1023595-19-8|9-Boc-2,9-diazaspiro[5.5]undecane| Ambeed

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Quality Control of [ 1023595-19-8 ] Purity: 97% SDS Specification

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Product Details of [ 1023595-19-8 ]

CAS No. :	1023595-19-8
Formula :	C₁₄H₂₆N₂O₂
M.W :	254.37
SMILES Code :	O=C(N(CC1)CCC21CCCNC2)OC(C)(C)C
MDL No. :	MFCD10700117
InChI Key :	QDWTYWWOUAIWGI-UHFFFAOYSA-N
Pubchem ID :	46912008

Safety of [ 1023595-19-8 ]

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

Computational Chemistry of [ 1023595-19-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	0
Fraction Csp3	0.93
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	80.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	41.57 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.16
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	1.77
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.63
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.	1.97
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	1.82
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.07

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.33
Solubility	1.18 mg/ml ; 0.00463 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.	-2.26
Solubility	1.39 mg/ml ; 0.00548 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	-2.66
Solubility	0.559 mg/ml ; 0.0022 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	Yes
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.	-6.59 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	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<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)	2.9

Application In Synthesis of [ 1023595-19-8 ]

* 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 [ 1023595-19-8 ]

[ 1023595-19-8 ] Synthesis Path-Downstream 1~35

1
[ 1023595-19-8 ]
[ 7379-35-3 ]
[ 1246507-83-4 ]

Yield	Reaction Conditions	Operation in experiment
51.4%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 15h;Reflux;	Step (i): tert-Butyl 2-(pyridin-4-yl)-2,9-diazaspiro[5.5]undecane-9-carboxylate tert-Butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate (1 g, 3.931 mmol), 4-chloropyridinium chloride (1.765 g, 11.794 mmol) and N-ethyl-diisopropylamine (2.7 ml, 15.724 mmol) were refluxed in 2-propanol (8 ml) for 15 h, saturated NaHCO3 solution (20 ml) and ethyl acetate (8 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (2*80 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/methanol/ammonia (25 aq.) 100:10:0.25). Yield: 0.67 g (51.4%)

References: [1]Patent: US2010/249095,2010,A1 .Location in patent: Page/Page column 121.

2
[ 1023595-19-8 ]
[ 1246506-61-5 ]
[ 1246508-28-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		Step 1: (R)-tert-Butyl 2-(3-(2-chlorobenzamido)-2,3-dihydro-1H-indene-5-carbonyl)-2,9-diazaspiro[5.5]undecane-9-carboxylate N-Ethyl-diisopropylamine (4 eq.) was added to a solution of (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid (E-03) (0.952 mmol, 1 eq.) in methylene chloride (18 ml). The reaction mixture was cooled to 0 C. and N-ethyl-N'-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before <strong>[1023595-19-8]tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate</strong> (1.1 eq.) was added. The reaction mixture was stirred at room temperature for 2.5 d. Then, the reaction mixture was washed in each case 1* with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica; ethyl acetate/hexane/ammonia (25 aq.) 70:10:0.8). Yield: 70%

References: [1]Patent: US2010/249095,2010,A1 .Location in patent: Page/Page column 174-175.

3
[ 1023595-19-8 ]
[ 1313733-33-3 ]
[ 1313802-12-8 ]
[ 1313802-11-7 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 180 - 185℃;Microwave irradiation;	A solution of the appropriate chloride (1 eq) (ex: 5-chloro-6-methyl-3-(3- trifluoromethoxy-phenyl)-7,8-dihydro-6H-9-oxa-1 ,2,3a,4,6-pentaaza-cyclopenta- (ajnaphthalene) and the appropriate amine (3 to 5 eq) (ex: 1-methyl-piperidin-4- ylamine) in nBuOH (15 mL/mmol) was heated up to 180- 185C under microwave irradiation for 5 h - 10 h (or 24 h at 160-180C in a silicon bath). The solvent was evaporated under vacuum and the residue was purified by flash chromatography (Isolute/Flash, Sill, 2.5% MeOH with 7N ammonia in DCM) or by semi-preparative HPLC (Gemini C18 (150 10 mm; 5 m), Solvent A: water with 0.1 % formic acid; Solvent B: acetonitrile with 0.1 % formic acid. Gradient: 40% of A to 0% of A).The NH-BOC-protected amines got deprotected in the reaction conditions and reacted giving a mixture of regioisomers. Amine: <strong>[1023595-19-8]2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester</strong>HPLC-MS (method 1 ): Rt = 3.44 min, [M+H]+ m/z 504.3.1H NMR (300 MHz, MeOD) S 8.40 (m, 2H), 7.71 (m, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 4.46 (m, 2H), 3.70 (m, 2H), 3.54 (m, 2H), 3.41 (m, 2H), 3.15 (m, 4H), 3.02 (s, 3H), 1.82 (m, 8H).Example 685-(2,9-Diaza-spiro[5.5]undec-2-yl)-6-methyl-3-(3-trifluoromethoxy-phenyl)- 7,8-dihydro-6H-9-oxa-1 ,2,3a,4,6-pentaaza-cyclopenta[a]naphthalene; HCI saltAmine: <strong>[1023595-19-8]2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester</strong>HPLC-MS (method 1): Rt = 4.50 min, [M+H)+ m/z 504.3.1H NMR (300 MHz, MeOD) delta 8.52 (s, 1 H), 8.38 (d, J = 7.5 Hz, 1 H), 7.74 (m, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 4.49 (m, 2H), 3.54 (m, 2H), 3.43 (m, 4H), 3.21 (m, 4H), 3.02 (s, 3H), 1.83 (m, 8H).

References: [1]Patent: WO2011/80510,2011,A1 .Location in patent: Page/Page column 86-87; 118.

4
[ 1023595-19-8 ]
[ 1276676-86-8 ]
[ 1276676-03-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; N,N-dimethyl acetamide;bis(tri-t-butylphosphine)palladium(0); at 100℃; for 18h;	Anhydrous dimethylacetamide (95 mu, degassed prior to use) was added to a mixture of 5-chloro-l-(2,2-dimethylpropyl)-3-methyl-l,3-dihydro-2H-imidazo[4,5-¾]pyridin-2- one (1-4, 20 mg, 0.079 mmol), potassium phosphate tribasic (33.5 mg, 0.158 mmol), bis(tri-t- butylphosphine)palladium(O) (1.61 mg, 3.15 muiotaetaomicron), and tert-butyl 2,9-diazaspiro-[5.5]undecane- 9-carboxylate (30.1 mg, 0.118 mmol). The resulting suspension was heated to 100 C for 18 h. Following this duration, the reaction contents were cooled to room temperature, filtered, and washed with acetonitrile . Purification using reverse-phase chromatography (10-100%, 0.1% TFA in F£20: acetonitrile) affordedJert-butyl 2-[l-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3- dihydro-lH-imidazo[4,5-¾]pyridin-5-yl]-2,9-diazaspiro[5.5]undecane-9-carboxylate (22-1) as a white solid. MS m/z (Mu+Eta): calculated = 472.3282; observed = 472.3275.

References: [1]Patent: WO2011/34741,2011,A1 .Location in patent: Page/Page column 105.

5
[ 1023595-19-8 ]
[ 1417848-17-9 ]
[ 1417839-87-2 ]

References: [1]Patent: WO2013/4984,2013,A1 .

6
[ 1023595-19-8 ]
[ 1417848-17-9 ]
C₃₁H₃₇F₃N₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Exam le: Synthesis of final product 19A solution of Intermediate 1-46 (120 mg, 0.291 mmol) and 2,9-diaza- spiro[5.5]undecane-9-carboxylic acid fert-butyl ester (296 mg, 1.16 mmol) in DMA (10 ml.) was heated at 100 C for 48 h. Et3N (0.081 mL, 0.58 mmol) was added ad the reaction was heated at 100 C for 24 h. The solvent was removed in vacuo, water was added (20 mL) and the mixture was extracted with DCM. The combined organic layers were dried (MgS04), filtered and evaporated. The residue was purified by column chromatography (Biotage, EtOAc:cHex 70:30). The product obtained was dissolved in MeOH (4 mL) and HCI 4M in dioxane (10 mL) was added. The reaction was stirred at rt for 4 h. The mixture was evaporated, and the residue was treated with 7N NH3 in MeOH. The residue was purified by column chromatography (Biotage, 7N NH3 in MeOH: DCM, 0:100 to 8:92) to afford Final Product 19 (100 mg, 65%) as a white solid.

References: [1]Patent: WO2013/4984,2013,A1 .Location in patent: Page/Page column 91.

7
[ 1023595-19-8 ]
[ 87-42-3 ]
C₁₉H₂₈N₆O₂ [ No CAS ]