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[ CAS No. 13734-41-3 ]

{[proInfo.proName]} (Synonyms:Boc-L-Valine) ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 13734-41-3
Chemical Structure| 13734-41-3
Structure of 13734-41-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 13734-41-3 ]

CAS No. :13734-41-3 MDL No. :MFCD00065605
Formula : C10H19NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :SZXBQTSZISFIAO-ZETCQYMHSA-N
M.W :217.26 Pubchem ID :83693
Synonyms :
Boc-L-Valine

Calculated chemistry of [ 13734-41-3 ]

Physicochemical Properties

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 : 56.47
TPSA : 75.63 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) : -6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.07
Log Po/w (XLOGP3) : 1.54
Log Po/w (WLOGP) : 1.62
Log Po/w (MLOGP) : 1.13
Log Po/w (SILICOS-IT) : 0.48
Consensus Log Po/w : 1.37

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.76
Solubility : 3.76 mg/ml ; 0.0173 mol/l
Class : Very soluble
Log S (Ali) : -2.74
Solubility : 0.398 mg/ml ; 0.00183 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.08
Solubility : 17.9 mg/ml ; 0.0824 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.71

Safety of [ 13734-41-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13734-41-3 ]

* 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 [ 13734-41-3 ]
  • Downstream synthetic route of [ 13734-41-3 ]

[ 13734-41-3 ] Synthesis Path-Upstream   1~19

  • 1
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YieldReaction ConditionsOperation in experiment
100% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 72 h; Inert atmosphere; Sealed tube Step A: To a round-bottom flask was weighed Boc-L-valine (1.03 g, 4.74 mmol), N-hydroxysuccinimide (1.22 g, 10.6 mmol), and EDC (1.60 g, 8.35 mmol). The reagents were dissolved in dry DCM (30 mL), the flask sealed via rubber septum, purged with argon, and the reaction stirred at ambient temperature. After 3 days no Boc-valine remained by TLC (after staining with ninhydrin), so the reaction was washed with water and sat. aq. NaHCO3, the aqueous layer extracted with DCM, combined organic layers washed with brine, dried over Na2SO4, and filtered. The filtrate was then evaporated and dried in vacuo giving Boc-L-valine-succinate as a white solid (1.52 g, 100percent). 1H-NMR (300 MHz, CDCl3): ^ 4.98 (br d, 1H), 4.58 (dd, 1H), 2.82 (m, 4H), 2.27 (m, 1H), 1.44 (s, 9H), 1.03 (dd, 6H). Boc-L-valine-L-citrulline (3):
13.28 g
Stage #1: at 20℃; for 0.05 h;
Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 0 - 20℃; for 18 h;
[000701 A solution of N-Hydroxysuccinimide (5.0 g, 43.44 mmol) and Boc-Val-OH (la, 9.462 g, 43.44 mmol ) in THF (83 mL) was stirred in room temperature for 3.0 minutes. Then DCC (9.856 g, 45.57 mmol) in CH2C12 (83 mL) was slowly added to the solution at 0°C and then warmed to room temperature. The reaction mixture was stirred for further 18 hours. The solution was cooled to 0°C and the precipitate was filtered and washed with EA (100 mL), dried over reduced pressure to give Boc-Val-OSu (ib, 13.28 g). ‘H NMR (500 MHz, DMSO-d6): ö: 5.02 (d, 1H), 4.60 (d, 1H), 2.85 (s, 4H), 2.31 (m, 1H), 1.48 (m, 9H), 1.05 (m, 6H). MS (M+1 ): 314.8.
Reference: [1] Patent: WO2016/160615, 2016, A1, . Location in patent: Paragraph 0444; 0445
[2] Journal of Medicinal Chemistry, 1998, vol. 41, # 14, p. 2461 - 2480
[3] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2852 - 2857
[4] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1984, p. 2305 - 2308
[5] Journal of Organic Chemistry, 1986, vol. 51, # 24, p. 4580 - 4585
[6] Journal of the American Chemical Society, 1992, vol. 114, # 17, p. 6653 - 6661
[7] Nucleosides and Nucleotides, 1998, vol. 17, # 9-11, p. 2135 - 2141
[8] Synlett, 2005, # 18, p. 2802 - 2804
[9] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4280 - 4295
[10] Patent: US2011/65796, 2011, A1, . Location in patent: Page/Page column 23-24
[11] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4182 - 4187
[12] Patent: WO2014/100762, 2014, A1, . Location in patent: Paragraph 240; 244
[13] Biochimica et Biophysica Acta - General Subjects, 2015, vol. 1850, # 9, p. 1849 - 1854
[14] Patent: WO2015/196167, 2015, A1, . Location in patent: Paragraph 0269; 0273
[15] Patent: WO2016/109802, 2016, A1, . Location in patent: Paragraph 00068; 00069; 00070
[16] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
  • 2
  • [ 13734-41-3 ]
  • [ 3392-12-9 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1661 - 1664
  • 3
  • [ 13734-41-3 ]
  • [ 107960-02-1 ]
  • [ 3392-12-9 ]
Reference: [1] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2364 - 2367
  • 4
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  • [ 96935-01-2 ]
  • [ 3392-12-9 ]
Reference: [1] Synthesis, 1991, # 9, p. 689 - 691
  • 5
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  • [ 35150-08-4 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5 h;
Stage #2: With ammonium chloride In tetrahydrofuran; water at 0℃; for 0.5 h;
General procedure: To a colorless solution of 150mg (0.50mmol) of Cbz-L-Phe-OH 3a in 10mL of THF were added 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N at 0°C.
After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) were added at 0°C to the colorless suspension.
The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture.
The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc.
The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4.
The crude product was chromatographed on silica gel with EtOAc to afford 129mg (86percent yield) of Cbz-L-Phe-NH2 4a. 4.3.11
Boc-l-Val-NH2 4f
106 mg (98percent); >99percent ee; coloress solid; mp: 149-152 °C; [α]30D = -2.4 (c 1.00, MeOH); 1H NMR (400 MHz, CDCl3): δ 0.94 (d, J = 6.8 Hz, 3H, CH3CH), 0.99 (d, J = 6.8 Hz, 3H, CH3CH), 1.45 (s, 9H, (CH3)3C), 2.16 (ddd, J = 6.7, 6.8, 6.8 Hz, 1H, CH(CH3)2), 3.96 (dd, J = 6.7, 7.8 Hz, 1H, CHCO), 5.03, 5.42, 5.89 (br, br, br, 1H, 1H, 1H, NH, NH2); 13C NMR (100 MHz, CDCl3): δ 17.8, 19.3, 28.3, 30.8, 59.5, 79.9, 156.0, 174.4; IR (KBr, vmax/cm-1): 3386 (CONH), 3345 (CONH), 3205 (CONH), 1680 (CON), 1641 (CON); HRMS (ESI-TOF): Calcd for C10H20N2O3Na (M+Na)+: 239.1366, found: 239.1340; The enantiomeric ratio was determined by HPLC (Chiralcel OD: hexane/2-propanol = 95/5): Tr 9.4 min.
Reference: [1] Tetrahedron Asymmetry, 2017, vol. 28, # 12, p. 1690 - 1699
[2] Angewandte Chemie - International Edition, 2007, vol. 46, # 25, p. 4771 - 4774
[3] Angewandte Chemie, International Edition, 2009, vol. 48, # 23, p. 4198 - 4201
[4] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 7, p. 2647 - 2648
[5] Tetrahedron, 2009, vol. 65, # 46, p. 9536 - 9541
[6] Organic Letters, 2016, vol. 18, # 11, p. 2560 - 2563
[7] Organic Letters, 2017, vol. 19, # 13, p. 3454 - 3457
[8] Helvetica Chimica Acta, 1963, vol. 46, p. 870 - 889
[9] Journal of Organic Chemistry, 1996, vol. 61, # 23, p. 8207 - 8215
[10] European Journal of Medicinal Chemistry, 1998, vol. 33, # 6, p. 423 - 436
[11] Farmaco, 2000, vol. 55, # 11-12, p. 719 - 724
[12] Heterocycles, 2001, vol. 55, # 5, p. 835 - 840
[13] Tetrahedron Letters, 2007, vol. 48, # 8, p. 1465 - 1468
[14] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 591 - 600
[15] Tetrahedron Letters, 1991, vol. 32, # 39, p. 5359 - 5362
[16] Journal of Organic Chemistry, 1973, vol. 38, p. 3565 - 3570
[17] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[18] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[19] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9845 - 9851
[20] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7355 - 7358
[21] European Journal of Organic Chemistry, 2013, # 36, p. 8154 - 8161
[22] ChemBioChem, 2014, vol. 15, # 1, p. 157 - 169
[23] Journal of Organic Chemistry, 2014, vol. 79, # 9, p. 3895 - 3907
[24] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6831 - 6835
[25] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
[26] Amino Acids, 2018, vol. 50, # 11, p. 1595 - 1605
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Reference: [1] International Journal of Chemical Kinetics, 2006, vol. 38, # 6, p. 376 - 385
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 4014 - 4018
[3] Helvetica Chimica Acta, 1994, vol. 77, # 4, p. 1124 - 1165
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1992, # 7, p. 1187 - 1193
[5] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1986, p. 1655 - 1664
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 3055 - 3064
  • 7
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  • [ 74-88-4 ]
  • [ 45170-31-8 ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydride In tetrahydrofuran at 20℃; for 24 h; To a solution of N-BOC-valine 1 (217 mg, 1 mmol) and iodomethane(1.42 g, 10 mmol) in anhydrous tetrahydrofuran (THF,20 mL) was added neat sodium hydride (240 mg, 10 mmol). Thereaction mixture was stirred at room temperature for 24 h. The mixture was then quenched with water (30 mL). The reaction mixturewas extracted with ethyl acetate (EtOAc, 2 15 mL) and theaqueous solution was acidified to pH 3, after which it wasextracted with EtOAc (3 20 mL). The combined organic phasewas dried over anhydrous Na2SO4 and evaporated to afford the corresponding N-methylated product 2 (thick colorless oil), 99percentyield.
94% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h; Example 14 Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Val-OH (2.0(3 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 "C. The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t. and stirred for 24 h. The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (50 mL x 3) and the aqueous solution was acidified to pH 3 then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over Na2S04 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percent yield) as a white solid. 1H NMR (500 MHz, CDC13) δ 4.10 (d, / = 10.0 Hz, 1H), 2.87 (s, 3H), 2.37 - 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 8.6 Hz, 3H).
94% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h; Example 37. Preparation of compound Boc-N-Me-Val-OH To a solution of Boc-L-Vai-OH (2.00 g, 9.2 mmoi) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THE (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C.The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t, and stirred for 24 h, The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (50 mL x 3) and the aqueous soIuion was acidified to pH 3 then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percentyield) as a white solid. ‘H NMR (500 MHz, CDC13) 4.10 (d, J = 10.0 Hz, 1H), 2.87 (s,3H), 2.37 — 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J =8.6 Hz, 3H).
94% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 25.5 h; To a solution of Boc-L-Val-OH (2.00 g, 9.2 mmol) and methyl iodide (5.74 mL, 92 mmol) in anhydrous THF (40 mL) was added sodium hydride (3.68 g, 92 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then warmed to r.t. and stirred for 24 h. The reaction was quenched by ice water (50 mL). After addition of water (100 mL), the reaction mixture was washed with ethyl acetate (3 × 50 mL) and the aqueous solution was acidified to pH 3 then extracted with ethyl acetate (3 × 50 mL). The combined organic phase was dried over Na2SO4 and concentrated to afford Boc-N-Me-Val-OH (2.00 g, 94percent yield) as a white solid.1H NMR (500 MHz, CDCl3) ^ 4.10 (d, J = 10.0 Hz, 1H), 2.87 (s, 3H), 2.37– 2.13 (m, 1H), 1.44 (d, J = 26.7 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 8.6 Hz, 3H).
91% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
89% With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere (2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89% With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere (2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89% With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere (2S)-2-[[(tert-butoxy)carbonyl] amino] -3 -methylbutanoic acid (63 g,289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before addingsodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
89% With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere Compound 1ZA: (2S)—2—[ [(tert—butoxy)carbonyl] (methyl)amino]—3—methyl butanoic acid (2S)—2—[[Qert—butoxy)carbonyl]amino]—3—methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitationcontinued for 18 hours. The reaction was neutralised with 200 mL of water and thenconcentrated under reduced pressure. The residual aqueous phase was diluted with 4litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3times with 1.2 L of EtOAc. The organic phases were combined, dried over sodiumsulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form ofa yellow oil.
89% With sodium hydride In tetrahydrofuran at 0℃; for 1.5 h; Inert atmosphere Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.
89% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 19.5 h; Inert atmosphere (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (1 16 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at 0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a IN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound IZA in the form of a yellow oil.
89% With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h; Inert atmosphere Compound 1ZA: (2S)-2-[[(tert-butoxy)carbonyl](methyl)amino]-3-methyl butanoic acid
(2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (63 g, 289.97 mmol, 1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence of iodomethane (181 mL).
The solution was cooled to 0° C. before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions.
The reaction mixture was agitated for 1.5 hours at 0° C., the cold bath was then removed and agitation continued for 18 hours.
The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure.
The residual aqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a 1N solution of hydrochloric acid.
The mixture obtained was extracted 3 times with 1.2 L of EtOAc.
The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89percent) of compound 1ZA in the form of a yellow oil.
89%
Stage #1: at 0℃; Inert atmosphere
Stage #2: With sodium hydride In tetrahydrofuran at 0℃; for 19.5 h;
(2S)—2—[ [Qert—butoxy)carbonyl] amino]—3—methylbutanoic acid (63 g, 289.97 mmo 1,1.00 equiv) was dissolved in an inert atmosphere in THF (1000 mL) in the presence ofiodomethane (181 mL). The solution was cooled to 0°C before adding sodium hydride (116 g, 4.83 mol, 16.67 equiv) in small portions. The reaction mixture was agitated for 1.5 hours at0°C, the cold bath was then removed and agitation continued for 18 hours. The reaction was neutralised with 200 mL of water and then concentrated under reduced pressure. The residualaqueous phase was diluted with 4 litres of water, washed once with 200 mL of EtOAc and its pH adjusted to between 3 and 4 with a iN solution of hydrochloric acid. The mixture obtained was extracted 3 times with 1.2 L of EtOAc. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to yield 60 g (89 percent) of compound 1ZA in the form of a yellow oil.
1.29 g With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Na2CO3 (1.26 g, 12.15 mmol) and Boc2O (1.94 g, 9.12 mmol) were added to a solution of L-valine 9 (0.712 g, 6.75 mmol) in H2O (10 mL) and THF (5 mL) at 0 °C. After the reaction mixture had been stirred at RT for 12 h, it was neutralized with HCl (10percent) until pH 2 was reached. The mixture was then extracted with EtOAc (3 × 25 mL), washed with brine and dried over anhyd. Na2SO4. Concentration gave the crude N-Boc-Valine 10 (1.3 g, 100percent). NaH (60percent in mineral oil, 1.22 g, 30.15 mmol) was added in portions to a solution of N-Boc-Valine (1.32 g, 6.72 mmol) and MeI (3.02 mL) in THF (25 mL) at 0 °C. After the reaction mixture had been stirred at RT for 36 h, it was poured into saturated aqueous NH4Cl solution (125 mL), extracted with EtOAc (3 × 150mL) and dried over anhyd. Na2SO4. Concentration gave N-methyl-N-Boc-Valine 11 (1.29 g, 92percent). K2CO3 (1.54 g 11.15 mmol), and allyl bromide (0.75 mL, 8.45 mmol) were added to a solution of N-methyl-N-Boc-Valine (1.25 g, 5.46 mmol) in DMSO (20 mL). After the mixture had been stirred at RT for 12 h, it was portioned between EtOAc (35 mL) and brine (35 mL). The organic phase was separated and aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phase was dried over anhyd. Na2SO4 and concentrated. Flash chromatography gave 12 (1.25 g, 80.9percent) as colorless oil. [α]D −85.1° (c 1.1 in CHCl3); IR (CDCl3): 2971, 2935, 1741, 1700, 1473, 1392, 1368, 1330, 1313, 1147, 993, 879, 773 cm−1; 1H NMR (300 MHz CDCl3): δ 5.97-5.84 (m, 1H), 5.34-5.20 (m, 2H), 4.62-4.60 (m, 2H), 4.47, 4.12 (due to the rotamers, both a d, J = 10.5 Hz, 1H), 2.85, 2.21 (due to the rotamers both as a s, 3H), 2.21-2.27 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 172.3, 171.4, 157.4, 156.3, 133.6, 133.3, 119.5, 119.2, 81.2, 80.6, 66.4, 65.8, 64.6, 63.8, 32.8, 31.8, 28.6, 20.4, 19.8; HRMS (ESI+): m/z Calcd for C14H25NNaO4 (M+Na): 294.197. Found: 294.144.

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YieldReaction ConditionsOperation in experiment
31%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0 - 20℃;
Stage #2: at 0 - 20℃;
EΞxample - 1: Preparation of 1-(2-Amino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid [3-oxo-1- (2,4,5-trifluoro-benryl)-3-(3-trmuoromethyl-6,6-dihydro-8H-['1.2,4]triazolo[4,3-a]pyra-.in-7- yl)-propyl]-amlde Hydrochloride STEP -1 : Preparation 1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidiπfr-2-carboxylic acidTo a stirred solution of N-Boc L-Valine (Compound of formula 2) [8 gm, 0.037 mole] and tri ethyl amine (5.15 ml. 0.037 mole) in THF (120 ml), ethyl chloro formate (3 52 ml, 0.037 mole) was added dropwise at 0-5 0C. The reaction was stirred at 0 0C for 15 minutes and stirred at room temperature for 1 hour. Then keep the reaction at 0 C and add mixture of tri ethyl amine (10.3 ml, 0.074 mole) and THF (60 ml).Finally L-Proline (4.25 gm, 0-037 mole) was added to above mixture at 0 C. Reaction was stirred at 0 C for 30 minutes and stirred at room temperature for over night After being stirred, THF was concentrated under vacuum and residue was acidified with 1N HCI (till pH - 3). The product layer was extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated to give (B). The resulted product was subjected to column chromatography using EtoAC / Hexane 5/5 as an elυentto give N-Boc Val-Pro (Compound of formula 3). (Yield = 3.Q gm, 31percent)
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