[ CAS No. 3143-02-0 ] {[proInfo.proName]}

Name: 3143-02-0|3-Methyl-3-oxetanemethanol|97%
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Quality Control of [ 3143-02-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 3143-02-0 ]

CAS No. :	3143-02-0	MDL No. :	MFCD00010273
Formula :	C₅H₁₀O₂	Boiling Point :	-
Linear Structure Formula :	OC₃H₄(CH₃)(CH₂OH)	InChI Key :	NLQMSBJFLQPLIJ-UHFFFAOYSA-N
M.W :	102.13	Pubchem ID :	137837
Synonyms :

Calculated chemistry of [ 3143-02-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	26.02
TPSA :	29.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.42
Log Po/w (XLOGP3) :	-0.18
Log Po/w (WLOGP) :	0.02
Log Po/w (MLOGP) :	-0.16
Log Po/w (SILICOS-IT) :	1.1
Consensus Log Po/w :	0.44

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.29
Solubility :	51.9 mg/ml ; 0.508 mol/l
Class :	Very soluble
Log S (Ali) :	0.02
Solubility :	106.0 mg/ml ; 1.04 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.58
Solubility :	26.8 mg/ml ; 0.262 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.19

Safety of [ 3143-02-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3143-02-0 ]

* 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 [ 3143-02-0 ]
Downstream synthetic route of [ 3143-02-0 ]

[ 3143-02-0 ] Synthesis Path-Upstream 1~14

1
[ 77-85-0 ]
[ 3143-02-0 ]

Yield	Reaction Conditions	Operation in experiment
83.7%	at 115℃; for 1 h;	Equipped with a stirrer, a reflux condenser and a thermometer three-necked flask, followed by adding diethyl carbonate 215ml, trimethylolethane 180g and Κ0Η0. Lg. Heated under stirring to 115 ° C, the reaction was refluxed for lh, the means to reflux distillation apparatus, collecting by-product alcohol was distilled, heating was continued and then distilled collecting the fraction 205~210 ° C to give product 3-hydroxymethyl-3 - methyl-oxetane (2) total 128. 2g. The yield was 83.7percent. Its 1HNMR see Figure 2.

Reference： [1] Patent: CN103772347, 2016, B, . Location in patent: Paragraph 0019; 0020; 0021
[2] Acta Chemica Scandinavica, 1991, vol. 45, # 1, p. 82 - 91
[3] Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 884 - 887
[4] Liebigs Annalen, 1995, # 12, p. 2059 - 2068
[5] Polymer, 2011, vol. 52, # 25, p. 5716 - 5722
[6] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1994, vol. 336, # 8, p. 663 - 677
[7] Journal of the American Chemical Society, 1957, vol. 79, p. 3455
[8] Tetrahedron Letters, 1983, vol. 24, # 50, p. 5571 - 5574

2
[ 1620017-21-1 ]
[ 3143-02-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 2 h;	General procedure: A 1M solution of TBAF in THF (6.73 mL, 6.73 mmol) was added to tert-butyl[(3-methoxyoxetan-3-yl)methoxy]diphenylsilane (2.4 g,6.73 mmol) in THF (20 mL) at ambient temperature. The resulting solution was stirred for 2 h. The reaction mixture was evaporated to dryness to give a crude product, which was purified by flash silica gel chromatography, eluted with a gradient of 0 to 100percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford(3-methoxyoxetan-3-yl)methanol (0.650 g, 82percent) as a colourless oil.
84%	With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 2 h;	General procedure: A 1M solution of TBAF in THF (6.73 mL, 6.73 mmol) was added to tert-butyl[(3-methoxyoxetan-3-yl)methoxy]diphenylsilane (2.4 g, 6.73 mmol) in THF (20 mL) at ambienttemperature. The resulting solution was stirred for 2 h. The reaction mixture was evaporatedto dryness to give a crude product, which was purified by flash silica gel chromatography,eluted with a gradient of 0 to 100percent EtOAc in heptane. Pure fractions were evaporated todryness to afford (3-methoxyoxetan-3-yl)methanol

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119
[2] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119

3
[ 77-85-0 ]
[ 105-58-8 ]
[ 3143-02-0 ]

Reference： [1] Patent: US5214166, 1993, A,

4
[ 1256651-65-6 ]
[ 3143-02-0 ]
[ 111-26-2 ]

Reference： [1] Journal of the American Chemical Society, 2010, vol. 132, # 47, p. 16756 - 16758

5
[ 2210-03-9 ]
[ 3143-02-0 ]

Reference： [1] Synthesis, 1990, # 2, p. 106 - 109

6
[ 72999-08-7 ]
[ 3143-02-0 ]

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119
[2] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119

7
[ 1620017-20-0 ]
[ 3143-02-0 ]

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119
[2] Tetrahedron Letters, 2014, vol. 55, # 30, p. 4117 - 4119

8
[ 3032-55-1 ]
[ 3143-02-0 ]
[ 77-85-0 ]
[ 84051-80-9 ]
[ 84051-79-6 ]
[ 84051-81-0 ]

Reference： [1] Journal of Organic Chemistry, 1983, vol. 48, # 3, p. 315 - 321

9
[ 3143-02-0 ]
[ 78385-26-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 0.333333 h;	10 ml (0.1 mol) of 3-methyl-3-(hydroxymethyl)oxetane and 36.58 g (0.11 mol) of carbone tetrabromide were dissolved in 100 ml of CH₂Cl₂. The solution was cooled to 0°C under nitrogen atmosphere, and 31.56 g (0.12 mol) of triphenylphosphine was gradually added thereto. The mixture was heated to room temperature and stirred for 20 minutes. After the reaction terminated, the solvent was removed under reduced pressure. 100 ml of ethylene acetate was added thereto and the mixture was filtered using celite to remove impurities. After the solvent was removed from the mixture, hexane was added thereto. The mixture was filtered using celite, and concentrated under reduced pressure. The resultant product was fractionally distilled to obtain 16 g of 3-methyl-3-(bromomethyl)oxetane (Yield: 95percent). NMR spectroscopy of the resulting product was: ¹H NMR (CDCl₃, 300MHz): δ4.46-4.38 (d+d, 4H), 3.65(s, 2H), 1.44(s, 3H).

Reference： [1] Journal of Organic Chemistry, 1998, vol. 63, # 11, p. 3631 - 3646
[2] Patent: EP1927592, 2008, A1, . Location in patent: Page/Page column 11
[3] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1981, p. 1406 - 1414
[4] Acta Chemica Scandinavica, 1991, vol. 45, # 1, p. 82 - 91
[5] Journal of Organic Chemistry, 1998, vol. 63, # 11, p. 3631 - 3646
[6] Patent: US2005/227997, 2005, A1, . Location in patent: Page/Page column 41
[7] Bulletin of the Chemical Society of Japan, 2011, vol. 84, # 1, p. 26 - 39
[8] Patent: WO2018/75698, 2018, A1,

10
[ 3143-02-0 ]
[ 558-13-4 ]
[ 603-35-0 ]
[ 78385-26-9 ]

Reference： [1] Patent: EP1081137, 2001, A1,

11
[ 3143-02-0 ]
[ 98-59-9 ]
[ 99314-44-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1-methyl-1H-imidazole; triethylamine In dichloromethane at 25℃; for 2 h;	1. To a solution of N-014-005_1 (10 g, 97.9 mmol) in DCM (100 mL) was added 1-methyl-1H- imidazole (16.0 g, 195 mmol) and TEA (19.7 g, 195 mmol) at 25°C. TsCl (37.1 g, 195 mmol) was added into the solution. The reaction mixture was stirred at 25°C for 2 hours. The mixture was washed with water (2 x 100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to give N-014-005_2 (25 g, crude) as a light yellow solid, which was purified by column chromatography on silica gel (0~15percent of EtOAc in PE) to give N-014-005_2 (23.6 g, 95percent) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.80-7.68 (m, 2H), 7.41-7.26 (m, 2H), 3.40-3.29 (m, 4H), 4.12- 4.00 (s, 2H), 2.44 (s, 3H), 1.28 (s, 3H).
90%	With pyridine In dichloromethane at 0℃; for 2 h;	57.20 g (0.3 mmol) of p-toluene sulfonyl chloride was added to 250 ml of pyridine under nitrogen atmosphere mixture, and the mixture was cooled in ice water. When the mixture was cooled, 20 ml (MOMT: 20.68g, 0.20 mmol) of 3-methyl-3-oxetane-methanol) was gradually added thereto and the mixture was reacted for 2 hours. After the reaction terminated, the resultant mixture was added to 2L of ice water (1:1, v/v) and stirred for 30 minutes. The obtained precipitate was filtered, washed with water, and dried in a vacuum to obtain toluene-4-sulfonic acid 3-methyl-oxetane-3-yl methyl ester (Yield: 90percent). NMR spectroscopy of the resulting product was: ¹H NMR (CDCl₃, 300MHz): δ 7.78(d, 2H), 7.34(d, 2H), 4.31(m, 4H), 4.04(s, 2H), 2.43(s, 3H), 1.27(s, 3H)
85.6%	With triethylamine In dichloromethane at 20℃; for 2 h; Inert atmosphere; Cooling with ice	Intermediate-36: (3-Methyloxetan-3-yl) methyl 4-methylbenzenesulfonate: To an ice cooled solution of 3-methyloxetan-3-yl) methanol (5.0 g) g, 0.48 mmol) in dry dichloromethane (60 mL) was added triethylamine (7.4 g, 0.73mmol) followed by /7-toluene sulfonyl chloride (10.2g, 0.53 mmol) under nitrogen atmosphere. The reaction was stirred at ambient temperature for 2 hours. After the completion of reaction, the reaction mixture was quenched with of ice water. The organic compound was extracted and organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, with an isocratic elution of 20 percent ethyl acetate to result the desired compound (10.7g, 85.6 percent). 1H NMR (400 MHz, DMSO-6): δ 7.83 (d, J = 6.8 Hz, 2H),7.07 (d, J= 7.6 Hz, 2H)), 4.25-4.18 (m, 4H), 4.1 1 (s, 2H), 2.43 (s, 3H), 1.18 (s, 3H); MS (ES+) m/z: 257.1 (M+l).

74.7%	With triethylamine In dichloromethane at 0 - 20℃; for 5 h;	Step 1 a Synthesis of 3-Methyloxetan-3-yl)methyl 4-methylbenzenesulfonate To a solution of (3-methyloxetan-3-yl)methanol (1 g, 9.79 mM) in DCM (15 ml), triethylamine (2.71 ml, 19.58 mM) was added at 0 ^QC followed by the addition of 4- methylbenzene-1 -sulfonyl chloride (1 .867 g, 9.79 mM). The reaction mixture was stirred at RT for 3h to 5h. The reaction mixture was then quenched with water, extracted with ethyl acetate and purified by column chromatography to afford the title compound (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1 .875 g) as a white solid. Yield: 74.7percent; ¹ H NMR (DMSO-d₆, 300 MHz): δ 7.82 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 4.25 (d, J=5.7 Hz, 2H), 4.19 (d, J=6.0 Hz, 2H), 4.1 1 (s, 2H), 2.43 (s, 3H), 1 .18 (s, 3H); MS (ESI): m/z 279.0 (M+Na).
72%	at 0 - 20℃; for 1.75 h; Inert atmosphere	Exam le 429: A solution of p-toluenesulfonyl chloride (74.36 g, 0.39 mol, 1 .5 equiv) in anhydrous pyridine (300 mL) is dropwise added 3-methyl-3-oxetane- methanol (26.52 g, 0.26 mol) over 10 min at 0°C under argon. After 5 min, the reaction mixture is allowed to warm to room temperature with the stirring is continued for an additional 1 .5h. The mixture is then slowly added to a vigorously stirring mixture of milliQ water 800 mL and crushed ice 800 g for 30 min. Then the white precipitate is collected on whatman filter No.1 and washed with cold water (300 mL). The product is dried under high vacuum to obtain a white power of oxetane tosylate 29 (47.88 g 72percent yield). ¹H NMR (300 MHz, CDCI₃) 51 .28 (s, 3H), 2.43 (s, 3H), 4.08 (s, 2H), 4.29-4.35 (m, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H); ¹³C NMR (75 MHz, CDCI₃) 520.85, 21 .86, 39.45, 74.50, 79.13, 128.15, 130.22, 132.81 , 145.34; LC/MS m/s [M+H]⁺164.9.
50%	at 0℃; for 2 h;	Synthesis of Intermediate (3-methyloxetan-3'Vl)methyl 4-methylbenzenesulfonate (1-16a):p-Toluene sulfonyl chloride (5.6 g, 29.41 mmol) was added to a cooled solution of (3-methyloxetan-3-yl)methanol (2 g, 19.60 mmol) in pyridine (25 mL) at 0°C and the resulting reaction mass was stirred at 0°C for 2 hours. The reaction was monitored by TLC (20percent ethyl acetate in hexane). The reaction mass was poured into ice-water, stirred for 30 minutes, the solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.5 g of the product (50percent yield).¹HNMR (CDCI₃, 300MHz): δ 7.8 (d, 2H), 7.4 (d, 2H), 4.4 (m, 4H), 4.1 (s, 2H), 2.5 (s, 3H), 1.3 (s, 3H). LCMS: 99.13percent, m/z = 256 (M+1)
50%	With pyridine In methanol at 0℃; for 2 h;	p-Toluene sulfonyl chloride (5.6 g, 29.41 mmol) was added to a cooled solution of (3-methyloxetan-3-yl)methanol (2 g, 19.60 mmol) in pyridine (25 mL) at 0° C. and the resulting reaction mass was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (20percent ethyl acetate in hexane). The reaction mass was poured into ice-water, stirred for 30 minutes, the solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.5 g of the product (50percent yield).¹HNMR (CDCl₃, 300 MHz): δ 7.8 (d, 2H), 7.4 (d, 2H), 4.4 (m, 4H), 4.1 (s, 2H), 2.5 (s, 3H), 1.3 (s, 3H). LCMS: 99.13percent, m/z=256 (M+1)
47%	With pyridine In dichloromethane at 0 - 20℃; for 16 h;	To a solution of scheme 9-1 compound 51 (10.2 g, 100 mmol) and pyridine (60 mL) in anhydrous DCM (60 mL) at 0 °C was added TsC1 (22.92 g, 120 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (100 mL). The resulting mixture was extracted with DCM (150 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by column chromatography on silica gel to afford scheme 9-1 compound S2 (12 g, 47percent yield). LC-MS: m/z 257 (M+H)t
43%	With dmap; triethylamine In dichloromethane at 20℃; for 3 h;	To a solution of (3-methyloxetan-3-yl)methanol (1.02 g, 10 mmol) inDCM (20 ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.0 g, 20mmol) and 4-methylbenzenesulfonyl chloride (1.9 g, 10 mmol). The mixture was stirred at rtfor 3 h, concentrated, and the residue purified by column chromatography eluting with ethylacatate in petroleum ether (1/4) to afford (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1.1 g, 43percent yield). LCMS (ESI) m/z: 257.4 (M + 1t.
1.05 g	With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 0℃; for 0.25 h;	EXAMPLE 17 3-Methyl-3-oxetanylmethyl-4-methylbenzene-sulfonate At 0° C., to a solution of 3-methyl-3-oxetanyl methanol (507 mg, 4.97 mmol, commercially available) in CH₂Cl₂ (15 mL) was added DABCO (1.12 g, 9.94 mmol) and TsCl (1.09 g, 5.72 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH₂Cl₂ and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum to afford the residue (1.05 g), which was used for the next step without further purification.

Reference： [1] Chemistry of Materials, 2016, vol. 28, # 18, p. 6628 - 6636
[2] Organic Syntheses, 2002, vol. 79, p. 216 - 216
[3] Patent: WO2018/75698, 2018, A1, . Location in patent: Paragraph 00272
[4] Journal of Organic Chemistry, 1998, vol. 63, # 11, p. 3631 - 3646
[5] Tetrahedron, 2001, vol. 57, # 8, p. 1497 - 1507
[6] Journal of the American Chemical Society, 1999, vol. 121, # 23, p. 5459 - 5466
[7] Patent: EP1927592, 2008, A1, . Location in patent: Page/Page column 10
[8] Patent: WO2012/49555, 2012, A1, . Location in patent: Page/Page column 65-66
[9] Bulletin of the Chemical Society of Japan, 2011, vol. 84, # 1, p. 26 - 39
[10] Acta Chemica Scandinavica, 1992, vol. 46, # 3, p. 271 - 277
[11] Synthetic Communications, 2011, vol. 41, # 17, p. 2539 - 2543
[12] Patent: WO2017/40537, 2017, A1, . Location in patent: Page/Page column 42
[13] Patent: WO2013/128378, 2013, A1, . Location in patent: Page/Page column 108
[14] Patent: WO2013/59651, 2013, A1, . Location in patent: Sheet 32
[15] Patent: WO2012/31298, 2012, A2, . Location in patent: Page/Page column 53-54
[16] Journal of Medicinal Chemistry, 2013, vol. 56, # 17, p. 6954 - 6966
[17] Journal of Medicinal Chemistry, 2012, vol. 55, # 8, p. 3960 - 3974
[18] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9769 - 9789
[19] Patent: WO2011/54828, 2011, A1, . Location in patent: Page/Page column 82
[20] Patent: US2011/190334, 2011, A1, . Location in patent: Page/Page column 30-31
[21] Patent: WO2017/35411, 2017, A1, . Location in patent: Paragraph 0623; 0634
[22] Patent: WO2018/154466, 2018, A1, . Location in patent: Paragraph 00473; 00475; 00476
[23] Patent: WO2006/60494, 2006, A1, . Location in patent: Page/Page column 61
[24] Patent: US2009/76062, 2009, A1, . Location in patent: Page/Page column 19
[25] Patent: US2009/156610, 2009, A1, . Location in patent: Page/Page column 86
[26] Patent: US2003/232863, 2003, A1, . Location in patent: Page 68
[27] Patent: WO2010/6191, 2010, A1, . Location in patent: Page/Page column 32
[28] Assay and Drug Development Technologies, 2012, vol. 10, # 3, p. 269 - 277
[29] Patent: WO2012/133861, 2012, A1, . Location in patent: Page/Page column 209-210
[30] Patent: US2013/324464, 2013, A1, . Location in patent: Paragraph 0158; 0159
[31] Patent: EP2676965, 2013, A1, . Location in patent: Paragraph 0105; 0106
[32] RSC Advances, 2015, vol. 5, # 110, p. 90422 - 90427
[33] Patent: WO2015/186056, 2015, A1, . Location in patent: Page/Page column 105
[34] Patent: WO2016/41892, 2016, A1, . Location in patent: Page/Page column 50
[35] Patent: US2017/107190, 2017, A1, . Location in patent: Paragraph 0167

12
[ 3143-02-0 ]
[ 99314-44-0 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 46, p. 5747 - 5750

13
[ 3143-02-0 ]
[ 153209-97-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 45, p. 8661 - 8664

14
[ 3143-02-0 ]
[ 99419-31-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With trichloroisocyanuric acid In dichloromethane at -5 - 20℃; for 0.666667 h;	Preparation 193 -Methyloxetane-3 -carbaldehyde(3-Methyloxetan-3-yl)methanol (6.0 g, 58.75 mmol) is dissolved in dichloromethane (1 17 mL). Trichloroisocyanuric acid (13.93 g, 59.92 mmol) is added portionwise at -5 °C followed by the addition of 2,2,6,6-tetramethylpiperidine- 1-oxyl (TEMPO) (0.92 g, 5.87 mmol). The reaction mixture is stirred at -5 °C for 20 min, allowed to warm to RT, and stirred for 20 additional min. The mixture is filtered through a pad of CELITE.(R)., diluted with dichloromethane (200 mL), and washed with saturated aqueous Na₂C0₃ (100 mL), 1 N HC1 (100 mL) and brine (50 mL). The organic portion is concentrated to afford the title compound as an orange oil (4.17 g, 71percent) that is used without further purification. ^XH NMR(400 MHz, CDC1₃); δ 1.48 (s, 3H), 4.50 (d, 2H, J= 6.34 Hz), 4.88 (d, 2H, J= 6.34 Hz), 9.95 (s, 1H).
62%	With pyridinium chlorochromate In dichloromethane at 20℃; for 5 h;	(Method b) 3-Methyloxetane-3-carbaldehyde A solution of (3-methyloxetan-3-yl)methanol (20.4 g, 0.2 mol) in 200 ml of dichloromethane was added dropwise to a mixture of pyridinium chlorochromate (68.9 g, 0.32 mol) and celite (20.4 g) in 700 ml of dichloromethane. The reaction medium was stirred at ambient temperature for 5 hours. The reaction medium was filtered on 250 g of silica and diluted with dichloromethane. The organic phases were combined and evaporated at 30° C. at ˜500 mbar then 3 times 30 seconds at 10° C. at ˜30 mbar. 12.42 g of 3-methyloxetan-3-carbaldehyde were obtained in the form of a volatile pale green oil. Yield=62percent.
51%	With silica gel; pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 6.5 h; Inert atmosphere	To a stirred solution of (3-methyloxetan-3-yl)methanol (Int-18a,10.0 g, 97.9 mmol) in methylene chloride (400 mL) at 0 °C, under inert atmosphere, was added silica gel (20 g). PCC (29.5 g, 137 mmol) was then added in portions over a 2 minutesute period. The solution was allowed to slowly warm to room temperature and stirred for 6.5 hours. The reaction mixture was then filtered through a mixture of Celite:silica gel (1 : 1, 400 g total) and the Celite: Silica gel was washed with methylene chloride (4 L). The filtrate and washing were combined and concentrated in vacuo to provide 4.98 g (51percent) of Int-18b as a clear solution (48.5 wtpercent) in methylene chloride. NMR (CDC1₃ 500 MHz): 5 9.94 (s, 1H), 4.89 4.83 (m, 2H), 4.52 4.46 (m, 2H), 1.48 (s, 3H).

51%	With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 6.5 h; Inert atmosphere	lnt-18a Int-18b To a stirred solution of (3-methyloxetan-3-yl)methanol (Int-18a, 10.0 g, 97.9 mmol) in methylene chloride (400 mL) at 0 °C, under inert atmosphere, was added silica gel (20 g). PCC (29.5 g, 137 mmol) was then added in portions over a 2 minute period. The solution was allowed to slowly warm to room temperature and stirred for 6.5 hours. The reaction mixture was then filtered through a mixture of Celite: silica gel (1 : 1, 400 g total) and the Celite: Silica gel was washed with methylene chloride (4 L). The filtrate and washing were combined and concentrated in vacuo to provide 4.98 g (51percent) of Int-18b as a clear solution (48.5 wtpercent) in methylene chloride. 1H NMR (CDC1₃ 500 MHz): δ 9.94 (s, 1H), 4.89-4.83 (m, 2H), 4.52-4.46 (m, 2H), 1.48 (s, 3H).
47%	With pyridinium chlorochromate In dichloromethane at 20℃; for 4 h; Molecular sieve	Preparation No.3: S-Methyloxetane-S-carbaldehyde; <n="53"/>To a 100 mL round-bottomed flask charged with PCC (1.7 g, 5.9 mmol) was added DCM (25 mL) to give an orange solution. (3-Methyloxetan-3-yl)methanol (0.50 g, 4.90 mmol) was added dropwise as a solution in DCM (5 mL). About 0.5 g of Celite^.(R). was added, and the reaction was allowed to stir for about 4 h at ambient temperature. The reaction was then filtered through about 20 g of SiO₂ and concentrated under reduced pressure to provide the title compound as a colorless oil (0.23 g, 47percent). IH NMR (CDCl₃ δ 9.95 (s, IH), 8.86 (s, IH), 4.87 (d, J = 3.2 Hz, 2H), 4.50 (d, J = 3.2 Hz, 2H).
1.55 g	With pyridinium chlorochromate In dichloromethane at 20℃; for 0.5 h;	75 g (31.3 mmol) ofpyridinium chlorochromate were initially charged in 100 ml of dichloromethane,and a solution of 2.00 g (19.6 mmol) of (3-methyloxetan-3-yl)methanol in 20 mlof dichloromethane was added at room temperature. 7 g of Celite were thenadded, and the mixture was stirred at room temperature for another 4 h. Themixture was filtered off with suction through silica gel and the solvent wasremoved under reduced pressure at room temperature. The crude product was usedfor the next step without further purification. Yield: 1.55 g (79percent of theory)

Reference： [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 11, p. 1843 - 1850
[2] Patent: WO2012/74761, 2012, A1, . Location in patent: Page/Page column 19-20
[3] Patent: US2014/309208, 2014, A1, . Location in patent: Paragraph 0363; 0365
[4] Patent: WO2012/41014, 2012, A1, . Location in patent: Page/Page column 123-124
[5] Patent: WO2012/40923, 2012, A1, . Location in patent: Page/Page column 105
[6] Patent: WO2008/63287, 2008, A2, . Location in patent: Page/Page column 51-52
[7] Journal of the American Chemical Society, [8] Journal of the American Chemical Society, 2009, vol. 131, p. 2786 - 2787
[9] Patent: US5354865, 1994, A,
[10] Patent: US2011/166124, 2011, A1, . Location in patent: Page/Page column 39
[11] Patent: WO2013/188856, 2013, A1, . Location in patent: Paragraph 0283
[12] Patent: US2014/309208, 2014, A1, . Location in patent: Paragraph 0363; 0364
[13] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 9811 - 9831
[14] Patent: US2016/52884, 2016, A1, . Location in patent: Paragraph 1730-1732
[15] Patent: WO2016/123391, 2016, A1, . Location in patent: Page/Page column 90
[16] Patent: KR2015/137095, 2015, A, . Location in patent: Paragraph 2532-2535
[17] Angewandte Chemie - International Edition, 2017, vol. 56, # 39, p. 11958 - 11962[18] Angew. Chem., 2017, vol. 129, # 39, p. 12120 - 12124,5

[ 3143-02-0 ] Synthesis Path-Downstream 1~45

1
[ 77-85-0 ]
[ 3143-02-0 ]

Yield	Reaction Conditions	Operation in experiment
83.7%	With potassium hydroxide; Diethyl carbonate at 115℃; for 1h;	1.1 1,Synthetic route for preparing the compound (2) 3-methyl-3-hydroxymethyl oxetane Equipped with a stirrer, a reflux condenser and a thermometer three-necked flask, followed by adding diethyl carbonate 215ml, trimethylolethane 180g and Κ0Η0. Lg. Heated under stirring to 115 ° C, the reaction was refluxed for lh, the means to reflux distillation apparatus, collecting by-product alcohol was distilled, heating was continued and then distilled collecting the fraction 205~210 ° C to give product 3-hydroxymethyl-3 - methyl-oxetane (2) total 128. 2g. The yield was 83.7%. Its 1HNMR see Figure 2.
81%	With potassium hydroxide; Diethyl carbonate In ethanol for 2h; Heating;
77%	Stage #1: 2-(hydroxymethyl)-2-methylpropane-1,3-diol With potassium hydroxide; carbonic acid dimethyl ester In methanol Heating; Stage #2: at 130 - 140℃;

64%	With potassium hydroxide; Diethyl carbonate In ethanol for 0.25h; Heating;
63%	With potassium carbonate; Diethyl carbonate at 130℃;
48%	With Diethyl carbonate
	With potassium hydroxide; Diethyl carbonate at 180℃; unter vermindertem Druck;
	With potassium hydroxide In various solvent(s) for 0.25h; Heating; Yield given;

Reference： [1]Current Patent Assignee: HIGH TEC RESEARCH INSTITUTE OF NANJING UNIVERSITY - CN103772347, 2016, B Location in patent: Paragraph 0019; 0020; 0021
[2]Dale, Johannes; Fredriksen, Siw B. [Acta Chemica Scandinavica, 1991, vol. 45, # 1, p. 82 - 91]
[3]Zhdanko, Alexander G.; Nenajdenko, Valentine G. [Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 884 - 887]
[4]Rakus, Klaus; Verevkin, Sergey P.; Peng, Wei-Hong; Beckhaus, Hans-Dieter; Ruechardt, Christoph [Liebigs Annalen, 1995, # 12, p. 2059 - 2068]
[5]Location in patent: experimental part Mindemark, Jonas; Bowden, Tim [Polymer, 2011, vol. 52, # 25, p. 5716 - 5722]
[6]Laatsch, Hartmut; Pudleiner, Alke [Journal fur Praktische Chemie - Chemiker-Zeitung, 1994, vol. 336, # 8, p. 663 - 677]
[7]Pattison [Journal of the American Chemical Society, 1957, vol. 79, p. 3455]
[8]Corey, E. J.; Raju, Natarajan [Tetrahedron Letters, 1983, vol. 24, # 50, p. 5571 - 5574]

2
[ 3143-02-0 ]
[ 110-52-1 ]
[ 103781-33-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydroxide; tetrabutylammomium bromide In hexane; water at 20℃; for 4.5h; Heating / reflux;	1.1.5 (1-5) A three-neck flask having a capacity of 2 liters is charged with 50 g of compound 7, 8.2 g of tetrabutylammonium bromide, 400 ml of hexane, 640 g of a 50 wt% sodium hydroxide aqueous solution, and 317 g of 1,4-dibromobutane. The reaction mixture is reacted at room temperature for 30 minutes, and for 4 hours while refluxing. After the reaction solution is washed with water, the solvent is removed. The reaction product is refined by distillation to obtain 87 g of compound 8.
80%	With tetrabutylammomium bromide; sodium hydroxide In hexane; water for 0.5h; Reflux;	2 Example 2 MeBr₄Preparation Ox monomers: 1,4-dibromobutane (20g, 93mmol) and 3-methyl-3-hydroxymethyl-oxetane (3.1g, 31mmol), sodium hydroxide (20g, 500mmol) in water and hexane stir in two-phase system, with tetrabutylammonium bromide as phase transfer catalyst, the reaction for 0.5 hours under reflux.After completion of the reaction by extraction, purified by distillation under reduced pressure to give a colorless liquid.Yield: 80%.
76.2%	With sodium hydroxide; tetrabutylammomium bromide In hexane; water 1) RT, 30 min, 2) reflux, 1.5 h;

With tetrabutylammomium bromide; sodium hydroxide In hexane; water at 20℃; Reflux;

Reference： [1]Current Patent Assignee: FUJIFILM HOLDINGS CORP. - WO2008/62900, 2008, A1 Location in patent: Page/Page column 44; 46
[2]Current Patent Assignee: SUZHOU RYAN NANOMEDICINE CO., LTD. - CN105523946, 2016, A Location in patent: Paragraph 0023
[3]Motoi, Masatoshi; Suda, Hiroshi; Shimamura, Katsuhiko; Nagahara, Shinsuke; Takei, Mitsuru; Kanoh, Shigeyoshi [Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 5, p. 1653 - 1660]
[4]Lin, Chih-Hung [Asian Journal of Chemistry, 2015, vol. 27, # 4, p. 1495 - 1500]

3
[ 3143-02-0 ]
[ 67-56-1 ]
[ 21398-89-0 ]

Reference： [1]Acta Chemica Scandinavica,1992,vol. 46,p. 271 - 277

4
[ 3143-02-0 ]
[ 61542-10-7 ]
[ 141100-26-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride 1.) THF, reflux, 1 d, 2.) THF, reflux, 2 d; Yield given. Multistep reaction;

Reference： [1]Dale, Johannes; Fredriksen, Siw B. [Acta Chemica Scandinavica, 1992, vol. 46, # 3, p. 271 - 277]

5
[ 3143-02-0 ]
[ 927-58-2 ]
[ 89276-32-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With pyridine In dichloromethane at 0℃; for 2h;
72%	With pyridine In dichloromethane at 0 - 20℃; for 16h;	2 Step 2: Preparation of (3-methyloxetan-3-yl)methyl 4-bromobutanoate Into a 250-mL round-bottom flask, was placed (3-methyloxetan-3-yl)methanol (6.14 g, 60.12 mmol, 1.00 equiv), dichloromethane (100 mL), pyridine (5.70 g, 72.06 mmol, 1.20 equiv). This was followed by the addition of a solution of 4-bromobutanoyl chloride (11.08 g, 59.75 mmol, 0.99 equiv) in dichloromethane (100 mL) dropwise with stirring at 0. The resulting solution was stirred for 16 h at room temperature. The resulting solution was extracted with dichloromethane (50 mL x 2) and the organic layers combined. The resulting mixture was washed with brine (10 mL x 2). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 11.4 g (72%) of 5-bromo-1-[(3-methyloxetan-3-yl)methoxy]pentan-2-one as light yellow oil.
	With pyridine In dichloromethane at 0℃;

	With pyridine; 4 A molecular sieve In tetrahydrofuran at 0℃; for 1h;
	With pyridine In dichloromethane at 0℃;	1 3-Methyl-3-hydroxymethyloxetane (10.2 g, 0.1 mole) (Sigma-Aldrich Corporation, St. Louis, Mo.) was dissolved in anhydrous dichloromethane (200 ml). Pyridine (9.8 ml, 0.12 moles) was then added to the solution. Thereafter, the solution was cooled to 0° C. and 4-bromobutyryl chloride (18.5 g, 0.1 mole) (Sigma-Aldrich Corporation, St. Louis, Mo.) dissolved in anhydrous dichloromethane (50 ml) was added dropwise over 20 minutes. The mixture was stirred overnight under argon atmosphere. Next, the reaction mixture was washed with water and dried with anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. Yield 23.6 g. NMR (d6-DMSO): 1.26 ppm (s, 3H), 2.07 ppm (m, 2H), 2.51 ppm (t, 2H), 3.56 ppm (t, 2H), 4.14 ppm (s, 2H), 4.24 ppm (d, 2H), 4.38 ppm (d, 2H).
	With pyridine In tetrahydrofuran at 0℃; for 1h;
	With pyridine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;	2.1.1.1 Preparation of (3-methyloxetan-3-yl)methyl ω-bromoalkanoate (9a-d) General procedure: Pyridine (10.5 mmol) was dissolved into dry tetrahydrofuran (18 mL) and the solution cooled to 0 °C in an ice bath. 3-Methyl-3-oxetanemethanol (8.75 mmol) was added and then the appropriate ω-bromoalkanoyl chloride (9.75 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was poured into an ice-water mixture and then extracted with methylene chloride (5× 30 mL). The aqueous phase was concentrated under reduced pressure to remove remaining tetrahydrofuran and methylene chloride, and then extracted with methylene chloride (2× 100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford the desired (3-methyloxetan-3-yl)methyl ω-bromoalkanoates (9a-d) in quantitative yields that were used without further purification at the next step.

Reference： [1]Jones, Raymond C. F.; Schofield, Julie [Journal of the Chemical Society. Perkin transactions I, 1990, # 2, p. 375 - 383]
[2]Current Patent Assignee: YALE UNIVERSITY; ARVINAS - WO2020/51564, 2020, A1 Location in patent: Paragraph 2303; 2304
[3]Corey, E. J.; Raju, Natarajan [Tetrahedron Letters, 1983, vol. 24, # 50, p. 5571 - 5574]
[4]Cano, Montserrat; Ladlow, Mark; Balasubramanian, Shankar [Journal of Organic Chemistry, 2002, vol. 67, # 1, p. 129 - 135]
[5]Current Patent Assignee: NEKTAR THERAPEUTICS - US2005/36978, 2005, A1 Location in patent: Page/Page column 22-23
[6]Champeil, Elise; Crean, Conor; Larraya, Carlos; Pescitelli, Gennaro; Proni, Gloria; Ghosez, Léon [Tetrahedron, 2008, vol. 64, # 45, p. 10319 - 10330]
[7]Saha, Pijus; Fortin, Sebastien; Leblanc, Valerie; Parent, Sophie; Asselin, Eric; Berube, Gervais [Steroids, 2012, vol. 77, # 11, p. 1113 - 1122]

6
[ 3143-02-0 ]
[ 99314-44-0 ]
[ 141100-23-4 ]

Reference： [1]Acta Chemica Scandinavica,1992,vol. 46,p. 271 - 277

7
[ 3143-02-0 ]
[ 4296-15-5 ]
[ 141100-05-2 ]

Reference： [1]Acta Chemica Scandinavica,1992,vol. 46,p. 271 - 277

8
[ 3143-02-0 ]
[ 98-59-9 ]
[ 99314-44-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1-methyl-1H-imidazole; triethylamine; In dichloromethane; at 25℃; for 2h;	1. To a solution of N-014-005_1 (10 g, 97.9 mmol) in DCM (100 mL) was added 1-methyl-1H- imidazole (16.0 g, 195 mmol) and TEA (19.7 g, 195 mmol) at 25C. TsCl (37.1 g, 195 mmol) was added into the solution. The reaction mixture was stirred at 25C for 2 hours. The mixture was washed with water (2 x 100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to give N-014-005_2 (25 g, crude) as a light yellow solid, which was purified by column chromatography on silica gel (0~15% of EtOAc in PE) to give N-014-005_2 (23.6 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.80-7.68 (m, 2H), 7.41-7.26 (m, 2H), 3.40-3.29 (m, 4H), 4.12- 4.00 (s, 2H), 2.44 (s, 3H), 1.28 (s, 3H).
90%	With pyridine; In dichloromethane; at 0℃; for 2h;	57.20 g (0.3 mmol) of p-toluene sulfonyl chloride was added to 250 ml of pyridine under nitrogen atmosphere mixture, and the mixture was cooled in ice water. When the mixture was cooled, 20 ml (MOMT: 20.68g, 0.20 mmol) of 3-methyl-3-oxetane-methanol) was gradually added thereto and the mixture was reacted for 2 hours. After the reaction terminated, the resultant mixture was added to 2L of ice water (1:1, v/v) and stirred for 30 minutes. The obtained precipitate was filtered, washed with water, and dried in a vacuum to obtain toluene-4-sulfonic acid 3-methyl-oxetane-3-yl methyl ester (Yield: 90%). NMR spectroscopy of the resulting product was: 1H NMR (CDCl3, 300MHz): delta 7.78(d, 2H), 7.34(d, 2H), 4.31(m, 4H), 4.04(s, 2H), 2.43(s, 3H), 1.27(s, 3H)
85.6%	With triethylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere; Cooling with ice;	Intermediate-36: (3-Methyloxetan-3-yl) methyl 4-methylbenzenesulfonate: To an ice cooled solution of 3-methyloxetan-3-yl) methanol (5.0 g) g, 0.48 mmol) in dry dichloromethane (60 mL) was added triethylamine (7.4 g, 0.73mmol) followed by /7-toluene sulfonyl chloride (10.2g, 0.53 mmol) under nitrogen atmosphere. The reaction was stirred at ambient temperature for 2 hours. After the completion of reaction, the reaction mixture was quenched with of ice water. The organic compound was extracted and organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography, with an isocratic elution of 20 % ethyl acetate to result the desired compound (10.7g, 85.6 %). 1H NMR (400 MHz, DMSO-</6): delta 7.83 (d, J = 6.8 Hz, 2H),7.07 (d, J= 7.6 Hz, 2H)), 4.25-4.18 (m, 4H), 4.1 1 (s, 2H), 2.43 (s, 3H), 1.18 (s, 3H); MS (ES+) m/z: 257.1 (M+l).

74.7%	With triethylamine; In dichloromethane; at 0 - 20℃; for 5h;	Step 1 a Synthesis of 3-Methyloxetan-3-yl)methyl 4-methylbenzenesulfonate To a solution of (3-methyloxetan-3-yl)methanol (1 g, 9.79 mM) in DCM (15 ml), triethylamine (2.71 ml, 19.58 mM) was added at 0 QC followed by the addition of 4- methylbenzene-1 -sulfonyl chloride (1 .867 g, 9.79 mM). The reaction mixture was stirred at RT for 3h to 5h. The reaction mixture was then quenched with water, extracted with ethyl acetate and purified by column chromatography to afford the title compound (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1 .875 g) as a white solid. Yield: 74.7%; 1 H NMR (DMSO-d6, 300 MHz): delta 7.82 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 4.25 (d, J=5.7 Hz, 2H), 4.19 (d, J=6.0 Hz, 2H), 4.1 1 (s, 2H), 2.43 (s, 3H), 1 .18 (s, 3H); MS (ESI): m/z 279.0 (M+Na).
72%	With pyridine; at 0 - 20℃; for 1.75h;Inert atmosphere;	Exam le 429: A solution of p-toluenesulfonyl chloride (74.36 g, 0.39 mol, 1 .5 equiv) in anhydrous pyridine (300 mL) is dropwise added 3-methyl-3-oxetane- methanol (26.52 g, 0.26 mol) over 10 min at 0C under argon. After 5 min, the reaction mixture is allowed to warm to room temperature with the stirring is continued for an additional 1 .5h. The mixture is then slowly added to a vigorously stirring mixture of milliQ water 800 mL and crushed ice 800 g for 30 min. Then the white precipitate is collected on whatman filter No.1 and washed with cold water (300 mL). The product is dried under high vacuum to obtain a white power of oxetane tosylate 29 (47.88 g 72% yield). 1H NMR (300 MHz, CDCI3) 51 .28 (s, 3H), 2.43 (s, 3H), 4.08 (s, 2H), 4.29-4.35 (m, 2H), 7.34 (d, J=7.8 Hz, 2H), 7.78 (d, J=7.5 Hz, 2H); 13C NMR (75 MHz, CDCI3) 520.85, 21 .86, 39.45, 74.50, 79.13, 128.15, 130.22, 132.81 , 145.34; LC/MS m/s [M+H]+164.9.
50%	With pyridine; at 0℃; for 2h;	Synthesis of Intermediate (3-methyloxetan-3'Vl)methyl 4-methylbenzenesulfonate (1-16a):p-Toluene sulfonyl chloride (5.6 g, 29.41 mmol) was added to a cooled solution of (3-methyloxetan-3-yl)methanol (2 g, 19.60 mmol) in pyridine (25 mL) at 0C and the resulting reaction mass was stirred at 0C for 2 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was poured into ice-water, stirred for 30 minutes, the solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.5 g of the product (50% yield).1HNMR (CDCI3, 300MHz): delta 7.8 (d, 2H), 7.4 (d, 2H), 4.4 (m, 4H), 4.1 (s, 2H), 2.5 (s, 3H), 1.3 (s, 3H). LCMS: 99.13%, m/z = 256 (M+1)
50%	With pyridine; In methanol; at 0℃; for 2h;	p-Toluene sulfonyl chloride (5.6 g, 29.41 mmol) was added to a cooled solution of (3-methyloxetan-3-yl)methanol (2 g, 19.60 mmol) in pyridine (25 mL) at 0 C. and the resulting reaction mass was stirred at 0 C. for 2 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was poured into ice-water, stirred for 30 minutes, the solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.5 g of the product (50% yield).1HNMR (CDCl3, 300 MHz): delta 7.8 (d, 2H), 7.4 (d, 2H), 4.4 (m, 4H), 4.1 (s, 2H), 2.5 (s, 3H), 1.3 (s, 3H). LCMS: 99.13%, m/z=256 (M+1)
47%	With pyridine; In dichloromethane; at 0 - 20℃; for 16h;	To a solution of scheme 9-1 compound 51 (10.2 g, 100 mmol) and pyridine (60 mL) in anhydrous DCM (60 mL) at 0 C was added TsC1 (22.92 g, 120 mmol). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (100 mL). The resulting mixture was extracted with DCM (150 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by column chromatography on silica gel to afford scheme 9-1 compound S2 (12 g, 47% yield). LC-MS: m/z 257 (M+H)t
43%	With dmap; triethylamine; In dichloromethane; at 20℃; for 3h;	To a solution of (3-methyloxetan-3-yl)methanol (1.02 g, 10 mmol) inDCM (20 ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.0 g, 20mmol) and 4-methylbenzenesulfonyl chloride (1.9 g, 10 mmol). The mixture was stirred at rtfor 3 h, concentrated, and the residue purified by column chromatography eluting with ethylacatate in petroleum ether (1/4) to afford (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (1.1 g, 43% yield). LCMS (ESI) m/z: 257.4 (M + 1t.
	With pyridine; at 20℃; for 2h;	Example 9; Synthesis of iy-(l-cyanocyclopropyl)-2(.S)-[2,2-difluoro-2-pyridin-2-yl-l(5)-(4- fluorophenyl)ethylamino]pentamide EPO <DP n="62"/>Step l(3-Methyloxetan-3-yl)methanol (20 g, 190 mmol) was added to a solution of toluene sulfonylchloride (54.3g, 285 mmol) in dry pyridine (100 ml) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into crushed ice and stirred vigorously for 30 min. The precipitates were filtered and dried to give toluene-4-sulfonic acid 3-methyl-oxetan- 3-ylmethyl ester (37g) as a white powder.
	With triethylamine; In dichloromethane; at 0 - 20℃;	To a solution of (3-methyl-oxetan-3-yl)-methanol (3 mL, 30 mmol) and NEt3 (4.7 mL, 33 mmol) in CH2Cl2 (30 mL) is added toluene-4-sulfonyl chloride (6.4 g, 33 mmol) at 0 C. The reaction is allowed to warm to RT overnight. For workup, a saturated solution of NaHCO3 is added and the mixture is extracted with EtOAc. The crude product is purified by flash column chromatography (n-hexane/EtOAc 1:1) to give the title compound.
	With dmap; In dichloromethane; at 20℃; for 1h;	EXAMPLE 108a Preparation of intermediate toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester To a mixture of (3-methyl-oxetan-3-yl)-methanol (10.2 g, 0.1 mol) and DMAP (18.3 g, 0.15 mol) in DCM (100 mL) was added 4-methyl-benzenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature for 1 h, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (18 g).
	With pyridine; for 1.5h;	p-Toluenesulfonyl chloride (57.2 g, 300 mmol) was dissolved in dry pyridine (400 mL) under nitrogen atmosphere. 3-methyl-3-(hydroxymethyl)oxetane (20.4 g, 200 mmol) was added slowly, and the solution was stirred for 1.5 h. Crushed ice (400 g) was then added to vigorously stirring mixture, which was allowed to stir for an additional 0.5 h. The white precipitate was then collected on Whatman filter paper No.1 and washed with cold water. The product was dried under high vacuum to obtain 3-methyl-3-(toluenesulfonyl-oxymethyl)oxetane (oxetane tosylate) as a white powder of oxetane tosylate.
	With pyridine; at 20℃;	To a solution of /j-toluenesulfonyl chloride (14.3 g, 75 mmol) in pyridine (60 niL) is slowly added 3-methyl-3-oxetanemethanol A3a (5.1 g, 50 mmol) over 10 min. The resulting suspension is stirred at rt for 1.5 h and poured into vigorously stirred ice water (300 mL). The slurry is stirred for 45 min. The solid is collected by filtration, washed with ice-cold H2O (100 mL), and dried under high vacuum to afford (3- methyloxetan-3-yl)methyl 4-methylbenzenesulfonate A3b as a white powder. The compound is used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) delta = 7.83 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.39 (d, J = 6.4 Hz, 2H), 4.36 (d, J = 6.4 Hz, 2H), 4.13 (s, 2H), 2.49 (s, 3H), 1.33 (s, 3H).
	With pyridine; for 4.5h;Inert atmosphere; Cooling with ice;	Under nitrogen atmosphere, a mixture of 1.5 g of (3- methyloxetan-3-yl ) methanol of the following formulaand 150 ml of pyridine, 33 g of p-toluenesulfonyl chloride was added, and stirred for 4.5 hours under ice-cooling. To the reaction mixture, water was added and extracted with ethyl acetate 2 times. The organic layer was washed with 1 mol/1 of hydrochloric acid and brine successively. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 28 g of p-toluenesulfonic acid 3- methyloxetan-3-ylmethyl ester of the following formula.XH NMR (CDC13) : delta ppm: 7.81 (2H, d) , 7.37 (2H, d) , 4.36 (4H, dd) , 4.11 (2H, s) , 2.47 (3H, s), 1.31 (3H, s)
1.05 g	With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 0℃; for 0.25h;	EXAMPLE 17 3-Methyl-3-oxetanylmethyl-4-methylbenzene-sulfonate At 0 C., to a solution of 3-methyl-3-oxetanyl methanol (507 mg, 4.97 mmol, commercially available) in CH2Cl2 (15 mL) was added DABCO (1.12 g, 9.94 mmol) and TsCl (1.09 g, 5.72 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum to afford the residue (1.05 g), which was used for the next step without further purification.
	With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 0℃; for 0.25h;	Example 17 3-Methyl-3-oxetanylmethyl-4-methylbenzene-sulfonate At 0C, to a solution of 3-methyl-3-oxetanyl methanol (507 mg, 4.97 mmol, commercially available) in CH2Cl2 (15 mL) was added DABCO (1.12 g, 9.94 mmol) and TsCl (1.09 g, 5.72 mmol) was then added dropwise, the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with CH2Cl2 and the filtrate was washed twice with water. The organic phase was dries over anhydrous sodium sulphate. The solvent was evaporated under vacuum to afford the residue (1.05 g), which was used for the next step without further purification.
	With pyridine; In dichloromethane; at 20℃; for 4h;	p-Toluenesulfonyl chloride (2.17 g, 11.4 mmol) is dissolved in CH2CI2 (9.5 mL) at it Pyridine (1.53 mL, 19 mmol) is added, followed by 3-methyl-3- oxetanemethanol (0.977 mL, 9.5 mmol). The sol. is stirred at rt for 4 h. The sol. is diluted with CH2CI2 and washed with aq. 0.1 M HCI and with aq. sat. NaHC03. The org. layer is dried over Na2S04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC (Combiflash, EtOAc/heptane 0: 100? 60:40) yields the title product. LC-MS: tR = 0.80 min, MH+ = 257.17 (conditions 3).
	With pyridine; In dichloromethane; at 20℃; for 4h;	(3-Methyloxetan-3-yl)methyl 4-methylbenzenesulfonate. p-Toluenesulfonyl chloride (2.17 g, 11.4 mmol) is dissolved in CH2CI2 (9.5 mL) at rt. Pyridine (1.53 mL, 19 mmol) is added, followed by 3-methyl-3- oxetanemethanol (0.977 mL, 9.5 mmol). The sol. is stirred at rt for 4 h. The sol. is diluted with CH2CI2 and washed with aq. 0.1 M HCI and with aq. sat. NaHCC>3. The org. layer is dried over Na2SC>4, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC (Combiflash, EtOAc/heptane 0:100? 60:40) yields the title product. LC-MS: tR= 0.80 min, MH+= 257.17 (conditions 3).
	With dmap; triethylamine; In dichloromethane; at 0 - 20℃;	(3-methyloxetan-3-yl)methanol (CAS No: 3143-02-0, 2.0 ml_, 20 mmol) was dissolved in dichloromethane (30 mL) and cooled down to 0C. Triethylamine (3.0 ml_, 22 mmol), 4- dimethylaminopyridine (239 mg, 1.96 mmol) and 4-methylbenzene-1 -sulfonyl chloride (4.1 1 g, 21.5 mmol) were added, the ice bath removed, and the reaction stirred overnight at room temperature. The crude was then diluted with dicloromethane and treated with a 2M HCI solution. The organic pahse was separated and washed with sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The crude product was used in the following reaction with no further purification. LC-MS (Method 1 ): Rt = 1 .06 min; MS (ESIpos): m/z = 257 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1 .18 (s, 3H), 2.43 (s, 3H), 4.1 1 (s, 2H), 4.19 (d, 2H), 4.26 (d, 2H), 7.50 (d, 2H), 7.85 (d, 2H).
	With dmap; triethylamine; In dichloromethane; at 25℃; for 3h;	Compound WX010-1 (200 mg, 1.96 mmol, 194.17 muL, 1 eq) and dichloromethane (5 mL) were added into a pre-dried 40 mL reaction vial, followed by sequential addition of triethylamine (297.24 mg, 2.94 mmol, 408.85 muL, 1.5 eq), dimethylaminopyridine (23.92 mg, 195.83 mumol, 0.1 eq) and p-toluenesulfonyl chloride (448.01 mg, 2.35 mmol, 1.2 eq). The reaction solution was stirred at 25C for 3 hours. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction solution, and extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by thin layer chromatography silica gel plate (petroleum ether: ethyl acetate = 3:1) to give WX010-2. 1H NMR (400MHz, CHLOROFORM-d) delta = 7.82 (d, J=8.2 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 4.44 - 4.30 (m, 4H), 4.12 (s, 2H), 2.47 (s, 3H), 1.32 (s, 3H).

Reference： [1]Chemistry of Materials,2016,vol. 28,p. 6628 - 6636
[2]Organic Syntheses,2002,vol. 79,p. 216 - 216
[3]Patent: WO2018/75698,2018,A1 .Location in patent: Paragraph 00272
[4]Journal of Organic Chemistry,1998,vol. 63,p. 3631 - 3646
[5]Journal of the American Chemical Society,1999,vol. 121,p. 5459 - 5466
[6]Patent: EP1927592,2008,A1 .Location in patent: Page/Page column 10
[7]Patent: WO2012/49555,2012,A1 .Location in patent: Page/Page column 65-66
[8]Bulletin of the Chemical Society of Japan,2011,vol. 84,p. 26 - 39
[9]Acta Chemica Scandinavica,1992,vol. 46,p. 271 - 277
[10]Synthetic Communications,2011,vol. 41,p. 2539 - 2543
[11]Patent: WO2017/40537,2017,A1 .Location in patent: Page/Page column 42
[12]Patent: WO2013/128378,2013,A1 .Location in patent: Page/Page column 108
[13]Patent: WO2013/59651,2013,A1 .Location in patent: Sheet 32
[14]Patent: WO2012/31298,2012,A2 .Location in patent: Page/Page column 53-54
[15]Journal of Medicinal Chemistry,2013,vol. 56,p. 6954 - 6966
[16]Journal of Medicinal Chemistry,2012,vol. 55,p. 3960 - 3974
[17]Journal of Medicinal Chemistry,2017,vol. 60,p. 9769 - 9789
[18]Patent: WO2011/54828,2011,A1 .Location in patent: Page/Page column 82
[19]Patent: US2011/190334,2011,A1 .Location in patent: Page/Page column 30-31
[20]Patent: WO2017/35411,2017,A1 .Location in patent: Paragraph 0623; 0634
[21]Patent: WO2018/154466,2018,A1 .Location in patent: Paragraph 00473; 00475; 00476
[22]Patent: WO2006/60494,2006,A1 .Location in patent: Page/Page column 61
[23]Patent: US2009/76062,2009,A1 .Location in patent: Page/Page column 19
[24]Patent: US2009/156610,2009,A1 .Location in patent: Page/Page column 86
[25]Patent: US2003/232863,2003,A1 .Location in patent: Page 68
[26]Patent: WO2010/6191,2010,A1 .Location in patent: Page/Page column 32
[27]Assay and Drug Development Technologies,2012,vol. 10,p. 269 - 277
[28]Patent: WO2012/133861,2012,A1 .Location in patent: Page/Page column 209-210
[29]Patent: US2013/324464,2013,A1 .Location in patent: Paragraph 0158; 0159
[30]Patent: EP2676965,2013,A1 .Location in patent: Paragraph 0105; 0106
[31]RSC Advances,2015,vol. 5,p. 90422 - 90427
[32]Patent: WO2015/186056,2015,A1 .Location in patent: Page/Page column 105
[33]Patent: WO2016/41892,2016,A1 .Location in patent: Page/Page column 50
[34]Patent: US2017/107190,2017,A1 .Location in patent: Paragraph 0167
[35]Patent: WO2019/16071,2019,A1 .Location in patent: Page/Page column 422
[36]Patent: EP3572412,2019,A1 .Location in patent: Paragraph 0160-0162

9
[ 3143-02-0 ]
[ 74-88-4 ]
[ 34493-11-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 3-hydroxymethyl-3-methyloxethane With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃;	Intermediate 472 3-(methoxymethyl)-3-methyloxetane (3-methyloxetan-3-yl)methanol (CAS No: 3143-02-0, 2.0 ml_, 20 mmol) was dissolved in THF (80 ml_, 1 .0 mol), put under argon and cooled down to 0°C. Sodium hydride (862 mg, 60 % purity, 21.5 mmol) was added portionwise, and the resulting suspension was stirred for 30 min. iodomethane (1 .3 ml_, 21 mmol) was added dropwise, the ice batch was removed and the temperature was allowed to rise over 2h. The reaction was quenched with water, and extracted with hexanes (x2). The organic layers were dried over sodium sulfate, filtered, and the solvent removed under vacuum to yield the title compound (2.10 g, 83 % yield). 1H-NMR (400 MHz, CHLOROFORM-d) δ [ppm]: 1 .32 (s, 3H), 3.46 (s, 2H), 4.37 (d, 2H), 4.52 (d, 2H).
	With sodium 1.) THF, reflux, 2.) 35 deg C, 2 h; Yield given. Multistep reaction;

Reference： [1]Current Patent Assignee: Helmholtz Association; BAYER AG - WO2019/16071, 2019, A1 Location in patent: Page/Page column 419
[2]Dale, Johannes; Fredriksen, Siw B. [Acta Chemica Scandinavica, 1991, vol. 45, # 1, p. 82 - 91]

10
[ 3143-02-0 ]
[ 78385-26-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 0.333333h;Product distribution / selectivity;	10 ml (0.1 mol) of 3-methyl-3-(hydroxymethyl)oxetane and 36.58 g (0.11 mol) of carbone tetrabromide were dissolved in 100 ml of CH2Cl2. The solution was cooled to 0C under nitrogen atmosphere, and 31.56 g (0.12 mol) of triphenylphosphine was gradually added thereto. The mixture was heated to room temperature and stirred for 20 minutes. After the reaction terminated, the solvent was removed under reduced pressure. 100 ml of ethylene acetate was added thereto and the mixture was filtered using celite to remove impurities. After the solvent was removed from the mixture, hexane was added thereto. The mixture was filtered using celite, and concentrated under reduced pressure. The resultant product was fractionally distilled to obtain 16 g of 3-methyl-3-(bromomethyl)oxetane (Yield: 95%). NMR spectroscopy of the resulting product was: 1H NMR (CDCl3, 300MHz): delta4.46-4.38 (d+d, 4H), 3.65(s, 2H), 1.44(s, 3H).
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 23℃; for 1.33333h;	3-Bromomethyl-3-methyl-oxetane; To a dichloromethane (600 ml) solution of (3-Methyl-oxetan-3-yl)-methanol (50 g, 0.4896 mol, prepared as in Corey, E. J., Raju, N., Tetrahedron Lett., 1983, 5571) at about 0 C. was added carbon tetrabromide (165.35 g, 0.4986 mol) followed by the addition of triphenyl phosphine (179 g, 0.683 mol) slowly in portions over about 20 minutes. The reaction was allowed to warm to about 23 C. and was stirred at that temperature for about 1 hour then was concentrated in vacuo. The residue was diluted with diethyl ether and cooled to about 0 C., then was filtered through Celite and the organic layer was concentrated in vacuo. The residue was then diluted with hexanes and filtered then concentrated in vacuo and distilled under vacuum to give 124.3 g of 3-bromomethyl-3-methyl-oxetane as a colorless oil.

Reference： [1]Journal of Organic Chemistry,1998,vol. 63,p. 3631 - 3646
[2]Patent: EP1927592,2008,A1 .Location in patent: Page/Page column 11
[3]Journal of the Chemical Society, Dalton Transactions,1981,p. 1406 - 1414
[4]Acta Chemica Scandinavica,1991,vol. 45,p. 82 - 91
[5]Journal of Organic Chemistry,1998,vol. 63,p. 3631 - 3646
[6]Patent: US2005/227997,2005,A1 .Location in patent: Page/Page column 41
[7]Bulletin of the Chemical Society of Japan,2011,vol. 84,p. 26 - 39
[8]Patent: WO2018/75698,2018,A1

11
[ 3143-02-0 ]
[ 99314-44-0 ]

Reference： [1]Tetrahedron Letters,1987,vol. 28,p. 5747 - 5750

12
[ 3143-02-0 ]
[ 2035-75-8 ]
[ 57570-85-1 ]
[ 264601-69-6 ]

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 1899 - 1906

13
[ 3143-02-0 ]
[ 6214-35-3 ]
[ 339177-46-7 ]

Reference： [1]Tetrahedron Letters,2001,vol. 42,p. 1691 - 1694
[2]Journal of Organic Chemistry,2002,vol. 67,p. 4127 - 4137

14
[ 3143-02-0 ]
[ 5219-65-8 ]
[ 444168-93-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: acide phenylthio-3 propanoique With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 0.5h; Stage #2: 3-hydroxymethyl-3-methyloxethane In dichloromethane at 20℃; for 34h;

Reference： [1]Ding, Pingyu; Ghosez, Léon [Tetrahedron, 2002, vol. 58, # 8, p. 1565 - 1571]

15
[ 3143-02-0 ]
[ 16696-65-4 ]
[ 239803-53-3 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide; tetrabutylammomium bromide In hexane for 3h; Heating;

Reference： [1]Cowling, Stephen J.; Goodby, John W. [Chemical Communications, 2006, # 39, p. 4107 - 4109]

16
[ 3143-02-0 ]
[ 53293-00-8 ]
[ 89276-33-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 1h; Cooling with ice;	1 (3-Methyloxyethan-3-yl)methyl-5-hexynoate (40) (3-Methyloxyethan-3-yl)methyl-5-hexynoate (40)[0073][0074] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.3 g, 53.5 mmol) and N,N-dimethyl-4-aminopyridine (545 mg, 4.46 mmol) were added to a CH 2Cl2 (20 mL) solution of the 5-hexynoic acid 38 (5 mL, 44.6 mmol)and 3-methyl-3-oxetane methanol 39 (4.5 mL, 44.6 mmol) at 0°C. The obtained mixture was stirred under cooling onice for 1 hour. After that, water and brine were added to the reaction solution, and the obtained mixture was then extractedwith CH2Cl2. The organic layer was washed with brine and was then dried, and the solvent was then distilled away underreduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane-ethyl acetate),so as to obtain 8.5 g of the title compound (yield: 97%, a colorless oily substance).1H NMR (CDCl3): δ = 1.33 (s, 3H), 1.83-1.89 (m, 2H), 2.04 (s, 1H), 2.27 (td, J= 6.9, 2.9 Hz, 2H), 2.51 (t, J= 7.5 Hz, 2H),4.17 (s, 2H), 4.38 (d, J= 5.7 Hz, 2H), 4.51 (d, J= 5.7 Hz, 2H)
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 0.75h;	8 REFERENCE EXAMPLE 8; 5-Hexynoic Acid (3-Methyloxetan-3-yl)methyl Ester REFERENCE EXAMPLE 8 5-Hexynoic Acid (3-Methyloxetan-3-yl)methyl Ester To a solution of 5-hexynoic acid (10.0 g) and 3-methyl-3-oxetane methanol (10.0 g) in methylene chloride (50 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.5 g), and 4-dimethylaminopyridine (1.09 g) were added under cooling with ice.. The mixture was stirred at room temperature for 45 minutes.. The reaction mixture was poured into iced water and extracted with ethyl acetate.. The organic layer was washed by water and an aqueous saturated solution of sodium chloride, sucessively, dried over anhydrous magnesium sulfate and concentrated.. The residue was purified with silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (16.7 g) having the following physical data. TLC: Rf 0.38 (n-hexane:ethyl acetate=3:1); NMR (CDCl3): δ 4.52 (d, J=6.0 Hz, 2H), 4.42 (d, J=6.0 Hz, 2H), 4.18 (s, 2H), 2.52 (t, J=7.0 Hz, 2H), 2.29 (dt, J=2.6, 7.0 Hz, 2H), 1.98 (dt, J=2.6 Hz, 1H), 1.87 (tt, J=7.0, 7.0 Hz, 2H), 1.34 (s, 3H).

Reference： [1]Current Patent Assignee: SAVID THERAPEUTICS - EP2960243, 2015, A1 Location in patent: Paragraph 0073; 0074
[2]Current Patent Assignee: ONO PHARMACEUTICAL CO LTD - US6664281, 2003, B1 Location in patent: Page column 87

17
[ 3143-02-0 ]
[ 55394-81-5 ]
[ 845272-38-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine; In dichloromethane; for 16.5h;	(3-Methyl-3-oxetanyl)methyl 3-(4-bromophenyl)propionate. <strong>[55394-81-5]3-(4-Bromophenyl)propionic acid chloride</strong> was prepared in usual manner from 3-(4-bromophenyl)propionic acid (5.50 g, 24 mmol) and oxalyl chloride (4.2 ml, 50 mmol) in benzene (30 mL) with following evaporation. 3-Methyl-3-oxetanemethanol (2.30 ml, 23 mmol) and pyridine (3.8 mL, 48 mmol) were dissolved in DCM (50 mL) and crude <strong>[55394-81-5]3-(4-bromophenyl)propionyl chloride</strong> in DCM (10 mL) was added dropwise within 30 min with stirring and cooling on a water bath. The mixture was stirred for 16 h, then diluted with CHCl3 (200 mL), washed with water (2x200 mL), 5% NaHCO3 (2x200 mL), 5% citric acid (3x100 mL) and 10% NaHCO3 (100 mL), dried over Na2SO4, evaporated and chromatographed on silica gel in CHCl3. Yield 5.90 g (82%). Colorless oil which solidifies upon storage, mp around 30C. Rf 0.20 (toluene-EtOAc, 9:1). NMR (CDCl3): 7.39 (d, 2H, J= 8.2 Hz, ArH); 7.07 (d, 2H, J= 8.2 Hz, ArH); 4.44 (d, 2H, J= 6.0 Hz), 4.34 (d, 2H, J= 6.0 Hz) (CH2OCH2); 4.13 (s, 2H, CH2OCO); 2.91 (t, 2H, J = 7.6 Hz, ArCH2), 2.66 (t, 2H, J= 7.6 Hz, CH2CO); 1.27 (s, 3H, CH3).

Reference： [1]Patent: EP1506959,2005,A2 .Location in patent: Page 32
[2]Organic and Biomolecular Chemistry,2008,vol. 6,p. 4593 - 4608

18
[ 3143-02-0 ]
[ 79-37-8 ]
[ 27912-85-2 ]
3-methyl-3-oxetanylmethyl 3-benzyloxypropionate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; N-methyl-acetamide; ethyl acetate; benzene;	(2) Oxalyl chloride (880 mg) was added to a solution of <strong>[27912-85-2]3-benzyloxypropionic acid</strong> (1.04 g) in benzen (10 ml). Subsequently, dimethylformamide (100 mg) was added. After the resultant mixture was stirred for 30 minutes at room temperature, benzen was distilled off. Azeotropic distillation was performed twice through use of benzen (10 ml), and the resultant residue was dissolved in tetrahydrofuran (10 ml). To the solution were added 3-methyl-3-oxetanyl-methyl alcohol (620 mg) and then triethylamine (620 mg). The mixture was stirred for 5 hours at room temperature. Ethyl acetate was added to the reaction mixture, followed by washing with sat. aq. K2 CO3, water, 1N-HCl, water, and saturated brine and then drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 2:1), to give 1.01 g of 3-methyl-3-oxetanylmethyl 3-benzyloxypropionate as a pale yellow oil. 1 H-NMR(CDCl3, ppm, TMS): 1.32(3H, s), 2.67(2H, t, J=6.4 Hz), 3.77(2H, t, J=6.4 Hz), 4.20(2H, s), 4.36(2H, d, J=6.1 Hz), 4.51(2H, t, J=6.1 Hz), 4.53(2H, s), 7.24-7.39(5H, m); IR(CDCl3)cm-1: 3012, 2968, 2878, 1736, 1455, 1379, 1365, 1249, 1183, 1103, 1072, 981, 834

Reference： [1]Patent: US6008224,1999,A

19
[ 3143-02-0 ]
[ 54326-16-8 ]
[ 4909-78-8 ]
5-Chloro-1-(3-methyloxetan-3-ylmethyl)pyrimidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 24 5-Chloro-1-(3-methyloxetan-3-ylmethyl)pyrimidin-2-one N,N-Dimethylformamide dineopentyl acetal (6.75 ml) was added to a stirred suspension of <strong>[54326-16-8]5-chloropyrimidin-2-one</strong> (1.958 g) and 3-hydroxymethyl-3-methyloxetane (2.145 g) in dry N,N-dimethylformamide (37 ml) under nitrogen and the mixture was then heated at 95 C. After 44.5 h the reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate (600 ml), washed with water (100 ml, 3*50 ml), dried (MgSO4) and evaporated to a brown gum. The gum was triturated with diethylether to give a solid which was crystallized from ethyl acetate to give buff crystals of the title pyrimidinone (154 mg), m.p. 209-211 C., numax (nujol) 1670, 1570 cm-1 (C=O), 1612, 1585 cm-1 (C=C, C=N).

Reference： [1]Patent: US4399140,1983,A

20
[ 3143-02-0 ]
[ 558-13-4 ]
[ 603-35-0 ]
[ 78385-26-9 ]
NHCH₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	3-Bromomethyl-3-methyl-oxetane To a dichloromethane (600 ml) solution of (3-Methyl-oxetan-3-yl)-methanol (50 g, 0.4896 mol, prepared as in Corey, E.J., Raju, N., Tetrahedron Lett.,1983, 5571) at about 0C was added carbon tetrabromide (165.35 g, 0.4986 mol) followed by the addition of triphenyl phosphine (179 g, 0.683 mol) slowly in portions over about 20 minutes. The reaction was allowed to warm to about 23C and was stirred at that temperature for about 1 hour then was concentrated in vacuo.The residue was diluted with diethyl ether and cooled to about 0C, then was filtered through Celite and the organic layer was concentrated in vacuo.Theresidue was then diluted with hexanes and filtered then concentrated in vacuoand distilled under vacuum to give 124.3 g of 3-bromomethyl-3-methyl-oxetane as a colorless oil.

Reference： [1]Patent: EP1081137,2001,A1

21
[ 3143-02-0 ]
C₁₀H₁₇NO₂ [ No CAS ]
[ 153209-97-3 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 8661 - 8664

22
[ 3143-02-0 ]
[ 2491-15-8 ]
[ 1159414-65-9 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 884 - 887

23
[ 3143-02-0 ]
[ 163839-73-4 ]
[ 779329-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-(4-(trifluoromethyl)phenoxy)acetic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 72h; Stage #2: 3-hydroxymethyl-3-methyloxethane With triethylamine In dichloromethane for 2h;	44.ii (ii) [4- (Trifluoromethyl) phenoxy]- acetic acid, (3-methyl-3-oxetanyl) methyl ester Oxalyl chloride (14ML) was added to a solution of the product from step (i) (12.42g) and N, N-DIMETHYLFORMAMIDE (2 drops) in dichloromethane (100ML), and stirred at RT for 72h. The mixture was evaporated under reduced pressure, the residue dissolved in dichloromethane (100ml) then triethylamine (20ML) and 3-methyl-3-oxetanemethanol (17ML) added. After 2h the mixture was washed with water, evaporated under reduced pressure and the residue purified by chromatography on silica eluting with dichloromethane, yield 14.2g. 1H NMR DMSO-d6: 87. 66 (2H, d); 7.14 (2H, d); 4.98 (2H, s), 4.34 (2H, d); 4.24 (2H, s); 4.19 (2H, d), 1.21 (3H, s).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/89885, 2004, A1 Location in patent: Page 55-56

24
[ 3143-02-0 ]
[ 73724-43-3 ]
[ 1227042-45-6 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 2282 - 2285

25
[ 3143-02-0 ]
[ 77-78-1 ]
[ 34493-11-3 ]

Yield	Reaction Conditions	Operation in experiment
63.3%	Stage #1: 3-hydroxymethyl-3-methyloxethane With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: dimethyl sulfate In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere;

Reference： [1]Location in patent: experimental part Darensbourg, Donald J.; Moncada, Adriana I.; Wei, Sheng-Hsuan [Macromolecules, 2011, vol. 44, # 8, p. 2568 - 2576]

26
[ 3143-02-0 ]
[ 1346562-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogen bromide / tetrahydrofuran; water / 0 - 20 °C 2: dichloromethane / 1 h / 20 °C

Reference： [1]Mindemark, Jonas; Bowden, Tim [Polymer, 2011, vol. 52, # 25, p. 5716 - 5722]

27
[ 3143-02-0 ]
[ 3993-78-0 ]
[ 1431655-13-8 ]

Yield	Reaction Conditions	Operation in experiment
65%		NaH (1.23 g, 0.03 mol) was washed with pentane and dried under vacuum for 15 min. THF (10 mL) was added to the flask under N2 and the mixture was stirred. To this, (3-methyloxetan-3-yl)methanol (3.15 g, 0.03 mmol) was added dropwise. 10 mL of THF was added at room temp and solids were scraped to facilitate stirring. The dense mixture was stirred at room temp for 1 h. A slurry of 4-chloropyrimidin-2-amine (2.0 g, 0.02 mol) in THF was added to the reaction and it was refluxed for 15 h. After cooling to room temp, H2O (100 mL) was added and the aqueous layer was extracted with EtOAc. The crude product was purified by flash chromatography (0-100% EtOAc + pentane). The recovered material was taken up in diethyl ether and the solid that separated was isolated by filtration to afford 4-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine (1.9 g, 65%). MS (ESI) calcd for C9H13N3O2 195.1; found 196.0 [M+H]
65%		NaH (1.23 g, 0.03 mol) was washed with pentane and dried under vacuum for 15 min. THF (10 mL) was added to the flask under N2 and the mixture was stirred. To this, (3-methyloxetan-3-yl) methanol (3.15 g, 0.03 mmol) was added dropwise. 10 mL of THF was added at room temp and solids were scraped to facilitate stirring. The dense mixture was stirred at room temp for 1 h. A slurry of 4-chloropyrimidin-2-amine (2.0 g, 0.02 mol) in THF was added to the reaction and it was refluxed for 15 h. After cooling to room temp, H2O (100 mL) was added and the aqueous layer was extracted with EtOAc. The crude product was purified by flash chromatography (0-100% EtOAc + pentane). The recovered material was taken up in diethyl ether and the solid that separated was isolated by filtration to afford 4-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine (1.9 g, 65%). MS (ESI) calcd for C9H13N3O2 195.1; found 196.0 [M+H].

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 210
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0869; 0870

28
[ 3143-02-0 ]
[ 5600-21-5 ]
[ 1431654-80-6 ]

Yield	Reaction Conditions	Operation in experiment
41%		NaH (60% in oil, 2.23 g, 55.7 mmol) was washed twice with pentane and dried under vacuum. THF (35 mL) was added, followed by (3-methyloxetan-3-yl)methanol (5.5 mL, 55.7 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 5 mL more THF and 4-chloro-6-methylpyrimidin-2-amine (4.0 g, 27.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was triturated with Et2O and the white solid was dried under vacuum to give 4-methyl-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine (2.42 g, 41%). MS (ESI) calcd for C10H15N3O2: 209.12; found: 210 [M+H]
41%		NaH (60% in oil, 2.23 g, 55.7 mmol) was washed twice with pentane and dried under vacuum. THF (35 mL) was added, followed by (3-methyloxetan-3-yl)methanol (5.5 mL, 55.7 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 5 mL more THF and 4-chloro-6-methylpyrimidin-2-amine (4.0 g, 27.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was triturated with Et2O and the white solid was dried under vacuum to give 4-methyl-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine (2.42 g, 41%). MS (ESI) calcd for C10H15N3O2: 209.12; found: 210 [M+H].

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 171; 172
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0646; 0647

29
[ 3143-02-0 ]
[ 7461-50-9 ]
[ 1431654-79-3 ]

Yield	Reaction Conditions	Operation in experiment
30%		NaH (60% in oil, 2.47 g, 61.8 mmol) was washed twice with pentane and dried under vacuum. THF (25 mL) was added, followed by (3-methyloxetan-3-yl)methanol (6.1 mL, 61.8 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 15 mL more THF and 4-amino-2-chloropyrimidine (4.0 g, 30.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and enough saturated NH4Cl to bring the pH down to 8. The mixture extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2) to give 2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (1.84 g, 30%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H]
30%		NaH (60% in oil, 2.47 g, 61.8 mmol) was washed twice with pentane and dried under vacuum. THF (25 mL) was added, followed by (3-methyloxetan-3-yl)methanol (6.1 mL, 61.8 mmol) dropwise. This was allowed to stir 1 h at room temp before addition of 15 mL more TNF and 4-amino-2-chloropyrimidine (4.0 g, 30.9 mmol). The reaction was heated to reflux for 17 h, cooled and concentrated. Water was added (50 mL), and enough saturated NH4Cl to bring the pH down to 8. The mixture extracted with EtOAc (3x75 mL), and the combined organics were washed with saturated aqueous NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2) to give 2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (1.84 g, 30%). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H].

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 170; 171
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0644; 0645

30
[ 3143-02-0 ]
[ 33332-28-4 ]
[ 1431654-81-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		NaH (60percent in oil, 1.24 g, 30.9 mmol) was washed twice with pentane and dried under vacuum. Dioxane (50 mL) was added, followed by (3-methyloxetan-3-yl)methanol (3.0 mL, 30.9 mmol) dropwise. This was allowed to stir 2 h at room temp before addition of 6-chloropyrazin-2-amine (2.0 g, 15.4 mmol). The reaction was heated to reflux for 16 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with water and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10percent MeOH/CH2 ) to give 6-((3-methyloxetan-3- yl)methoxy)pyrazin-2-amine (3.02 g, quant). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H]
100%		NaH (60percent in oil, 1.24 g, 30.9 mmol) was washed twice with pentane and dried under vacuum. Dioxane (50 mL) was added, followed by (3-methyloxetan-3-yl)methanol (3.0 mL, 30.9 mmol) dropwise. This was allowed to stir 2 h at room temp before addition of 6-chloropyrazin-2-amine (2.0 g, 15.4 mmol). The reaction was heated to reflux for 16 h, cooled and concentrated. Water was added (50 mL), and the mixture was extracted with EtOAc (3x75 mL), and the combined organics were washed with water and brine, dried with Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (0-10percent MeOH/CH2Cl2) to give 6-((3-methyloxetan-3-yl)methoxy)pyrazin-2-amine (3.02 g, quant.). MS (ESI) calcd for C9H13N3O2: 195.10; found: 196 [M+H].

Reference： [1]Patent: WO2013/59587,2013,A1 .Location in patent: Page/Page column 172
[2]Patent: EP2768509,2017,B1 .Location in patent: Paragraph 0648; 0649

31
[ 3143-02-0 ]
[ 113305-56-9 ]
3-[(4-Iodo-3-nitrophenoxy)methyl]-3-methyloxetane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
971 mg	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 18h;	17.1 Step 1: 3- [(4-Iodo-3 -nitrophenoxy)methyl] -3 -methyloxetane To a stirred mixture of 4-iodo-3-nitrophenol (1.02 g, 3.849 mmol), 3-methyl-3-oxetanemethanol (393 mg, 3.849 mmol) and triphenylphosphine (1.51 g, 5.773 mmol) in THF (20mL) was added a diethyl azadicaboxylate (DEAD) (0.91 mL, 5.773 mmol) at 0 °C. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to yield 971 mg of the title product as yellow solid. ‘H NIVIR (300 MHz, CDC13) ö 1.44 (s, 3H), 4.07 (s, 2H), 4.48 (d, J 6.0 Hz, 2H), 4.60 (d, J= 6.0 Hz, 2H), 6.89-6.93 (m, 1H), 7.45-7.47 (m, 1H), 7.91 (d, J 8.7 Hz, 1H).

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2015/52675, 2015, A1 Location in patent: Page/Page column 52; 53

32
[ 3143-02-0 ]
[ 50530-12-6 ]
[ 1208238-87-2 ]

Yield	Reaction Conditions	Operation in experiment
29.0 g		To a solution of lO-bromooctanoic acid (25.0 g, 0.100 moles), 3-methyl-3-oxetanemethanol (10.9 g, 0.107 moles), and 1-hydroxybenzotriazole (1.6 g) in anhydrous dichloromethane (500 ml) cooled to 0-5 C., a solution of N,N?25 dicycloxehyldicarbodiimide (22.1 g, 0.107 moles) in anhydrous dichioromethane (110 ml) was added dropwise during45 minutes. Next 4-(dimethylamino)pyridine (1.8 g) was added and the mixture was stirred overnight at room temperature under argon atmosphere. The solution was filtered andwashedtwo times with 5-% phosphoric acid (2x250 ml). Next it was dried with anhydrous Mg504 and the solvent wasdistilled off Yield 29.0 g.

Reference： [1]Patent: US9220790,2015,B2 .Location in patent: Page/Page column 60

33
[ 3143-02-0 ]
[ 696-82-2 ]
6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine [ No CAS ]
4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		In a 20 mL vial, the mixture isolated above was heated to 40 C. overnight in 10 mL of 7N NH3 in methanol. Upon completion, the reaction was cooled and concentrated onto silica gel under reduced pressure. 6-fluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidin-4-amine (INT-15a) was isolated by silica gel chromatography (0-100% ethyl acetate in heptane) as the more polar fraction (0.557 g, 2.6 mmol, 35.0% yield). A small amount of 4-fluoro-6-((3-methyloxetan-3-yl)methoxy)pyrimidin-2-amine (INT-15b) was also isolated as a byproduct.

Reference： [1]Patent: US2016/75720,2016,A1 .Location in patent: Paragraph 0267

34
[ 3143-02-0 ]
[ 696-82-2 ]
4-fluoro-6-(2-methoxyethoxy)pyrimidin-2-amine [ No CAS ]
6-fluoro-2-(2-methoxyethoxy)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		In a 20 mL vial, a mixture (1:1) of 2,4-difluoro-6-(2-methoxyethoxy)pyrimidine (INT-17) and 4,6-difluoro-2-(2-methoxyethoxy)pyrimidine (INT-16) was then heated to 65 C. in 10 mL of 30% NH3 in water. Upon completion, the reaction was cooled, extracted thrice with dichloromethane, and the combined organic extracts were dried over sodium sulfate. The organic fraction was then concentrated onto silica gel and purified by silica gel chromatography (0-100% ethyl acetate in heptane) to give the title compounds INT-18 1H NMR (400 MHz, DMSO-d6): delta 5.62 (1H), 5.09 (br s, 2H), 4.40 (m, 2H), 3.69 (m, 2H), 3.39 (s, 3H) and INT-19 1H NMR (400 MHz, DMSO-d6): delta 5.67 (1H), 5.10 (br s, 2H), 4.42 (m, 2H), 3.67 (m, 2H), 3.40 (s, 3H) as separate fractions

Reference： [1]Patent: US2016/75720,2016,A1 .Location in patent: Paragraph 0268; 0269

35
[ 3143-02-0 ]
[ 696-82-2 ]
4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine [ No CAS ]
C₉H₁₀F₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In tetrahydrofuran; at 20℃; for 1h;	In a 20 mL vial (3-methyloxetan-3-yl)methanol (0.744 ml, 7.46 mmol), cesium carbonate (2.430 g, 7.46 mmol), and <strong>[696-82-2]2,4,6-trifluoropyrimidine</strong> (S3-1) (1 g, 7.46 mmol) were dissolved in 10 mL of dry THF to give a colorless suspension. The reaction was stirred at room temperature for 1 hour, poured into saturated sodium bicarbonate (aq.) and extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate, decanted, concentrated onto silica gel, and purified by chromatography (0-100% ethyl acetate in heptane) to give an inseparable 1.3:1 mixture of isomers INT-13 and INT-14, favoring 4,6-difluoro-2-((3-methyloxetan-3-yl)methoxy)pyrimidine INT-13. The mixture was used as-is for subsequent steps.

Reference： [1]Patent: US2016/75720,2016,A1 .Location in patent: Paragraph 0266

36
[ 3143-02-0 ]
[ 10154-71-9 ]
[ 1394135-60-4 ]

Reference： [1]Organic Syntheses,2016,vol. 92,p. 328 - 341

37
[ 3143-02-0 ]
[ 627-31-6 ]
C₈H₁₅IO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrabutylammomium bromide; sodium hydroxide; In hexane; water; for 0.5h;Reflux;	1,3-iodopropane (27.5g, 93mmol) and 3-methyl-3-hydroxymethyl-oxetane (3.1g, 31mmol), sodium hydroxide (20g, 500mmol) in water and hexane stir in two-phase system, with tetrabutylammonium bromide as phase transfer catalyst, the reaction for 0.5 hours under reflux.After completion of the reaction by extraction, purified by distillation under reduced pressure to give a colorless liquid.Yield: 62%.

Reference： [1]Patent: CN105523946,2016,A .Location in patent: Paragraph 0035

38
[ 3143-02-0 ]
[ 112823-30-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2: sodium iodide / acetone / 3 h / Reflux
	With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran; acetonitrile at 20℃; Inert atmosphere; Cooling with ice;

Reference： [1]Fang, Xiaofeng; Zhang, Yu-Mo; Chang, Kaiwen; Liu, Zhihe; Su, Xing; Chen, Haobin; Zhang, Sean Xiao-An; Liu, Yifei; Wu, Changfeng [Chemistry of Materials, 2016, vol. 28, # 18, p. 6628 - 6636]
[2]Hazra, Avijit; Chen, Jason; Lalic, Gojko [Journal of the American Chemical Society, 2019, vol. 141, # 32, p. 12464 - 12469]

39
[ 3143-02-0 ]
[ 54965-21-8 ]
(3-methyloxetan-3-yl)methyl N-[5-(propylsulfanyl)-1H-1,3-benzodiazol-2-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; at 90℃;	The mixture of albendazole (530 mg) and 3-hydroxyl-3-methyl-oxetane (1 mL) in triethylamine (15 mL) was heated at 90 C overnight. The solvent was removed under vacuum. The desired product was isolated by silica gel chromatography (hexanes: ethyl acetate === 1 : 1) as a white solid. MS (ES): 336.5 (M+H)+
	With triethylamine; at 90℃;	General procedure: To a stirred mixture of each bendazole in base/solvent (100mM) were added 10 equiv of alcohols indicated in Scheme 1. The reaction proceeded at 90, 100, or 110C for 3h to o/n. For compounds 5 and 7, the reaction mixture was exposed to microwave irradiation for 5-15minat 60 or 70C. Workup: Once the reaction was complete, the solvent was removed under reduced pressure, diluted with four times the reaction volume of EtOAc and washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo, followed by purification performed on automated flash chromatography system with the desired method commented below.

Reference： [1]Patent: WO2017/95950,2017,A2 .Location in patent: Paragraph 00159
[2]European Journal of Medicinal Chemistry,2018,vol. 144,p. 372 - 385

40
[ 3143-02-0 ]
[ 670220-88-9 ]

Reference： [1]Patent: CN107382983,2017,A
[2]Patent: CN107382984,2017,A
[3]Patent: CN109678849,2019,A

41
[ 3143-02-0 ]
[ 41292-65-3 ]
5-(3-methyloxetane-3-methoxy)benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.8%		Compound 3-methyl-3-oxetane methanol 30.77 g, THF 140 ml, and sodium metal 6.95 g were added to a 250 ml three-necked flask, heated to 66 C. under reflux for 4 hours while stirring, and cooled to 55 C.Then, 40.4 g of <strong>[41292-65-3]5-hydroxybenzimidazole</strong> was added, and the mixture was heated to reflux under stirring for 20-24 hours. Ethyl acetate (100 ml) was added to the reaction flask, and the mixture was stirred at 30-50 C. for 0.5 h, then it was reduced to -5 C., and n-hexane (30 ml) was added dropwise.Stirred for 1 h and suction-filtered to give a pale yellow solid which was dried to constant weight at 40 C. to give 56.41 g, yield 85.8%.
85.8%		The compound 3 - methyl -3 - oxygen oxetane methanol 30.77 g, THF140ml, metal sodium 6.95 g added to the 250 ml in [...], stirring under heating to 65 - 68 C reflux 4 h, cooling to 55 C, then add 5 - hydroxy benzimidazole 40.4 g, stirring under heating to reflux, the reaction 20 - 24 of H;Adding ethyl acetate to the reaction bottle 100 ml, in the 30 - 50 C stirring 0.5 h dissolved, then lowered to the -5 C, [...] hexane 30 ml, stirring 1 h, filtered to obtain pale yellow solid, 40 C drying to constant weight, to obtain 56 . 41 g, yield 85.8%.

Reference： [1]Patent: CN107382984,2017,A .Location in patent: Paragraph 0006; 0016
[2]Patent: CN109678849,2019,A .Location in patent: Paragraph 0045; 0054-0056

42
[ 3143-02-0 ]
[ 634-97-9 ]
(3-methyloxetan-3-yl)methyl 1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	1.1 1. Preparation of (3-Methyloxetan-3-yl)methyl 1H-pyrrole-2-carboxylate (1-1 1H-Pyrrol-5-carboxylic acid (111.1 mg, 1.0 mmol), DCC (309·5 mg, 1.5 mmol) and DMAP (183.3 mg, 1.5 mmol) were dissolved in dichloromethane (2 mL) Stir at room temperature for 5 minutes.(3-methyloxetan-3-yl) methanol (153.2 mg, 1.5 mmol) was slowly added to the reaction system by a syringe, and stirred at room temperature overnight.The reaction was completed by TLC, and the solvent was removed by concentration under reduced pressure.After adding methyl tert-butyl ether (5 mL), the mixture was stirred and filtered, and the filtered cake was washed with ethyl t-butyl ether.The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v/v) = 1/1)The fractions of Rf = 0.4 to 0.6 were collected to give Compound 1-1 (146 mg, yield: 75%).

Reference： [1]Current Patent Assignee: CHENGDU ANNUO CHENCHUANG MEDICINE TECH - CN110003188, 2019, A Location in patent: Paragraph 0243-0247

43
[ 3143-02-0 ]
[ 6939-93-1 ]
4-bromo-1,3-benzenedicarboxylic acid 1,3-bis[(3-methyl-3-oxetanyl)methyl]ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	2.1 1) Synthesis of 4-bromo-1,3-benzenedicarboxylic acid 1,3-bis[(3-methyl-3-oxetanyl)methyl]ester 4-Bromoterephthalic acid (5.04 g, 20.53 mmol), WSCD.HCl (8.46 g, 44.32 mmol), DMAP (718 mg, 5.88 mmol), and 3-methyl-3-oxetanemethanol (5.02 mL, 51.18 mmol) were dissolved in dehydrated CH2Cl2 and stirred overnight at room temperature. The product was washed with aqueous saturated NaHCO3 and saturated saline, dried with anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/n-hexane=1/1), and 2-bromo-1,4-benzenedicarboxylic acid 1,4-bis[(3-methyl-3-oxetanyl)methyl]ester was obtained (4.0:3 g, yield 47%). (0228) 1H NMR (400 MHz, CDCl3): δ=1.42 (s, 3H), 1.44 (s, 3H), 4.44 (s, 2H), 4.47 (s, 4H), 4.48 (s, 2H), 4.61 (d, J=2.1 Hz, 2H), 4.63 (d, J=1.2 Hz, 2H) 7.78 (d, J=8.4 Hz, 1H), 8.05 (dd, J=8.4 Hz, 1.5 Hz, 2H), 8.31 (d, J=1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ=21.0, 21.2, 39.1, 39.2, 69.9, 70.1, 79.3, 79.4, 121.3, 128.1, 131.1, 1:33.5, 135.1, 136.2, 164.3, 165.6

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TOKYO - US2020/87326, 2020, A1 Location in patent: Paragraph 0227-0228

44
[ 3143-02-0 ]
[ 54941-44-5 ]
(3-methyloxetan-3-yl)methyl 2-(4-methyl-3-nitrophenyl)acetate [ No CAS ]

Reference： [1]Organic and biomolecular chemistry,2020,vol. 18,p. 2650 - 2660

45
[ 3143-02-0 ]
[ 1679-64-7 ]
methyl ((3-methyloxetan-3-yl)methyl) terephthalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 25℃; for 18h; Inert atmosphere;
95%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 25℃; for 18h; Inert atmosphere;
93%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Schnell, Simon D.; Schilling, Mauro; Sklyaruk, Jan; Linden, Anthony; Luber, Sandra; Gademann, Karl [Organic Letters, 2021, vol. 23, # 7, p. 2426 - 2430]
[2]Schnell, Simon D.; González, Jorge A.; Sklyaruk, Jan; Linden, Anthony; Gademann, Karl [Journal of Organic Chemistry, 2021, vol. 86, # 17, p. 12008 - 12023]
[3]Fang, Yinzhi; Fox, Joseph M.; Huang, Zhen; Tallon, Amanda M.; Xie, Yixin; am Ende, Christopher W. [Angewandte Chemie - International Edition, 2020, vol. 59, # 39, p. 16967 - 16973][Angew. Chem., 2020, vol. 132, # 39, p. 17115 - 17121,7]

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Isomers

Technical Information

• Add Hydrogen Cyanide to Aldehydes and Ketones to Produce Alcohols • Alcohol Syntheses from Aldehydes, Ketones and Organometallics • Alcohols are Weakly Basic • Alcohols as Acids • Alcohols Convert Acyl Chlorides into Esters • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alcoholysis of Anhydrides • Aldehydes and Ketones Form Hemiacetals Reversibly • Aldol Addition • Alkene Hydration • Alkene Hydration • Appel Reaction • Base-Catalyzed Hydration of α,β -Unsaturated Aldehydes and Ketones • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Carboxylic Acids React with Alcohols to Form Esters • Chloroalkane Synthesis with SOCI2 • Chromium Reagents for Alcohol Oxidation • Chugaev Reaction • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Convert Esters into Aldehydes Using a Milder Reducing Agent • Convert Haloalkanes into Alcohols by SN2 • Corey-Kim Oxidation • Decarboxylation of 3-Ketoacids Yields Ketones • Decomposition of Lithium Aluminum Hydride by Protic Solvents • Dess-Martin Oxidation • Esters Are Reduced by LiAlH4 to Give Alcohols • Esters Hydrolyze to Carboxylic Acids and Alcohols • Ether Synthesis by Oxymercuration-Demercuration • Ethers Synthesis from Alcohols with Strong Acids • Friedel-Crafts Alkylations Using Alcohols • Geminal Diols and Acetals Can Be Hydrolyzed to Carbonyl Compounds • Grignard Reagents Transform Esters into Alcohols • Grignard Reagents Transform Esters into Alcohols • Haloalcohol Formation from an Alkene Through Electrophilic Addition • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Halogen and Alcohols Add to Alkenes by Electrophilic Attack • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • HIO4 Oxidatively Degrades Vicinal Diols to Give Carbonyl Derivatives • Hydration of the Carbonyl Group • Hydride Reductions • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydride Reductions of Aldehydes and Ketones to Alcohols • Hydroboration-Oxidation • Hydroboration-Oxidation • Hydrolysis of Haloalkanes • Jones Oxidation • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Martin's Sulfurane Dehydrating Reagent • Mitsunobu Reaction • Moffatt Oxidation • Osmium Tetroxide Reacts with Alkenes to Give Vicinal Diols • Osmium TetroxideReacts with Alkenes to Give Vicinal Diols • Oxidation of Alcohols by DMSO • Oxymercuration-Demercuration • Preparation of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkenes by Dehydration of Alcohols • Preparation of Alkoxides with Alkyllithium • Preparation of Amines • Primary Ether Cleavage with Strong Nucleophilic Acids • Reactions of Alcohols • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of Carboxylic Acids by LiAlH4 • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Reduction of Carboxylic Acids by Lithium Aluminum Hydride • Ring Opening of an Oxacyclopropane by Lithium Aluminum Hydride • Ritter Reaction • Sharpless Olefin Synthesis • Swern Oxidation • Synthesis of Alcohols from Tertiary Ethers • Synthesis of an Alkyl Sulfonate • The Nucleophilic Opening of Oxacyclopropanes • Thiazolium Salt Catalysis in Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Thiazolium Salts Catalyze Aldehyde Coupling • Transesterification • Use 1,3-dithiane to Prepare of α-Hydroxyketones • Vicinal Anti Dihydroxylation of Alkenes • Williamson Ether Syntheses

Historical Records

Pharmaceutical Intermediates of
[ 3143-02-0 ]

Crenolanib Related Intermediates

[ 343788-51-2 ]

8-(Benzyloxy)-2-chloroquinoline

[ 670220-88-9 ]

1-[2-[5-[(3-Methyl-3-oxetanyl)methoxy]-1-benzimidazolyl]-8-quinolyl]-4-piperidinamine

[ 15450-76-7 ]

2,8-Dihydroxyquinoline

[ 73874-95-0 ]

tert-Butyl piperidin-4-ylcarbamate

[ 610-81-1 ]

4-Hydroxy-2-nitroaniline

Related Functional Groups of
[ 3143-02-0 ]

Alcohols

[ 6246-06-6 ]

Oxetan-3-ylmethanol

Similarity: 0.93

[ 3047-32-3 ]

(3-Ethyloxetan-3-yl)methanol

Similarity: 0.82

[ 22633-44-9 ]

(3-(Bromomethyl)oxetan-3-yl)methanol

Similarity: 0.70

[ 162816-08-2 ]

3-Methyloxetan-3-ol

Similarity: 0.67

[ 4704-94-3 ]

2-(Hydroxymethyl)propane-1,3-diol

Similarity: 0.64

Related Parent Nucleus of
[ 3143-02-0 ]

Aliphatic Heterocycles

[ 6246-06-6 ]

Oxetan-3-ylmethanol

Similarity: 0.93

[ 3047-32-3 ]

(3-Ethyloxetan-3-yl)methanol

Similarity: 0.82

[ 18934-00-4 ]

3,3'-(Oxybis(methylene))bis(3-ethyloxetane)

Similarity: 0.78

[ 22633-44-9 ]

(3-(Bromomethyl)oxetan-3-yl)methanol

Similarity: 0.70

[ 99419-31-5 ]

3-Methyl-oxetane-3-carbaldehyde

Similarity: 0.68

Oxetanes

[ 6246-06-6 ]

Oxetan-3-ylmethanol

Similarity: 0.93

[ 3047-32-3 ]

(3-Ethyloxetan-3-yl)methanol

Similarity: 0.82

[ 18934-00-4 ]

3,3'-(Oxybis(methylene))bis(3-ethyloxetane)

Similarity: 0.78

[ 22633-44-9 ]

(3-(Bromomethyl)oxetan-3-yl)methanol

Similarity: 0.70

[ 99419-31-5 ]

3-Methyl-oxetane-3-carbaldehyde

Similarity: 0.68

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
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:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
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.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
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
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
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. 3143-02-0 ] {[proInfo.proName]}

Quality Control of [ 3143-02-0 ]

Related Doc. of [ 3143-02-0 ]

Product Details of [ 3143-02-0 ]

Calculated chemistry of [ 3143-02-0 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 3143-02-0 ]

Application In Synthesis of [ 3143-02-0 ]

[ 3143-02-0 ] Synthesis Path-Upstream 1~14

[ 3143-02-0 ] Synthesis Path-Downstream 1~45

Technical Information

Pharmaceutical Intermediates of [ 3143-02-0 ]

Crenolanib Related Intermediates

Related Functional Groups of [ 3143-02-0 ]

Alcohols

Related Parent Nucleus of [ 3143-02-0 ]

Aliphatic Heterocycles

Oxetanes

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 3143-02-0 ]

Related Functional Groups of
[ 3143-02-0 ]

Related Parent Nucleus of
[ 3143-02-0 ]