67630-01-7|(S)-Ethyl 3-(4-aminophenyl)-2-((tert-butoxycarbonyl)amino)propanoate| Ambeed

Structure of 67630-01-7

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Quality Control of [ 67630-01-7 ] Purity: 95% SDS Specification

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Product Details of [ 67630-01-7 ]

CAS No. :	67630-01-7
Formula :	C₁₆H₂₄N₂O₄
M.W :	308.37
SMILES Code :	O=C(OCC)[C@@H](NC(OC(C)(C)C)=O)CC1=CC=C(N)C=C1
MDL No. :	MFCD18207036
InChI Key :	YGUWRFUPGXSHNX-ZDUSSCGKSA-N
Pubchem ID :	10638537

Safety of [ 67630-01-7 ]

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

Computational Chemistry of [ 67630-01-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	9
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	84.87
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	90.65 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.05
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	1.76
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.28
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.	1.93
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	1.9
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.47
Solubility	1.05 mg/ml ; 0.0034 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.28
Solubility	0.161 mg/ml ; 0.000523 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	-3.91
Solubility	0.038 mg/ml ; 0.000123 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.	-6.93 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	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	1.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 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)	3.09

Application In Synthesis of [ 67630-01-7 ]

* 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 [ 67630-01-7 ]

[ 67630-01-7 ] Synthesis Path-Downstream 1~35

1
[ 38184-47-3 ]
[ 67630-01-7 ]
[ 85676-47-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 4435 - 4443.

2
[ 67630-00-6 ]
[ 67630-01-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydrogen;palladium 10% on activated carbon; In ethanol; under 2068.65 - 2585.81 Torr; for 1h;	A solution of N-BOC-4-nitro-L-phenyl alanine ethyl ester (78.3 g, 0.22 mol) in absolute ethanol (300 mL) was purged with nitrogen, and 10% palladium on carbon (1.0 g) was added. After hydrogenated at 40-50 psi for 1 h, the reaction mixture was filtered through Celite, and the cake was washed with EtOH followed by EtOAc. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 4:1 to 1:1 EtOAc/Hexanes to afford the title compound (60 g 89% yield). lH NMR (400 MHz, CDCI3) delta 6.90 (d, 2H), 6.63 (d, 2H), 4.20-4.50 (m,lH), 4.14 (q, 2H), 3.76-3.00 (m, 2H), 1.36 (s, 9H).1.20 (t, 3H).
	With hydrogen;palladium 10% on activated carbon; In ethanol; under 2068.65 - 2585.81 Torr; for 1h;	Step C : A solution of the compound of Step B (78. 3 g, 0. 22 mol) in absolute ethanol (300 mL) was purged with nitrogen, and 10% palladium on carbon (1. 0 g) was added. After hydrogenated at 40-50 psi for 1 h, the reaction mixture was filtered through Celite, and the cake was washed with EtOH followed by EtOAc. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel eluting with 4 : 1 to 1 : 1 EtOAc/Hexanes to afford N-BOC-4-amino-L-phenylalanine, ethyl ester (60 g). 1H NMR (400 MHz, Cd13) 8 6. 90 (d, 2H), 6. 63 (d, 2H), 4. 20-4. 50 (m, lH), 4. 14 (q, 2H), 3. 76-3. 00 (m, 2H), 1. 36 (s, 9H), 1. 20 (t, 3H).
	palladium-carbon; In ethanol;	(9-1) In 120 ml of ethanol was dissolved 4.95 g (14.6 mmol) of N-t-butoxycarbonyl-DL-4-nitrophenylalanine ethyl ester, and 500 mg of 10% palladium carbon was added to the solution and the mixture was stirred under hydrogen atmosphere at 50-60 C. for 6 hours. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by the silica gel column chromatography ethod (eluent: chloroform/ethyl acetate=50/1) to obtain 3.97 g (12.8 mmol) of N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester as white solid. 1H-NMR (CDCl3) delta; 6.92 (d, J=8 Hz, 2H), 6.63 (d, J=8 Hz, 2H), 5.03-4.85 (m, 1H), 4.56-4.38 (m, 1H), 4.16 (q, J=7.3 Hz, 2H), 3.15-2.82 (m, 2H), 1.42 (s, 9H), 1.25 (t, J=7.3 Hz, 3H). CI-MS (m/z); 253

	With hydrogen;10% palladium on activated carbon; In ethanol;	The mixture of 4.6 g of Boc-Phe(4-NO2)-Oet, 900 mg of 10% palladium charcoal (containing 50% water) and ethanol was stirred overnight under the hydrogen atmosphere. After Celite filtration, the solvent was removed to obtain the objective compound. Yield: 4.4 g H-NMR (CDCl3) delta 1. 25 (3H, t), 1. 40 (9H, s), 2. 95 (2H, br), 4. 15 (2H, q), 4.45 (1H, m), 4.95 (1H, br), 6.60 (2H, d), 6.95 (2H, d).
	With hydrogen;palladium on carbon; In N,N-dimethyl-formamide; for 8h;Product distribution / selectivity;	3) Hydrogen conversion reaction of Boc-3-(4-nitro-phenyl)-2-tert-butoxycarbonylamino-propionic acid ethyl ester (Boc-ntrPhe-OEt) 1 g of Boc-ntrPhe-OEt, 30 ml of DMF and 0.05 g of palladium-carbon (Pd-C) were mixed, gas-filling by hydrogen was conducted using a balloon, and the solution was stirred for approximately 8 hours. During the stirring, hydrogen was changed every 2 hours. The product was analyzed by 1H-NMR spectroscopy.
	With palladium 10% on activated carbon; hydrogen; In methanol;	The intermediate (17) was dissolved in methanol, 10% Pd / C was added, and the hydrogen was pressurized. Filtered, concentrated under reduced pressure to the give intermediate (18).
	With palladium 10% on activated carbon; hydrogen; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere; Large scale;	N-tert-butoxycarbonyl-L-4-nitrophenylalanine ethyl ester (3.385 kg, 10.0 mol) was added to a 100 L enamel kettle containing N,N-dimethylformamide (26 L).Stir and dissolve until clear, add 10% Pd on carbon (170g), replace with nitrogen three times, replace with hydrogen three times, heat up to 50C and continue to pass hydrogen,After sampling and detecting the reaction of N-tert-butoxycarbonyl-L-4-nitrophenylalanine ethyl ester, the hydrogen gas was stopped and the reaction was allowed to come to room temperature, filtered, and the mother liquor was directly used in the next step.

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.
[2]Patent: WO2006/115918,2006,A2 .Location in patent: Page/Page column 18.
[3]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 4435 - 4443.
[4]Patent: WO2005/87760,2005,A1 .Location in patent: Page/Page column 18-19.
[5]Patent: US6265418,2001,B1 .
[6]Patent: EP1454898,2004,A1 .Location in patent: Page 40.
[7]Patent: US7928236,2011,B2 .Location in patent: Page/Page column 8-9.
[8]Patent: CN106995439,2017,A .Location in patent: Paragraph 0036; 0111; 0112.
[9]Patent: CN107935875,2018,A .Location in patent: Paragraph 0057-0060.

3
[ 75-21-8 ]
[ 67630-01-7 ]
[ 189744-27-2 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.

4
[ 67630-01-7 ]
[ 229328-97-6 ]
[ 263276-03-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (S)-ethyl-3-(4-aminophenyl)-2-(t-butoxycarbonylamino)propionate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0 and treated with NMM (56.0 ml, 0.51 mol), stirred 5 minutes and then a solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keeping the reaction temperature below 5.. The reaction was stirred for 1 h, quenched with NaHCO3 solution (500 ml), the organic layer separated, washed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml), dried (MgSO4) and concentrated in vacuo to give a yellow solid which was recrystallized (EtOAc/Hexane) to give the title compound (140 g, 69%): deltaH (DMSO d6) 8.80 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.00 (3H, m), 3.40 (2H, br. s), 2.90 (1H, m), 2.80 (1H, m), 1.30 (9H, s), 1.25 (3H, t); m/z (EI+, 70V) 504.
		A slurry of the compound of Intermediate 1 (51.2g, 0. 267mol) in DCM [(195MUT)] and thionyl chloride [(195MOI,] 2. [67MOL)] was treated with DMF (5 drops) and heated to reflux for 4h. The reaction was concentrated in vacuo and azeotroped with toluene [(2X50M1)] to give a yellow solid which was used without further purification. A solution of [ETHYL- (S)-3- (4-] aminophenyl)-2- (t-butoxycarbonylamino) propanoate (130.8g, 0. [425MOL)] in [DCM (800ML) WAS COOLED TO 0XB0; AND TREATED WITH NMM 0.51MOL),] stirred for 5 minutes and then a solution of the acid chloride (98.3g, 0. [468MOL)] in DCM [(200ML)] was added dropwise keeping the reaction temperature [BELOW 5XB0;.] The reaction was stirred for 1h, quenched with NaHCO3 solution [(500ML),] the organic layer separated, washed with NaHCO3 [SOLUTION (500ML),] 10% citric acid solution [(500MOI)] and [NAHCO3] [SOLUTION (500M1),] dried [(MGS04)] and concentrated in vacuo to give a yellow solid which was [RECRYSTALLISED] (EtOAc/hexane) to give the title compound, (140g, [69%).] [8H] (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5Hz), 7.23 (2H, d, J 8.5Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 [(1 H,] m), 1.3 (9H, s), 1.25 (3H, t); m/z (ES+, 70V) 504 (MNa+).
	With 4-methyl-morpholine; In dichloromethane; at 0℃; for 1.08333h;	To a nitrogen flushed 500 mL round bottom flask was charged with 3,5-dichloro- isonicotinic acid (46.5 g, 0.24 mol), CH2CI2 (150 mL), DMF (0.5 mL), and thionyl chloride (20 mL,33.9 g 0.28 mol). After the slurry was refluxed for 5 h, additional thionyl chloride (5 mL, 0.70 mol) and CH2CI2 (100 mL) were added, and the reaction was refluxed for additional 45 min. The reaction mixture was concentrated, and the residue was azeotroped with toluene to give the crude acyl chloride, which was used immediately. Thus, the crude acyl chloride was dissolved in CH2CI2 (150 mL) and was added to N-BOC-4-amino-L-phenylalanine ethyl ester (60 g, 0.20 mol) and 4-methylmorpholine (44 mL, EPO <DP n="20"/>0.40 mol) in CH2CI2 (400 mL) at O0C over 5 min. After stirring at 00C for 1 h, the reaction was quenched with dilute aqueous NaHCtheta3. The organic layer was separated and the aqueous layer was extracted with CH2CI2 (500 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with 4:1 to 3:2 EtOAc/hexanes to afford the title compound (95 g, 100% yield). lH NMR (400 MHz, CD3OD) delta 8.60 (s, 2H), 7.54 (d, 2H), 7.20 (d, 2H), 4.20-4.36 (m, IH), 4.10 (q, 2H), 3.02-3.12 (m, IH)5 ),2.82-2.92 (in, IH), 1.34/1.30 (s, 9H).1.20 (t, 3H).

References: [1]Bioorganic and medicinal chemistry letters,2002,vol. 12,p. 1591 - 1594.
[2]Patent: US6348463,2002,B1 .Location in patent: Page column 18-19.
[3]Patent: WO2004/6918,2004,A1 .Location in patent: Page/Page column 15; 16.
[4]Journal of Medicinal Chemistry,2009,vol. 52,p. 3449 - 3452.
[5]Patent: WO2006/115918,2006,A2 .Location in patent: Page/Page column 18-19.

5
[ 24424-99-5 ]
[ 67630-01-7 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.
[2]Patent: WO2006/115918,2006,A2 .

6
[ 58816-66-3 ]
[ 67630-01-7 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.

7
[ 67630-01-7 ]
[ 189744-28-3 ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.
[2]Patent: WO2014/191426,2014,A1 .

8
[ 67630-01-7 ]
4-(bis(2-chloroethyl)amino)-L-phenylalanine ethyl ester trifluoroacetate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 1726 - 1730.

9
[ 33305-77-0 ]
[ 67630-01-7 ]

References: [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 4435 - 4443.
[2]Patent: US7928236,2011,B2 .

10
[ 4792-30-7 ]
[ 67630-01-7 ]
ethyl (2S)-2-(tert-butoxycarbonylamino)-3-[4-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)phenyl]propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In benzene;Heating / reflux;	The mixture of 2.75 g of Boc-Phe(4-NH2)-Oet, 1.67 g of 3-methyl phthalic anhydride and 40 ml of benzene was heated to reflux. After adding ethyl acetate, the mixture was washed with 1N hydrochloric acid, an aqueous solution of 1N sodium hydroxide and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate to remove the solvent. Dioxane containing 4N hydrogen chloride was added to ethyl (2S)-2-(t-butoxyamino)-3-[4-(4-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl) phenyl] propionate obtained by washing the residue with hexane, and stirred for two hours. The solvent was removed and the residue was washed with ethyl acetate to obtain the objective compound. Yield: 1.9 g H-NMR (DMSO-d6) delta 1. 15 (3H, m), 2. 65 (3H, s), 3.10-3.40 (2H, m), 4. 15 (2H, m), 4. 30 (1H, t), 7. 40 (4H, s), 7. 65-7. 80 (3H, m), 8. 70 (3H, br).

References: [1]Patent: EP1454898,2004,A1 .Location in patent: Page 40.

11
[ 69042-30-4 ]
[ 67630-01-7 ]
[ 369648-61-3 ]
[ 369648-62-4 ]

Yield	Reaction Conditions	Operation in experiment
	In 2-ethoxy-ethanol; at 100 - 120℃; for 1.25h;	A solution of ethyl- (S)-3- [4-aminophenyl]-2- [t-butoxycarbonylamino] propanoate (638mg, 2. [07MMOL)] and Intermediate 3 (310mg, 1. [88MMOL)] in ethoxyethanol [(2ML)] was stirred at [120-FOR] 15 min and at [1002 FOR LH] under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70ml) and saturated aqueous [NAHC03] [(10MUT).] The phases were separated and the aqueous layer re-extracted with EtOAc (2x30ml). The combined organic extracts were washed with brine [(10ML),] dried [(NA2SO4)] and evaporated in vacuo to afford a dark foam. Chromatography [(SI02] ; 5 to 10% MeOH/DCM) afforded a mixture of [ETHYL- (S)-3- [4- ( [2,] 7] [NAPHTHYRIDIN-1-YLAMINO) PHENYL]-2- [ (T-BUTOXYCARBONYL)] amino] propanoate and some of the title compound (730mg). This mixture was treated with a solution of trifluoroacetic acid [(5ML)] and DCM (5ml) at room temperature for 1h. The volatiles were removed in vacuo and the residue partitioned between EtOAc [(75MOI)] and saturated aqueous [NAHCO3] (20ml). The phases were separated and the aqueous layer re- extracted with EtOAc (3x30ml). The combined organic extracts were washed with brine (10ml), dried [(NA2SO4)] and evaporated in vacuo to afford an orange solid. Chromatography [(SI02] ; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420mg, 60% over two steps). 8H [(CDC13)] 10.70 [(1 H,] s), 10.31 [(1 H,] s), 9.44 [(1 H,] d, J 5.6Hz), 8.94 (1H, d, J 5.6Hz), 8.55 [(1H,] d, J 7.3Hz), 8.54 (2H, d, J 8.5Hz), 8.46 [(1 H,] d, J 5.6Hz), 7.94 (2H, d, J 8.5Hz), 4.84 (2H, q, [J] 7. [1 HZ),] 4.35 [(1 H,] t, J 6.6Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4Hz), 3.56 [(1H,] dd, J 13.5, 7. [0HZ)] and 1.95 (3H, t, J 7. [1 HZ)] ; m/z (ES+, 70V) 337 (MH+).

References: [1]Patent: WO2004/7494,2004,A1 .Location in patent: Page 16-17.

12
[ 67630-01-7 ]
[ 263276-03-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step D : A nitrogen flushed 500 mL round bottom flask was charged with 3, 5-dichloroisonicotinic acid (46. 5 g, 0. 24 mol), CH2C12 (150 mL), DMF (0. 5 mL), and thionyl chloride (20 mL, 33. 9 g 0. 28 mol). After the slurry was refluxed for 5 h, additional thionyl chloride (5 mL, 0. 70 mol) and CH2Cl2 (100 mL) were added, and the reaction mixture was refluxed for additional 45 min and concentrated, and the residue was azeotrope with toluene to give the crude acyl chloride, which was used immediately. The crude acyl chloride was dissolved in CH2C12 (150 mL) and added to the compound of Step C (60 g, 0. 20 mol) and 4-methylmorpholine (44 mL, 0. 40 mol) in CH2C12 (400 mL) at 0C over 5 min. After stirring at 0C for 1 h, the reaction was quenched with dilute aqueous NaHC03. The organic layer was separated and the aqueous layer was extracted with CH2C12 (500 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with 4 : 1 to 3 : 2 EtOAc/hexanes to afford N-BOC-4- ( (3', 5'-dichloro- isonicotinoyl) amino)-L-phenylalanine, ethyl ester (95 g). 1H NMR (400 MHz, CD30D) o 8. 60 (s, 2H), 7. 54 (d, 2H), 7. 20 (d, 2H), 4. 20-4. 36 (m, 1H), 4. 10 (q, 2H), 3. 02-3. 12 (m, 1H), 2. 82-2. 92 (m, 1H), 1. 34/1. 30 (s, 9H), 1. 20 (t, 3H).

References: [1]Patent: WO2005/87760,2005,A1 .Location in patent: Page/Page column 19.

13
[ 67630-01-7 ]
[ 1939-99-7 ]
N-t-butoxycarbonyl-DL-4-(benzylsulfonylamino)phenylalanine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example II-13 N-t-butoxycarbonyl-DL-4-(benzylsulfonylamino)phenylalanine In the same manner as in Example II-(11-2) and Example II-(11-3) except for using N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester in place of N-t-butoxycarbonyl-L-4-aminophenylalanine ethyl ester and using benzylsulfonyl chloride in place of benzenesulfonyl chloride, the reactions were carried out to obtain the title compound (overall yeield 92%) as palye yellowish foay product. 1H-NMR (CDCl3) delta; 7.33-7.25 (m, 5H), 7.12-6.99 (m, 4H), 6.90 (s, 1H), 5.06-4.88 (m, 1H), 4.63-4.57 (m, 1H), 4.32 (s, 2H), 3.18-3.02 (m, 2H), 1.43 (s, 9H). CI-MS (m/z); 291

References: [1]Patent: US6265418,2001,B1 .

14
[ 124-63-0 ]
[ 67630-01-7 ]
[ 204856-74-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example II-12 N-t-butoxycarbonyl-DL-4-(methylsulfonylamino)phenylalanine In the same manner as in Example II-(11-2) and Example II-(11-3) except for using N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester in place of N-t-butoxycarbonyl-L-4-aminophenylalanine ethyl ester and using methanesulfonyl chloride in place of benzenesulfonyl chloride, the reactions were carried out to obtain the title compound (overall yeield 84%) as white solid. 1H-NMR (CDCl3+DMSO-d6) delta; 9.13 (brs, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 5.18-4.48 (m, 1H), 3.30-3.08 (m, 2H), 2.92 (s, 3H), 1.42 (s, 9H). CI-MS (m/z); 259

References: [1]Patent: US6265418,2001,B1 .

15
[ 349-88-2 ]
[ 67630-01-7 ]
N-t-butoxycarbonyl-DL-4-[(4-fluorophenyl)sulfonylamino]phenylalanine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example II-14 N-t-butoxycarbonyl-DL-4-[(4-fluorophenyl)sulfonylamino]-phenylalanine In the same manner as in Example II-(11-2) and Example II-(11-3) except for using N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester in place of N-t-butoxycarbonyl-L-4-aminophenylalanine ethyl ester and using 4-fluorobenzenesulfonyl chloride in place of benzenesulfonyl chloride, the reactions were carried out to obtain the title compound (overall yeield-quantitative) as white solid. 1H-NMR (CDCl3) delta; 7.78-7.71 (m, 2H), 7.21 (s, 1H), 7.13-6.91 (m, 6H), 5.03-4.88 (m, 1H), 4.67-4.49 (m, 1H), 3.19-2.89 (m, 2H), 1.42 (s, 9H). CI-MS (m/z); 383

References: [1]Patent: US6265418,2001,B1 .

16
[ 67630-01-7 ]
[ 220388-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;	Example II-15 N-t-butoxycarbonyl-DL-4-(phenylsulfonylamino)phenylalanine In the same manner as in Example II-(11-2) and Example II-(11-3) except for using N-t-butoxycarbonyl-DL-4-aminophenylalanine ethyl ester in place of N-t-butoxycarbonyl-L-4-aminophenylalanine ethyl ester and using triethylamine in place of pyridine, the reactions were carried out to obtain the title compound (overall yeield 57%) as white foamy product. 1H-NMR (400 MHz, CDCl3) delta; 7.74 (d, J=7.3 Hz, 2H), 7.53 (d, J=7.3 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H), 7.04 (d, J=7.3 Hz, 2H), 6.93 (d, J=7.3 Hz, 2H), 6.91 (brs, 1H), 4.97-4.88 (m, 1H), 4.60-4.52 (m, 1H), 3.14-3.00 (m, 2H), 1.40 (s, 9H). CI-MS (m/z); 365

References: [1]Patent: US6265418,2001,B1 .

17
[ 5470-18-8 ]
[ 67630-01-7 ]
[ 1031337-78-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 18h;	Example 1Ethyl N-(tert-butoxycarbonyl)-4-[(3-nitropyridin-2-yl)amino]-L-phenylalaninate (Intermediate 1)To a stirred solution of <strong>[67630-01-7]N-(tert-butyloxycarbonyl)-4-amino-L-phenylalanine ethyl ester</strong> (2Og) (CAS No. 67630-01-7) and DIPEA (13ml) in EtOH (200ml) is added 2-Chloro- 3-nitropyridine (11.85g) (CAS No. 34515-82-7). The reaction is heated at 85C for 18 hours. The reaction is allowed to cool and the majority of the EtOH removed in vacuo. The residue is partitioned between EtOAc (100ml) and water (50ml). The aqueous layer is extracted with EtOAc (50ml) and the combined organic layers are washed with brine (20ml), dried (MgSO4) and concentrated in vacuo. The residue is purified in two batches by chromatography on silica, eluting with EtOAc-heptane to afford the title compound as an orange solid (13.17g, 46%). LCMS (Method A) 429 [M-H]-, RT 4.17 mins. 1 H NMR 300 MHz (CDCI3) 51.25 (t, 3H), 1.40 (s, 9H), 3.1 (m, 2H), 4.2 (q, 2H), 4.6 (dd, 1 H), 5.00 (d,1 H), 6.8 (dd, 1 H), 7.15 (d, 2H), 7.6 (d, 2H), 8.45-8.55 (m, 2H).
46%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 18h;	Example 1Ethyl N-(tert-butoxycarbonyl)-4-[(3-nitropyridin-2-yl)amino]-L-phenylalaninate(Intermediate 1)To a stirred solution of <strong>[67630-01-7]N-(tert-butyloxycarbonyl)-4-amino-L-phenylalanine ethyl ester</strong> (2Og) (CAS No. 67630-01-7) and DIPEA (13mL) in EtOH (20OmL) is added 2-Chloro- 3-nitropyridine (11.85g) (CAS No. 34515-82-7). The reaction is heated at 85C for 18 hours. The reaction is allowed to cool and the majority of the EtOH removed in vacuo. The residue is partitioned between EtOAc (10OmL) and water (5OmL). The aqueous phase is extracted with EtOAc (5OmL) and the combined organic extracts washed with brine (2OmL), dried (MgSO4) and concentrated in vacuo. The residue is purified in two batches by chromatography on silica, eluting with EtOAc-heptane to afford the title compound as an orange solid (13.17g, 46%). LCMS (Method A) 429 [M-H]-, RT 4.17 mins. 1H NMR 300 MHz (CDCI3) .51.25 (t, 3H), 1.40 (s, 9H), 3.1 (m, 2H), 4.2 (q, 2H), 4.6 (dd, 1 H), 5.00 (d, 1 H), 6.8 (dd, 1 H), 7.15 (d, 2H), 7.6 (d, 2H), 8.45-8.55 (m, 2H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4146 - 4149.
[2]Patent: WO2008/64823,2008,A1 .Location in patent: Page/Page column 26.
[3]Patent: WO2008/64830,2008,A1 .Location in patent: Page/Page column 33.

18
[ 2578-45-2 ]
[ 67630-01-7 ]
[ 1031339-11-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 85℃; for 2.5h;	Example 20Ethyl N-(tert-butoxycarbonyl)-4-[(3,5-dinitropyridin-2-yl)amino]-L-phenylalaninate(Intermediate 72)To a stirred solution of (S)-3-(4-Amino-phenyl)-2-tert-butoxycarbonylamino- propionic acid ethyl ester (CAS No. 67630-01-7) (1 Og) and DIPEA (6.2mL) in EtOH(10OmL) is added 2-Chloro-3,5-dinitropyridine (7.26g) (CAS No. 2578-45-2). The reaction is heated at 85C for 2.5 hours. The reaction is allowed to cool and the majority of the EtOH removed in vacuo. The residue is partitioned between EtOAc (10OmL) and water (5OmL). The aqueous phase is extracted with EtOAc (5OmL) and the combined organic extracts washed with brine (2OmL), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid (17.2g, 100%). LCMS (Method A) 474 [M-H]", RT 4.14 mins. 1 H NMR 300 MHz (d6-DMSO) delta 1.2 (t, 3H), 1.35 (s, 9H), 2.9 (dd, 1 H), 3.0 (dd, 1 H), 4.0-4.2 (m, 3H), 7.3-7.4 (m, 3H), 7.5 (d, 2H), 9.05 (d, 1 H)1 9.2 (d, 1 H), 10.5 (s, 1 H).

References: [1]Patent: WO2008/64830,2008,A1 .Location in patent: Page/Page column 52.

19
[ 67630-01-7 ]
badAla-OEt [ No CAS ]

References: [1]Patent: US7928236,2011,B2 .

20
[ 67630-01-7 ]
[ 916834-72-5 ]

References: [1]Patent: US7928236,2011,B2 .

21
[ 19411-56-4 ]
[ 67630-01-7 ]
[ 916834-70-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With 2-methoxy-ethanol; copper; potassium carbonate;copper(I) oxide; at 120℃; for 1.5h;Inert atmosphere;Product distribution / selectivity;	4) Ullmann coupling between Boc-aminoPhe-OEt and 3-chloro-naphthalene-2-carboxylic acid According to Table 1, reagents except for 2-methoxyethanol were mixed. Flask was subjected to degassing by nitrogen, added with 2-methoxyethanol, and heated to 120 C. under reflux. One and a half hours later, the reaction was terminated when the spot which corresponds to CNCA was disappeared on TLC developed by a mix solvent (ethyl acetate and hexane (2:1)). The reaction solution was filtered through cotton and sellite to remove Cu. The obtained filtrate was dropped into 15 ml of distilled water. The suspension that observed precipitate, was centrifuged at 3000 rpm for 5 minutes to collect the precipitate. This precipitate was dissolved in ethyl acetate, and washed two times with respectively 5% KHSO4, 4% NaHCO3 and saturated NaCl. After dehydration using MgSO4, column purification was conducted. The column purification was conducted using developing solvents in the following order: chloroform and methanol (8:2)?chloroform and ethyl acetate (9:1)?chloroform and methanol (95:5). The obtained purified product was analyzed by 1H-NMR for identification. While comparative example 1 as shown below used DMF and Cu for coupling, obtaining extremely low yield, a substantial improvement was shown in the yield, with the yield of the target substance being 205.7 mg and 57% in the case where Cu2O was added and methoxyethanol was used for solvent, this time.

References: [1]Patent: US7928236,2011,B2 .Location in patent: Page/Page column 9-10.
[2]Chemistry Letters,2010,vol. 39,p. 818 - 819.

22
[ 67630-01-7 ]
[ 148-82-3 ]

References: [1]Patent: WO2014/191426,2014,A1 .

23
[ 67630-01-7 ]
L-4-[bis(2-chloroethyl)amino]phenylalanine hydrochloride [ No CAS ]

References: [1]Patent: WO2014/191426,2014,A1 .

24
[ 624-76-0 ]
[ 67630-01-7 ]
[ 189744-27-2 ]

Yield	Reaction Conditions	Operation in experiment
1.8 kg	With sodium carbonate; In acetonitrile; at 23 - 85℃; for 2h;Large scale;	EXAMPLE 1 Preparation of 4-(bis-(2-hydroxyethyl)-amino-N-BOC-L-phenylalanine ethyl ester Into a suitable reactor A, 2.0 kg of N-BOC-L-phenylalanine ethyl ester and acetonitrile were loaded. The suspension was let under stirring until complete dissolution, maintaining the temperature at 23C and 1 .5 kg of sodium carbonate were then added. Subsequently, 3.2 L of 2-iodoethanol were added dropwise, the solution was heated up to 85C and these conditions were maintained for 2 hours. At the end of the reaction the mixture was quickly cooled down to 20C. In another suitable reactor B, 35L of water and 4 kg of Celite were loaded and the mixture was left under stirring for at least 5 minutes. The compound obtained into reactor A was transferred into reactor B and the suspension was kept under stirring for an hour. The suspension was filtered and washed with 12L of water. The wet Celite obtained into the reactor B and 140 L of ethyl acetate were loaded into a reactor C and the mixture was kept under stirring for 30 minutes then filtered by collecting the filtrate into a reactor D and letting the phases separate. The organic phase was distilled at reduced pressure. The residue was purified by chromatography using methylene chloride/ethyl acetate about 2:1 . About 1 .8 kg of 4-(bis-(2-hydroxyethyl)-amino-N-BOC-L-phenilalanine ethyl ester were then obtained.

References: [1]Patent: WO2014/191426,2014,A1 .Location in patent: Page/Page column 10.

25
[³H]-2-bromoethanol [ No CAS ]
[ 67630-01-7 ]
N-t-Boc-4-(2-hydroxy-2-[³H]ethyl)amino-L-phenylalanine ethyl ester [ No CAS ]

References: [1]Molecular Cancer Therapeutics,2016,vol. 15,p. 2575 - 2585.

26
[ 67630-01-7 ]
N-[[2-(6-benzofurancarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl-D₃]carbonyl]-3-(methylsulfonyl-D₃)-L-phenylalanine [ No CAS ]