21962-49-2|4-Formyl-2-methoxybenzonitrile| Ambeed

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Structure of 21962-49-2

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Quality Control of [ 21962-49-2 ] Purity: 95% SDS Specification

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Product Details of [ 21962-49-2 ]

CAS No. :	21962-49-2
Formula :	C₉H₇NO₂
M.W :	161.16
SMILES Code :	N#CC1=CC=C(C=O)C=C1OC
MDL No. :	MFCD16295254
InChI Key :	RIKJENUWHKDHIW-UHFFFAOYSA-N
Pubchem ID :	60048534

Safety of [ 21962-49-2 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301+H311+H331-H315-H319-H335
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P310+P330-P302+P352+P312-P304+P340+P311-P305+P351+P338-P312-P321-P332+P313-P337+P313-P362-P403+P233-P405-P501
Class:	6.1
UN#:	3439
Packing Group:	Ⅲ

Computational Chemistry of [ 21962-49-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.11
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	43.04
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	50.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.53
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	1.28
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.38
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.	0.47
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	1.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.88
Solubility	2.11 mg/ml ; 0.0131 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.	-1.93
Solubility	1.89 mg/ml ; 0.0117 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	-2.55
Solubility	0.455 mg/ml ; 0.00282 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.	-6.37 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	1.0 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)	1.5

Application In Synthesis of [ 21962-49-2 ]

* 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 [ 21962-49-2 ]

[ 21962-49-2 ] Synthesis Path-Downstream 1~35

1
[ 194018-68-3 ]
[ 21962-49-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With dicyanozinc;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 110℃; for 4h;	4-Formyl-2-methoxybenzonitrile [0276] In an oven-dried flask purged with argon, a mixture of sulfonate (880 mg, 3,096 mmol), zinc cyanide (1,454 g, 12,385 mmol) and tetrakis triphenylphosphine palladium (0) (537 mg, 0,464 mmol) in DMF (30 ml) were stirred at 110C for 4h. Et20 was added to the reaction mixture and the organic layer was washed 3 times with water, dried, filtered and concentrated. The crude compound was then purified by flash chromatography (ethyl acetate-hexanes/3: 7) to provide nitrile (280 mg, 56%). 1H RMN (400 MHz, acetone d6) 8 : 4.11 (s, 3H), 7.68 (dd, 1H, J= 1.2 and 7.7 Hz), 7.72 (d, lH, J= 1. 2 Hz), 7.95 (d, 1H, J= 7.7 Hz), 10.14 (s, 1H),

References: [1]Patent: WO2005/66194,2005,A1 .Location in patent: Page/Page column 161.

2
[ 21962-49-2 ]
[ 73289-83-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridine hydrochloride; for 0.5h;Heating / reflux;	4-Formyl-2-hydroxybenzonitrile [0277] A mixture of nitrile (280 mg, 1, 737mmol) and pyridine hydrochloride (excess) was stirred and refluxed for 30 min. Water was added to the reaction mixture and extracted 3 times with ethyl acetate. The organic layer was washed 3 times with 10% HC1, dried, filtered and concentratrated to provide crude hydroxynitrile (230 mg, 90%). 1H RMN (400 MHz, acetone d6) 8 : 7.58 (d, 1H, J= 6. 2 Hz), 7.59 (d, 1H, J= 2.1 Hz), 7. 88 (dd, 1H, J= 2.1 and 6.2 Hz), 10. 07 (s, 1H), 10.4 (s, 1H).

References: [1]Patent: WO2005/66194,2005,A1 .Location in patent: Page/Page column 162.

3
[ 557-21-1 ]
[ 194018-68-3 ]
[ 21962-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 8h;	A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110 0C for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile.1H NMR (CDCl3, 500 MHz) δ 10.08 (s, IH), 7.80 (d, J= 7.5 Hz, IH), 7.55 (d, J= 7.5 Hz. IH),7.51 (s, IH), 4.06 (s, 3H); LC/MS (IE, m/z) 162.07 [M + I]+.
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 8h;	Step B: 4-Formyl-2-methoxybenzonitrile: A mixture ofthe sulfonate (37.0 g, 130 mmol), zinc cyanide (61.1 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.57 g, 19.53 mmol)in DMF (300 mL) were stirred at 110 C for 8 hr. EtOAc was added to the reaction mixture andthe organic layer was washed two times with water, dried, filtered and concentrated. The crudeproduct was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) whichafforded the title compound: LC/MS: (IE, mlz) [M + 1 t = 162.34.

References: [1]Organic Letters,2021,vol. 23,p. 8766 - 8771.
[2]Patent: WO2010/129379,2010,A1 .Location in patent: Page/Page column 57.
[3]Patent: WO2013/28474,2013,A1 .Location in patent: Page/Page column 79.

4
[ 21962-49-2 ]
[ 1255207-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylsulphonium iodide; sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; at 0 - 20℃;Inert atmosphere;	To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 ml). The resulting mixture was stirred at 00C under N2 for 20 min. The solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resulting reaction mixture was stirred at O 0C under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0 0C and quenched by drop- wise addition of water. The S mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J= 8 Hz, IH), 6.99 (dd, J- 1.1 Hz, J- 1.2 Hz, IH), 6.89 (s, IH), 3.97 (s, 3H), 3.94-3.92 (m, IH), 3.22 (dd, J =0 5.2, Hz, J= 4.1 Hz, IH), 2.77 (J= 2.5 Hz, IH); LC/MS (IE, m/z) 176.33 [M + I]+; tR = 2.55min.
	With trimethylsulphonium iodide; sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; at 0 - 20℃;Inert atmosphere;	Step C: 2-Methoxy-4-(oxiran-2-yl)benzonitrile: To a cool solution ofNaH (0.16 g, 3.9 mmol) inTHF (40 mL) was added dropwise a solution oftrimethylsulfonium iodide (0.91 g, 4.5 mmol) inDMSO (20 mL). The resulting mixture was stirred at 0C under N2 for 20 min. A solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.72 mmol) in THF (20 mL) was added. The resultingreaction mixture was stirred at ooc under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed asindicated by TLC (25%ethyl acetate/hexanes). The reaction mixture was cooled to 0C andquenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2 x 70mL). The combined organic layers were washed with water, brine, then dried (MgS04) and2530filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile: 1H NMR (CDCb, 500 MHz) <> 7.57 (d, .=8Hz, 1H), 6.99 (dd, .= 1.1 Hz,.=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J = 5.2, Hz, J = 4.1 Hz, 1H),2.77 (d, .= 2.5 Hz, 1H); LC/MS: (IE, mlz) [M +It= 176.33.
	With trimethylsulphonium iodide; sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; at 0 - 20℃; for 12h;Inert atmosphere;	Step C: 2-Methoxy-4-(oxiran-2-yl)benzonitrile: To a cool solution of NaH (0.16 g, 3.9 mmol) inTHF (40 mL) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) inDMSO (20 mL). The resulting mixture was stirred at 0C under N2 for 20 mm. A solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.72 mmol) in THF (20 mL) was added. The resultingreaction mixture was stirred at 0C under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25%ethyl acetate/hexanes). The reaction mixture was cooled to 0C and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) andfiltered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile: 111 NMR (CDC13, 500 MHz) ö 7.57 (d, J= 8 Hz, 1H), 6.99 (dd, J= 1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J= 5.2, Hz, J= 4.1 Hz, 1H),2.77 (d, J= 2.5 Hz, 1H); LCIMS: (IE, m/z) [M + 1] = 176.33.

With trimethylsulfonium iodide; sodium hydride; In tetrahydrofuran; dimethyl sulfoxide; mineral oil; at 0 - 20℃; for 13h;Inert atmosphere;

To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 mL) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 mL). The resulting mixture was stirred at 0C under N2 for 20 min. The solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.7 mmol) in THF (20 mL) was added. The resulting reaction mixture was stirred at 0C under N2 for 1 h, and then it was warmed gradually to room temperature and stirred at that temperature for 12 h. After the starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes), the reaction mixture was cooled to 0C and quenched by the dropwise addition of water. The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic layers were washed with water, brine, then dried (MgS04) and filtered. The filtrates were concentrated in vacuo. The residue was purified by column chromatography (10-30% EtOAc/hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile. 1H- NMR (500 MHz, CDC13) δ 7.57 (d, J= 8Hz, 1H), 6.99 (dd, J= 1.1 Hz, J = 1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.93 (m, 1H), 3.22 (dd, J= 5.2 Hz, J= 4.1 Hz, 1H), 2.77 (J= 2.5 Hz, 1H); LC/MS: [(M+l)] = 176. Resolution of the epoxide was carried out on prep SFC in similar fashion to that described for INTERMEDIATE 2A and 2B to provide fast eluted 7A and slow eluted 7B.

References: [1]Patent: WO2010/129379,2010,A1 .Location in patent: Page/Page column 57-58.
[2]Patent: WO2013/28474,2013,A1 .Location in patent: Page/Page column 80.
[3]Patent: WO2014/99633,2014,A2 .Location in patent: Page/Page column 70; 71.
[4]Patent: WO2016/60941,2016,A1 .Location in patent: Page/Page column 42.

5
[ 21962-49-2 ]
[ 1426072-37-8 ]
[ 1426072-38-9 ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/126944,2014,A2 .
[3]Patent: EP2744499,2016,B1 .

6
[ 21962-49-2 ]
[ 1443737-21-0 ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/99633,2014,A2 .
[3]Patent: WO2014/126944,2014,A2 .
[4]Patent: EP2744499,2016,B1 .

7
[ 21962-49-2 ]
tert-butyl (9aR)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate [ No CAS ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/99633,2014,A2 .
[3]Patent: EP2744499,2016,B1 .

8
[ 21962-49-2 ]
[ 1426072-40-3 ]
tert-butyl (3R, 9aS)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate [ No CAS ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/126944,2014,A2 .
[3]Patent: EP2744499,2016,B1 .

9
[ 21962-49-2 ]
tert-Butyl (3S)-4-[2-(4-cyano-3-methoxyphenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/99633,2014,A2 .
[3]Patent: WO2014/126944,2014,A2 .
[4]Patent: EP2744499,2016,B1 .

10
[ 21962-49-2 ]
tert-Butyl (9aS)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate [ No CAS ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/99633,2014,A2 .
[3]Patent: WO2014/126944,2014,A2 .
[4]Patent: EP2744499,2016,B1 .

11
[ 121-33-5 ]
[ 21962-49-2 ]

References: [1]Patent: WO2013/28474,2013,A1 .
[2]Patent: WO2014/126944,2014,A2 .
[3]Patent: EP2744499,2016,B1 .
[4]Patent: WO2016/60941,2016,A1 .

12
zinc cyanide [ No CAS ]
[ 17763-80-3 ]
[ 33513-42-7 ]
[ 21962-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); at 110℃; for 8h;	Step B: 4-Formyl-2-methoxybenzonitrile: A mixture of the sulfonate (37.0 g, 130 mmol), zinc cyanide (61.1 g, 521 mmol) and tetrakis triphenyiphosphine palladium (0) (22.57 g, 19.53 mmol) in DMF (300 mL) were stirred at 110 C for 8 hr. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) whichafforded the title compound: LC/MS: (IE, m/z) [M + 1] = 162.34.

References: [1]Patent: WO2014/99633,2014,A2 .Location in patent: Page/Page column 70.

13
[ 21962-49-2 ]
tert-butyl (3R, 9aS)-3-(4-cyano-3-methoxyphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate [ No CAS ]

References: [1]Patent: WO2014/99633,2014,A2 .

14
[ 21962-49-2 ]
[ 1426072-40-3 ]

References: [1]Patent: WO2014/99633,2014,A2 .

15
[ 21962-49-2 ]
2-methoxy-4-[(3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile hydrochloride [ No CAS ]

References: [1]Patent: WO2014/99633,2014,A2 .

16
[ 21962-49-2 ]
[ 1426072-37-8 ]

References: [1]Patent: WO2014/99633,2014,A2 .

17
[ 21962-49-2 ]
2-methoxy-4-[(3R,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile hydrochloride [ No CAS ]

References: [1]Patent: WO2014/99633,2014,A2 .

18
[ 21962-49-2 ]
[ 1426072-38-9 ]

References: [1]Patent: WO2014/99633,2014,A2 .

19
[ 21962-49-2 ]
2-methoxy-4-[(3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile hydrochloride [ No CAS ]

References: [1]Patent: WO2014/99633,2014,A2 .

20
[ 21962-49-2 ]
2-methoxy-4-[(3S,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile hydrochloride [ No CAS ]

References: [1]Patent: WO2014/99633,2014,A2 .

21
[ 748101-41-9 ]
[ 194018-68-3 ]
[ 21962-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 8h;	A mixture of 4-formyl-2-methoxyphenyltrifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (6 1.0 g, 521 mmol) and tetrakistriphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DME (300 mL) were stirred at 110 c for 8 h. EtOAc was added to the reaction mixture and the organie layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetatelhexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile._Lc/MS (IE, miz) 162.07 [M + 11+.
	With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 110℃; for 8h;	General procedure: A mixture of the sulfonate (37.0 g, 130 mmol), zinc cyanide (61.1 g, 521mmol) and tetrakis triphenylphosphine palladium (0) (22.57 g, 19.53 mmol) in DMF (300 mL) were stirred at 110 Cfor 8 hr. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried,filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded the title compound: LC/MS: (IE, m/z) [M + 1]+ = 162.34.

References: [1]Patent: WO2014/126944,2014,A2 .Location in patent: Page/Page column 45.
[2]Patent: EP2744499,2016,B1 .Location in patent: Paragraph 0184.

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Yield	Reaction Conditions	Operation in experiment
		To a cool solution of NaH (0.16 g, 3.9 mmol) inTHF (40 ml) was added dropwise a solution of trimethylsulfonium iodide (0.9 1 g, 4.5 mmol) inDMSO (20 ml). The resulting mixture was stirred at 0 under N2 for 20 min. The solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.7 mmol) in THF (20 ml) was added. The resultingreaction mixture was stirred at O c under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetatelhexanes). The reaction mixture was cooled to O c and quenched by drop-wise addition of water. The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organie layers were washed with water, brine, then dried (Mg504) andfiltered. The filtrate was concentrated in yacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2- yl)benzonitrile. lH NMR (CDC13, 500 MHz) 7.57 (d, J= 8Hz, 1H), 6.99 (dd, J= 1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J= 5.2, Hz, J= 4.1 Hz, 1H),2.77 (J = 2.5 Hz, 1H); LC/MS (IE, miz) 176.33 [M + 11+
		General procedure: To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 mL) wasadded dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 mL). The resulting mixturewas stirred at 0C under N2 for 20 min. A solution of <strong>[21962-49-2]4-formyl-2-methoxybenzonitrile</strong> (0.60 g, 3.72 mmol) in THF(20 mL) was added. The resulting reaction mixture was stirred at 0C under N2 for 1 hr, and then it was warmedgradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed asindicated by TLC (25%ethyl acetate/hexanes). The reaction mixture was cooled to 0C and quenched with dropwiseaddition of water. The mixture was extracted with ethyl acetate (2 x 70 mL). The combined organic layers werewashed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile:1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J = 8 Hz, 1H), 6.99 (dd, J = 1.1 Hz, J = 1.2 Hz, 1H), 6.89 (s, 1H),3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J = 5.2, Hz, J = 4.1 Hz, 1H), 2.77 (d, J = 2.5 Hz, 1H); LC/MS: (IE, m/z) [M+ 1]+ = 176.33.

References: [1]Patent: WO2014/126944,2014,A2 .Location in patent: Page/Page column 45; 46.
[2]Patent: EP2744499,2016,B1 .Location in patent: Paragraph 0184.

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