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CAS No. : | 59483-84-0 | MDL No. : | MFCD00368353 |
Formula : | C13F10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IOVVFSGCNWQFQT-UHFFFAOYSA-N |
M.W : | 394.12 | Pubchem ID : | 2734833 |
Synonyms : |
|
Num. heavy atoms : | 26 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 13.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 59.12 |
TPSA : | 35.53 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.41 cm/s |
Log Po/w (iLOGP) : | 2.87 |
Log Po/w (XLOGP3) : | 4.64 |
Log Po/w (WLOGP) : | 8.86 |
Log Po/w (MLOGP) : | 6.87 |
Log Po/w (SILICOS-IT) : | 6.76 |
Consensus Log Po/w : | 6.0 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.28 |
Solubility : | 0.00205 mg/ml ; 0.0000052 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.11 |
Solubility : | 0.00304 mg/ml ; 0.00000772 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.06 |
Solubility : | 0.000034 mg/ml ; 0.0000000863 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 3h; | A solution of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (0.38 g, 0.94 mmol) in CH2C12 (5 ml) is cooled to 0C, and the tyrosine PNA monomer is added (Sforza, S.; Nielsen, P. et al. Tetrahedron Lett. (1998), 39, 4707) (0.5 g, 0.93 mmol). Diisopropylamine (DIPEA)(160 ml) is dripped into the suspension thus obtained and the solution becomes clear. It is left under stirring for 3h and a 5% NaHC03 solution (2x10ml) is added extracting the aqueous phase with CH2C12 (3x10 ml) . The combined organic phases are washed with H20 (20 ml) dried over Na2S04 and evaporated up to about 2 ml. To one side, in an atmosphere of N2, a solution of tris(ferrocenyloxymethyl)aminomethane inCH2C12 (5 ml) cooled to 0C is prepared into which DIPEA (180 ml, 0.5 mmol) and the previous solution of pentafluoro ester are dripped. It is left under stirring at room temperature for 5 hours. It is washed with a 10% NaHC03 solution (2x10ml) removing the aqueous phase with CH2C12 (3x10 ml). The combined organic phases are washed with H20 (20 ml) dried over Na2S04 and evaporated. The crude product is purified with a chromatography column on silica gel, eluent AcOEt. 0,4 g (80%) of orange solid are obtained.m.p. 98-103 C (pentane) . XH NMR (CHC13, 5): 1.84(s, 3H, CH3) ; 2.6 (d,lH, J= 10.5 Hz, CH2) ; 3.0-3.1 (m,4H, CH2) ; 3.67 (bs, 6H; CH2OCH2Pc) ; 3.77 (s, 3H, COOCH3) ;3.82-3.86 (m, 2H, CH + CH2) ; 4.11 (s, 9H, Pc) ; 4.14 (s,6H, Fc) ; 4.19 (s, 6H, Fc) ; 4.24 (s, 6H, CH2Fc) ; 4.52 (d,1H, J= 16.2 Hz, CH2) ; 4.99 (d, 1H, J = 12 Hz, CH2) ; 5.19(d, 1H, J= 12 Hz, CH2) ; 5.46 (bs, 1H, NH) ; 5.61 (bs, 1H,NH) ; 6.58 (s, 1H, CH=) ; 7.02 (d, 2H, J= 8.47 Hz,PhO);7.10 (d, 2H, J= 8.47 Hz,PhO); 7.25-7.35 (m, 5H, Ph); 8.01(S, 1H, NH) . 13C NMR (CHCI3, 5): 12.3; 33.50; 39.03; 48.7;49.5; 50.34; 60; 63.6; 66.9; 69.6; 68.5; 68.6; 69.2;83.0; 110.8; 122.14; 127; 128.4; 129.9; 136; 141.0;151.4; 155.0; 156.0; 164.1; 166.95; 172. M/z (HRSM) :1279.30 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; at 20℃; for 0.5h; | D) Zu einer Loesung von 0, 30 g des oben unter C) erhaltenen N-(4-Chlorbenzyl)-N-[(9H-fluoren-9-ylmethoxy)-carbonyl]-N'-(tert-butoxycarbonyl)-hydrazins in 2,5 ml Dichlormethan gab man 0,1 ml Triisopropylsilan und kuehlte die Mischung auf. 0 C ab. Dann tropfte man ueber einen Zeitraum von 5 Min. 2,5 ml TFA hinzu und liess die Loesung anschliessend 30 Min. lang ruehren. Das Loesungsmittel wurde im Wasserstrahlvakuum unter Stickstoffkuehlung eingedampft und der Rueckstand wurde in einer Loesung von 77 mg DMAP (0,63 mmol) in 10 ml trockenem Dichlormethan wieder aufgenommen. Diese Mischung fuegte man ueber einen Zeitraum von 20 Min. tropfenweise und unter Ruehren zu einer Loesung von 0,25 g Di-pentafluorphenylcarbonat (0,63 mmol) in 20 ml trockenem Dichlormethan hinzu. Nach vollstaendiger Zugabe gab man zu der so erhaltenen Vorlage unter Ruehren eine Loesung von 0,26 g tert-Butyl-3-[(2R)-2-amino-2-(phenethylcarbamoyl)-ethyl]-1H-1-indolcarboxylat (Herstellung siehe Beispiel 3D)), 77 mg DMAP (0,63 mmol) und 10 ml trockenem Dichlormethan hinzu. Man liess 30 Min. lang bei RT ruehren, dampfte das Loesungsmittel im Wasserstrahlpumpenvakuum ein und nahm den Rueckstand in 4 ml Dichlormethan auf. Nun gab man 0,1 ml Triisopropylsilan hinzu und kuehlte auf 0C ab. Dann tropfte man ueber einen Zeitraum von 5 Min. 4 ml TFA hinzu und liess anschliessend 30 Min. lang ruehren. Das Loesungsmittel wurde im Oelpumpenvakuum entfernt und der getrocknete Rueckstand wurde 30 Min. lang bei RT mit 10 ml einer 20%igen (v/v) Loesung von Piperidin in DMF versetzt. Man dampfte das Loesungsmittel im Wasserstrahlpumpenvakuum mit stickstoffgekuehlter Vorlage ein, nahm den verbliebenen Rueckstand in DMSO auf und reinigte diesen durch Reversed-Phase-HPLC [(HPLC-System Amersham Pharmacia Biotech Aekta Basic 100F; Pumpensystem P-900 und Detektor UV-900; Saeule ODS-A C18 von Omnicrom YMC (250 mm * 20 mm, 10 mu:m, Flussrate : 8 mL/min); Elution mit linearem Gradienten (30 Min.) von Wasser (Solvens A) in Acetonitril (Solvens B) und 0.1% (v/v) TFA]. Lyophilisierung der gereinigten Fraktionen lieferte 26,8 mg der Titelverbindung als farbloses Pulver vom Schmelzpunkt 75-80 C. 1H-NMR (500 MHz, ACN-d3, 300 K) delta = 9.74 (bs, 1H, NH), 7.91 (d, J = 7.7 Hz, 1H, arom), 7.98 (d, J = 8.1 Hz, 1H, arom), 7.58-7.83 (m, 12H, arom), 6.99 (bs, 1H, NH-CH), 6.89 (bs, 1H, NH-CH2-CH2), 4.87 (q, J = 6.9 Hz, NH-CH), 4.34 (bs, 2H, NH-CH2-C6H4Cl), 3.87-3.94 (m, 1H, NH-CH2-CH2), 3.76-3.82 (m, 1H, NH-CH2-CH2), 3.66 (d, J = 6.2 Hz, 2H, NH-CH-CH2), 3.17 (t, J = 7.3 Hz, 2H, NH-CH2-CH2). HPLC-MS (ESI) m/z 490.1 (70) [M+H]+, 512.3 (50) [m+Na]+, 754.8 (100), 978.9 (25) [2M+H]+, 1001.0 (90) [2M+Na]+, 1063.1 (20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In dichloromethane; | 4,4'-Bis[3-(pentafluorophenyloxyacarbonyl)propoxyl-4''-methoxy-tritanol. This compound was made in the same way as the previous one except the pentafluorophenol was used instead of the N-hydroxysuccinimide. To a stirred solution of 4,4'-bis(3-carboxypropoxy)-4"-methoxy-tritanol (742 mg; 1.5 mmol) in dry DCM (20 mL) triethylamine (0.56 mL, 4.0 mmol) pentafluorophenyl carbonate (1.97 g, 5.0 mmol) were added and the mixture was stirred overnight, then evaporated, coevaporated with DCM and chromatographed on solica gel (5?10% EtOAc in toluene). Yield 980 mg (79%), dark red oil Rf 0.25 (toluene-EtOAc, 3:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at -10 - 20℃; for 48h; | A solution of 2, 6-dimethyl-pyridin-4-ylamine (Example C1. 2., 1.23 g, 10 MMOL) in THF (30 mL) is slowly added to a cooled (-10C) SOLUTION of bis (pentafluorophenyl) carbonate (3.94 g, 10 MMOL) in THF (10 mL). The mixture is stirred at r. t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 18h; | Fmoc-NHNH2 (750 mg, 2.95 MMOL) and bis (pentafluorophenyl) carbonate (1221 mg, 3.1 MMOL) were stirred in dry THF (15 mL) at rt for 18 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (x3). The combined organic fractions were washed with 1 M HCI (X1) and brine (X1), dried (MgSO4), and concentrated to give a clear oil, which solidified in vacuo. Off- white solid. Yield : 1.32 g (96percent). Rf = 0.4 (PE: EA 3: 1). This compound was used crude, since it was partially unstable to purification by both recrystallization and silica chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 20℃; for 48h; | A solution of 2-ethyl-6-methyl-pyridin-4-ylamine (1.33 g, 9. 8 MMOL) in THF (25 mL) is slowly added to a solution of bis (PENTAFLUOROPHENYL) carbonate (3.99 g, 10.1 MMOL) in THF (10 mL). The mixture is stirred at r. t. for 48 h and the solution of title compound is used as stock solution for subsequent coupling reactions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | In tetrahydrofuran; at 60℃; for 42h;Product distribution / selectivity; | Example 6 (Synthesis of N-Carboxyisoleucine Anhydride) Into a two-neck round-bottom flask having a capacity of 25 mL and equipped with a Dimroth condenser were introduced 131 mg (1 mmol) of isoleucine and 10 mL of tetrahydrofuran in a nitrogen atmosphere. To the resultant solution was added 396 mg (1 mmol) of <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong>. The mixture was stirred at 60 C. for 42 hours. This reaction mixture was analyzed by NMR spectroscopy using dioxane as an internal reference. As a result, it was ascertained that N-carboxyisoleucine anhydride had been obtained in a yield of 69%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In tetrahydrofuran; at 60℃; for 60.0h;Product distribution / selectivity; | Example 3 (Synthesis of N-Carboxyphenylalanine Anhydride) Into a two-neck round-bottom flask having a capacity of 25 mL and equipped with a Dimroth condenser were introduced 165 mg (1 mmol) of phenylalanine and 10 mL of tetrahydrofuran in a nitrogen atmosphere. To the resultant solution was added 396 mg (1 mmol) of bis(pentafluorophenyl) carbonate. The mixture was stirred at 60 C. for 60 hours. This reaction mixture was analyzed by NMR spectroscopy using dioxane as an internal reference. As a result, it was ascertained that N-carboxyphenylalanine anhydride had been obtained in a yield of 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | In tetrahydrofuran; at 60℃; for 149h;Product distribution / selectivity; | Example 9 (Synthesis of N-Carboxy-gamma-benzyl-alpha-glutamic Acid Anhydride) Into a two-neck round-bottom flask having a capacity of 25 mL and equipped with a Dimroth condenser were introduced 237 mg (1 mmol) of gamma-benzyl-L-glutamic acid and 10 mL of tetrahydrofuran in a nitrogen atmosphere. To the resultant solution was added 396 mg (1 mmol) of <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong>. The mixture was stirred at 60 C. for 149 hours. This reaction mixture was analyzed by NMR spectroscopy using dioxane as an internal reference. As a result, it was ascertained that N-carboxy-gamma-benzyl-alpha-glutamic acid anhydride had been obtained in a yield of 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 1h;Product distribution / selectivity; | Into a solution of <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (115 mg, 0.3 0 mmol) in N-methyl pyrrolidone (1.5 ml), at 0C, the solid compound (20) (example 1) (210 mg, 0.30 mmol), diisopropylamine (DIPEA) (130 ml, 0.74 mmol) and DMF (0.3 ml) are added. It is left under stirring at 0C for lh, to allow the formation of the compound of the title (Rf = 0.75, AcOEt/ETP, 6:4). The compound (32) can be isolated and purified, for example, withchromotography or else used as such in the anchoring reaction with organic molecules (see example 12).; EXAMPLE 12. Reaction between the compound (32) and a PNA monomer (aminoethylglycinic monomer) to give {{2-[3-(2-ferrocene methylene oxy-1,1-bis-ferrocene methylene oxymethyl-ethyl)-ureido]-ethyl}-[2-(5- methy1-2,4-dioxo-3,4-dihydro-2H-pyrimidine-l-il)-acetyl]-amino}- acetic acid methyl ester (36). Into a solution of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (115 mg, 0.30 mmol) in N-methyl pyrrolidone (1.5 ml), at 0C, the solid compound (20) (example 1) (210 mg, 0.30 mmol), diisopropylamine (DIPEA) (130 ju.1, 0.74 mmol) and DMF (0.3 ml) are added. It is left under stirring at 0C for lh,to allow the formation of the corxesponding pentafluorophenyl carbonate (Rf = 0.75, AcOEt/ETP, 6:4). In a second balloon a solution of PNA aminoethylglycinic trifluoroacetate1 monomer (35 mg, 0.08 mmol) in DMF (0.5 ml) and DIPEA (0.35 ml, 2.0 mmol) is prepared in which the previously separated solution is slowly dripped, at room temperature. It is heated to 45C for 2h, then the reaction mixture is diluted with CH2C12 (25 ml) and washing is carried out with a saturated NaHC03 solution (3x15 ml) and H20 (2x3 0 ml) . The organic phase is dried over Na2S04, filtered and evaporated under vacuum. The crude reaction product is purified through a chromatography column on silica gel (ETP/AcOEt,4:6 progressively increasing the polarity in (AcOEt/ETP, 6:4 Rf = 0.1) obtaining 74 mg of product that is redissolved in CH2C12 (0.5ml) and repxecipitated from pentane. 63 mg of yellow solid are obtained, with a yield of 78%. *H NMR (CDC13, 5): 1.8 (s, 3H, CH3) ; 3.3-3.4 (m, 4H, CH2CH2) ; 3.62 (s, 6H, C(CH2)3); 3.72 (s, 3H, OCH3) ; 3.96 (S, 2H, CH2COO) ; 4.10 (s, 15 H, Fc) , 4.12 (t, 6H, Fc) , 4.17 (t, 6H, Fc) , 4.20 (s, 6H, CH2Fc) , 4.28 (s, 2H, CH2CO) ; 5.7 (bs, 2H, NH) ; 6.76 (s, 1H, CH=) ; 8.11 (bs, 1H, NH) ; 13C NMR (CDCl3, 8): 12.3; 37.7; 48.8; 49.0; 49.5; 52.5; 58.9; 68.4-68.5; 69.3; 69.4; 69.7; 83.5; 110.0; 141.9 ; 150.9;157.2; 163.9; 167.6; 170.1. m/z (ESI+) 1039(M+) ; 1062 (M++ "Na) IR- (nujol) (cm"1) 1651 (CO) , 1455-(NHCONH).; EXAMPLE 13. Reaction between lysine and the compound (32) to give 2-carbobenzyloxyamino-6-[3-(2-ferrocene methylene oxy-l,l-bis-ferrocene methylene oxymethyl-ethyl)-ureido] hexanoic acid (37).; Into a solution of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (73 mg, 0.18 irunol) in anhydrous DMF (1 ml) at 0C a solution of the compound (20) (example 1) (120 mg, 0.17 mmol) in anhydrous DMP (1 ml) and DIPEA (31 il, 0.18 mmol) is slowly dripped. It is left under stirring at 0C for In, to give the corresponding pentafluorophenyl carbamate. In a second reaction balloon a solution of (L)-N-Cbz lysine (73 mg, 0.25 mmol) in anhydrous DMF (0.5 ml), H20 (0.1ml) and DIPEA (0.6 ml) is prepared. Into this solution the previously prepared solution is dripped slowly and at room temperature, maintaining the pH at 9-10. The solution is then heated to 45C for 1 h. The mixture is then diluted with CH2C12 (3 0 ml) and washed with NaHC03 5% (25 ml) . The aqueous phase is extracted with CH2C12 (3x20 ml), the combined organic phases are washed with a 0.3 M solution of KHS04 (3x10 ml) and then with H20 (20 ml) , dried over Na2S04, filtered and evaporated. The crude reaction product is purified through a chromatography column on silica gel (ETP:AcOEt,4/6) followed by CH2Cl2:MeOH, l/l to elute the product, which is precipitated from pentane. It is filtered recovering 135 mg of (3 7) as a yellow solid in a yield of 77%. *H NMR (CDC13; 5): 1.2-1.8 (m, 6H, CH2) ; 2.9-3.0 (m, 2H, CH2NH) ; 3.6 (bs, 7H, CH2 + CH) ; 4.1-4.3 (m, 33-H,- Pc+ CH2Pc) ; 5.12 (bs, 2H, CH2Ph) ; 7.3-7.4 (m, 5H, Ph) . 13C(CDC13,5) : 22.32; 29.2; 32.11; 39.8; 53.1; 58.8; 66.7; 68.5-69.3; 69.6; 83.6; 128.0-128.3; 136.4; 156.1; 158.5; 177.m/z (ESI+) 1021 (M+) ; 1044 (M++Na) . M.p. 140-145 C (dec). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Mono-phenol 12 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL dry tetrahydrofuran. To this was added triethylamine (0.0445 mL, 0.32 mmol) and bispentafluorophenyl carbonate (0.063 g, 0.16 mmol) and catalytic dimethylaminopyridine. Stirred at room temperature. After three hours, added methyl piperazine (0.04 mL, 0.36 mmol. ) After two hours TLC indicated product formed however TIPSCI was removed. Diluted with dichloromethane, washed with saturated NH4C1 solution, concentrated organics to give crude. Dissolved in 1.5 mL dichloroethane, added triethylamine (0.11 mL, 0.8 mmol) and TIPSCl (0.085 mL, 0.4 mmol) and stirred at 50 C. Stirred for four hours until starting material was consumed. Diluted with dichloromethane, washed with saturated brine, concentrated organics to give crude. Chromatographed (50% ethylacetate/hexanes to 20% methanol/60% ethylacetate/20%hexanes) to give product 90 (0.027 g, 0.0435 mmol, 54% for two steps.) IH NMR (CDCl3) No. 9.05 (d, 1H), 8.60 (d, 1H), 7.61 (dd, 1H), 7.41 (dd, 2H), 7.03 (dd, 2H), 4.81 (s, 2H), 3.71 (br m, 8H), 2.43 (s, 3H), 1.60 (m, 3H), 1.15 (d, 18H.) MS: 621 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Mono-phenol 45 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL tetrahydrofuran. To this was added diisopropylethylamine (0.052 mL, 0.3 mmol), bis- pentafluorophenyl carbonate (0.047 g, 0.119 mmol) and catalytic dimethylaminopyridine. Stirred at room temperature. After 75 minutes, cooled to 0 C, n-butylamine (0.079 mL, 0.08 mmol) added. Stirred for 1.5 hours, then diluted with dichloromethane, washed with saturated brine, 1 M HCI, concentrated organics to give crude. Chromatographed (25% ethylacetate/hexanes to give product 94 (0.0028 g, 0.0048 mmol, 6 %. ) ¹H NMR (CDC13) 8 9.12 (d, 1H), 8.41 (d, 1H), 7.98 (s, 1H), 7.61 (d, 4H), 7.43 (dd, 2H), 7.27 (m, 7H), 7.043 (dd, 2H), 5.37 (m, 1H), 4.82 (s, 2H), 3.35 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.01 (t, 3H.) MS: 604 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cesium fluoride; In tetrahydrofuran; for 21h; | A 100 mL round bottom flask was charged with bis-MPA, (7), (5.00 g, 37 mmol), bis-(pentafluorophenol)carbonate (PFC, 31.00 g, 78 mmol), and CsF (2.5 g, 16.4 mmol rinsed in with 70 //mis of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with sodium bicarbonate, water and was dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethylacetate/hexane mixture) to give MTC-PhF5, (8), as a white crystalline powder (GCMS single peak with mass of 326 g/mol, calculated molecular weight for C12H7F5O5 (326 g/mol) consistent with the assigned structure. FIG. 1 shows 1H NMR and 19F NMR spectrographs of MTC-PhF5. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). | |
With cesium fluoride; In tetrahydrofuran; for 21h; | A 100 mL round bottom flask was charged with bis-MPA, (7), (5.00 g, 37 mmol, MW 134.1), bis-(pentafluorophenol) carbonate (PFC, 31.00 g, 78 mmol, MW 394.1), and CsF (2.5 g, 16.4 mmol) rinsed with 70 mls of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with sodium bicarbonate, water and was dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethyl acetate/hexane mixture) to give MTC-C6F5 as a white crystalline powder. The GCMS had a single peak with mass of 326 g/mol. The calculated molecular weight for C12H7F5O5 was consistent with the assigned structure. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). | |
With cesium fluoride; In tetrahydrofuran; for 21h; | A 100 mL round bottom flask was charged with bis-MPA (5.00 g, 37 mmol, MW 134.1), bis-(pentafluorophenol) carbonate (PFC, 31.00 g, 78 mmol, MW 394.1), and CsF (2.5 g, 16.4 mmol) rinsed with 70 mls of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with sodium bicarbonate, water and was dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethyl acetate/hexane mixture) to give MTC-C6F5 as a white crystalline powder. The GCMS had a single peak with mass of 326 g/mol. The calculated molecular weight for C12H7F5O5 was consistent with the assigned structure. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). |
With cesium fluoride; In tetrahydrofuran; for 20h; | A 100 mL round bottom flask was charged with bis-MPA (5.00 g, 37 mmol, MW 134.1), bis-(pentafluorophenol) carbonate (PFC, 31.00 g, 78 mmol, MW 394.1), and CsF (2.5 g, 16.4 mmol) rinsed with 70 mls of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with sodium bicarbonate, water and was dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethyl acetate/hexane mixture) to give MTC-C6F5 as a white crystalline powder. The GCMS had a single peak with mass of 326 g/mol. The calculated molecular weight for C12H7F5O5 was consistent with the assigned structure. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). | |
With cesium fluoride; In tetrahydrofuran; for 21h; | (0155) Preparation of MTC-C6F5 (MW 326.2). (0156) A 100 mL round bottom flask was charged with bis-MPA, (7), (5.00 g, 37 mmol, MW 134.1), bis-(pentafluorophenol) carbonate (PFC, 31.00 g, 78 mmol, MW 394.1), and CsF (2.5 g, 16.4 mmol) rinsed with 70 mls of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with aqueous sodium bicarbonate and dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethyl acetate/hexane mixture) to give MTC-C6F5 as a white crystalline powder. The GCMS had a single peak with mass of 326 g/mol. The calculated molecular weight for C12H7F5O5 was consistent with the assigned structure. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). | |
With cesium fluoride; In tetrahydrofuran; for 21h; | A 100 mL round bottom flask was charged with bis-MPA, (7), (5.00 g, 37 mmol, MW 134.1), <strong>[59483-84-0]bis-(pentafluorophenyl) carbonate</strong> (PFC, 31.00 g, 78 mmol, MW 394.1), and CsF (2.5 g, 16.4 mmol) rinsed with 70 mLs of tetrahydrofuran (THF). Initially the reaction was heterogeneous, but after one hour a clear homogeneous solution was formed that was allowed to stir for 20 hours. The solvent was removed in vacuo and the residue was re-dissolved in methylene chloride. The solution was allowed to stand for approximately 10 minutes, at which time the pentafluorophenol byproduct precipitated and could be quantitatively recovered. This pentafluorophenol byproduct showed the characteristic 3 peaks in the 19F NMR of pentafluorophenol and a single peak in the GCMS with a mass of 184. The filtrate was extracted with sodium bicarbonate, water and was dried with MgSO4. The solvent was evaporated in vacuo and the product was recrystallized (ethyl acetate/hexane mixture) to give MTC-C6F5 as a white crystalline powder. The GCMS had a single peak with mass of 326 g/mol. The calculated molecular weight for C12H7F5O5 was consistent with the assigned structure. 1H-NMR (400 MHz in CDCl3): delta 4.85 (d, J=10.8 Hz, 2H, CHaHb), 4.85 (d, J=10.8 Hz, 2H, CHaHb), 1.55 (s, 3H, CCH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With cesium fluoride; In tetrahydrofuran; at 20℃; for 16h;Product distribution / selectivity; | In a 20 mL glass vial, Bn-MPA (500 mg, 2.25 mmol), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (1.32 g, 3.35 mmol), cesium fluoride (67 mg, 0.44 mmol, 0.20 eq), and dry THF (5 mL) were added and stirred for 16 hours at room temperature. After the solvent was evaporated from the inhomogeneous mixture methylene chloride (15 mL) was added to the residue, and the insoluble material was filtered. The filtrate was then washed with saturated aqueous NaHCO3 (2×20 mL), dried over MgSO4, filtered and evaporated to give MTC-Bn as a white solid (402 mg, 71.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Amino-1-propanol, (6), (2.29 mL, 30.0 mmol) was dissolved in THF (40 mL) in a 100 mL round-bottom flask and the solution was cooled to -5 C. with ice-salt bath. A solution of PFC (13.02 g, 33.1 mmol) in dry THF (25 mL) was added stepwise over 30 min, at which point the reaction mixture was allowed to warm to room temperature for 2 hours. CsF (0.91 g, 6.0 mmol, 0.20 eq) was added to the mixture prior to overnight stirring. The solvent was removed in vacuo, and the resulting residue was dissolved in methylene chloride, cooled and filtered to remove insoluble material. The filtrate was dried under vacuum to yield a pale amber solid as a crude product, which was recrystallized in a mixture of ethyl acetate and hexane. The crystalline compound was then heated to about 100 C. under vacuum until no signal was observed in 19F NMR. The molten residue was cooled to room temperature to provide the isolated product, TMU, as a white solid (1.86 g, 61.2%). 1H NMR (400 MHz, CDCl3): delta 5.87 (b, 1H, NH), 4.30 (t, 2H, CH2O), 3.38-3.36 (m, 2H, CH2N), 2.02-1.96 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): delta 152.7, 66.1, 38.8, 20.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With cesium fluoride; In tetrahydrofuran; at 20℃; for 20h; | To a 100 mL round bottom flask, 1,1-bis(hydroxymethyl)butanoic acid (3.0 g, 20 mmol) was combined with bis(pentafluorophenyl carbonate) (18.4 g, 47 mmol, 2.3 eq) and cesium fluoride (0.92 g, 6.0 mmol) in tetrahydrofuran (29 mL) and stirred for 20 hours at room temperature. The reaction was concentrated (bath temperature: 30 C. pressure: 100 mm Hg), and redissolved in methylene chloride. Upon sitting (10 min) the pentafluorophenol byproduct fell out of solution and could be recovered. After removal of the byproduct by filtration, the mother liquid was washed with aqueous sodium bicarbonate (3×50 mL) (pH of aqueous layer 8) and brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated to give the crude product.The crude was dissolved in ethyl acetate (6 mL) at 65 C. n-Hexane (24 mL) was added to the solution at the same temperature after which the solution was slowly cooled to room temperature. After stirring the solution over night, the crystal was separated by filtration (5.1 g, 75% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Tetrabutylammonium fluoride (1M in THF) (2.86 mL, 2.86 mmol) was added to oxetan-3-one (2.06 g, 28.59 mmol) and trimethyl(trifluoromethyl)silane (2M in THF) (23.58 mL, 47.17 mmol, 1.65 eq.) in THF (25 mL) at 20 C. under nitrogen. An ice bath was used to control the exotherm. The resulting dark brown solution was stiffed at 20 C. for 2 hours. 6M hydrochloric acid (60 mL) was added at 0 C. then the temperature was allowed to rise to and stirred at 20 C. for 2 hours. The reaction mixture was diluted with Et2O (100 mL), and washed with saturated brine (50 mL). The aqueous was extracted with DCM (2×100 ml). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was gently evaporated (stopped at 400 mbar) to remove solvent then to the mixture was added bis(perfluorophenyl)carbonate (13.52 g, 34.31 mmol) and acetonitrile (15 mL). To this mixture was added triethylamine (12.75 mL, 91.49 mmol) dropwise at 0 C. over a period of 5 minutes under nitrogen. The resulting solution was allowed to warm to room temperature then stirred at 20 C. for 18 hours. All volatiles were removed under reduced pressure to leave a purple oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% DCM in isohexane. Pure fractions were evaporated to dryness to afford perfluorophenyl 3-(trifluoromethyl)oxetan-3-yl carbonate (8.38 g, 83%) as a yellow oil.1H NMR (400 MHz, CDCl3, 30 C.) 4.88-4.93 (2H, m), 5.02-5.07 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; N,N-dimethyl-formamide; | Preparation of bis(4-(3-(5-hydroxypentyl)ureido)benzyl)terephthalamide (HPUBT) To a DMF solution (4 mL) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (1.0 g, 2.53 mmol) was added a solution of BAMT (0.37 g, 1.0 mmol) in DMF (4 mL). The reaction mixture was stirred for 1 hour at room temperature, 5-amino-1-pentanol (0.45 mL, 4.15 mmol) was added, and the mixture was kept stirring for additional 2 hours. Methanol (200 mL) was added to the mixture to stir for 3 h where only the product was precipitated. The precipitate was then filtered and dried in vacuum at 80 C. to give HPUBT as a yellowish solid (0.56 g, 89%). 1H NMR (400 MHz, DMSO-d6): delta 9.09 (t, 2H; PhNH), 8.37 (s, 2H; PhCONH), 7.95 (s, 4H; Ph), 7.32 (d, 4H; Ph), 7.17 (d, 4H; Ph), 6.08 (t, 2H; NHCH2), 4.43-4.34 (m, 6H; PhCH2NH and OH), 3.38 (q, 4H; CH2OH), 3.05 (q, 4H; NHCH2CH2), 1.47-1.35 (m, 8H; CH2), 1.34-1.23 (m, 4H; CH2). 13C NMR (125 MHz, DMSO-d6): delta 165.4, 155.1, 139.3, 136.6, 131.8, 127.7, 127.2, 117.4, 60.6, 42.3, 32.2, 29.6, 22.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With cesium fluoride; In tetrahydrofuran; dichloromethane; ethyl acetate; | Example 1 Preparation of (5-methyl-2-oxo-1,3-dioxan-5-yl)methyl perfluorophenyl carbonate (TMCPFP) To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30 C.) and the residue was dissolved in methylene chloride (~50 mL). Upon standing (~10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3*50 mL) until the pH of aqueous layer was ~8 and then with brine (1*50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65 C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131 C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) -154.3~-154.3 (m, 2F), -157.8 (t, 1F, J=22 Hz), -162.6~-162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With cesium fluoride; In tetrahydrofuran; at 20℃; for 4h; | Example 1. Preparation of (5-methyl-2-oxo-l,3-dioxan-5-yl)methyl per fluorophenyl carbonate (TMCPFP).TMCPFP To a 100 mL round bottom flask, l,l,l-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30 C) and the residue was dissolved in methylene chloride (-50 mL). Upon standing (~10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3 x 50 mL) until the pH of aqueous layer was ~8 and then with brine (1 x 50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65 C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield), m.p. 130-131 C. 1H NMR (CDC13, 400Hz) 1.22(s, 3H), 4.23(d, 2H, J = 1 lHz), 4.37(s, 2H), 4.38(d, 2H, J = 1 lHz). 19F NMR(CDC13, 376Hz) - 154.3~-154.3(m, 2F), -157.8(t, IF, J= 22Hz), -162.6~-162.7(m, 2F). 13C NMR(CDC13, 100Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With cesium fluoride; In tetrahydrofuran; at 20℃; for 6h; | Example 2. Preparation of (2-oxo-l,3-dioxolan-4-yl)methyl perfluorophenyl carbonate(GLCPFP).GLCPFPGlycerin (1.0 g, 0.011 mmol) was combined with bis(pentafluorophenyl carbonate) (9.8 g, 0.025 mmol, 2.3 eq) and CsF (0.49 g, 0.033 mmol, 0.3 eq) in THF (15.6 mL) and stirred for 6 hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated, and redissolved in methylene chloride. After sitting for 10 minutes, the pentafluorophenol byproduct fell out of the solution. After removal of the byproduct by filtration, the mother liquid was washed brine. The organic layer was separated and dried by NaS04. The solution was concentrated to give the crude product. The crude was dissolved with n-hexane (2 mL), and a seed crystal was added to the solution. After keeping the solution at 0 C for one hour, the crystal was separated by filtration (2.97 g, y. 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere; | 2.3 (Pentafluorophenyl)[(3beta-22E)-stigmasta-5,22-dien-3-yl]succinate (3) A solution of 4-oxo-4-[(3beta,22E)-stigmasta-5,22-dien-3-yl-oxy]butanoic acid (2, 0.998 mmol), bis(pentafluorophenyl)-carbonate (0.512 g, 0.998 mmol) and 4-methylmorpholine (0.1 mL) in DMF (4 mL) was stirred at r. t. and under argon atmosphere for 1.5 h. Then dioxane (4 mL) was added, the mixture was frozen and lyophilized. Purification by column chromatography on silica gel afforded 0.6 g (89%) of the product (3). 1H NMR (CDCl3): delta (ppm) 1.10-1.14 + 1.84-1.89 (m, 2H, 1'-CH2), 1.53-1.57 + 1.84-1.89 (m, 2H, 2'-CH2), 4.66 (dddd, 1H, J = 4.1; 8.0; 8.9; 11.5 Hz, 3'-CH), 2.31-2.34 (m, 2H, 4'-CH2), 5.37 (ddt, 1H, J = 1.6; 1.6; 2.0; 5.5 Hz, 6'-CH), 1.36-1.40 + 1.94-1.97 (m, 2H, 7'-CH2), 1.45-1.80 (m, 1H, 8'-CH), 0.92-0.99 (m, 1H, 9'-CH), 1.39-1.45 (m, 2H, 11'-CH2), 1.18-1.22 + 1.97-2.02 (m, 2H, 12'-CH2), 1.02-1.07 (m, 1H, 14'-CH), 1.13-1.19 + 1.43-1.48 (m, 2H, 15'-CH2), 1.23-1.28 + 1.59-1.63 (m, 2H, 16'-CH2), 1.15-1.19 (m, 1H, 17'-CH), 0,70 (s, 3H, 18'-CH3), 1.02 (s, 1H, 19'-CH3), 2.01-2.05 (m, 1H, 20'-CH), 1.02 (d, 3H, J = 6.6 Hz, 21'-CH3), 5.15 (dd, 1H, J = 8.7; 15.2 Hz, 22'-CH), 5.01 (ddd, 1H, J = 0.5; 8.9; 15.2 Hz, 23'-CH), 1.53-1.56 (m, 1H, 24'-CH), 1.51-1.57 (m, 1H, 25'-CH), 0.85 (d, 3H, J = 6.5 Hz, 26'-CH3), 0,80 (d, 3H, J = 6.5 Hz, 27'-CH3), 1.23-1.29 + 1.67-1.73 (m, 2H, 28'-CH2), 0.81 (t, 3H, J = 7.3 Hz, 29'-CH3), 2.73-2.76 (m, 2H, 2-CH2), 2.98-3.01 (m, 2H, 3-CH2). 13C NMR (CDCl3): delta (ppm) 36.90 (t, 1'-CH2), 27.63 (t, 2'-CH2), 74.81 (d, 3'-CH), 37.95 (t, 4'-CH2), 139.40 (s, 5'-C), 122.83 (d, 6'-CH), 31.81 (t, 7'-CH2), 31.87 (t, 8'-CH), 49.98 (d, 9'-CH), 36.56 (10'-C), 20.99 (t, 11'-CH2), 39.58 (t, 12'-CH2), 42.17 (s, 13'-C), 56.74 (d, 14'-CH), 24.33 (t, 15'-CH2), 28.91 (t, 16'-CH2), 55.89 (d, 17'-CH), 12.02 (q, 18'-CH3), 19.26 (q, 19'-CH3), 40.51 (d, 20'-CH), 21.21 (q, 21'-CH3), 138.31 (d, 22'-CH), 129.24 (d, 23'-CH), 51.22 (d, 24'-CH), 31.86 (d, 25'-CH), 21.09 (q, 26'-CH3), 18.96 (q, 27'-CH3), 25.41 (t, 28'-CH2), 12.26 (q, 29'-CH3), 168.49 (s, 1-C), 29.16 (t, 2-CH2), 28.47 (t, 3-CH2), 170.70 (s, 4-C), 141.92 (s, 1"-C), 140.29 (s, 2"-C), 138.67 (s, 3"-C), 127.01 (s, 4"-C), 138.67 (s, 5"-C), 140.29 (s, 6"-C). 19F NMR: delta (ppm) -148.62 (d, 2"-CF), -158.38 (dd, 3"-CF), -154.60 (dd, 4"-CF), -158.38 (dd, 5"-CF), -148.62 (d, 6"-CF). For C39H51F5O4 (678.81) calculated m/z: 701.3600 [M+Na]+, found m/z: 701.3599 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.1% | With triethylamine; In tetrahydrofuran; acetonitrile; at 0 - 20℃; for 23h;Inert atmosphere; | To a solution of 3-(trifluoromethyl)oxetan-3-ol in THF under nitrogen was added bis(perfluorophenyl) carbonate (6.43 g, 16.3 mmol) and MeCN (6 mL). To this at 0 C was added triethylamine (6.10 mL, 43.5 mmol) dropwise. The mixture was stirred at room temperature for 23 h. The mixture was concentrated under reduced pressure to dryness and the residue was purified by Biotage column chromatography to afford the title compound as a yellow oil (2.35 g, 49.1 %). Exact mass calculated for CiiH4F804: 352.0, found: LCMS mlz = 353.2 [M+H]+; lU NMR (400 MHz, CDC13) delta ppm 4.91 (d, J = 9.85 Hz, 2H), 5.04 (d, J = 8.59 Hz, 2H). |
49.1% | With triethylamine; In acetonitrile; at 0 - 20℃; for 23h; | To this solution was added bis(perfluorophenyl) carbonate (6.432 g, 16.32 mmol) and MeCN (6 mL). To this at 0 C was added triethylamine (6.10 mL, 43.5 mmol) dropwise. The mixture was stirred at rt for 23 h. The mixture was concentrated under reduced pressure and the residue was purified by Biotage column chromatography to afford the title compound (2.3514 g, 6.678 mmol, 49.1%) as yellow oil. ?H NMR (400 MHz, CDC13) oe ppm 4.91 (d, J= 9.85 Hz, 2H), 5.04 (d, J = 8.59 Hz, 2H). |
Step A: Preparation of Perfluorophenyl 3-(Trifluoromethyl)oxetan-3-yl carbonate.To a solution of oxetan-3-one (0.98 g, 13.60 mmol) and trimethyl(trifluoromethyl)silane (3.506 mL, 22.44 mmol) in THF (10 mL) was slowly added 1 M tetrabutylammonium fluoride solution in THF (1.360 mL, 1.360 mmol). The mixture was stirred at room temperature for 2 h and then cooled to 0 C. The mixture was quenched with 6 N HC1 (aq) and then stirred at room temperature for 2 h. The mixture was extracted with ether (2X) and the combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure (350 mmHg, room temperature, water bath) to give a solution of 3- (trifluoromethyl)oxetan-3-ol. lU NMR (400 MHz, CDC13) delta ppm 4.62 (d, J = 8.34 Hz, 2H), 4.80 (d, J = 7.33 Hz, 2H).To this solution was added bis(perfluorophenyl) carbonate (6.432 g, 16.32 mmol) andMeCN (6.000 mL). To this at 0 C was added triethylamine (6.066 mL, 43.52 mmol) dropwise. The reaction was stirred at room temperature for 23 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give the title compound (2.3514 g, 6.678 mmol, 49.1 %) as a yellow oil. lU NMR (400 MHz, CDC13) delta ppm 4.91 (d, J = 9.85 Hz, 2H), 5.04 (d, J = 8.59 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
251 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of N-(2-Tetradecylhexadecanoyl)-15-amino-4,7,10,13- tetraoxapentadecanoic acid (general formula VIII; where n1= 3 and n5 = 13; 206 mg, 0.29 mmol) in dry N,N-dimethylformamide (10 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (128 mg, 0.32 mmol) and 4-methylmophiholine (0.25 ml, 2.45 mmol) were added and the stirring was continued at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2x 20 ml) to give pentafluorophenyl ester of N-(2- Tetradecylhexadecanoyl)-15-amino-4,7,10,13-tetraoxapentadecanoic acid (251 mg), which was immediately used at the next condensation step. |
251 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of N-(2-Tetradecylhexadecanoyl)-15-amino-4,7,10,13-tetraoxapentadecanoic acid (general formula VIII; where n1=3 and n5=13; 206 mg, 0.29 mmol) in dry N,N-dimethylformamide (10 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (128 mg, 0.32 mmol) and 4-methylmorpholine (0.25 ml, 2.45 mmol) were added and the stirring was continued at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2×20 ml) to give pentafluorophenyl ester of N-(2-Tetradecylhexadecanoyl)-15-amino-4,7,10,13-tetraoxapentadecanoic acid (251 mg), which was immediately used at the next condensation step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of cholest-5-en-3p-yloxyacetic acid (general formula IX, where n2 = 1;134 mg, 0.3 mmol) in dry N,N-dimethylformamide (4 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (130 mg, 0.33 mmol) and 4-methylmorpholine (0.1 ml, 1 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2x 20 ml) to give pentafluorophenyl ester of cholest-5-en-3p- yloxyacetic acid (140 mg), which was immediately used at the next condensation step. |
164 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of Cholest-5-en-3beta-yloxyacetic acid (general formula IX, where n2 = 1 ; 160 mg, 0.36 mmol) in dry N,N-dimethylformamide (5 ml) <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (156 mg, 0.39 mmol) and 4-methylmorpholine (0.25 ml, 2.45 mmol) were added. The mixture was stirred at room temperature for 1 h and then lyophilized from dioxane (2 x 50 ml) to give pentafluorophenyl ester of Cholest-5-en-3beta-yloxyacetic acid (164 mg), which was immediately used in the next reaction step |
164 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of Cholest-5-en-3beta-yloxyacetic acid (general formula IX, where n2=1; 160 mg, 0.36 mmol) in dry N,N-dimethylformamide (5 ml) <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (156 mg, 0.39 mmol) and 4-methylmorpholine (0.25 ml, 2.45 mmol) were added. The mixture was stirred at room temperature for 1 h and then lyophilized from dioxane (2×50 ml) to give pentafluorophenyl ester of Cholest-5-en-3beta-yloxyacetic acid (164 mg), which was immediately used in the next reaction step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of 2-tetradecylhexadecanoic acid (formula VII where n5 = 13; 51.5 mg, 0.1 1 mmol) in dry N,N-dimethylformamide (4 mL), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (49 mg, 0.12 mmol) and 4-methylmorpholine (0.1 mL, 1 mmol) were added and the stirring was continued at room temperature for 1 h. The mixture was lyophilized from dioxane (2x 20 mL), to give pentafluorophenyl ester of 2-tetradecylhexadecanoic acid (67 mg), which was immediately used at next condensation step |
67 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of 2-tetradecylhexadecanoic acid (formula VII where n5=13; 51.5 mg, 0.11 mmol) in dry N,N-dimethylformamide (4 mL), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (49 mg, 0.12 mmol) and 4-methylmorpholine (0.1 mL, 1 mmol) were added and the stirring was continued at room temperature for 1 h. The mixture was lyophilized from dioxane (2×20 mL), to give pentafluorophenyl ester of 2-tetradecylhexadecanoic acid (67 mg), which was immediately used at next condensation step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of (cholest-5-en-3p-yloxy)acetyl-15-amino-4,7,10,13- tetraoxapentadecanoic acid (general formula X; where n3 = 1 and n = 3; 149 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (100 mg, 0.39 mmol) and 4-methylmorpholine (0.25 ml; 2.45 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2x 20 ml) to give pentafluorophenyl ester of (cholest-5-en-3P- yloxy)acetyl-15-amino-4,7,10,13-tetraoxapentadecanoyl acid (140 mg), which was immediately used in the next condensation step. |
140 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of (cholest-5-en-3beta-yloxy)acetyl-15-amino-4,7,10,13-tetraoxapentadecanoic acid (general formula X; where n3=1 and n4=3; 149 mg, 0.22 mmol) in dry N,N-dimethylformamide (5 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (100 mg, 0.39 mmol) and 4-methylmorpholine (0.25 ml; 2.45 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2×20 ml) to give pentafluorophenyl ester of (cholest-5-en-3beta-yloxy)acetyl-15-amino-4,7,10,13-tetraoxapentadecanoyl acid (140 mg), which was immediately used in the next condensation step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
382 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of 4-(cholest-5-en-3beta-yloxy)butanoic acid (general formula IX; where n2 = 3; 283 mg; 0.6 mmol) in dry N,N-dimethylformamide (4 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (260 mg, 0,66 mmol) and 4-methylmorpholine (0.1 ml, 1 mmol) were added and the stirring was continued at room temperature for 1 h. The crude reaction mixture was lyophilized from dioxane (2x 20 ml) to give pentafluorophenyl ester of 4-(cholest-5-en-3 -yloxy)butanoic acid (382 mg), which was immediately used at next reaction step. |
382 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a solution of 4-(Cholest-5-en-beta-yloxy)butanoic acid (general formula IX, where n2 = 3; 283 mg, 0.6 mmol) in dry N,N-dimethylformamide (4 ml) <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (260 mg, 0.66 mmol) and 4-methylmorpholine (0.1 ml, 1 mmol) were added. The mixture was stirred at room temperature for 1 h and then lyophilized from dioxane (2 x 20 ml) to give pentafluorophenyl ester of 4-(Cholest-5-en-3p-yloxy)butanoic acid (382 mg), which was immediately used in the next reaction step. |
382 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of 4-(cholest-5-en-3beta-yloxy)butanoic acid (general formula IX; where n2=3; 283 mg; 0.6 mmol) in dry N,N-dimethylformamide (4 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (260 mg, 0.66 mmol) and 4-methylmorpholine (0.1 ml, 1 mmol) were added and the stirring was continued at room temperature for 1 h. The crude reaction mixture was lyophilized from dioxane (2×20 ml) to give pentafluorophenyl ester of 4-(cholest-5-en-3beta-yloxy)butanoic acid (382 mg), which was immediately used at next reaction step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
184 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of [4-(Cholest-5-en-3 -yloxy)butanoyl]-15-amino-4,7,10,13- tetraoxapentadecanic acid (general formula X, where n3 = 3 and ri4 = 3; 1 17 mg, 0.17 mmol) in dry N,N-dimethylformamide (5 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (73 mg, 0.18 mmol) and 4-methylmorpholine (0.1 ml; 1 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2x 20 ml) to give pentafluorophenyl ester of [4-(Cholest-5-en-3beta-yloxy)butanoyl]-15- amino-4,7,10,13-tetraoxapentadecanoic acid (184 mg), which was immediately used in the next condensation step. |
184 mg | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a stirred solution of [4-(Cholest-5-en-3beta-yloxy)butanoyl]-15-amino-4,7,10,13-tetraoxapentadecanic acid (general formula X, where n3=3 and n4=3; 117 mg, 0.17 mmol) in dry N,N-dimethylformamide (5 ml), <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (73 mg, 0.18 mmol) and 4-methylmorpholine (0.1 ml; 1 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was lyophilized from dioxane (2×20 ml) to give pentafluorophenyl ester of [4-(Cholest-5-en-3beta-yloxy)butanoyl]-15-amino-4,7,10,13-tetraoxapentadecanoic acid (184 mg), which was immediately used in the next condensation step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | In toluene; at 10 - 15℃; | Example 1: Preparation of solifenacin intermediate [115] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of toluene and then stirred at 10 ~ 15 for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 10 ~ 15 for 7 ~ 8 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1 ~ 2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, 1270 mL of water was added to the reaction solution, and then the pH of the reaction solution was adjusted to 9 ~ 10 using ammonium hydroxide. Then, an organic layer was separated from the reaction solution. Finally, the reaction solution was washed with 1270 mL of water, dried with MgSO4 and then concentrated under reduced pressure to obtain 304.9 g (90.4%) of (3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate.[116] 1H NMR (MeOD, 400MHz) : 1.79-1.89(m, 2H, -CH-CH 2 ), 1.97-2.12(m, 2H, -CH-CH 2 ), 2.30-2.40(m, 1H, -O-CH-CH), 3.18-3.30(m, 6H, N-CH 2 -CH2,N-CH 2 -CH2,N-CH 2 -CH2), 3.59-3.75(m, 1H, -O-CH-CH2)[117] Elementary analysis of C14H12F5NO3 [118] Theoretical value: C: 49.8, H: 3.6, N: 4.1 [119] Experimental value: C: 49.1, H: 4.4, N: 3.8 |
90.4% | Example 1 Preparation of Solifenacin Intermediate 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of toluene and then stirred at 10?15 C. for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 10?15 C. for 7?8 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1?2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, 1270 mL of water was added to the reaction solution, and then the pH of the reaction solution was adjusted to 9?10 using ammonium hydroxide. Then, an organic layer was separated from the reaction solution. Finally, the reaction solution was washed with 1270 mL of water, dried with MgSO4 and then concentrated under reduced pressure to obtain 304.9 g (90.4%) of (3R)-1-azabicyclo[2,2,2]oct-3-yl pentafluorophenylcarbonate. 1H NMR (MeOD, 400 MHz): 1.79-1.89 (m, 2H, -CH-CH2), 1.97-2.12 (m, 2H, -CH-CH2), 2.30-2.40 (m, 1H, -O-CH-CH), 3.18-3.30 (m, 6H, N-CH2-CH2,N-CH2-CH2,N-CH2-CH2), 3.59-3.75 (m, 1H, -O-CH-CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | Example 11: Preparation of solifenacin succinate [148] 127.2 g (1.0 mol) of (R)-quinuclidinol was dissolved in 1270 mL of toluene and then stirred at 25 ~ 30 for 20 minutes to obtain a reaction solution. Subsequently, 472.9 g (1.2 mol) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> was added to the reaction solution to form a suspended reaction solution, and then the suspended reaction solution was stirred at 25 ~ 30 for 3 ~ 4 hours. After confirming the completion of a reaction using thin layer chromatography (TLC), 209.3 g (1.0 mol) of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline was added to the reaction solution, and then stirred at 25 ~ 30 for 4 ~ 5 hours. After confirming the completion of a reaction using high performance liquid chromatography (HPLC), the reaction solution was concentrated under reduced pressure. Subsequently, 1270 mL water was added to the reaction solution, and concentrated hydrochloric acid was added dropwise into the reaction solution to adjust the pH of the reaction solution to 1 ~ 2. Then, the reaction solution was washed with 1270 mL of toluene to remove pentafluorophenol (a by-product formed during the reaction) from the reaction product. Then, an aqueous layer was extracted from the reaction solution using 1270 mL of dichloromethane, and then the reaction solution was concentrated under reduced pressure. Then, 1270 mL of water was added to the reaction solution, the pH of the reaction solution was adjusted to 9 ~ 10 using ammonium hydroxide, and then an aqueous layer was further extracted from the reaction solution using 1270 mL of toluene. Subsequently, 1270 mL of acetone and 118.1 g (1.0 mol) of succinic acid were added to the reaction solution, stirred at 55 ~ 60 for 30 minutes, further stirred at 10 ~ 15 for 2 hours, and then filtered to obtain a reaction product. Finally, the reaction product was washed with 640 mL of toluene and 640 mL of acetone, and then dried in vacuum at 40 to obtain 390.2 g (81.2%) of solifenacin succinate.[149] HPLC content: 99.9%, optical purity: 99.95% [150] Melting point: 146 ~ 148 [151] 1H NMR (MeOD, 400MHz) : 1.89-2.21(m, 4H, -CH-CH 2 ,-CH-CH 2 ), 2.34(m, 1H, -CH-CH-CH2), 2.49(s, 4H, -O-CO-CH 2 -CH 2 -), 2.75-3.10(m, 3H, -N-CH2-CH 2 -CH, -N-CH2-CH 2 -CH), 3.17-3.40(m, 5H, -N-CH2-CH 2 -CH, -N-CH 2 -CH2, -N-CH 2 -CH2), 3.60-3.63(m, 2H, -N-CH 2 -CH2-CH), 3.93(m, 1H, -N-CH 2 -CH2-CH), 5.03(m, 1H, -O-CH-CH), 6.22-6.35(m, 1H, -N-CH-CH), 7.08-7.28(m, 9H, aromatic H) [152] Elementary analysis of C27H32N2O6 [153] Theoretical value: C: 67.4, H: 6.7, N: 5.8 [154] Experimental value: C: 66.7, H: 6.7, N: 5.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
900 mu THF (anhydrous, mol. sieve) and 300 mu of a 1 M LiOEt solution in THF (300 muiotaetaomicron) were drawn to 30 mg treprostinil loaded TCP resin (21,6 muiotaetaomicron) in a single use 2 mL syringe reactor equipped with a PE frit. Reactor was agitated for 40 min at RT. Solution was dispelled and resin was washed with THF (2x). A solution of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (lOOmg, 254 muiotaetaomicron) in 1 mL THF was drawn into the syringe which was agitated for 90 min at RT. Solution was dispelled and resin was washed with THF (5x) and DMF (5x). A solution of linker building block 15a (50 mg, 83 muiotaetaomicron), DIPEA (50 mu, 287 muiotaetaomicron) and DMAP (1 mg, 8 muiotaetaomicron) in 300 mu DMF (anhydrous, mol. sieve) was drawn into the syringe. Syringe was agitated for 3 h at RT. Solution was dispelled and resin was washed with DMF (lOx) and DCM (lOx). Product was cleaved from resin by incubation with 500 mu of cleavage cocktail HFIP/DCM/TES 90/10/2 v/v/v for 10 min (3x). Resin was washed with 500 mu DCM (2x). TFA (250 mu) was added to the combined cleavage and washing solutions and the mixture was incubated at RT for 10 min. Volatiles were removed under reduced pressure. Residue was subjected to HPLC purification which gave thiols 16a/16b as a mixture of the two regioisomers. HPLC eluate was used in the next step without further processing. MS: m/z 678.1 = [M+H]+ (MW calculated = 678.0 g/mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of urea: Resin was washed with DCM (10 times) and reacted with <strong>[59483-84-0]bis(pentafluorophenyl) carbonate</strong> (MW 394 g/mol, 414 mg, 1.05 mmol) and DIEA (365 iL,2.1 mmol) in DCM at RT for 45 mm. Resin was washed with DCM (5 times) and DMF (10 times) and reacted with ic (MW 482.5 g/mol, 203 mg, 0.42 mmol) and 2.5 eq DIEA (183 iL, 1.05 mmol) in DMF for 75 mm at RT. Resin was washed with DMF (10 times). Cleavage from resin and boc deprotection: Resin was washed with DCM (10 times) and treated three times for 30 minutes with 7/3 (v/v) DCM/HFIP. Eluates were combined andvolatiles were removed under reduced pressure. Residue was incubated in TFA for 10 mm atRT. TFA was removed under a stream of nitrogen and id was purified by RP-HPLC.Yield: 160 mg (0.25 8 mmol, HC1 salt).MS: m/z 412.2 = [M+H] (MW calculated = 411.5 g/mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,4,6-trimethyl-pyridine; In dichloromethane; at 20℃; for 16h; | 4c (bis HC1 salt, 196 mg, 0.155 mmol) was dissolved in 12 mL DCM (anhydrous, mol. sieve). Bis(pentafluorophenyl) carbonate (MW 394 g/mol, 122 mg, 0.3 10 mmol) and sym-collidine (205 jiL, 1.55 mmol) were added and mixture was stirred for 16 h at RT. Product was precipitated from reaction mixture by adding 30 mL MTBE (puriss., p.a.; > 99.5%) and separated by centrifugation. Precipitate was redissolved in DCM and precipitation procedurewas repeated. Precipitate was redissolved in DCM and volatiles were removed in vacuo (waterbath at 20C). Product 4d was dried by means of lyophilizer.Yield: 185 mg (88 %)MS: m/z 1357.52 = [M+H] (MW calculated = 1357.40) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
430 mg | With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 0.25h; | Synthesis of intermediate 3f 485 mg <strong>[59483-84-0]bis-(pentafluorophenyl)carbonate</strong>, 12 mg DMAP and 400 mg (TFA salt) 3e were dissolved in 6 mL acetonitrile (dry, mol. sieve). 435 jiL DIEA was added and reaction mixture was stirred for 15 mm at RT, cooled to 0C, and acidified with acetic acid (0.5 mL). Product 3f was purified by RP-HPLC.Yield: 430 mg (TFA salt). MS: [M+Na] = 988.1 (MW calculated = 964.4 g/mol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
900 muL THF (anhydrous, mol. sieve) and 300 mu of a 1 M LiOEt solution in THF (300 muiotaetaomicron) were drawn to 30 mg treprostinil loaded TCP resin (21.6 muiotaetaomicron) in a single use 2 mL syringe reactor equipped with a PE frit. Reactor was agitated for 40 min at RT. Solution was dispelled and resin was washed with THF (2x). A solution of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (lOOmg, 254 muetaiotaomicron) in 1 mL THF was drawn into the syringe which was agitated for 90 min at RT. Solution was dispelled and resin was washed with THF (5x) and DMF (5x). A solution of linker building block 2a (50 mg, 83 muetaiotaomicron), DIPEA (50 mu, 287 muetaiotaomicron) and DMAP (1 mg, 8 muetaiotaomicron) in 300 mu DMF (anhydrous, mol. sieve) was drawn into the syringe. Syringe was agitated for 3 h at RT. Solution was dispelled and resin was washed with DMF (lOx) and DCM (lOx). Product was cleaved from resin by incubation with 500 mu of cleavage cocktail HFIP/DCM/TES 90/10/2 v/v/v for 10 min (3x). Resin was washed with 500 mu DCM (2x). TFA (250 mu) was added to the combined cleavage and washing solutions and the mixture was incubated at RT for 10 min. Volatiles were removed under reduced pressure. Residue was subjected to HPLC purification which gave thiols 3a/3b as a mixture of the two regioisomers. HPLC eluate was used in the next step without further processing. MS: m/z 678.1 = [M+H]+ (MW calculated = 678.0 g/mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,4,6-trimethyl-pyridine; In dichloromethane; at 20℃; for 16h;Molecular sieve; | Synthesis of intermediate id ic (bis HC1 salt, 196 mg, 0.155 mmol) was dissolved in 12 mL DCM (anhydrous, mol. sieve). Bis(pentafluorophenyl) carbonate (MW 394 g/mol, 122 mg, 0.3 10 mmol) and sym-collidine(205 jiL, 1.55 mmol) were added and mixture was stirred for 16 h at RT. Product was precipitated from reaction mixture by adding 30 mL MTBE (puriss., p.a.; > 99.5%) and separated by centrifugation. Precipitate was redissolved in DCM and precipitation procedure was repeated. Precipitate was redissolved in DCM and volatiles were removed in vacuo (waterbath at 20C). Product id was dried by means of lyophilizer. Yield: 185 mg (88 %)MS: m/z 1357.52 = [M+H] (MW calculated = 1357.40)Pfp ester of id is partially hydrolyzed under LCMS conditions. A purity of 95 % (LCMS, 215 nm) was confirmed after derivatization of id with 1-dodecylamine. For derivatization purpose0.1 mg id is reacted with 0.3 mg 1-dodecylamine for 5 mm at RT in DCM and analyzed by means of LCMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Step 2: Preparation of { (R)- 1- [4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yll-piperidin-3-yl } - carbamic acid pentafluorophenyl ester To a solution of crude 2-((R)-3-amino-piperidin- 1 -yl)-5-(pyridin-2-ylamino)-thiazole-4-carbonitrile (- 15 mg, -50 tmol) in tetrahydrofuran (1 mL) at 0 C under argon was added diisopropylethylamine (18 tL, 100 imol) followed by <strong>[59483-84-0]carbonic acid dipentafluorophenyl ester</strong> (22 mg, 55 tmol). The reaction mixture was allowed to warm slowly to ambient temperature and then stuffed for an additional 1 hour. An aliquot was analyzed by LC-MS to ensure complete reaction prior to subjecting the reaction mixture to the subsequent step in the synthetic sequence.LC/MS: nz/zcalculatedfor C21H15F5N6025 ([M+Hf): 511.5. Found: 511.2 (positive mode electrospray ionization). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: To a solution/suspension of carboxylic acid 19a,b, or 25a,b, or 27a,b (1equiv) in anhydrous DMF under argon BPC (1.05equiv) and Et3N (1.05equiv) were added and the resulting mixture was stirred at room temperature for 2h. Then, Et3N (1.05equiv) and amine 4a,g-l (1.05equiv) were added and the resulting mixture was stirred for additional 24h at room temperature. If amine hydrochloride was used, two equivalents of Et3N need to be added in the second step (amide formation). Volatile components were evaporated in vacuo and the residue was purified by column chromatography (CC). Fractions containing the product were combined and volatile components evaporated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 1) Coupling of 5-amino-1-pentanol to 4ABTA to produce HPUBT. DMF solution (20 mL) of PFC (9.07 g, 23.0 mmol) was added a solution of 4ABTA (3.75 g, 10.0 mmol) in dry DMF (30 mL). The reaction mixture was stirred for 1 hour at room temperature. Subsequently, a DMF solution (5 mL) of 5-amino-1-pentanol (3.98 g, 38.6 mmol) was added, and the mixture was kept stirring overnight. To remove excess PFC and the amine reagent, the reaction mixture was precipitated in methanol (400 mL) and rinsed with methylene chloride a few times. Thereafter, the product was filtered and dried in vacuum (60 C.) to yield bis(4-(3-(5-hydroxypentyl)ureido)benzyl)terephthalamide (HPUBT: 5.50 g, 87%, MW 632.75, Chemical Formula: C34H44N606). 1H-NMR (400 MHz, DMSO-d6): delta 9.09 (t, J=6.0 Hz, 2H, Ar-CONH), 8.37 (s, 2H, Ar-NH), 7.95 (s, 4H, Ar-H), 7.32 (d, J=8.4 Hz, 4H, Ar-H), 7.17 (d, J=8.8 Hz, 4H, Ar-H), 6.08 (t, J=5.8 Hz, 2H, NHCH2), 4.43-4.34 (m, 6H, OH and Ar-CH2), 3.38 (ddd, J=5.8, 5.8, 6.4 Hz, 4H, CH2OH), 3.05 (ddd, J=6.2, 6.2, 6.4 Hz, 4H, NHCH2), 1.47-1.35 (m, 8H, CH2), 1.34-1.23 (m, 4H, CH2). 13C NMR (125 MHz, DMSO-d6): delta 165.4, 155.1, 139.3, 136.6, 131.8, 127.7, 127.2, 117.4, 60.6, 42.3, 32.2, 29.6, 22.9. (One signal was not detectable, presumably due to overlapping with DMSO signals) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 1) Preparation of C-1, by coupling of 3-(dimethylamino)-1-propylamine to ABTA: To a dry DMF solution (8 mL) of <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (PFC, 2.02 g, 5.13 mmol) was added a solution of 4ABTA (0.75 g, 2.0 mmol) in dry DMF (5 mL). The reaction mixture was stirred for 1 hour at room temperature. Subsequently, 3-(dimethylamino)-1-propylamine (0.71 g, 6.96 mmol) was added, and the mixture was kept stirring for 2 hours. To remove excess PFC and the amine reagent, the product was precipitated in diethylether (200 mL). Thereafter, the product was filtered and dried in vacuum (60 C.) to yield C-1 (1.10 g, 86%). 1H-NMR (400 MHz, DMSO-d6): delta 9.09 (t, J=5.4 Hz, 2H, Ar-CONH), 8.49 (s, 2H, Ar-NH), 7.95 (s, 4H, Ar-H), 7.33 (d, J=8.4 Hz, 4H, Ar-H), 7.17 (d, J=8.4 Hz, 4H, Ar-H), 6.19 (t, J=5.6 Hz, 2H, NHCH2), 4.39 (d, J=5.6 Hz, 2H, Ar-CH2), 3.08 (ddd, J=6.4, 6.4, 6.4 Hz, 4H, CH2NH), 2.33 (t, J=7.2 Hz, 4H, NCH2), 2.21 (s, 12H, CH3), 1.57 (quin, J=7.0 Hz, 4H, CH2). 13C-NMR (100 MHz, DMSO-d6): delta 165.3, 155.2, 139.3, 136.6, 131.8, 127.7, 127.2, 117.5, 56.3, 44.6, 42.2, 37.2, 27.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 1) Coupling of tert-butyl(4-aminobutyl)carbamate to 4ABTA to form: [0092] To a dry DMF solution (16 mL) of PFC (3.97 g, 10.1 mmol) was added a solution of 4ABTA (1.50 g, 4.0 mmol) in dry DMF (8 mL). The reaction mixture was stirred for 1 hour at room temperature. Subsequently, tert-butyl(4-aminobutyl)carbamate (2.36 g, 12.6 mmol) was added, and the mixture was kept stirring overnight. To remove excess PFC and the amine reagent, the reaction mixture was precipitated in diethylether (250 mL). Thereafter, the product was filtered and dried in vacuum (60 C.) to yield C-3 (2.87 g, 90%, MW 802.96, Chemical Formula: C42H58N8O8). 1H-NMR (400 MHz, DMSO-d6): delta 9.08 (t, J=5.8 Hz, 2H, Ar-CONH), 8.36 (s, 2H, Ar-NH), 7.95 (s, 4H, Ar-H), 7.32 (d, J=8.4 Hz, 4H, Ar-H), 7.17 (d, J=8.4 Hz, 4H, Ar-H), 6.82 (t, J=5.6 Hz, 2H, NHCOO), 6.07 (t, J=5.6 Hz, 2H, NHCH2), 4.39 (d, J=5.6 Hz, 2H, Ar-CH2), 3.09-3.00 (m, 4H, CH2NHCOO), 2.95-2.86 (m, 4H, NHCH2), 1.41-1.32 (m, 26H, CH2 and CH3). 13C-NMR (100 MHz, DMSO-d6): delta 165.3, 155.5, 155.1, 139.3, 136.6, 131.8, 127.7, 127.2, 117.4, 77.3, 42.2, 39.6, 38.7, 28.2, 27.2, 27.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 7 Synthesis of Cationic Compound C-10 [0105] [0106] In a small vial, N1,N4-bis(4-aminobenzyl)terephthalamide (4ABTA) (748.9 mg, 2.0 mmol) was dissolved in DMF (4 mL). This solution was slowly added to a solution of PFC (1.97 g, 5 mmol) dissolved in DMF (8 mL) and the resulting solution was stirred for 1.5 hours. To this solution, tert-butyl(2-aminoethyl)carbamate (0.96 g, 6 mmol) was added and the reaction mixture was stirred overnight. The compound C-9 was precipitated into ether and isolated as an off-white powder by filtration. The compound was dissolved in 4 mL of trifluoroacetic acid (TFA) and stirred overnight at 50 C. to ensure deprotection, forming C-10 (MW 774.67, Chemical Formula: C32H36F6N8O8). 1H-NMR (400 MHz, DMSO-d6): delta 10.3 (s, 2H,), 8.82 (s, 2H, 9), 8.06 (s, 4H,), 7.72 (d, J=8.8 Hz, 4H,), 7.37 (d, J=8.8 Hz, 4H,), 6.10 (t, J=5.8 Hz, 2H,),), 4.43-4.34 (m, 4H), 3.37-3.39 (m, 4H), 2.73-2.9 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 8 Synthesis of Cationic Compound C-12 [0107] [0108] In a small vial, N1,N4-bis(4-aminobenzyl)terephthalamide (4ABTA) (700.0 mg, 1.87 mmol) was dissolved in DMF (4 mL). This solution was slowly added to a solution of PFC (1.97 g, 5 mmol) dissolved in DMF (8 mL) and the resulting solution was stirred for 1.5 hours. To this solution, tert-butyl(6-aminohexyl)carbamate (1.20 g, 6 mmol) was added and the reaction mixture was stirred overnight. The compound C-11 was precipitated into ether and isolated as an off-white powder by filtration. The compound was dissolved in 4 mL of TFA and allowed to react overnight at 50 C. to ensure deprotection forming C-12 (MW 886.88 Chemical Formula: C40H52F6N8O8). 1H-NMR (400 MHz, DMSO-d6): delta 10.3 (s, 2H,), 8.82 (s, 2H, 9), 8.06 (s, 4H,), 7.72 (d, J=8.8 Hz, 4H,), 7.37 (d, J=8.8 Hz, 4H,), 6.10 (t, J=5.8 Hz, 2H,), 4.43-4.34 (m, 4H), 3.3-3.45 (m, 4H), 2.85-2.95 (m, 4H), 1.50-1.60 (m, 4H), 1.35-1.44 (m, 4H), 1.20-1.33 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 9 Synthesis of Cationic Compound C-14 [0109] [0110] In a small vial, N1,N4-bis(4-aminobenzyl)terephthalamide (4ABTA) (600.0 mg, 1.60 mmol) was dissolved in DMF (4 mL). This solution was slowly added to a solution of PFC (1.97 g, 5 mmol) dissolved in DMF (8 mL) and the resulting solution was stirred for 1.5 hours. To this solution, tert-butyl 4-(aminomethyl)benzylcarbamate (1.13 g, 6 mmol) was added and the reaction mixture was stirred overnight. The compound C-13 was dissolved in 4 mL of TFA and allowed to react overnight at 50 C. to ensure deprotection forming C-14 (MW 926.86, Chemical Formula: C44H44F6N8O8). 1H-NMR (400 MHz, DMSO-d6): delta 9.1 (s, 2H,), 8.87 (s, 2H), 8.06 (s, 4H,), 7.9-8.0 (d, J=8.8 Hz, 4H,), 2.21 (m, 4H), 7.15 (d, J=8.8 Hz, 4H,), 6.10 (t, J=5.8 Hz, 2H,),), 4.43-4.34 (m, 4H), 2.2-4.35 (m, 4H), 3.9-4.1 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | 1) Coupling of 3-(dimethylamino)-1-propylamine to 4APTA to form C-5 KF512: [0096] To a dry DMF solution (4 mL) of PFC (1.0 g, 2.53 mmol) was added a solution of 4APTA (0.35 g, 1.0 mmol) in dry DMF (4 mL). The reaction mixture was stirred for 1 hour at room temperature. Subsequently, 3-(dimethylamino)-1-propylamine (0.38 g, 3.68 mmol) was added, and the mixture was kept stirring overnight. To remove excess PFC and the amine reagent, the reaction mixture was precipitated in diethylether (100 mL). Thereafter, the product was filtered and dried in vacuum (60 C.) to yield C-5 (0.51 g, 84%, MW 602.73, Chemical Formula: C32H42N804). 1H-NMR (400 MHz, DMSO-d6): delta 10.3 (s, 2H, Ar-CONH), 8.52 (s, 2H, Ar-NH), 8.06 (s, 4H, Ar-H), 7.63 (d, J=9.2 Hz, 4H, Ar-H), 7.37 (d, J=8.8 Hz, 4H, Ar-H), 6.23 (t, J=5.6 Hz, 2H, NHCH2), 3.12 (ddd, J=6.4, 6.4, 6.0 Hz, 4H, CH2NH), 2.57 (t, J=7.2 Hz, 4H, NCH2), 2.40 (s, 12H, CH3), 1.66 (quin, J=7.0 Hz, 4H, CH2). 13C-NMR (100 MHz, DMSO-d6): delta 164.3, 155.4, 137.3, 136.6, 132.4, 127.5, 121.1, 117.8, 55.6, 43.6, 36.8, 26.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 4-methyl-morpholine; In N,N-dimethyl-formamide; at 20℃; | A solution of 2 (0.519 g, 1.09 mmol), <strong>[59483-84-0]bis(pentafluorophenyl)carbonate</strong> (0.593 g, 1.51 mmol) and 4-metylmorpholine (0.1 g) in DMF (4 mL) was stirred at r.t. with excluding air moisture, then evaporated to dryness, and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate (40:1) as mobile phase, affording the product 3 in a 88% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | [00275j Synthesis of N- [(CR2)5 COO-t-Buj -N?-Boc-N?-methyl-ethylene-diamine 6- hydroxybenzo [dj thiazole-2-carbonitrile-carbamate. To the mixture of 2-cyano-6- hydroxybezothiazole (0.366 g, 2.08 mmol) and bis(pentafluorophenyl) carbonate (0.902 g, 2.29 mmol) in 20 ml of dry THF, TEA (580 uL, 4.16 mmol) was added at room temperature under nitrogen. The mixture was stirred for 30 mm minutes, and N-[(CH2)5-COO-t-Bu]-N?-Boc-N?- methyl-ethylenediamine (1.43 g, 4.16 mmol) in 10 mL dry THF was added. The resulting mixture was stirred at room temperature for over 30 minutes. The solvent was removed, and then the product mixture was dissolved in methylene chloride and washed with saturated K2C03 solution 3 times and once with water. The organic layer was dried over Na2SO4, and the solvent was removed. The compound was purified by flash column chromatography using heptane/ethyl acetate as eluent to give the product in a yield of 77 percent (0.875 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | [00243j Synthesis of N- [(PEG)2 COO-t-Buj -N?-Boc-N?-methyl-ethylene-diamine 6- hydroxybenzo [dj thiazole-2-carbonitrile- carbamate. To the mixture of 2-cyano-6- hydroxybezothiazole (0.803 g, 4.56 mmol) and bis(pentafluorophenyl) carbonate (1.98 g, 5.02 mmol) in 40 ml of dry THF, TEA (0.293 g, 2.89 mmol) was added at room temperature under nitrogen. The mixture was stirred for 1 hour, and N-t-butylCOO (PEG)3-N?-BOC-N?-methyl ethylenediamine (3 .56g, 9.12 mmol) in 18 mL dry THF was added. The resulting mixture was stirred at room temperature for over 30 minutes after which the solvent was removed. The product mixture was dissolved in methylene chloride and washed with sat K2C03 solution three times and once with water, then the organic layer was dried over Na2SO4. The compound was purified by flash column chromatography using heptane/ethyl acetate as eluent to give the product in a yield of 70 percent (1.90 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | [002591 Synthesis of N- [(CR2)3 COO-t-Buj -N?-Boc-N?-methyl-ethylene-diamine 6- hydroxybenzo [dl thiazole-2-carbonitrile-carbamate. To the mixture of 2-cyano-6- hydroxybezothiazole (0.5 87 g, 3.33 mmol) and bis(pentafluorophenyl) carbonate (1.44 g, 3.66 mmol) in 30 ml of dry THF, TEA (930 iL, 6.66 mmol) was added at room temperature under nitrogen. The mixture was stirred for 30 mm minutes, and N-[(CH2)3-COO-t-Bu]-N?-Boc-N?- methyl-ethylenediamine (2.11 g, 6.66 mmol) in 20 mL dry THF was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then dried down, and the product mixture was dissolved in methylene chloride and washed with saturated K2C03 solution 3 times and once with water, then dried over Na2SO4. The solvent was removed, and the compound was purified by flash column chromatography using heptane/ethyl acetate as eluent to give the product in a yield of 86 percent (1.5 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Bis(pentafluorophenyl) carbonate (77mg, 0.20mmol) and triethylamine (40mg, 0.39mmol) were added to a solution of 8-benzyl-2-(furan-2-ylmethyl)-6- phenyl-l,7-dihydroimidazo[l,2-a]pyrazin-3(2H)-one (50mg, 0.13mmol) in THF consecutively under nitrogen with an ice-water bath. The mixture was stirred for 5min, N-methyl-3-morpholin- 4-ylpropan-l -amine (HC1 salt, 38mg, 0.20mmol) was added, and the mixture was stirred for another lOmin. After TLC showed the disappearance of the starting material, the solvent was removed, and the residue was purified by flash chromatography to give the product as a yellowish solid. (42mg, 57%). 1HNMR (300 MHz, CD2C12, delta): 7.86 (m, 3H), 7.17 (m, 8H), 6.87 (s, IH), 6.23 (s, IH), 6.02 (s, IH), 4.48 (s, 2H), 4.08 (s, 3H), 3.60 (m, 6H), 3.35 (m, 2H), 2.41 (m, 6H), 1.74 (m, 2H). MS (ESI) m/z: 566.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Bis(pentafluorophenyl) carbonate (77mg, 0.20mmol) and triethylamine (40mg, 0.39mmol) were added to a solution of 8-benzyl-2-(furan-2-ylmethyl)-6- phenyl-l,7-dihydroimidazo[l,2-a]pyrazin-3(2H)-one (50mg, 0.13mmol) in THF consecutively under nitrogen with an ice-water bath. The mixture was stirred for 5min, N-methyl-3-morpholin- 4-ylpropan-l -amine (HC1 salt, 38mg, 0.20mmol) was added, and the mixture was stirred for another lOmin. After TLC showed the disappearance of the starting material, the solvent was removed, and the residue was purified by flash chromatography to give the product as a yellowish solid. (42mg, 57%). 1HNMR (300 MHz, CD2C12, delta): 7.86 (m, 3H), 7.17 (m, 8H), 6.87 (s, IH), 6.23 (s, IH), 6.02 (s, IH), 4.48 (s, 2H), 4.08 (s, 3H), 3.60 (m, 6H), 3.35 (m, 2H), 2.41 (m, 6H), 1.74 (m, 2H). MS (ESI) m/z: 566.5. Synthesis of 5422. Followed the same procedure as used for 5393. 1HNMR (300 MHz, CD2C12, delta): 7.95 (m, 2H), 7.42 (m, 12H), 6.97 (s, 5H), 5.02 (s, 3H), 4.58 (s, 2H), 3.71 (m, 6H), 3.05 (m, 2H), 1.82 (m, 4H). MS (ESI) m/z: 669.5. Synthesis of 5422. Followed the same procedure as used for 5393. 1HNMR (300 MHz, CD2C12, delta): 7.95 (m, 2H), 7.42 (m, 12H), 6.97 (s, 5H), 5.02 (s, 3H), 4.58 (s, 2H), 3.71 (m, 6H), 3.05 (m, 2H), 1.82 (m, 4H). MS (ESI) m/z: 669.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-12-1: tert-butyl ((S)-3-methyl- 1 -oxo- 1 -(((S)- 1 -oxo- 1 -((4- ((((perfluorophenoxy)carbonyl)oxy)methyl)phenyl)amino)-5 -ureidopentan-2-yl)amino)butan-2-yl)carbamate Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 tl, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-12-1: tert-butyl ((S)-3-methyl-l-oxo-l-(((S)-l- ((((perfluorophenoxy)carbonyl)oxy)methyl)phenyl)amino)-5-ureidopentan-2- yl)amino)butan-2-yl)carbamate Compound E-ll-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mu, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-ll-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mu, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0 C. under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.) was added, followed by DIEA (329 mul, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96%) of compound E-12-1 as an off-white solid. |
96% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.5h;Inert atmosphere; | Compound E-11-4 (670 mg, 1.26 mmol, 1 eq.) was dissolved in dry DMF (6 ml) at 0C under an inert atmosphere. Bis(perfluorophenyl) carbonate (991 mg, 2.51 mmol, 2 eq.)was added, followed by DIEA (329 tl, 1.89 mmol, 1.5 eq.), and the resulting colourless solution stirred for 30 minutes at room temperature. The DMF was evaporated under reduced pressure, and the residue purified on silica gel (DCM/MeOH) to yield 836 mg (96 %) of compound E-12-1 as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 1h; | Benzyl alcohol 25 (951.00 mg; 4.02 mmol; 1.00 eq.) was dissolved in acetonitrile (20 ml) and cooled to 0C in an ice bath. Bis(pentafluorophenyl) carbonate (3.97 g; 10.06 mmol; 2.50 eq.), DMAP (122.91 mg; 1.01 mmol; 0.25 eq.) and DIPEA (3.50 ml; 20.12 mmol; 5.00 eq.) were added. The reaction mixture was stirred at room temperature for 1 hour.An LCMS chromatogram showed complete conversion of the starting material. The reaction mixture was diluted with 75 ml of diethyl ether. The organic layer was washed twice with 80 ml of water. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography.Yield: 1.13 g; 63% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.1% | 32.5 g (0.10 mol) of <strong>[361442-00-4](2S)-2-((t-butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1-yl)acetic acid</strong> was added to 163 ml of ethyl acetate at 25 ° C and stirred for 20 minutes. To the reaction solution was added 16.7 ml (0.12 mol) of triethylamine and the mixture was stirred for 20 minutes. 43.3 g (0.11 mol) of bis(pentafluorophenyl)carbonate was added to the reaction solution, and the suspension was stirred at 25 °C for 2 hours. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4: 1) to obtain 45.7 g (93.1percent) of pentafluorophenyl(2S)-2-((t-butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1-yl)acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h; | General procedure: To a cold (0 oC) solution of 4-(3-hydroxyphenyl)thiomorpholine 1,1-dioxide (227 mg, 1 mmol), and N, N-diisopropylethylamine (0.26 mL, 1.5 mmol) in dichloromethane (15 mL) was added bis(pentafluorophenyl) carbonate (433 mg, 1.1 mmol). The reaction mixture was gradually allowed to come to room temperature and stirred for 2 h. Then, the reaction was diluted in dichloromethane (25 mL) and washed with water and brine. The organic extracts were dried over anhydrous Na2SO4. The solvents were removed under vacuum and the residue was purified on silica gel (Biotage; eluting solvents hexanes: EtOAc 4/1 ratio) to afford 3-(1,1-dioxidothiomorpholino)phenyl (perfluorophenyl) carbonate as colorless solid (400 mg, 91% yield). 1H NMR (500 MHz, CDCl3) delta 7.37-7.33 (m, 1H),6.86-6.80 (m, 3H), 3.90-3.87 (m, 4H), 3.12-3.10 (m, 4H). |
Tags: 59483-84-0 synthesis path| 59483-84-0 SDS| 59483-84-0 COA| 59483-84-0 purity| 59483-84-0 application| 59483-84-0 NMR| 59483-84-0 COA| 59483-84-0 structure
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P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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