1446332-69-9|tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate| Ambeed

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Quality Control of [ 1446332-69-9 ] Purity: 98% SDS Specification

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Product Details of [ 1446332-69-9 ]

CAS No. :	1446332-69-9
Formula :	C₁₆H₂₂N₂O₄
M.W :	306.36
SMILES Code :	O=C(N1CCN(C2=CC=C(C=O)C(O)=C2)CC1)OC(C)(C)C
MDL No. :	MFCD26407296
InChI Key :	ZCZVQJLBRKFTDC-UHFFFAOYSA-N
Pubchem ID :	71744136

Safety of [ 1446332-69-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 1446332-69-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	5
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	91.05
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	70.08 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.6
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	2.36
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.5
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.	0.99
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	1.41
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.1
Solubility	0.244 mg/ml ; 0.000798 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.	-3.47
Solubility	0.103 mg/ml ; 0.000337 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	-2.44
Solubility	1.11 mg/ml ; 0.00364 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	Yes
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.	-6.49 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.	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<0.0
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)	2.45

Application In Synthesis of [ 1446332-69-9 ]

* 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 [ 1446332-69-9 ]

[ 1446332-69-9 ] Synthesis Path-Downstream 1~35

1
[ 1446332-69-9 ]
[ 105-56-6 ]
[ 1446333-12-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 1.0h;	Step A: A mixture of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l- carboxylate (6.5 g, 21.2 mmol, prepared in Example 1, Part 2), ethyl cyanoacetate (2.87 mL, 29.6 mmol), piperidine (2.6 mL, 26 mmol), AcOH (1.6 mL, 29.3 mmol) and CH3CN (50 mL) was heated at 80 C for 1 h. The reaction mixture was diluted with H20 and extracted with CH2C12. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EtOAc in CH2C12), followed by trituration with hexane/EtOAc (1 : 1), yielding tert-butyl 4-(3-cyano-2-oxo-2H- chromen-7-yl)piperazine-l-carboxylate (5.05 g, 67%) as a yellow solid. 1H NMR (500 MHz, CDC13): delta 8.05 (1H, s), 7.41 (1H, d, J= 8.5 Hz), 6.84 (1H, dd, J= 8.5 Hz, 2.5 Hz), 6.66 (1H, d, J = 2.5 Hz), 3.65 (4H, m), 3.51 (4H, m), 1.52 (9H, s).
67%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 1.0h;	Step A: A mixture of <strong>[1446332-69-9]tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate</strong> (6.5 g, 21.2 mmol, prepared in Example 1, Part 2), ethyl cyanoacetate (2.87 mL, 29.6 mmol), piperidine (2.6 mL, 26 mmol), AcOH (1.6 mL, 29.3 mmol) and CH3CN (50 mL) was heated at 80 C. for 1 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EtOAc in CH2Cl2), followed by trituration with hexane/EtOAc (1:1), yielding tert-butyl 4-(3-cyano-2-oxo-2H-chromen-7-yl)piperazine-1-carboxylate (5.05 g, 67%) as a yellow solid. 1H NMR (500 MHz, CDCl3): delta 8.05 (1H, s), 7.41 (1H, d, J=8.5 Hz), 6.84 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.66 (1H, d, J=2.5 Hz), 3.65 (4H, m), 3.51 (4H, m), 1.52 (9H, s).

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00679; 00680.
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 340; 341.

2
[ 1446332-69-9 ]
[ 141-97-9 ]
[ 1446333-18-1 ]

Yield	Reaction Conditions	Operation in experiment
89%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 2.0h;	Step A: A mixture of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l- carboxylate (2.9 g, 9.5 mmol, prepared in Example 1, Part 2), ethyl acetoacetate (1.28 mL, 11.8 mmol), AcOH (725 mu, 13.3 mmol), piperidine (1.16 mL, 11.8 mmol), and CH3CN (23 mL) were heated at 80 C for 2 h. The reaction mixture was partitioned between EtOAc and 0. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10%> EtOAc in CH2CI2), followed by ether trituration, yielding tert-butyl 4-(3-acetyl-2-oxo-2H-chromen-7-yl)piperazine-l-carboxylate (3.15 g, 89%) as a yellow solid. 1H NMR (500 MHz, CDC13): delta 8.47 (1H, s), 7.49 (1H, d, J= 9 Hz), 6.83 (1H, dd, J= 9 Hz, 2.5 Hz), 6.67 (1H, d, J= 2.5 Hz), 3.64 (4H, m), 3.47 (4H, m), 2.72 (3H, s), 1.52 (9H, s).
89%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 2.0h;	Step A: A mixture of <strong>[1446332-69-9]tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate</strong> (2.9 g, 9.5 mmol, prepared in Example 1, Part 2), ethyl acetoacetate (1.28 mL, 11.8 mmol), AcOH (725 muL, 13.3 mmol), piperidine (1.16 mL, 11.8 mmol), and CH3CN (23 mL) were heated at 80 C. for 2 h. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EtOAc in CH2Cl2), followed by ether trituration, yielding tert-butyl 4-(3-acetyl-2-oxo-2H-chromen-7-yl)piperazine-1-carboxylate (3.15 g, 89%) as a yellow solid. 1H NMR (500 MHz, CDCl3): delta 8.47 (1H, s), 7.49 (1H, d, J=9 Hz), 6.83 (1H, dd, J=9 Hz, 2.5 Hz), 6.67 (1H, d, J=2.5 Hz), 3.64 (4H, m), 3.47 (4H, m), 2.72 (3H, s), 1.52 (9H, s).

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00685; 00686.
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 342; 343.

3
[ 1446332-69-9 ]
[ 4949-44-4 ]
[ 1446333-28-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 4.0h;	Step A: A mixture of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l- carboxylate (3.0 g, 9.8 mmol, prepared in Example 1, Part 2), ethyl 3-oxopentanoate (1.62 mL, 11.3 mmol), AcOH (650 mu, 12 mmol), piperidine (1.1 mL, 11.3 mmol), and CH3CN (24 mL) were heated at 80 C for 4 h. The reaction mixture was partitioned between CH2CI2 and H2O. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10%> EtOAc in CH2CI2), followed by ether trituration, yielding tert-butyl 4-(2-oxo-3-propionyl-2H-chromen-7-yl)piperazine-l-carboxylate (3.6 g, 95%) as a yellow solid. 1H NMR (500 MHz, CDC13): delta 8.49 (1H, s), 7.50 (1H, d, J= 8.5 Hz), 6.83 (1H, dd, J= 8.5 Hz, 2.5 Hz), 6.67 (1H, d, J= 2 Hz), 3.63 (4H, m), 3.47 (4H, m), 3.16 (2H, q, J= 7 Hz), 1.52 (9H, s), 1.19 (3H, t, J= 7 Hz).
95%	With piperidine; acetic acid; In acetonitrile; at 80.0℃; for 4.0h;	Step A: A mixture of <strong>[1446332-69-9]tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate</strong> (3.0 g, 9.8 mmol, prepared in Example 1, Part 2), ethyl 3-oxopentanoate (1.62 mL, 11.3 mmol), AcOH (650 muL, 12 mmol), piperidine (1.1 mL, 11.3 mmol), and CH3CN (24 mL) were heated at 80 C. for 4 h. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (10% EtOAc in CH2Cl2), followed by ether trituration, yielding tert-butyl 4-(2-oxo-3-propionyl-2H-chromen-7-yl)piperazine-1-carboxylate (3.6 g, 95%) as a yellow solid. 1H NMR (500 MHz, CDCl3): delta 8.49 (1H, s), 7.50 (1H, d, J=8.5 Hz), 6.83 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.67 (1H, d, J=2 Hz), 3.63 (4H, m), 3.47 (4H, m), 3.16 (2H, q, J=7 Hz), 1.52 (9H, s), 1.19 (3H, t, J=7 Hz).

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00699; 00700.
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 346.

4
[ 2033-24-1 ]
[ 1446332-69-9 ]
[ 1446332-76-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In ethanol; at 60.0℃; for 4.0h;	Step A: tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l-carboxylate (918 mg, 3 mmol, prepared in Example 1, Part 2), 2,2-dimethyl-l,3-dioxane-4,6-dione (648 mg, 4.5 mmol) and triethylamine (0.14 mL, 1 mmol) were combined in EtOH (6 mL). The mixture was heated at 60 C for 4 h. The mixture was cooled to room temperature and filtered. The collected material was washed with EtOH and dried under vacuum to afford 7-(4-(tert- butoxycarbonyl)piperazin-l-yl)-2-oxo-2H-chromene-3-carboxylic acid (1.05 g, 94%) as a yellow powder. MS m/z 373.2 [M-H]~.
94%	With triethylamine; In ethanol; at 60.0℃; for 4.0h;	Step A: tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate (918 mg, 3 mmol, prepared in Example 1, Part 2), 2,2-dimethyl-1,3-dioxane-4,6-dione (648 mg, 4.5 mmol) and triethylamine (0.14 mL, 1 mmol) were combined in EtOH (6 mL). The mixture was heated at 60 C. for 4 h. The mixture was cooled to room temperature and filtered. The collected material was washed with EtOH and dried under vacuum to afford 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-oxo-2H-chromene-3-carboxylic acid (1.05 g, 94%) as a yellow powder. MS m/z 373.2 [M-H]-.

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00608; 00609.
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 326.

5
[ 29182-42-1 ]
[ 1446332-69-9 ]
[ 1446332-70-2 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; acetic acid; In ethanol; for 1.0h;Reflux;	Step A: tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l-carboxylate (49 mg, 0.16 mmol) and ethyl 2-(benzo[d]thiazol-2-yl)acetate (35 mg, 0.16 mmol) were combined with piperidine (10 mu, 0.1 mmol) and acetic acid (6 mu, 0.1 mmol) in EtOH (1 mL). The mixture was heated at reflux for 1 h. After cooling the mixture to room temperature, a precipitate formed. The solid was collected by vacuum filtration, washed with 1 :1 EtOH:H20 (1 mL) and dried under vacuum to afford tert-butyl 4-(3-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromen-7- yl)piperazine- 1 -carboxylate.
	With piperidine; acetic acid; In ethanol; for 1.0h;Reflux;	Step A: tert-Butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate (49 mg, 0.16 mmol) and ethyl 2-(benzo[d]thiazol-2-yl)acetate (35 mg, 0.16 mmol) were combined with piperidine (10 muL, 0.1 mmol) and acetic acid (6 muL, 0.1 mmol) in EtOH (1 mL). The mixture was heated at reflux for 1 h. After cooling the mixture to room temperature, a precipitate formed. The solid was collected by vacuum filtration, washed with 1:1 EtOH:H2O (1 mL) and dried under vacuum to afford tert-butyl 4-(3-(benzo[d]thiazol-2-yl)-2-oxo-2H-chromen-7-yl)piperazine-1-carboxylate.

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00580; 00581.
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 6070 - 6085.
[3]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 320; 321.

6
[ 29182-42-1 ]
[ 1446332-69-9 ]
3-(1,3-benzothiazol-2-yl)-7-(piperazin-1-yl)-2H-chromen-2-one hydrochloride [ No CAS ]

References: [1]Patent: WO2013/101974,2013,A1 .

7
[ 348-28-7 ]
[ 57260-71-6 ]
[ 1446332-69-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	In dimethyl sulfoxide; at 100.0℃; for 27.0h;	Part 2: Preparation of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-l- carboxylate [00579] A mixture of 4-fluoro-2-hydroxybenzaldehyde (10 g, 71.4 mmol), 1-boc-piperazine (15.3 g, 82.2 mmol), and DMSO (100 mL) was heated at 100 C for 27 h. The reaction mixture was diluted in an aqueous K2CO3 solution and extracted with EtO Ac. The organic layer was washed with H20 and brine, dried over MgS04, filtered, and concentrated under vacuum. The residue was triturated with hexane/ether (1 : 1), yielding the title compound (18.8 g, 86%) as a yellow solid. MS m/z 307.2 [M+H]+; 1H NMR (500 MHz, CDC13): delta 11.50 (1H, s), 9.60 (1H, s), 7.36 (1H, d, J= 9 Hz), 6.27 (1H, d, J= 2 Hz), 6.45 (1H, dd, J= 9 Hz, 2 Hz), 3.58 (4H, m), 3.42 (4H, m), 1.49 (9H, s).
86%	In dimethyl sulfoxide; at 100.0℃; for 27.0h;	Part 2: Preparation of tert-butyl 4-(4-formyl-3-hydroxyphenyl)piperazine-1-carboxylate A mixture of 4-fluoro-2-hydroxybenzaldehyde (10 g, 71.4 mmol), 1-boc-piperazine (15.3 g, 82.2 mmol), and DMSO (100 mL) was heated at 100 C. for 27 h. The reaction mixture was diluted in an aqueous K2CO3 solution and extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was triturated with hexane/ether (1:1), yielding the title compound (18.8 g, 86%) as a yellow solid. MS m/z 307.2 [M+H]+; 1H NMR (500 MHz, CDCl3): delta 11.50 (1H, s), 9.60 (1H, s), 7.36 (1H, d, J=9 Hz), 6.27 (1H, d, J=2 Hz), 6.45 (1H, dd, J=9 Hz, 2 Hz), 3.58 (4H, m), 3.42 (4H, m), 1.49 (9H, s).

References: [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00578; 00579.
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 319; 320.
[3]Journal of Medicinal Chemistry,2016,vol. 59,p. 6070 - 6085.

8
[ 1446332-69-9 ]
[ 1446333-14-7 ]