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 82911-69-1 * 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] Organic Preparations and Procedures International, 2002, vol. 34, # 5, p. 531 - 537
[2] Chinese Journal of Chemistry, 2010, vol. 28, # 8, p. 1508 - 1509
17
[ 27473-62-7 ]
[ 82911-69-1 ]
[ 135944-07-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 1, p. 224 - 236
[2] Journal of the American Chemical Society, 2003, vol. 125, # 23, p. 6852 - 6853
18
[ 82795-51-5 ]
[ 82911-69-1 ]
[ 135944-09-1 ]
Reference：
[1] Chemical Biology and Drug Design, 2013, vol. 82, # 4, p. 429 - 437
19
[ 82911-69-1 ]
[ 1499-56-5 ]
[ 122350-59-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2334 - 2344
Stage #1: With sodium hydrogencarbonate In water; acetonitrile at 20℃; Stage #2: With hydrogenchloride In water; acetonitrile
1- (((9H-Fluoren-9-yl)methoxy)carbonylamino)cyclopentanecarboxylic acid(compound 4 of example A): Fmoc-OSu (3.13 g, 9.3 mmol) was added to a solution of 1- aminocyclo- pentanecarboxylic acid (1.0 g, 7.8 mmol) and NaHC03 (1.63 g, 19.4 mmol) in acetonitrile/water (100 mL, 1 : 1). The reaction mixture was stirred at room temperature overnight. Most of the solvent was removed under reduced pressure and the resulting mixture was adjusted to pH = 2 with 2 N HCI and extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EA = 20: 1) to afford compound 4 of example A (0.75 g, 28percent yield) as a white solid.
Reference：
[1] Journal of the American Chemical Society, 2000, vol. 122, # 37, p. 8898 - 8909
[2] Patent: WO2012/119941, 2012, A1, . Location in patent: Page/Page column 110
[3] Journal of the American Chemical Society, 2003, vol. 125, # 23, p. 6852 - 6853
[4] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 18, p. 5694 - 5706
31
[ 82911-69-1 ]
[ 146803-41-0 ]
Reference：
[1] Patent: WO2018/175927, 2018, A2,
32
[ 82911-69-1 ]
[ 146552-76-3 ]
[ 150308-80-8 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 3, p. 502 - 506
[2] Journal of Peptide Science, 2013, vol. 19, # 2, p. 65 - 73
[3] Organic Letters, 2001, vol. 3, # 9, p. 1331 - 1334
[4] Helvetica Chimica Acta, 2007, vol. 90, # 9, p. 1651 - 1666
[5] Journal of Peptide Science, 2012, vol. 18, # 3, p. 155 - 162
33
[ 82911-69-1 ]
[ 4425-82-5 ]
[ 150308-80-8 ]
Reference：
[1] Journal of the American Chemical Society, 2001, vol. 123, # 21, p. 5140 - 5141
34
[ 4378-10-3 ]
[ 82911-69-1 ]
[ 117872-75-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 5, p. 621 - 624
35
[ 82911-69-1 ]
[ 141-43-5 ]
[ 105496-31-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine In tetrahydrofuran at 20℃;
Into a 2000-mL round-bottom flask was placed a solution of 2-aminoethan-1-ol 7a (30 g, 491 mmol) in THF (600 mL), Fmoc-OSu (166 g, 491 mmol), and NEt3 (199 g, 1 .97 mol). The resulting solution was stirred overnight at rt. The mixture was concentrated under vacuum and purified by silica gel chromatography (ethyl acetate/petroleum ether), giving 7b (130 g, 93percent) as a white solid.
93%
With triethylamine In tetrahydrofuran at 20℃;
j0607] Into a 2000-mE round-bottom flask was placed a solution of 2-aminoethan-1-ol 7a (30 g, 491 mmol) in THF (600 mE), Fmoc-OSu (166 g, 491 mmol), and NEt3 (199 g, 1.97 mol). The resulting solution was stirred overnight at it. The mixture was concentrated under vacuum and purified by silica gel chromatography (ethyl acetatepetroleum ether), giving 7b (130 g, 93percent) as a white solid.
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 47, p. 16683 - 16688
[2] Tetrahedron Letters, 2008, vol. 49, # 41, p. 5890 - 5893
[3] Patent: WO2015/51045, 2015, A2, . Location in patent: Page/Page column 160
[4] Patent: US2016/215288, 2016, A1, . Location in patent: Paragraph 0602; 0607
[5] Tetrahedron, 2007, vol. 63, # 28, p. 6577 - 6586
[6] RSC Advances, 2015, vol. 5, # 78, p. 63407 - 63420
[7] New Journal of Chemistry, 2012, vol. 36, # 8, p. 1556 - 1559
[8] Tetrahedron Letters, 2011, vol. 52, # 22, p. 2808 - 2811
36
[ 2002-24-6 ]
[ 82911-69-1 ]
[ 105496-31-9 ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate In water; acetonitrile at 20℃; for 0.5 h;
Example 12 Synthesis of 2: 1.44 Grams (0.015 Moles) of the HCl salt of 2-aminoethanol (1), 5.0 grams (0.018 Moles) of Fmoc-succinimide (2) were dissolved in 20 mL of acetonitrile and 20 mL of 10percent aqueous potassium carbonate solution in a round bottom flask and stirred at room temperature for 30 minutes. The reaction was quenched with a 10percent citric acid solution and concentrated to remove the acetonitrile. The aqueous layer was extracted 3 times with 30 mL of ethyl acetate and the organic layer was washed with brine twice with 20 mL. Although the compound was pure enough it was purified over silica gel with 2-5percent MeOH in DCM to give 2.5 grams of 2 in 64percent yield.
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 9, p. 1467 - 1474
42
[ 82911-69-1 ]
[ 42294-52-0 ]
[ 136050-67-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 1, p. 189 - 194
43
[ 82911-69-1 ]
[ 136050-67-4 ]
Reference：
[1] Protein and Peptide Letters, 2014, vol. 21, # 12, p. 1257 - 1264
44
[ 82911-69-1 ]
[ 133464-46-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 14, p. 2478 - 2484
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 9, p. 1467 - 1474
[3] Chemistry - A European Journal, 2005, vol. 11, # 9, p. 2756 - 2772
45
[ 82911-69-1 ]
[ 156-87-6 ]
[ 157887-82-6 ]
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 41, p. 5890 - 5893
[2] Tetrahedron, 2006, vol. 62, # 11, p. 2648 - 2656
[3] Russian Journal of Bioorganic Chemistry, 2006, vol. 32, # 4, p. 389 - 399
With sodium hydrogencarbonate; sodium carbonate In water; acetone
General procedure: Suitable N-protected amino alcohols (e.g. Fmoc and boc) can be obtained by reacting an amino alcohol with a desired protecting group precursor that protects the amine group with the desired protecting group Pgi . For example, N-Fmoc protected amino alcohols were prepared (in an Erlenmeyer flask) by suspending/dissolving Fmoc-O-Su in acetone (in a ratio of about 2.5-6 mL acetone per mmol of Fmoc-O-Su) with stirring. To this briskly stirring solution was added dropwise a solution of the amino alcohol (in a ratio of about 1 to 1 .2 eq. per mmol of Fmoc-O-Su) dissolved in acetone (in a ratio of about 0.4- 1 .2 mL acetone per mmol of the amino alcohol) and occasionally some water if the amino alcohol is not completely soluble in the acetone alone. When addition was complete, a solution containing NaHC03 and Na2C03 (in a ratio of about 1 to 1 .1 mmol NaHC03 and 0.5 to 0.55 mmol Na2C03 per mmol of Fmoc-O-Su) dissolved in deionized water (in a ratio of about 1 mL deionized water per 1 mL of acetone originally added to the Fmoc-O-Su) was added dropwise to the stirring reaction. After stirring and analysis by TLC (indicating complete reaction), a solution containing enough HCI (dissolved in about 0.3 mL water per 1 mL of acetone originally added to the Fmoc-O-Su) to completely neutralize the NaHC03 and Na2C03 was added dropwise over 30 minutes to one hour. The pH of the solution was then adjusted to approximately 4-5 (pH paper) by addition of 1 N HCI. The flask was then heated on a hot plate stirrer until the solid dissolved. The solution was then allowed to cool overnight and the product crystallized. The crystalline product was then collected by vacuum filtration. The product was then optionally recrystallized (usually by a mixture of acetonitrile and water) to the desired level of purity.
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 13, p. 2410 - 2417
[2] Organic Letters, 2006, vol. 8, # 22, p. 5009 - 5012
51
[ 82911-69-1 ]
[ 162558-25-0 ]
Reference：
[1] Patent: WO2017/2089, 2017, A1,
52
[ 82911-69-1 ]
[ 161420-87-7 ]
Reference：
[1] Journal of Peptide Science, 2017, vol. 23, # 3, p. 202 - 214
53
[ 16874-12-7 ]
[ 82911-69-1 ]
[ 133852-23-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃; for 18 h; Stage #2: With hydrogenchloride; water In 1,4-dioxane
[00284] tButyl N-(9-fluorenylmethoxycarbonyl)-L-tyrosine (83): To a stirring suspension of L-tyrosine O-f-butyl ester (LOOg, 4.21 mmol) and NaHCO3 (354 mg, 4.21 mmol) in 1 ,4-dioxane/water (1 :1 , 20 ml_) was added 9-fluorenylmethyl-N-succinimidyl carbonate (1.42 g, 4.21 mmol) and the resulting mixture was stirred for 18 hr at room temperature. The solvent was reduced to 10 ml. followed by the addition of 50 ml. of cold 1 N HCl. The product was extracted with ethyl acetate (3x). The organic extracts were washed with H2O and saturated aqueous NaCl then dried over Na2SO4. The solution was then concentrated after filtration to give the colourless solid 83 (1.94 g, 100percent) which was used without purification: 1H NMR (400 MHz, CDCI3) δ 1.43 (s, 9H), 2.97-3.06 (m, 2H), 4.21 (bt, J=7.1 , 1 H), 4.33 (dd, J=7.1 , 10.5, 1 H), 4.41-4.53 (m, 2H), 5.01 (bs, 1 H), 5.30, (d, J=8.2, 1 H), 6.73 (d, J=8.5, 2H), 7.00 (d, J=8.5, 2H), 7.31 (t, J=7.5, 2H), 7.40 (t, J=7.5, 2H), 7.57 (dd, J=3.3, 7.3, 2H), 7.76 (d, J=7.5, 2H).
95.8%
With N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 12 h;
10 mmol of L-tyrosine tert-butyl ester and10 molecules of N, N-diisopropylethylamine were dissolved in 75 mL of acetone,A 75 mL portion of acetone solution containing 9.8 mmol of Fmoc-OSu was added under stirring,Stirred at room temperature for 12 hours,And then separated by silica gel column chromatography,To obtain 4.4 g of product Fmoc-L-Tyr-OtBu (i.e., compound 3 in the above synthesis step)The yield was 95.8percent
Reference：
[1] Patent: WO2010/19511, 2010, A2, . Location in patent: Page/Page column 125-126
[2] Chemical Communications, 2011, vol. 47, # 15, p. 4439 - 4441
[3] Patent: CN104274839, 2017, B, . Location in patent: Paragraph 0036; 0038; 0040; 0041
[4] Angewandte Chemie - International Edition, 2009, vol. 48, # 11, p. 2024 - 2026
[5] Tetrahedron Letters, 1995, vol. 36, # 27, p. 4733 - 4736
[6] Chinese Journal of Chemistry, 2012, vol. 30, # 1, p. 53 - 58
54
[ 82911-69-1 ]
[ 133852-23-0 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2014, vol. 12, # 9, p. 1383 - 1386
55
[ 56-89-3 ]
[ 82911-69-1 ]
[ 135273-01-7 ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium carbonate In water; acetone at 50℃;
General procedure: Procedure adapted from that of Agan et al[28]. 407 mg Na2CO3 (3.82 mmol) was dissolved in 30 mL distilled water with stirring. 35 mL acetone was then added followed by 1.91 mmol L-cystine or L-selenocystine. The temperature of the reaction was brought to 50 °C and 1.93g (5.73 mmol) Fmoc-OSu was added in portions over 5 minutes. Heating was removed and the reaction was allowed to progress overnight. At the end of this time, 40 mL 1 HCl was added followed by 50 mL EtOAc. Following vigorous shaking, the layers were separated, and the organic portionwas dried over MgSO4 and concentrated in vacuo to afford the crude bis N-Fmoc dichalcogenide which was purified by recrystallization from CHCl3.
Reference：
[1] Protein and Peptide Letters, 2014, vol. 21, # 12, p. 1257 - 1264
56
[ 82911-69-1 ]
[ 37535-49-2 ]
[ 169555-95-7 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 11, p. 1335 - 1340
57
[ 721-90-4 ]
[ 82911-69-1 ]
[ 169624-67-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1995, # 4, p. 723 - 730
58
[ 62574-13-4 ]
[ 82911-69-1 ]
[ 139592-37-3 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 44, p. 9101 - 9109
[2] Journal of the American Chemical Society, 2017, vol. 139, # 36, p. 12559 - 12568
[3] Angewandte Chemie - International Edition, 2008, vol. 47, # 49, p. 9472 - 9475
[4] Journal of the American Chemical Society, 2012, vol. 134, # 18, p. 7648 - 7651
[5] ACS Chemical Biology, 2011, vol. 6, # 7, p. 753 - 760
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 36, p. 9558 - 9562[2] Angew. Chem., 2013, vol. 125, # 36, p. 9737 - 9741,5
61
[ 82911-69-1 ]
[ 170642-21-4 ]
[ 170642-27-0 ]
Reference：
[1] Journal of the American Chemical Society, 1997, vol. 119, # 4, p. 656 - 673
62
[ 2623-91-8 ]
[ 82911-69-1 ]
[ 170642-27-0 ]
Reference：
[1] Catalysis Science and Technology, 2018, vol. 8, # 19, p. 4994 - 5002
63
[ 82911-69-1 ]
[ 170642-21-4 ]
[ 90-82-4 ]
[ 170642-27-0 ]
Reference：
[1] Journal of the American Chemical Society, 1995, vol. 117, # 32, p. 8488 - 8489
64
[ 82911-69-1 ]
[ 172169-88-9 ]
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14743 - 14747[2] Angew. Chem., 2016, vol. 128, p. 14963 - 14967,5
65
[ 1197-18-8 ]
[ 82911-69-1 ]
[ 167690-53-1 ]
Reference：
[1] Organic Process Research and Development, 2001, vol. 5, # 4, p. 445 - 449
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 8, p. 1445 - 1449
[3] Biological Chemistry, 2015, vol. 396, # 1, p. 45 - 52
66
[ 56-91-7 ]
[ 82911-69-1 ]
[ 164470-64-8 ]
Yield
Reaction Conditions
Operation in experiment
23%
With sodium hydrogencarbonate In water; acetone at 20℃;
4-(Aminomethyl)benzoic acid (304 mg, 2.0 mmol) was stirred in 10percent Sodium hydrogencarbonate (sat aq, 10 ml). N-(9-Fluorenylmethoxycarbonyloxy)succinimide (680 mg, 2.0 mmol) and acetone (10 ml) was added and thick suspension was formed. Water (10 ml) was added to give an almost clear mixture that was stirred at room temperature over week-end. The mixture was washed with dichloromethane (a thick precipitate was formed in the water layer). The water layer was acidified with HCI (1 M) and extracted with dichloromethane (the precipitate moved into the dichloromethane layer). The precipitate was filtered off, dissolved in acetone and the insoluble material was filtered off. This latter filtrate was evaporated and dried on pump to yield a pure product (174 mg, 0.466 mmol, 23 percent). H NMR (400 MHz, DMSO-cfe) δ ppm 4.25 (m, 3 H) 4.38 (d, J^6.6 Hz, 2 H) 7.26 - 7.46 (m, 6 H) 7.70 (d, J=7.6 Hz, 2 H) 7.81 - 7.99 (m, 5 H) 12.85 (br. s., 1 H). 3C NMR (101 MHz, DMSO-cfe) δ ppm 43.55, 46.82, 65.33, 120.1 1 , 125.14, 126.96, 127.03, 127.59, 129.37, 140.78, 143.86, 144.90, 156.41 , 167.19.
Reference：
[1] Organic letters, 2001, vol. 3, # 26, p. 4239 - 4242
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 528 - 530
[3] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 1, p. 161 - 175
[4] Angewandte Chemie - International Edition, 2011, vol. 50, # 19, p. 4423 - 4427
[5] Patent: WO2015/63694, 2015, A1, . Location in patent: Page/Page column 39
[6] Chemical Communications, 2010, vol. 46, # 8, p. 1221 - 1223
[7] Organic Process Research and Development, 2001, vol. 5, # 4, p. 445 - 449
[8] Biological Chemistry, 2015, vol. 396, # 1, p. 45 - 52
67
[ 82911-69-1 ]
[ 56-12-2 ]
[ 116821-47-7 ]
Yield
Reaction Conditions
Operation in experiment
73%
With sodium hydrogencarbonate In water; acetonitrile at 20℃; for 3 h;
To a solution of GAB A (2.00 g, 19.4 mmol, in 14 mL 10percent NaHC03), Fmoc-OSu (4 g, 11.7 mmol, in 40 mL ACN) was added drop-wise over a period of 2 h at room temperature. The mixture was allowed to stir at room temperature for an additional hour. ACN was removed under reduced pressure and the aqueous layer acidified to pH 1 with 10percent HCl. The precipitate was washed with two 20 mL portions of water, 20 mL ethyl acetate and dried under reduced pressure. Fmoc-GABA was obtained as a white solid in 73percent yield (2.8 g). [65] NMR (DMSO-d6, 400 MHz): δ 7.89 (d, 2H, J = 7.4 Hz), 7.44 (d, 2H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.35 (s, 1H), 7.33 (t, 2H, J = 7.0 Hz), 4.30 (d, 2H, J = 7 Hz), 4.21 (t, 1H, J = 6.7 Hz), 3.01 ( q, 2H, J = 5.6 Hz ), 2.20 ( t, 2H, J = 7.3 Hz ), 1.63 (q, 2H, J = 7.1 Hz); 13C NMR (DMSO-d6, 100 MHz): δ 142.6, 139.4, 137.4, 128.9, 127.2, 124.2, 121.3, 120.0, 109.6, 77.5, 61.8, 51.1, 31.6; MS (ESI+): m/z (intensity), 325.8 ([M+H]+, 100percent).
Reference：
[1] Chemical Biology and Drug Design, 2015, vol. 86, # 4, p. 837 - 848
[2] Patent: WO2018/144880, 2018, A1, . Location in patent: Paragraph 64-65
68
[ 82911-69-1 ]
[ 167479-78-9 ]
[ 173963-93-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 7, p. 1372 - 1382
69
[ 82911-69-1 ]
[ 69955-57-3 ]
[ 167015-23-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 7, p. 1361 - 1371
Reference：
[1] Journal of Organic Chemistry, 2002, vol. 67, # 14, p. 4882 - 4892
[2] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9516 - 9529
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 18, p. 4858 - 4862[4] Angew. Chem., 2013, vol. 125, # 18, p. 4958 - 4962
73
[ 82911-69-1 ]
[ 132622-69-6 ]
[ 176486-63-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1771 - 1782
74
[ 82911-69-1 ]
[ 90495-99-1 ]
[ 141743-15-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium bicarbonate In tetrahydrofuran; water
4a N-(2-tert-Butoxycarbonylaminoethyl)-N-(9-fluorenylmethoxycarbonyl)aminoacetic acid 10.9 g (50 mmol) of N-(2-tert-butoxycarbonylaminoethyl)aminoacetic acid are stirred together with 50 ml of water, 11.3 g (135 mmol) of sodium hydrogen carbonate and 50 ml of tetrahydrofuran. Subsequently, 24.3 g (72 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide are added. The mixture is stirred at room tmeperature for 20 h and the salt removed by filtration; the filtrate is acidified and the phases separated, and the organic phase is then concentrated. Yield: 21.0 g (99percent)
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, # 2, p. 411 - 416
[2] Patent: US5681838, 1997, A,
75
[ 82911-69-1 ]
[ 183673-71-4 ]
[ 183673-66-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 18, p. 5694 - 5706
76
[ 1492-24-6 ]
[ 82911-69-1 ]
[ 135112-27-5 ]
Yield
Reaction Conditions
Operation in experiment
135g
With sodium hydrogencarbonate In tetrahydrofuran; water at 20 - 25℃; for 5 h;
The L-2-Aminobutyric acid (50.Og) and NaHCO3 (81.5g) was dissolved in water (750mL) at 20-25°C. Slowly Fmoc-OSu solution [171.7g of FMOC-OSU was dissolved in 1050 ml of THFj was added to the reaction mixture and stir for 5 hour. After reaction completion the reaction mixture was acidified with diluted HC1 up to pH<1.0 Filtered the obtained solid and dried.The obtained crude compound was recrystallized with toluene and dried to get the title compound. Yield: 135g;HPLC purity: 99.7percent
Reference：
[1] Journal of Peptide Science, 2017, vol. 23, # 3, p. 202 - 214
78
[ 82911-69-1 ]
[ 190656-01-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
With hydroxylamine hydrochloride; sodium hydrogencarbonate In water; ethyl acetate at 5 - 20℃; for 4 h;
Hydroxylamine hydrochloride (834 mg, 12 mmol) was dissolved in 40 mL of aqueous sodium hydrogen carbonate (2.2 g, 26 mmol), and cooled to 5 °C. N-(9-fluorenylmethoxycarbonyloxy) succinimide (Fmoc-OSu, 4.0 g, 12 mmol) dissolved in 40 mL ethyl acetate was added drop wise to the rapidly stirred hydroxylamine solution in an ice-bath and stirred for 4 h at room temperature. The reaction was monitored by TLC (ethyl acetate/hexane = 1:1, Rf = 0.4). After the water layer was removed, the organic layer was washed with saturated aqueous potassium hydrogen sulfate and brine. This organic extract was concentrated in high vacuum, and then N-Fmoc protected hydroxylamine (Fmoc-NHOH) was obtained as a white crystalline solid after trituration in hexane and stored overnight (80percent yield). Its structure was identified by 1H NMR (JNM-LA300 spectrometer, JEOL Ltd, Tokyo, Japan): (δH, CDCl3) 4.21 (1H, t, Fmoc CH), 4.32 (2H, d, Fmoc CH2), 7.28–7.43, 7.68, 7.86 (8H, m, Fmoc Ar. CH), 8.77 (1H, s, NH), 9.75 (1H, br s, OH). Fmoc-NHOH (2 equiv) was coupled to 2-chlorotrityl chloride (CTC) resin (1.43 mmol/g) with N,N’-diisopropylethylamine (DIPEA; 4 equiv) in dichloromethane (DCM) for 48 h. Fmoc-NHOH loaded CTC resin was treated with 10percent DIPEA/methanol (v/v) to block the remaining chloride groups. The resulting resin was filtered, and its loading level was 1.0 mmol/g, which was determined by Fmoc titration. After treating with 20percent piperidine/N-methyl-2-pyrrolidone (NMP) for 30 min to remove Fmoc groups, Fmoc-l-Pro-OH or Fmoc-l-Phe-OH (2 equiv) was coupled to the resin with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyl uronium hexafluorophosphate methanaminium (HATU), 1-hydroxy-7-azabenzotriazole (HOAt), and DIPEA (4 equiv) for 1.5 h at room temperature. After removing Fmoc groups by 20percent piperidine/NMP, HCA (2 equiv) was coupled to the amino acid anchored resin with benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP; 2 equiv), hydroxybenzotriazole (HOBt; 2 equiv) and DIPEA (3 equiv) for 5 h. The final product was cleaved from the resin by 30percent trifluoroacetic acid (TFA)/DCM (v/v) for 1 h. The resin was filtered, and the filtrate was concentrated in high vacuum, followed by precipitation with cold diethyl ether. The resulting HCA-Phe-NHOH and HCA-Pro-NHOH were identified by QUATTRO Triple Quardrupole Tandem mass spectrometer (Micromass & Waters, Milford, MA, USA) at National Instrumentation Center for Environmental Management (NICEM): CA-Phe-NHOH (m/z calcd: 343.1 [M+H]+; found: 343.0), CA-Pro-NHOH (m/z calcd: 293.1 [M+H]+; found: 293.1), DHCA-Phe-NHOH (m/z calcd: 345.1 [M+H]+; found: 345.1), DHCA-Pro-NHOH (m/z calcd: 295.1 [M+H]+; found: 295.1), pCoA-Phe-NHOH (m/z calcd: 327.1 [M+H]+; found: 327.1), pCoA-Pro-NHOH (m/z calcd: 277.1 [M+H]+; found: 277.0), FA-Phe-NHOH (m/z calcd: 357.1 [M+H]+; found: 357.1), FA-Pro-NHOH (m/z calcd: 307.1 [M+H]+; found: 307.0), SA-Phe-NHOH (m/z calcd: 387.1 [M+H]+; found: 387.0), SA-Pro-NHOH (m/z calcd: 337.1 [M+H]+; found: 337.1). Their purities were analyzed by RP-HPLC (Thermo Scientific Spectra System AS300; Thermo-Fisher, Waltham, MA, USA) using C18 reverse phase column (120 Å, 5 μm, 4.6 × 250 mm; AAPPTec, Louisville, KY, USA) using the following conditions: gradient elution with A: 0.1percent TFA/water, B: 0.1percent TFA/acetonitrile; from 10percent to 90percent over 30 min, a flow rate: 1.0 mL/min; detection: UV, 280 or 326 nm. HCA-Phe-NHOH were purified by a semi-preparative RP-HPLC column using an A to B gradient (A: 0.1percent TFA in water, B: 0.1percent TFA in acetonitrile; from 10percent to 90percent B over 30 min, at a flow rate of 4.0 mL/min) and freeze-dried.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 1136 - 1142
79
[ 82911-69-1 ]
[ 150-13-0 ]
[ 185116-43-2 ]
Reference：
[1] European Journal of Organic Chemistry, 2008, # 9, p. 1582 - 1588
[2] Biological Chemistry, 2015, vol. 396, # 1, p. 45 - 52
With sodium hydrogencarbonate In tetrahydrofuran; 1,2-dimethoxyethane; water
To a 200mL flask were added 5.0g BP103a (1.0eq), 50 ml water, 3.5 g NaHCO3(2.0eq), and stirred. A solution of 7.3 gFmoc-HOSU (1.0eq) in 50ml DME (ethylene glycol dimethyl ether) was added dropwise, it was replenished with 50ml THF, and stirred overnight. After the completion of the reaction under the monitor of TLC, the organic solvents were evaporated off, adjusted to pH=2 with dilute hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 7.6g compound BP103a06 as an off-white solid.
The In a 2L beaker, 300 ml of H-thr(tbu)-ol 60g, 500 ml of acetone, 45 g of sodium carbonate and 60 g of fmoc-osu were added. The reaction was completed, 1000 ml of ethyl acetate was added, 300 ml of water was washed with 300 ml of saturated brine, Dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and petroleum ether was added to obtain Fmoc-thr (tbu) -ol 118g, yield 86.4. HPLC 99.85percent. Refer to Figure 1-4.
Reference：
[1] Patent: CN106631900, 2017, A, . Location in patent: Paragraph 0015
89
[ 2013-12-9 ]
[ 82911-69-1 ]
[ 144701-24-6 ]
Reference：
[1] Catalysis Science and Technology, 2018, vol. 8, # 19, p. 4994 - 5002
90
[ 1002-57-9 ]
[ 82911-69-1 ]
[ 126631-93-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 3, p. 409 - 414
[2] Farmaco, 1999, vol. 54, # 4, p. 213 - 217
91
[ 82911-69-1 ]
[ 23356-96-9 ]
[ 148625-77-8 ]
Yield
Reaction Conditions
Operation in experiment
74%
for 1 h;
(1) Fmoc-L-Prolinol (Compound 2)L-prolinol (Compound 1) (0.61 g, 6.0 mmol) was dissolved in 70 ml of pure water, thus preparing an L-prolinol aqueous solution. N-(9-Fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (2.0 g, 6.0 mmol) was dissolved in 10 ml ofTHF. This THF solution was added to the L-prolinol aqueous solution, and this was stirred for 1 hour so as to react the L-prolinol and the Fmoc-OSu. The reaction solution was separated into a liquid fraction and a precipitate fraction. These fractions respectively were subjected to extraction with ethyl acetate, and organic layers respectively were collected therefrom. The thus-obtained organic layers were mixed together, and anhydrous sodium sulfate was added thereto to absorb moisture (hereinafter, this process is referred to as a “drying” process). The organic layers were filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by silica gel column chromatography (the eluent: hexane:ethyl acetate=1 :1). Thus, Compound 2 was obtained (1.4 g, yield: 74percent). The result of NMR analysis with respect to this compound is shown below.‘H-NMR (CDC13): ö7.77 (2H, d, J=7.7 Hz, Ar——H), 7.60 (2H, d, J=7.3 Hz,Ar—H), 7.40(2H,t, J=7.5 Hz,Ar—H), 7.31 (2H, t, J=7.6 Hz, Ar—-H), 4.40-4.50 (2H, m, COOCH2), 4.22(1H, t, J=6.5 Hz,Ar-CH), 3.20-3.80 (5H, m, H-5, H-6), 1.75(3H, m, H-3, H-4), 1.40 (1H, m, H-3).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2334 - 2344
97
[ 82911-69-1 ]
[ 187223-15-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2334 - 2344
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2334 - 2344
98
[ 5147-00-2 ]
[ 82911-69-1 ]
[ 171778-17-9 ]
Yield
Reaction Conditions
Operation in experiment
74.52%
With hydrogenchloride; sodium carbonate In water; ethyl acetate at 20 - 30℃;
The intermediate O-acetyl-L-serine is dissolved in 10percent by mass sodium carbonate, which is configured with anhydrous sodium carbonateIn sodium solution,The intermediate O-acetyl-L-serine is fully dissolved by stirring,A solution of 337 g (1.0 mol) of 9-fluorenylmethyl-N-succinimidyl carbonate dissolved in ethyl acetate (340 to 3400 ml) was added dropwise at 20-30°C.Add 30-60 minutes.The end of the drip,Stir for 1-8 hours at 20-30°C.Stably layered,Excess 9-fluorenylmethyl-N-succinimidyl carbonate is removed,The resulting aqueous phase is acidified with hydrochloric acid to pH = 1-2.Then it was extracted with ethyl acetate (30000 ml).The resulting oil phase is washed with water,Remove hydrochloric acid,The oil phase is concentrated to remove the ethyl acetateWhite crystals precipitate,It was filtered and dried to yield 273.0 g of the product Nα-9-fluorenylmethyloxycarbonyl-O-acetyl-L-serine.The total yield is 74.0percent.HPLC: 99.56percent, melting point: 161.5-162.2°C, ratioOptical rotation [α]D=-22.6 (C=1 DMF).
Reference：
[1] Patent: CN107501127, 2017, A, . Location in patent: Paragraph 0014; 0028; 0029; 0030
99
[ 82911-69-1 ]
[ 693-57-2 ]
[ 128917-74-8 ]
Yield
Reaction Conditions
Operation in experiment
43%
With sodium hydrogencarbonate In water; acetone at 20℃; for 20 h;
Fmoc-OSu (6.55 g; 21.9 mmol) and NaHCO3 (2.39 g; 28.5 mmol) were added to a solution of12-aminododecanoic acid (4.71 g; 21.9 mmol) in acetone (90 mL) and water (90 mL), and then themixture was stirred at rt for 20 h. The reaction mixture was quenched with concentrated HCl until pH4–5, and the resulting precipitate was extracted into with EtOAc (3 x 50 mL). The resulting combinedorganic phases were dried with Na2SO4, filtered, and evaporated. The crude product was purifiedon a silica column (Hexane–EtOAc 3:1) to provide Fmoc-12-aminododecanoic acid (4.20 g; 43percent) asa white solid. 1H NMR and 13C NMR were as reported [28].
A solution of H-Phe(4-I)-OH [1] (3 g, 10.31 mmol, 1 equiv) in dioxane (38 mL) was neutralized to pH 7-8 by addition of aqueous 10% Na2CO3. The reaction mixture was stirred atroom temperature for 30 min and Fmoc-OSu (3.65 g, 10.82 mmol, 1.05 equiv) was then added. After stirring for 24 h at room temperature, the reaction mixture was concentrated in vacuo. EtOAc(50 mL) was added, and the solution was washed with 1 N HCl (30 mL) and H2O (3 × 30 mL). The aqueous layers were combined and adjusted to pH 1 and the solution was washed with EtOAc (3 ×40 mL). All the organic layers were combined, washed with brine (30 mL) and dried overanhydrous magnesium sulfate. Removal of the solvent followed by digestion of the resultingprecipitate in pentane/diethyl ether (1:1, 60 mL) for 2 h afforded Fmoc-Phe(4-I)-OH [5] as a whitesolid (3.21 g, 61% yield). tR = 8.96 min (96% purity).
With sodium hydrogencarbonate; In water; acetone; at 20℃;
4-(Aminomethyl)benzoic acid (304 mg, 2.0 mmol) was stirred in 10% Sodium hydrogencarbonate (sat aq, 10 ml). N-(9-Fluorenylmethoxycarbonyloxy)succinimide (680 mg, 2.0 mmol) and acetone (10 ml) was added and thick suspension was formed. Water (10 ml) was added to give an almost clear mixture that was stirred at room temperature over week-end. The mixture was washed with dichloromethane (a thick precipitate was formed in the water layer). The water layer was acidified with HCI (1 M) and extracted with dichloromethane (the precipitate moved into the dichloromethane layer). The precipitate was filtered off, dissolved in acetone and the insoluble material was filtered off. This latter filtrate was evaporated and dried on pump to yield a pure product (174 mg, 0.466 mmol, 23 %). H NMR (400 MHz, DMSO-cfe) delta ppm 4.25 (m, 3 H) 4.38 (d, J^6.6 Hz, 2 H) 7.26 - 7.46 (m, 6 H) 7.70 (d, J=7.6 Hz, 2 H) 7.81 - 7.99 (m, 5 H) 12.85 (br. s., 1 H). 3C NMR (101 MHz, DMSO-cfe) delta ppm 43.55, 46.82, 65.33, 120.1 1 , 125.14, 126.96, 127.03, 127.59, 129.37, 140.78, 143.86, 144.90, 156.41 , 167.19.
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 3h;
To a solution of (2S)-3-amino-2-(tert-butoxycarbonylamino)propanoic acid (1 .0 g, 4.90 mmol) in THF (10.0 ml_) and water (10.0 ml_) were added FmocOSu (1 .82 g, 5.39 mmol) and NaHCC>3 (822.69 mg, 9.79 mmol). The mixture was stirred at 20 C for 3 hours. The reaction mixture was adjusted to pH 4 with citric acid solution. The solution was extracted with EtOAc (10.0 ml_ * 3). The organic layer was washed with brine (20.0 ml_), dried over Na2SC>4 and filtered. The filtrate was concentrated to give a residue. The residue was triturated with MTBE (10.0 ml_). The solution was filtered and the filter cake was dried under vacuum to give intermediate i-45a as a white solid. LCMS (ESI) m/z: [M+Na]+ = 449.3
In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product (Intermediate 3) was dissolved in 1000 ml of ethanol, and 350 g of 30% NaOH solution was added dropwise.After the completion of the dropwise addition, the mixture was heated to reflux, and monitored by TLC, the intermediate 3 was completely disappeared, and the temperature was lowered. The pH was adjusted to 9 with hydrochloric acid, and a solution of 337 g of Fmoc-Osu in 1000 ml of ethanol was added dropwise.If the pH has dropped, add sodium bicarbonate and keep it at around 8.TLC was monitored until Intermediate 4 disappeared. The pH was adjusted to 1-2 with hydrochloric acid, the ethanol was distilled off, 1000 ml of water was added, and the mixture was extracted three times with ethyl acetate 500*3, and washed twice with saturated brine.The ethyl acetate was concentrated to give 285 g of crude material.Recrystallization from 1000 ml of ethyl acetate gave 200 g of product[2-[1-(Fmoc-Amino)ethoxy]ethoxy]acetic acid, yield 51.9%.
With triethylamine; In water; acetonitrile; at 40.0℃; for 2.5h;
4. (2S, 4R) -Pro (4-OCO-NH-CH2-CH2-NH-Boc) -OH (5.0 g, 15 MMOL) is dissolved in a mixture of water (25 mi) and triethylamine (1.5 g, 15 MMOL) at 40 °C. A solution of Fmoc- OSu (4.65 g, 14 MMOL) in acetonitrile (25 ml) is added to the clear solution over 30 minutes and stirred for 2 hours. Then the reaction mixture is adjusted to pH 3 with hydrochloric acid (1 m, 13 mi) and stirred for a further hour. Acetonitrile is distilled off (40 °C, 80 mbar) and replaced by isopropyl acetate, affording a two-phase mixture. The lower aqueous phase is separated off, whilst the remaining organic layer is washed with water and distilled two times with replacement with isopropylacetate and then concentrated to a brownish foam. This foam is dissolved in ISOPROPYLACETATE (25 ML) and added dropwise to heptane (200 ML) whereby the product is precipitated. The solid is filtered, washed with isopropylacetate/heptane and dried in VACUO AT 40 °C to leave FMOC- (2S, 4R) -Pro (4-OCO-NH-CH2-CH2-NH-Boc)-OH.
(a) Synthesis of N1 -Fluoren-9-ylmethoxycarbonyl-N2 -succinimido-oxy-carbonylhydrazine (Fmoc-Azgly-OSu) A solution of 95percent aqueous hydrazine (1.28 ml) in acetonitrile (100 ml) was added dropwise during 2 hours at laboratory temperature to a stirred solution of fluoren-9-ylmethyl succinimido carbonate (Fmoc-OSu, 13.48 g) in acetonitrile (200 ml) and the mixture was stirred for a further 16 hours and then filtered. The solid residue was washed with a 1:1 v/v mixture of acetonitrile and diethyl ether and then with diethyl ether, and then dried. There was thus obtained fluoren-9-ylmethoxycarbonylhydrazine (Fmoc-hydrazine, 7.81 g). A further 0.96 g of this material was obtained by concentration of the filtrate and washings, filtration and crystallisation of the solid residue from ethanol.
N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H1-fluoren-9-ylmethoxy)carbonyl]amnino-L-alanine[ No CAS ]
[ 131570-56-4 ]
Yield
Reaction Conditions
Operation in experiment
88%
With pyridine; sodium bicarbonate; In water; N,N-dimethyl-formamide; acetone;
A. N-[(1,1-Dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine Bis(trifluoroacetoxy)iodobenzene (44.4 g, 103.2 mmol) was added to a solution of N-[(1,1-dimethylethoxy)carbonyl]-L-asparagine (Boc-Asn; 20.00 g, 86.1 mmol) in N,N-dimethylformamide/water (2:1; 300mL). The solution was stirred at room temperature for 30 min and then pyridine (10 mL, 123.6 mmol) was added. The solution was stiffed at room temperature for 4.5 h and then the solvent was evaporated (45 C., ~0.5 mm Hg). The residue was dissolved in acetone/water (1:1; 400 mL) and sodium hydrogen carbonate (31.8 g, 378.5 mmol) and 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-pyrrolidinedione (Fmoc-OSu; 34.74 g, 103.0 mmol) were added. The mixture was stirred at room temperature overnight, then the acetone was evaporated and the mixture was acidified to pH 1 with 1 M HCl and extracted with ethyl acetate (200 mL, then 100 mL). The combined organic layers were washed with brine (3*50 mL), dried (NaSO4), filtered, evaporated (45 C., ~0.5 mm Hg), and chromatographed (50-60% ethyl acetate/hexanes) to give N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H1-fluoren-9-ylmethoxy)carbonyl]amnino-L-alanine (32.33 g, 88%) as a white solid.
Anisomycin 19 (0.5 g 1.88 mmol) was suspended in 15 mL of acetonitrile. 9-Fluorenylmethyl succinimide (0.762 g 2.26 mmol) was added to the suspension. Upon addition, all solid dissolved. After stirring for 16 hours at room temperature, water was added to the reaction solution, and it was extracted with ethyl acetate. The organics were combined and dried over sodium sulfate. After filtration and concentration, purification was accomplished by column chromatography using 3:1 hexanes:ethyl acetate as the mobile phase. This gave 9-fluorenylmethyl carbamate 20 as foam in quantitative yields (0.916 g).
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of (2S,4 ?)-4-amino-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (30 g, 0.13 mol) in tetrahydrofuran (600 niL), aqueous sodium bicarbonate solution (Na2C03, 40 g, 0.377 mol in 240 mL H20) was added. The mixture was cooled to 0 C, and a solution of N- (9-Fluorenylmethoxycarbonyloxy)succinimide (12.3 g, 36.45 mmol) dissolved in tetrahydrofuran (20 mL) was then added. The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo to remove tetrahydrofuran. The aqueous layer was adjusted pH to 6 by hydrochloric acid (IN) and extracted with ethyl acetate and the organic layers were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude residue (2S,4 ?)- 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-l-(ieri-butoxycarbonyl)pyrrolidine-2- carboxylic acid (59 g) which was used to the next step without further purification as a white solid. MS(ESI) m/z 353.1 [M-Boc]+
<Synthesis of Ia, Ig and Ic>7.68 g (50 mmol) of N-methylamino butyric acid hydrochloride was dissolved in 50 mL of water, 4.20 g (50 mmol) of NaHCO3 was added, and all of these were agitated for 10 min. This solution was agitated for two days at room temperature, with 13.49 g (40 mmol) of 9-fluorenylmethyl succinimidyl carbonate, 100 mL of acetonitrile and 0.14 g (0.4 mmol) of tetrabutylammonium hydrogen sulfide added. After being concentrated under reduced pressure, the solution was diluted with methylene chloride and washed with water. After being concentrated under reduced pressure and subjected twice to azeotropy with dehydrated acetonitrile, the methylene chloride solution was subjected to azeotropy with dehydrated methylene chloride. A residue was dissolved in 200 mL of dehydrated methylene chloride, 4.13 g (20 mmol) of N,N'-dicyclohexylcarbodiimide was added at 0° C., and all of these were agitated for 2 hr at room temperature. After unnecessary materials were filtered out, this solution was concentrated under reduced pressure, and a residue A was obtained.A deoxynucleoside (dA, dG or dC, 20 mmol) was suspended in dehydrated pyridine, and these were concentrated under reduced pressure three times. A residue was suspended in 100 mL of dehydrated pyridine, 8.45 mL (66 mmol) of trimethylchlorosilane was added at 0° C., all of these were agitated for 1 hr at room temperature and then cooled to 0° C. again, and this solution was introduced into the residue A. A reaction mixture was agitated for 2 hr at room temperature. With 20 mL of water added under ice-cold conditions, the reaction mixture was then agitated overnight at room temperature. This solution was diluted with methylene chloride and washed with water. The methylene chloride solution was concentrated under reduced pressure, and a residue was purified by medium-pressure chromatography (dichloromethane-ethanol 19:1 --> 4:1) to yield desired products: 6.91 g (60percent) of Ia, 9.43 g (80percent) of Ig and 8.80 g (80percent) of Ic.
(R)-beta-hydroxy-N-(Fmoc)valine was prepared from (R)-beta-hydroxy-N-(Boc)valine (Dettwiler and Lubell, J. Org. Chem. 68:177-179, 2003) by removal of the Boc group (1:1 TFA(trifluoroacetic acid)/CH2Cl2), protection with Fmoc-OSu and NaHCO3 in aqueous acetone (Capatsanis et al. 1983), followed by purification by chromatography over silica gel (1:1:98 MeOH/HOAc/CHCl3) and lyophilization from aqueous acetonitrile (78percent yield).
[00105] HCI-L-Asp(OMe)-OH was synthesized according to the procedure of Gmeiner et a/."v Acetyl chloride (3.75 ml_, 52.6 mmol) was added to dry MeOH (13 mL) at 5 0C. The solution was stirred for 30 min in an ice bath and then added to a cooled (ice bath) suspension of L-aspartic acid (5 g, 37.6 mmol) in dry MeOH (13 mL). L-Aspartic acid was dissolved completely within a few minutes and the solution was stirred at 8-10 0C for 3 h, at which point the ice bath was removed and stirring was continued for 15 h. The reaction mixture was then poured into ice-cold Et2theta (70 ml.) and upon cooling and stirring, a white solid precipitated, which was filtered immediately and washed with ice-cold diethyl ether. The filtrate and washes were combined and evaporated to give residue from which a second crop was obtained by solubilization in MeOH (6 mL) and addition of cold Et2O (20 ml_). The white solid (5.5 g) was then dried under high vacuum for two hours and consisted in a 85/15 mixture of HCI-L-Asp(OMe)-OH and HCI-L-Asp(OMe)-OMe (as judged by 1H NMR) which was used as such for the next step. The mixture was dissolved in water (250 mL) and treated with sodium carbonate (9.9 g, 93.9 mmol). After complete dissolution of the solids, the solution was cooled to 5 0C in an ice bath and treated dropwise over 1 h with a solution of 9- fluorenylmethyl Lambda/-succinimidyl carbonate (Fmoc-OSu, 16.5 g, 48.8 mmol) in dioxane (500 mL). The reaction mixture was allowed to warm slowly to room temperature and stirring was continued for 15 h. The volatiles were then removed by rotary evaporation to furnish an aqueous solution, which was washed with EtOAc (3 x 200 mL), acidified with 12 N HCI to pH = 2 and extracted with EtOAc (3 x 200 mL). The later organic layers were combined, dried (MgSO4) and concentrated to give a colorless oil which yielded a white solid after trituration with hexanes for 2 h. The solid was filtered and dryed under vacuum to provide L-(2S)-gamma-methyl-Lambda/-(9- fluorenylmethoxycarbonyl)aspartate (15, 11.4 g, 82% over two steps) ; mp : 122-125 0C, [(X]23D 14.6 (c 1.05, CHCI3); 1H NMR (CDCI3, 400 MHz) delta 2.91 (dd, 1 H, beta-CHH, J = 17.4, 4.5), 3.11 (dd, 1 H, beta-CHH, J = 17.4, 4.5), 3.73 (s, 3H, CH3), 4.23 (t, 1 H, Fmoc-CH, J = 7.1 ), 4.38 (dd, 1 H, Fmoc-CHH, J = 10.5, 7.3), 4.44 (dd, 1 H, Fmoc-CHH, J = 10.5, 7.3), 4.71 (dt, 1 H, beta-CH, J = 8.5, 4.5), 5.92 (d, 1 H, NH, J = 8.5), 7.31 (dt, 2H, 2 x ar-H, J = 7.4, 1.1 ), 7.40 (t, 2H, 2 x ar-H, J = 7.4), 7.60 (d, 2H, 2 x ar-H, J = 7.1 ), 7.76 (d, 2H, 2 x ar-H, J = 7.5), 9.72 (s, 1 H, CO2H); 13C NMR (75 MHz, CDCI3) delta 37.1 (CH2), 47.9 (CH), 51.0 (CH), 53.1 (CH3), 67.3 (CH2), 120.9 (ar-CH), 126.0 (ar-CH), 128.0 (ar-CH), 128.6 (ar-CH), 142.1 (ar-C), 144.5 (ar-C), 157.0 (C=O), 172.5 (C=O), 176.2 (C=O); HRMS calcd. for C20H19NO6Na [M+Na]+: 392.1104, found : 392.10984; Omax/cm"1 (KBr): 3376 (N-H), 3064 (O- H), 2948 (C-H), 1741 , 1738, 1695 (C=O), 1533 (N-H), 1449 (C-H alkyl), 1211 , 1 168 and 739.
In tetrahydrofuran; water; at 20℃; for 2.5h;Cooling with ice;
Example 101. Synthesis of CDP-phosphonamide-agent BSynthesis of Fmoc-NH-(CH2)2-PO(OH)2 2-Aminoethylphosphonic acid (5.0 g, 0.040 mol) will be dissolved in a tetrahydrofuran/ water mixture (1:1) (40 mL). To the mixture, Fmoc N- hydroxysuccinimide ester (16 g, 0.048 mmol) in THF (10 mL) will be added slowly in an ice bath and stirred for ½ h. It will be stirred at ambient temperature for an additional 2 h. The solvent will be removed under vacuum (Scheme 15).Scheme 15
In tetrahydrofuran; water; at 20℃; for 2.5h;Cooling with ice;
2-Aminoethylphosphonic acid (5.0 g, 0.040 mol) will be dissolved in a tetrahydrofuran/water mixture (1:1) (40 mL). To the mixture, Fmoc N-hydroxysuccinimide ester (16 g, 0.048 mmol) in THF (10 mL) will be added slowly in an ice bath and stirred for ½ h. It will be stirred at ambient temperature for an additional 2 h. The solvent will be removed under vacuum (Scheme 15).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃;
(A) 1 -(9/-/-fluoren-9-yl)methyl 5-terf-butyl hexahydropyrrolo[3,4-£>]pyrrole-1 ,5- dicarboxylateA solution of te/t-butyl hexahydropyrrolo[3,4-£>]pyrrole-5(1 /-/)-carboxylate (424 mg, 2 mmol), /V-(9-fluorenylmethoxycarbonyloxy) succinimide (600 mg, 1 .8 mmol) and DIPEA (310 mg, 2.4 mmol) in dioxane (20 mL) was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with EtOAc/H2O, separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 355 (M-boc+H)+.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃;
(A) 1 -(9/-/-fluoren-9-yl)methyl 5-terf-butyl hexahydropyrrolo[3,4-£>]pyrrole-1 ,5- dicarboxylate[0127] A solution of te/t-butyl hexahydropyrrolo[3,4-£>]pyrrole-5(1 /-/)-carboxylate (424 mg, 2 mmol), /V-(9-fluorenylmethoxycarbonyloxy) succinimide (600 mg, 1 .8 mmol) and DIPEA (310 mg, 2.4 mmol) in dioxane (20 mL) was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with EtOAc/H2O, separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 355 (M-boc+H)+.
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 20℃;
A solution of <strong>[132414-81-4]tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate</strong> (424 mg, 2 mmol), N-(9-fluorenylmethoxycarbonyloxy) succinimide (600 mg, 1.8 mmol) and DIPEA (310 mg, 2.4 mmol) in dioxane (20 mL) was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with EtOAc/H2O, separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 355 (M-boc+H)+.
7.68 g (50 mmol) of N-methylaminobutyrate hydrochloride was dissolved in 50 mL of water and 4.20 g (50 mmol) of NaHCO3 was added thereto and agitated for 10 minutes. Then, 13.49 g (40 mmol) of 9-fluorenylmethyl succinimidyl carbonate, 100 mL of acetonitrile and 0.14 g (0.4 mmol) tetrabutylammonium hydrogen sulfate were added to the solution and agitated at room temperature for 2 days. After concentrating the solution under reduced pressure, it was diluted by methylene chloride and washed with water. The methylene chloride solution was then concentrated under reduced pressure and subjected to azeotropy by means of dehydrated acetonitrile and then by means of dehydrated methylene chloride. The residue was dissolved in 200 mL of dehydrated methylene chloride and 4.13 g (20 mmol) of N,N?-dicyclohexylcarbodiimide was added and agitated at room temperature for 2 hours. After filtering the undissolved substance, the solution was concentrated under reduced pressure to obtain residue A. Dioxynucleoside (dA, dG or dC, 20 mmol) was suspended in dehydrated pyridine and an operation of concentrating it under reduced pressure was repeated three times. The residue was suspended in 100 mL of dehydrated pyridine and 8.45 mL (66 mmol) of trimethylchlorosilane was added thereto at 0° C. Then, the mixture solution was agitated at room temperature for 1 hour and subsequently cooled to 0° C. again before it was introduced to the residue A. The reaction mixture was agitated at room temperature for 2 hours. Then, 20 mL of water was added to the reaction mixture while the latter was being cooled with ice and the solution was agitated at room temperature overnight. The solution was diluted by methylene chloride and washed with water. The methylene chloride solution was concentrated under reduce pressure and the residue was purified by medium pressure chromatography (dichloromethane-ethanol 19:1?4:1) to obtain target products Ia, Ig and Ic in amounts of 6.91 g (60percent), 9.43 g (80percent) and 8.80 g (80percent), respectively.
With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 18h;pH 8 - 9;
General procedure: To 250 mL round-bottomed flask add 1a or 1c or 1g or 1h, 2.5 equiv Fmoc-OSu, 50 mL THF/H2O (1:1, v/v), pH of the solution was adjusted with saturated sodium carbonate to 8?9, and the reaction continued at room temperature for about 18h. After that, the solution was extracted twice with ether, and pH of aqueous layer was adjusted with concentrated HCl to 5, white precipitation was obtain and dried in vacuum to gave corresponding product (2a or 2c or 2g or 2h).
With sodium carbonate; In tetrahydrofuran; water; at 20 - 25℃;pH 8.5 - 9;Large scale;
Example 1g Preparation of Crystalline N-Fmoc-(R)-alpha-methyl-alpha-aminodec-9-enoic acid 1.55 kg (1.0 equiv.) of 37 2-amino-2-methyl-dec-9-enoic acid.HCl (XIII) was suspended in 22 water and polished filtered to remove trace amounts of D-BPB.HCl from the solution. 17 Methyl tert-butyl ether was added and the aqueous product layer was extracted once with methyl tert-butyl ether. The aqueous product layer was re-charged and 7 tetrahydrofuran was added. A 20% aqueous sodium carbonate solution (2.75 equiv.) was charged to the mixture followed by Fmoc-OSu (0.89 equiv.). The mixture was allowed to react at 20-25 C. while maintaining the pH between 8.5-9.0 with additional amounts of the 20% 42 sodium carbonate solution until the reaction was complete. The mixture was pH adjusted down to pH 2.0-2.5 with conc. hydrochloric acid. Tetrahydrofuran was distilled off and methyl tert-butyl ether was charged. The layers were separated and the organic layer was washed 3 more times with additional water. The organic layer was then concentrated under vacuum and co-stripped with methyl tert-butyl ether. The resulting crude 4 oil was re-dissolved in methyl tert-butyl ether and cyclohexylamine (1.10 equiv.) was added slowly to obtain a pH range of 8.5-9.0. The slurry was agitated at ambient temperature (20-25 C.) for 3 hours and the solid product salt (XIV) was isolated by filtration. The solids were rinsed twice with additional methyl tert-butyl ether and the solid wetcake was recharged to a clean reactor. The wetcake was recrystallized from tetrahydrofuran and methyl tert-butyl ether to improve the purity. The solid salt was suspended in methyl tert-butyl ether and water and the pH adjusted to 2.0-2.5 with 25% sulfuric acid. The organic product layer was washed with water until all of the cyclohexylamine was removed. The organic product layer was concentrated and co-stripped with hexanes to a loose oil. The product (IIa) was then crystallized out of chloroform and hexanes and dried at <0 C. under a 1.0 cfm nitrogen sweep. Yield: 1.12 kg, 41.5%
With sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 20℃; for 168h;
7.03 g (50 mmol) of L-alpha,beta-diaminopropionic acid chloride was dissolved in 150 mL of distilled water, and 4.22 g (52.5 mmol) of sodium hydrogen carbonate was added to the solution, followed by agitating for 5 minutes. Subsequently, 300 mL of dimethoxyethane and 35.4 g (110 mmol) of N-(9-fluorenylmethoxycarbonyl)succinimide were added thereto, followed by agitating at room temperature for 1 week. The reaction mixture was concentrated under reduced pressure. The residue was suspended in 250 mL of distilled water and 250 mL of 36percent hydrochloric acid and dichloromethane, and the suspension was filtrated to obtain 24.57 g (90percent) of target product XIV.
formyl-Nle-Leu-Phe-Nle-Tyr-D-Lys(Fmoc)-D-Lys-NH2 trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1) Synthesis of Protected Peptide Resin (0201) Using the automated peptide synthesizer (Model 433A, Applied Biosystems, Inc.), the peptide was synthesized by a method which involves binding amino acids one by one from the carboxyl terminal sides according to the attached software (a solid-phase synthesis method). A protected peptide resin was synthesized. Using Fmoc-SAL resin (0.65 mol/g, 0.32 mmol scal) as the starting resin carrier, a peptide chain was successively extended according to the sequence, using, as raw materials, Fmoc-amino acid derivatives employed in a common Fmoc-peptide synthesis method. An Fmoc-amino acid derivative was set in the reaction vessel of the peptide synthesizer, and a solution of 1-[bisdimethylaminomethylene]-1H-benzotriazolium-3-oxido-hexafluorophosphate (HBTu) and 1-hydroxybenzotriazole (HOBt) as activators in dimethylformamide (DMF) was added to the reactor for reaction according to the software included with the synthesizer. The resulting resin was slowly stirred in piperidine-containing N-methylpyrrolidone to remove the Fmoc group, and the subsequent condensation of the amino acid derivative was conducted. (0202) Tyr (OBu), Lys (Boc) and Lys (p-methyltrityl(hereinafter Mtt)) were used as the amino acids each having a functional group in the side chain constituting the Fmoc amino acid derivatives used. Amino acids were successively added according to the sequence to provide a protected peptide resin of H-Leu-Phe-Nle-Tyr(OBu)-DLys(Mtt)-DLys(Boc)-SAL resin. Thereafter, formyl-Nle was condensed using DIC-HOOBt to construct a protected peptide resin having the sequence of interest. Consequently, Mtt group is selectively deleted using TFA-TIS-DCM (1/5/94, v/v), followed Fmoc group is condensed into the amide group in the side chain of Lys using Fmoc-OSu to provide a protected peptide resin having the sequence of formyl-Nle-Leu-Phe7Nle-Tyr(OBu)-DLys (Fmoc)-DLys(BOC)-SAL Resin. (0203) (2) Deprotection and Cutting Out from Resin (0204) The resulting protected peptide resin was treated at room temperature for 2 hours under TFA-TIS-H2O-(95/2.5/2.5, v/v) deprotection conditions for an ordinary method using trifluoroacetic acid to perform deprotection and cutting out of the peptide from the resin simultaneously. The carrier resin was filtered off from the reaction solution, followed by distilling off TFA. Ether was added to the residue, and the precipitate of the resulting crude product peptide was collected by filtration. (0205) (3) Isolation and Purification of Peptide (0206) The resulting crude product peptide was dissolved in acetonitrile and separated and purified in a water-acetonitrile system containing 0.1% trifluoroacetic acid using the HPLC separation device LC-8A-1 (column: ODS 30×250 mm), manufactured by Shimadzu Corporation, to provide a peptide fraction of interest; acetonitrile was distilled off before making a lyophilized powder to provide the product of interest in the form of its trifluoroacetate. (0207) To verify that the resulting peptide is the one of interest, EMI-MS and HPLC analyses were performed. (0208) HPLC analysis conditions: HPLC analysis conditions: (0209) Column: YMC A-302 (ODS, 150×4.6 mm I.D.) (0210) Column Temperature: 40 C. (0211) Eluants: Solution A: Water/0.1% TFA, Solution B: MeCN/0.1% TFA (0212) Gradient: A/B: 70/30?20/80, 0?25 min linear (0213) Flow Rate: 1.0 mL/min (0214) Detector: 220 nm (0215) Amount Injected: 1 muL (0216) Sample Solution: 1 mg/200 muL 25% MeCN/H2O (0217) Analysis Results: Analysis Results: (0218) Retention Time: 17.0 min, Purity: 98.4% (0219) m/z 1173.9 ([M+H]+ 1174.4), m/z 587.6 ([M+2H]2+ 587.7) (0220) Molecular Weight: 1173.4
formyl-Met-Leu-Phe-Nle-Tyr-D-Lys-D-Lys(Fmoc)-NH2 trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1) Synthesis of Protected Peptide Resin (0245) Using the automated peptide synthesizer (Model 433A, Applied Biosystems, Inc.), the peptide was synthesized by a method which involves binding amino acids one by one from the carboxyl terminal sides according to the included software (a solid-phase synthesis method). A protected peptide resin was synthesized. Using Fmoc-SAL resin (0.65 mol/g, 0.32 mmol scal) as the starting resin carrier, a peptide chain was successively extended according to the sequence, using, as raw materials, Fmoc-amino acid derivatives employed in a common Fmoc-peptide synthesis method. An Fmoc-amino acid derivative was set in the reaction vessel of the peptide synthesizer, and a solution of 1-[bisdimethylaminomethylene]-1H-benzotriazolium-3-oxido-hexafluorophosphate (HBTu) and 1-hydroxybenzotriazole (HOBt) as activators in dimethylformamide (DMF) was added to the reactor for reaction according to the software included with the synthesizer. The resulting resin was slowly stirred in piperidine-containing N-methylpyrrolidone to remove the Fmoc group, and the subsequent condensation of the amino acid derivative was conducted. (0246) As the amino acids each having a functional group in the side chain constituting the Fmoc amino acid derivatives used, Tyr (OBu), Lys (Boc) and Lys (Mtt) were used. Amino acids were successively added according to the sequence to provide a protected peptide resin of H-Leu-Phe-Nle-Tyr(OBu)-DLys(Boc)-DLys(Mtt)-SAL resin. Thereafter, formyl-Met was condensed using DIC-HOOBt to construct a protected peptide resin having the sequence of interest. Consequently, Mtt group is selectively deleted using TFA-TIS-DCM (1/5/94, v/v), followed Fmoc group is condensed into the amide group in the side chain of Lys using Fmoc-OSu to provide a protected peptide resin having the sequence of formyl-Met-Leu-Phe-Nle-Tyr(OBu)-DLys(Boc)-DLys(Fmoc)-SAL Resin. (0247) (2) Deprotection and Cutting Out from Resin (0248) The resulting protected peptide resin was treated at room temperature for 2 hours under TFA-TIS-H2O-(95/2.5/2.5, v/v) deprotection conditions for an ordinary method using trifluoroacetic acid to perform deprotection and cutting out of the peptide from the resin simultaneously. The carrier resin was filtered off from the reaction solution, followed by distilling off TFA. Ether was added to the residue, and the precipitate of the resulting crude product peptide was collected by filtration. (0249) (3) Isolation and Purification of Peptide (0250) The resulting crude product peptide was dissolved in acetonitrile and separated and purified in a water-acetonitrile system containing 0.1% trifluoroacetic acid using the HPLC separation device LC-8A-1 (column: ODS 30×250 mm), manufactured by Shimadzu Corporation, to provide a peptide fraction of interest; acetonitrile was distilled off before making a lyophilized powder to provide the product of interest in the form of its trifluoroacetate. (0251) To verify that the resulting peptide is the one of interest, EMI-MS and HPLC analyses were performed. (0252) HPLC analysis conditions: (0253) Column: YMC A-302 (ODS, 150×4.6 mm I.D.) (0254) Column Temperature: 40 C. (0255) Eluants: Solution A: Water/0.1% TFA, Solution B: MeCN/0.1% TFA (0256) Gradient: A/B: 70/30?20/80, 0?25 min linear (0257) Flow Rate: 1.0 mL/min (0258) Detector: 220 nm (0259) Amount Injected: 1 muL (0260) Sample Solution: 1 mg/200 muL 25% MeCN/H2O (0261) Analysis Results: (0262) Retention Time: 15.6 min, Purity: 96.7% (0263) m/z 1191.9 ([M+H]+ 1192.5), m/z 596.7 ([M+2H]2+ 596.7) (0264) Molecular Weight: 1191.5
formyl-Met-Leu-Phe-Nle-Tyr-D-Lys(Fmoc)-D-Lys-NH2 trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(1) Synthesis of Protected Peptide Resin (0287) Using the automated peptide synthesizer (Model 433A, Applied Biosystems, Inc.), the peptide was synthesized by a method which involves binding amino acids one by one from the carboxyl terminal sides according to the included software (a solid-phase synthesis method). A protected peptide resin was synthesized. Using Fmoc-SAL resin (0.65 mol/g, 0.32 mmol scal) as the starting resin carrier, a peptide chain was successively extended according to the sequence, using, as raw materials, Fmoc-amino acid derivatives employed in a common Fmoc-peptide synthesis method. An Fmoc-amino acid derivative was set in the reaction vessel of the peptide synthesizer, and a solution of 1-[bisdimethylaminomethylene]-1H-benzotriazolium-3-oxido-hexafluorophosphate (HBTu) and 1-hydroxybenzotriazole (HOBt) as activators in dimethylformamide (DMF) was added to the reactor for reaction according to the software included with the synthesizer. The resulting resin was slowly stirred in piperidine-containing N-methylpyrrolidone to remove the Fmoc group, and the subsequent condensation of the amino acid derivative was conducted. (0288) As the amino acids each having a functional group in the side chain constituting the Fmoc amino acid derivatives used, Tyr (OBu), Lys (Boc) and Lys (Mtt) were used. Amino acids were successively added according to the sequence to provide a protected peptide resin of H-Leu-Phe-Nle-Tyr(OBu)-DLys(Mtt)-DLys(Boc)-SAL resin. Thereafter, formyl-Met was condensed using DIC-HOOBt to construct a protected peptide resin having the sequence of interest. Consequently, Mtt group is selectively deleted using TFA-TIS-DCM (1/5/94, v/v), followed Fmoc group is condensed into the amide group in the side chain of Lys using Fmoc-OSu to provide a protected peptide resin having the sequence of formyl-Met-Leu-Phe-Nle-Tyr(OBu)-DLys(Fmoc)-DLys(BOC)-SAL Resin. (0289) (2) Deprotection and Cutting Out from Resin (0290) The resulting protected peptide resin was treated at room temperature for 2 hours under TFA-TIS-H2O-(95/2.5/2.5, v/v) deprotection conditions for an ordinary method using trifluoroacetic acid to perform deprotection and cutting out of the peptide from the resin simultaneously. The carrier resin was filtered off from the reaction solution, followed by distilling off TFA. Ether was added to the residue, and the precipitate of the resulting crude product peptide was collected by filtration. (0291) (3) Isolation and Purification of Peptide (0292) The resulting crude product peptide was dissolved in acetonitrile and separated and purified in a water-acetonitrile system containing 0.1% trifluoroacetic acid using the HPLC separation device LC-8A-1 (column: ODS 30×250 mm), manufactured by Shimadzu Corporation, to provide a peptide fraction of interest; acetonitrile was distilled off before making a lyophilized powder to provide the product of interest in the form of its trifluoroacetate. (0293) To verify that the resulting peptide is the one of interest, EMI-MS and HPLC analyses were performed. (0294) HPLC analysis conditions: HPLC analysis conditions: (0295) Column: YMC ODS-A (ODS, 150×4.6 mm I.D.) (0296) Column Temperature: 40 C. (0297) Eluants: Solution A: Water/0.1% TFA, Solution B: MeCN/0.1% TFA (0298) Gradient: A/B: 70/30?20/80, 0?25 min linear (0299) Flow Rate: 1.0 mL/min (0300) Detector: 220 nm (0301) Amount Injected: 1 muL (0302) Sample Solution: 1 mg/200 muL 50% MeCN/H2O (0303) Analysis Results: Analysis Results: (0304) Retention Time: 15.5 min, Purity: 98.0% (0305) m/z 1191.9 ([M+H]+ 1192.5), m/z 597.0 ([M+2H]2+ 596.7) (0306) Molecular Weight: 1191.5
2.3 Diethyl 2-thienyl malonate was saponified by sodium hydroxide,And then treated with L-acylaseAdd fmoc-osu and acetone, and sodium carbonate aqueous solution to adjust the pH value of 8-9 reaction, the reaction is completed after the solid solution is fmoc-thi-oh (save another use), the mother liquor cryopreservation.2.4 About 2L of the obtained mother liquor was added to a 5L three-necked flask, and then 1L of a mixture of hydrochloric acid and methanol was added. The mixture was heated to reflux for 60 hours. TLC was tracked and analyzed by NMR. After the basic reaction was completed, Fmoc-osu solid, and TLC tracking monitoring reaction process, the reaction is completed after the filter, the system with 500ml of ethyl acetate and petroleum ether mixed solvent washed 4 times, followed by hydrochloric acid acidification system pH value of 1 or so, and cooling Stir, resulting in 48 g of brown crystals.
9H-fluoren-9-ylmethyl N-[[3-chloro-6-fluoro-2-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate[ No CAS ]
9H-fluoren-9-ylmethyl N-[[3-chloro-2-fluoro-6-[(3-formyl-2-pyridyl)sulfanyl]phenyl]methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution <strong>[190011-87-1]3-chloro-2,6-difluoro-benzaldehyde</strong> (2.0 g, 12.88 mmol) in ethanol (80 mL, argon purged) was added sodium ethoxide (2.192g, 32.21 mmol) and 2-Mercapto-nicotinic acid(2.26 g, 12.88 mmol) at room temperature and the reaction mixture was heated to reflux for 4h.Progress of the reaction was monitored by TLC. After completion, volatiles were removed underreduced pressure to afford a mixture of 2-(6-chloro-3-fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylic acid and 2-(4-chloro-3-fluoro-2-formyl-phenyl) sulfanylpyridine-3-carboxylic acid(6 g, crude) as brown solid which was used as such in next step without further purification; To an ice-cooled solution of above mentioned mixture (6.0 g, crude) in DMF (25 mL) under argon atmosphere was added K2C03 (2.66 g, 19.24 mmol) and the reaction mixture was stuffed at 0 C for 30 mm. To the resulting reaction mixture was added Mel (1.198 mL, 19.248 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was diluted with water (100 mL) and the aqueous phase was extracted with ethyl acetate (50 mL x 3). Combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to get crude compound. The crude compound thus obtainedwas purified by flash-chromatography (10% ethyl acetate in hexane) to afford a mixture of methyl 2- (4-chloro-3 -fluoro-2-formyl-phenyl)sulfanylpyridine-3-carboxylate and methyl 2- (4- chloro-3-fluoro-2-formyl-phenyl) sulfanylpyridine-3-carboxylate (2.3 g, 57% over two steps) as yellow solid; To a stirred solution of of above mentioned mixture (2.3 g, 7.06 mmol) in dry THF (100mL) under argon atmosphere was added titanium(IV) ethoxide (4.027 g, 17.65 mmol) followedby tert-butyl sulphinamide (2.139 g,17.65 mmol) and the resulting reaction mixture was stirred at room temperature for lh and heated to 60C for 4h. Then the reaction mixture was cooled to room temperature, poured onto water (100 mL) and filtered through celite bed. Celite bed was washed with ethyl acetate. Organic layer was separated off and the aqueous layer was extractedwith ethyl acetate (50 mL x 3). Combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude compound. The crude compound thus obtained was purified by flash-chromatography (25% ethyl acetate in hexane) to afford a mixture of methyl 2- [2- [(E)-tert-butylsulfinyliminomethyl] -4-chloro-3 -fluoro-phenyl] sulfanylpyridine-3- carboxylate and methyl 2- [2- [(E)-tert-butylsulfinyliminomethyl] -4-chloro-3-fluoro-phenyl]sulfanylpyridine-3-carboxylate (1.9 g, 63%) as viscous oil; To an ice-cooled solution of above mentioned mixture (1.9 g, 4.43 mmol) in THF (50 mL) under argon atmosphere was added LAH (0.42 g, 11.07 mmol) portion wise and the reaction mixture was stined at 0C for 1 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ethyl acetate and saturated sodium sulfatesolution. Then the reaction mixture was filtered through celite and washed with EtOAc. Filtrate was concentrated to get a mixture of N-[[3-chloro-2-fluoro-6-[[3-(hydroxymethyl)-2- pyridyl] sulfanyl]phenyl] methyl] -2-methyl-propane-2- sulfinamide and N- [ [3-chloro-2-fluoro-6- [[3- (hydroxymethyl)-2-pyridyl] sulfanyl]phenyl] methyl] -2-methyl-propane-2-sulfinamide (1.6 g, 90%) as an off-white solid; To an ice-cooled solution of above mentioned mixture (1.6 g, 3.97 mmol) in DCM (50 mL) was added Dess Martin periodinane (2.128 g, 5.162 mmol) portion-wise and the reaction mixture was stined at room temperature for 2h under argon atmosphere. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM (50 mL) and saturated solution of sodium bicarbonate (50 mL). Organic layer was separated off and theaqueous layer was extracted with DCM (50 mL x 2). Combined organic layer was washed with sodium thiosulphate solution followed by brine. Volatiles were removed under reduced pressure to get a mixture of N- [ [2-fluoro-6- [(3-formyl-2-pyridyl)sulfanyl] -3-methyl-phenyl] methyl] -2- methyl-propane-2- sulfinamide and N- [[3-chloro-2-fluoro-6- [(3-formyl-2- pyridyl)sulfanyl]phenyl]methyl]-2-methyl-propane-2-sulfinamide (1.6 g, quan) as viscous oil; To an ice-cooled solution of above mentioned mixture (2.0 g, crude) in dioxane (20 mL) was added 4M HC1 in dioxane (30 mL) and the reaction mixture was stirred at room temperature for a period of 2 h. Progress of the reaction was monitored by LCMS. Volatiles were removed under reduced pressure to get the crude compound which was washed with diethyl ether (30 mL x 2) and dried to get a mixture of 2-[2-(aminomethyl)-4-chloro-3-fluoro-phenyl] sulfanylpyridine-3-carbaldehyde and 2- [2- (aminomethyl)-4-chloro-3-fluoro- phenyl]sulfanylpyridine-3-carbaldehyde (2.0 g, crude) as yellow solid; To a stirred suspension of above mentioned mixture (2.0 g, crude) in 5% sodium bicarbonate solution and ace...
3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With N-ethyl-N,N-diisopropylamine; In water; acetonitrile; at 20℃; for 10.0h;
To a solution of <strong>[66315-15-9]3-amino-4-(methylamino)benzoic acid</strong> (5) (0.50 g, 3.01 mmol) in H2O/MeCN (1:1, 6.26 mL) were added DIPEA (0.57 ml, 3.31 mmol) and Fmoc-OSu (1.02 g, 3.01 mmol) in MeCN (3.2 mL). The reaction mixture was stirred at room temperature for 10 h. The product was collected by filtration, washed with MeCN and dried to give Fmoc-<strong>[66315-15-9]3-amino-4-(methylamino)benzoic acid</strong> (0.72 g, 61 %) as a gray solid. 1H NMR (DMSO-d6, 500 MHz) delta: 2.74 (3H, s), 4.10-4.50 (3H, m), 6.57 (1H, d, J = 8.5 Hz), 7.20-7.50 (4H, m), 7.50-8.00 (6H, m), 8.71 (1H, brs). The 1H NMR spectrum of synthetic compound was identical to those of the reported compound from Dawson?s group.16
N-[(9H-fluoren-9-yl)methoxy]carbonyl}-S-propyl-L-homocysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.3%
A solution of NaOH (600 mg, 15 mmol) in 1 :1 mixture of water/EtOH (10 ml) was bubbled with nitrogen and heated at 40 °C. It was added with L-homocysteine (675.5 mg, 5 mmol), followed by propyl p-toluenesulfonate (1 .09 g, 5.05 mmol). The mixture was stirred under nitrogen at 40 °C for 1 .5 hours, then to room temperature overnight. EtOH was partially removed by rotary evaporation, and the residue was extracted with DCM (~ 30 ml). THF (10 ml) was added to the aqueous solution, followed by Fmoc- Osu (1 .7 g, 5 mmol). After the mixture was stirred for 1 hour, it was added with an additional amount of Fmoc-Osu (337 mg, 1 mmol). The reaction was continued for one more hour. THF was partially removed by rotary evaporation. The white suspension residue was directly purified through RPLC (150 g, 5 to 58 percent acetonitrile and water, using 0.1 percent TFA as modifier). Yield 1 .05 g, 50.3 percent. Ion found by LCMS: [M+1 ]+ = 400.
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 18h;
At 0 ° C,WillMethoxycarbonyl succinimide (Fmoc-OSu) (3.44 g, 33.7 mmol)Added with NaHCO3 (3.52g, 41.9mmol)And (R)-methyl 2-amino-2-(4-hydroxyphenyl)acetic acid methyl ester hydrochloride (5.04 g, 27.8 mmol)In a three-necked solution of THF (60 mL) / H 2 O (20 mL),The temperature was raised to room temperature and stirring was continued for 18 h.The THF was then concentrated under reduced pressure.Water is added to the aqueous phase until the solid dissolves.Then extracted with DCM (50 mL×2).The organic phases were combined and dried over anhydrous sodium sulfate.Concentrated under reduced pressure,A pale yellow solid (10 g, 100percent) was obtained.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;
To a stirred solution of 4-hydroxy-(Z))-phenylglycine (50.0 g, 0.299 mol) in methanol (500 mL) was added thionyl chloride (32.66 mL, 0.499 mol) at 0-5 °C. The mixture was then allowed to stir overnight at room temperature. Reaction mixture was concentrated under reduced pressure at 50 °C to get hydrochloride salt of ( ?)-amino-(4-hydroxyphenyl)acetic acid methyl ester. To the above obtained compound (40.0 g, 0.184 mol) was added tetrahydrofuran (400.0 mL) and triethylamine (56.3 mL, 0.404 mol), followed by 9- fluorenmethylsuccimidyl carbonate (68.2 g, 0.202 mol) at 0-5 °C. The mixture was then stirred at room temperature for 2 hours. Reaction mixture was concentrated under reduced pressure at 35 °C to get crude which was purified by column chromatography (silica gel 230- 400 mesh, ethyl acetate: n-hexane, 50: 50) to get ( ?)-[(9H-fluoren-9- ylmethoxycarbonylamino)]-(4-hydroxyphenyl)acetic acid methyl ester.
2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2,2-diphenylacetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
With N-ethyl-N,N-diisopropylamine; In water; acetonitrile; at 20℃;
General procedure: DIPEA (2-3 eq.) and Fmoc-OSu (0.9 eq) are added to the amino acid or its hydrochloride (1 eq.) in a 1:1 mixture of acetonitrile/water (20 mL/1 mmol amino acid) and the mixture is stirred for at least 90 min at room temperature. After acidification with 1M HCl, the reaction mixture is extracted withdichloromethane (3x). The combined organic phases are washed with brine, dried with MgSO4, filteredand the solvent is evaporated under reduced pressure to afford the crude Fmoc-protected amino acid. If necessary, the residue is crystallized from dichloromethane/hexane to afford the desired product as a solid.
A mixture containing <strong>[16682-12-5]ornithine hydrochloride</strong> 5 (1.0 g, 5.93 mmol) and basic copper carbonate CuCO3 (656 mg, 2.97 mmol) dissolved in dest. H2O (8 mL) was stirred under reflux for 15 min. The blue reaction mixture was filtered, evaporated and dried under vacuum to afford a blue solid (1.22 g, quant). Part of the blue solid (600 mg) was suspended in formamide (6 mL) and DIPEA (1.2 mL, 880 mg, 6.81 mmol) was added. To the blue solution was added drop wise bis-boc-pyrazolocarboxamidine (939 mg, 3.02 mmol) in dioxane (3 mL). The blue solution was stirred at r.t. overnight, and then quenched with H2O (20 mL) to yield a light blue solid precipitate. The suspension was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to yield blue foam (1.48 g). The crude product was suspended in H2O (6 mL) and EDTA·2Na·2H2O (676 mg, 1.82 mmol) and sat. aq. NaHCO3 (597 mg, 7.11 mmol) were added, then 9-fluorenylmethyl-succinimidyl carbonate (1.22 g, 3.63 mmol), dissolved in acetone (13.5 mL), was added drop wise to the reaction mixture at r.t. The blue suspension turned light blue and the reaction mixture was stirred at r.t. overnight. Subsequently, the solvent was evaporated under vacuum, and H2O (25 mL) was added resulting in a slight basic light blue turbid mixture (pH 8). The mixture was acidified by adding 10% aq. citric acid solution (pH 2-3). The resulting solution was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography over a silica gel column (mobile phase: cyclohexane/EtOAc + 1% AcOH 10:1 to 1:1). The appropriate fractions were collected and evaporated to afford triprotected arginine C (1.22 g, 2.05 mmol, 70% yield over two steps) as colorless foam. 1H-NMR (600 MHz, CDCl3): delta = 11.37 (br. s, 1H, NHCO2tBu), 8.50, 8.42* (s, 1H, NHCO2tBu), 7.75-7.74 (m, 2H, Ar), 7.62-7.59, 7.56* (m, 2H, Ar), 7.39-7.37 (m, 2H, Ar), 7.31-7. 28 (m, 2H, Ar), 5.89*, 5.83 (d, J= 8.1 Hz, NH(1)), 4.62*, 4.52*, 4.42-4.37 (m, 3H, 2-H, 8-H), 4.21 (t, J= 7.0 Hz, 1H, 9-H), 3.46-3.39, 3.32* (m, 2H, 5-H), 1.98-1.94 (m, 1H, 3-H), 1.76-1.66 (m, 3H, 3-H, 4-H), 1.48 (s, 9H, NHCO2tBu), 1.47 (s, 9H, NHCO2tBu) ppm *minor rotamer. 13C-NMR (150 MHz, CDCl3): delta = 174.9, 172.5* (s, C-1), 163.3*, 162.8 (s, C-6), 156.6*, 156.4 (s, C-7), 156.4 (s, NHCO2tBu), 153.3, 152.9* (s, NHCO2tBu), 144.0*, 143.8 (2s, Ar), 141.4 (s, 2Ar), 127.8 (d, 2Ar), 127.2 (d, 2Ar), 125.3, 124.9* (d, Ar), 120.1 (d, 2Ar), 84.3*, 83.7, 83.4* (2s, NHCO2tBu), 80.5*, 80.1, 79.7* (2s, NHCO2tBu), 67.3*, 67.1 (t, C-8), 54.1*, 53.7 (d, C-2), 47.3 (d, C-9), 40.6, 40.4* (t, C-5), 29.8*, 29.7 (t, C-3), 28.4*, 28.3 (q, NHCO2tBu), 28.2*, 28.2 (q, NHCO2tBu), 25.5, 25.3* (t, C-4) ppm *minor rotamer. HRMS (ESI-TOF): calculated for C31H41N4O8 [M + H]+ 597.2919; found 597.2924.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
