* 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.
With hydrogenchloride; sodium carbonate; mercury In 1,4-dioxane; water
160 g of 11-aminoundecanoic acid, 2 liters of dioxane, 1.3 liters of distilled water, 208 g of sodium carbonate and 173 g of di-tert-butyl dicarbonate are successively introduced into a 4-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser. The reaction mixture is heated at boiling point for 16 hours. A clear solution is thus obtained. After cooling to 20° C., the reaction mixture is poured onto 800 g of ice and then acidified to pH=3-4 by addition of 4N hydrochloric acid. A white precipitate is thus obtained which is separated by filtration, washed with 300 cm3 of water and dried at 20° C. under reduced pressure (20 mm of mercury, 2.7 kPa). 232 g of N-(tert-butoxycarbonyl)-11-aminoundecanoic acid are thus obtained, with a yield of 95percent, the melting point of which (68° C.) is in agreement with that which is given in J. Org. Chem., 41, 1350 (1976).
80%
With triethylamine In methanol at 60℃; for 1.5 h;
Preparation of intermediate 24f2 To a solution of 24f1 (1.0g, 4.97mmol) in MeOH (40ml), TEA (1.04ml, 7.45mmol) was added, followed by di t-butyl dicarbonate (2.17g, 9.94mmol). The reaction was heated at 60oC for 1.5hr. The reaction was concentrated and purified over Si02 column with 5percent MeOH/DCM to afford 1 .2g compound 24f2 (80percent yield). 1H NMR (CHLOROFORM-d, 400MHz) d: 4.51 (br. s, 1 H), 3.00-3.22 (m, 2H), 2.37 (t, J=7.4 Hz, 2H), 1 .59-1 .71 (m, 2H), 1.46 (s, 1 1 H), 1.29 (br. s., 12H).
80%
With triethylamine In methanol at 60℃; for 1.5 h;
To a solution of 24f1 (1.0g, 4.97mmol) in MeOH (40ml), TEA (1 .04ml, 7.45mmol) was added, followed by di t-butyl dicarbonate (2.17g, 9.94mmol). The reaction was heated at 60oC for 1 .5hr. The reaction was concentrated and purified over Si02 column with 5percent MeOH/DCM to afford 1 .2g compound 24f2 (80percent yield). 1H NMR (CHLOROFORM-d, 400MHz) d: 4.51 (br. s, 1 H), 3.00-3.22 (m, 2H), 2.37 (t, J=7.4 Hz, 2H), 1.59-1 .71 (m, 2H), 1 .46 (s, 1 1 H), 1.29 (br. s., 12H).
40%
With sodium hydroxide In water; <i>tert</i>-butyl alcohol for 18 h; Inert atmosphere
General procedure: To a mixture of NaOH (43 mg, 1.1 mmol), in water/tert-BuOH 1:1 (1.0 mL) was added di-tert-butyl dicarbonate (225 μL, 1.05 mmol) and 12-amino-dodecan-1-ol (199 mg, 1.00 mmol). After the viscous mixture was stirred for 18 h, 0.3 M HCl solution (1.5 mL) was added and the aqueous layer was extracted with ethyl acetate (3 .x. 30 mL). The combined organic layers were washed with brine (5 mL) and dried over MgSO4. The solvent was removed under reduced pressure and 294 mg (98percent) of the product was obtained as white solid.
Reference：
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2
[ 24424-99-5 ]
[ 10436-25-6 ]
Yield
Reaction Conditions
Operation in experiment
93%
Stage #1: With sodium hydroxide In tetrahydrofuran; water for 0.166667 h; Stage #2: at 20℃; for 14 h; Stage #3: With hydrogenchloride In chloroform; water
Sodium hydroxide (2.18 g, 54.5 mmol) was added to a suspension of 11-aminoundecanoic acid (1) (5.00 g, 24.8 mmol) in a mixture of tetrahydrofuran and water (260 mL, 1:1). The resulting solution was stirred for 10 minutes, then di-tert-butyl dicarbonate (6.50 g, 29.8 mmol) added and the reaction stirred at ambient temperature for 14 hours. The solvent was then removed under vacuum. The resulting white solid was dissolved in chloroform, and the solution washed with a 1 N HC1 (3 x 100 mL), dried over anhydrous magnesium sulfate and concentrated to give 3 (6.99 g, 93percent) as a white solid: *H NMR (500 MHz, CDC13) 5 1.28 (s, 12H), 1.44 (br, 11H), 1.56-1.66 (m, 2H), 2.34 (t, 2H, J = 7.4 Hz), 3.08-3.11 (m, 2H).
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0℃; for 0.333333 h; Stage #2: at 20℃; for 26 h;
Into a flask were added 11-aminoundecanoic acid (12a, 1.00 g, 4.97 mmol, 1 equiv) and dioxane (6.2 mL, 0.8 M). Sodium hydroxide (0.19 g, 5.0 mmol, 1 equiv) was dissolved in water (10 mL, 0.8 M) and added to the dioxane solution. The mixture was cooled in an ice bath (0 °C, 20 min). Di-tert-butyl dicarbonate (1.19 g, 5.46 mmol, 1.1 equiv) was dissolved in dioxane (6.2 mL) and added. The suspension was stirred vigorously and allowed to gradually warm to ambient temperature (26 h). Volatiles were removed under reduced pressure. The residue was dissolved in a mixture of water (40 mL) and saturated sodium bicarbonate (10 mL), washed with EtOAc (2 x 30 mL), acidified with sodium bisulfate (1 M, 30 mL, to pH 2), extracted with EtOAc (40 mL plus 2 x 30 mL), and dried with sodium sulfate. Volatiles were removed under reduced pressure to yield pure carbamate 12b (1.16 g, 3.85 mmol, 79percent yield), which was used directly in the next step. Compound analysis is consistent with published data. 1H NMR (CDCl3, 200 MHz) δ 4.51 (brs, 1H, NH), 3.10 (q, J =6.6 Hz 2H, N–CH2), 2.35 (t, J = 7.3 Hz, 2H, O=C–CH2), 1.69–1.55 (m, 2H, N–C–CH2), 1.44 (s, 9H, Boc), 1.38–1.22 (m, 14H, (CH2)7).
With hydrogenchloride; sodium carbonate; mercury; In 1,4-dioxane; water;
160 g of 11-aminoundecanoic acid, 2 liters of dioxane, 1.3 liters of distilled water, 208 g of sodium carbonate and 173 g of di-tert-butyl dicarbonate are successively introduced into a 4-liter three-necked flask equipped with a mechanical stirrer and a reflux condenser. The reaction mixture is heated at boiling point for 16 hours. A clear solution is thus obtained. After cooling to 20 C., the reaction mixture is poured onto 800 g of ice and then acidified to pH=3-4 by addition of 4N hydrochloric acid. A white precipitate is thus obtained which is separated by filtration, washed with 300 cm3 of water and dried at 20 C. under reduced pressure (20 mm of mercury, 2.7 kPa). 232 g of N-(tert-butoxycarbonyl)-11-aminoundecanoic acid are thus obtained, with a yield of 95%, the melting point of which (68 C.) is in agreement with that which is given in J. Org. Chem., 41, 1350 (1976).
80%
With triethylamine; In methanol; at 60℃; for 1.5h;
Preparation of intermediate 24f2To a solution of 24f1 (1.0g, 4.97mmol) in MeOH (40ml), TEA (1.04ml, 7.45mmol) was added, followed by di t-butyl dicarbonate (2.17g, 9.94mmol). The reaction was heated at 60oC for 1.5hr. The reaction was concentrated and purified over Si02 column with 5% MeOH/DCM to afford 1 .2g compound 24f2 (80% yield). 1H NMR (CHLOROFORM-d, 400MHz) d: 4.51 (br. s, 1 H), 3.00-3.22 (m, 2H), 2.37 (t, J=7.4 Hz, 2H), 1 .59-1 .71 (m, 2H), 1.46 (s, 1 1 H), 1.29 (br. s., 12H).
80%
With triethylamine; In methanol; at 60℃; for 1.5h;
To a solution of 24f1 (1.0g, 4.97mmol) in MeOH (40ml), TEA (1 .04ml, 7.45mmol) was added, followed by di t-butyl dicarbonate (2.17g, 9.94mmol). The reaction was heated at 60oC for 1 .5hr. The reaction was concentrated and purified over Si02 column with 5% MeOH/DCM to afford 1 .2g compound 24f2 (80% yield). 1H NMR (CHLOROFORM-d, 400MHz) d: 4.51 (br. s, 1 H), 3.00-3.22 (m, 2H), 2.37 (t, J=7.4 Hz, 2H), 1.59-1 .71 (m, 2H), 1 .46 (s, 1 1 H), 1.29 (br. s., 12H).
40%
With sodium hydroxide; In water; tert-butyl alcohol; for 18h;Inert atmosphere;
General procedure: To a mixture of NaOH (43 mg, 1.1 mmol), in water/tert-BuOH 1:1 (1.0 mL) was added di-tert-butyl dicarbonate (225 muL, 1.05 mmol) and 12-amino-dodecan-1-ol (199 mg, 1.00 mmol). After the viscous mixture was stirred for 18 h, 0.3 M HCl solution (1.5 mL) was added and the aqueous layer was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (5 mL) and dried over MgSO4. The solvent was removed under reduced pressure and 294 mg (98%) of the product was obtained as white solid.
With sodium hydroxide; In 1,4-dioxane; water;
EXAMPLE 2 Synthesis of N-[3-O-(3',3'-dimethylsuccinyl)-lup-20(29)-ene -28-oyl]-11-aminoundecanoic acid (compound 12). The Boc protected aminoundecanoic acid methyl ester (5) was obtained with a two-step synthesis: 1).di-tert-butyl dicarbonate and NaOH was added to the aqueous solution (dioxane/water) of aminoundecanoic acid.The reaction was performed overnight and the product was extracted with EtOAc. 2).The boc-aminoundecanoic acid was subsequently subjected to methylation with MeOH catalyzed with DCC. The resulted compound 5 was obtained after chromatographed on Si-gel.The Boc group was removed with 55% TFA/DCM at room temperature for 45 min.The crude product 6 was used for the next step without purification.The coupling of compound 6 with acid chloride species yielded compound 10 under the same reaction conditions described above for compound 8.Compound 10 was subsequently subjected to the same reactions as described for compound 8 and yielded the final compound 12 (see Scheme II above).
With sodium hydroxide; In methanol;
Synthesis of N-t-BOC-11-aminoundecanoic Acid (BADA) Di-tert-butyl pyrocarbonate (26 g) was added to a solution of 11-aminoundecanoic acid (25 g) and sodium hydroxide (7 g) in methanol (100 mL). The reaction mixture was stirred at room temperature overnight. The solution was then filtered, diluted with water, acidified with dilute hydrochloric acid and the resultant suspension was extracted with methylene chloride. The organic fractions were dried over magnesium sulphate, filtered and the solvent was removed under reduced pressure. The resultant crystalline solid was broken up and dried on a lyophilizer, to provide N-t- BOC-11-aminoundecanoic acid as a white powder (33 g). This material was used in the following reactions without further purification.
With sodium hydroxide; In water; tert-butyl alcohol; at 20℃; for 16h;
General procedure: To a solution of sodium hydroxide (800 mg, 19.5 mmol) and di-tert-butyl dicarbonate (4.3 g,19.5 mmol) in tertiary butyl alcohol (11 mL) and H2O (9 mL) the corresponding amino acids 1a-e (19.5 mmol) were added. After the mixture was stirred at room temperature for 16 h, diluted with 10%HCl (100 mL), and extracted with ethyl acetate, and the organic layer was washed with water and brine successively, dried over anhydrous sodium sulfate, filtered and concentrated to give 2a-e.
With sodium hydroxide; In water; tert-butyl alcohol; at 0 - 20℃;
General procedure: Aqueous sodium hydroxide (sodium hydroxide: 170.0mg, 4.3mmol; water: 2.0mL) and di-tert-butyl dicarbonate were dissolved in tert-butyl alcohol and X2-X6 (3.8mmol) were added with stirring respectively, reacted at room temperature for 18-24h. It was diluted with water and 1.0mol/L hydrochloric acid, extracted with ethyl acetate rapidly, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Then it gave intermediates X7-X11, respectively.
N-<2-O-<2-acetamido-6-O-<11-(tert-butoxycarbonylamino)-undecanoyl>-1-S-decanoyl-2,3-dideoxy-1-thio-β-D-glucopyranose-3-yl>-D-lactoyl>-L-alanyl-D-isoglutamine methyl ester[ No CAS ]
N-<2-O-<2-acetamido-6-O-<11-(tert-butoxycarbonylamino)-undecanoyl>-2,3-dideoxy-1-S-octadecanoyl-1-thio-β-D-glucopyranose-3-yl>-D-lactoyl>-L-alanyl-D-isoglutamine methyl ester[ No CAS ]
(R)-4-{(S)-2-[(R)-2-((4aR,6S,7R,8R,8aS)-7-Acetylamino-6-hydroxysulfanyl-2,2-dimethyl-hexahydro-pyrano[3,2-d][1,3]dioxin-8-yloxy)-propionylamino]-propionylamino}-4-carbamoyl-butyric acid methyl ester[ No CAS ]
(10-{(S)-2-tert-Butoxy-1-[(S)-5-tert-butoxycarbonylamino-1-(2-cyclohexyl-ethylcarbamoyl)-pentylcarbamoyl]-ethylcarbamoyl}-decyl)-carbamic acid tert-butyl ester[ No CAS ]
With triethylamine; In 1,4-dioxane; water; at 22℃; for 23h;Inert atmosphere;
General procedure: A solution of a commercially available aminoacid alkyl chain 9 (7.77 mmol, 1.00 eq.) in water (10.0 mL) and dioxane (15.0 mL) was stirred at room temperature. Trielthyamine (11.65 mmol, 1.50 eq.) was added slowly followed by Boc-ON (8.54 mmol, 1.10 eq.). The solution was kept for 23 h under nitrogen. Afterwards, the mixture was diluted with diethyl ether (75 mL) and water (50 mL) and then washed with water (6x 50 mL). The aqueous layers were then combined and a few drops of 10% aqueous HCl solution were slowly added in order to reach pH 2.5. The resulting solution was then washed with dichloromethane (3x 60 mL). The organic layers were washed with saturated sodium chloride salt solution (1x 50 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated. Flash chromatography (hexanes:acetone, 4:1) was performed to yield a colorless yellow viscous oil in 63-97% yield.
(S)-2-[(S)-2-((S)-2-Amino-3-benzyloxy-propionylamino)-6-benzyloxycarbonylamino-hexanoylamino]-4-methyl-pentanoic acid methyl ester; hydrochloride[ No CAS ]
2,4,6-tri-O-benzyl-3-O-methoxycarbonylmethyl-β-D-galactopyranosyl-(1-1)-6-amino-2,3,4-tri-O-benzyl-6-deoxy-α-D-mannopyranoside[ No CAS ]
((2R,3S,4S,5R,6R)-3,5-Bis-benzyloxy-2-benzyloxymethyl-6-{(2R,3S,4S,5R,6R)-3,4,5-tris-benzyloxy-6-[(11-tert-butoxycarbonylamino-undecanoylamino)-methyl]-tetrahydro-pyran-2-yloxy}-tetrahydro-pyran-4-yloxy)-acetic acid methyl ester[ No CAS ]
(2S,4R)-4-Benzyloxy-1-[(2S,3R)-3-tert-butoxy-2-(11-tert-butoxycarbonylamino-undecanoylamino)-butyryl]-pyrrolidine-2-carboxylic acid methyl ester[ No CAS ]
(2R,5S,20S,22aS)-2-Hydroxy-5-((R)-1-hydroxy-ethyl)-20-[2-(4-hydroxy-phenyl)-ethyl]-octadecahydro-3a,6,18,21-tetraaza-cyclopentacyclohenicosene-4,7,19,22-tetraone[ No CAS ]
(2R,5S,20S,22aS)-2-Benzyloxy-20-[2-(4-benzyloxy-phenyl)-ethyl]-5-((R)-1-hydroxy-ethyl)-octadecahydro-3a,6,18,21-tetraaza-cyclopentacyclohenicosene-4,7,19,22-tetraone[ No CAS ]
(S)-2-({(2S,4R)-4-Benzyloxy-1-[(2S,3R)-3-tert-butoxy-2-(11-tert-butoxycarbonylamino-undecanoylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-4-(4-benzyloxy-phenyl)-butyric acid[ No CAS ]
11-Amino-undecanoic acid 1-(11-amino-undecanoyloxymethyl)-2-((2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yloxy)-ethyl ester[ No CAS ]
(2S)-(2-{11-[3-(2,2-diphenyl-ethylcarbamoyl)-(Z)-acryloylamino]-undecanoylamino}-acetylamino)-4-methyl-pentanoic acid 2,2-diphenyl-ethyl ester[ No CAS ]
11-Amino-undecanoic acid (3S,3aR,4S,6S,6aR,7S,8S,9bS)-6-acetoxy-3,3a-dihydroxy-3,6,9-trimethyl-8-((Z)-2-methyl-but-2-enoyloxy)-7-octanoyloxy-2-oxo-2,3,3a,4,5,6,6a,7,8,9b-decahydro-azuleno[4,5-b]furan-4-yl ester[ No CAS ]
((2R,3R,4S,5S,6R)-2-{(2R,3S,4S,5S,6R)-6-[(11-Amino-undecanoylamino)-methyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yloxy}-3,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-acetic acid[ No CAS ]
((2R,3R,4S,5S,6R)-2-{(2R,3S,4S,5S,6R)-6-[(11-tert-Butoxycarbonylamino-undecanoylamino)-methyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yloxy}-3,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-acetic acid[ No CAS ]
((2R,3R,4S,5S,6R)-2-{(2R,3S,4S,5S,6R)-6-[(11-tert-Butoxycarbonylamino-undecanoylamino)-methyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-yloxy}-3,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-4-yloxy)-acetic acid methyl ester[ No CAS ]
11-Amino-undecanoic acid {(S)-1-[(S)-5-amino-1-(2-cyclohexyl-ethylcarbamoyl)-pentylcarbamoyl]-2-hydroxy-ethyl}-amide; compound with trifluoro-acetic acid[ No CAS ]
11-Amino-undecanoic acid (2R,3S,4R,5R,6S)-5-acetylamino-4-{(R)-1-[(S)-1-((R)-1-carbamoyl-3-methoxycarbonyl-propylcarbamoyl)-ethylcarbamoyl]-ethoxy}-3-hydroxy-6-octadecanoylsulfanyl-tetrahydro-pyran-2-ylmethyl ester; compound with trifluoro-acetic acid[ No CAS ]
Octadecanoic acid (2R,3S,4R,5R,6S)-5-acetylamino-6-(11-amino-undecanoylsulfanyl)-4-{(R)-1-[(S)-1-((R)-1-carbamoyl-3-methoxycarbonyl-propylcarbamoyl)-ethylcarbamoyl]-ethoxy}-3-hydroxy-tetrahydro-pyran-2-ylmethyl ester; compound with trifluoro-acetic acid[ No CAS ]
N-<2-O-<2-acetamido-1-S-<11-(tert-butoxycarbonylamino)undecanoyl>-6-O-decanoyl-2,3-dideoxy-1-thio-β-D-glucopyranose-3-yl>-D-lactoyl>-L-alanyl-D-isoglutamine methyl ester[ No CAS ]
N-<2-O-<2-acetamido-1-S-<11-(tert-butoxycarbonylamino)undecanoyl>-6-O-octadecanoyl-2,3-dideoxy-1-thio-β-D-glucopyranose-3-yl>-D-lactoyl>-L-alanyl-D-isoglutamine methyl ester[ No CAS ]
Decanoic acid (2R,3S,4R,5R,6S)-5-acetylamino-6-(11-amino-undecanoylsulfanyl)-4-{(R)-1-[(S)-1-((R)-1-carbamoyl-3-methoxycarbonyl-propylcarbamoyl)-ethylcarbamoyl]-ethoxy}-3-hydroxy-tetrahydro-pyran-2-ylmethyl ester; compound with trifluoro-acetic acid[ No CAS ]
11-Amino-undecanoic acid (2R,3S,4R,5R,6S)-5-acetylamino-4-{(R)-1-[(S)-1-((R)-1-carbamoyl-3-methoxycarbonyl-propylcarbamoyl)-ethylcarbamoyl]-ethoxy}-6-decanoylsulfanyl-3-hydroxy-tetrahydro-pyran-2-ylmethyl ester; compound with trifluoro-acetic acid[ No CAS ]
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); for 18h;
[BOC-11-AMINO-UNDECANOIC] acid (115 mg, 0. [38] mmol, 1.2 equiv), EDAC (91 mg, 0.48 mmol, 1.5 equiv), and HOBt (65 mg, 0.48 mmol, 1.5 equiv) in DMF (10 mL) were added to a dry round bottom flask equipped with a magnetic stir bar. Composition 14 (115 mg, 0.32 mmol) and N-methylmorpholine (twice distilled, 0.14 mL, 0.96 mmol, 3.0 equiv) dissolved in minimal quantity of DMF were added with constant stirring. The colorless solution slowly turned yellow as the reaction proceeded. The reaction was allowed to stir for 18 h, then EtOAc (20 mL) was added and the organic layer was washed with saturated [NAHCO3] (20 mL), [HA0] (20 mL) and brine (20 mL), dried over [NA2S04,] and concentrated in vacuo. The resulting oil was purified via column chromatography (silica gel, 1: 1, hexane/EtOAc) to give 15 (56 mg, 0.088 mmol, 24% yield) as a clear, thick oil. ESMS: 637.6 (M + [H+),] 659.2 [(M] + [NA+).]
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); for 18h;
[BOC-11-AMINO-UNDECANOIC] acid (87 mg, 0.29 mmol, 1.2 equiv), EDAC (69 mg, 0. [36] mmol, 1.5 equiv), and HOBt (49 mg, 0.36 mmol, 1.5 equiv) in DMF (10 mL) were added to a dry round bottom flask equipped with a magnetic stir bar. With constant stirring was added Composition 18 (94 mg, 0.24 mmol, ) and N-methylmorpholine (twice distilled, 0.9 mL, 0.72 mmol, 3.0 equiv) dissolved in minimal quantity of DMF. The colorless solution slowly turned yellow during the course of the reaction overnight (18 hr). EtOAc (20 mL) was added to the reaction and the organic layer was washed with saturated [NAHCO3] (20 mL), H20 (20 mL), and brine (20 mL), dried over [NA2S04,] and concentrated in vacuo. The resulting oil was purified via column chromatography (silica gel, 1: 1, [HEXANES/ETOAC)] to give 19 (63 mg, 0.084 mmol, 24% yield) as a clear, thick oil. ESMS: 746.3 [(M] + [H+),] 768.1 (M + [NA+).]
The Boc protected aminoundecanoic acid methyl ester (5) was obtained with a two-step synthesis: 1). di-tert-butyl dicarbonate and NaOH was added to the aqueous solution (dioxane/water) of aminoundecanoic acid. The reaction was performed overnight and the product was extracted with EtOAc. 2). The Boc-aminoundecanoic acid was subsequently subjected to methylation with MeOH catalyzed with DCC. The resulted compound 5 was obtained after chromatographed on Si-gel. The Boc group was removed with 55% TFA/DCM at room temperature for 45 min. The crude product 6 was used for the next step without purification. The coupling of compound 6 with acid chloride species yielded compound 10 under the same reaction conditions described above for compound 8. Compound 10 was subsequently subjected to the same reactions as described for compound 8 and yielded the final compound 12 (see Scheme II above).
Sodium hydroxide (2.18 g, 54.5 mmol) was added to a suspension of 11-aminoundecanoic acid (1) (5.00 g, 24.8 mmol) in a mixture of tetrahydrofuran and water (260 mL, 1:1). The resulting solution was stirred for 10 minutes, then di-tert-butyl dicarbonate (6.50 g, 29.8 mmol) added and the reaction stirred at ambient temperature for 14 hours. The solvent was then removed under vacuum. The resulting white solid was dissolved in chloroform, and the solution washed with a 1 N HC1 (3 x 100 mL), dried over anhydrous magnesium sulfate and concentrated to give 3 (6.99 g, 93%) as a white solid: *H NMR (500 MHz, CDC13) 5 1.28 (s, 12H), 1.44 (br, 11H), 1.56-1.66 (m, 2H), 2.34 (t, 2H, J = 7.4 Hz), 3.08-3.11 (m, 2H).
l,l'-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of 3 (200 mg, 0.66 mmol) in tetrahydrofuran (5 mL) and the mixture stirred at 55. C for 3 hour. The solution was then cooled to ambient temperature and ammonia gas passed through the solution for 15 min. The reaction vessel was then sealed and the mixture stirred for 14 hours at room temperature. After this time, the solvent was removed under vacuum and the white residue purified by column chromatography (silica gel, gradient 99:1 to 90:10 dichloromethane/methanol, v/v) to afford product 10 (163 mg, 82 %) as a white solid: JH NMR (300 MHz, CDC13) 5 1.28 (s, 12H), 1.44 (br, 11H), 1.56-1.66 (m, 2H), 2.20-2.36 (m, 2H), 3.08-3.11 (m,2H).
Compound of formula 18 is prepared by a active-ester (isobutylchloroformate) condensation of BOC-aminoundecanoicacid with 11-aminoundecanoicacid-methylester followed by a cleavage of the BOC-group with p-toluenesulfonicacid in acetonitrile.
To a 250 ml, three necked, round bottomed flask were added 6.75 g of 11-(N-tert-butoxycarbonyl)-aminoundecanoic acid, 5.55 g of 1,3-dicyclohexylcabodiimide, 3.65 g of 1-hydroxybenzotriazole, and 50 ml of DMF. The resulting solution was stirred at 0 C. for 2 hr. At this time, 5 g of 3-aminophenylboronic acid hemisulfate and 3.5 g of diisopropylethylamine were added to the above solution and the resulting reaction mixture was stirred first at 0 C. for 1 hr and subsequently at room temperature for 48 hr. After filtering off the solid, deionized water was added to the solution to precipitate a solid. After drying this residue it was recrystallized from hot ethyl acetate yielding 6.4 g of a white solid. To 5 g of the above solid dissolved in 20 ml of dioxane was added 9 ml of 4N HCl in dioxane. After stirring for 2 hr at room temperature, 15 ml of ethanol and another 9 ml of 4N HCl were added to the reaction mixture. The resulting reaction mixture was stirred for additional 2 hr. To this reaction mixture was added 200 ml of diethyl ether and the solution was kept at 0 C. to crystallize the product. Filtration and drying of the solid offered 4.2 g of the product as a white solid.
To <strong>[10436-25-6]11-(tert-butoxycarbonylamino)undecanoic acid</strong> (200mg, 0.664mmol) in 2ml THF was dropwise-added BH3-THF(1.33mmol, 1.0M THF solution) at 0 oC with stirring. Then stirred at room temperature for another 2hrs. After cooling to 0 oC again, 159mg Acetic acid in 2ml methanol was added. The acid was removed with high vacuum. The crude product was purified by silica gel column chromatography (Methanol:Methanol=5:95, Rf=0.4) afforded 2 in 95% yield (181mg, 0.637mmol) as a white powder. 1H-NMR (600MHz, CDCl3, 295K): delta=1.25 (s, 10H, CH2), 1.30 (m, 4H, CH2), 1.42 (S, 11H, C(CH3)3+CH2CH2NH), 1.54(m, 3H, OH+CH2CH2OH), 3.08(m, J=6.3Hz, 6.6Hz, 2H, CH2NH), 3.61(m, J=5.6Hz, 6.3Hz, 2H, CH2OH), 4.54 (s, 1H, NH). 13C{1H}-NMR (150MHz, CDCl3, 295K): delta=25.8, 26.8, 28.5, 29.3, 29.5, 29.5, 29.6, 29.6, 30.1, 32.8, 40.7, 63.1, 79.1, 156.1.
With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 28h;
General procedure: The N-Boc-p-hydroxyphenyl-L-para-tyrosinamide derivative 8 (0.57 mmol, 1.00 eq.) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (5.70 mmol, 10.00 eq.) was added. Thesolution was stirred at room temperature for 29 h. After evaporation, the resulting trifluoroacetic salt was dissolved in dimethylformamide (2.0 mL) and neutralized with triethylamine (0.57 mmol, 1.00 eq.). Separately, N-Boc-amino acid alkyl chain 10 (m = 5, 0.60 mmol, 1.05 eq.) was dissolved in dimethylformamide (2.0 mL), and DCC (0.63 mmol, 1.10 eq.) followed by HOBt (0.63 mmol, 1.10 eq.) were added. Then, the p-hydroxyphenyltyrosamide solution was added to the activated amino acid chain solution. The resulting mixture was stirred at room temperature for 28 h. A precipitate of dicyclohexylurea was formed during the course of the reaction. The reaction mixture was diluted with ethyl acetate (30 mL) and water (20 mL), and then washed with water (4x 20 mL). The organic phase was dried with sodium sulfate, filtered and evaporated. The product was further purified by flash chromatography (hexanes:acetone, 7:3) to give a pure compound in 45-46% yield.
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