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Quality Control of [ 149057-19-2 ] Purity: 95% SDS Specification

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Product Details of [ 149057-19-2 ]

CAS No. :	149057-19-2
Formula :	C₁₈H₂₄N₂O₆
M.W :	364.39
SMILES Code :	O=C(N1C(C(O)=O)CN(C(OCC2=CC=CC=C2)=O)CC1)OC(C)(C)C
MDL No. :	MFCD02683055
InChI Key :	SREPAMKILVVDSP-UHFFFAOYSA-N
Pubchem ID :	2756778

Safety of [ 149057-19-2 ]

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

Computational Chemistry of [ 149057-19-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	26
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	8
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	100.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	96.38 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.07
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	1.91
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.42
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.	1.29
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	0.6
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.66

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.95
Solubility	0.413 mg/ml ; 0.00113 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.	-3.56
Solubility	0.101 mg/ml ; 0.000277 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	-2.27
Solubility	1.98 mg/ml ; 0.00542 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	Yes
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.	-7.17 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.	0.56

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	1.0 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<2.0
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)	3.48

Application In Synthesis of [ 149057-19-2 ]

* 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 [ 149057-19-2 ]

[ 149057-19-2 ] Synthesis Path-Downstream 1~31

1
[ 129799-14-0 ]
[ 149057-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol;	(A) 1-tert-Butoxycarbonyl-4-Benzyloxycarbonylpiperazine-2-Carboxylic Acid 1 N Sodium hydroxide solution (0.92 mL) was added to a solution of methyl 1-tert-butoxycarbonyl-4-benzyloxycarbonylpiperazinyl-2-carboxylate (346 mg) in methanol (5 mL). After stirring at room temperature for 3 hr, the solvents were removed in vacuo. The residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (237 mg) as a pale yellow oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) delta 1.44 and 1.47 (each s, total 9H), 2.82-3.05 (m, 1H), 3.05-3.42 (m, 2H), 3.72-3.97 (m, 1H), 3.97-4.19 (m, 1H), 4.554.90 (m, 2H), 5.00-5.28 (m, 2H), and 7.20-7.42 (m, 5H).

References: [1]Patent: US6399629,2002,B1 .

Yield	Reaction Conditions	Operation in experiment
35%		Step A. 4-(Benzyloxycarbonyl)-1-(t-butyloxycarbonyl)piperazine-2(R,S)-carboxylic Acid. This compound was prepared by the method of Dale J. Kempf et al. U.S. Pat. No. 5,455,351. Starting with (R,S)-piperazic acid (5.0 g, 25 mmol), 4-(benzyloxycarbonyl)-1-(t-butyloxycarbonyl)piperazine-2(R,S)-carboxylic acid was obtained (2.9 g, 35% yield). 400 MHz 1H NMR (CDCl3): delta 1.4-1.5 (m, 9H), 2.85-3.0(bm, 1H), 3.1-3.3 (bm, 2H), 3.8-4.0 (bm, 1H), 4.0-4.15 (m, 1H), 4.6-4.7 (m, 1H), 5.05-5.2 (b-dd, 2H), 7.25-7.35 (m, 5H).

3
[ 24424-99-5 ]
[ 934630-06-5 ]
[ 149057-19-2 ]

Yield	Reaction Conditions	Operation in experiment
48%		Step 3 Synthesis of piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester NaHCO3(1.9 g, 22.6 mmol) was added to a stirred solution of piperazine-1,3-dicarboxylic acid 1-benzyl ester (1.9 g, 7.2 mmol) in water (10 mL) and stirring was continued for 30 minutes at ambient temperature. To the above mixture at 0 C., was added di-tert-butyl dicarbonate (4 g, 19.8 mmol) dropwise and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water and further acidified with aqueous 2N HCl to pH 5 and extracted with ethyl acetate and dried over sodium sulphate, concentrated under reduced pressure to afford the residue. The residue obtained was purified by column chromatography (using 60-120 silica gel and 1% MeOH in CHCl3 as eluent) to afford 1.25 g (48%) of piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester.
	With sodium hydroxide; In acetonitrile; at 0 - 20℃;	General Process for the Preparation of Compound O-In-2 from O-In-1 : [00168] A three necked round bottom flask was charged with O-In-1 (1 eq.), sodium hydroxide (2 eq.) and acetonitrile. The reaction mixture was cooled to 0 0C and Boc anhydride (1 eq.) was added into the reaction mixture very slowly. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After consumption of starting material, the reaction mixture was washed with petroleum ether. The aqueous layer was acidified with citric acid to pH~6 and extracted with dichloro methane. The combined organic layer was washed with brine solution and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated to afford O-In-2.
25 g	With sodium hydrogencarbonate; In water; at 0 - 20℃; for 17h;	Example 51 - Preparation of Intermediate 16 The synthesis of Intermediate 16 followed the procedure of General Procedure 12 following: Intermediate 15 Intermediate 16 To a cooled solution (0C) of 4-(benzyloxycarbonyl)piperazine-2-carboxylic acid (Intermediate 15, 48 g, 181.8 mmol) in water (10 volumes, 480 mL) was added solid NaHCO3 (45.8 g, 545.4 mmol) followed by di-tert-butyl dicarbonate ((Boc)2O, 109 mL, 490.9 mmol). The reaction mixture was stirred at room temperature for 17 hours. After cooling to room temperature it was extracted into EtOAc (4 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 50% EtOAc/n-hexane, to afford 4- (benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (Intermediate 16, 25 g, yield: 55%) as an off-white solid; TLC: 5% Methanol- dichloromethane, Rf: 0.3.

References: [1]Patent: US2010/160323,2010,A1 .Location in patent: Page/Page column 47.
[2]Patent: WO2009/158394,2009,A1 .Location in patent: Page/Page column 109; 112.
[3]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0286.

4
[ 149057-19-2 ]
[ 569348-20-5 ]

Yield	Reaction Conditions	Operation in experiment
		General Process for the Preparation of Compound O-In-3 from O-In-2:; [00169] A three necked round bottom flask was charged with O-In-2 (1 eq.), triethyl amine (2 eq.) and dry dichloromethane under nitrogen atmosphere. The reaction mixture was cooled to 0 0C and methyl chloroformate (1.3 eq.) was added into the reaction mixture very slowly. The reaction mixture was stirred at -10 0C for 30min and further cooled to -30 0C. Ammonia gas was purged in the reaction mixture for 30min at -30 0C. The reaction mixture was allowed to stir at room temperature for 16h. After consumption of starting material, ice-cold water was added to reaction mixture. The organic layer was separated and aqueous layer was extracted with dichloromethane. The combined organic layers was washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using 60-120 silica gel and chloroforrrDeltamethanol (6%) as eluant to afford O-In-3.
36 g	With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; for 14h;	Step A: 4-Benzyl 1-(tert-butyl) 2-carbamoylpiperazine-1,4-dicarboxylate. NH4HCO3 (9 g, 114 mmol) was added to a solution of <strong>[149057-19-2]4-((benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid</strong> (33 g, 91 mmol), Boc2O (25.7 g, 118 mmol), pyridine (4.3 g, 54 mmol), and 1,4-dioxane (462 mL). After 14 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (36 g). This material was used in the next step without further purification. MS (ESI): mass calcd. for C18H25N3O5, 363.2; m/z found, 386.0 [M+Na]+.

References: [1]Patent: WO2009/158394,2009,A1 .Location in patent: Page/Page column 109; 112.
[2]Patent: US2020/55874,2020,A1 .Location in patent: Paragraph 1894-1895.

5
[ 149057-19-2 ]
[ 74-88-4 ]
[ 129799-14-0 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	Step 4 Synthesis of <strong>[149057-19-2]piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester</strong> 2-methyl ester K2CO3 (910 mg, 6.6 mmol) was added to a stirred solution of <strong>[149057-19-2]piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester</strong> (1.2 g, 3.3 mmol) in DMF (10 mL) at ambient temperature. To the above mixture was added at 0 C., CH3I (1.4 g, 9.9 mmol) and stirred 20 C. for 2 hr. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulphate, concentrated under reduced pressure to afford 1.2 g(96.4%) of <strong>[149057-19-2]piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester</strong> 2-methyl ester.
55%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	Example 52 - Preparation of Intermediate 17 The synthesis of Intermediate 17 followed the procedure of General Procedure 13 following: Intermediate 16 Intermediate 17 To a cooled solution (0C) of 4-(benzyloxycarbonyl)-1-(tert- butoxycarbonyl)piperazine-2-carboxylic acid (Intermediate 16, 20 g, 54.9 mmol) in dry DMF (200 mL) was added cesium carbonate (Cs2CO3, 35.8 g, 109.9 mmol) followed by methyl iodide (10.26 mL, 164.83 mmol). The reaction mixture was stirred at room temperature for 4 hours. After cooling to 0 C the mixture was quenched with ice-cold water (90 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh), eluting with 20% EtOAc/n-hexane, to afford 4- benzyl 1-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (Intermediate 17, 25 g, yield-55%) as an off-white solid. TLC: 30% ethyl acetate in hexane. Rf: 0.5.

References: [1]Patent: US2010/160323,2010,A1 .Location in patent: Page/Page column 47.
[2]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0287.

6
[ 2762-32-5 ]
[ 13139-17-8 ]
[ 58632-95-4 ]
[ 149057-19-2 ]

Yield	Reaction Conditions	Operation in experiment
80%		54a. 4-((Benzyloxy)carbonyl)-1 -(tert-butoxycarbonyl)piperazine-2- carboxylic acidThe tile compound was prepared according to the procedure of [Kempf, D. J.; Norbeck, D. W.; Sham, H. L U.S. Patent 5,455,351 , Oct 3, 1995]. Piperazine-2-carboxylic acid (10.0 g, 77.0 mmol) was dissolved in a 1 :1 solution of 1 ,4-dioxane:water (100 mL) at room temperature with vigorous stirring. The clear solution was adjusted to pH 11 by the addition of an aqueous solution of sodium hydroxide (80 mL of a 1Lambda/ solution). The pH was monitored in situ with a pH meter throughout the reaction. The reaction flask was fitted with an addition funnel that contained a solution of Lambda/-alpha- (benzyloxycarbonyloxy) succinamide (13.6 g, 55 mmol) in 1 ,4-dioxane (50 mL). The Lambda/-alpha-(benzyloxycarbonyloxy) succinamide solution was added over 45 minutes at room temperature and the pH was kept above 10 by the periodic addition of 1 Lambda/ sodium hydroxide. The pH of the solution was adjusted to 9.5 and 2-(teAf-butoxycarbonyloxyimino)-2-phenylacetonitrile (13.4 g, 55 mmol) was added as a solution in 1 ,4-dioxane (50 mL) over 10 minutes. The pH was maintained at 9.5 and the solution was stirred at room temperature for 17 hours. The solution was then acidified to pH 2 and the aqueous solution was washed with diethyl ether (3 x 150 mL). The aqueous solution was cooled to O0C and acidified by adding of concentrated hydrochloric acid. The acidic solution was extracted with ethyl acetate (5 x 150 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a 1 :1 solution of dichloromethane: hexanes (150 mL) and the solvent was removed in vacuo to provide the product as a viscous yellow oil (15.7 g, 43 mmol, 80%). Rf = 0.60 (66:34 dichloromethane: ethyl acetate + 0.1% (v/v acetic acid); 1H-NMR (400 MHz, DMSO) delta 13.0 (br s, 1 H), 7.37-7.36 (m, 5H), 5.05 (s, 2H), 4.54-4.33 (m, 2H), 3.90-3.66 (m, 2H), 3.07-2.81 (m, 4H), 1.38 (s, 9H); Mass spectrum (ESI +ve) m/z 365.1 (MH+).

References: [1]Patent: WO2010/147653,2010,A1 .Location in patent: Page/Page column 117-118.

7
[ 149057-19-2 ]
[ 593-51-1 ]
[ 1259014-00-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	54b. 4-Benzyl 1-terf-butyl 2-(methylcarbamoyl)piperazine-1,4- dicarboxylate4-((Benzyloxy)carbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.70 g, 4.70 mmol), DMF (20 ml_), diisopropylethylamine (2.50 mL, 14.1 mmol) and methylamine hydrochloride (0.350 g, 5.20 mmol) were mixed together at room temperature under argon for 10 minutes. 2-(7-aza-1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HATU, 2.00 g, 5.20 mmol) was then added to the reaction mixture in one portion. The mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was then poured into water (100 mL) and extracted with ethyl acetate (4 x 25 mL). The combined organic phases were washed with saturated ammonium chloride (3 x 15 mL), water (3 x 15 mL) and brine (70 mL). The combined organic phases were then dried over sodium sulfate, filtered and concentrated in vacuo. The product, obtained as a white foam (0.91 g, 2.4 mmol, 51%) was purified by column chromatography (gradient elution 20:80 ethyl acetate: hexanes to 100% ethyl acetate), Rf = 0.10 (50:50 ethyl acetate: hexanes); 1H-NMR (400 MHz, CDCI3) delta 7.39-7.33 (m, 5H), 5.17 (br s, 2H), 4.68-4.58 (m, 2H), 3.98-3.88 (m, 2H), 3.23-3.08 (m, 4H), 2.07 (s, 3H), 1.50 (S, 9H); Mass spectrum (ESI +ve) m/z 378.0 (MH+)

References: [1]Patent: WO2010/147653,2010,A1 .Location in patent: Page/Page column 118.

8
[ 1279816-75-9 ]
[ 149057-19-2 ]