1181816-12-5|tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate| Ambeed

Structure of 1181816-12-5

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Quality Control of [ 1181816-12-5 ] Purity: 98% SDS Specification

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Product Details of [ 1181816-12-5 ]

CAS No. :	1181816-12-5
Formula :	C₁₁H₁₇NO₃
M.W :	211.26
SMILES Code :	O=C(N1CC2(CC(C2)=O)C1)OC(C)(C)C
MDL No. :	MFCD15071430
InChI Key :	HQHRAGXKFOTSQE-UHFFFAOYSA-N
Pubchem ID :	52333005

Safety of [ 1181816-12-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1181816-12-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.82
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	59.23
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.61 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.37
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	0.45
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.21
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.	1.05
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	1.3

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.24
Solubility	12.3 mg/ml ; 0.0582 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.	-1.0
Solubility	21.3 mg/ml ; 0.101 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	-1.66
Solubility	4.62 mg/ml ; 0.0219 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.	-7.27 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<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)	2.54

Application In Synthesis of [ 1181816-12-5 ]

* 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 [ 1181816-12-5 ]

[ 1181816-12-5 ] Synthesis Path-Downstream 1~35

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[ 1181816-12-5 ]

References: [1]Organic Letters,2009,vol. 11,p. 3523 - 3525.

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Yield	Reaction Conditions	Operation in experiment
66%	With ammonium chloride; zinc; In methanol; at 20℃; for 18h;Inert atmosphere;	Butyl-5,5-dichloro-6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.65 g, 5.89 mmol, 1.0 eq)Zinc powder (0.85 g, 15.0 mmol, 2.6 eq)Ammonium chloride (1.2 g, 22.0 mmol, 3.8 eq) was added to methanol (30 mL) and reacted at room temperature for 18 h under nitrogen. After completion of the reaction, water (40 mL) was added, EA (30 mL x 2) was extracted, dried, , PE: EA (v / v) = 5: 1 column chromatography to give 0.8 g of product as a white solid in 66.0percent yield.
	With ammonium chloride; zinc; In methanol; at 20℃; for 12h;Cooling with ice;	11.2.tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate15.13 g (0.283 mmol) of ammonium chloride are added to a solution containing 13.21 g (47.15 mmol) of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in the preceding step, in 250 mL of methanol.The reaction medium is cooled with the aid of an ice/water bath, and 30.83 g (0.471 mmol) of zinc are added.After stirring at room temperature for 12 hours, the Celite is filtered off and rinsed with methanol.The filtrate is evaporated to dryness.The residue obtained is taken up in water and extracted several times with ethyl acetate.The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure.After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate.1.78 g of pure product are thus obtained in the form of a white powder.m.p. (° C.): 117-119° C.LC-MS: M+H=2121H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).
	With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 16h;	9.66 g (147.73 mmoles) of Zn powder are suspended in 150 ml of glacial acetic acid. The medium is cooled to 0° C. and the crude solution of tert-butyl 5,5-dichloro-6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.1, in 30 ml of dioxan is added drop by drop. After stirring for 16 hrs at ambient temperature, the medium is slowly poured in portions into a saturated aqueous solution of sodium carbonate. After rebasification with sodium carbonate, the medium is stirred for one hour, then filtered on a fritted filter and the filtrate is extracted three times with ethyl acetate. The combined organic phases are washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography eluting with a 90/10 then 80/20 and 60/40 mixture of cyclohexane and ethyl acetate. 2.4 g of the expected product are obtained in the form of a brown gum.1H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).

0.42 g

With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 15h;

Step 3: Preparation tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate [0219] A solution of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.5 mmol) in dioxane (20 mL) was added drop wise to a suspension of zinc powder (0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered through celite, filtrate was basified with 33percent sodium hydroxide solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (0.42 g, 58 percent yield) as a pale yellow solid. 1H NMR (400 MHz, CDC13) delta 4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).

References: [1]Patent: CN106565706,2017,A .Location in patent: Paragraph 0176; 0177; 0178.
[2]Organic Letters,2009,vol. 11,p. 3523 - 3525.
[3]Patent: US2011/319381,2011,A1 .Location in patent: Page/Page column 15.
[4]Patent: US2012/129830,2012,A1 .Location in patent: Page/Page column 13.
[5]Patent: WO2015/48507,2015,A1 .Location in patent: Paragraph 0219.

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Yield	Reaction Conditions	Operation in experiment
100%	With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;Inert atmosphere;	Step 8 terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [00179] To a solution of ferf-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (507 mg, 2.4 mmol) in MeOH (5.0 mL) was added NaBH4 (182 mg, 4.8 mmol) at 0 C under N2. It was stirred at 0 C for 30 min. The solution was concentrated by evaporator in vacuo to give crude solid. A saturated solution of NaHCO3 (30 mL) was added. The aqueous mixture was extracted with DCM (4x30 mL). The combined organic solution was dried over anhydrous Na2SO4 and then concentrated by evaporation in vacuo to afford terf-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (5 mg, 100%) as a white solid. [00180] 1HNMR (300 MHz, CDCI3): delta 4.18 (m, 1 H), 3.88 (d, 4 H), 2.53 (m, 2 H), 2.08 (m, 2 H), 1.42 (s, 9 H).
100%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 6h;	To a solution of <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (845 mg) in MeOH (20 mL) was added NaBH4(152 mg) at 0 C. The mixture was stirred at r.t. for 6 hrs. TLC showed the reaction was complete. The mixture was concentrated and the residue was purified by column chromatography (silica gel, 1 % ~ 10 % MeOH in DCM) to give tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (853 mg, quantitive) as white solid. 1H NMR (400 MHz, DMSO-d6 ) d 5.00 (d, J = 6.2 Hz, 1H), 3.92 (q, J = 7.0 Hz, 1H), 3.75 (d, J = 21.0 Hz, 4H), 2.37 (ddd, J = 11.8, 6.1, 2.6 Hz, 2H), 1.95 - 1.86 (m, 2H), 1.35 (s, 9H). LC MS: m/z (M+l)+ 214.
95%	With sodium tetrahydroborate; In methanol; at 20℃; for 1h;	Tert-Butyl tert-butyl tert-butyl tert-butyl tert-butyl t-butyl-6-oxo-2-azaspiro [3.3] heptane-2-carboxylate (0.23 g, 1.1 mmol, 1 eq)To the methanol (8 mL), sodium borohydride (0.12 g, 3.2 mmol, 2.9 eq) was added in portions and reacted at room temperature for 1 h. After the reaction, water (20 mL) was added and extracted with EA (20 mL x 2) The residue was dried over sodium sulf

93.7%	With methanol; sodium tetrahydroborate; at 0 - 25℃; for 1h;Inert atmosphere;	Tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (4.22 g, 20 mmol) was added in methanol (30 mL), cooled under nitrogen gas protection to 0C, and sodium borohydride (1.52 g, 40 mmol) was added. After addition, the reaction solution was heated to 25C and stirred for 1 h, after completing reaction as measured by LC-MS, water (1 mL) was added to quench reaction, solvent was removed by vacuum distillation, water (100 mL) and ethyl acetate (100 mL) were added, the phases were separated, the organic phase was washed with hydrochloric acid (1 mol/L, 50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain the title compound in white color (4.0 g, yield 93.7 %).
89.2%	With sodium tetrahydroborate; In ethyl acetate; at 0 - 20℃; for 0.666667h;	t-Butyl 2-oxo-6-azaspiro[3.3]heptane-6-carboxylate (2.00 g, 9.47 mmol) was dissolvedin EtOAc (40 mL). The mixture was cooled to 0 C, and sodium borohydride (548 mg, 14.19 mmol) was added in portions, the mixture was stirred for 10 min at 0 C, and then further stirredat rt for 30 min. The mixture was cooled to 0 C, and quenched with saturated aqueousammonium chloride (2.0 mL). The mixture was stirred for 30 min, water (20 mL) and ethylacetate (50 mL) were added, and the mixture was stirred for 10 min. After the mixture waspartitioned, the water phase was extracted with ethyl acetate (100 mL x 2). The combined organicphases were washed with saturated aqueous NaCl and dried over anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo to get the title compound as an off-white solid(1.80 g, 89.2%).MS (ESI, pos. ion) m/z:236.1 [M+Ht
	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	0.494 g (13.06 mmoles) of sodium borohydride is added in portions at 0 C. to a solution of 2.30 g (10.89 mmoles) of tert-butyl 6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.2, in 55 ml of methanol. The reaction mixture is stirred for 1 hr at ambient temperature. After evaporation of the solvent, water is added to the reaction mixture, the aqueous phase is separated, it is extracted several times with dichloromethane, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and the filtrate is concentrated under reduced pressure. After crystallisation of the residue in diisopropyl ether, filtration of the solid obtained and drying under vacuum at 60 C., 2.24 g of product are obtained in the form of a beige powder.1H NMR (DMSO) delta (ppm): 5.00 (d, 1H); 3.95 (hex, 1H); 3.75 (d, 4H); 2.40 (m, 2H); 1.95 (m, 2H); 1.40 (s, 9H).

References: [1]Patent: WO2013/13308,2013,A1 .Location in patent: Paragraph 00178-00180.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 5663 - 5672.
[3]Patent: WO2019/118612,2019,A1 .Location in patent: Paragraph 0271.
[4]Patent: CN106565706,2017,A .Location in patent: Paragraph 0179; 0180; 0181.
[5]Patent: EP3281942,2018,A1 .Location in patent: Paragraph 0105; 0106.
[6]Patent: WO2018/133858,2018,A1 .Location in patent: Paragraph 00221.
[7]Patent: US2012/129830,2012,A1 .Location in patent: Page/Page column 13.
[8]Tetrahedron,2016,vol. 72,p. 7268 - 7275.
[9]Organic Letters,2018,vol. 20,p. 8022 - 8025.

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References: [1]Patent: US2011/319381,2011,A1 .
[2]Patent: US2012/129830,2012,A1 .
[3]Patent: WO2015/48507,2015,A1 .
[4]Patent: CN106565706,2017,A .

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References: [1]Patent: WO2013/13308,2013,A1 .

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References: [1]Patent: WO2013/13308,2013,A1 .

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[ 1421270-71-4 ]

References: [1]Patent: WO2013/13308,2013,A1 .

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[ 1181816-12-5 ]
[ 1421270-66-7 ]

References: [1]Patent: WO2013/13308,2013,A1 .

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[ 1181816-12-5 ]
tert-butyl 6-(4-(5-fluoro-2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [ No CAS ]