156353-01-4|N-Methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide| Ambeed

Structure of 156353-01-4

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Quality Control of [ 156353-01-4 ] Purity: 95% SDS Specification

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Product Details of [ 156353-01-4 ]

CAS No. :	156353-01-4
Formula :	C₈H₁₅NO₃
M.W :	173.21
SMILES Code :	CON(C)C(=O)C1CCOCC1
MDL No. :	MFCD07370048
InChI Key :	QURBKRFUFINPQC-UHFFFAOYSA-N
Pubchem ID :	23144693

Safety of [ 156353-01-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 156353-01-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	0
Fraction Csp3	0.88
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	43.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.16
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	0.08
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.43
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.	0.24
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	0.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.65

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.77
Solubility	29.7 mg/ml ; 0.171 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.	-0.45
Solubility	61.7 mg/ml ; 0.356 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	-0.57
Solubility	46.2 mg/ml ; 0.267 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.	-7.3 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)	2.15

Application In Synthesis of [ 156353-01-4 ]

* 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 [ 156353-01-4 ]

[ 156353-01-4 ] Synthesis Path-Downstream 1~35

1
[ 110238-91-0 ]
[ 6638-79-5 ]
[ 156353-01-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With isopropylmagnesium chloride; In tetrahydrofuran; at -30 - -5℃; for 1h;	Step 1 Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) was added thereto, and the mixture was stirred. A THF solution (15.0 mL, 30.0 mmol) of 2.0 mol/L isopropyl magnesium chloride was added dropwise to the reaction mixture at -30C under an argon atmosphere, and the mixture was stirred at -5C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was purified by distillation under reduced pressure, whereby N-methoxy-N-methyl tetrahydropyran-4-carboxylic acid amide (1.00 g, 58%) was obtained. Boiling point: 125 to 129C/8.0 hPa 1H NMR (CDCl3, delta ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H)
58%	With isopropylmagnesium chloride; In tetrahydrofuran; at -30 - -5℃; for 1h;Inert atmosphere;	Methyl tetrahydropyran-4-carboxylate (1.33 mL, 10.0 mmol) was dissolved in THF (20 mL), and N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.5 mmol) added thereto , then the mixture was stirred. Under an argon atmosphere, THF solution of isopropyl magnesium chloride (2.0 mol/L; 15.0 mL, 30.0 mmol) was added dropwise to the reaction mixture at -30C, and the mixture was stirred at -5C for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to give N-methoxy-N-methyltetrahydropyran-4-carboxamide (1.00 g, 58%). Boiling point: 125-129 C / 8.0 hPa, 1H NMR (CDCl3, delta ppm): 1.57-1.66 (m, 2H), 1.77-1.93 (m, 2H), 2.85-2.94 (m, 1H), 3.18 (s, 3H), 3.44 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H), 3.69 (s, 3H), 4.00 (ddd, J = 2.4, 11.9, 11.9 Hz, 2H).
	With isopropylmagnesium chloride; In tetrahydrofuran; at -20℃;Inert atmosphere;	Add 2 M isopropylmagnesium chloride in tetrahydrofuran (520.22 mL, 3.0 eq) to a mixture of methyl tetrahydro-2H-pyran-4-carboxylate (46.30 mL, 346.81 mmol) and Nu,Omicron-dimethylhydroxylamine hydrochloride (52.44 g, 1.6 eq) in tetrahydrofuran (2.43 L) during 15 minutes at -20C under nitrogen. After 30 min, add saturated aqueous ammonium chloride (400 mL) to the reaction at -20C. Extract the aqueous solution with methyl tert-butyl ether (250 mL x 3). Wash the combined organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Add dichloromethane (500 mL), filter through Celite and concentrate in vacuo. Add tetrahydrofuran (700 mL), then add 3 M methyl magnesium chloride intetrahydrofuran (231.21 mL, 2.0 eq) dropwise over 15 minutes at 7C. After 40 minutes, add saturated aqueous ammonium chloride (250 mL) to the reaction. Extract the aqueous solution with methyl tert-butyl ether (250 mL x 2). Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 2: 1 hexanes: ethyl acetate to 1 : 1 hexanes: ethyl acetate, to give 1 -(tetrahydro-pyran-4-yl)- ethanone (33.18 g, 75%). 'H NMR (300 MHz, DMSO-d6) delta 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).

References: [1]Patent: WO2007/15528,2007,A1 .Location in patent: Page/Page column 230.
[2]Patent: EP1894930,2008,A1 .Location in patent: Page/Page column 31.
[3]Patent: EP1921077,2017,B1 .Location in patent: Paragraph 0742.
[4]MedChemComm,2016,vol. 7,p. 1016 - 1021.
[5]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 99-100.

2
[ 40191-32-0 ]
[ 6638-79-5 ]
[ 156353-01-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With 4-methyl-morpholine; In dichloromethane; for 2h;	N,O-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N-methyl morpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2*100 mL), 1M aq Na2CO3 (100 mL) and water (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil (1.87 g, 94%). LCMS (ES+): 174.1 [MH]+.
	With 4-methyl-morpholine; In dichloromethane; for 2h;	Nu,Omicron-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N- methylmorpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop- wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2 x 100 mL), 1M aq Na2C03 (100 mL) and water (100 mL), dried(MgS04) and concentrated in vacuo to give the crude title compound as a yellow oil(1.87 g, 94%). LCMS (ES+): 174.1 (M+H)+.
	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 2h;	N,O-Dimethylhydroxylamine hydrochloride (1.23 g, 12.7 mmol) and N-methylmorpholine (3.80 mL, 34.5 mmol) were dissolved in DCM (20 mL) and a solution of oxane-4-carbonyl chloride (1.71 g, 11.5 mmol) in DCM (20 mL) was added drop-wise. The reaction mixture was stirred for 2 h, then diluted to 200 mL with DCM, washed with 1 M aq HCl (2*100 mL), 1M aq Na2CO3 (100 mL) and water (100 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound as a yellow oil (1.87 g, 94%). LCMS (ES+): 174.1 (M+H)+.

References: [1]Patent: US2014/357623,2014,A1 .Location in patent: Paragraph 0125; 0126.
[2]Patent: WO2011/113798,2011,A2 .Location in patent: Page/Page column 44.
[3]Patent: US2013/102587,2013,A1 .Location in patent: Paragraph 0227; 0228.

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 12h;	General procedure: A mixture of cis-2-fluorocyclopropanecarboxylic acid (500 mg, 4.80 mmol), Nu,Omicron- dimethylhydroxylamme hydrochloride (610 mg, 6.25 mmol), l -[bis(dimethylamino)methylene]-lH- l ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (2375 mg, 6.25 mmol) and N,N- diisopropylethylamine (1552 mg, 12.0 mmol) in N,N-dimethylformamide (15 mL) was stirred at 25 C for 12 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to give cis-2-fluoro-N-methoxy-N -methyl - cyclopropanecarboxamide (420 mg, 59%) as a colorless oil. NMR (400 MHz, CDCl3) delta 4.87 - 4.67 (m, 1H), 3.78 (s, 3H), 3.26 (s, 3H), 2.35 - 2.33 (m, 1 H), 1.94 - 1.86 (m, 1H), 1.11 - 1.05 (m, 1H).

4
[ 35369-13-2 ]
[ 156353-01-4 ]
2-(benzoimidazol-2-yl)-4-(2-furyl)thiazol-5-yltetrahydropyran-4-yl ketone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		Step 2 2-(Benzimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 8 was dissolved in THF (5 mL), and an n-hexane solution (1.01 mL, 1.56 mmol) of 1.58 mol/L n-butyl lithium was added thereto at - 78C under an argon atmosphere, and the mixture was stirred at -78C for 10 minutes. A THF solution (1 mL) of <strong>[156353-01-4]N-methoxy-N-methyl tetrahydropyran-4-carboxylic acid amide</strong> (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), whereby the title Compound (191 mg, 81%) was obtained. 1H NMR (DMSO-d6, delta ppm): 1.51-1.67 (m, 4H), 3.21-3.38 (m, 3H), 3.80-3.86 (m, 2H), 6.74 (dd, J = 1.8, 3.5 Hz, 1H), 7.29-7.32 (m, 2H), 7.41 (d, J = 3.5 Hz, 1H), 7.63-7.66 (m, 2H), 7.94 (d, J = 1.8 Hz, 1H). APCIMS m/z: [M+H]+ 380 Melting point: 250 to 251C
81%		2-(Benzoimidazol-2-yl)-4-(2-furyl)thiazole (167 mg, 0.625 mmol) obtained in Reference Example 562 was dissolved in THF (5 mL). To the solution was added n-hexane solution of n-butyl lithium (1.58 mol/L; 1.01 mL, 1.56 mmol) at -78C under an argon atomospher, and the mixture was stirred at -78C for 10 minutes. The THF solution (1 mL) of <strong>[156353-01-4]N-methoxy-N-methyltetrahydropyran-4-carboxamide</strong> (270 mg, 1.56 mmol) obtained in Step 1 was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give a title compound (191 mg, 81%).H NMR (DMSO-d6, delta ppm): 1.51-1.67 (m, 4H), 3.21-3.38 (m, 3H), 3.80-3.86 (m, 2H), 6.74 (dd, J = 1.8, 3.5 Hz, 1H), 7.29-7.32 (m, 2H), 7.41 (d, J = 3.5 Hz, 1H), 7.63-7.66 (m, 2H), 7.94 (d, J = 1.8 Hz, 1H). APCIMS m/z: [M+H] 380. mp: 250-251 C

References: [1]Patent: WO2007/15528,2007,A1 .Location in patent: Page/Page column 230-231.
[2]Patent: EP1894930,2008,A1 .Location in patent: Page/Page column 32.
[3]Patent: EP1921077,2017,B1 .Location in patent: Paragraph 0742.

5
[ 5337-03-1 ]
[ 6638-79-5 ]
[ 156353-01-4 ]

Yield	Reaction Conditions	Operation in experiment
96%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; water; at 0 - 20℃; for 2h;	N,N- diisopropylethylamine (8.1 mL, 46 mmol) was slowly added to a cold (0 C) solution of tetrahydro-2H-pyran-4-carboxylic acid (2 g, 15 mmol) and O,N-Dimethyl-hydroxylamine hydrochloride (2.25 g, 23.05 mmol) in DCM (20 mL). To the above solution was added 2,4,6- tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (11 mL, 50 %w/w; 18.4 mmol) slowly while at 0 C. The mixture was warmed to rt and allowed to stir for 2 h. The reaction mixture was quenched with ice cubes then diluted with water (10 mL) and extracted with DCM (2 X 30 mL). The organic fractions were combined, washed with aq. sodium bicaronate solution, dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound as an oily liquid (2.56 g, 96%). 1H NMR (400MHz, CD3OD) ^ = 3.96 (ddd, J = 1.7, 4.0, 11.5 Hz, 2H), 3.75 (s, 3H), 3.49 (dt, J = 2.4, 11.7 Hz, 2H), 3.19 (s, 3H), 3.10 - 2.92, (m, 1H), 1.83 - 1.60 (m, 4H); [M+H] = 174.2.
89%		In a 1 L RB flask, a solution of tetrahydro-2H-pyran-4-carboxylic acid (46.0 g, 353 mmol) in dichloromethane (250 mL) was treated with 1,1?-carbonyldiimidazole (63.0 g, 389 mmol) portion-wise-caution bubbling. After the addition was complete the mixture was stirred at room temperature for 2 h and then treated portion wise with N,O-dimethylhydroxylamine, HCl (37.9 g, 389 mmol) and then stirred overnight at room temperature. Washed with water and brine, dried over MgSO4, filtered, and concentrated to give N-methoxy-N-methyloxane-4-carboxamide (55.0 g, 302 mmol, 85%) as light amber oil. 1H NMR (400 MHz, CDCl3) delta 4.02 (ddd, J=11.4, 4.2, 2.1 Hz, 2H), 3.71 (s, 3H), 3.46 (td, J=11.8, 2.2 Hz, 2H), 3.19 (s, 3H), 1.93-1.80 (m, 2H), 1.69-1.62 (m, 2H).
87%		Tetrahydro-2H-pyran-4-carboxylic acid (13 g, 100 mmol) was dissolved in dichloromethane (200 mL), and cooled in an ice water bath. N,N-dimethyl formamide (0.1 mL) was added, and then oxalyl chloride (15.2 g, 120 mmol) was added dropwise slowly. After the dropwise addition was completed, the resulting mixture was stirred at 0C for additional 1h. The solvent was removed under vacuum to obtain an oily substance, which was dissolved in dichloromethane (100 mL). The resulting solution was added to a mixed solution of N,N-dimethylhydroxylamine hydrochloride (9.75 g, 100 mmol), diisopropyl ethylamine (39 g, 300 mmol) and dichloromethane (200 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. The solvent was removed under vacuum to obtain the product (15 g, 87%). 1H NMR (400 MHz, CDCl3): delta 4.00-4.05 (m, 2H), 3.72 (s, 3H), 3.44-3.50 (m, 2H), 3.20 (s, 3H), 2.89-2.95 (m, 1H), 1.82-1.92 (m, 2H), 1.64-1.68 (m, 2H).

81%	With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h;	[0239] To a solution of tetrahydro-2H-pyran-4-carboxylic acid 1 (4.0 g, 31 mmol) in DCM (65 mL) was added sequentiallyN,O-dimethylhydroxylamine hydrochloride (3.3 g, 34 mmol), 4-methylmorpholine (7.4 mL, 68 mmol), and N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (6.5 g, 34 mmol). The resulting mixture was stirred at RT for 18 h. Atthat time, the reaction was diluted with 1 N HCl and EtOAc and stirred vigorously until both phases cleared. The phases were separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed withbrine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2(4.3 g, 24.8 mmol, 81%). LCMS for 2 (conditions D): tR = 1.12 min, m/e = 174.3 (M+H, base).
73.3%	With 1,1'-carbonyldiimidazole; In dichloromethane; at 20℃; for 16h;	The racemate of the methyl ester of the title compound was prepared according the literature using the scheme described above (US 2016/0176864). [00237] Methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)- 5H-pyrido[3,2-b]indole-7-carboxylate (0.22 g, prepared according to literature and the synthetic route above) was separated by chiral HPLC to give (R)-methyl 3-(3,5- dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7- carboxylate (0.095 g) and (S)-methyl 3-(3,5-dimethylisoxazol-4-yl)-5-(phenyl(tetrahydro-2H- pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (0.090 g) as a yellow solid. H NMR (racemate) (400 MHz, CDC13) delta 0.98-1.02 (IH, m), 1.32-1.36 (2H, m), 1.95 (IH, s), 2.15 (3H, s), 2.31 (3H, s), 3.00-3.08 (IH, m), 3.24-3.31 (IH, m), 3.45-3.51 (IH, m), 3.76-3.80 (IH, m), 3.96 (3H, s), 4.00-4.01 (IH, m), 5.52 (IH, d, J = 10.8 Hz), 7.22-7.29 (3H, m), 7.38-7.40 (2H, m), 7.51 (IH, d, J = 1.6 Hz), 7.99 (IH, dd, / = 8.0, 1.2 Hz), 8.36 (IH, d, J = 8.0 Hz), 8.39 (2H, s); LC/MS 496.3 [M+H]+. [00238] The chiral material ester was hydrolyzed under basic condition (aq. NaOH in MeOH) to provide (R)-PTM-3-l-A and (S)-PTM-3-l-B.
		Add Iota, Gamma-carbonyldiimidazole (333.41 g, 1.2 eq) to a solution of tetrahydro-2H- pyran-4-carboxylic acid (223 g, 1.71 mol) in dichloromethane (2.23 L) portion wise over 15 minutes. Stir for two hours. Add Nu,Omicron-dimethylhydroxylamine hydrochloride (183.86 g, 1.1 eq) portionwise and stir for three hours. Wash the organics with saturated aqueous ammonium chloride, then with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give N-methoxy-N-methyl- tetrahydropyran-4-carboxamide (339 g, 1 14%) as crude material and use as such in next reaction. XH NMR (300 MHz, DMSO-d6) delta 4.02 (m, 2H), 3.71 (s, 3H), 3.46 (m, 2H), 3.19 (s, 3H), 2.91 (m, 1H), 1.86 (m, 2H), 1.65 (m, 2H).
831 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 10 - 35℃;	A) N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide To a solution of tetrahydro-2H-pyran-4-carboxylic acid (800 mg) in N,N-dimethylformamide (60.0 mL) were added 1-hydroxybenzotriazole monohydrate (1.17 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g), N,O-dimethylhydroxylamine hydrochloride (600 mg) and triethylamine (1.73 mL). The reaction mixture was stirred overnight at room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (831 mg). MS (API+): [M+H]+174.3.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	Triethylamine (10.6 mL, 76.4 mmol) was added slowly to a mixture of tetrahydro-2H-pyran-4-carboxylic acid (4.97 g, 38.2 mmol), N,O-dimethylhydroxylamine hydrochloride (4.18 g, 42.0 mmol), and EDCI (8.79 g, 45.8 mmol) in DCM (48 mL). The white suspension was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHCO3 and water and was stirred for 30 minutes. The phases were separated and the organic phase was washed with 1 N aqueous HCl followed by water. The organic phase was dried (Na2SO4), filtered, and concentrated to provide the title compound as a colorless oil.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	Intermediate 1: step a Procedure A Triethylamine (10.6 mL, 76,4 mmol) was added slowly to a mixture of tetrahydro-2H-pyran-4- carboxylic acid (4.97 g, 38.2 mmol), N,0-dim.ethy3.hydroxylamine hydrochloride (4.18 g, 42.0 mmol), and EDO (8,79 g, 45.8 mmol) in DCM (48 mL). The white suspension was stirred at room temperature overnight. The mixture was diluted with saturated aqueous NaHC03and water and was stirred for 30 minutes. The phases were separated and the organic phase was washed with 1 N aqueous HC1 followed by water. The organic phase was dried (Na2S04), filtered, and concentrated to provide the title compound as a colorless oil.
		To a solution of tetrahydro-2H-pyran-4-carboxylic acid (5.2 g, 39.9 mmol) in DCM (8.3 mL), CDI (7.12 g, 43.9 mmol) was added and the mixture was stirred for 45 minutes after which N,O-dimethylhydroxylamine hydrochloride (4.29 g, 43.9 mmol) was added and the mixture was stirred for 48 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgSO4) and concentrated. The crude product was used without any further purification.

References: [1]Patent: WO2016/73424,2016,A1 .Location in patent: Page/Page column 63.
[2]Patent: US2016/176864,2016,A1 .Location in patent: Paragraph 0491; 0492; 0775.
[3]Patent: EP3412669,2018,A1 .Location in patent: Paragraph 0372; 0373.
[4]Patent: EP2485920,2016,B1 .Location in patent: Paragraph 0238-0239.
[5]Patent: WO2017/30814,2017,A1 .Location in patent: Paragraph 00236-00237.
[6]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 100.
[7]Patent: EP2848618,2015,A1 .Location in patent: Paragraph 1039.
[8]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0183; 0184.
[9]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 58; 59.
[10]Patent: US2015/111870,2015,A1 .Location in patent: Paragraph 0533; 0534.

6
[ 156353-01-4 ]
[ 676-58-4 ]
[ 137052-08-5 ]

Yield	Reaction Conditions	Operation in experiment
		Add 2 M isopropylmagnesium chloride in tetrahydrofuran (520.22 mL, 3.0 eq) to a mixture of methyl tetrahydro-2H-pyran-4-carboxylate (46.30 mL, 346.81 mmol) and Nu,Omicron-dimethylhydroxylamine hydrochloride (52.44 g, 1.6 eq) in tetrahydrofuran (2.43 L) during 15 minutes at -20C under nitrogen. After 30 min, add saturated aqueous ammonium chloride (400 mL) to the reaction at -20C. Extract the aqueous solution with methyl tert-butyl ether (250 mL x 3). Wash the combined organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Add dichloromethane (500 mL), filter through Celite and concentrate in vacuo. Add tetrahydrofuran (700 mL), then add 3 M methyl magnesium chloride intetrahydrofuran (231.21 mL, 2.0 eq) dropwise over 15 minutes at 7C. After 40 minutes, add saturated aqueous ammonium chloride (250 mL) to the reaction. Extract the aqueous solution with methyl tert-butyl ether (250 mL x 2). Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 2: 1 hexanes: ethyl acetate to 1 : 1 hexanes: ethyl acetate, to give 1 -(tetrahydro-pyran-4-yl)- ethanone (33.18 g, 75%). 'H NMR (300 MHz, DMSO-d6) delta 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).

References: [1]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 99-100.

7
[ 156353-01-4 ]
[ 75-16-1 ]
[ 137052-08-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	In tetrahydrofuran; diethyl ether; at -60 - 0℃; for 6h;	[0240] A flask was charged with <strong>[156353-01-4]N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide</strong> 2 (11.7 g, 67.5 mmol) andTHF (350 mL). The resulting mixture was immersed in a cooling bath at -60C, and methylmagnesium bromide (3.0 Min ether, 33.8 mL, 101.4 mmol) was added via syringe over ? 8 min. The temperature of the bath was allowed to rise to0 C over 6h. At that time, the reaction was diluted with water and EtOAc and stirred vigorously for 10 min. The phaseswere separated, and the aqueous layer was extracted with EtOAc. The organic portions were combined, washed withbrine, dried over MgSO4, filtered, and concentrated. The crude residue was subjected to column chromatography (120g silica, 80 mL/min, 0% to 100% EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81%). 1HNMR (400 MHz, CDCl3) for 3: delta 3.95 (ddd, J = 11.6, 4.4, 2.8 Hz, 2 H), 3.38 (dt, Jd = 2.8 Hz, Jt = 11.6 Hz, 2 H), 2.50 (m,1 H), 2.12 (s, 3 H), 1.75 (m, 2 H), 1.65 (m, 2 H). LCMS for 3 (conditions D): tR = 0.83 min, m/e = 129.4 (M+H, base).
	In tetrahydrofuran; diethyl ether; at 0℃;	Add 3 M methyl magnesium bromide in diethyl ether (1.14 L, 2.0 eq) to a solution of <strong>[156353-01-4]N-methoxy-N-methyl-tetrahydropyran-4-carboxamide</strong> (296 g, 1.71 mol) intetrahydrofuran (2.96 L) over one hour at 0C. Stir for an additional two hours, then pour the contents into a mixture of ice/water. Extract with methyl tert-butyl ether. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 1-(tetrahydro-pyran-4-yl)-ethanone (105 g, 48%). ¾ NMR (300 MHz, DMSO-d6) delta 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).

References: [1]Patent: EP2485920,2016,B1 .Location in patent: Paragraph 0238; 0240.
[2]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 100.

8
[ 110238-91-0 ]
[ 156353-01-4 ]

References: [1]Patent: WO2011/50016,2011,A1 .

9
[ 156353-01-4 ]
[ 1295517-21-3 ]