1158758-77-0|tert-Butyl 3-amino-3-methylazetidine-1-carboxylate| Ambeed

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Quality Control of [ 1158758-77-0 ] Purity: 97% SDS Specification

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Product Details of [ 1158758-77-0 ]

CAS No. :	1158758-77-0
Formula :	C₉H₁₈N₂O₂
M.W :	186.25
SMILES Code :	O=C(N1CC(C)(N)C1)OC(C)(C)C
MDL No. :	MFCD12408556
InChI Key :	LDWZHGRHSCFIJE-UHFFFAOYSA-N
Pubchem ID :	56924482

Safety of [ 1158758-77-0 ]

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

Computational Chemistry of [ 1158758-77-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	0
Fraction Csp3	0.89
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	54.53
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.56 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.46
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	0.2
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.57
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.	0.56
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	0.23
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.8

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.92
Solubility	22.3 mg/ml ; 0.119 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.	-0.93
Solubility	22.1 mg/ml ; 0.119 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-0.96
Solubility	20.2 mg/ml ; 0.109 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.	-7.29 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.	0.55

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	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)	2.11

Application In Synthesis of [ 1158758-77-0 ]

* 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 [ 1158758-77-0 ]

[ 1158758-77-0 ] Synthesis Path-Downstream 1~14

1
[ 1572515-74-2 ]
[ 1158758-77-0 ]
[ 1572512-54-9 ]

Yield	Reaction Conditions	Operation in experiment
721 mg	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 20h;	Compound 154 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (500 mg, 1.53 mmol) and DIPEA (657 mu, 3.8 mmol, 2.5 eq) dissolved in CH2CI2 (15 mL) were added to a tube containing 3-amino-l-Boc-3-methyl-azetidine (1.1 eq). The reaction mixture was stirred for 20 hours. 1M HC1 (5 mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated and loaded on a silica gel column. The mixture was purified using gradient elution from heptane to EtOAc, resulting in compound 154 (721 mg). Method F; Rt: 1.11 min. m/z: 478.2 (M+H)+ Exact mass: 477.2.
721 mg	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 20h;	Compound 154 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]benzenesulfonyl chloride (500 mg, 1.53 mmol) and DIPEA (657 mu, 3.8 mmol, 2.5 eq) dissolved in CH2CI2 (15 mL) were added to a tube containing 3-amino-l-Boc-3-methyl-azetidine (1.1 eq). The reaction mixture was stirred for 20 hours. 1M HC1 (5 mL) was added and the mixture was stirred for 5 minutes. The organic layer was separated and loaded on a silica gel column. The mixture was purified using gradient elution from heptane to EtOAc, resulting in compound 154 (721 mg). Method F; Rt: 1.11 min. m/z: 478.2 (M+H)+ Exact mass: 477.2.

References: [1]Patent: WO2014/33170,2014,A1 .Location in patent: Page/Page column 90.
[2]Patent: WO2014/33176,2014,A1 .Location in patent: Page/Page column 90.

2
[ 1158758-77-0 ]
[ 1613719-81-5 ]
[ 1613720-35-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; for 10h;Reflux;	A mixture of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example 53, Step E, 2.0 g, 4.05 mmol), tert-butyl 3-amino azetidine-1-carboxylate (0.904 g, 4.85 mmol), diacetoxypalladium (0.091 g, 0.405 mmol), Cs2CO3 (2.64 g, 8.10 mmol) and BINAP (0.252 g, 0.405 mmol) in toluene (10 mL) was heated at reflux for 10 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (2.2 g, 91%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): delta 7.16 (s, 1H), 5.96 (brs, 1H), 5.13 (q, J=9.2 Hz, 2H), 4.61 (m, 1H), 4.56 (q, J=13.2 Hz, 2H), 4.41 (brs, 1H), 4.04 (m, 2H), 3.95 (d, J=12.4 Hz, 2H), 3.68 (m, 2H), 1.66 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.46 (s, 9H), 0.99 (m, 2H), 0.02 (s, 9H).

References: [1]Patent: US2014/206663,2014,A1 .Location in patent: Paragraph 1209; 1210.
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 222 - 236.

3
[ 1158758-77-0 ]
[ 1613719-81-5 ]
(R)-3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanylethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-ylamino]azetidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 333 - 346.

4
[ 1158758-77-0 ]
[ 1613719-81-5 ]
(R)-3-methyl-3-{methyl-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanylethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triazaphenanthren-6-yl]amino}azetidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 333 - 346.

5
[ 1158758-77-0 ]
2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid ammonium salt [ No CAS ]
[ 76-05-1 ]
2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxy-N-(3-methylazetidin-3-yl)propanamide trifluoroacetate salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.5%		To a suspension of 2-(3-(8-amino-6-(trifluoromethyl)imidazo[l,2-a]pyrazin-3-yl)-4- methylphenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (20 mg, 0.046 mmol) (from Example 120) in CH2CI2 (0.72 mL) at 0 C was added oxalyl chloride (46 mu,, 0.092 mmol, 2.0 M in CH2CI2) and one drop of N-dimethylformamide. The reaction mixture was stirred 2 h during which the 0 C bath slowly warmed to rt. A solution of 3-amino-l-Boc-3-methyl- azetidine (130 mg, 0.69 mmol) (Advanced ChemBlocks, C-2457) in CH2C12 (0.25 mL) was added dropwise. The bath was removed, and the reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated, and the resulting residue dissolved in TFA (0.36 mL). After stirring 1 h at rt, the reaction mixture was added dropwise to MeOH. Purification via preparative HPLC on a C-18 column (pH = 2, 30^12% MeCN/0.1% TFA (aq) over 5 min, 60 mL/min) afforded the title compound as a yellow residue (2.4 mg, 8.5%). LCMS for C2iH2iF6N602 (M+H)+: calculated m/z = 503.2; found 503.1.

References: [1]Patent: WO2019/79469,2019,A1 .Location in patent: Page/Page column 259.

6
[ 1158758-77-0 ]
[ 5783-36-8 ]
C₂₃H₂₈N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	General procedure: To a stirred solution of 3'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (228 mg, 1 mmol),and <strong>[1158758-77-0]tert-butyl 3-amino-3-methylazetidine-1-carboxylate</strong> (189.2 mg, 1.02 mmol.) and N,Ndiisopropyl-ethylamine (452.4 mg, 3.5 mmol) in DMF (5 mL) was added HBTU (1.32g, 3.48mmol). The resulting mixture was stirred at room temperature for 18 hours. The reactionmixture was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueouslayer was extracted with ethyl acetate (50 mL). The combined organic extracts were washedwith saturated NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried overNa2SO4 and concentrated under reduced pressure. The residue was purified on silica gel(Biotage; eluting solvents hexane: EtOAc 4/1 ratio) to afford tert-butyl 3-(3'-methoxy-[1,1'-biphenyl]-4-carboxamido)-3-methylazetidine-1-carboxylate as a colorless solid in 80% yield. 1H NMR (500 MHz, CDCl3) delta 7.83 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.34 (t, J =7.9 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.10 (d, J = 1.7 Hz, 1H), 7.04 (s, 1H), 6.94 - 6.87 (m,1H), 4.16 (s, 2H), 3.89 (d, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.67 (s, 3H), 1.43 (s, 9H).

References: [1]Bioorganic and Medicinal Chemistry,2020,vol. 28.

7
[ 1158758-77-0 ]
3'-methoxy-[1,1'-biphenyl]-4-sulfonyl chloride [ No CAS ]
C₂₂H₂₈N₂O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	General procedure: To a stirred solution of 3'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (228 mg, 1 mmol),and <strong>[1158758-77-0]tert-butyl 3-amino-3-methylazetidine-1-carboxylate</strong> (189.2 mg, 1.02 mmol.) and N,Ndiisopropyl-ethylamine (452.4 mg, 3.5 mmol) in DMF (5 mL) was added HBTU (1.32g, 3.48mmol). The resulting mixture was stirred at room temperature for 18 hours. The reactionmixture was partitioned between water (30 mL) and ethyl acetate (30 mL) and the aqueouslayer was extracted with ethyl acetate (50 mL). The combined organic extracts were washedwith saturated NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried overNa2SO4 and concentrated under reduced pressure. The residue was purified on silica gel(Biotage; eluting solvents hexane: EtOAc 4/1 ratio) to afford tert-butyl 3-(3'-methoxy-[1,1'-biphenyl]-4-carboxamido)-3-methylazetidine-1-carboxylate as a colorless solid in 80% yield.

References: [1]Bioorganic and Medicinal Chemistry,2020,vol. 28.

8
[ 39906-04-2 ]
[ 1158758-77-0 ]
C₁₅H₂₀ClN₅O₂ [ No CAS ]