralpha"5f-4-[(?ert-butoxycarbonyl)amino]- methyl} cyclohexyl)methyl]carbamoyl}quinolin-2-yl)benzyl]carbamate, which was used in the next step with no further purification, m/z 725.4 (M+eta)+.The crude 9H-fluoren-9-ylmethyl [4-(4-[(?ralpha"5f-4-[(?ert-butoxycarbonyl)amino]methyl}- cyclohexyl)methyl]carbamoyl}quinolin-2-yl)benzyl]carbamate (0.14 g, 0.19 mmol) was dissolved in DCM (4 mL) and treated with piperidine (1 mL). The reaction mixture was stirred at rt for 5 min. The reaction mixture was concentrated in vacuo to leave a residue. The residue was dissolved in DMSO and purified by etaPLC (Standard method D) to give <n="136"/>the title compound (35 mg, 32percent). 1R NMR (400 MHz, DMSO-J6) delta 8.77 (t, IH), 8.21 (d, 2H), 8.10-8.05 (m, IH), 8.03 (s, IH), 7.77 (t, IH), 7.61-7.46 (m, 4H), 6.74 (t, IH), 3.77 (s, 2H), 3.19 (t, 2H), 2.74 (t, 2H), 1.83 (s, 2H), 1.79 (d, 2H), 1.68 (d, 2H), 1.55-1.45 (m, IH), 1.33 (s, 9H), 1.30-1.23 (m, IH), 1.00-0.76 (m, 4H); m/z 503.4 (M+H)+.
With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 2h;
Example 25; Preparation of [3-(9H-Fluoren-9-ylmethoxycarbonylamino)propyl] methylcarbamicAcid tert-Butgamma Ester To a stirred solution of Lambda/-(3-aminopropyl)-iV-methylcarbamic acid tert-butyi ester(2.00 g, 10.6 mmol) and sodium carbonate (2.81 g, 26.6 mmol) in water (7 mL) at 0 0C was added a solution of 9-fluorenylmethyl chloro formate (2.75 g, 10.6 mmol) in 1,4- dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 h and then poured into water (10 mL). This mixture was extracted with diethyl ether (2 x 50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear oil. The oil was purified by silica gel flash chromatography (0-70% EtOAc in hexanes) to give the title compound (4.24 g, 77 % yield) as a clear oil (product contained a minor impurity, but was used without further purification).LC-MS (Method 2-90): Rt 4.05 min; mlz 411.2[M + H]+. 1H NMR (CD3OD) delta 7.96(d, 2H); 7.81(d, 2H), 7.56(t, 2H); 7.48(t, 2H);4.55 (d, 2H); 4.37(t, IH); 3.41(t, 2H); 3.27(t, 2H); 3.01(s, 3H); 1.89-1.85(m, 2H); 1.61(s, 9H).
With triethylamine; In dichloromethane; at -18℃;Cooling with ice;
Synthesis of Compound 2b A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at -18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100percent yield).
With pyridine; In tetrahydrofuran; at 20℃; for 16h;
Step 1 : 3-(Aminomethvl)-1 -N-boc-pvrrolidine (Astatech) (500 mg, 2.50 mmol) and pyridine (494 mg, 6.24 mmol, 2.50 eq) are charged in a round-bottom flask and dissolved in THF (70 mL). 9- Fluorenylmethyloxycarbonyl chloride (1 .29 g, 5.00 mmol, 2 eq) is added and the solution is stirred at RT for 16 h. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by flash column chromatography (100% hexanes to 100% EtOAc) to provide intermediate 1028A.
Trifluoroacetic acid (10 niL) was added to a solution of (5)-4-(tert-butoxycarbonyl) morpholine-3-carboxylic acid (5.00 g, 21.64 mmol) in CH2CI2 (40 mL) dropwise at 0 C and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated to dryness and the crude residue (2.80 g, 21.30 mmol) was dissolved in a mixture of dioxane (30 mL) and water (10 mL). The suspension was cooled to 0 C, FMOC-C1 (6.60 g, 25.60 mmol) and K2C03 (11.60 g, 84.2 mmol) were added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, diluted with water (20 mL) and acidified with 1M aqueous HC1 (30 mL) to pH 2-3. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine solution (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford the title compound (6.41 g) as colorless oil which was used in the next step without further purification.
With sodium hydroxide; In water; at 20℃; for 1h;Cooling with ice;
1-Methyl-L-tryptophan (1-Me-W; Aldrich Cat. No. 447439) is dissolved in the minimum amount of water and carefully treated with one equivalent of IN sodium hydroxide (NaOH) solution. Then 1.5 equivalents of FMOC chloride (Aldrich Cat. No. 23185) and 1.5 equivalents of IN NaOH are added alternately with stirring and cooling (ice-bath) under Schotten-Baumann conditions. After addition of both reagents is complete, the reaction mixture is stirred and allowed to warm slowly to room temperature for one hour. The reaction mixture is carefully acidified to pH about 2 with IN hydrochloric acid (HC1) to yield an off- white solid. This material is collected by vacuum filtration and dried in a vacuum dessicator to yield the desired product, N-FMOC-l-methyl-L-tryptophan. The material is stored at - 20°C until needed.
N-9-fluorenylmethoxycarbonyl-5-bromocytosine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.4%
With sodium carbonate; In 1,4-dioxane; at 10 - 20℃; for 3h;
<strong>[2240-25-7]5-<strong>[2240-25-7]bromocytosine</strong></strong> (95g, 0.5 mol), saturated sodium carbonate solution 200mL, 100 mL of dioxane was added the reaction flask was cooled to 10-15 °C dropwise loading fluorenylmethoxycarbonyl chloride (155.2g, 0.6mol mixed solu tion) and I00mL dioxane, the addition was complete, the reaction was warmed to room temperature and 3h, filtered, and the filter cake water (50mLX 2) washing and drying to give N- Fmoc-<strong>[2240-25-7]5-<strong>[2240-25-7]bromocytosine</strong></strong> (196.7g , 95.4percent).
(9H-fluoren-9-yl)methyl N-[(1s,4s)-4-[(tert-butoxy)carbonyl]amino}cyclohexyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 16.0833h;
A solution of 9/-/-fluoren-9-ylmethyl carbonochloridate (4.04 g, 15.6 mmol) in THF (30 ml) was added dropwise over 5 min to a cooled (0 C) mixture of te/f-butyl A/-[(1 s,4s)-4- aminocyclohexyl]carbamate (3.35 g, 15.6 mmol) and aqueous sodium carbonate solution (1 M, 30 ml, 30 mmol) in THF (60 ml). The reaction was allowed to warm to RT then left to stir at RT for 16 h. The reaction mixture was diluted with water (100 ml) then extracted with EtOAc (100 ml). The organic phase was washed with water (100 ml) and brine (50 ml) then dried over Na2S04 and concentrated in vacuo to afford the product as a pale beige foam (6.71 g, 91 %). 1 H NMR (500 MHz, DMSO-cfe) delta 7.92 - 7.83 (m, 2H), 7.74 - 7.56 (m, 2H), 7.45 - 7.36 (m, 2H), 7.36 - 7.28 (m, 2H), 7.17 (d, J = 5.4 Hz, 1 H), 6.70 - 6.58 (m, 1 H), 4.44 - 4.19 (m, 3H), 3.43 - 3.33 (m, 2H), 1.65 - 1.21 (m, 17H). LC/MS (System A): m/z (ESI+) = 459 [M+Na+], Rt = 1.35 min, UV purity = 93%.
(R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In 1,4-dioxane; at 20℃;Inert atmosphere;
To a solution of <strong>[7729-30-8](R)-azetidine-2-carboxylic acid</strong> (200 mg, 2 mmol) and potassium carbonate (138 mg, 1 mmol) in 1 : 1 dioxane (1 mL) under nitrogen was added 9-fiuorenylmethyl chloroformate (435 mg, 1.68 mmole) in dioxane (3 mL) and the resulting mixture was stirred at room temperature ovemight. The resultant reaction mixture was poured onto 10% aqueous sodium bicarbonate and washed with ether (3X). The ether washes were discarded. The aqueous phase was acidified to pH = 2 with 10% aqueous potassium sulfate/10% sodium sulfate buffer and extracted with DCM (3X). The combined DCM extracts were dried over sodium sulfate and concentrated in vacuo to afford (R)-l-(((9H-fluoren-9-yl)methoxy)carbonyl)azetidine-2-carboxylic acid (488 mg, 90% yield) as a white foam. MS (ESI) m/z 346.1 [M + Na]+.
tert-butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)(4-bromo-2-chloro-3-methylbenzyl)amino)ethyl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 59A tert-butyl 4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)(4-bromo-2-chloro-3-methylbenzyl)amino)ethyl)piperazine-1-carboxylate To a mixture of Example 10A (3.13 g) in dichloromethane (143 mL) with <strong>[192130-34-0]tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate</strong> (3.69 g) was added acetic acid (3.84 mL), sodium cyanoborohydride (1.685 g) and methanol (35.7 mL). The mixture was stirred at ambient temperature for 30 minutes. 9-Fluorenylmethyl chloroformate (4.16 g) was added and stirring was continued for another hour. Triethylamine (15 mL) was added, and the material that formed were redissolved with methanol (50 mL). The resulting mixture was concentrated onto silica gel and purification by silica gel chromatography on a CombiFlash® Teledyne Isco system using a Teledyne Isco RediSep® Rf gold 220 g silica gel column (eluting with 0-70percent ethyl acetate/heptane) provided the title compound. LC/MS (APCI) m/z 670.1 (M+H)+.
General procedure: The N-FMOC derivatizedracemic and L-amino acids and methyl esters were preparedaccording to conventional methods.22 Racemic or L-alpha-amino acid (5 mmol) was dissolved in 10% aqueoussodium carbonate solution (12.5 mmol). Dioxane (7.5 mL)was then added and the mixture was stirred in an ice-bath.After that, 9-FMOC chloride (5 mmol) was added slowlyand stirred at room temperature for 5 h. Now, the reactionmixture was poured into water and extracted with ether.The aqueous solution obtained was acidified with c-HCl inan ice-bath. Finally, the resulting N-FMOC alpha-amino acidwas filtered and dried under vacuum. In order to prepareracemic or L-FMOC alpha-amino acid methyl ester, the correspondingFMOC alpha-amino acid (1 mmol) synthesized in theprevious step was dissolved in 5 mL of anhydrous methanolwith N,N0-dicyclohexylcarbodiimide (1.1 mmol). Themixture was stirred at room temperature for 12 h, filteredand dried under vacuum to get N-FMOC alpha-amino acidmethyl ester.
4-tert-butyl 1-(9H-fluoren-9-ylmethyl) 2-(hydroxymethyl)piperazine-1,4-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With sodium carbonate; In 1,4-dioxane; water; at 0 - 30℃; for 12h;Inert atmosphere;
At 0C , sodium carbonate (0.99g, 9.2mmol) with FMOC chloride (1.5g, 5.6mmol) was added to <strong>[301673-16-5]3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester</strong> 6a (1.0 g, 4.6mmol) in dioxane (15mL) and water (5mL) was stirred at rt for 12 h.The solvent was removed and concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 mL), separated, the organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography Analysis [petroleum ether / ethyl acetate (v / v) = 3/1] to give the title compound 6b (1.6g, 79% yield) as a colorless oil.
In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product was dissolved in 1000 ml of ethanol, and 400 g of 30% NaOH solution was added dropwise.After the addition is completed, the mixture is heated to reflux, and the TLC is monitored. The etherification intermediate disappears completely and the temperature is lowered.The pH was adjusted to 9 with hydrochloric acid, and 259 g of Fmoc-Cl was added dropwise to dissolve in 1000 ml of ethanol solution.If the pH has dropped, add sodium bicarbonate and keep it at around 8.TLC was monitored until the free amino intermediate disappeared. Adjust the pH to 1-2 with hydrochloric acid,Distill the ethanol, add 1000 ml of water, and extract three times with ethyl acetate 500*3.Wash twice with saturated brine and concentrate ethyl acetate to give 288 g of crude material.Recrystallization from 1000 ml of ethyl acetate gave 203 g of product[2-[1-(Fmoc-Amino)ethoxy]ethoxy]acetic acid, yield 52.68%.
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