Structure of 106946-74-1
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| CAS No. : | 106946-74-1 |
| Formula : | C11H23NO3 |
| M.W : | 217.31 |
| SMILES Code : | CC[C@H](C)[C@@H](CO)NC(OC(C)(C)C)=O |
| English Name : | tert-Butyl ((2S,3S)-1-hydroxy-3-methylpentan-2-yl)carbamate |
| MDL No. : | MFCD00235929 |
| InChI Key : | BPLDQMXXYMKQPW-DTWKUNHWSA-N |
| Pubchem ID : | 14237729 |
| Num. heavy atoms | 15 |
| Num. arom. heavy atoms | 0 |
| Fraction Csp3 | 0.91 |
| Num. rotatable bonds | 7 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 60.67 |
| TPSA ? Topological Polar Surface Area: Calculated from |
58.56 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.74 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.0 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.92 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.55 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.29 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.9 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-1.99 |
| Solubility | 2.25 mg/ml ; 0.0103 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.86 |
| Solubility | 0.302 mg/ml ; 0.00139 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.95 |
| Solubility | 2.47 mg/ml ; 0.0114 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 |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
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 |
-6.21 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
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) |
3.08 |
* 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 borane-THF In tetrahydrofuran at 0 - 20℃; for 5.83333h; Inert atmosphere; | 5.10. N-Boc-L-isoleucinol (10) To a solution of N-Boc-L-isoleucine (13.86 g, 60 mmol) in THF (150 mL) was added dropwise 1 M BH3THF (90 mL, 90 mmol) at 0 C over 20 min under argon atmosphere. After stirring at 0 C for another 30 min, the reaction was allowed to warm to room temperature and stirred for 5 h. The mixture was cooled to 0 C again, quenched by dropwise addition of water. Removing most of the THF under reduced pressure, then ethyl acetate (180 mL) and water (60 mL) was added to the residue. The mixture was separated and the organic layer was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 6 (12.89 g, 99%) as a colorless oil. The compound was used for next step without further purification. [a] 25D 14.8 (c 1.0, MeOH); 1 H NMR (400 MHz, CDCl3) d 5.04 (dd, J 48.3, 13.9 Hz, 1H), 3.73e3.55 (m, 2H), 3.48 (s, 1H), 3.37 (s, 1H), 1.58 (d, J 14.5 Hz, 1H), 1.56e1.48 (m, 1H), 1.45 (s, 10H), 1.23e1.05 (m, 1H), 0.91 (t, J 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 156.7, 79.3, 63.4, 56.8, 35.9, 28.4, 25.3, 15.5, 11.4; HRMS (ESI; m/z) [MNa] calcd for C11H23NO3Na 240.1570, found 240.1530. |
| 90% | Stage #1: N-(tert-butyloxycarbonyl)-L-isoleucine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium tetrahydroborate; water In tetrahydrofuran at 0℃; for 0.5h; | |
| 84% | Stage #1: N-(tert-butyloxycarbonyl)-L-isoleucine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.0166667h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 15℃; for 0.00833333h; Further stages.; |
| 77% | With sodium tetrahydroborate; 2-(6-nitro-1-oxy-benzotriazol-3-yl)-1,1,3,3-Me4-uronium*PF6; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; | |
| 59% | With (i-PrO)2TiBH4 In dichloromethane for 4h; Ambient temperature; | |
| With diborane In tetrahydrofuran for 1h; 0 deg C to r. t.; Yield given; | ||
| With borane-THF at 0℃; | ||
| Multi-step reaction with 2 steps 1: potassium hydrogen carbonate / dimethylformamide / 5 h / Ambient temperature 2: LiCl, NaBH4 / tetrahydrofuran; ethanol / Ambient temperature | ||
| Multi-step reaction with 2 steps 1: KHCO3 / dimethylformamide / Ambient temperature 2: anhydrous lithium chloride, sodium borohydride / tetrahydrofuran; ethanol / Ambient temperature | ||
| Multi-step reaction with 2 steps 1: 4-methyl-morpholine / 1,2-dimethoxyethane / -15 - 20 °C / Inert atmosphere 2: sodium tetrahydroborate / 1,2-dimethoxyethane; water / -15 °C / Inert atmosphere | ||
| Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide 2: sodium tetrahydroborate | ||
| Stage #1: N-(tert-butyloxycarbonyl)-L-isoleucine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -20 - -10℃; for 0.5h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0 - 20℃; for 2h; Inert atmosphere; | ||
| 96% | Stage #1: N-(tert-butyloxycarbonyl)-L-isoleucine With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -20℃; Inert atmosphere; Stage #2: With sodium tetrahydroborate In water at 0℃; | |
| Multi-step reaction with 2 steps 1.1: thionyl chloride / 3.5 h / 0 - 20 °C / Reflux 2.1: sodium hydrogencarbonate / tetrahydrofuran; water / 15 h 2.2: 3 h / 20 °C / Reflux |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at -10℃; | |
| 92% | With Dess-Martin periodane In dichloromethane at 20℃; for 2.25h; | 5.11. N-Boc-L-isoleucinal (11) To a solution of N-Boc-L-isoleucinol 10 (11.94 g, 55 mmol) in CH2Cl2 (150 mL) was added Dess-Martin periodinane (28 g, 66 mmol) in portions over 15 min. The resulting suspension was stirred at room temperature for 2 h and filtered through a pad of celite. The filtrate was washed with saturated aqueous solution of sodium bicarbonate (75 mL) and saturated brine (75 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 11 (10.88 g, 92%) as a colorless oil. The compound was used for next step without further purification. [a] 25D 2.5 (c 1.0, MeOH); 1 H NMR (400 MHz, CDCl3) d 9.66 (s, 1H), 5.42 (d, J 6.3 Hz, 1H), 4.27 (s, 1H), 2.03 (s, 1H), 1.58e1.34 (m, 10H), 1.34e1.21 (m, 1H), 1.06e0.83 (m, 6H); 13C NMR (100 MHz, CDCl3) d 200.6, 155.6, 79.5, 64.0, 36.1, 28.1, 25.1, 15.5, 11.6; HRMS (ESI; m/z) [MNa] calcd for C11H21NO3Na 238.1414, found 238.1379. |
| 90% | With sulfur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide at 0℃; | 20.A Part A. ((75, 25)-l-Formyl-2-methyl-butyl)-carbamic acid tert-butyl esterTo a suspension of N-Boc- -isoleucinol (5g, 23 mmol) in dichloromethane (250 mL) and DMSO (50 mL) at 0°C was added TEA (10 mL, 73 mmol) followed by slow addition of the solution of sulfur trioxide pyridine complex (11 mL, 69 mmol) in DMSO (50 mL) via syringe. The reaction mixture was concentrated and was diluted with ether (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 200 mL), which was then washed with brine (150 mL), water ( 150 mL) and aHC03 (150 mL) sequentially. The organic layers were dried over MgS04, filtered and concentrated. The residue was dried on pump to afford ((lS,25)-l-formyl-2-methyl-butyl)-carbamic acid tert-butyl ester ( 4.47 g, 90% yield) as light-yellow clear liquid. |
| 72% | With pyridine; chromium(VI) oxide In dichloromethane for 1.5h; 5 deg C to r. t.; | |
| 70% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile for 0.5h; Reflux; | |
| 63% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -60 - -50℃; for 1.25h; | |
| With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In benzene at 20 - 25℃; for 0.333333h; | ||
| With sulfur trioxide pyridine complex; dimethyl sulfoxide In dichloromethane; triethylamine at 10 - 20℃; for 0.166667h; | ||
| With pyridinium chlorochromate In dichloromethane | ||
| With Dess-Martin periodane In dichloromethane; water at 20℃; for 1h; | ||
| Inert atmosphere; | ||
| With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile Inert atmosphere; Reflux; | ||
| With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 20℃; | 1.3 The compound 13 (31.3 g, 144 mmol) is dissolved in acetonitrile (i.e., MeCN) (300 mL), and 2-iodoxybenzoic acid (IBX) (44.8 g, 160 mmol) is added to obtain a mixture. After heating and refluxing of the mixture for reacting for 2 h, the mixture is cooled to the room temperature, and the mixture is filtered to obtain a filter residue and a filtrate. The filter residue is washed for once with acetonitrile (200 mL), and the filtrate is concentrated under reduced pressure to obtain an intermediate aldehyde. | |
| With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile Reflux; | ||
| With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile for 1h; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | With di-isopropyl azodicarboxylate; ZnN6-pyridine2; triphenylphosphine In toluene for 3h; Ambient temperature; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With lithium borohydride In 1,2-dimethoxyethane | |
| 86% | With sodium tetrahydroborate; acetic acid In 1,4-dioxane at 80℃; | |
| 83% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; |
| With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol Ambient temperature; | ||
| With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol Ambient temperature; Yield given; | ||
| With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol | ||
| With lithium borohydride In methanol; diethyl ether for 15h; Heating; | ||
| With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 4h; | 3.5.3. General method for preparation of compounds (5) General procedure: To a dried methanol (50 mL) solution of 4 (3.3 g, 20 mmol), thionyl chloride (3.57 g, 30 mmol) was slowly added over 30 minat 0 °C, and then, the solution was maintained at room temperature for 18 h. The solvent was evaporated to obtain a solid in quantitative yield, which was dissolved in dichloromethane (120 mL), and triethylamine (12.1 g, 120 mL) and di-tert-butyldicarbonate (9.6 g, 40 mmol) were added to the dichloromethane solution. The reaction mixture was stirred at 25 °C for 24 h. Afterc ompletion of the reaction, the solution was washed with phosphoric acid (50 x 3 mL), saturated sodium bicarbonate (50 x 3 mL) and saturated sodium chloride (50 x 3 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford a solid to which lithium aluminum hydride (13 mmol) in the presence of dried tetrahydrofuran (25 mL) was added at 0 °C. The reaction mixture was maintained at room temperature for 4 h, and then water was added until the lithium aluminum hydride reacted completely. Next, the solution was filtered, and the residue was washed with tetrahydrofuran (20 x 2 mL).The combined organic solvent phase was evaporated under reduced pressure to yield the crude product, which was purified using column chromatography (petroleum ether/acetone) to afford 5a-5g. | |
| With sodium tetrahydroborate | ||
| With sodium tetrahydroborate; ethanol; water; lithium chloride In tetrahydrofuran for 3h; Reflux; | 3 (3) A synthesis process of a compound 14 and a compound 14′ is as follows: The first intermediate obtained in the previous step is dissolved in a mixed solvent of THF/H2O (1:1, 1000 mL), NaHCO3solid (40.3 g, 480 mmol) is added, and after stirring evenly, Boc2O (36.8 mL, 160.0 mmol) is added to obtain a mixture. After stirring of the mixture for reacting for 15 h, the mixture is concentrated under reduced pressure to remove THF thereof, diluted by adding water (200 mL), and extracted for three time with EA (500 mL) to obtain organic phases. The organic phases are merged, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a second intermediate.The second intermediate obtained in the previous step is dissolved in ethanol (EtOH) (1000 mL), and a sodium borohydride (NaBH4) solid (12.2 g, 320 mmol) and a lithium chloride (LiCl) (13.6 g, 320 mmol) are sequentially added to obtain a mixture. After heating and refluxing of the mixture for reacting for 3 h, the mixture is cooled to the room temperature, and the mixture is concentrated under reduced pressure to remove the ethanol, to thereby obtain a solid. Water (800 mL) is added to dissolve the solid to obtain a solution. Hydrochloric acid is slowly added dropwise into the solution to make pH=5 to obtain an acidic solution. The acidic solution is extracted for three times by using EA (500 mL) to thereby obtain organic phases. The organic phases are merged, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a compound 13 (31.3 g), and a total yield thereof is 90% through the above three steps. | |
| With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | In pyridine | |
| With pyridine In dichloromethane at 0 - 20℃; for 8h; | ||
| With pyridine; triethylamine In dichloromethane at 0 - 20℃; for 8h; |
| With dmap; triethylamine In dichloromethane | 4.4. General procedure for the synthesis of intermediates (11a-g) General procedure: To a solution of intermediates 10a-g (1 equiv) in dichloromethane, TsCl (1.2 equiv), DMAP (0.2 equiv) and trimethylamine(3 equiv) were added. The solutionwas stirred at 20 °C.The reaction was followed by TLC and quenched with water. Theorganic phase was washed with citric acid (1 N) and saturatedNaHCO3 then dried over Na2SO4 and filtered. The filtrate wasconcentrated and purified by a silica column to afford compounds11a-g as a white solid. |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With boron trifluoride diethyl etherate In acetone at 20℃; for 2h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With triethylamine; In dichloromethane; | General procedure: L-amino alcohol (1 equiv), (Boc)2O (1.2 equiv) and trimethylamine(2 equiv) were added to dichloromethane. The mixture wasstirred under ice bath conditions. The reactionwas followed by TLCand diluted with dichloromethane. The organic phase was washedwith citric acid (1 N) and saturated NaHCO3 then dried over Na2SO4and filtered. The filtrate was concentrated and purified by a silicacolumn to afford compounds 10a-g. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99% | With triethylamine In tetrahydrofuran at 0 - 20℃; | |
| With triethylamine In dichloromethane Cooling with ice; | ||
| 74 % | With triethylamine In dichloromethane at 0℃; |
| With dmap; triethylamine In dichloromethane at 20℃; for 2h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 25℃; for 12.5h; Inert atmosphere; | General procedure: To diisopropyl azodiformate (DIAD) (0.41 g, 2 mmol), triphenylphosphine (0.41 g, 2 mmol) and dried tetrahydrofuran (5 mL) were slowly added. After 30 min, 5 (3 mmol) in tetrahydrofuran (5 mL) was slowly added to the solution, and then, the tetrahydrofuran (10 mL) solution of 3 (0.24 g, 1 mmol) was added to the solution over the course of 30 min under a nitrogen atmosphere at °0 Cand allowed to proceed for 12 h. After completion of the reaction, the solvent was evaporated to obtain an oil, which was extracted with ethyl acetate/petroleum ether (1:3, 4 10 mL). The organic phase was evaporated under reduced pressure to yield an oil, which was purified by column chromatography with petroleum ether/ethyl acetate (15:1) to obtain a solid. To the solid (0.5 mmol), ethyl acetate with saturated hydrochloric acid (15 mL) was added and reacted for 1 h. The solvent was evaporated under reduced pressure to obtain the crude product, which was recrystallized with methanol/ether to obtain 6a-6s. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | With p-toluenesulfonyl chloride; potassium hydroxide In diethyl ether at 40℃; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90 % | Stage #1: di-<i>tert</i>-butyl dicarbonate; N-(tert-butoxycarbonyl)isoleucine methyl ester With sodium hydrogencarbonate In tetrahydrofuran; water Stage #2: di-<i>tert</i>-butyl dicarbonate With sodium tetrahydroborate; lithium chloride In ethanol at 20℃; Reflux; | 1.3 The first intermediate obtained in the previous step is dissolved in a mixed solvent of THF/water (1:1, 1000 mL), NaHCO3 solid (40.3 g, 480 mmol) is added, after stirring evenly, di-tert-butyl decarbonate ((Boc)2O) (36.8 mL, 160.0 mmol) is added to obtain a mixture. After stirring of the mixture for reacting for 15 h, the mixture is concentrated under reduced pressure to remove THF therein, diluted by adding water (200 mL), and extracted for three times with EA (500 mL) to obtain organic phases. The organic phases are merged, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a second intermediate (i.e., a first intermediate compound). The second intermediate obtained in the previous step is dissolved in ethanol (EtOH) (1000 mL), and a sodium borohydride (NaBH4) solid (12.2 g, 320 mmol) and anhydrous lithium chloride (LiCI) (13.6 g, 320 mmol) are sequentially added to obtain a mixture. After heating and refluxing of the mixture for reacting for 3 h, the mixture is cooled to the room temperature, and the mixture is concentrated under reduced pressure to remove EtOH therein, to thereby obtain a solid. Water (800 mL) is added to dissolve the solid to obtain a solution. Hydrochloric acid is slowly added dropwise into the solution to make pH=5 to thereby obtain an acidic solution. The acidic solution is extracted for three times by using EA (500 mL) to obtain organic phases. The organic phases are merged, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a compound 13 (31.3 g), and a total yield thereof is 90% through the above three steps. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 54 % | With sodium hydride; potassium iodide In N,N-dimethyl acetamide at 5 - 15℃; Inert atmosphere; | 3 Under nitrogen protection, NaH (4.8 g, 0.12 mol), KI (2.5 g, 0.01 mol), benzyl chloride: 20.0 mL, DMAc: 20 mL were added with stirring to a 100 mL three-necked flask equipped with mechanical stirring, a thermometer, a 25 mL constant pressure adding funnel and a drying tube. The temperature was lowered to 5-15 °C, and a solution of the compound (4.34 g, 0.02 mol) in DMAc (8 mL) was added dropwise. After the addition was completed, the system was kept warm and stirred for 2 h before the reaction was stopped. After the reaction is completed, the reaction solution is poured into 320 mL of stirred water, and then 160 mL of dichloromethane is added for extraction, and the organic phase and the aqueous phase are collected separately; the aqueous phase is extracted once with 160 mL of dichloromethane, and the organic phase is collected; the organic phases are combined, and water is added: 160 mL of water is washed once, and the organic phase is collected; the water washing is repeated 4 times until the pH of the aqueous phase is 7-8, and the organic phase is collected; the organic phase is dried with anhydrous magnesium sulfate, filtered, and the filtrate is collected; the filtrate is concentrated under reduced pressure at 40-45°C until no obvious liquid drips out; the obtained crude product is subjected to column chromatography to obtain a light yellow oily compound: 1.66 g, yield: 54.0%. |