[ CAS No. 137052-08-5 ] {[proInfo.proName]}

Name: 137052-08-5|1-(Tetrahydro-2H-pyran-4-yl)ethanone|97%
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Quality Control of [ 137052-08-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 137052-08-5 ]

SDS Specification

Alternatived Products of [ 137052-08-5 ]

Product Details of [ 137052-08-5 ]

CAS No. :	137052-08-5	MDL No. :	MFCD08704647
Formula :	C₇H₁₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VNMXIOWPBADSIC-UHFFFAOYSA-N
M.W :	128.17	Pubchem ID :	9877365
Synonyms :

Calculated chemistry of [ 137052-08-5 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.93
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.72
Log Po/w (XLOGP3) :	0.26
Log Po/w (WLOGP) :	1.0
Log Po/w (MLOGP) :	0.42
Log Po/w (SILICOS-IT) :	1.7
Consensus Log Po/w :	1.02

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.73
Solubility :	23.7 mg/ml ; 0.185 mol/l
Class :	Very soluble
Log S (Ali) :	-0.37
Solubility :	54.3 mg/ml ; 0.423 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.07
Solubility :	10.8 mg/ml ; 0.0843 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.69

Safety of [ 137052-08-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 137052-08-5 ]

* 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.

Upstream synthesis route of [ 137052-08-5 ]
Downstream synthetic route of [ 137052-08-5 ]

[ 137052-08-5 ] Synthesis Path-Upstream 1~9

1
[ 345216-96-8 ]
[ 137052-08-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 120℃; for 1.5 h;	Example 1 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99percent and synthesised in the same manner as in Reference example 1 and 1.08 ml (10 mmol) of 9 mol/l sulfuric acid, and the mixture was reacted at 120°C for 1.5 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.25 g (Reaction yield: 96percent) of 4-acetyltetrahydropyran was found to be formed.
90%	at 120℃; for 4 h;	Example 2 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99percent and synthesised in the same manner as in Reference example 1 and 2.52 ml (10 mmol) of 4 mol/l hydrochloric acid, and the mixture was reacted at 120°C for 4 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.23 g (Reaction yield: 90percent) of 4-acetyltetrahydropyran was found to be formed.
85%	With sodium hydroxide; water; dihydrogen peroxide In methanol at 40℃; for 5 h;	In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 202 g (1.0 mol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 95percent and synthesized in the same manner as in Reference example 1 and 720 ml of methanol, and the temperature of the mixture was raised to 35°C with stirring. Then, to the mixture was gently added dropwise a mixed solution comprising 201 g (2.0 mol) of 35percent by weight aqueous hydrogen peroxide solution and 91 ml (0.73 mol) of 8 mol/l aqueous sodium hydroxide solution, and the mixture was reacted at 40°C for 5 hours with stirring. After completion of the reaction, to the resulting reaction mixture was added a saturated aqueous sodium sulfate solution to decompose the remaining hydrogen peroxide, then, the mixture was concentrated under reduced pressure, and the concentrate was extracted three times with 500 ml of ethyl acetate. The organic layer was distilled under reduced pressure (90 to 92°C, 2.0 kPa) to give 113 g (Isolation yield: 85percent) of 4-acetyltetrahydropyran with a purity of 99percent (areal percentage by gas chromatography) as a colorless liquid. Physical properties of the 4-acetyltetrahydropyran are as follows. CI-MS (m/e); 129 (M+1) ¹H-NMR (CDCl₃, δ (ppm)); 1.60 to 1.82 (4H, m), 2.16 (3H, s), 2.50 to 2.61 (1H, m), 3.39 to 3.47 (2H, m), 3.96 to 4.02 (2H, m)

65%	at 120℃; for 1 h;	Example 3 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99percent and synthesised in the same manner as in Reference example 1 and 1.70 g (10 mmol) of 47percent hydrobromic acid, and the mixture was reacted at 120°C for 1 hour with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.17 g (Reaction yield: 65percent) of 4-acetyltetrahydropyran was found to be formed.
10.874 g	With sulfuric acid In water; isopropyl alcohol for 48 h; Reflux	The mixture of methyl acetylacetate (24.770 g, 211.18 mmol), bis(2-chloroethyl) ether (30.506 g, 211.18 mmol), potassium carbonate (64.861 g, 464.59 mmol) and sodium iodide (31.974 g, 211.18 mmol) in N,N-dimethylformamide (1065 ml) was heated at 80°C for 18 hours. The mixture was cooled to room temperature, further portions of potassium carbonate (29.430 g, 210.80 mmol) and sodium iodide (31.974 g, 211.18 mmol) were added and the whole was heated at 80°C for further 2 hours. The reaction mixture was filtered over celite, washed with ethyl acetate (500 ml), then organic layer was washed with water (300 ml), brine (150 ml) and dried over sodium sulphate. Drying agent and solvent were removed to obtain 26.600 g of the intermediate compound methyl 4-acetyl- tetrahydro-2H-pyran-4-carboxylate. To the obtained compound (26.600 g, 112.47 mmol) isopropanol (125 ml), water (125 ml) and concentrated sulphuric acid (55.151 g, 562.37 mmol) were added and the whole was heated at reflux for 48 hours. The mixture was alkalized with sodium hydroxide solution (45.5 g NaOH in 500 ml of water). Aqueous layer was extracted with chloroform (3 x 100 ml). Extracts were dried over sodium sulphate. Crude product obtained after removing drying agent and solvent in the form of a brown liquid was distilled under reduced pressure using Vigreux column and collecting fraction boiling at 75-83°C/20 mm Hg. 10.874 g of the title product were obtained (yield 36.4percent) in the form of a colorless liquid.¹H NMR (300 MHz, CDCl₃): δ 4.03-3.97 (m, 2H), 3.47-3.38 (m, 2H), 2.54 (m, 1 H), 2.16 (s, 3H), 1.78-1.69 (m, 4H). ¹³C NMR (75 MHz, CDCl₃): δ 209.86, 67.13, 48.03, 28.00, 27.48.

Reference： [1] Patent: EP1700852, 2006, A1, . Location in patent: Page/Page column 7-8
[2] Patent: EP1700852, 2006, A1, . Location in patent: Page/Page column 8
[3] Patent: EP1700852, 2006, A1, . Location in patent: Page/Page column 8
[4] Patent: EP1700852, 2006, A1, . Location in patent: Page/Page column 8
[5] Patent: WO2011/50016, 2011, A1, . Location in patent: Page/Page column 35-36
[6] Patent: WO2014/24125, 2014, A1, . Location in patent: Page/Page column 26

2
[ 156353-01-4 ]
[ 75-16-1 ]
[ 137052-08-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	at -60 - 0℃; for 6 h;	[0240] A flask was charged with N-methoxy-N-methyltetrahydro-2H-pyran-4-carboxamide 2 (11.7 g, 67.5 mmol) andTHF (350 mL). The resulting mixture was immersed in a cooling bath at -60°C, 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, 0percent to 100percent EtOAc/hexanes) to give 4-acetyltetrahydro-4H-pyran 3 (7.05 g, 55.0 mmol, 81percent). 1HNMR (400 MHz, CDCl3) for 3: δ 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).

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

3
[ 156353-01-4 ]
[ 676-58-4 ]
[ 137052-08-5 ]

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

4
[ 156353-01-4 ]
[ 137052-08-5 ]

Reference： [1] Patent: US2012/195881, 2012, A1,

5
[ 110238-91-0 ]
[ 917-54-4 ]
[ 137052-08-5 ]

Reference： [1] ChemMedChem, 2010, vol. 5, # 1, p. 65 - 78

6
[ 110238-91-0 ]
[ 137052-08-5 ]

Reference： [1] Patent: WO2011/50016, 2011, A1,
[2] Patent: WO2011/50016, 2011, A1,
[3] Patent: WO2011/50016, 2011, A1,
[4] Patent: WO2011/50016, 2011, A1,

7
[ 5337-03-1 ]
[ 137052-08-5 ]

Reference： [1] Patent: WO2011/50016, 2011, A1,
[2] Patent: WO2011/50016, 2011, A1,
[3] Patent: EP2485920, 2016, B1,

8
[ 110238-91-0 ]
[ 75-16-1 ]
[ 137052-08-5 ]

Reference： [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 23, p. 6646 - 6650[2] Angew. Chem., 2017, vol. 56, # 23, p. 6646 - 6650,5

9
[ 40191-32-0 ]
[ 18815-73-1 ]
[ 137052-08-5 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1938, vol. 10, p. 399,409[2] Justus Liebigs Annalen der Chemie, 1940, vol. 545, p. 229,236

[ 137052-08-5 ] Synthesis Path-Downstream 1~88

1
[ 137052-08-5 ]
6-benzoyl-1'-methyl-3,5-diphenyldispiro[cyclohexa-2,4-diene-1,2'-indoline-3',4"-tetrahydropyrane] [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2002,vol. 39,p. 255 - 262

2
[ 137052-08-5 ]
[ 705289-63-0 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1938,vol. 10,p. 399,409
Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,236

3
[ 137052-08-5 ]
1-(tetrahydro-2H-pyran-4-yl)ethanamine [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

4
[ 137052-08-5 ]
3-tetrahydropyran-4-yl-butyric acid ethyl ester [ No CAS ]

Reference： [1]Justus Liebigs Annalen der Chemie,1940,vol. 545,p. 229,244

5
[ 137052-08-5 ]
[ 616-38-6 ]
3-oxo-3-(tetrahydropyran-4-yl)propionic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydride; In 1,4-dioxane; mineral oil; for 3h;Reflux;	NaH (60% dispersion in mineral oil) (0.340 g; 8.5 mmol) was added to a solution of dimethyl carbonate (0.83 mL; 9.85 mmol) in 1,4-dioxane (4.00 mL) (1847) The mixture was heated at 90 C and l-(tetrahydro-2H-pyran-4-yl) ethanone (0.5 g; 3.90 mmol) in 1,4-dioxane (1.00 mL) was added to the suspension. The reaction mixture was stirred at reflux for 3 hours. Water was added and few drops of an aqueous solution of 3N HC1. (1848) The mixture was extracted twice with ethylic ether. The organic layer was decanted and the solvent was evaporated until dryness to give 0.65 g of intermediate 754 (89%).
76%		In a flask made of glass having an inner volume of 500 ml and equipped with a stirring device, a thermometer, a dropping funnel and a distillation device were charged 35.0 g (273 mmol) of <strong>[137052-08-5]4-acetyltetrahydropyran</strong> synthesized in the same manner as in Example 4, 280.0 g (3.1 mol) of dimethyl carbonate and 16.3 g (302 mmol) of sodium methoxide, and the mixture was reacted at 80 to 85C for 2 hours with distilling by-producing methanol off. After completion of the reaction, the reaction mixture was cooled to 5 to 10C, and to the reaction mixture were added 175 ml of toluene, 55 ml (330 mmol) of 6 mol/l hydrochloric acid and 35 ml of water in this order. After the organic layer was separated, the aqueous layer was extracted twice with 70 ml of toluene. The organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=1/1 (volume ratio)) to give 40.9 g (Isolation yield: 76%) of methyl 3-(4-tetrahydropyranyl)-3-oxopro-panoate with a purity of 93.9% (analytical value by differential diffractometry) as a colorless liquid. Methyl 3-(4-tetrahydropyranyl)-3-oxopropanoate is a novel compound shown by the following physical properties. CI-MS (m/e); 187 (M+1) 1H-NMR (CDCl3, delta (ppm)); 1.68 to 1.82 (4H, m), 2.66 to 2.72 (1H, m), 3.38 to 3.47 (2H, m), 3.51 (2H, s), 3.75 (3H, s), 3.97 to 4.04 (2H, m)

Reference： [1]Patent: WO2018/2217,2018,A1 .Location in patent: Page/Page column 345
[2]Patent: WO2006/13920,2006,A1 .Location in patent: Page/Page column 11
[3]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 8

6
[ 137052-08-5 ]
[ 105-58-8 ]
3-oxo-3-(tetrahydropyran-4-yl)propionic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%		Example 8 (Synthesis of ethyl 3-(4-tetrahydropyranyl)-3-oxopropanoate) In an apparatus made of glass having an inner volume of 100 ml and equipped with a stirring device, a thermometer, a reflux condenser and a dropping funnel were charged 4.56 g (31 mmol) of diethyl carbonate and 3.98 g (58 mmol) of sodium ethoxide, and the temperature of the liquid was raised to 85C. Then, 5.0 g (39 mmol) of <strong>[137052-08-5]4-acetyltetrahydropyran</strong> was gently added dropwise to the mixture. Further, 4.56 g (31 mmol) of diethyl carbonate was added to the mixture, and the mixture was reacted at 80 to 90C for 1 hour. After completion of the reaction, 5 ml of 2-butanol was added to the mixture at the same temperature, and after cooling to room temperature, 5 ml of ethanol was added to the mixture (this is called to as the reaction mixture A). In an apparatus made of glass having an inner volume of 100 ml and equipped with a stirring device, a thermometer, a reflux condenser and a dropping funnel were charged 4.22 g (70 mmol) of acetic acid and 10 ml of saturated brine and to the mixed solution was gently added dropwise the reaction mixture A with maintaining the liquid temperature to 0 to 10C. Then, after the temperature was raised to room temperature, 10 ml of ethyl acetate and 10 ml of water were added and the liquids were separated. The resulting organic layer was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane: ethyl acetate=10: 1?10: 2) to give 1.0 g (Isolation yield: 13%) of ethyl 3-(4-tetrahydropyranyl)-3-oxopropanoate as a colorless liquid. Ethyl 3-(4-tetrahydropyranyl)-3-oxopropanoate is a novel compound shown by the following physical properties. CI-MS (m/e); 201 (M+1) 1H-NMR (CDCl3, delta (ppm)); 1.28 (3H, t, J=7.1Hz), 1.68 to 1.83 (4H, m), 2.66 to 2.77 (1H, m), 3.39 to 3.47 (2H, m), 3.50 (2H, s), 3.97 to 4.04 (2H, m), 4.20 (2H, q, J=7.1Hz)

Reference： [1]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 9-10

7
[ 345216-96-8 ]
[ 137052-08-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sulfuric acid; water; at 120℃; for 1.5h;Product distribution / selectivity;	Example 1 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesised in the same manner as in Reference example 1 and 1.08 ml (10 mmol) of 9 mol/l sulfuric acid, and the mixture was reacted at 120C for 1.5 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.25 g (Reaction yield: 96%) of 4-acetyltetrahydropyran was found to be formed.
90%	With hydrogenchloride; water; at 120℃; for 4h;Product distribution / selectivity;	Example 2 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesised in the same manner as in Reference example 1 and 2.52 ml (10 mmol) of 4 mol/l hydrochloric acid, and the mixture was reacted at 120C for 4 hours with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.23 g (Reaction yield: 90%) of 4-acetyltetrahydropyran was found to be formed.
85%	With sodium hydroxide; water; dihydrogen peroxide; In methanol; at 40℃; for 5h;Product distribution / selectivity;	In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 202 g (1.0 mol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 95% and synthesized in the same manner as in Reference example 1 and 720 ml of methanol, and the temperature of the mixture was raised to 35C with stirring. Then, to the mixture was gently added dropwise a mixed solution comprising 201 g (2.0 mol) of 35% by weight aqueous hydrogen peroxide solution and 91 ml (0.73 mol) of 8 mol/l aqueous sodium hydroxide solution, and the mixture was reacted at 40C for 5 hours with stirring. After completion of the reaction, to the resulting reaction mixture was added a saturated aqueous sodium sulfate solution to decompose the remaining hydrogen peroxide, then, the mixture was concentrated under reduced pressure, and the concentrate was extracted three times with 500 ml of ethyl acetate. The organic layer was distilled under reduced pressure (90 to 92C, 2.0 kPa) to give 113 g (Isolation yield: 85%) of 4-acetyltetrahydropyran with a purity of 99% (areal percentage by gas chromatography) as a colorless liquid. Physical properties of the 4-acetyltetrahydropyran are as follows. CI-MS (m/e); 129 (M+1) 1H-NMR (CDCl3, delta (ppm)); 1.60 to 1.82 (4H, m), 2.16 (3H, s), 2.50 to 2.61 (1H, m), 3.39 to 3.47 (2H, m), 3.96 to 4.02 (2H, m)

65%	With water; hydrogen bromide; at 120℃; for 1h;Product distribution / selectivity;	Example 3 (Synthesis of 4-acetyltetrahydropyran) In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 0.38 g (2.0 mmol) of 4-acetyl-4-methoxycarbonyltetrahydropyran with a purity of 99% and synthesised in the same manner as in Reference example 1 and 1.70 g (10 mmol) of 47% hydrobromic acid, and the mixture was reacted at 120C for 1 hour with stirring. After completion of the reaction, when the reaction mixture was analyzed by gas chromatography (Internal standard method), 0.17 g (Reaction yield: 65%) of 4-acetyltetrahydropyran was found to be formed.
		Add butanoic acid, 3-oxo-, methyl ester (18.60 mL, 172.20 mmol), bis(2- chloroethyl)ether (20.20 mL, 1.0 eq), potassium carbonate (52.42 g, 2.2 eq), and sodium iodide (25.88 g, 1.0 eq) in dimethylformamide (861 mL). Heat the reaction mixture at 80C overnight. Cool to room temperature. Add additional potassium carbonate (23.78 g) and sodium iodide (25.88 g). Heat the reaction mixture at 80C for two hours, then allow the mixture to cool to room temperature. Filter through Celite and wash with ethyl acetate. Wash the filtrate with water and brine. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give methyl 4-acetyltetrahydro-2H- pyran-4-carboxylate (23.06 g).Combine methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (23.06 g, 123.84 mmol) with isopropyl alcohol (124 mL) and water (124 mL). Add sulfuric acid (33.00 mL, 5.0 eq). Heat the reaction mixture to 100C over two nights. Cool and add the reaction mixture slowly to a mixture of sodium bicarbonate (136 g) in water (1 L).Extract with dichloromethane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 25% ethyl acetate in hexanes to 50% ethyl acetate in hexanes, to give the title compound (7.39 g, 34%). ¾ NMR (400 MHz, DMSO-d6) delta 3.79 (m, 2H), 3.27 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.66 (m, 2H), 1.38 (m, 2H).
10.874 g	With sulfuric acid; In water; isopropyl alcohol; for 48h;Reflux;	The mixture of methyl acetylacetate (24.770 g, 211.18 mmol), bis(2-chloroethyl) ether (30.506 g, 211.18 mmol), potassium carbonate (64.861 g, 464.59 mmol) and sodium iodide (31.974 g, 211.18 mmol) in N,N-dimethylformamide (1065 ml) was heated at 80C for 18 hours. The mixture was cooled to room temperature, further portions of potassium carbonate (29.430 g, 210.80 mmol) and sodium iodide (31.974 g, 211.18 mmol) were added and the whole was heated at 80C for further 2 hours. The reaction mixture was filtered over celite, washed with ethyl acetate (500 ml), then organic layer was washed with water (300 ml), brine (150 ml) and dried over sodium sulphate. Drying agent and solvent were removed to obtain 26.600 g of the intermediate compound methyl 4-acetyl- tetrahydro-2H-pyran-4-carboxylate. To the obtained compound (26.600 g, 112.47 mmol) isopropanol (125 ml), water (125 ml) and concentrated sulphuric acid (55.151 g, 562.37 mmol) were added and the whole was heated at reflux for 48 hours. The mixture was alkalized with sodium hydroxide solution (45.5 g NaOH in 500 ml of water). Aqueous layer was extracted with chloroform (3 x 100 ml). Extracts were dried over sodium sulphate. Crude product obtained after removing drying agent and solvent in the form of a brown liquid was distilled under reduced pressure using Vigreux column and collecting fraction boiling at 75-83C/20 mm Hg. 10.874 g of the title product were obtained (yield 36.4%) in the form of a colorless liquid.1H NMR (300 MHz, CDCl3): delta 4.03-3.97 (m, 2H), 3.47-3.38 (m, 2H), 2.54 (m, 1 H), 2.16 (s, 3H), 1.78-1.69 (m, 4H). 13C NMR (75 MHz, CDCl3): delta 209.86, 67.13, 48.03, 28.00, 27.48.

Reference： [1]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 7-8
[2]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 8
[3]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 8
[4]Patent: EP1700852,2006,A1 .Location in patent: Page/Page column 8
[5]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 35-36
[6]Patent: WO2014/24125,2014,A1 .Location in patent: Page/Page column 26

8
[ 110238-91-0 ]
[ 917-54-4 ]
[ 137052-08-5 ]

Reference： [1]ChemMedChem,2010,vol. 5,p. 65 - 78

9
[ 137052-08-5 ]
[ 38875-53-5 ]
[ 1207623-91-3 ]

Yield	Reaction Conditions	Operation in experiment
		2,3-Diamino-5-bromopyridine (1.07 g) and <strong>[137052-08-5]1-(tetrahydro-2H-pyran-4-yl)ethanone</strong> (0.80 g) were dissolved in methanol (20 ml), and acetic acid (0.98 ml) was added. After stirring at room temperature for a while, sodium cyanoborohydride (1.08 g) was added and the mixture was stirred at room temperature for 20 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (developed with ethyl acetate-hexane) to give the title compound (334 mg).MS (ESI) m/z: 300 (M+H)+.

Reference： [1]Patent: US2011/82138,2011,A1 .Location in patent: Page/Page column 26

10
[ 110238-91-0 ]
[ 137052-08-5 ]

Reference： [1]Patent: WO2011/50016,2011,A1
[2]Patent: WO2011/50016,2011,A1
[3]Patent: WO2011/50016,2011,A1
[4]Patent: WO2011/50016,2011,A1

11
[ 5337-03-1 ]
[ 137052-08-5 ]

Reference： [1]Patent: WO2011/50016,2011,A1
[2]Patent: WO2011/50016,2011,A1
[3]Patent: EP2485920,2016,B1

12
[ 137052-08-5 ]
[ 1295517-21-3 ]

Reference： [1]Patent: WO2011/50016,2011,A1

13
[ 137052-08-5 ]
C₇H₁₀O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With selenium(IV) oxide; acetic acid; In 1,4-dioxane; water; at 90℃;	Combine selenium dioxide (181.80 g, 1.64 mol), 1,4-dioxane (630 mL), acetic acid (31.5 mL, 0.67 eq), and water (31.5 mL). Heat to 90C and add l-(tetrahydro-pyran- 4-yl)-ethanone (105.0 g, 1.0 eq) dropwise. Stir at 90C overnight. After cooling, filter through a plug of silica/Celite and wash with tetrahydrofuran (2.5 L). Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Dissolve the crude material in methanol (500 mL) and add to a solution of tert-butyl 4-formylpiperidine- 1 - carboxylate (174.72 g, 1.0 eq) and ammonium acetate (315.74 g, 5.0 eq) in methanol(1.45 L) at 0C. Stir overnight. Filter through silica/Celite and wash with ethyl acetate and methanol. Concentrate the filtrate in vacuo. Dilute with methyl tert-butyl ether (400 mL) and water (400 mL), then adjust the pH to 2 by addition of aqueous 85% phosphoric acid. Separate the layers and wash the aqueous phase with methyl tert-butyl ether (200 mL). Basify the resulting aqueous phase with solid sodium carbonate to pH 10 and extract with ethyl acetate (3 x 200 mL). Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to afford tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2- yl)piperidine- 1-carboxylate (105.1 g, 38%). MS (ES) m/z = 336 [M]+.
	With selenium(IV) oxide; acetic acid; In 1,4-dioxane; water; at 90℃;	Combine selenium dioxide (181.80 g, 1.64 mol), 1,4-dioxane (630 mL), acetic acid (31.5 mL, 0.67 eq), and water (31.5 mL). Heat to 90 C and add 1-(tetrahydro-pyran-4-yl)-ethanone (105.0 g, 1.0 eq) dropwise. Stir at 90 C overnight. After cooling, filter through a plug of silica/Celite and wash with tetrahydrofuran (2.5 L). Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Dissolve the crude material in methanol (500 mL) and add to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (174.72 g, 1.0 eq) and ammonium acetate (315.74 g, 5.0 eq) in methanol (1.45 L) at 0 C. Stir overnight. Filter through silica/Celite and wash with ethyl acetate and methanol. Concentrate the filtrate in vacuo. Dilute with methyl tert-butyl ether (400 mL) and water (400 mL), then adjust the pH to 2 by addition of aqueous 85% phosphoric acid. Separate the layers and wash the aqueous phase with methyl tert-butyl ether (200 mL). Basify the resulting aqueous phase with solid sodium carbonate to pH 10 and extract with ethyl acetate (3 x 200 mL). Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to afford title compound 19c, tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (105.1 g, 38%). MS (ES) m/z = 336 [M]+, 1H NMR (300.16 MHz, CDCl3): 6.63 (s, 1H), 4.26-4.11 (m, 2H), 4.07-4.00 (m, 2H), 3.51 (td, J=11.7, 1.8 Hz, 2H), 2.95-2.73 (m, 2H), 2.05-1.87 (m, 3H), 1.79-1.61 (m, 3H), 1.61-1.51 (m, 4H), 1.46 (s, 9H).

Reference： [1]Patent: WO2011/50016,2011,A1 .Location in patent: Page/Page column 101
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1887 - 1891

14
[ 137052-08-5 ]
[ 1295521-50-4 ]

Reference： [1]Patent: WO2011/50016,2011,A1

15
[ 137052-08-5 ]
[ 1295515-82-0 ]

Reference： [1]Patent: WO2011/50016,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1887 - 1891

16
[ 137052-08-5 ]
[ 1295520-35-2 ]

Reference： [1]Patent: WO2011/50016,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1887 - 1891

17
[ 137052-08-5 ]
4-(1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/50016,2011,A1
[2]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1887 - 1891

18
[ 137052-08-5 ]
(R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	titanium(IV) tetraethanolate; In tetrahydrofuran; water; ethyl acetate;	Step 3 A 200 mL sealed tube was charged with <strong>[137052-08-5]4-acetyltetrahydro-4H-pyran</strong> 3 (7.0 g, 55 mmol), THF (100 mL), and a solution of titanium(IV) ethoxide (28.6 mL, 136 mmol) in THF (30 mL). The resulting mixture was degassed by evacuation and back-fill with N2 (3), sealed, and immersed in a 85 C. oil bath. After 30 h, the reaction was poured into an erlenmeyer containing 300 mL of water, and the mixture was further diluted with EtOAc (200 mL) and stirred vigorously for 15 minutes. The mixture was then filtered through paper with copious EtOAc washes. The phases of the filtrate were separated and the aqueous portion was extracted 2 with EtOAc. The organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. This crude sample was subjected to column chromatography (ISCO, 330 g silica, 100 mL/min, 0% to 100% EtOAc/hexanes) to give (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethylidene)propane-2-sulfinamide 4 (9.2 g, 73%). LCMS (conditions D): tR=1.85 min, m/e=232.2 (M+H, base).

Reference： [1]Patent: US2012/195881,2012,A1

19
[ 137052-08-5 ]
[ 1232035-08-3 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9089 - 9106,18

20
[ 137052-08-5 ]
[ 1232038-73-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9089 - 9106,18

21
[ 137052-08-5 ]
[ 1560898-04-5 ]

Reference： [1]Patent: WO2014/24125,2014,A1

22
[ 137052-08-5 ]
[ 1560898-08-9 ]

Reference： [1]Patent: WO2014/24125,2014,A1

23
[ 137052-08-5 ]
[ 1560898-09-0 ]

Reference： [1]Patent: WO2014/24125,2014,A1

24
[ 137052-08-5 ]
[ 1560898-10-3 ]

Reference： [1]Patent: WO2014/24125,2014,A1

25
[ 137052-08-5 ]
5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one [ No CAS ]

Reference： [1]Patent: WO2014/24125,2014,A1

26
[ 137052-08-5 ]
(-)-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one [ No CAS ]
(-)-5-[(3,4-trans)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one [ No CAS ]

Reference： [1]Patent: WO2014/24125,2014,A1

27
[ 137052-08-5 ]
[ 95-92-1 ]
[ 1560898-02-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In ethanol; at 0 - 20℃; for 3h;	General procedure: To the mixture of sodium ethanolate (21% solution in ethanol, 9.898 ml, 26.52 mmol) in ethanol (20 ml) at 0C 1 -(tetrahydro-2H-pyran-4-yl)ethanone (Intermediate P20, 2.000 g, 15.60 mmol) and diethyl oxalate (3.916 g, 26.52 mmol) were added consecutively. The whole was stirred for 1 hours at 0C, then for 2 hours at room temperature. The mixture was added with 30 ml of water and acidified with 6M hydrochloric acid to pH = 3. Aqueous layer was extracted with ethyl acetate ( 3 x 50 ml). Organic layer was dried over sodium sulphate. Solvent and drying agent were removed to obtain 5.056 g of the title product, which was used without purification for further reactions. MS-ESI (m/z) calculated for CnHi604Na [M+Na]+: 251.09, determined 251.1

Reference： [1]Patent: WO2014/24125,2014,A1 .Location in patent: Page/Page column 27

28
[ 137052-08-5 ]
[ 4637-24-5 ]
(E)-3-(dimethylamino)-1-(tetrahydro-2H-pyran-4-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 100℃;Sealed tube;	Compound 294.1. (E)-3-(Dimethylamino)-l-(tetrahydro-2H-pyran-4-yl)prop-2- en-l-one. To a sealed tube were added l-(tetrahydro-2H-pyran-4-yl)ethanone (3.00 g, 23.4 mmol) and DMF-DMA (6.2 mL, 46.8 mmol). The reaction mixture was heated at 100 C overnight. The resulting mixture was concentrated under reduced pressure to afford 4.00 g (crude) of the title compound as light yellow oil.

Reference： [1]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 328

29
[ 137052-08-5 ]
3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2015/95767,2015,A1
[2]Patent: WO2017/40757,2017,A1

30
[ 137052-08-5 ]
4-chloro-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2015/95767,2015,A1

31
[ 137052-08-5 ]
4-chloro-5-iodo-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: WO2015/95767,2015,A1

32
[ 137052-08-5 ]
2-{4-[(4-[1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl]oxy}pyridin-2-yl)amino]pyridin-2-yl}propan-2-ol methanesulfonate [ No CAS ]