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Product Details of [ 20859-02-3 ]

CAS No. :20859-02-3 MDL No. :MFCD00064218
Formula : C6H13NO2 Boiling Point : -
Linear Structure Formula :H2NCH(C4H9)COOH InChI Key :NPDBDJFLKKQMCM-SCSAIBSYSA-N
M.W : 131.17 Pubchem ID :164608
Synonyms :
(S)-2-amino-3,3-dimethylbutanoic acid
Chemical Name :(S)-2-Amino-3,3-dimethylbutanoic acid

Calculated chemistry of [ 20859-02-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.83
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 35.18
TPSA : 63.32 Ų

Pharmacokinetics

GI absorption : High
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) : -8.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.06
Log Po/w (XLOGP3) : -1.77
Log Po/w (WLOGP) : 0.44
Log Po/w (MLOGP) : -1.82
Log Po/w (SILICOS-IT) : -0.31
Consensus Log Po/w : -0.48

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : 0.59
Solubility : 515.0 mg/ml ; 3.92 mol/l
Class : Highly soluble
Log S (Ali) : 0.96
Solubility : 1180.0 mg/ml ; 9.03 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : -0.12
Solubility : 100.0 mg/ml ; 0.762 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.28

Safety of [ 20859-02-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 20859-02-3 ]

* 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.

  • Upstream synthesis route of [ 20859-02-3 ]
  • Downstream synthetic route of [ 20859-02-3 ]

[ 20859-02-3 ] Synthesis Path-Upstream   1~66

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Reference: [1] Journal of Molecular Catalysis B: Enzymatic, 2014, vol. 105, p. 11 - 17
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YieldReaction ConditionsOperation in experiment
75%
Stage #1: With methanesulfonic acid In dichloromethane at 25℃; for 3 h;
Stage #2: With triethylamine In dichloromethane at 25℃; for 1 h;
Example 9
Production of (S)-tert-leucine
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)-N-(tert-butoxycarbonyl)-tert-leucine (1155 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours.
When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated.
The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 30 minutes.
Thereafter, the solid was separated by filtration under reduced pressure.
The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying.
Thereby, the titled compound was produced as a white solid (514 mg, yield of 75percent).
Titled Compound:
1H-NMR (D2O): δ (ppm) 0.87 (s, 9H), 3.40 (s, 1H)
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[3] Patent: EP2423187, 2012, A1, . Location in patent: Page/Page column 15
  • 3
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YieldReaction ConditionsOperation in experiment
80% With ammonium hydroxide; D-glucose; ammonium chloride; sodium hydroxide In water for 5.5 h; Enzymatic reaction Bioconversion of TMP to l-tert-leucine was carried out by recombinant whole-cells harboring pET28a-E-G. In a reactor (2L), 1L of water was added to a mixture of 178.2g glucose (0.9mol), 78.1g TMP (0.6mol), 26.8g NH4Cl (0.5mol) and 10.0g of the whole cells of E. coli BL21/pET28a-E-G. The reaction pH was adjusted to 8.5 with NaOH solution. During the reaction process, the pH was automatically adjusted to 8.5 by titrating 50percent (v/v) NH3·H2O. When the reaction was terminated, the reaction mixture was heated to 60°C, followed by centrifugation to remove the biocatalysts. The remained solution was adjusted to pH 5.9 and concentrated via rotary evaporator. Then the solution temperature was decreased slowly to 25°C and continued to decrease to 4°C, the l-tert-leucine crystals were obtained.
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[3] Patent: US2012/245379, 2012, A1,
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[5] Patent: EP2502896, 2012, A1,
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  • 46
  • [ 20859-02-3 ]
  • [ 24424-99-5 ]
  • [ 62965-35-9 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In methanol at 0 - 5℃; STEP A: 2(S)-tert-Butoxycarbonylamino-3,3-dimethyl-butyric Acid
To a suspension of L-tert-leucine (26.1 g, 0.2 mol) in methanol (150 ML) was added triethylamine (56 ML, 0.4 mol) and the mixture cooled to 0° C.
To the mixture was added slowly a solution of di-tert-butyldicarbamate (48 g, 0.22 mol) in methanol (40 ML) such that an internal temperature of between 0 and 5° C. was maintained..
The reaction was allowed to stir overnight and the solvents were removed in vacuo..
The residue was dissolved in ethyl acetate (200 ML) and washed with 10percent w/v aqueous citric acid solution (3*100 ML)..
The organic layer was dried over MgSO4, filtered and the solvents removed in vacuo to give the title product as a pale yellow oil (48.9 g, >100percent, residual solvent).
1H NMR (CDCl3): δ/ppm 9.20 (1H, bs), 5.10 (1H, m), 4.15 (1H, m), 1.45 (9H, s), 1.00 (9H, s).
100% With triethylamine In methanol at 0 - 5℃; To a suspension of L-tert-leucine (26.1 g, 0.2 mol) in methanol (150 mL) was added triethylamine (56 mL, 0.4 mol) and the mixture cooled to 0 C. To the mixture was added slowly a solution: of di-tert-butyldicarbamate (48 g, 0.22 mol) in methanol (40 mL) such that an internal temperature of between 0 and 5 C. was maintained. The reaction was allowed to stir overnight and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with 10percent w/v aqueous citric acid solution (3100 mL). The organic layer was dried over MgSO4, filtered and the solvents removed in vacuo to give the title product as a pale yellow oil (48.9 g, >100percent, residual solvent). 1H NMR (CDCl3): ?/ppm 9.20 (1H, bs), 5.10 (1H, m), 4.15 (1H, m), 1.45 (9H, s), 1.00 (9H, s).
100% With sodium hydroxide In 1,4-dioxane at 20℃; for 12 h; (1) adding sodium hydroxide, L-tert-leucine and water according to a molar ratio of 1: 1: 10 into a reactor,Then, an equimolar amount of (Boc) 2O and L-tert-leucine were dissolved in 10 times of 1,4-dioxane,Slowly dripped into the reactor, stirred at room temperature for 12 hours after dripping finished, after the solvent was concentrated to half and the same volume of ethyl acetate was added and the reaction solution was concentrated, then added 4mol / L hydrochloric acid half of the volume of ethyl acetate, liquid separation , The organic phase was washed once with an equal volume of water, dried over anhydrous sodium sulfate and evaporated to give the compound 5, the structure is shown in Formula 8;
99% With triethylamine In 1,4-dioxane; water Triethylamine (890 uL, 6.40 mmol) was added dropwise to a stirred solution of L-tert- leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/water 1: 1 (8 mL) and the solution was stirred overnight. The mixture was extracted with petroleum ether (2x) and the aqueous phase was cooled to 0 °C and carefully acidified to pH 3 by slow addition of 4M NaHS04 H20. The acidified water phase was extracted with EtOAc (3x) and the combined organic phases were washed with brine (2x) and was then dried, filtered and concentrated to give compound 36 (522 mg, 99 percent) as a colorless powder. No further purification was needed. 1H-NMR (300 MHz, CD30D) 8 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD30D) 5 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
99% With sodium hydroxide In water; isopropyl alcohol at 25℃; for 3 h; Example 20 An aqueous solution (1150 g) containing L-tert-leucine (100 g, 762 mmol) was stirred, and the pH of the solution was adjusted to 9 using a 30percent by weight of sodium hydroxide aqueous solution. Then, isopropanol (160 g) was added thereto. Further, di-tert-butyl dicarbonate (174.7 g, 800 mmol) was added thereto at 25°C with maintaining the pH between 8.5 and 9.5 using a 30percent by weight of sodium hydroxide aqueous solution. The mixture was stirred for about 3 hours, and the resultant was analyzed; as a result, 175 g of N-tert-butoxycarbonyl-L-tert-leucine was produced (yield: 99percent).
96% With sodium hydroxide In water at 7 - 20℃; for 14 h; Example 17 An aqueous solution (250.5 g) containing L-tert-leucine (20.5 g, 0.16 mol) was cooled to 7°C, and a 48percent by weight of sodium hydroxide aqueous solution (16.5 g) was added thereto. Then, di-tert-butyl dicarbonate (34.92 g, 0.16 mol, 1.00 equivalent) was slowly added with maintaining the pH in 9.4-10.8. After the addition, the mixture was stirred at not more than 20°C for 14 hours. Then, the yield and the amount of the generated impurity were analyzed by HPLC. Yield: 96percent, Reaction selectivity: 98percentExample 18 The reaction was carried out in the same condition
92%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16 h;
Stage #2: With hydrogenchloride In water; ethyl acetate
Step 6: Preparation of N-(tert-Butoxycarbonyl)-L-tert-leucine; To a suspension of L-tert-leucine (5.0 g, 38 mmol) in dioxane (50 mL) and H2O (35 mL) at 0° C. was added 1M NaOH (38 mL, 1 equiv.) followed by Boc2O (9.3 g, 42 mmol, 1.1 equiv.). The reaction mixture was stirred at 0° C. to room temperature over 16 h then concentrated to approx half volume under reduced pressure. The aqueous residue was treated with EtOAc (75 mL) and 1 M HCl (50 mL), the aqueous phase separated and further extracted with EtOAc (50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give the product as a colourless glassy solid (7.99 g, 92percent).
89%
Stage #1: With sodium hydroxide In 1,2-dioxacyclohexane; water at 0 - 20℃; for 4 h;
Stage #2: With potassium hydrogensulfate In water
Preparation of N-(tert-Butoxycarbonyl)-L-tert-leucine (MD009)
L-tert-Leucine (2.63 g, 20 mmol) was dissolved in a mixture of water (50 ml), 1,2-dioxan (20 ml), and 0.8 g sodium hydroxide, cooled in an ice bath. Di-tert-butylcarbonate (4.8 g, 22 mmol) in 1,2-dioxan (20 ml) was added dropwise to the cooled solution.
The reaction mixture was stirred at room temperature for 4 h and the pH was adjusted between 8 and 9.
Dioxane was then evaporated in vacuo and the resulting solution was acidified with 10percent aqueous potassium hydrogen sulfate to pH 3 and extracted with ethyl acetate (4*50 ml).
The combined organic layers were washed with 10percent aqueous potassium hydrogen sulfate (3*30 ml), brine (3*30 ml), and water (3*30 ml).
The organic phase was dried with anhydrous magnesium sulfate and concentrated in vacuo to give a white solid.
This resulted in a 89percent yield (4.133 g, 17.87 mmol).
1H-NMR (CDCl3, 400 MHz), doubling of peaks caused by rotamers around the N-Boc group, 5.81 (bs, 0.2H, NH), 5.09 (d, 0.8H, J=8.8 Hz, NH), 4.13 (d, 0.8H, J=9.6 Hz, H-2), 3.91 (bs, 0.2H, H-2), 1.45 (s, 9H, H-9, H-10, H-11), 1.02 (s, 9H, H-4, H-5, H-6). TLC (MeOH:CH2Cl2 5:20) Rf=0.91, (MeOH:H2O:CH2Cl2 45:5:200) Rf0.86.

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YieldReaction ConditionsOperation in experiment
99% With triethylamine In 1,4-dioxane; water Example 8
Boc-L-tert-leucine-OH (8)
Triethylamine (890 uL, 6.40 mmol) was added dropwise to a stirred solution of L-tert-leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/ water 1:1 (8 mL) and the solution was stirred overnight.
The mixture was extracted with petroleum ether (2*) and the aqueous phase was cooled to 0°C and carefully acidified to pH 3 by slow addition of 4M NaHSO4*H2O.
The acidified water phase was extracted with EtOAc (3*) and the combined organic phases were washed with brine (2*) and was then dried, filtered and concentrated to give the title compound 8 (522 mg, 99 percent) as a colorless powder.
No further purification was needed.
1H-NMR (300 MHz, CD3OD) δ 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD3OD) δ 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
99% With triethylamine In 1,4-dioxane; water Example 2
Boc-L-tert-leucine-OH (2).
Triethylamine (890 μL, 6.40 mmol) was added dropwise to a stirred solution of L-tert-leucine (300 mg, 2.29 mmol) and di-tert-butyl dicarbonate (599 mg, 2.74 mmol) in dioxane/ water 1:1 (8 ml) and the solution was stirred overnight.
The mixture was extracted with petroleum ether (2*) and the aqueous phase was cooled to 0°C and carefully acidified to pH 3 by slow addition of 4M NaHSO4*H2O.
The acidified water phase was extracted with EtOAc (3*) and the combined organic phases were washed with brine (2*) and were then dried, filtered and concentrated to give the title compound 2 (522 mg, 99 percent) as a colorless powder.
No further purification was needed. 1H-NMR (300 MHz, CD3OD)δ 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1H); 13C-NMR (75.5 MHz, CD3OD) δ 27.1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7.
Reference: [1] Patent: EP1881001, 2008, A1,
[2] Patent: EP1881002, 2008, A1,
  • 48
  • [ 20859-02-3 ]
  • [ 62965-35-9 ]
Reference: [1] Patent: EP618221, 1994, A2,
  • 49
  • [ 20859-02-3 ]
  • [ 58632-95-4 ]
  • [ 62965-35-9 ]
Reference: [1] Tetrahedron, 1991, vol. 47, # 29, p. 5453 - 5462
  • 50
  • [ 1070-19-5 ]
  • [ 20859-02-3 ]
  • [ 62965-35-9 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, p. 1069 - 1076
  • 51
  • [ 13139-17-8 ]
  • [ 20859-02-3 ]
  • [ 62965-10-0 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In methanol at 20℃; for 14 h; Step A: 2S-Benzyloxycarbonylamino-3,3-dimethyl-butyric acid; To a suspension of L-tert-leucine (11.88 g, 90.7 mmol) in methanol (200 ml) were added triethylamine (26.56 ml, 190 mmol) and N-(benzyloxycarbonyl- oxy)-succinimide (24.88 g, 99.8 mmol). The reaction mixture was stirred at room temperature for 14 h. Methanol was removed in vacuo to afford a viscous pale yellow oil, which was dissolved in ethyl acetate (100 ml). The organic layer was washed with 1M hydrochloric acid (15 ml) and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to fumish the title compound as an oil (24 g, quant.). 1H-NMR; δ(CDCl3), 7.43-7.36 (5H, m), 5.36 (1H, d, J = 9.4 Hz), 5.12 (2H, br s), 4.20 (1H, d, J = 9.6 Hz) and 1.02 (9H, s). LRMS: +ve ion 266 [M+H], -ve ion 264 [M-H], 529 [2M-H].
Reference: [1] Patent: EP1210330, 2005, B1, . Location in patent: Page/Page column 9-10
  • 52
  • [ 20859-02-3 ]
  • [ 501-53-1 ]
  • [ 62965-10-0 ]
YieldReaction ConditionsOperation in experiment
81.5% With sodium hydrogencarbonate In water at 0 - 20℃; for 21 h; 2-Benzyloxycarbonylamino-3,3-dimethyl-butyric acid (2) ;To a solution of L-tert-leucine (1) (50.0 g, 38.0 mmol) and NaHCO3 (96.0 g, 114 mmol) in ice (500 g) and water (500 ml) was added benzyl chloroformate (65.0 ml, 74.0 mmol) and the reaction stirred at 0° C. for 3 hours then at room temperature for 18 hours. 0.1N Na2CO3 was added until the oily layer dissolved and the solution was washed with 10percent EtOAc in hexanes (2*500 ml).
The iced aqueous phase was acidified to pH 1 using 12N HCl then extracted using EtOAc (3*350 ml).
The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (82.4 g, 81.5percent yield): 1H-NMR (500 MHz, CDCl3) δ 1.02 (s, 9H), 4.22 (d, 1H), 5.10-5.14 (m, 2H), 5.31 (d, 1H), 7.26-7.37 (m, 5H).
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 7, p. 1203 - 1212
[2] Organic Letters, 2009, vol. 11, # 4, p. 907 - 910
[3] Patent: EP2423187, 2012, A1, . Location in patent: Page/Page column 12-13
[4] Patent: EP696593, 1996, A2,
[5] Patent: EP618221, 1994, A2,
[6] Patent: EP675112, 1995, A1,
[7] Patent: US9487555, 2016, B2, . Location in patent: Page/Page column 14-15
[8] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, p. 1069 - 1076
[9] Chemische Berichte, 1971, vol. 104, p. 687 - 690
[10] Patent: US6020371, 2000, A,
[11] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
[12] Patent: WO2015/95227, 2015, A2, . Location in patent: Page/Page column 177; 178
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  • [ 20859-02-3 ]
  • [ 13795-24-9 ]
  • [ 62965-10-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2016, vol. 55, # 10, p. 3364 - 3368[2] Angew. Chem., 2016, vol. 128, p. 3425 - 3429,5
  • 54
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  • [ 62965-10-0 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1977, vol. 42, p. 1069 - 1076
  • 55
  • [ 20859-02-3 ]
  • [ 112245-13-3 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With lithium borohydride; chloro-trimethyl-silane In tetrahydrofuran at 10 - 65℃; for 3.58333 h;
Stage #2: With methanol In tetrahydrofuran at 10℃; for 0.333333 h;
Stage #3: at 20℃; for 1 h;
Example 8-1 <Synthesis of (S)-t-leucinol>; To a 100 mL Schlenk tube purged with nitrogen, 4.00 g (30.5 mmol) of (S)-tert-leucine and 40 mL of tetrahydrofuran were added and the inner temperature was adjusted to 10°C. To this suspension, 1.46 g (61.0 mmol) of lithium borohydride was added over 5 minutes and the inner temperature thereof was adjusted to 20°C. 7.44 g (67.1 mmol) of trimethylsilyl chloride was added dropwise thereto over 30 minutes and the mixture was heated to the inner temperature of 65°C and stirred at the same temperature for 3 hours. After the reaction mixture was cooled to 10°C, 4 mL of methanol was added dropwise thereto over 20 minutes. After reaction mixture was concentrated using an evaporator, 40 mL of 4M aqueous sodium hydroxide solution was added thereto and stirred at room temperature for 1 hour. Next, the extraction was conducted by adding 40 mL of tert-butyl methyl ether and the organic layer obtained was dehydrated over sodium sulfate. Sodium sulfate was removed by filtration and tert-butyl methyl ether was distilled away by atmospheric distillation. Further, 2.96 g of (S)-tert-leucinol was obtained as a fraction of 70 to 75°C by reduced-pressure distillation (0.3 kPa). Yield: 83percent.
80%
Stage #1: With borane-THF In tetrahydrofuran at 10 - 65℃; for 5.5 h;
Stage #2: With methanol In tetrahydrofuran at 10℃; for 0.166667 h;
Stage #3: at 20℃; for 1 h;
Example 7-1 <Synthesis of (S)-t-leucinol>; To a 100 mL Schlenk tube purged with nitrogen, 2.00 g (15.3 mmol) of (S)-tert-leucine and 10 mL of tetrahydrofuran were added and the inner temperature was adjusted to 10°C. To this suspension, 30.5 mL (30.5 mmol) of 1M borane-tetrahydrofuran solution was added dropwise over 30 minutes and the resulting mixture was heated to an inner temperature of 65°C and stirred at the same temperature for 5 hours. After the reaction mixture was cooled to 10°C, 4 mL of methanol was added dropwise thereto over 10 minutes. After reaction mixture was concentrated using an evaporator, 20 mL of 4M aqueous sodium hydroxide solution was added thereto and stirred at room temperature for 1 hour. Next, the extraction was conducted by adding 30 mL of chloroform and the organic layer obtained was dehydrated over sodium sulfate. Sodium sulfate was removed by filtration and chloroform was distilled away by atmospheric distillation. Further, 1.43 g of (S)-tert-leucinol was obtained as a fraction of 70 to 75°C by reduced-pressure distillation (0.3 kPa). Yield: 80percent.
79%
Stage #1: With borane-THF In tetrahydrofuran at 10 - 65℃; for 5.5 h;
Stage #2: With methanol In tetrahydrofuran at 10℃; for 0.333333 h;
Stage #3: at 20℃; for 1 h;
To a 100 mL Schlenk tube purged with nitrogen, 4.00 g (30.5 mmol) of (S)-tert-leucine and 20 mL of tetrahydrofuran were added and the inner temperature was adjusted to 10°C. To this suspension, 61.0 mL (61.0 mmol) of 1M borane-tetrahydrofuran complex was added dropwise over 30 minutes and the resulting mixture was stirred at the same temperature for 1 hour. After that, The mixture was heated to an inner temperature of 65°C and stirred at the same temperature for 4 hours. After the reaction mixture was cooled to 10°C, 8 mL of methanol was added dropwise thereto over 20 minutes. After reaction mixture was concentrated using an evaporator, 20 mL of 4M aqueous sodium hydroxide solution was added thereto and stirred at room temperature for 1 hour. Next, the extraction was conducted by adding 40 mL of tert-butyl methyl ether and the organic layer obtained was dehydrated over sodium sulfate. Sodium sulfate was removed by filtration and tert-butyl methyl ether was distilled away by atmospheric distillation. Further, 2.82 g of (S)-tert-leucinol was obtained as a fraction of 70 to 75°C by reduced-pressure distillation (0.3 kPa). Yield: 79percent.
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[9] Journal of Organic Chemistry, 1993, vol. 58, # 13, p. 3568 - 3571
[10] Journal of Organic Chemistry, 1993, vol. 58, # 13, p. 3568 - 3571
[11] Patent: EP1698617, 2006, A1, . Location in patent: Page/Page column 13
[12] Organic and Biomolecular Chemistry, 2008, vol. 6, # 18, p. 3337 - 3348
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  • 56
  • [ 20859-02-3 ]
  • [ 21641-92-9 ]
YieldReaction ConditionsOperation in experiment
67% With sulfuric acid; sodium nitrite In water at 20℃; for 48 h; To a solution of 3,3-dimethyl butanoic acid (1 g, 7.5 mmol) in 1 M sulfuric acid (15 ml, 1 M aqueous solution), cooled to 0°C, was added a solution of sodium nitrite (1.0 g, 15 mmol) in water (8 ml). The temperature was maintained below 5°C during the addition, and the mixturewas stirred at such overnight. The solution was then saturated with ammonium sulfate, extracted with diethyl ether (5x25 ml), dried over sodium sulfate and evaporated under reduced pressure giving the title compound (0.27 g, 67percent) as a colorless oil that crystallized on standing. 1H NMR (400 MHz, ODd3) 63.41 (s, 1H), 1.25 (s, 9H). LCMS (m/z) 133.2 [M+H], Tr = 0.39 mm(Gemini 5u 018 iioA, 50 x 4.60mm 5 micron column, 3.5 mi 2m1/min, 5—100percentacetonitrile/water, 0.1percent acetic acid modifier gradient).
Reference: [1] Liebigs Annalen der Chemie, 1982, vol. No. 11, p. 1952 - 1970
[2] Journal of Organic Chemistry, 1991, vol. 56, # 7, p. 2499 - 2506
[3] Patent: WO2013/185093, 2013, A1, . Location in patent: Page/Page column 261
[4] Journal of Organic Chemistry, 2017, vol. 82, # 9, p. 4949 - 4957
[5] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 15, p. 3540 - 3546
[6] Tetrahedron, 2004, vol. 60, # 41, p. 9163 - 9170
[7] Organic and Biomolecular Chemistry, 2012, vol. 10, # 8, p. 1625 - 1638
  • 57
  • [ 20859-02-3 ]
  • [ 22146-57-2 ]
  • [ 130062-37-2 ]
  • [ 130062-38-3 ]
  • [ 21641-92-9 ]
Reference: [1] Chemische Berichte, 1991, vol. 124, # 4, p. 849 - 859
  • 58
  • [ 20859-02-3 ]
  • [ 130062-37-2 ]
  • [ 23985-53-7 ]
  • [ 21641-92-9 ]
  • [ 32659-48-6 ]
Reference: [1] Chemische Berichte, 1991, vol. 124, # 4, p. 849 - 859
  • 59
  • [ 20859-02-3 ]
  • [ 19547-38-7 ]
  • [ 117408-98-7 ]
Reference: [1] Chemistry - A European Journal, 2013, vol. 19, # 1, p. 74 - 77
  • 60
  • [ 20859-02-3 ]
  • [ 117408-98-7 ]
Reference: [1] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1637 - 1642
[2] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1637 - 1642
[3] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1637 - 1642
  • 61
  • [ 20859-02-3 ]
  • [ 28920-43-6 ]
  • [ 132684-60-7 ]
YieldReaction ConditionsOperation in experiment
96% With sodium carbonate In 1,4-dioxane at 0 - 20℃; Take 500mL of the reaction bottle,Chiral amino acids S-3b (5.1 g, 38.6 mmol) were added to the reaction flask, respectively,Dioxane (40 mL) and10percent sodium carbonate (100 mL),The reaction flask was placed in an ice bath, mechanically stirred,To the dropping funnel was added l-chloroformate-9-fluorenylmethyl ester (10.0 g, 38.6 mmol) andDioxane (100 mL),Slowly drop into the reaction flask and gradually return to room temperature and stir overnight.After completion of the reaction, add water 100mL, extracted with 50mL ether three times, take the water phase into the ice bath to cool, add 1M dilute HCl to PH 1.The aqueous solution was extracted three times with 50 mL of ethyl acetate.The oil phase was combined and dried over magnesium sulfate and filtered to dryness to give intermediate S-4b (14.3 g, 96percent).
Reference: [1] Patent: CN106588987, 2017, A, . Location in patent: Paragraph 0195; 0196; 0197
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 45, p. 11846 - 11851[3] Angew. Chem., 2013, vol. 125, # 45, p. 12062 - 12067,6
[4] Chemistry - A European Journal, 2014, vol. 20, # 21, p. 6526 - 6531
[5] Patent: WO2018/145021, 2018, A1, . Location in patent: Page/Page column 134
  • 62
  • [ 20859-02-3 ]
  • [ 82911-69-1 ]
  • [ 132684-60-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 8, p. 1391 - 1394
  • 63
  • [ 20859-02-3 ]
  • [ 154701-60-7 ]
Reference: [1] Organic Syntheses, 2009, vol. 86, p. 181 - 193
  • 64
  • [ 20859-02-3 ]
  • [ 79-22-1 ]
  • [ 162537-11-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide In 1,4-dioxane; water at 60℃; for 18 h; Step 1: Synthesis of (S)-2-(methoxycarbonylaniino)-3,3-dimethylb tanoic acid:A stirred solution of (S)-2-amino-3,3-dimethylbutanoic acid (about 5.0 g, 38. 16 mmol) in Dioxane (about 20 ml) and sodium hydroxide (2N, 62 ml, PH = 8-9) at about 0 °C, methychlroformate (about 5.88 ml, 76.33 mmol) was added drop wise and stirred at about 60 °C for about 18 hours. The reaction mixture was cooled to room temperature, extracted with DCM, the aqueous layer was separated and acidified with I N HCl. The resulting solution was extracted with EtOAc, dried over Na2S04 and the solvent was evaporated under reduced pressure. The resulting crude was stirred in hexane and decants to afford the title compound as a solid. Wt: 8.5 g: Yield: quantitative; NMR (300 MHZ, CDCI3): δ 5.25 (d, 1 H, J = 10.5 Hz), 4. 19(d, 1 H, J = 9.6 Hz) 3.70 (s, 3H), 1 .03 (s, 9H); Mass: [M- l ]' 188 ( 100percent); IR ( Br, cm 1 ): 3379, 2974, 1727, 1688, 1546, 1466, 1332, 1263. 121 1 , 1070, 1034, 1018, 843, 696.
98% With sodium hydroxide In 1,4-dioxane; water at 25 - 60℃; for 22 h; Example 1; methyl (1S)-1-( (12- [ (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyl]-2- [4- (2- pyridinyl) benzyl] hydrazino} carbonyl)-2, 2-dimethylpropylcarbamate; Example 1A; (2S)-2-[(methoxycarbonyl) amino] -3,3-dimethylbutanoic acid; (L)-tert-Leucine (10 g, 0.076 mol) was dissolved in 1,4-dioxane (40 mL) and treated with 2M NaOH (125 mL, 3.2 equivalents) followed by dropwise addition of methyl chlorofonnate (11.2 mL, 1.9 equivalents) at 25°C. The mixture was heated at 60°C for 22 hrs, cooled, and extracted twice with dichloromethane. The aqueous layer was separated, cooled in ice bath, and acidified with 4N HC1 (60 mL). The mixture was extracted three times with ethyl acetate, and the organic layer was separated, dried with sodium sulfate, filtered, and the solvents were evaporated to give 14.1 g (98percent) of the title compound
98%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 25 - 60℃; for 22 h;
Stage #2: With hydrogenchloride In water
EXAMPLE 1A
(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic Acid
(L)-tert-Leucine (10 g, 0.076 mol) was dissolved in 1,4-dioxane (40 mL) and treated with 2M NaOH (125 mL, 3.2 equivalents) followed by dropwise addition of methyl chloroformate (11.2 mL, 1.9 equivalents) at 25° C.
The mixture was heated at 60° C. for 22 hrs, cooled, and extracted twice with dichloromethane.
The aqueous layer was separated, cooled in ice bath, and acidified with 4N HCl (60 mL).
The mixture was extracted three times with ethyl acetate, and the organic layer was separated, dried with sodium sulfate, filtered, and the solvents were evaporated to give 14.1 g (98percent) of the title compound.
98% With sodium hydroxide In water at 25℃; for 2 h; Example 1 A 15percent by weight sodium hydroxide aqueous solution was added to the aqueous solution (72.4 g) containing L-tert-leucine (13.2 g, 0.10 mol), to adjust the pH to 13.0. Then, methyl chloroformate (9.52 g, 0.10 mol, 1.00 equivalent) was slowly added thereto with maintaining the temperature of the mixture below 25°C. At the time, the pH was decreased by adding methyl chloroformate; however, the pH of the solution was maintained at 10.0-12.8 by simultaneously adding a 15percent by weight of sodium hydroxide aqueous solution. After the addition of methyl chloroformate, the mixture was stirred for 2 hours. Then, the yield and quality were analyzed by HPLC. Yield: 98percent, Reaction selectivity: 100percent
92%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 50 - 60℃; for 18 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water at 0℃;
A solution of L-tert-Leucine (25 g, 190.58 mmol) in a mixture of dioxane (100 mL) and aqueous NaOH solution (315 mL, 2N) was treated dropwise with methyl chloroformate (29.3 mL, 379.19 mmol), keeping the internal temperature below 50° C. The mixture was warmed to 60° C. and stirred for 18 hours, cooled to 25° C. and extracted with dichloromethane. The aqueous phase was cooled to 0° C. and the pH was adjusted to about 1-2 with concentrated HCl. The mixture was partitioned between ethyl acetate and water. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. A solution of the concentrate in ether was treated with hexanes to afford the crystalline product (33.22 g, 92percent yield), which was collected by filtration.
92%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 50 - 60℃; for 18 h;
Stage #2: With hydrogenchloride In water at 0℃;
EXAMPLE 1F
(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutanoic acid
A solution of L-tert-Leucine (25 g, 190.58 mmol) in a mixture of dioxane (100 mL) and aqueous NaOH solution (315 mL, 2N) was treated dropwise with methyl chloroformate (29.3 mL, 379.19 mmol), keeping the internal temperature below 50° C.
The mixture was warmed to 60° C. and stirred for 18 hours, cooled to 25° C. and extracted with dichloromethane.
The aqueous phase was cooled to 0° C. and the pH was adjusted to about 1-2 with concentrated HCl.
The mixture was partitioned between ethyl acetate and water.
The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated.
A solution of the concentrate in ether was treated with hexanes to afford the crystalline product (33.22 g, 92percent yield), which was collected by filtration.
89% at 60℃; for 20 h; 2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (3) (0136) Into a 250 mL flask was placed L-tert-Leucine (5.0 gm, 38 mmol), 2N NaOH (66 mL), and methyl chloroformate (5.86 mL, 76 mmol, 2.0 equivalents). The reaction mixture was heated to 60° C., turning light-yellow. After approximately 20 hours, the heat was removed and the mixture cooled to room temperature, and then to 0° C. The reaction mixture was quenched at 0° C. with 2 N HCl (40 mL) to pH 1. The acidified mixture was transferred to a separatory funnel and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×150 mL), and saturated NaCl (150 mL), and then dried over Na2SO4. The organic layer was filtered and concentrated under reduced pressure to give a clear oil. The oil was azeotroped with toluene (3×50 mL), and then dried under high vacuum to give 6.4 gm (89percent) of 3 as a white solid. 1H NMR (DMSO) δ 12.51 (bs, 1H), 7.28 (d, 1H), 3.80 (d, 1H), 3.53 (s, 3H), 0.93 (s, 9H); MS (M)+=190; HPLC tR 2.8 minutes.
76%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20 - 60℃; for 20 h;
Stage #2: With hydrogenchloride In 1,3-dioxane; water
Compound 1; L-tert-leucine (12.251 g, 93.4 mmol) was dissolved in a mixture of NaOH (2N, 154 mL) and dioxane (50.5 mL). Methyl chloroformate (14.30 mL, 185.84 mmol) was added slowly (e.g., dropwise) to the solution at room temperature ("r.t."). The resulting reaction mixture was heated to 600C and stirred for 20 <n="454"/>hours ("h"). The reaction mixture was cooled to r.t. and washed with dichloromethane ("DCM.") The aqueous layer was acidified to pH 2 using concentrated HCl. The aqueous layer was then extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, and concentrated. The resulting oil was crystallized from hexane to give Compound 1 as a white solid (13.354 g, 70.6 mmol, 76percent). TLC Rf (silica gel 60 plate, methanol /EXTM, 1:19) = 0.78.
71% With sodium carbonate; sodium hydroxide In water at 20℃; for 3.25 h; Cooling with ice General procedure: Na2CO3 (276mg, 2.6mmol) was added to aq NaOH (5mL of 1M/H2O, 5mmol) solution of d-valine (586mg, 5.00mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (0.420mL, 5.40mmol) was added dropwise, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25h. The reaction mixture was washed with ether (3×9mL), and the aqueous phase was cooled with ice-water bath and acidified with conc HCl to a pH region of 1–2, and extracted with CH2Cl2 (3×9mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford Cap-1 as a white solid (760mg, 87percent).

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