Boc-DL-Ala-OH | tert-Butoxycarbonyl-DL-alanine | N-protective Amino Acid

CAS No. :	3744-87-4
Formula :	C₈H₁₅NO₄
M.W :	189.21
SMILES Code :	CC(OC(NC(C(O)=O)C)=O)(C)C
Synonyms :	tert-Butoxycarbonyl-DL-alanine
MDL No. :	MFCD00063124
InChI Key :	QVHJQCGUWFKTSE-UHFFFAOYSA-N
Pubchem ID :	268471

Safety of [ 3744-87-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 3744-87-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.75
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	46.86
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	75.63 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.92
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.98
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.51
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.81

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.26
Solubility	10.3 mg/ml ; 0.0546 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.09
Solubility	1.52 mg/ml ; 0.00805 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.64
Solubility	43.0 mg/ml ; 0.228 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

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) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.8 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.54

Application In Synthesis of [ 3744-87-4 ]

* 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.

Downstream synthetic route of [ 3744-87-4 ]

[ 3744-87-4 ] Synthesis Path-Downstream 1~22

1
[ 6066-82-6 ]
[ 3744-87-4 ]
[ 34404-33-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; at 0℃;	General procedure: The general scheme for the synthesis of AA-CAMderivatives is shown in Fig. S1 and the details ofchemical synthesis are provided in the SupplementaryMethods section. CAM [(1R,2R)-2-amino-1-(4--nitrophenyl)propane-1,3-diol)] was prepared asdescribed previously [23]. Amino acids with protectedalpha- and side-chain amino groups wereactivated by reaction with N-hydroxysuccinimide inthe presence of N,N?-dicyclohexylcarbodiimide at0 C. The resulting succinimide-reactive esters wereused for the acylation of CAM in the presence ofdiisopropylethylamine as a base at room temperature.Subsequent deprotection was achieved bytreatment of the obtained amino-acid CAM derivativeswith trifluoroacetic acid and appropriate scavengers.Synthesized AA-CAM derivatives were purifiedby columnchromatography on silica gel using suitablesystems of solvents. For generating N-acetylatedvariants of AA-CAM, additional acetylation wasperformed by reacting the unprotected AA-CAMderivatives with the N-acetylsuccinimide. Purity andchemical structures of obtained compounds wereconfirmed by HPLC, LC-MS, and NMR spectroscopy(see Supplementary Methods).

References: [1]Journal of the Chemical Society. Chemical communications,1987,p. 1155 - 1156.
[2]Journal of the American Chemical Society,1996,vol. 118,p. 6975 - 6985.
[3]Journal of Molecular Biology,2018,vol. 430,p. 842 - 852.

2
[ 3744-87-4 ]
[ 74-88-4 ]
[ 91103-47-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		Intermediate 57 Boc-D-AlaOMe Boc-D-AlaOH (10.0 g, 52.9 mmol) was dissolved in dry DMF (60 mL), then potassium carbonate (8.0 g, 58.0 mmol) was added, the mixture was stirred at rt for 15 min, and methyl iodide (6.58 mL, 106.0 mmol) was added dropwise. The stirring was maintained for 18h. Then, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (lOOmL). The organic layer was washed with water, brine, dried over MgSCU, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, DCM/MeOH 0 to 1%) to give 10.36 g (51.0 mmol, 96% yield) of the title compound. *Eta NMR (DMSO-d6) delta 7.46 (1H, d), 4.35 (1H, m), 3.66 (3H, s), 1.30 (9H, s), 1.18 (3H, d).
82%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 452-tert-Butoxycarbonylamino-propionic acid methyl ester Boc-D-Ala-OH (4.0 g, 21 mmol) and potassium carbonate (11.7 g, 84.6 mmol) was dissolved in dimethylformamide (90 mL) and iodomethane (1.6 mL, 25 mmol) was added to the reaction mixture. The reaction was allowed to stir at room temperature. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with portions of water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a colorless oil (3.53 g, 82%).1H NMR (300 MHz, CDCl3): delta (ppm) 5.14 (broad s, 1 h), 4.33 (broad s, 1H), 3.51 (s, 3H), 1.49 (s, 9H).

References: [1]Patent: WO2016/8946,2016,A1 .Location in patent: Page/Page column 72-73.
[2]Patent: US2007/259860,2007,A1 .Location in patent: Page/Page column 34.
[3]Journal of Organic Chemistry,1987,vol. 52,p. 1252 - 1255.
[4]Angewandte Chemie - International Edition,2012,vol. 51,p. 5239 - 5243.

3
[ 4530-20-5 ]
[ 6404-26-8 ]
[ 3744-87-4 ]
[ 55297-72-8 ]
Boc-Ala-OH [ No CAS ]
[ 76491-51-5 ]

References: [1]Collection of Czechoslovak Chemical Communications,1980,vol. 45,p. 1424 - 1446.

4
[ 4530-20-5 ]
[ 6404-26-8 ]
[ 3744-87-4 ]
[ 55297-72-8 ]
Boc-Ala-OH [ No CAS ]
[ 76491-50-4 ]

References: [1]Collection of Czechoslovak Chemical Communications,1980,vol. 45,p. 1424 - 1446.

5
[ 186581-53-3 ]
[ 3744-87-4 ]
[ 91103-47-8 ]

References: [1]Tetrahedron Letters,2002,vol. 43,p. 9691 - 9693.

6
[ 3744-87-4 ]
[ 1479-58-9 ]
(R)-{1-[4-bromo-2-(2-fluoro-benzoyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester [ No CAS ]
[ 2387-23-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 8.5h;	{1-[4-Bromo-2-(2-fluorobenzoyl)-phenylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester 136; To a stirred solution of (2-amino-5-bromophenyl)-(2'-fluoro-phenyl)-methanone 115 (60 g, 204 mmol) and the N-Boc-D-alanine 129 (38.59 g, 204 mmol) in CH2Cl2 (500 mL) was added dicyclohexylcarbodiimide (DCC) (42.09 g, 204 mmol) in CH2Cl2 (200 mL) dropwise, over a 30 min period at 0° C. The reaction mixture was allowed to stir an additional 8 h at rt. The dicyclohexyl urea which formed was filtered off and the filtrate concentrated under reduced pressure. The crude solid product 136 was purified by recrystallization from hexane and EtoAc to afford 136 (73 g, 77percent). mp 158-159° C.; IR (KBr, cm-1) 3332, 2931, 255, 1694, 1643, 1613, 1582, 1537, 1450; 1H NMR (CDCl3) delta 11.68 (s, 1H), 8.71 (d, J=9.0 Hz, 1H), 7.69 (dd, J=9.0, 2.3 Hz, 1H), 7.55-7.62 (m, 2H), 7.46 (td, J=7.6, 1.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.21 (t, J=9.1 Hz, 1H), 5.13 (b, 1H), 4.37 (b, 1H), 1.51 (d, J=7.2 Hz, 3H), 1.45 (S, 9H). MS (EI) m/e (relative intensity) 467 (M++2, 14), 466 (M++1, 44), 465 (M+, 14), 464 (42), 329 (15), 321 (60), 295 (100), 224 (26); [alpha]26D=59.6 (c 0.51, EtOAc).

References: [1]Patent: US2006/3995,2006,A1 .Location in patent: Page/Page column 65-66.

7
[ 3744-87-4 ]
[ 17664-93-6 ]
[ 1207335-46-3 ]

References: [1]Helvetica Chimica Acta,2009,vol. 92,p. 2698 - 2721.

8
[ 3744-87-4 ]
[ 74-88-4 ]
[ 13734-31-1 ]

References: [1]British Journal of Pharmacology,2016,p. 2657 - 2668.
[2]Helvetica Chimica Acta,2012,vol. 95,p. 973 - 982.

9
Fmoc-D-allo-MeIle-OH [ No CAS ]
[ 3744-87-4 ]
[ 35661-60-0 ]
[ 109425-51-6 ]
[ 104091-08-9 ]
C₅₄H₇₃N₇O₁₀ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7739 - 7741.

10
[ 3744-87-4 ]
[ 13130-79-5 ]
[ 1452573-04-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 20℃; for 72h;	HATU (7.5 g, 19.7 mmol) is added to a mixture of l-bromoisoquinolin-3-amine (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M-H=392/394; tR=1.97 min (*Method_l).
94%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 72h;	B4a) tert-butyl-N-[1-[(1-bromoisoquinolin-3-yl)amino]-1-oxopropan-2-yl]carbamate HATU (7.5 g, 19.7 mmol) is added to a mixture of <strong>[13130-79-5]1-bromoisoquinolin-3-amine</strong> (2.0 g, 9.0 mmol), 2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (1.7 g, 9.0 mmol) and DIPEA (3.4 ml, 200 mmol) in DMA (10 ml). After stirring for 3 days at RT the mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 3.3 g (94%). HPLC-MS: M-H=392/394; tR=1.97 min (*Method-1).

References: [1]Patent: WO2013/127729,2013,A1 .Location in patent: Page/Page column 50; 51.
[2]Patent: US2013/225567,2013,A1 .Location in patent: Paragraph 0253; 0254.

11
[ 3744-87-4 ]
[ 18107-18-1 ]
[ 91103-47-8 ]

References: [1]MedChemComm,2015,vol. 6,p. 300 - 305.

12
[ 3744-87-4 ]
[ 97682-44-5 ]
camptothecin [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2690 - 2693.

13
[ 13734-41-3 ]
[ 13139-15-6 ]
[ 15761-38-3 ]
[ 3744-87-4 ]
[ 15260-10-3 ]
[ 13836-37-8 ]
C₁₀₆H₁₅₇ClN₁₉O₂₃PolS [ No CAS ]
[ 73821-95-1 ]
[ 18942-49-9 ]
[ 73821-97-3 ]
[ 6404-28-0 ]
[ 108-24-7 ]
[ 55260-24-7 ]
Boc-C^αMeLeu-OH [ No CAS ]
[ 25024-53-7 ]
cyclo(30−33)[D-Phe¹², Nle^21,38,D-Ala^27,40,Glu³⁰,Lys³³]-acetyl-{human/rat corticotropin releasing factor}(9−41) [ No CAS ]