Structure of Boc-β-HoAib-OH
CAS No.: 129765-95-3
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CAS No. : | 129765-95-3 |
Formula : | C10H19NO4 |
M.W : | 217.26 |
SMILES Code : | CC(C)(NC(OC(C)(C)C)=O)CC(O)=O |
MDL No. : | MFCD09031500 |
InChI Key : | LHJVMOIOTPJSLS-UHFFFAOYSA-N |
Pubchem ID : | 10376046 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 56.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
75.63 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.04 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.76 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.13 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.5 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.31 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.45 |
Solubility | 7.78 mg/ml ; 0.0358 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.22 |
Solubility | 1.31 mg/ml ; 0.00604 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.44 |
Solubility | 7.87 mg/ml ; 0.0362 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.89 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.25 |
* 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 |
---|---|---|
99% | With water; sodium hydroxide; In tetrahydrofuran; methanol; at 20.0℃; for 19.0h; | (Step 2) 3-(tert-Butoxycarbonylamino)-3-methylbutanoic acid Ethyl 3-(tert-butoxycarbonylamino)-3-methylbutanoate (10.4 g, 42.5 mmol) synthesized in step 1 was dissolved in tetrahydrofuran (200 mL). To the solution, a 1 N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was stirred at room temperature for 16 hours. Methanol (50 mL) was added thereto, and the mixture was further stirred for 3 hours. The organic solvent was distilled off under reduced pressure. To the obtained aqueous solution, 1 N hydrochloric acid (120 mL) was added, followed by extraction with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.2 g, yield: 99.0%) as an oil substance. 1H-NMR (CDCl3) delta: 4.97 (1H, br s), 2.73 (2H, br s), 1.45 (9H, s), 1.40 (6H, s). MS (APCI) m/z : 216 [(M-H)-]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; lithium borohydride; triethylamine; In tetrahydrofuran; methanol; | 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. STR39 At 0 C., ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) (cf. Schoen et al. J. Med. Chem., 1994, vol. 37, p. 897-906, and references cited herein) and triethylamine (1.92 ml, 13.8 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 ml). The liquid was immediately cooled to 0 C. A 2M solution of lithium borohydride in tetrahydrofuran (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0 C. and methanol (5 ml) was added. 1N Hydrochloric acid (100 ml) was added and the solution was extracted with ethyl acetate (2*100 ml, 3*50 ml). The combined organic extracts were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl aceteate/heptane (1:2) to give 1.84 g of 3-hydroxy-1,1dimethylpropylcarbamic acid tert-butyl ester. 1 H-NMR (CDCl3): δ1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q,2H; 4.98 (br, 1H). | |
With hydrogenchloride; lithium borohydride; triethylamine; In tetrahydrofuran; methanol; | 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. At 0C, ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) (cf. Schoen et al. J. Med. Chem., 1994, vol. 37, p. 897-906, and references cited herein) and triethylamine (1.92 ml, 13.8 mmol) in tetrahydrofuran (10 ml). The solution was stirred for 40 min at 0C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 ml). The liquid was immediately cooled to 0C. A 2M solution of lithium borohydride in tetrahydrofuran (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0C for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0C and methanol (5 ml) was added. 1N Hydrochloric acid (100 ml) was added and the solution was extracted with ethyl acetate (2 x 100 ml, 3 x 50 ml). The combined organic extracts were washed with saturated sodium hydrogencarbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl aceteate/heptane (1:2) to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1H-NMR (CDCl3): δ 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). | |
With hydrogenchloride; lithium borohydride; In tetrahydrofuran; methanol; at 0 - 20℃; for 4.66667h; | 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester At 0 C., ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in THF (10 ml).. The solution was stirred for 40 min at 0 C. The obtained precipitate was filtered off and washed with THF (20 ml).. The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in THF (14.4 ml, 28.8 mmol) was added dropwise.. The solution was stirred at 0 C. for 2 h, and then warmed to room temp. over a period of 4 h.. It was cooled to 0 C. methanol (5 ml) was added carefully. 1N hydrochloric acid (100 ml) was added.. The solution was extracted with ethyl acetate (2*100 ml, 3*50 ml).. The combined organic layers were washed with saturated solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulfate.. The solvent was removed in vacuo.. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 400 MHz-1H-NMR (CDCl3): 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In tetrahydrofuran; methanol; | Buildingblocks: N-methylated aminoacids used in the following examples were prepared as in Can. J. Chem. 1977, 55, 906. 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester: At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature. over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1H-NMR (CDCl3): δ1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). | |
With hydrogenchloride; sodium hydrogencarbonate; triethylamine; In tetrahydrofuran; methanol; | (2E)-5-Amino-5-methylhex-2-enoic acid {(1R)-1-[N-methyl-N-((1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl)carbamoyl]-2-(2-naphthyl)ethyl}amide STR81 Prepared according to method E. 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester STR82 At 0 C., ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in THF (10 ml). The solution was stirred for 40 min at 0 C. The obtained precipitate was filtered off and washed with THF (20 ml). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in THF (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temp. over a period of 4 h. It was cooled to 0 C. Methanol (5 ml) was added carefully. 1N Hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2*100 ml, 3*50 ml). The combined organic layers were washed with saturated solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 400 MHz-1H-NMR (CDCl3): 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q, 2H); 4.98 (br, 1H). | |
With hydrogenchloride; triethylamine; In tetrahydrofuran; methanol; | Step A At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature. over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1H-NMR (CDCl3): d 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). |
With hydrogenchloride; triethylamine; In tetrahydrofuran; methanol; | Step A At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was fiftered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1H-NMR (CDCl3): d 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). | |
With hydrogenchloride; triethylamine; In tetrahydrofuran; methanol; | N-methylated amino acids used in the following examples were prepared as in Can. J. Chem. 1977, 55, 906. 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester: At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1H-NMR (CDCl3): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q, 2H); 4.98 (br, 1H). 3-(tert-Butoxycarbonylamino)-3-methylbutanal: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; triethylamine; In tetrahydrofuran; methanol; | Step A At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | A solution of <strong>[625-05-8]3-amino-3-methylbutanoic acid</strong> (0.59 g, 5.04 mmol) and BOC-anhydride (1.228 mL, 5.29 mmol) in dioxane (10 mL) was treated with 1 M potassium hydroxide (5.04 mL, 5.04 mmol), and the mixture was stirred for about 16 h at rt. The dioxane was removed from the solution under reduced pressure, and the remaining cloudy aqueous solution was diluted with water (20 mL) and treated with lithium hydroxide to adjust the pH to 13. The mixture was washed 3.x. with diethyl ether, then the pH was adjusted to 3 with 2 N HCl. The cloudy solution was extracted 4.x. with ethyl acetate, then the combined ethyl acetate phases were washed with a small amount of brine, dried over sodium sulfate, and concentrated in vacuo to yield the title compound (860 mg, 3.96 mmol, 79percent yield) as a crystalline solid. | |
72.9% | 3-Amino-3-methylbutanoic acid (CAN 625-05-8, 2.0 g, 17 mmol) was combined with dioxane (60 mL) to give a colorless suspension. 1 N sodium hydroxide solution (17.0 mL, 17.0 mmol) was added dropwise at 0° C. within 10 min Di-tert-butyldicarbonate (4.8 g, 22.2 mmol) was added in three portions. The reaction was stirred for 30 min to give a colorless suspension. Then dioxane (30 mL) was added (using less solvent resulted in a thick suspension) and the mixture was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo to a volume of 50 mL and poured into 200 mL water. Then the mixture was washed with ethyl acetate (3.x.80 ml). The aqueous layers were combined, 2 N HCl was added and after adjusting the pH to 2 the mixture was extracted with ethyl acetate (3.x.60 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give product (2.7 g, 72.9percent). | |
72.9% | 3-Amino-3-methylbutanoic acid (CAN 625-05-8, 2.0 g, 17 mmol) was combined with dioxane (60 mL) to give a colorless suspension. 1 N sodium hydroxide solution (17.0 mL, 17.0 mmol) was added dropwise at 0°C within 10 min. Di-tert-butyldicarbonate (4.8 g, 22.2 mmol) was added in three portions. The reaction was stirred for 30 min to give a colorless suspension. Then dioxane (30 mL) was added (using less solvent resulted in a thick suspension) and the mixture was stirred for 17 hours at ambient temperature. The reaction mixture was concentrated in vacuo to a volume of 50 mL and poured into 200 mL water. Then the mixture was washed with ethyl acetate (3 x 80 ml). The aqueous layers were combined, 2 N HC1 was added and after adjusting the pH to 2 the mixture was extracted with ethyl acetate (3 x 60 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give product (2.7 g, 72.9percent). |
65% | With potassium hydroxide; In 1,4-dioxane; at 20℃; for 40h; | 1 M KOH (15.19 ml) was added to a mixture of <strong>[625-05-8]3-amino-3-methylbutanoic acid</strong> (1 .78 g, 15.19 mmol) and Boc20 (3.48 g, 15.95 mmol) in 1 ,4-dioxane (30 ml) and stirred at room temperature for 40 h. The solvent was concentrated and diluted with water (60 ml). 1 M LiOH was added until pH 13. The aqueous phase was extracted with Et20 (3 x 30 ml), then the pH adjusted to 3 using 2M HCI and extracted with EtOAc (4 x 60 ml). The combined organic layers were washed with brine(30 ml), dried (Na2S04), filtered and evaporated to give the title compound (2.13 g , 65percent) as an off-white solid . Compound will be used in the next step without further purification. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 5.07 (s, 1 H), 2.75 (s, 2H), 1 .44 (s, 9H) 1 .40 (s, 6H) |
55% | With sodium hydroxide; In water; at 0 - 20℃; for 12h; | 3-Amino-3-methylbutanoic acid (2.06 g, 17 olved in water (40 mL) and (Boc)2O (4.08 mL, 17.5 mmol) and sodium hydroxide (0.703 g, 17.5 mmol) in water (20 mL) was added at 0 °C. The mixture was stirred at room temperature for 12 hours. The solution was diluted with sat. NH4Cl solution (200 mL) and ethyl acetate (60 mL), the organic phase was separated, washed with water (30 mL ) and brine (30 mL), dried and concentrated under reduced pressure to give the product 3-((tert-butoxycarbonyl)amino)-3- methylbutanoic acid (2.1 g, 9.67 mmol, 55percent yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.17 (s, 1H), 7.03 (s, 1H), 1.37 (s, 9H), 1.30 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium borohydride; chloroformic acid ethyl ester; triethylamine; In tetrahydrofuran; | Example 4 (2E)-5-Amino-5-methyl-N-methyl-N-((1R)-1-(N-methyl-N-(2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)hex-2-enamide STR103 3-Hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester: STR104 At 0 C., ethyl chloroformate (1.101/2, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1 H-NMR (CDCl3):-- d 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1 H); 3.75 (q, 2 H); 4.98 (br, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium borohydride; chloroformic acid ethyl ester; triethylamine; In tetrahydrofuran; | Step A: At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature. over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1 N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1 H-NMR ((CDCl3): d 1.33 (s, 6H); 1.44 (s, 9H); 1.88 (t, 2H); 1.94 (br, 1H); 3.75 (q, 2H); 4.98 (br, 1H). | |
With lithium borohydride; chloroformic acid ethyl ester; triethylamine; In tetrahydrofuran; | Step A: At 0 C., ethyl chloroformate (1.10 mL, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 mL, 13.8 mmol) in tetrahydrofuran (10 mL). The solution was stirred for 40 min at 0 C. The formed precipitate was filtered off and washed with tetrahydrofuran (20 mL). The liquid was immediately cooled to 0 C. A 2M solution of lithium boronhydride in tetrahydrofuran (14.4 mL, 28.8 mmol) was added dropwise. The solution was stirred at 0 C. for 2 h, and then warmed to room temperature. over a period of 4 h. It was cooled to 0 C. Methanol (5 mL) was added carefully. 1N Hydrochloric acid (100 mL) was added. The solution was extracted with ethyl acetate (2*100 mL, 3*50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester. 1 H-NMR (CDCl3): d 1.33 (s, 6 H); 1.44 (s, 9 H); 1.88 (t, 2 H); 1.94 (br, 1H); 3.75 (q, 2 H); 4.98 (br, 1 H). |