21883-13-6|4-Methoxy-2-methylbenzonitrile| Ambeed

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Quality Control of [ 21883-13-6 ] Purity: 97% SDS Specification

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Product Details of [ 21883-13-6 ]

CAS No. :	21883-13-6
Formula :	C₉H₉NO
M.W :	147.17
SMILES Code :	N#CC1=CC=C(OC)C=C1C
MDL No. :	MFCD03425692
InChI Key :	PXAQQUKODRZAOZ-UHFFFAOYSA-N
Pubchem ID :	3801022

Safety of [ 21883-13-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 21883-13-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	42.62
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.09
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	1.63
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.88
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.	1.44
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	2.26
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.86

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.12
Solubility	1.12 mg/ml ; 0.00764 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.	-1.94
Solubility	1.71 mg/ml ; 0.0116 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	-2.98
Solubility	0.155 mg/ml ; 0.00105 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	Yes
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.	-6.04 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)	1.35

Application In Synthesis of [ 21883-13-6 ]

* 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 [ 21883-13-6 ]

[ 21883-13-6 ] Synthesis Path-Downstream 1~35

2
[ 27060-75-9 ]
[ 557-21-1 ]
[ 21883-13-6 ]

References: [1]Synlett,2003,p. 2237 - 2239.

3
[ 21883-13-6 ]
[ 86-81-7 ]
6-amino-2,9-dimethoxy-11,12-dihydro-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 635 - 638.

4
[ 21883-13-6 ]
6-amino-2,9-dimethoxy-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 635 - 638.

5
[ 924-88-9 ]
[ 21883-13-6 ]
3,6-Bis(2'-methyl-4'-methoxyphenyl)-2,5-dihydropyrrolo(3,4-c)-pyrrole-1,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.82 g (3.86%)	With potassium tert-butylate; In tert-Amyl alcohol;	EXAMPLE 12 3,6-Bis(2'-methyl-4'-methoxyphenyl)-2,5-dihydropyrrolo(3,4-c)-pyrrole-1,4-dione 36.79 g (250 mmol) of <strong>[21883-13-6]2-methyl-4-methoxybenzonitrile</strong> and 28.05 g of potassium tert-butylate in 60 ml of tert-amyl alcohol are reacted with 25.28 g (125 mmol) of diisopropyl succinate in 10 ml of tert-amyl alcohol. Yield 1.82 g (3.86%) of orange powder. Purification is carried out by extractive recrystallisation from toluene by the process described by H. Langhals in Chem. Ber. 118, (1985), 4641. Melting point 319 C. (dec.).=Rf (silica gel/CHCl3)=0.17. UV(DMSO): lambdamax (1 g epsilon)=460 nm (4,405). Fluorescence (DMSO): lambdamax =519 nm. C22 H20 N2 O4 (376.39) Calc.: C, 70.20; H, 5.35; N, 7.44. Found: C, 70.20; H, 5.46; N, 7.24.

References: [1]Patent: US5354869,1994,A .

6
[ 21883-13-6 ]
[ 14143-26-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With boron dimethyl-trifluoro sulphide; In dichloromethane; at 0 - 20℃; for 16h;	To a dry flask of dichloromethane (34 mL) was added <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (14, 1.5 g, 10.2 mmol). Boron trifluoride-dimethyl sulfide complex(10.7 mL, 102 mmol) was then added slowly to the reaction mixture over 5 minutes. The reaction was allowed to stir 16 hours at room temperature. The reaction was quenched by the addition of water, and was allowed to stir for 15 minutes until fuming stopped. The reaction was diluted with EtOAc (~100 mL) and partitioned via separatory funnel. The aqueous layer was extracted 2 more times with EtOAc, then the combined organic extract was washed with water 2x and brine. The organic layer was isolated, dried over MgSO4, vacuum filtered and concentrated in vacuo to a light pink solid (1.305 g, 96% yield over 2 steps). This phenol intermediate was combined with dry DMF (1.7mL) in a flask at room temperature. Imidazole (1.67 g, 24.5 mmol) and TBS-Cl (1.77 g, 11.8 mmol) were added,and the reaction was allowed to stir for 16h. The reaction mixture was thenpoured into diethyl ether and washed 3x with water and 1x with brine. The organic layer was isolated, dried over MgSO4, vacuum filtered, and concentrated in vacuo to a transparent red oil. After further solvent removal via vacuum pump, the resulting oil (2.41g, 96% yield over 2 steps) was carried on without further purification.
68%		Boron trichloride in dichloromethane (61.2 ml_, 1 M) was added slowly todichloromethane (93 ml.) and cooled to -78 degrees Celsius. To this was added a solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (3.00 g, 20.4 mmol) andtetrabutylammonium iodide (7.17 g, 61.2 mmol) in dichloromethane (20 ml_). The reaction mixture was allowed to stir at -78 degrees Celsius for 5 minutes. The reaction mixture was then gradually warmed to room temperature and stirred for 2 hours. An ice slurry was slowly added to quench the reaction. The reaction was allowed to stir for 30 minutes and the layers were separated. The aqueous layer was extracted with dichloromethane (2x) and the combined organic extracts were passed through a phase separated cartridge and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting with 0% to 60% ethyl acetate in pentane to give the target compound as a yellow solid (1.85 g, 68 %). 1 H NMR deuteromethanol delta ppm 7.40 (d, 1 H), 6.80 (s, 1 H), 6.70 (d, 1 H), 2.40 (s, 3H); GCMS (CI method) ES+= 133 [M] AP+ = 133 [M].
36.4%		Boron trichloride (1M in dichloromethane, 747 ml, 747 mmol) was added dropwise, at -78 C., to a suspension of commercially available <strong>[21883-13-6]4-methoxy-2-methyl-benzonitrile</strong> (44 g, 298 mmol) and tetrabutylammonium iodide (121 g, 327 mmol) in dichloromethane (750 ml), under nitrogen, over 40 minutes. Once the addition was complete, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was then quenched by dropwise addition of water maintaining the internal at temperature below 10 C. The mixture was then filtered through Arbocel, and the layers were separated. The aqueous layers were extracted with dichloromethane (250 ml). The organic layers were combined, washed with a sodium thiosulphate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a thick yellow oil. Trituration of the oil in dichloromethane, followed by filtration, provided a first crop of the title compound (10.85 g, 27:4%) as a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel, eluting with pentane:ethyl acetate (70:30, by volume) to provide more of the title compound as a white solid (14.44 g, 36.4%). 1H-NMR (400 MHz, CDCl3): delta=2.46 (s, 3H), 6.68 (d, 1H), 6.72 (s, 1H), 7.45 (d, 1H); LRMS: APCl-: m/z 132 [M-H]-.

36%		Preparation 42 4-Hydroxy-2-methyl benzonitrile Boron trichloride (1M in dichloromethane, 747 ml, 747 mmol) was added dropwise, at -78 C., to a suspension of commercially available <strong>[21883-13-6]4-methoxy-2-methyl-benzonitrile</strong> (44 g, 298 mmol) and tetrabutylammonium iodide (121 g, 327 mmol) in dichloromethane (750 ml), under nitrogen, over 40 minutes. Once the addition was complete, the yellow solution was warmed to room temperature and stirred for 16 hours at room temperature. The reaction mixture was then quenched by dropwise addition of water maintaining the internal temperature below 10 C. The mixture was filtered through Arbocel and the layers were separated. The aqueous layers were extracted again with dichloromethane (250 ml). The organic layers were combined, washed with a sodium thiosulphate solution (150 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give thick yellow oil. Trituration of the oil in dichloromethane, followed by filtration, provided a first crop of the title compound (10.8 g, 27%) as a white solid. The filtrate was evaporated and purified by flash chromatography on silica gel, eluding with pentane:ethyl acetate (70:30, by volume) to provide more of the title compound as a white solid (14.4 g, 36%). 1H-NMR (400 MHz, CDCl3): delta=2.46 (s, 3H), 6.68 (d, 1H), 6.72 (s, 1H), 7.45 (d, 1H); LRMS: APCl-: m/z 132 [M-H]-.
		4-Hydroxy-2-methyl-benzonitrile A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0 C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45 C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4*100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H).
		A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.0 g, 33.97 mmol) in DCM (150 mL) is cooled down to 0 C. before adding dropwise a 1M BBr3 in DCM solution (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45 C. for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted with DCM (200 mL then 4×100 mL) and the combined organic extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g); LC-MS: tR=0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J=8.5, 2.0 Hz, 1H), 6.79 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 10.49 (s, 1H).
		Description for D33 4-Hydroxy-2-methylbenzonitrile (D33)To a solution of 2-methyl-4-(methyloxy)benzo?iotat?le (7 g) in anhydrous DCM (100 mL) was added drapwise BBr3 (51 5 g) at -78 C The resulting mixture was allowed to warm to RT and stirred for 24 hours LCMS indicated the reaction was completed Water was added dropwise slowly to quech the reaction. The mixture was extracted with EA (3x100 mL) and the combined organic layer was washed with brine dried over sodium sulfate, and concentrated to give 5 4 g of 4-hydroxy-2-methylbenzo nitrile (D33) as a white solid. deltaH (DMSO-Cf6, 400MHz). 2.45(3H, s), 6.67(1H1 d), 6 69(1H1 d), 7 51(1H, d), 1043(1H1 s). MS (ES) C8H7NO requires 133, found 134 1 (M+ H+)
	With decylthiol; potassium tert-butylate; In N,N-dimethyl-formamide; at 110℃; for 3h;	Decanethiol (261 mg, 1.5 mmol) and t-BuOK (168 mg, 1.5 mmol) were added to a solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (147 mg, 1 mmol) in DMF (5 mL). The reaction mixture was stirred at 110 C for 3 h. The mixture was then diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The extracts were washed with brine (10 mL x 3), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel column with (petroleum ether:EtOAc = 10:1) to provide 4-hydroxy-2-methylbenzonitrile (70 mg, yield: 52.6%). LC-MS (011): 134.70 [M+H]+; Rt: 1.44 min, Purity: 80% (254 nm).
		A solution of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (5.O g, 33.97 mmol) in DCM (15O mL) is cooled down to 00C before adding dropwise a 1IW solution of BBr3 in DCM (136 mL, 136 mmol). The reaction mixture is allowed to reach rt and stirring is then continued at 45C for 5 days. Ice water (500 mL) is then added and the reaction mixture is stirred for 1 h before sat. aq. NaHCO3 (250 mL) is added. The mixture is extracted wit DCM (200 mL then 4 x 100 mL) and the combined org. extracts are dried over MgSO4, filtered and evaporated to give the title compound as a brown solid (4.7 g). LC-MS: tR = 0.76 min. 1H NMR (D6-DMSO): delta 2.38 (s, 3H), 6.73 (dd, J = 8.5, 2.0 Hz, 1 H), 6.79 (d, J = 2.0 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 10.49 (s, 1 H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1538 - 1544.
[2]Patent: WO2012/69948,2012,A1 .Location in patent: Page/Page column 70-71.
[3]Patent: US2006/241125,2006,A1 .Location in patent: Page/Page column 20.
[4]Patent: US2007/105909,2007,A1 .Location in patent: Page/Page column 26.
[5]Patent: US2010/234346,2010,A1 .Location in patent: Page/Page column 16.
[6]Patent: US2010/261702,2010,A1 .Location in patent: Page/Page column 13.
[7]Patent: WO2010/148650,2010,A1 .Location in patent: Page/Page column 38-39.
[8]Patent: WO2013/19621,2013,A1 .Location in patent: Page/Page column 81.
[9]Patent: WO2009/109904,2009,A1 .Location in patent: Page/Page column 31.

7
[ 21883-13-6 ]
[ 28970-91-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 16h;	2-(bromomethyl)-4-methoxybenzonitrileInto a 50-mL round-bottom flask, was placed a mixture of <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (2 g, 13.59 mmol, 1.00 equiv), CCl4 (30 mL), NBS (2.67 g, 15.00 mmol, 1.10 equiv) and BPO (100 mg, 0.39 mmol, 0.03 equiv). The resulted solution was stirred for 16 h at 80 C. After the reaction, it cooled to rt. The reaction mixture was washed with 3×20 mL of water. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.50 g (81%) of 2-(bromomethyl)-4-methoxybenzonitrile as a yellow solid. LC-MS (ESI) m/z: calculated for C9H8BrNO: 224. found: 395 [M+H]+. Rt: 1.44 min.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane;Heating / reflux;	Compound 235 Isomers; N-(3, 4-difluorophenyl)-3-methyl-L-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((9-methoxy-4-methyl-3,4-dihydro-2H-[1,4]oxazino[3,2-c]isoquinolin-6-yl)oxy)-L-prolinamide andN-(3, 4-difluorophenyl)-3-methyl-D-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((9-methoxy-4-methyl-3,4-dihydro-2H-[1,4]oxazino[3,2-c]isoquinolin-6-yl)oxy)-L-prolinamide; Example 235; Preparation of Compounds 235A and 235B; Step 1; <strong>[21883-13-6]4-methoxy-2-methylbenzonitrile</strong> (50 g, 340 mmole) and NBS (62 g, 350 mmole) were suspended in CCl4 (500 ml) and AIBN (5 g, 10% wt) was added. The mixture was heated at flux overnight. Filtered off precipitate and removed the solvent. The brown oil was purified by flash column (2-5% acetone:hexanes). White crystal (36 g) were obtained.

References: [1]Patent: US2015/315198,2015,A1 .Location in patent: Paragraph 0786; 0787.
[2]European Journal of Organic Chemistry,2015,vol. 2015,p. 4922 - 4930.
[3]Chemical Communications,2016,vol. 52,p. 553 - 556.
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 336 - 343.
[5]Patent: US2008/119461,2008,A1 .Location in patent: Page/Page column 127-128.

8
[ 124-38-9 ]
[ 21883-13-6 ]
[ 55086-19-6 ]

Yield	Reaction Conditions	Operation in experiment
83%		Compound 20 Isomers; 3-methyl-N-phenyl-L-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((3,6-dimethoxy-1-isoquinolinyl)oxy)-L-prolinamide and3-methyl-N-phenyl-D-valyl-(4R)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-4-((3,6-dimethoxy-1-isoquinolinyl)oxy)-L-prolinamide; Example 20; Preparation of Compounds 20A and 20B; Step 1:; To a solution of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 7.02 g, 55 mmol) in THF (100 mL) was added LDA (2.0M in THF, 27.5 mL, 55 mmol) dropwise at -78 C. The resulting orange solution was kept at this temperature for 10 minutes with stirring and then 4-methoxy-2-methylbezonitrile (7.36 g, 50 mmol in 5 mL THF) was added dropwise. The resulting dark orange solution was kept at this temperature for 30 minutes with stirring. CO2 gas was then bubbled into this solution at -78 C. until it became colorless. The final solution was kept at this temperature for an additional 30 minutes with stirring before being purged with N2 for 5 minutes. The mixture was quenched with H2O (80 mL) at -78 C., then allowed to warm up to room temperature. 10.0M NaOH (aq, 20 mL, 200 mmol) was added, resulting in a homogeneous solution which was extracted with diethyl ether (100 mL). The aqueous layer was acidified by concentrated HCl to pH=2, and the resulting precipitate was collected by filtration. The cake was washed with H2O thoroughly and dried in vacuo overnight to furnish the desired product (7.90 g 83.0% yield) as a white fakes. 1H NMR (300 MHz, CD3OD) delta ppm 3.83 (s, 2H), 3.86 (s, 3H), 6.99 (m, 2H), 7.64 (d, J=8.42 Hz, 1H).

References: [1]Patent: US2008/119461,2008,A1 .Location in patent: Page/Page column 59-60.
[2]Synthetic Communications,2009,vol. 39,p. 1264 - 1272.

9
[ 5445-17-0 ]
[ 21883-13-6 ]
[ 941693-87-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 Methyl 3-(4-methoxy-2-methylphenyl)-2-methyl-3-oxopropanoate Methyl 2-bromopropanoate (0.3 mL) was added to anhydrous tetrahydrofuran (100 mL) of zinc powder (11 g) under argon gas atmosphere, followed by refluxing by heat for 15 minutes. 4-methoxy-2-dimethylbenzonitrile (5.0 g) was added to the resultant reaction solution, and further methyl 2-bromopropanoate (15 mL) was dropped thereinto taking 40 minutes, followed by refluxing by heat for 1 hour. The resultant reaction solution was cooled into room temperature, and was diluted with tetrahydrofuran (50 mL) and 50% potassium carbonate solution (30 mL), followed by stirring for 30 minutes. The supernatant of the reaction solution was separated, and concentrated under reduced pressure. The residual was poured to water, and was extracted with ethyl acetate. The extracted solution was washed by a saturated saline solution, and concentrated under reduced pressure after drying with anhydrous magnesium sulfate. Methanol (110 mL) and IN hydrochloric acid (33 ml) were added to the residue, and stirred at room temperature for 15 hours. The resultant reaction solution was concentrated under reduced pressure, was poured to water, and was extracted with ethyl acetate. The extracted solution was washed by a saturated solution of sodium chloride, and concentrated under reduced pressure after drying with anhydrous magnesium sulfate. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0?71:29), to thereby obtain a title compound (5.4 g) having the following physical properties. TLC: Rf 0.55 (hexane:ethyl acetate=3:1); 1H-NMR(300 MHz, CDCl3): delta 7.72 (d, J=9.3 Hz, 1H), 6.81-6.73 (m, 2H), 3.85 (s, 3H), 3.68 (d, J=0.6 Hz, 3H), 2.54 (s, 3H), 1.56 (d, J=0.6 Hz, 3H), 1.45 (dd, J=7.2, 0.3 Hz, 3H).

References: [1]Patent: EP1961754,2008,A1 .Location in patent: Page/Page column 20.

10
[ 1458-98-6 ]
[ 21883-13-6 ]
[ 1062612-72-9 ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 12594 - 12595.

11
[ 4685-47-6 ]
[ 21883-13-6 ]

References: [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10573 - 10576.
Angew. Chem.,2013,vol. 125,p. 10767 - 10770,4.
[2]Angewandte Chemie - International Edition,2009,vol. 48,p. 7094 - 7097.
Angewandte Chemie,2009,vol. 121,p. 7228 - 7231.

12
[ 21883-13-6 ]
[ 21883-14-7 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3073 - 3083.

13
C₈H₉BrMgO*ClLi [ No CAS ]
[ 31892-41-8 ]
[ 21883-13-6 ]

References: [1]Chemistry - A European Journal,2010,vol. 16,p. 4725 - 4728.

14
[ 21883-13-6 ]
[ 54818-95-0 ]
3-(4-methoxy-2-methylphenyl)-6-methylisoquinolin-1(2H)-one [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 5493 - 5497.

15
[ 21883-13-6 ]
[ 1428447-16-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1880 - 1897.

16
[ 21883-13-6 ]
[ 1239648-13-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1880 - 1897.

17
[ 21883-13-6 ]
[ 1428447-17-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1880 - 1897.

18
[ 21883-13-6 ]
[ 1239648-20-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1880 - 1897.

19
[ 638-10-8 ]
[ 21883-13-6 ]
[ 1239648-19-1 ]

Yield	Reaction Conditions	Operation in experiment
59%		General procedure: A dry round bottom flask was charged with anhydrous diglyme (24 mL) and diisopropylamine (2.91 mL, 20.4 mmol), then cooled to -78 C in a dry ice/acetone bath. To this solution was added n-butyllithium (2.5 M in hexanes, 8.15 mL, 20.4 mmol). The reaction was removed from the dry ice/acetone bath for 10 min, then re-cooled to -78 C. The desired o-tolunitrile 9a-d (6.79 mmol), dissolved in anhydrous diglyme (2 mL), was then added slowly dropwise then allowed to stir at -78 C for 45 min. (0048) A separate dry flask was charged with anhydrous diglyme (8.0 mL) and zinc powder (1.11 g, 17.0 mmol). Molecular iodine (3.45 g, 13.6 mmol) was added portionwise over the course of 10 min. The suspension was subsequently heated via heat gun in 30-s intervals until a silver precipitate of ZnI2 had formed and all iodine color had disappeared (caution: exothermic). (0049) Ethyl-3,3-dimethyl acrylate (1.42 mL, 10.2 mmol) was added to the first flask dropwise over 10 min. The flask containing the ZnI2 suspension was then added to the reaction vessel and the resulting suspension allowed to stir for an additional 2 h, slowly warming to room temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and the resulting biphasic suspension was extracted with diethyl ether (3 × 30 mL), then washed with water (4 × 50 mL) and brine (1 × 50 mL). The organic extract was dried over MgSO4, vacuum filtered, and concentrated in vacuo. Further purification via flash chromatography (silica gel, 5% EtOAc/hex) delivered the desired 10a-d in 33-59% yields.

References: [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 1880 - 1897.

20
[ 100-84-5 ]
(3,5-bis(trifluoromethyl)phenyl)(cyano)-l3-iodanyl trifluoromethanesulfonate [ No CAS ]
[ 21883-13-6 ]

References: [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 2186 - 2189.
Angew. Chem.,2014,vol. 53,p. 2218 - 2221,4.

21
[ 21883-13-6 ]
[ 1579956-89-0 ]