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Structure of Fmoc-Cl
CAS No.: 28920-43-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 28920-43-6 |
Formula : | C15H11ClO2 |
M.W : | 258.70 |
SMILES Code : | O=C(Cl)OCC1C2=CC=CC=C2C3=CC=CC=C13 |
MDL No. : | MFCD00001138 |
InChI Key : | IRXSLJNXXZKURP-UHFFFAOYSA-N |
Pubchem ID : | 34367 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.13 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 70.97 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.74 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
4.52 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.17 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.26 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.92 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.72 |
Log S (ESOL):? ESOL: Topological method implemented from |
-4.59 |
Solubility | 0.0067 mg/ml ; 0.0000259 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from |
-4.79 |
Solubility | 0.00416 mg/ml ; 0.0000161 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.67 |
Solubility | 0.000554 mg/ml ; 0.00000214 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-4.67 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.83 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: With sodium carbonate In 1,4-dioxane; water at 20℃; for 2.5 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water |
Step 1: Dissolve 4-Aminomethyl-cyclohexanecarboxylic acid ((39); 1.15g, 7.30mmol) in 1,4-dioxane (12.0mL) and 10percent aqu. Na2CO3 (23.2mL) and add Fmoc-Cl (2.26g, 8.76mmol). Stir the reaction mixture for 2.5h at rt. Add 1M aqu HCl (42.0mL) to the mixture and extract with EtOAc (3 times). Wash the combined organic layers with 1M aqu HCl, water and brine, extract the combined aqu layers once again with EtOAc, dry the combined organic layers with Na2SO4 and remove solvent under reduced pressure. The left crude product is washed with ice cold EtOAc and dried in oil pump vacuum to obtain (40) as a white solid (2.28g, 83percent). No further purification. [M. Nichifor; E. H. Schacht; Tetrahedron;1994; 50; 12; 3747-3760]. 1H NMR (400MHz, CDCl3): 0.87-1.02 (br.m, 2 H); 1.34-1.52 (br.m, 4 H); 1.81 (br.d, 2 H, J 6Hz); 1.90-2.11 (br.s, 1 H); 2.12-2.35 (br.m, 1 H); 3.03 (Ψt, 2 H, J = 6.2Hz); 4.19 (br.Ψt, 1 H, J = 6.5Hz); 4.42 (br.Ψd, 2 H, J = 6.5Hz); 4.74 (br.s, 1 H); 7.30 (Ψt, 2 H, J = 7.4Hz); 7.38 (Ψt, 2 H, J = 7.4Hz); 7.57 (d, 2 H, J = 7.4Hz); 7.75 (d, 2 H, J = 7.4Hz). |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydrogencarbonate In 1,4-dioxane; water for 6 h; | To a cooled solution of 6-chloro-Ltryptophan-OH (0.5 g, 2.1 mmol) in dioxane/water (9:1) was added 2 equiv of NaHCO3 and 1.2 equiv of Fmoc-Cl in dioxane, and the mixture was stirred for 6 hr. The solution was concentrated, followed by 3x washing with ethyl acetate. The aqueous layer was acidified and the precipitate was collected and dried in vacuum to give the desired product (0.84 g, 87percent): 1H-NMR (400 MHz, CD3OD) δ 7.70 (d, J = 7.6 Hz, 2H), 7.30-7.60 (m, 7H) ,7.17-7.26 (m, 2H), 7.09 (s, 1H), 6.92-6.96 (m, 1H), 4.45 (m, 1H), 4.23 (m, 1H), 4.13 ( m, 1H), 3.96-4.06 (m, 1H), 3.84 (d, J = 6.8 Hz, 1H), 3.30-3.36 (m, 1H), 3.13-3.16 (m, 1H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | 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]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | EXAMPLE 53 Preparation of Nalpha,Ndelta-di-(9-Fluorenylmethoxycarbonyl)-L-ornithine (Compound No. 73) The reaction of 9-fluorenylmethyl chloroformate with L-ornithine according to the conditions described in example 2 provided the title product in 79% yield. 1H NMR (DMSO6): 1.42-1.80 (m, 4H), 3.00 (m, 2H), 3.94 (m, 1H), 4.20 (t, J=6.3, 2H), 4.29 (d, J=7.0, 4H), 7.28 (t, J=5.2, 1H), 7.30-7.48 (m, 8H), 7.63 (d, J=7.6, 1H), 7.67-7.73 (m, 4H), 7.88 (m, 4H), 12.50 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; sodium carbonate; | C. To a solution of 0.50 g of (S)-2-azetidine carboxylic acid in 15 ml of 10% aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethylchloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl)azetidine-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; | C. To a solution of 0.50 g of (S)-(-)-2-azetidine carboxylic acid in 15 ml of 10 aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethyl chloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution was washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl) azetidine-2-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; N-ethyl-N,N-diisopropylamine; In dichloromethane; | Example 74A N5-[Benzyloxycarbonyl]-N2-[(9H-fluoren-9-ylmethoxy)carbonyl]-D-ornithine N5-[(Benzyloxy)carbonyl]-D-ornithine (3.8 g, 14.27 mmol) [Ulhaq, Saraj et al.; Bioorg. Med. Chem.; EN; 7; 9; 1999; 1787-1796] is provided in dichloromethane (190 ml), DIEA (2.4 ml, 1.8 g, 17.27 mmol, 1 eq.) and chlorotrimethylsilane (3.6 ml, 3.1 g, 28.53 mmol, 2 eq.) are added, and the mixture is stirred under reflux overnight. The reaction is cooled (0 C.) and DIEA (4.7 ml, 3.7 g, 28.54 mmol, 2 eq.) again and (9-fluorenylmethyl) chloroformate (3.7 g, 14.27 mmol, 1 eq.) are added, and the mixture is warmed to RT and stirred at this temperature overnight. For the workup, the reaction is diluted with dichloromethane and washed with a 10% aq. citric acid solution, the organic phase is dried over sodium sulfate, the solvent is removed on a rotary evaporator and the mixture is dried in vacuo. 6.5 g (93.2% of theory) of the title compound are obtained. LC-MS (Method 18): Rt=2.57 min; MS (ESIpos): m/z (%)=489 (100) [M+H]+, 977 (100) [2M+H]+; MS (ESIneg.): m/z (%)=487 (80) [M-H]-, 975 (100) [2M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; | To a mixture of (S)-2-aminopropan-l-ol (2 g, 26.6 mmol) and Na2C03 (5.6 g, 53.2 mmol) in 1,4-dioxane and water (25 mL / 25 mL) at 0 C was added FmocCl (10.2 g, 39.9 mmol) and the resulting mixture was then warmed to room temperature gradually. After the amine was consumed completely as indicated by TLC, water (25 mL) was added. The mixture was extracted with DCM (3 x 50 mL). The organic phase was washed with brine (50 mL), and dried over anhydrous Na2S04. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (7.1 g, 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium carbonate; In 1,4-dioxane; water; at 0℃; for 18h; | (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 0C 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 0C 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, 97% yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H- NMR (400 MHz, CDCI3) delta 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 18h; | 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 0C 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 0C 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, 97% yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDCI3) delta 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 18h; | 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 0C 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 0C 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, 97% yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDCI3) delta 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 18h; | 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 0C 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 0C 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, 97% yield). LC/MS 2.85 mm (ES+) rn/z (relative intensity) 410.60 ; ?H-NMR (400 MHz, CDC13) oe 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 18.16h; | 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 0C 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 0C 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, 97% 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 18h; | 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 0C 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 0C 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, 97% yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1 H- NMR (400 MHz, CDCI3) delta 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 18.16h; | 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 0C 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 0C 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, 97% 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 18.16h; | 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 0C 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 0C 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, 97% 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% | 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 0C 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 0C 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, 97% yield). LC/MS 2.85 min (ES+) m/z (relative intensity) 410.60 ; 1H-NMR (400 MHz, CDC13) delta 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 2.16667h; | (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 0C 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 0C 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, 97% 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 18h; | H-<strong>[1115-74-8]Val-Ala</strong>-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 0C 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 0C 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, 94%). LC/MS (2.758min (ES+)), m/z: 41 1 .0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 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). |
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h; | To a solution of <strong>[1115-74-8]Val-Ala</strong>-OH (1 g, 5.31 mM) in water (40 ml) is added Na2C03(1.42 g, 13.28 mM) and cooled to 0C before dioxane (40 mL) is added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) is added dropwise over 10 min at 0C. The reaction mixture is stirred at 0C for 2h, then allowed to stir at RT for 16 h. Dioxane is removed under vacuum, the reaction mixture diluted with water (450 mL), pH is adjusted to 2 using IN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers are washed with brine, dried over MgS04, filtered, concentrated under reduced pressure and dried to yield Fmoc- Val- Ala-OH. This product is suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.971 g, 7.97mM) are added. The resulting mixture is treated under Argon with methanol until a clear solution is obtained. The reaction is stirred overnight and filtered. The filtrate is washed with diethyl ether (4x) and dried under high vacum to yield EC 1930 (1.85 g, 68%). 1H NMR (500 MHz, CD3OD): delta 7.79 (d, = 8.0 Hz, 2H), 7.65 (t, = 7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, = 8.0 Hz, 2H), 7.38 (t, = 7.5 Hz, J2= 7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J = 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t, J1=7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, Ji= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, Jl=7.5 Hz, 3H), 0.97 (d, Jl=7.0 Hz, 3H), 0.95 (d, Ji= 7.0 Hz, 3H); LCMS (ESI): (M + H)+= Calculated for C30H33N3O5, 516.24; found 516.24 | |
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h; | To a solution of <strong>[1115-74-8]Val-Ala</strong>-OH (1 g, 5.31 mM) in water (40 ml) was added Na2CO3 (1.42 g, 13.28 mM) and cooled to 0C before dioxane (40 mL) was added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 mm at 0C. The reaction mixture was stirred at 0C for 2h. Then the reaction mixture was allowed to stir at RT for 16 h. Dioxanewas removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2 using iN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure and dried to yield Fmoc-<strong>[1115-74-8]Val-Ala</strong>-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.971 g, 7.97mM) were added. The resulting mixture was treated underArgon with methanol until a clear solution was obtained. The reaction was stuffed overnight andfiltered. The filtrate was washed with diethyl ether (4x) and dried under high vacum to yieldEC1930 (1.85 g, 68%). ?H NMR (500 MHz, CD3OD): 5 7.79 (d, J,= 8.0 Hz, 2H), 7.65 (t, J,=7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, J,= 8.0 Hz, 2H), 7.38 (t, J,= 7.5 Hz, J2= 7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J,= 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t,J,= 7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, J,= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, J,= 7.5 Hz, 3H),0.97 (d, J,= 7.0 Hz, 3H), 0.95 (d, J,= 7.0 Hz, 3H); LCMS (ESI): (M + H) = Calculated for C30H33N305, 516.24; found 516.24 | |
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h; | To a solution of <strong>[1115-74-8]Val-Ala</strong>-OH (1 g, 5.31 mM) in water (40 ml) was added Na2CO3 (1.42 g, 13.28 mM) and cooled to 0C before dioxane (40 mL) was added. A solution of Fmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 mm at 0C. The reaction mixture was stirred at 0C for 2h. Then the reaction mixture was allowed to stir at RT for 16 h.Dioxane was removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2 using iN HC1 and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine, dried over Mg504, filtered, concentrated under reduced pressure and dried to yield Fmoc-<strong>[1115-74-8]Val-Ala</strong>-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g, 6.38 mM) and EEDQ (1.97 1 g, 7.97mM) were added. The resulting mixture was treated under Argon with methanol until a clear solution was obtained. The reaction was stirred overnight and filtered. The filtrate was washed with diethyl ether (4x) and dried under high vacum to yield Compound 48 (1.85 g, 68%). ?H NMR (500 MHz, CD3OD): (57.79 (d, J,= 8.0 Hz, 2H), 7.65 (t, J,= 7.0 Hz, J2= 7.5 Hz, 2H), 7.54 (d, J,= 8.0 Hz, 2H), 7.38 (t, J,= 7.5 Hz, J2=7.5 Hz, 2H), 7.33-7.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, J,= 14.0 Hz, J2= 7.0 Hz, 1H), 4.42-4.32(m, 2H), 4.22 (t, J,= 7.0 Hz, J2= 6.5 Hz, 1H), 3.94 (d, J,= 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d,J,= 7.5 Hz, 3H), 0.97 (d, J,= 7.0 Hz, 3H), 0.95 (d, J,= 7.0 Hz, 3H); LCMS (ESI): (M + H) =Calculated for C30H33N305, 516.24; found 516.24. | |
With sodium carbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h; | To a solution of<strong>[1115-74-8]Val-Ala</strong>-OH (1 g, 5.31 mM) in water (40 ml) was addedNa2C03 (1.42 g, 13.28 mM) and cooled to 0C before dioxane (40 mL) was added. A solutionofFmoc-Cl (1.44 g, 5.58 mM) in dioxane (40 mL) was added dropwise over 10 min at 0C. Thereaction mixture was stirred at 0C for 2h, then allowed to stir at R T for 16 h. Dioxane was20 removed under vacuum, the reaction mixture diluted with water (450 mL), pH was adjusted to 2using 1N HCl and extracted with EtOAc (3 x 250 mL). The combined organic layers arewashed with brine, dried over MgS04, filtered, concentrated under reduced pressure and driedto yield Fmoc-<strong>[1115-74-8]Val-Ala</strong>-OH. This product was suspended in dry DCM (25 ml), PABA (0.785 g,6.38 mM) and EEDQ (1.971 g, 7.97mM) are added. The resulting mixture was treated under25 Argon with methanol until a clear solution was obtained. The reaction was stirred overnight andfiltered. The filtrate was washed with diethyl ether ( 4x) and dried under high vacum to yieldCompound 18 (1.85 g, 68%). 1H NMR (500 MHz, CD30D): J 7.79 (d, h= 8.0 Hz, 2H), 7.65 (t,h= 7.0 Hz, h= 7.5 Hz, 2H), 7.54 (d, h= 8.0 Hz, 2H), 7.38 (t, h= 7.5 Hz, h= 7.5 Hz, 2H), 7.337.24 (m, 4H), 4.54 (s, 2H), 4.48 (q, lF 14.0 Hz, h= 7.0 Hz, 1H), 4.42-4.32 (m, 2H), 4.22 (t,lF 7.0 Hz, h= 6.5 Hz, 1H), 3.94 (d, lF 7.0 Hz, 1H), 2.07 (m, 1H), 1.43 (d, lF 7.5 Hz, 3H),0.97 (d, h= 7.0 Hz, 3H), 0.95 (d, h= 7.0 Hz, 3H); LCMS (ESI): (M + Ht =Calculated forC3oH33N30s, 516.24; found 516.24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[106825-79-0](S)-<strong>[106825-79-0]morpholine-3-carboxylic acid</strong></strong> (2.00 g, 15.3 mmol) was added to dioxane (20 mL).Add potassium carbonate (5.50 g, 40.0 mmol) and stir at room temperature for 30 minutes.Subsequently, fluorenylmethoxycarbonyl chloride (6.54 g, 25.0 mmol) was added to the reaction system.After stirring at room temperature for 3 hours, the reaction was completed.Column chromatography (petroleum ether: ethyl acetate = 1:1) gave the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium carbonate; In tetrahydrofuran; at 0 - 25℃; for 12h; | 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1, compound 8) [0225] A solution of 4-amino-1 -(terf-butoxycarbonyl)piperidine-4- carboxylic acid (5 g, 20.5 mmol) in THF (300 mL) and Na2CO3 (6.45 g, 61 .5 mmol, 3.0 eq in 64.5 mL of water) was cooled to 0C before the dropwise addition of a solution of Fmoc chloride (5.3 g, 30.7 mmol, 1 .5 eq) in THF (30 mL). The resulting mixture was slowly warmed to 25C and stirred for an additional 12 hours. Upon completion, the reaction contents were carefully acidified with HCI (1 M), and the crude material was extracted with EtOAc (three times). The combined organic layers were dried (Na2SO4), concentrated, and the crude material was purified by combiflash 0 to 10% MeOH in DCM to provide 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1 -(te/t- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1 , compound 8) (4.02 g, 42% yield). [0226] 1 H NMR (400 MHz, Ch lore-form -c/) delta 7.75 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.45-7.34 (m, 2H), 7.30 (td, J = 6.9, 6.3, 1 .4 Hz, 2H), 4.68-4.26 (m, 2H), 4.19 (t, J = 6.5 Hz, 1 H), 3.96-3.65 (m, 3H), 3.08 (s, 2H), 1 .91 -1 .77 (m, 2H), 1 .48 (s, 9H). 13C NMR (101 MHz, CDCI3) 177.19, 154.73, 143.67, 141 .32, 127.72, 127.08, 124.95, 1 19.97, 80.06, 67.90, 66.86, 57.49, 47.19, 31 .98, 28.42, 25.57. HRMS (m/z): [M+] cald for C26H30N2O6, 466.53, found 466.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.54% | With sodium hydrogencarbonate; In tetrahydrofuran; water; at 15℃; for 14h;Inert atmosphere; | The mixture of tert-butyl N-[(4-fluoro-4- piperidyl)methyl]carbamate (150.00 mg, 645.74 //mol, 1.00 eq) and 9H-fluoren-9-ylmethyl carbonochloridate (250.58 mg, 968.61 //mol, 1.50 eq) were dissolved in THF (20.00 mP) and H20 (4.00 mP), to which NaHCCp (162.75 mg, 1.94 mmol, 75.35 //F, 3.00 eq) was added in one portion. The resulting mixture was then stirred at 15 C for 14 h. The reacting solution was diluted with water (50 mP) and extracted with EA (50 mP x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (pure PE to PE:EA = 5:1) to afford 9H-fluoren-9-ylmethyl 4-[(tert- butoxycarbonylamino)methyl]-4-fluoro-piperidine-l -carboxylate (163.00 mg, 358.61 //mol, 55.54% yield) as an off-white solid. The product was confirmed by PC-MS and used directly for the next step without further purification |
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 15℃; for 14h; | The mixture of tert-butyl N-[(4-fluoro-4- piperidyl)methyl]carbamate (150.00 mg, 645.74 mupiiotaomicron, 1.00 eq) and 9H-fluoren-9-ylmethyl carbonochloridate (250.58 mg, 968.61 mupiiotaomicron, 1.50 eq) were dissolved in THF (20.00 mL) and H20 (4.00 mL), to which NaHC03 (162.75 mg, 1.94 mmol, 75.35 /L, 3.00 eq) was added in one portion. The resulting mixture was then stirred at 15 C for 14 h. The reacting solution was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (pure PE to PE:EA = 5: 1) to afford 9H-fluoren-9-ylmethyl 4-[(tert- butoxycarbonylamino)methyl]-4-fluoro-piperidine- l -carboxylate (163.00 mg, 358.61 mupiiotaomicron, 55.54% yield) as an off-white solid. The product was confirmed by LC-MS and used directly for the next step without further purification. |
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)+. |
Tags: 28920-43-6 synthesis path| 28920-43-6 SDS| 28920-43-6 COA| 28920-43-6 purity| 28920-43-6 application| 28920-43-6 NMR| 28920-43-6 COA| 28920-43-6 structure
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