121138-01-0|3-Iodotetrahydrofuran| Ambeed

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Quality Control of [ 121138-01-0 ] Purity: 98% SDS Specification

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Product Details of [ 121138-01-0 ]

CAS No. :	121138-01-0
Formula :	C₄H₇IO
M.W :	198.00
SMILES Code :	IC1COCC1
MDL No. :	MFCD09878873
InChI Key :	BKIQORJIKOPRCG-UHFFFAOYSA-N
Pubchem ID :	22139264

Safety of [ 121138-01-0 ]

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

Computational Chemistry of [ 121138-01-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	6
Num. arom. heavy atoms	0
Fraction Csp3	1.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	33.28
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	9.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.71
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	1.21
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.	1.14
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	2.28
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.51

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.83
Solubility	2.93 mg/ml ; 0.0148 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	19.8 mg/ml ; 0.0999 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	-1.45
Solubility	6.98 mg/ml ; 0.0352 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	Low
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.	-6.65 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	3.0
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	2.0 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)	2.7

Application In Synthesis of [ 121138-01-0 ]

* 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 [ 121138-01-0 ]

[ 121138-01-0 ] Synthesis Path-Downstream 1~35

1
[ 627-27-0 ]
[ 121138-00-9 ]
[ 121138-01-0 ]

References: [1]Synthesis,1988,p. 862 - 868.
[2]RSC Advances,2015,vol. 5,p. 56780 - 56788.

2
[ 13694-84-3 ]
[ 121138-01-0 ]

References: [1]Synthesis,1988,p. 862 - 868.

3
[ 627-27-0 ]
[ 121138-01-0 ]

References: [1]Journal of Organic Chemistry,1996,vol. 61,p. 962 - 968.

4
[ 487-89-8 ]
[ 121138-01-0 ]
[ 312973-23-2 ]

Yield	Reaction Conditions	Operation in experiment
14%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 6h;	Indole-3-carboxaldehyde (0.72 g, 0.005 mol), 3-iodo tetrahydrofuran (0.99 g, 0.005 mol) and anhydrous potassium carbonate (0.69 g, 0.005 mol) in anhydrous N,N-dimethylformamide (7 ml) was stirred at 120 C. for 6 h. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed on a silica gel column using toluene:ethyl acetate 95:5 as eluent to yield 0.15 g (14%) of the entitled product as an oil.

References: [1]Patent: US7049312,2006,B1 .Location in patent: Page/Page column 111.

5
[ 121138-01-0 ]
[ 929626-16-4 ]
[ 1442416-22-9 ]

References: [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 933 - 937.
Angew. Chem.,2012,vol. 125,p. 967 - 971,5.

6
[ 453-20-3 ]
[ 121138-01-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane;Reflux; Inert atmosphere;	Mixture of 3-hydroxy tetrahydrofuran (8.8g, 0.1mol) in dichloromethane (200 mL) were added successively triphenylphosphine (52.4g, 0.2mol), imidazole (13.6g, 0.2mol) and iodine (50.7g, 0.2 mol), the reaction solution in N2Protection under reflux overnight, 0.2MNa2S2O3(30 mL) to quench the reaction, the organic layer was separated, aqueous phase extracted with dichloromethane The combined organic phases were extracted three times, dried over anhydrous MgSO4Dried, filtered, and concentrated to give a wet, yellow solid, the solid was added to pentane (100 mL) was stirred 2h, the insoluble solid was filtered to give the desired product (18.6 g of, 94% yield) after the filtrate was concentrated.

References: [1]Patent: CN103965174,2016,B .Location in patent: Paragraph 0171; 0173-0175.
[2]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6170 - 6174.
[3]Angewandte Chemie - International Edition,2013,vol. 52,p. 933 - 937.
Angew. Chem.,2012,vol. 125,p. 967 - 971,5.
[4]Chemistry - A European Journal,2021,vol. 27,p. 3694 - 3699.
[5]Organic Letters,2021,vol. 23,p. 4002 - 4007.

7
1-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-l,4-dihydro-5H-tetrazol-5-one [ No CAS ]
[ 121138-01-0 ]
1-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)-4-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With caesium carbonate; In N,N-dimethyl acetamide; at 70℃;	Compounds 109- 115 were prepared according to the following synthetic scheme:A mixture of l-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7- yl)amino)-5-fluoropyrimidin-2-yl)amino)-4-fluoro-2-hydroxyphenyl)-4-methyl-l,4-dihydro- 5H-tetrazol-5-one (0.16g, l.Oeq, 0.35mmol), iodooxetane (0.2g, 3.0eq, l.OOmmol) and CS2CO3 (0.12g, l.leq, 0.36 mmol) was taken in DMA (lOmL). The reaction mixture was heated at 70C and stirred overnight. After the completion of the reaction the crude mixture was diluted with EtOAc (50 mL) and partitioned with H20 (50 mL). The layers were seperated and the aqueous layer was washed with EtOAc (2 x 50mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to leave a crude oil. The crude mixture was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH / CH2C12 (gradient system from 0: 1 to 1:9) as eluent to give the product as a solid. [00757] l-(5-((4-(((7/?,8a5)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5- fluoropyrimidin-2-yl)amino)-4-fluoro-2-(((/i)-tetrahydrofuran-3-yl)oxy)phenyl)-4- methyl-l,4-dihydro-5H-tetrazol-5-one (Compound 109): Yield = 66%, 1H NMR (300 MHz, -DMSO) δ 8.41 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.24 (dd, J = 27.0, 9.9 Hz, 2H), 5.07 (s, 1H), 3.96 (s, 1H), 3.83 (dd, J = 10.2, 4.5 Hz, 1H), 3.67 (ddd, J = 18.9, 9.7, 4.4 Hz, 3H), 3.30 (d, J = 0.6 Hz, 3H), 2.81 (s, 1H), 2.30 - 1.99 (m, 3H), 2.02 - 1.76 (m, 2H), 1.76 - 1.45 (m, 5H), 1.38 (t, J = 12.1 Hz, 1H), 1.17 (s, 1H), 1.03 (s, 3H), 0.76 (s, 3H); 19F NMR (282 MHz 6-DMSO) δ -116.0 (s), -166.9 (d); LCMS (m/z): 558 (M+H)+

References: [1]Patent: WO2013/152198,2013,A1 .Location in patent: Paragraph 00756; 00757.

8
[ 1616634-99-1 ]
[ 121138-01-0 ]
[ 1616695-74-9 ]

References: [1]Organic Letters,2014,vol. 16,p. 3692 - 3695.

9
[ 121138-01-0 ]
[ 97-62-1 ]
ethyl 2-methyl-2-(tetrahydrofuran-3-yl)propionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.48%		To a solution of diisopropylamine (0.736 mL, 5.17 mmol) in dry THF (30 mL) under nitrogen atmosphere n-butyl lithium (3.23 mL, 5.17 mmol) was added and stirred at 0Cfor 30 minutes. The reaction mixture was cooled to -78C and the solution of ethyl isobutyrate (0.5g mg, 4.30 mmol) in dry THF (30 mL) was addeddrop wise and allowed to stirred at same temperature for 30 minutes. Then the solution of <strong>[121138-01-0]3-iodotetrahydrofuran</strong> (1.28 g, 6.46 mmol) in THF (30 mL) was added drop wise and the reaction mixture was warm to room temperature and stirred for 8h. The reaction mixture was quenched with 10% ammonium chloride solution (100 mL) and extracted with ethyl acetate (250 mL). The combined organic layer was washedwith water (100 mL), brine(100 mL), dried over sodium sulfate and concentrated invacuo. The crude was purified by vacuum distillation. The fraction collected at 10torr 130C as yellow liquid (68 mg, 8.48% yield). ‘H NMR (CDC13, ö = 7.26 ppm,300 MHz): ö4.17 -4.08 (m, 2 H), 3.88-3.80 (m, 2 H), 3.77-3.70 (m, 1 H), 3.69-3.55 (m, 1 H), 2.61 - 2.52 (m, 1 H), 1.97 - 1.84 (m, 1 H), 1.74 - 1.66 (m, 1 H), 1.29 -1.22 (m, 3 H), 1.17 (s, 6 H).

References: [1]Patent: WO2015/5901,2015,A1 .Location in patent: Page/Page column 724; 725.

10
[ 637-69-4 ]
[ 121138-01-0 ]
3-(4-methoxystyryl)tetrahydrofuran [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6170 - 6174.

11
[ 1746-23-2 ]
[ 121138-01-0 ]
(E)-3-(4-(tert-butyl)styryl)tetrahydrofuran [ No CAS ]
(Z)-3-(4-(tert-butyl)styryl)tetrahydrofuran [ No CAS ]

References: [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6170 - 6174.

12
[ 29415-97-2 ]
[ 121138-01-0 ]
methyl 3-bromo-4-(tetrahydrofuran-3-yloxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
298 mg	With potassium carbonate; In acetonitrile; at 80℃; for 16h;Inert atmosphere;	Step 1: Methyl 3-bromo-4-(tetrahydrofuran-3-yloxy)benzoate To a suspension of methyl 3-bromo-4-hydroxybenzoate (200 mg, 848 μιηο) in acetonitrile (2 mL) were added potassium carbonate (234 mg, 1.7 mmol) and <strong>[121138-01-0]3-iodotetrahydrofuran</strong> (354 mg, 1.70 mmol). The reaction mixture was heated at 80C for 16 h and then partitioned between ice water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to produce the title compound (298 mg, orange oil), which was directly used in the next step.

References: [1]Patent: WO2015/144605,2015,A1 .Location in patent: Page/Page column 84.

13
methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate [ No CAS ]
[ 121138-01-0 ]
2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetic acid [ No CAS ]
methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.3%; 16.5%		A cooled (0 C.) solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate (Cpd T, 800 mg, 0.487 mmol) in anhydrous N,N-dimethylformamide (70 mL) was treated with sodium hydride (60 wt % dispersion in mineral oil, 125 mg, 3.12 mmol), then stirred at 10 C. for 15 minutes. The mixture was cooled again to 0 C. and <strong>[121138-01-0]3-iodotetrahydrofuran</strong> (463 mg, 2.34 mmol) was added. After stirring at room temperature for 12 hours, glacial acetic acid (2 drops) and water (10 mL) were added, and the mixture extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, Petroleum ether/EtOAc=5:1-1:1) to obtain 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetic acid (1a, 500 mg, 56.3%) as a white solid; and methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetate (1b, 150 mg, 16.5%) as a yellow solid.

References: [1]Patent: US2015/361067,2015,A1 .Location in patent: Paragraph 0532.
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 650 - 665.

14
[ 2150-43-8 ]
[ 121138-01-0 ]
3-hydroxy-4-(tetrahydrofuran-3-yloxy)benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%		3,4-dihydroxybenzoic acid methyl ester (15.7g, 0.09mol) was dissolved in DMF (200mL) was added K2CO3(13 g, 0.09mol), the mixture was stirred for 15min after 3-iodo-tetrahydrofuran (18.6g, 0.09mol) in DMF (50mL) was slowly added dropwise, the reaction solution was added dropwise at room temperature after stirring for 24h, after the reaction filtered, the filtrate was concentrated to give the crude product after dissolved with dichloromethane, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product by column chromatography to give the desired product (5.3g, yield 25% ).

References: [1]Patent: CN103965174,2016,B .Location in patent: Paragraph 0171; 0176-0178.

15
(6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-(1H-pyrazol-3-yl)hexahydropyrimidine-2,4-dione [ No CAS ]
[ 121138-01-0 ]
(6S)-3-[2,6-difluoro-4-(2-phenylethynyl)phenyl]-1,6-dimethyl-6-[1-[(3RS)-tetrahydrofuran-3-yl]pyrazol-3-yl]hexahydropyrimidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;	The title compound was obtained as a colorless gum, MS: mle = 491.4 (M+Hj, using chemistry similar to that described in Example 1, step 7 starting from (6S)-3-[2,6-difluoro-4-(2- phenylethynyl)phenyl] -1 ,6-dimethyl-6- (1 H-pyrazol-3-yl)hexahydropyrimidine-2,4-dione(Example JO) and (RS)-<strong>[121138-01-0]3-iodotetrahydrofuran</strong>. (122 mg, 0.29 mmol) (6S )-3- [2,6-Difluoro-4- (2-phenylethynyl)phenyl] -6-methyl-6-thiazol-2-yl-hexahydropyrimidine-2,4-dione (Example], step 7) was dissolved in DMF (2 ml) and cesiumcarbonate (141 mg, 0.43 mmol, 1.5 equiv.) and iodomethane (49 mg, 22 ul, 0.35 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated with isolute. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 0:100 to 100:0gradient.The desired (65)-3- [2,6-difluoro-4- (2-phenylethynyl)phenyl] -1 ,6-dimethyl-6-thiazol-2- yl-hexahydropyrimidine-2,4-dione (95 mg, 76 % yield) was obtained as a colorless oil, MS: mle = 438.2 (M+Hj.

References: [1]Patent: WO2016/146600,2016,A1 .Location in patent: Page/Page column 34; 69; 70.

16
tert-butyl 2-(3-acetyl-5-hydroxy-1H-indazol-1-yl)acetate [ No CAS ]
[ 121138-01-0 ]
tert-butyl 2-(3-acetyl-5-((tetrahydrofuran-3-yl)oxy)-1H-indazol-1-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere;	Step 1 : tert-Butyl 2-(3-acetyl-5-((tetrahydrofuran-3-yl)oxy)-lH-indazol-l-yl)acetate (241) [0743] A mixture of fert-butyl 2-(3-acetyl-5-hydroxy-lH-indazol-l-yl)acetate (1 equiv), <strong>[121138-01-0]3-iodotetrahydrofuran</strong> (1.1 equiv), K2CO3 (3 equiv) and 18-Crown-6 (1 equiv) in DMF (10 vol) under argon, the pressure vessel was sealed and heated at 100 C for 24 h. The reaction mixture was cooled to rt and diluted with water, then extracted with DCM. The organic layer was washed with brine, dried over anhydrous NazSiX filtered, and then concentrated. The residue was purified by column chromatography on silica gel (EtOAc DCM) to give compound 241.

References: [1]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0743.

17
ethyl 4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-3-oxo-1-phenyl-2H-pyrazolo[3,4-b]pyridine-6-carboxylate [ No CAS ]
[ 121138-01-0 ]
ethyl 4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-1-phenyl-3-tetrahydrofuran-3-yloxypyrazolo[3,4-b]pyridine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 1h;Sealed tube;	General procedure: Intermediate E153 (1.0 equiv), the alkyl iodide (from 3 to 5.7 equiv) and cesium carbonate (from 3 to 5.7 equiv) are charged in a sealed vial. NMP is added, and the vial is sealed. The reaction mixture is stirred at 130 C for 1 hour. The reaction mixture is cooled down to RT and partitioned between water and ethyl acetate. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.

References: [1]Patent: WO2017/60874,2017,A1 .Location in patent: Paragraph 00497; 00649.

18
[ 491-35-0 ]
[ 121138-01-0 ]
[ 87991-97-7 ]