1147557-97-8|tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate| Ambeed

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Quality Control of [ 1147557-97-8 ] Purity: 95% SDS Specification

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Product Details of [ 1147557-97-8 ]

CAS No. :	1147557-97-8
Formula :	C₁₁H₁₉NO₃
M.W :	213.27
SMILES Code :	O=C(N1CC2(CC(O)C2)C1)OC(C)(C)C
MDL No. :	MFCD15071431
InChI Key :	UMXXHZDEAZUQKZ-UHFFFAOYSA-N
Pubchem ID :	52987765

Safety of [ 1147557-97-8 ]

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

Computational Chemistry of [ 1147557-97-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.91
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	60.19
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.58
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	0.87
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.0
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.	1.15
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	0.82
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.28

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.51
Solubility	6.55 mg/ml ; 0.0307 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.	-1.5
Solubility	6.76 mg/ml ; 0.0317 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	-0.97
Solubility	23.1 mg/ml ; 0.108 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.	-6.98 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)	2.66

Application In Synthesis of [ 1147557-97-8 ]

* 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 [ 1147557-97-8 ]

[ 1147557-97-8 ] Synthesis Path-Downstream 1~35

1
[ 1181816-16-9 ]
[ 1147557-97-8 ]

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

2
[ 1147557-97-8 ]
[ 1181816-12-5 ]

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

3
[ 1239320-10-5 ]
[ 1147557-97-8 ]

References: [1]Patent: CN106565706,2017,A .

4
[ 1181816-12-5 ]
[ 1147557-97-8 ]

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.

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium tetrahydroborate; at 20℃; for 1h;Cooling with ice;	General procedure: Tert-butyl 2-oxo-7-azaspiro[3.5]nonan-7-carboxylate(490 mg, 2.05 mmol) is dissolved in methanol (10 mL), cooled in an ice bath, followed by adding sodium borohydride (156 mg, 4.10 mmol) in batches, and the reaction mixture reacts at room temperature for 1 hr, then rotated for drying, followed by adding water (20 mL), and the liquid is extracted with ethyl acetate (20 mL * 2), washed with saturated salt solution(20 mL * 2), and then the organic solution is dried with anhydrous Na2SO4, rotated to dryness and purified by column chromatography (eluent: PE : EA = 3 : 1), so as to obtain 450 mg of a white solid, that is tert-butyl 2-hydroxy-7-azaspiro[3.5]nonan-7-carboxylate, with a yield of 91percent. Spectrum is: 1H NMR (400 MHz, CDCl3) delta: 4.35(m, 1H), 3.33(m, 4H), 2.30(m, 2H), 1.70(m, 3H), 1.53(m, 4H), 1.47(m, 9H).

6
[ 934664-41-2 ]
[ 1147557-97-8 ]

References: [1]Patent: US2012/129830,2012,A1 .
[2]Patent: CN106565706,2017,A .

7
[ 1147557-97-8 ]
[ 1421270-71-4 ]

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

8
[ 1147557-97-8 ]
[ 1421270-66-7 ]

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

9
[ 1147557-97-8 ]
[ 124-63-0 ]
[ 1239320-11-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 0 - 20℃;	Compound 1 (5.0 g, 23.4 mmol) and triethylamine (2.9 g, 28.1 mmol) were dissolved in dichloromethane (50 mL)And then methanesulfonyl chloride (3.22 g, 28.13 mmol) was added dropwise at 0 C,Stir overnight at room temperature.TLC (petroleum ether / ethyl acetate volume ratio = 1/1, Rf = 0.5) showed completion of the reaction.The reaction solution was quenched with water, and the organic phase was washed with saturated ammonium chloride solution and dried to dryness to give Compound 2 (6.6 g) in a yield of 100%.
100%	With triethylamine; In dichloromethane; at 0 - 20℃;	To a solution of ferf -butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2 g , 9.4 mmol) in dichloromethane (25 mL) was added triethylamine (2.6 mL, 18.8 mmol). The solution was cooled to o C and a solution of methanesulfonylchloride (0.8 mL, 10.3 mmol) in dichloromethane (5 mL) was added dropwise. The mixture was stirred for 18 hours at room temperature and then washed with water and brine, dried (sodium sulfate), filtered and evaporated to afford the title compound (2.7 g, yield 100 %) as a white solid. (0905) NMR (CDC13): delta = 4.89 (m, 1 H), 3-94 (s, 4 H), 2.99 (s, 3 H), 2.70 (m, 2 H), 2.48 (m, 2 H) and 1.44 (s, 9 H).
99%	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 20h;	Step 9 tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2- carboxylate [00182] ferf-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0 C with an external ice-bath. Et3N (330 pL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 pL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0 C for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4CI (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3x30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford terf-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid. [00183] 1HNMR (300 MHz, CDCI3): delta 4.89 (m, 1 H), 3.93 (s, 4 H), 2.99 (s, 3 H), 2.68 (m, 1 H), 2.48 (m, 2 H), 1.43 (s, 9 H).

73.2%	With triethylamine; In dichloromethane; at 0 - 20℃;	To a stirred solution of <strong>[1147557-97-8]tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate</strong> 23-1 (500 mg, 2.34 mmol) in dichloromethane (10 mL) at 0C was added triethylamine (474.46 mg, 4.69 mmol, 653.53 uL) followed by rnesyl chloride (402.83 mg, 3.52 mmol, 272.18 uL) drop wise. The reaction mixture was allowed to stir at ambient temperature for 1 hour. The reaction mass was then diluted with DCM and washed with water, a saturated solution of NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford crude product that was triturated with diethyl ether to afford tert-butyl 6- methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate 23-2 (500 mg, 1.72 mmol, 73 20% yield) as white semisolid. NMR (d6-DMSO, 400 MHZ) d 4.89-4.85 (m, 1H), 3.85-3.81 (m, 4H), 3.13 (s, 3H), 2.63-2.60 (m, 2H), 2.37-2.34 (m, 2H), 1.35 (s, 9H),
	With triethylamine; In dichloromethane; at 0℃; for 2h;	To a solution of <strong>[1147557-97-8]tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate</strong> (26.1) (500 mg, 2.34 mmol) and TEA (472 mg, 4.68 mmol) in DCM (5 mL) was added MsCl (322 mg, 2.81 mmol) dropwise at 0 C. The resulting mixture was stirred at 0 C for 2 h. TLC showed complete reaction. The mixture was poured into water and extracted with DCM. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (26.2) (700 mg, crude), which was used in next step without further purification.
40.7 g	With triethylamine; In tetrahydrofuran; at 0 - 0.35℃; for 2h;Inert atmosphere;	To a solution of <strong>[1147557-97-8]tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate</strong> (30.0 g) and triethylamine (29.2 mL) in THF (600 mL) was added methanesulfonyl chloride (13.0 mL) at 0 C. The mixture was stirred at room temperature under nitrogen atmosphere for 2 hr. The mixture was quenched with water at 0 C. and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (40.7 g). 1H NMR (300 MHz, CDCl3) 51.43 (9H, s), 2.39-2.55 (2H, m), 2.61-2.76 (2H, m), 2.98 (3H, s), 3.93 (4H, s) 4.89 (1H, quin, J=7.18 Hz).
	With triethylamine; In dichloromethane; at 20℃; for 3.25h;	To a solution of <strong>[1147557-97-8]tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate</strong> (2.0 g, 9.38 mmol) in DCM (45 mL) at room temperature was added Et3N (3.27 mL, 23.4 mmol) and MsCl (1.1 mL, 14.1 mmol) sequentially. After 3.25 hours, the reaction was quenched by the addition of water and DCM. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered, and concentrated to afford crude material considered to be quantitative of tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (9.38 mmol, 100% yield).
	With dmap; triethylamine; In dichloromethane; at 0℃; for 3h;	Commercially available /ert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.0 equiv), TEA (360 mg, 3.0 equiv) and DMAP (10 mg) were combined in DCM (25 mL) at 0C. MsCl (162 mg, 1.2 equiv) was added dropwise. The mixture was stirred at 0C for 3h. The reaction mixture was diluted with DCM (30 mL) and then washed with 1N HC1, water, and brine to afford /ert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (324 mg, yield 95%) which was used without further purification.

References: [1]Patent: CN105646318,2016,A .Location in patent: Paragraph 0007.
[2]Patent: WO2019/8025,2019,A1 .Location in patent: Page/Page column 141.
[3]Patent: WO2013/13308,2013,A1 .Location in patent: Paragraph 00181-00183.
[4]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 397 - 402.
[5]Patent: WO2019/191112,2019,A1 .Location in patent: Page/Page column 323; 324.
[6]Patent: WO2016/90079,2016,A1 .Location in patent: Paragraph 00489.
[7]Patent: US2018/280389,2018,A1 .Location in patent: Paragraph 3468; 3629; 3630.
[8]Patent: US2019/185469,2019,A1 .Location in patent: Paragraph 0825-0826.
[9]Patent: WO2019/177997,2019,A1 .Location in patent: Paragraph 00251.

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[ 330786-24-8 ]
[ 1147557-97-8 ]
[ 1448850-34-7 ]

Yield	Reaction Conditions	Operation in experiment
78 mg	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;Inert atmosphere;	[00131] To a mixture of 3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- amine (100 mg, 0.33 mmol), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (141 mg, 0.66 mmol, 2 eq), triphenylphosphine (173 mg, 0.66 mmol, 2 eq) in a 40 ml reaction vial under vacuum, 5 mL of THF is added via a syringe. The mixture is refilled with N2 and DIAD (0.13 mL, 0.66 mmol, 2 eq) is added dropwise at rt. The mixture is then stirred at rt overnight. TLC showed that the reaction is almost completed. Then solvent is evaporated and the residue is purified with a 24 g silica gel cartridge by combi-flash (0-10percent gradient of methanol in DCM to afford 78 mg of tert-butyl 6-(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate. 1HNMR (300 MHz, acetone-d6): delta 8.26 (s, 1 H), 7.78 (d, 2 H), 7.46 (t, 2 H), 7.10- 7.23 (m, 5 H), 5.30-5.45 (m, 1 H), 4.11 (s, 2 H), 4.05 (s, 2 H), 2.71-3.0 (m, 4 H), 1.44 (s, 9 H).

References: [1]Patent: WO2013/113097,2013,A1 .Location in patent: Paragraph 00130; 00131.

11
[ 1147557-97-8 ]
[ 1374658-94-2 ]

References: [1]Patent: US2014/45813,2014,A1 .
[2]Patent: CN105646318,2016,A .
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 5663 - 5672.
[4]Patent: US2019/359565,2019,A1 .

12
[ 1147557-97-8 ]
[ 1558038-02-0 ]