[ CAS No. 61675-94-3 ] {[proInfo.proName]}

Name: 61675-94-3|Ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)acetate|95%
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Quality Control of [ 61675-94-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 61675-94-3 ]

Product Details of [ 61675-94-3 ]

CAS No. :	61675-94-3	MDL No. :	MFCD00128492
Formula :	C₉H₁₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GZVWKAGBBACFPD-UHFFFAOYSA-N
M.W :	188.22	Pubchem ID :	10899396
Synonyms :

Calculated chemistry of [ 61675-94-3 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.89
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	46.72
TPSA :	44.76 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) :	-6.57 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.48
Log Po/w (XLOGP3) :	1.23
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	0.56
Log Po/w (SILICOS-IT) :	1.43
Consensus Log Po/w :	1.36

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.45
Solubility :	6.65 mg/ml ; 0.0353 mol/l
Class :	Very soluble
Log S (Ali) :	-1.77
Solubility :	3.21 mg/ml ; 0.0171 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.41
Solubility :	7.39 mg/ml ; 0.0393 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.21

Safety of [ 61675-94-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 61675-94-3 ]

* 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 [ 61675-94-3 ]
Downstream synthetic route of [ 61675-94-3 ]

[ 61675-94-3 ] Synthesis Path-Upstream 1~2

1
[ 110-87-2 ]
[ 623-50-7 ]
[ 61675-94-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With toluene-4-sulfonic acid In toluene at 25℃; for 1 h;	To a solution of ethyl glycolate (10 g, 0.0961 mol) in toluene (100 mL) was added 3,4- dihydro-2H-pyran ( 8 g, 0.096 1 mol) followed by catalytic amount of pTSA (30 mg) and stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was washed with water and brine solution. The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to get 18 g (99 percent) ethyl 2-((tetrahydro-2H-pyran-2- yl)oxy)acetate, 2, as colorless liquid
94.7%	at 20℃; Industrial scale	Example 1.2Ethyl(tetrahydropyran-2-yloxy)-acetate (B) 100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20° C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20° C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25percent). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.Yield: 188.4 kg (94.7percent of theory)
91.5%	at 20℃;	To a stirred solution of ethyl glycolate (35.3 g, 0.339 mol) containing a few crystals of p-toluene sulfonic acid, 3,4-dihydropyran (30.0 g, 0.357 mol) was added dropwise (15 g over one hour followed by 15 g over 30 min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (80 mL) and washed with a NaHCO3 solution (from 30 mL sat. NaHCO3 and 10 mL water). The organic layer was separated and dried (Na2504) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4 g (91.5percent) of 28 as a clear liquid. 1H NMR (CDCl3, 400 MHz)δ: 1.29 (t, 3H, J=7.1 Hz, CH3), 1.53-1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, 1H, 6-THP-CH2), 3.83-3.89 (m, 1H, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J=7.1 Hz, CH2Me), 4.75 (m, 1H, THP-CH). 13C NMR (CDCl3, 100 MHz) δ: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.

91.5%	at 20℃;	(1) Preparation of tetrahydropyran-2-yloxy-acetic acid ethyl ester (Formula 28, Scheme 4)[0378] To a stirred solution of ethyl glycolate (35.3g, 0.339mol) containing a few crystals of />toluene sulfonic acid, 3,4-dihydropyran (30.Og, 0.357mol) was added1 1 <n="113"/>dropwise (15g over one hour followed by 15g over 30min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (8OmL) and washed with a NaHCO₃ solution (from 3OmL sat. NaHCO₃ and 1OmL water). The organic layer was separated and dried (Na₂SO₄) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4g (91.5percent) of 28 as a clear liquid. ¹H NMR (CDCL₃, 400MHz)δ: 1.29 (t, 3H, J = 7.1 Hz, CH₃), 1.53 -1.95 (m, 6H, 3,4,5-THP-CH₂'s), 3.50-3.55 (m, IH, 6-THP-CH₂), 3.83 - 3.89 (m, IH, 6-THP-CH₂), 4.19 (s, 2H, OCH₂CO₂R), 4.20 (t, 2H, J = 7.1 Hz, CH₂Me), 4.75 (m, IH, THP-CH). ¹³C NMR (CDCl₃, 100MHz) δ: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
81%	With pyridinium p-toluenesulfonate In dichloromethane	Step 1) ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH₂Cl₂ was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL*2), the combined organic phases were dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81percent). ¹H NMR (400 MHz, CDCl₃): δ 1.22-1.38 (m, 4H), 1.55-1.63 (m, 3H), 1.69-1.88 (m, 3H), 3.50-3.53 (m, 1H), 3.82-3.88 (m, 1H), 4.18-4.23 (m, 4H), 4.73-4.74 (t, J=4 Hz, 1H).
81%	With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4 h;	To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH₂Cl₂ was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mLx2), the combined organic phases were dried over Na₂SO₄ and concentrated in vacuo. The residure was purified by a silica gel column chromatography (PE: EtOAc =20:1) to give colorless oil (3.01 g, 81 percent). ¹H NMR (400MHz, CDCl₃): δ 1.22 - 1.38 (m, 4H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, 1H), 3.82 - 3.88 (m, 1H), 4.18 - 4.23 (m, 4H), 4.73 - 4.74 (t, J=4Hz, 1H).
81%	With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 4 h; Inert atmosphere	To a mixture of ethyl 2 -hydroxy acetate (2 g, 20 mmol, TCI) and 3,4- dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL Of CH₂Cl₂ was added PPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was then washed with brine, and the organic layer was separated and the combined organic phases were dried over Na₂SO₄, concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) petroleum ether / EtOAc) to give the desired compound as colorless oil (3.01 g, 81 percent ).¹H NMR (400MHz, CDCl₃): δ 1.25 - 1.32 (m, 3H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, IH), 3.82 - 3.88 (m, IH), 4.18 - 4.23 (m, 4H), 4.73 (t, J=3.2Hz, IH).
58%	With toluene-4-sulfonic acid In toluene at 20℃;	Step 1 Preparation of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate A mixture of 3,4-dihydro-2H-pyran (20.4 g, 242.3 mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol) and TsOH (0.794 g, 4.6 mmol) in toluene (150 mL) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2percent EtOAc in petroleum ether) to afford ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58percent) as a colorless oil.

Reference： [1] Patent: WO2017/83431, 2017, A2, . Location in patent: Paragraph 00216; 00217
[2] Patent: US2011/87021, 2011, A1, . Location in patent: Page/Page column 11
[3] Patent: US2005/8570, 2005, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2007/121453, 2007, A2, . Location in patent: Page/Page column 111; 112
[5] Patent: US2010/239576, 2010, A1,
[6] Patent: EP2408300, 2016, B1, . Location in patent: Paragraph 0343
[7] Patent: WO2010/45095, 2010, A1, . Location in patent: Page/Page column 76
[8] Patent: US2016/168090, 2016, A1, . Location in patent: Paragraph 0348-0349
[9] Journal of the Chemical Society, 1956, p. 2124,2126
[10] Journal of the Chemical Society, 1956, p. 4665
[11] Patent: WO2008/128961, 2008, A1, . Location in patent: Page/Page column 107

2
[ 142-68-7 ]
[ 623-50-7 ]
[ 61675-94-3 ]

Yield	Reaction Conditions	Operation in experiment
32 g	at 20℃;	EXAMPLE 1422-((l-(2-(3-Fluoro-6-methoxy-l,5-naphthyridin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-6H-pyrimido[5,4-b][l,4]oxazin-7(8H)-oneStep 1Ethyl 2-(Tetrahydro-2H-pyran-2-yloxy)acetateTo a stirred solution of ethyl hydroxyacetate (35.3 g) containing a few crystals of p-toluene sulfonic acid, dihydropyran (30.0 g) was added dropwise. After stirring overnight at room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with a sodium hydrogencarbonate solution. The organic layer was separated and dried followed by evaporation of the dichloromethane. The residue was distilled under high vacuum to give the title compound (32 g) as a clear liquid.¹H NMR (CDC1₃): δ 1.20-1.32 (m, 3H), 1.50-1.58 (m, 3H), 1.70-1.92 (m, 3H), 3.45-3.55 (m, 1H), 3.80-3.90 (m, 1H), 4.16-4.24 (m, 4H), 4.70-4.79 (m, 1H).

Reference： [1] Patent: WO2013/3383, 2013, A1, . Location in patent: Page/Page column 287-288

[ 61675-94-3 ] Synthesis Path-Downstream 1~49

1
[ 110-87-2 ]
[ 623-50-7 ]
[ 61675-94-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With toluene-4-sulfonic acid; In toluene; at 25℃; for 1h;	To a solution of ethyl glycolate (10 g, 0.0961 mol) in toluene (100 mL) was added 3,4- dihydro-2H-pyran ( 8 g, 0.096 1 mol) followed by catalytic amount of pTSA (30 mg) and stirred at 25 C for 1 h. After completion of the reaction, the reaction mixture was washed with water and brine solution. The organic layer was dried over anhydrous Na2504, filtered and concentrated under reduced pressure to get 18 g (99 %) ethyl 2-((tetrahydro-2H-pyran-2- yl)oxy)acetate, 2, as colorless liquid
94.7%	toluene-4-sulfonic acid; In toluene; at 20℃;Industrial scale;Product distribution / selectivity;	Example 1.2Ethyl(tetrahydropyran-2-yloxy)-acetate (B) 100.00 kg (960.52 mol) ethyl glycolate (A) were dissolved in 180.0 L toluene and 365.22 g (1.92 mol) 4-toluenesulphonic acid monohydrate were added. At 20 C. a solution of 80.80 kg (960.52 mol) 3,4-dihydro-2H-pyran was added dropwise to the reaction mixture obtained and then the mixture was washed with 20.0 L toluene. The reaction mixture was stirred for 1 hour at 20 C. and after the reaction was complete it was combined with 100.0 L water and 6.53 kg (96.05 mol) ammonia solution (25%). After phase separation the organic phase was washed with 100.0 L water and then the solvent was distilled off completely in vacuo.Yield: 188.4 kg (94.7% of theory)
91.5%	With toluene-4-sulfonic acid; at 20℃;	To a stirred solution of ethyl glycolate (35.3 g, 0.339 mol) containing a few crystals of p-toluene sulfonic acid, 3,4-dihydropyran (30.0 g, 0.357 mol) was added dropwise (15 g over one hour followed by 15 g over 30 min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (80 mL) and washed with a NaHCO3 solution (from 30 mL sat. NaHCO3 and 10 mL water). The organic layer was separated and dried (Na2504) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4 g (91.5%) of 28 as a clear liquid. 1H NMR (CDCl3, 400 MHz)delta: 1.29 (t, 3H, J=7.1 Hz, CH3), 1.53-1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, 1H, 6-THP-CH2), 3.83-3.89 (m, 1H, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J=7.1 Hz, CH2Me), 4.75 (m, 1H, THP-CH). 13C NMR (CDCl3, 100 MHz) delta: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.

91.5%	With toluene-4-sulfonic acid; at 20℃;	(1) Preparation of tetrahydropyran-2-yloxy-acetic acid ethyl ester (Formula 28, Scheme 4)[0378] To a stirred solution of ethyl glycolate (35.3g, 0.339mol) containing a few crystals of />toluene sulfonic acid, 3,4-dihydropyran (30.Og, 0.357mol) was added1 1 <n="113"/>dropwise (15g over one hour followed by 15g over 30min). After stirring overnight at room temperature, the mixture was diluted with diethyl ether (8OmL) and washed with a NaHCO3 solution (from 3OmL sat. NaHCO3 and 1OmL water). The organic layer was separated and dried (Na2SO4) followed by evaporation of the ether. The residue was distilled under high vacuum to give 58.4g (91.5%) of 28 as a clear liquid. 1H NMR (CDCL3, 400MHz)delta: 1.29 (t, 3H, J = 7.1 Hz, CH3), 1.53 -1.95 (m, 6H, 3,4,5-THP-CH2's), 3.50-3.55 (m, IH, 6-THP-CH2), 3.83 - 3.89 (m, IH, 6-THP-CH2), 4.19 (s, 2H, OCH2CO2R), 4.20 (t, 2H, J = 7.1 Hz, CH2Me), 4.75 (m, IH, THP-CH). 13C NMR (CDCl3, 100MHz) delta: 14.1, 18.7, 25.2, 30.0, 60.7, 61.9, 63.8, 170.4.
81%	With pyridinium p-toluenesulfonate; In dichloromethane;	Step 1) ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mL*2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=20:1) to give colorless oil (3.01 g, 81%). 1H NMR (400 MHz, CDCl3): delta 1.22-1.38 (m, 4H), 1.55-1.63 (m, 3H), 1.69-1.88 (m, 3H), 3.50-3.53 (m, 1H), 3.82-3.88 (m, 1H), 4.18-4.23 (m, 4H), 4.73-4.74 (t, J=4 Hz, 1H).
81%	With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 4h;	To a mixture of ethyl 2-hydroxyacetate (2 g, 20 mmol, Aldrich) and 3,4-dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL of CH2Cl2 was added PPTS (500 mg, 2 mmol) slowly at rt. The mixture was stirred at rt for 4 hours, and then the mixture was washed with brine (20 mLx2), the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residure was purified by a silica gel column chromatography (PE: EtOAc =20:1) to give colorless oil (3.01 g, 81 %). 1H NMR (400MHz, CDCl3): delta 1.22 - 1.38 (m, 4H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, 1H), 3.82 - 3.88 (m, 1H), 4.18 - 4.23 (m, 4H), 4.73 - 4.74 (t, J=4Hz, 1H).
81%	With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 4h;Inert atmosphere;	To a mixture of ethyl 2 -hydroxy acetate (2 g, 20 mmol, TCI) and 3,4- dihydro-2H-pyran (3.2 g, 40 mmol, Alfa) in 40 mL Of CH2Cl2 was added PPTS (500 mg, 2 mmol, Aldrich) in portions at rt. The mixture was stirred at rt for 4 hours. The reaction mixture was then washed with brine, and the organic layer was separated and the combined organic phases were dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) petroleum ether / EtOAc) to give the desired compound as colorless oil (3.01 g, 81 % ).1H NMR (400MHz, CDCl3): delta 1.25 - 1.32 (m, 3H), 1.55 - 1.63 (m, 3H), 1.69 - 1.88 (m, 3H), 3.50 - 3.53 (m, IH), 3.82 - 3.88 (m, IH), 4.18 - 4.23 (m, 4H), 4.73 (t, J=3.2Hz, IH).
58%	With toluene-4-sulfonic acid; In toluene; at 20℃;	Step 1 Preparation of ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate A mixture of 3,4-dihydro-2H-pyran (20.4 g, 242.3 mmol), ethyl 2-hydroxyacetate (24.0 g, 230.8 mmol) and TsOH (0.794 g, 4.6 mmol) in toluene (150 mL) was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (2% EtOAc in petroleum ether) to afford ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate (25.2 g, 58%) as a colorless oil.
	With toluene-4-sulfonic acid;	Preparation B: 7-Oxo-6,7-dihydro-lH-pyrimi do [5,4-6] [l,4]oxazine-2-carbaldehyde; (a) 2- [(E)-2-Phenylethenyl] -5 -(tetrahydro-2H-pyran-2-yloxy)-4( 1 H)-pyrimidinone; NaH (0.38g, 9.5mmol, 60% paraffin oil) was added slowly to a THF (20 mL) solution of ethyl (tetrahydro-2H-pyran-2-yloxy)acetate (prepared by treating ethyl hydroxyacetate with 3,4-dihydro-2H-pyran and p-toluenesulphonic acid) ( 1.Og, 5.3mmol) and dry ethyl formate (3.9g, 53mmol). The reaction mixture was stirred at room temperature for 15 min. and then heated at 65 0C for 45 min. The reaction mixture was concentrated to dryness to give a pale yellow solid. The solid was added to a MeOeta/EtOeta (20mL/20mL) solution of (2E)-3-phenyl-2-propenimidamide (for a synthesis see Preparation A(b)) (0.78g, 5.3mmol), the subsequent mixture was heated at 80 0C for 4h. The resulting material was poured into DCM (1OmL) containing silica gel (3g) and evaporated. Purification by column chromatography (silica gel) using a MeOeta/DCM gradient (0-10%) provided the desired product as a pale yellow solid (Ig , 63%). LCMS: m/z 299 (MH+).

Reference： [1]Patent: WO2017/83431,2017,A2 .Location in patent: Paragraph 00216; 00217
[2]Patent: US2011/87021,2011,A1 .Location in patent: Page/Page column 11
[3]Patent: US2005/8570,2005,A1 .Location in patent: Page/Page column 45
[4]Patent: WO2007/121453,2007,A2 .Location in patent: Page/Page column 111; 112
[5]Patent: US2010/239576,2010,A1
[6]Patent: EP2408300,2016,B1 .Location in patent: Paragraph 0343
[7]Patent: WO2010/45095,2010,A1 .Location in patent: Page/Page column 76
[8]Patent: US2016/168090,2016,A1 .Location in patent: Paragraph 0348-0349
[9]Journal of the Chemical Society,1956,p. 2124,2126
[10]Journal of the Chemical Society,1956,p. 4665
[11]Patent: WO2008/128961,2008,A1 .Location in patent: Page/Page column 107

2
[ 61675-94-3 ]
[ 109-94-4 ]
[ 99170-32-8 ]

Reference： [1]Journal of the Chemical Society,1956,p. 2124,2126

3
[ 61675-94-3 ]
[ 101109-54-0 ]

Reference： [1]Journal of the Chemical Society,1956,p. 2124,2126

4
[ 61675-94-3 ]
[ 123474-65-7 ]
[ 123492-33-1 ]

Reference： [1]Tetrahedron Letters,1989,vol. 30,p. 919 - 922

5
[ 61675-94-3 ]
[ 618-39-3 ]
[ 109-94-4 ]
[ 91073-91-5 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1983,vol. 37,p. 947 - 952

6
[ 61675-94-3 ]
[ 124-42-5 ]
[ 109-94-4 ]
[ 24614-14-0 ]

Reference： [1]Acta chemica Scandinavica. Series B: Organic chemistry and biochemistry,1983,vol. 37,p. 947 - 952

7
[ 61675-94-3 ]
[ 502-42-1 ]
[ 144149-64-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 3674 - 3685

8
[ 626-55-1 ]
[ 61675-94-3 ]
[ 160540-44-3 ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 13575 - 13582

Yield	Reaction Conditions	Operation in experiment
85%		(A) Ethyl 2-(2-tetrahydropyranyloxy)acetate. To a stirred solution of 15.5 g. (0.15 mol.) of ethyl glycolate in 60 ml. of methylene chloride, cooled to 5 C., was added 12.6 g. (0.15 mol.) of dihydropyran, followed by 50 mg. of 4-toluenesulfonic acid monohydrate. After the immediate exothermic reaction which ensued had subsided, the methylene chloride solution was washed successively with water, 5% sodium bicarbonate and water. The dried solution was then evaporated to give 23.8 g. (85% yield) of ethyl 2-(2-tetrahydropyranyloxy)acetate as a clear oil.

10
[ 61675-94-3 ]
[ 140-53-4 ]
2-(4-chloro-phenyl)-3-oxo-4-(tetrahydro-pyran-2-yloxy)-butyronitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3669 - 3673

11
[ 61675-94-3 ]
[ 321324-76-9 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 123 - 135

12
[ 61675-94-3 ]
[ 109-94-4 ]
3-oxo-2-(tetrahydro-pyran-2-yloxy)-propionic acid ethyl ester [ No CAS ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5469 - 5473

13
[ 61675-94-3 ]
[ 894421-78-4 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5469 - 5473

14
[ 61675-94-3 ]
[ 99170-32-8 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 5469 - 5473

15
[ 61675-94-3 ]
[ 847972-83-2 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 123 - 135

16
[ 61675-94-3 ]
4-(4-chloro-phenyl)-5-(tetrahydro-pyran-2-yloxymethyl)-2<i>H</i>-pyrazol-3-ylamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3669 - 3673

17
[ 61675-94-3 ]
3-(4-chloro-phenyl)-5-methyl-2-(tetrahydro-pyran-2-yloxymethyl)-pyrazolo[1,5-<i>a</i>]pyrimidin-7-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3669 - 3673

18
[ 61675-94-3 ]
3-bromo-4-(1-hydroxy-2-tetrahydropyranyloxyethyl)pyridine [ No CAS ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 13575 - 13582

19
[ 61675-94-3 ]
3-bromo-4-(1-benzyloxy-2-tetrahydropyranyloxyethyl)pyridine [ No CAS ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 13575 - 13582

20
[ 61675-94-3 ]
4-(1-benzyloxy-2-tetrahydropyranyloxyethyl)-3-trimethylsilylethynylpyridine [ No CAS ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 13575 - 13582

21
[ 61675-94-3 ]
1-(4-Fluoro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-1,4,5,6,7,8-hexahydro-cycloheptapyrazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 3674 - 3685

22
[ 61675-94-3 ]
2-(4-Fluoro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 3674 - 3685

23
[ 61675-94-3 ]
hexane-washed NaH [ No CAS ]
[ 502-42-1 ]
[ 144149-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; diethyl ether; ethanol;	EXAMPLE 6 2-(4-Fluorophenyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol (CP 175, RS step e, followed by RS step k) A solution of 2.80 g (25 mmol) of cycloheptanone and 4.71 g (25 mmol) of <strong>[61675-94-3]ethyl (tetrahydropyranyloxy)acetate</strong> (Ireland, R. E.; Wipf, P. Tetrahedron Lett., 1989, 30, 919-22) in 20 mL of Et2 O was added over the course of 1 h to an ice-cold, stirring mixture of hexane-washed NaH and 0.12 mL (2 mmol, 0.092 g) of absolute EtOH in 10 mL of Et2 O under N2. The light brown mixture was allowed to warm to room temperature and was stirred overnight. MeOH (5 mL) was added and the solution was poured onto 200 mL of saturated aqueous NH4 Cl. After acidification to pH 2 with 1N aqueous HCl, the mixture was extracted with Et2 O. The organic layer was washed with brine, dried over Na2 SO4, and concentrated to give 5.61 g of crude 2-[(tetrahydropyranyloxy)acetyl]cycloheptanone as a light brown oil.

Reference： [1]Patent: US5134155,1992,A

24
[ 61675-94-3 ]
[ 37101-62-5 ]

Yield	Reaction Conditions	Operation in experiment
46%	With hydrogenchloride; In water; acetone; mineral oil;	(B) 1-(2-tetrahydropyranyloxy)-2,4-pentanedione. Under an atmosphere of dry nitrogen, 2.35 g. of a 50% dispersion of sodium hydride in mineral oil was washed several times with hexane. To the oil-free sodium hydride was then added 25 ml. of ether, followed by 9.18 g. of ethyl 2-(2-tetrahydropyranyloxy)acetate, followed by 3.96 ml. of acetone dissolved in a 10 ml. of ether. The reaction mixture was stirred at ambient temperature for 1.5 hours, at which point a vigorous, exothermic reaction took place. After the exothermic reaction had subsided, the reaction mixture was stirred for an additional 30 minutes and then it was quenched by pouring it into an ice-cold mixture prepared from 49 ml. of 11N hydrochloric acid and 100 ml. of water. After 5 minutes, the organic phase was separated, washed with water, dried and evaporated to give 7.8 g. of an oil. This oil was distilled, to give 4.5 g. (46% yield) of 1-(2-tetrahydropyranyloxy)-2,4-pentanedione as a clear liquid, b.p. ca. 60 C. (0.4 mm).

Reference： [1]Patent: US3991053,1976,A

25
[ 61675-94-3 ]
[ 55978-61-5 ]
[ 109-94-4 ]
[ 1003946-49-3 ]

Yield	Reaction Conditions	Operation in experiment
63%		Preparation B: 7-Oxo-6,7-dihydro-lH-pyrimi do [5,4-6] [l,4]oxazine-2-carbaldehyde; (a) 2- [(E)-2-Phenylethenyl] -5 -(tetrahydro-2H-pyran-2-yloxy)-4( 1 H)-pyrimidinone; NaH (0.38g, 9.5mmol, 60% paraffin oil) was added slowly to a THF (20 mL) solution of ethyl (tetrahydro-2H-pyran-2-yloxy)acetate (prepared by treating ethyl hydroxyacetate with 3,4-dihydro-2H-pyran and p-toluenesulphonic acid) ( 1.Og, 5.3mmol) and dry ethyl formate (3.9g, 53mmol). The reaction mixture was stirred at room temperature for 15 min. and then heated at 65 0C for 45 min. The reaction mixture was concentrated to dryness to give a pale yellow solid. The solid was added to a MeOeta/EtOeta (20mL/20mL) solution of (2E)-3-phenyl-2-propenimidamide (for a synthesis see Preparation A(b)) (0.78g, 5.3mmol), the subsequent mixture was heated at 80 0C for 4h. The resulting material was poured into DCM (1OmL) containing silica gel (3g) and evaporated. Purification by column chromatography (silica gel) using a MeOeta/DCM gradient (0-10%) provided the desired product as a pale yellow solid (Ig , 63%). LCMS: m/z 299 (MH+).

Reference： [1]Patent: WO2008/128961,2008,A1 .Location in patent: Page/Page column 107

26
[ 61675-94-3 ]
[ 124-42-5 ]
C₁₆H₂₂N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.2%		THPO-ethyl glycolate (34.0 g, 0.195 mol) in ether (180 mL) was stirred with Na shot (2.24 g, 0.0974 mol) for 20 hrs under a N2 atmosphere, resulting in a yellow solution. NaH (0.54 eq.) can be used in place of Na, but usually requires the addition of 2-5% m/m EtOH to promote the reaction. The ether was removed and the residue covered with abs. ethanol (20 mL). An acetamidine solution was prepared from acetamidine.HCl (9.32 g, 0.0989 mol), which was stirred for 2 hr in sodium ethoxide in ethanol (130 mL, by addition of 2.36 g of Na). This suspension was filtered onto the ethanol covered residue from above and the filter cake washed with ethanol (5 mL). The reaction mixture was then stirred and heated at reflux 3.5 hr, cooled to room temperature and the solvent evaporated. The residue was dissolved in CH2Cl2 (80 mL) and HOAc was added (to pH 6, wet pH paper). After washing with water (2×80 mL) the organic layer was dried (Na2SO4) and most of the solvent removed. To the viscous CH2Cl2 solution, hexanes (100 mL) was added, producing a white precipitate which was filtered and washed with hexanes to afford 2, 20.6 g (65.2%). Mp: 113-114 C. (+)FABMS: m/z 325 +. 1H NMR (CDCl3, 300 Mhz): delta 1.4-2.0 (m, 12H, 3,4,5-THP-CH2), 2.42 (s, 3H, 2-CH3), 3.50-356 (m, 2H, 6-THP-CH2), 3.86-3.96 (m, 2H, 6-THP-CH2), 4.44-4.81(4 d's, 2H, CH2-OTHP), 4.79 (br m, 1H, THP-CH), 5.83 (br m, 1H, THP-CH), 11.44 (br s, 1H, NH). 13C NMR (CDCl3, 100 MHz): delta 10.5, 18.5, 18.5, 19.1, 19.3, 21.1, 25.0, 25.38, 25.40, 29.9, 30.3, 30.4, 61.9, 62.2, 62.70, 62.74, 63.6, 63.8, 82.8, 98.4, 98.6, 98.63, 98.7, 138.58, 138.63, 152.4, 152.9, 161.6. Anal. Calcd (found) for C15H24N2O5: C, 59.24 (59.10); H, 7.46 (7.51); N, 8.64(8.94).

Reference： [1]Patent: US2005/8570,2005,A1 .Location in patent: Page/Page column 15; 45

27
[ 61675-94-3 ]
[ 925-90-6 ]
1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		To a mixture of <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (1 g, 5.3 mmol) and Ti(O-ZPr)4 (1.06 mL, 3.5 mmol, Aldrich) in 18 mL of THF under N2 was added EtMgBr (4.5 mL, 13.25 mmol, 3M ether solution, Aldrich) dropwise over 2 hrs, and the temperature must be kept at 15-20C. After stirring for 2 hrs, and the reaction mixture was quenched with saturated NH4Cl aqueous solution at 0C and extracted with EtOAc (30 mLx3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20: 1 (v/v) petroleum ether / EtOAc) to afford l-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol as colorless oil (500 mg, 55 %).1H NMR (400MHz, CDCl3): delta 0.51 - 0.67 (m, 2H), 0.77 - 0.85 (m, 2H), 1.55 - 1.65 (m, 4H), 1.74 - 1.87 (m, 2H), 3.50 - 3.55 (m, 2H), 3.81 (d, J=I 1.6Hz, IH), 3.93 - 3.98 (m, 2H), 4.64 - 4.66 (m, IH).
54%	With titanium(IV) isopropylate; In diethyl ether; at 0 - 20℃; for 2h;	Step 2 Preparation of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol To a stirred solution of <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (1.0 g, 5.32 mmol) in anhydrous Et2O (30 mL) was added Ti(Oi-Pr)4 (0.997 g, 3.51 mmol) and ethylmagnesium bromide (13.1 mmol, 1 muM in Et2O) dropwise at 0 C. After being stirred at room temperature for 2 h, the resulting mixture was quenched with water (10 mL) at 0 C. and extracted with EtOAc (50 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (4% EtOAc in petroleum ether) to afford 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (0.5 g, 54%) as a colorless oil.

Reference： [1]Patent: WO2010/45095,2010,A1 .Location in patent: Page/Page column 76; 77
[2]Patent: US2016/168090,2016,A1 .Location in patent: Paragraph 0530-0351

28
[ 61675-94-3 ]
1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With ethylmagnesium bromide;Ti(Oi-Pr)4; In tetrahydrofuran;	Step 2) 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol To a mixture of <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (1 g, 5.3 mmol) and Ti(O-iPr)4 (1.06 mL, 3.5 mmol) in 18 mL THF was added EtMgBr (4.5 mL, 13.25 mmol, Aldrich) dropwise over 2 hrs under N2. The reaction temperature was kept between 15 to 20 C. After stirring for 2 hrs, the reaction was quenched with 15 mL of saturated NH4Cl solution and extracted with EtOAc (20 mL*5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE: EtOAc=5:1) to afford the title compound as colorless oil (500 mg, 55%). 1H NMR (400 MHz, CDCl3): delta 0.55-0.85 (m, 4H), 1.55-1.65 (m, 4H), 1.74-1.87 (m, 2H), 3.50-3.55 (m, 2H), 3.79-3.82 (m, 1H), 3.93-3.98 (m, 2H), 4.64-4.66 (m, 1H).
55%	With propane; titanium(IV)isopropoxide; In tetrahydrofuran; at 15 - 20℃; for 2h;Inert atmosphere;	To a mixture of <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (1 g, 5.3 mmol) and Ti(O-iPr)4 (1.06 mL, 3.5 mmol) in 18 mL THF was added EtMgBr (4.5 mL, 13.25 mmol, Aldrich) dropwise over 2 hrs under N2. The reaction temperature was kept between 15 to 20C. After stirring for 2 hrs, the reaction was quenched with 15 mL of saturated NH4Cl solution and extracted with EtOAc (20 mLx5). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residure was purified by a silica gel column chromatography (PE: EtOAc =5:1) to afford the title compound as colorless oil (500 mg, 55 %). 1H NMR (400MHz, CDCl3): delta 0.55 - 0.85 (m, 4H), 1.55 - 1.65 (m, 4H), 1.74 - 1.87 (m, 2H), 3.50 - 3.55 (m, 2H), 3.79 - 3.82 (m, 1H), 3.93 - 3.98 (m, 2H), 4.64 - 4.66 (m, 1H).

Reference： [1]Patent: US2010/239576,2010,A1
[2]Patent: EP2408300,2016,B1 .Location in patent: Paragraph 0344

29
[ 61675-94-3 ]
[ 143-37-3 ]
[ 109-94-4 ]
[ 99170-32-8 ]

Yield	Reaction Conditions	Operation in experiment
58%		Example 1 : 2-Methyl-5-(tetrahydro-2JH-pyran-2-yloxy)pyrimidin-4(3H)-one; 5a: To a suspension of sodium hydride (4.60 g in 55-60% paraffin oil), dry ether (50 cm3) and dry ethyl formate (7.84 g) were added. Then (tetrahydropyran-2-yloxy)-acetic acid ethyl ester (20 g) was added dropwise under continuous stirring. After the mixture was refluxed for 2 h, acetamidine (4.3 g) was added. After the removal of ether from the reaction mixture, the remained ethanolic solution was refluxed for 4 h. Then the mixture was cooled and the volatile solvents were removed by rotory- evaporator. The residue was redissolved in water and filtered. The filtrate was acidified by acetic acid in an ice bath and the white precipitate was filtered, washed with water and dried under reduced <n="13"/>pressure at 100 0C. (9.0 g, 58 %); (Found: C 55.25; H 47.54; N 13.19. CaIc. for C10H16N2O3; C 55.59; H 7.60; N 13.20 %). Mp 149-151 0C; deltaH (300 MHz; DMSOd) 1.23-2.03 (6H, m), 2.27 (3H, s), 3.23-4.04 (2H, m), 5.47 (IH, bs), 7.60 (IH, s), 10.73 (IH, bs). Vm^cm"1 1670, 1610, 1385, 1310, 1205, 1190, 1120, 980, 910, 820, 775 and 740; MS(EI): m/z (%) 210 (100, M+, C10H14N2O3,), 126 (M+, -C5H8O), 125 (M+-C5H9).

Reference： [1]Patent: WO2007/116412,2007,A1 .Location in patent: Page/Page column 11-12

30
[ 61675-94-3 ]
[ 143-37-3 ]
[ 389130-64-7 ]

Yield	Reaction Conditions	Operation in experiment
65.2%		(2) Preparation of 2-Methyl-3H-5-tetrahydropyran-2-yloxy-6-tetrahydropyran-2- yloximethyl-4-pyrimidinone 29[0379] THPO-ethyl glycolate (34.Og, 0.195mol) in ether ( 18OmL) was stirred with Na shot (2.24g, 0.0974mol) for 20hrs under a N2 atmosphere, resulting in a yellow solution. NaH (0.54 eq.) can be used in place of Na, but usually requires the addition of 2- 5% m/m EtOH to promote the reaction. The ether was removed and the residue covered with abs. ethanol (2OmL). An acetamidine solution was prepared from acetamidine.HCl (9.32g, 0.0989mol), which was stirred for 2hr in sodium ethoxide in ethanol (13OmL, by addition of 2.36g of Na). This suspension was filtered onto the ethanol covered residue from above and the filter cake washed with ethanol (5mL). The reaction mixture was then stirred and heated at reflux 3.5hr, cooled to room temperature and the solvent evaporated. The residue was dissolved in CH2Cl2 (8OmL) and HOAc was added (to pH 6, wet pH paper). After washing with water (2x80mL) the organic layer was dried (Na2SO4) and most of the solvent removed. To the viscous CH2Cl2 solution, hexanes (10OmL) was added, producing a white precipitate which was filtered and washed with hexanes to afford 2, 20.6g (65.2%). Mp: 1 13-1 14 0C. (+)FABMS: m/z 325 +. 1H NMR (CDCl3, 300Mhz): delta 1.4 - 2.0 (m, 12H, 3,4,5-THP-CH2), 2.42 (s, 3H, 2- CH3), 3.50-356 (m, 211, 6-THP-CH2), 3.86 -3.96 (m, 2H, 6-THP-CH2), 4.44- 4.81(4 d's, 2H, CH2-OTHP), 4.79 (br m, IH, THP-CH), 5.83 (br m, I H, THP-CH), 1 1.44 (br s, IH, NH). 13C NMR (CDCl3, 100MHz): delta 10.5, 18.5, 18.5, 19.1 , 19.3, 21.1 , 25.0, 25.38, 25.40, 29.9, 30.3, 30.4, 61.9, 62.2, 62.70, 62.74, 63.6, 63.8, 82.8, 98.4, 98.6, 98.63, 98.7,138.58, 138.63, 152.4, 152.9, 161.6. Anal. Calcd (found) for C15H24N2O,: C, 59.24 (59.10); H, 7.46 (7.51); N, 8.64(8.94).

Reference： [1]Patent: WO2007/121453,2007,A2 .Location in patent: Page/Page column 42; 112

31
[ 61675-94-3 ]
[ 144896-51-5 ]
[ 1117699-24-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium 2-methylbutan-2-olate; In tetrahydrofuran; at 20℃;Industrial scale;Product distribution / selectivity;	Example 2.1 Ethyl(3Z)-3-(4-benzyloxy-3,5-dimethyl-phenyl)-2-tetrahydro-pyran-2-yloxy)-acrylate (D) 20.00 kg (83.23 mol) 4-benzyloxy-3,5-dimethylbenzaldehyde (C) were dissolved in 50.0 L tetrahydrofuran and 31.68 kg (149.81 mol) ethyl(tetrahydropyran-2-yloxy)-acetate (B) were added. At 20 C. 25.68 kg (91.55 mol) potassium-tert-amylate (45% in tetrahydrofuran) were added dropwise. Then the reaction mixture obtained was stirred for 3.5 hours at 20 C. and after the reaction had ended 120.0 L water was added. The suspension obtained was cooled to 0 C. and stirred for 1 hour at this temperature. Then the product was removed by centrifuging and dried. Yield: 25.04 kg (73% of theory) Chemical purity (HPLC): 99.8% Melting point: 122.6 C.

Reference： [1]Patent: US2011/87021,2011,A1 .Location in patent: Page/Page column 11-12

32
[ 61675-94-3 ]
[ 1117699-25-8 ]

Reference： [1]Patent: US2011/87021,2011,A1

33
[ 61675-94-3 ]
[ 62-56-6 ]
[ 109-94-4 ]
[ 1417817-70-9 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium-6-oxo-5-(tetrahydro-2H-pyran-2-yloxy)-l ,6-dihydropyrimidine-2-thiolate A 100 ml round-bottomed flask was charged with diced sodium (2.30 g, 0.1 mol), in toluene (30 ml) to give a colourless suspension. A mixture of ethyl formate (8.14 ml, 0.10 mol) and <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (9.9 ml, 0.10 mol) were added drop-wise, taking care to make sure the temperature did not exceed 30C. The reaction was stirred at room temperature overnight by which point a brown viscous oil had settled out with some sodium remaining. The toluene was decanted off and ethanol (15 ml) was added and the reaction was stirred until remaining sodium had dissolved. Carbamimidothioic acid (7.61 g, 0.10 mol) was added and the reaction was stirred at room temperature for 1 hour and then heated to reflux for 4 hours. The reaction was cooled and diluted with water (50 ml) and diisopropyl ether and the aqueous layer separated. The diisopropyl ether layer was washed with water and the combined aqueous layers were washed with diisopropyl ether and then made up to 100 ml and used crude in the next step.
		Prepared According to Scheme 3 Step a Sodium-6-oxo-5-(tetrahydro-2H-pyran-2-yloxy)-1,6-dihydropyrimidine-2-thiolate A 100 ml round-bottomed flask was charged with diced sodium (2.30 g, 0.1 mol), in toluene (30 ml) to give a colourless suspension. A mixture of ethyl formate (8.14 ml, 0.10 mol) and <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (9.9 ml, 0.10 mol) were added drop-wise, taking care to make sure the temperature did not exceed 30 C. The reaction was stirred at room temperature overnight by which point a brown viscous oil had settled out with some sodium remaining. The toluene was decanted off and ethanol (15 ml) was added and the reaction was stirred until remaining sodium had dissolved. Carbamimidothioic acid (7.61 g, 0.10 mol) was added and the reaction was stirred at room temperature for 1 hour and then heated to reflux for 4 hours. The reaction was cooled and diluted with water (50 ml) and diisopropyl ether and the aqueous layer separated. The diisopropyl ether layer was washed with water and the combined aqueous layers were washed with diisopropyl ether and then made up to 100 ml and used crude in the next step.

Reference： [1]Patent: WO2013/4995,2013,A1 .Location in patent: Page/Page column 40
[2]Patent: US2014/248378,2014,A1 .Location in patent: Paragraph 0247; 0248

34
[ 61675-94-3 ]
2-(phenylsulfanyl)ethanimidamide [ No CAS ]
[ 109-94-4 ]
[ 1417817-97-0 ]

Yield	Reaction Conditions	Operation in experiment
23%		1.4.2 Intermediate 33 (prepared according to Scheme 4 step (b)) 2-[(Phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (182 mg, 4.55 mmol) in diethyl ether (10 ml) was added ethyl formate (281 mg, 3.79 mmol) followed by ethyl 2-(tetrahydro-2H-pyran-2- yloxy)acetate (713 mg, 3.79 mmol). The resulting mixture was stirred under reflux for 1.5 hours. To this mixture was then added a pre-mixed solution of 2- (phenylsulfanyl)ethanimidamide (Intermediate 32) (630 mg, 3.79 mmol) and sodium ethoxide (1.23 g, 3.79 mmol) in EtOH (10 ml). The ether was removed under vacuum and the resulting suspension stirred at reflux for 3 hours. The reaction mixture was concentrated and purified by column chromatography (Si02: 0-10% eOH in DCM) to yield 2-[(phenylsulfanyl)methyl]-5-(tetrahydro-2H-pj an-2-yloxy)pyrimidin-4(3H)-one (275 mg, 23 % yield). MS ES": 317.
23%		Prepared According to Scheme 4 Step (b) 2-[(Phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (182 mg, 4.55 mmol) in diethyl ether (10 ml) was added ethyl formate (281 mg, 3.79 mmol) followed by <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (713 mg, 3.79 mmol). The resulting mixture was stirred under reflux for 1.5 hours. To this mixture was then added a pre-mixed solution of 2-(phenylsulfanyl)ethanimidamide (Intermediate 32) (630 mg, 3.79 mmol) and sodium ethoxide (1.23 g, 3.79 mmol) in EtOH (10 ml). The ether was removed under vacuum and the resulting suspension stirred at reflux for 3 hours. The reaction mixture was concentrated and purified by column chromatography (SiO2: 0-10% MeOH in DCM) to yield 2-[(phenylsulfanyl)methyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (275 mg, 23% yield). MS ES-: 317.

Reference： [1]Patent: WO2013/4995,2013,A1 .Location in patent: Page/Page column 46
[2]Patent: US2014/248378,2014,A1 .Location in patent: Paragraph 0289 - 0292

35
[ 61675-94-3 ]
[ 169558-97-8 ]
[ 109-94-4 ]
[ 1417817-45-8 ]

Yield	Reaction Conditions	Operation in experiment
28%		1.1.2 Intermediate 2 (prepared according to Scheme 1 step (b)) 2-[(3-Chlorobenzyl)suIfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (0.26 g, 6.39 mmol) in Et20 (10 ml) was added ethyl formate (0.40 g, 5.33 mmol) and then ethyl 2-(tetrahydro-2H-pyran-2- yloxy)acetate (1.00 g, 5.33 mmol) drop-wise and the mixture stirred at reflux for 2 hours. 3-Chlorobenzyl carbamimidothioate HBr salt (Int 1) (1.5 g, 5.33 mmol) was then added followed by EtOH (10 ml). The ether was removed in vacuo and then the resulting ethanolic solution heated at reflux for 4 hours. The reaction mixture was evaporated and the resulting solid purified by column chromatography (Si02: 0-10% MeOH in DCM) to yield 2-[(3-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2- yloxy)pyrimidin-4(3H)-one (524 mg, 28 %). ? NMR (400 MHz, CD2C12): delta 7.79 (s, 1 H), 7.45 (s, 1 H), 7.18 - 7.39 (m, 3 H), 5.41 - 5.51 (m, 1 H), 4.42 (s, 2 H), 3.83 - 4.02 (m, 1 H), 3.56 - 3.69 (m, 1 H), 1.44 - 2.18 (m, 6 H). MS ES": 351.

Reference： [1]Patent: WO2013/4995,2013,A1 .Location in patent: Page/Page column 34-35

36
[ 61675-94-3 ]
[ 24442-03-3 ]
[ 109-94-4 ]
[ 1417818-03-1 ]

Yield	Reaction Conditions	Operation in experiment
35%		1.4.5 Intermediate 36 (prepared according to Scheme 4 step (b)) 2-(2-PhenyIethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (29.0 mg, 0.74 mmol) in diethyl ether (2 ml), ethyl formate (45.0 mg, 0.61 mmol) was added. Ethyl-2-(tetrahydro-2H-pyran-2- yloxy)acetate (1 15 mg, 0.61 mmol) was then added dropwise and the mixture stirred under reflux for 2 hours. To the reaction was then added a pre-stirred solution of trimethylaluminium (0.34 ml, 0.68 mmol) and 3-phenylpropanimidamide (100 mg, 0.68 mmol, CAS R 24442-03-3) in THF (1ml). The ether was taken off under vacuum and then the reaction stirred under reflux for 4 hours. The reaction mixture was poured onto a slurry of silica in DCM. The resulting slurry was stirred for 15 minutes and then concentrated in vacuo. The resulting solid (dry loaded crude product on silica) was then purified by column chromatography (Si02: 0-10% MeOH in DCM) to yield 2-(2- phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (65 mg, 35 % yield). ? NMR (400 MHz, CD3OD): delta 7.70 (br. s., 1 H), 6.98 - 7.37 (m, 5 H), 5.45 (br. s., 1 H), 3.79 - 3.96 (m, 1 H), 3.58 - 3.68 (m, 1 H), 2.97 - 3.12 (m, 2 H), 2.75 - 2.95 (m, 2 H), 1.13 - 2.18 (m, 6 H). MS ES+: 301.
35%		Prepared According to Scheme 4 Step (b) 2-(2-Phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (29.0 mg, 0.74 mmol) in diethyl ether (2 ml), ethyl formate (45.0 mg, 0.61 mmol) was added. Ethyl-2-(tetrahydro-2H-pyran-2-yloxy)acetate (115 mg, 0.61 mmol) was then added dropwise and the mixture stirred under reflux for 2 hours. To the reaction was then added a pre-stirred solution of trimethylaluminium (0.34 ml, 0.68 mmol) and 3-phenylpropanimidamide (100 mg, 0.68 mmol, CAS RN 24442-03-3) in THF (1 ml). The ether was taken off under vacuum and then the reaction stirred under reflux for 4 hours. The reaction mixture was poured onto a slurry of silica in DCM. The resulting slurry was stirred for 15 minutes and then concentrated in vacuo. The resulting solid (dry loaded crude product on silica) was then purified by column chromatography (SiO2: 0-10% MeOH in DCM) to yield 2-(2-phenylethyl)-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (65 mg, 35% yield). 1H NMR (400 MHz, CD3OD): delta 7.70 (br. s., 1H), 6.98-7.37 (m, 5H), 5.45 (br. s., 1H), 3.79-3.96 (m, 1H), 3.58-3.68 (m, 1H), 2.97-3.12 (m, 2H), 2.75-2.95 (m, 2H), 1.13-2.18 (m, 6H). MS ES+: 301.

Reference： [1]Patent: WO2013/4995,2013,A1 .Location in patent: Page/Page column 47
[2]Patent: US2014/248378,2014,A1 .Location in patent: Paragraph 0299 - 0302

37
[ 61675-94-3 ]
[ 1417817-72-1 ]

Reference： [1]Patent: WO2013/4995,2013,A1
[2]Patent: US2014/248378,2014,A1

38
[ 61675-94-3 ]
[ 1003946-50-6 ]

Reference： [1]Patent: WO2013/3383,2013,A1
[2]Patent: WO2008/128961,2008,A1

39
[ 61675-94-3 ]
[ 1003946-51-7 ]

Reference： [1]Patent: WO2013/3383,2013,A1
[2]Patent: WO2008/128961,2008,A1

40
[ 61675-94-3 ]
[ 55978-61-5 ]
[ 109-94-4 ]
(E)-2-styryl-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 3(E)-2-Styryl-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one A solution of the product from Step 1 (10 g) in tetrahydrofuran (200 mL) and dry ethyl formate (39 g) was added sodium hydride (3.8 g) slowly. The reaction mixture was concentrated to dryness to give a pale yellow solid. The solid was added to a methanol/ethanol (200 mL/200 mL) solution of the product from Step 2 (7.8 g), the subsequent mixture was heated at 80 C for 4 hours. The resulting material was poured into dichloromethane (100 mL) containing silica gel (30 g) and evaporated. The residue was purified by columnchromatography silica gel to give the title compound (5 g) as a pale yellow solid. MS m/z: 299 (MH+).

Reference： [1]Patent: WO2013/3383,2013,A1 .Location in patent: Page/Page column 288

41
[ 142-68-7 ]
[ 623-50-7 ]
[ 61675-94-3 ]

Yield	Reaction Conditions	Operation in experiment
32 g	With toluene-4-sulfonic acid; at 20℃;	EXAMPLE 1422-((l-(2-(3-Fluoro-6-methoxy-l,5-naphthyridin-4-yl)ethyl)-2- oxabicyclo[2.2.2]octan-4-ylamino)methyl)-6H-pyrimido[5,4-b][l,4]oxazin-7(8H)-oneStep 1Ethyl 2-(Tetrahydro-2H-pyran-2-yloxy)acetateTo a stirred solution of ethyl hydroxyacetate (35.3 g) containing a few crystals of p-toluene sulfonic acid, dihydropyran (30.0 g) was added dropwise. After stirring overnight at room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with a sodium hydrogencarbonate solution. The organic layer was separated and dried followed by evaporation of the dichloromethane. The residue was distilled under high vacuum to give the title compound (32 g) as a clear liquid.1H NMR (CDC13): delta 1.20-1.32 (m, 3H), 1.50-1.58 (m, 3H), 1.70-1.92 (m, 3H), 3.45-3.55 (m, 1H), 3.80-3.90 (m, 1H), 4.16-4.24 (m, 4H), 4.70-4.79 (m, 1H).

Reference： [1]Patent: WO2013/3383,2013,A1 .Location in patent: Page/Page column 287-288

42
[ 61675-94-3 ]
3-chlorobenzyl carbamidothioate hydrobromide [ No CAS ]
[ 109-94-4 ]
[ 1417817-45-8 ]

Yield	Reaction Conditions	Operation in experiment
28%		Prepared According to Scheme 1 Step (b) 2-[(3-Chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one To a suspension of sodium hydride (0.26 g, 6.39 mmol) in Et2O (10 ml) was added ethyl formate (0.40 g, 5.33 mmol) and then <strong>[61675-94-3]ethyl 2-(tetrahydro-2H-pyran-2-yloxy)acetate</strong> (1.00 g, 5.33 mmol) drop-wise and the mixture stirred at reflux for 2 hours. 3-Chlorobenzyl carbamimidothioate HBr salt (Int 1) (1.5 g, 5.33 mmol) was then added followed by EtOH (10 ml). The ether was removed in vacuo and then the resulting ethanolic solution heated at reflux for 4 hours. The reaction mixture was evaporated and the resulting solid purified by column chromatography (SiO2: 0-10% MeOH in DCM) to yield 2-[(3-chlorobenzyl)sulfanyl]-5-(tetrahydro-2H-pyran-2-yloxy)pyrimidin-4(3H)-one (524 mg, 28%). 1H NMR (400 MHz, CD2Cl2): delta 7.79 (s, 1H), 7.45 (s, 1H), 7.18-7.39 (m, 3H), 5.41-5.51 (m, 1H), 4.42 (s, 2H), 3.83-4.02 (m, 1H), 3.56-3.69 (m, 1H), 1.44-2.18 (m, 6H). MS ES-: 351.

Reference： [1]Patent: US2014/248378,2014,A1 .Location in patent: Paragraph 0198; 0199; 0200; 0201; 0202

43
[ 61675-94-3 ]
[ 1245931-64-9 ]

Reference： [1]Patent: EP2408300,2016,B1

44
[ 61675-94-3 ]
[ 1245931-96-7 ]

Reference： [1]Patent: EP2408300,2016,B1
[2]Patent: US2016/168090,2016,A1

45
[ 61675-94-3 ]
5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-2-((4-((trimethylsilyl)ethynyl)phenoxy)methyl)pyrimidin-4(3H)-one [ No CAS ]

Reference： [1]Patent: WO2017/83431,2017,A2

46
[ 61675-94-3 ]
2-((4-ethynylphenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one [ No CAS ]

Reference： [1]Patent: WO2017/83431,2017,A2

47
[ 61675-94-3 ]
2-((4-(phenylbuta-1,3-diyn-1-yl)phenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one [ No CAS ]

Reference： [1]Patent: WO2017/83431,2017,A2

48
[ 61675-94-3 ]
2-(4-iodophenoxy)acetimidamide hydrochloride [ No CAS ]
2-((4-iodophenoxy)methyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.8%		To a cooled solution of <strong>[61675-94-3]ethyl 2-((tetrahydro-2H-pyran-2-yl)oxy)acetate</strong>, 2 (2 g, 0.0 106 mol) in diethyl ether (20 mL), LDA (1M in THF, 6.3 mL, 0.0063 mmol) was added slowly at - 78 C and allowed to stir at 25 C for 1 h. After completion of the reaction, reaction mixture was quenched with saturated NH4C1 and reaction mixture was diluted with EtOAc and water. The layers were separated and aqueous layer was extracted with EtOAc, combined organic layers were washed with brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was dissolved in ethanol. To this mixture 2-(4-iodophenoxy)acetimidamide hydrochloride, 5 (6.6 g, 0.02 1 mol) and NaOEt (21% in ethanol, 6.8 mL, 0.021 mol) were added and heated to reflux for 2 h. After completion of the reaction, solvent was removed under reduced pressure. The crude product was dissolved in EtOAc and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using dichloromethane and 1-8% of methanol and to get 1.2 g (20.8%) pure 2- ((4-iodophenoxy)methyl)-5 -((tetrahydro-2H-pyran-2-yl)oxy)-6-(((tetrahydro-2H-pyran-2- yl)oxy)methyl) pyrimidin-4(3H)-one, 6 as an off white solid. UPLC = Calculated for C22H271N206: 542.37, Observed = 543.2

Reference： [1]Patent: WO2017/83431,2017,A2 .Location in patent: Paragraph 00216; 00220

49
[ 61675-94-3 ]
[ 389130-65-8 ]

Reference： [1]Patent: WO2007/121453,2007,A2

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Precautionary Statements-General
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P321
P322
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P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
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P378
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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Physical hazards
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H200	Unstable explosive
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H240	Heating may cause an explosion
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H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Code	Phrase
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H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 61675-94-3 ] {[proInfo.proName]}

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[ 61675-94-3 ] Synthesis Path-Upstream 1~2

[ 61675-94-3 ] Synthesis Path-Downstream 1~49

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Ethers

Esters

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Tetrahydropyrans

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[ 61675-94-3 ]

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