[ CAS No. 1303974-96-0 ]

Name: 1303974-96-0|1-tert-Butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate|98%
Brand: Ambeed
SKU: A369118
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Quality Control of [ 1303974-96-0 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 1303974-96-0 ]

CAS No. :	1303974-96-0	MDL No. :	MFCD18909956
Formula :	C₁₂H₁₉NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	257.28 g/mol	Pubchem ID :	-
Synonyms :

Calculated chemistry of of [ 1303974-96-0 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	67.69
TPSA :	72.91 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) :	-7.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.61
Log Po/w (XLOGP3) :	0.52
Log Po/w (WLOGP) :	0.6
Log Po/w (MLOGP) :	0.4
Log Po/w (SILICOS-IT) :	0.75
Consensus Log Po/w :	0.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.43
Solubility :	9.5 mg/ml ; 0.0369 mol/l
Class :	Very soluble
Log S (Ali) :	-1.62
Solubility :	6.14 mg/ml ; 0.0239 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.24
Solubility :	14.7 mg/ml ; 0.0571 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.94

Safety of [ 1303974-96-0 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P301+P312+P330	UN#:
Hazard Statements:	H302	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1303974-96-0 ]

* 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.

Downstream synthetic route of [ 1303974-96-0 ]

[ 1303974-96-0 ] Synthesis Path-Downstream 1~12

1
[ 1303974-96-0 ]
[ 1255667-06-1 ]

Yield	Reaction Conditions	Operation in experiment
67%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; Inert atmosphere;	3.2 Step 2 To a solution of 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (1.1 g, 4.06 mmol) in DCM (20 mL) cooled to -78° C. was added dropwise diethylaminosulfur trifluoride (2.0 g, 12.18 mmol). The mixture was stirred at RT for overnight and then H2O and DCM (30 mL) were added. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/PE (8:1) to afford 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate as colorless oil (800 mg, 67%). LCMS (ESI): m/z=224.1 [[M+l]-56]+.
67%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; Inert atmosphere;	3.2 Step 2 To a solution of 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (1.1 g, 4.06 mmol) in DCM (20 mL) cooled to -78° C. was added dropwise diethylaminosulfur trifluoride (2.0 g, 12.18 mmol). The mixture was stirred at RT for overnight and then H2O and DCM (30 mL) were added. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/PE (8:1) to afford 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate as colorless oil (800 mg, 67%). LCMS (ESI): m/z=224.1 [[M+l]-56]+.
67%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃;	41.2 step 2: 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate To a solution of 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (1.1 g, 4.06 mmol) in DCM (20 mL) cooled to -78° C. was added dropwise DAST (2.0 g, 12.18 mmol). The mixture was stirred at RT for overnight and then H2O and DCM (30 mL) were added. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/PE (8:1) to afford 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate as colorless oil (800 mg, 67%). LCMS (ESI): m/z=224.1 [ [M+1]-56]+.

50%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 3h;	39 Preparation 39: 1-(tert-butyl) 3-methyl 5,5-difluoropiperidine- 1,3-dicarboxylate [00221] To a solution of 1-(tert-butyl) 3-methyl 5-oxopiperidine-1,3-dicarboxylate (440 mg, 1.7 mmol) in dichloromethane (6 ml) at -78 OC was added diethylaminosulfur trifluoride (0.45 ml, 3.4 mmol). The reaction stirred at -78 OC for lh, then was warmed to room temperature over 2 h. The reaction was poured into dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purified by column chromatography (staining with potassium permanganate solution) eluting with 10-15% ethyl acetate in hexanes to afford the title compound as a colorless oil (240 mg, yield 50%).
87 g	With diethylamino-sulfur trifluoride In dichloromethane at -20℃; Inert atmosphere;	3.A.E Step E. 1-tert-Butyl 3-methyl 5,5-difluoropiperidine-l,3-dicarboxylate. Step E. 1-tert-Butyl 3-methyl 5,5-difluoropiperidine-l,3-dicarboxylate. To a solution of 1-tert-butyl 3-methyl 5-oxopiperidine-l ,3-dicarboxylate (102 g, 396.8 mmol) in anhydrous DCM (600 mL) was added a solution of DAST (95.8 g, 595.2 mmol) in DCM (200 mL) dropwise at -20 C. TLC (PE/EtOAc, 2: 1) showed the starting material was consumed completely. The mixture was quenched with a sat. aq. NH4CI (1 L). The organic layer was separated and the aqueous layer was extracted with DCM (2 x 300 mL). The combined organic layers were washed with water (500 mL), brine (500 mL), dried (Na2S04), filtered, and concentrated under reduce pressure. Purification (FCC, Si02, PE/EtOAc, 30: 1 to 5: 1) afforded the title compound (87 g, 78%) as a brown oil. 1H NMR (CDCI3, 400 MHz) δ 4.22-4.38 (m, 2H), 3.66 (s, 3H), 2.76-2.96 (m, 3H), 2.41 (bs, 1H), 1.85-2.00 (m, 1H), 1.40 (s, 9H).
326 mg	With triethylamine tris(hydrogen fluoride); ethanaminium,N-(difluoro-λ⁴-sulfanylidene)-N-ethyl-,tetrafluoroborate In 1,2-dichloro-ethane for 2.5h; Reflux;	80 Reference Example 80 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate To a dichloroethane solution (6 mL) of triethylamine hydrogen trifluoride complex (326 μL) and XtalFluor-E (687 mg), a dichloroethane solution (1 ml) of 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (515 mg) was added, and the reaction mixture was stirred under reflux for 2.5 hours. After cooling the reaction solution to room temperature, a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added to the reaction solution. The product was extracted with dichloromethane (20 mL) three times, and the organic layer was dried with anhydrous sodium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure, the residue was purified with silica gel column chromatography (chloroform/methanol=100/0 to 93/7) to give 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (326 mg) as an oil. MS m/z 180 [M-Boc], 302 [M+Na]
550 mg	With diethylamino-sulfur trifluoride In dichloromethane at -70 - 20℃; for 4.5h;	16.2 Step 2: Synthesis of 1-tert-butyl 3-methyl 5,5-difluoropiperidine-1,3-dicarboxylate (16-3) Compound (16-2) (1.0 g, 3.89 mmol) was dissolved in dichloromethane (20 mL), the reaction was cooled to -70°C after dissolved with stirring, DAST (1.9 g, 11.67 mmol) was slowly dropwise added, and the reaction was warmed to room temperature and allowed to proceed for 4.5 h after the dropwise addition. After complete reaction of the starting material monitored by LC-MS, the reaction solution was quenched with saturated aqueous sodium bicarbonate (20 mL), extracted with dichloromethane, dried, and purified to obtain the title compound 550 mg. ESI-MS (m/z): 224.1 [M + H-56]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2014/323477, 2014, A1 Location in patent: Paragraph 0198; 0199
[2]Current Patent Assignee: ROCHE HOLDING AG - US2014/323478, 2014, A1 Location in patent: Paragraph 0181; 0182
[3]Current Patent Assignee: ROCHE HOLDING AG - US2015/31674, 2015, A1 Location in patent: Paragraph 0391
[4]Current Patent Assignee: MICHIGAN STATE UNIVERSITY - WO2016/73847, 2016, A2 Location in patent: Paragraph 00221
[5]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1 Location in patent: Page/Page column 53
[6]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2016/221948, 2016, A1 Location in patent: Paragraph 0408-0410
[7]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - EP3508483, 2019, A1 Location in patent: Paragraph 0168; 0170

2
[ 1303974-96-0 ]
[ 1262412-64-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diethylamino-sulfur trifluoride / dichloromethane / -78 - 20 °C / 760.05 Torr / Inert atmosphere 2: sodium tetrahydroborate / dichloromethane / 0 - 20 °C / 760.05 Torr / Inert atmosphere
	Multi-step reaction with 2 steps 1: diethylamino-sulfur trifluoride / dichloromethane / -78 - 20 °C 2: sodium tetrahydroborate / dichloromethane / 0 - 20 °C
	Multi-step reaction with 2 steps 1: diethylamino-sulfur trifluoride / dichloromethane / 3 h / -78 - 20 °C 2: methanol; sodium tetrahydroborate / 96 h / 20 °C

Multi-step reaction with 2 steps 1: diethylamino-sulfur trifluoride / dichloromethane / 4.5 h / -70 - 20 °C 2: sodium tetrahydroborate; methanol / 0 - 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2014/323477, 2014, A1 Current Patent Assignee: ROCHE HOLDING AG - US2014/323478, 2014, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - US2015/31674, 2015, A1
[3]Current Patent Assignee: MICHIGAN STATE UNIVERSITY - WO2016/73847, 2016, A2
[4]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - EP3508483, 2019, A1

3
[ 1303974-96-0 ]
[ 1634725-87-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: diethylamino-sulfur trifluoride / dichloromethane / -78 - 20 °C / 760.05 Torr / Inert atmosphere 2: sodium tetrahydroborate / dichloromethane / 0 - 20 °C / 760.05 Torr / Inert atmosphere 3: dmap; triethylamine / dichloromethane / 20 °C / 760.05 Torr / Inert atmosphere
	Multi-step reaction with 3 steps 1: diethylamino-sulfur trifluoride / dichloromethane / -78 - 20 °C 2: sodium tetrahydroborate / dichloromethane / 0 - 20 °C 3: triethylamine; dmap / dichloromethane / 6220 °C

4
[ 1095010-47-1 ]
1-(tert-butyl) 3-methyl 5-oxopiperidine-1,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		[00220] To a solution of oxalyl chloride (0.49 ml, 5.6 mmol) in dichioromethane (20 ml) at-78 OC was added dimethyl sulfoxide (0.79 ml, 11 mmol). The reaction stuffed at -78 OC for 15 mm and a solution of <strong>[1095010-47-1]1-(tert-butyl) 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (1.0 g, 4.0 mmol) in 3 mL of dichloromethane was added. 15 mm later, triethylamine (2.4 ml, 17 mmol) was added. The reaction stuffed at -78 OC for 30 mm, and then was warmed to room temperature. After 2 h, the reaction was poured into dichloromethane and washed with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography eluting with 0-5% methanol in dichloromethane to afford the title compound as an orange oil (890 mg, 87% yield).
70.5%		Under nitrogen, a solution of ethanedioyl dichloride (4 mL, 47 mmol) in dichloromethane (200 mL) was added dimethyl sulfoxide (6.6 mL, 93 mmol) in (1560) dichloromethane (5 mL) at -78 C. The solution was stirred at -78 C for 1 h. A solution of 1- / -butyl 3-methyl 5-hydroxypiperidine-l,3-dicarboxylate (3.0 g, 11.6 mmol) in (1561) dichloromethane(lO mL) was added to the above solution at -78 C. The solution was stirred at -78 C for 1.5 h. A solution of triethylamine (16 mL, 115 mmol) in dichloromethane (10 mL) was added at -78 C. The solution was stirred at rt for 16 h. The mixture was diluted with water and extracted with dichloromethane. The organic layers were collected. The solution was concentrate under vacuum. The residue was purified by silica flash (1562) chromatography eluting with ethyl acetate/petroleum ether (1/3) to afford the title compound (2.1 g, 70.5% yield) as light brown oil. NMR (300 MHz, CDCb) d 4.05 (s, 2H), 3.95 - 3.84 (m, 2H), 3.73 (s, 3H), 3.16 - 3.03 (m, 1H), 2.82 - 2.57 (m, 2H), 1.48 (s, 9H).
61%	With Dess-Martin periodane; In dichloromethane; at 20℃; under 760.051 Torr;Inert atmosphere;	Step 1 To a solution of <strong>[1095010-47-1]1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (2.0 g, 7.7 mmol) in DCM (20 mL) was added slowly added Dess-Martin periodinane (6.5 mg, 15.4 mmol). The mixture was stirred at RT overnight and then filtered. The filtrate was washed with H2O and a saturated aqueous solution of Na2CO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo and the residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (PE) (5:1) to afford 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate as colorless oil (1.2 g, 61%). LCMS (ESI): m/z=202.0[[M+1]-56]+.

61%	With Dess-Martin periodane; In dichloromethane; at 20℃; under 760.051 Torr;Inert atmosphere;	Step 1 To a solution of <strong>[1095010-47-1]1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (2.0 g, 7.7 mmol) in DCM (20 mL) was added slowly added Dess-Martin periodinane (6.5 mg, 15.4 mmol). The mixture was stirred at RT overnight and then filtered. The filtrate was washed with H2O and a saturated aqueous solution of Na2CO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo and the residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (PE) (5:1) to afford 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate as colorless oil (1.2 g, 61%). LCMS (ESI): m/z=202.0[[M+1]-56]+.
61%	With Dess-Martin periodane; In dichloromethane; at 20℃;	step 1: 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate-To a solution of <strong>[1095010-47-1]1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (2.0 g, 7.7 mmol) in DCM (20 mL) was added slowly added Dess-Martin periodinane (DMP, 6.5 mg, 15.4 mmol). The mixture was stirred at RT overnight and then filtered. The filtrate was washed with H2O and a saturated aqueous solution of Na2CO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo and the residue was purified by SiO2 chromatography eluting with EtOAc/PE (5:1) to afford 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate as colorless oil (1.2 g, 61%). LCMS (ESI): m/z=202.0[ [M+1]-56]+
		Step D. 1-tert-Butyl 3-methyl 5-oxopiperidine-l,3-dicarboxylate. To a solution of oxalyl chloride (98 g, 772 mmol) in anhydrous DCM (400 mL) was added a solution of DMSO (60.2 g, 772 mmol) in DCM (400 mL) dropwise at a rate so as to keep the temperature of the mixture below -60 C under nitrogen. After stirring for 30 min, -tert- butyl 3-methyl 5-hydroxypiperidine-l,3-dicarboxylate (100 g, 386 mmol) was added. The mixture was stirred for 1 h at -60 C before TEA (195.3 g, 1.93 mol) was added. The solution was further stirred for 1 h then allowed to warm to rt prior to adding ice-water (1 L). The pH of the mixture was adjusted to 6 by adding aqueous critic acid. The organic layer was separated and the aqueous layer extracted with DCM (3 x 300 mL). The combined organic layer was washed with water (1 L), brine (1 L), dried (Na2S04), filtered and concentrated under reduce pressure to give the crude product as a brown oil, which was used in the next step without further purification. 1H NMR (CDC13, 400 MHz) delta 4.03 (s, 2H), 3.79-3.91 (m, 2H), 3.75 (s, 3H), 3.05-3.13 (m, 1H), 2.72-2.80 (m, 1H), 2.60-2.67 (m, 1H), 1.47 (s, 9H).
1.14 g	With Dess-Martin periodane; In dichloromethane; at 20℃; for 5.5h;	To a dichloromethane solution (25 mL) of <strong>[1095010-47-1]1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (1.30 g), Dess-Martin reagent (2.33 g) was added. After stirring for 3 hours at room temperature, Dess-Martin reagent (1.31 g) was further added to the reaction solution, and the mixture was stirred for further 2.5 hours. Then, saturated aqueous solution of sodium hydrogen carbonate (50 mL) and a 10% sodium thiosulfate aqueous solution (50 mL) were added sequentially to the mixture, and the organic layer was separated. The product was further extracted from the aqueous layer with dichloromethane (10 mL) four times. The obtained organic layer was dried with anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure, the residue was purified with silica gel column chromatography (chloroform/methanol=100/0 to 98/2) to give 1-tert-butyl 3-methyl 5-oxopiperidine-1,3-dicarboxylate (1.14 g) as an oil. 1H NMR (300 MHz, CDCl3) delta 1.46 (s, 9H), 2.58-2.79 (m, 2H), 3.03-3.11 (m, 1H), 3.73 (s, 3H), 3.77-3.93 (m, 2H), 4.02 (s, 2H)
1 g	With Dess-Martin periodane; In dichloromethane; at 0 - 20℃;	At room temperature, <strong>[1095010-47-1]1-tert-butyl 3-methyl 5-hydroxypiperidine-1,3-dicarboxylate</strong> (16-1) (1.0 g, 3.86 mmol) was dissolved in dichloromethane (20 mL), the reaction was cooled to 0Cafter complete dissolution, Dess-Martin reagent (3.27 g, 7.71 mmol) was added with stirring, and the reaction was stirred overnight at room temperature after the addition. A large amount of white solid precipitated in the reaction solution, which was filtered, and the filtrate was washed successively with water (50 mL) and saturated aqueous sodium carbonate (50 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, to afford the title compound 1.0 g. ESI-MS (m/z): 202.1 [M + H-56]+.

Reference： [1]Patent: WO2016/73847,2016,A2 .Location in patent: Paragraph 00220
[2]Patent: WO2020/56089,2020,A1 .Location in patent: Paragraph 0588
[3]Patent: US2014/323477,2014,A1 .Location in patent: Paragraph 0195-0197
[4]Patent: US2014/323478,2014,A1 .Location in patent: Paragraph 0178-0180
[5]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0390
[6]Patent: WO2015/164508,2015,A1 .Location in patent: Page/Page column 53
[7]Patent: US2016/221948,2016,A1 .Location in patent: Paragraph 0405-0407
[8]Patent: EP3508483,2019,A1 .Location in patent: Paragraph 0168; 0169

5
[ 30766-22-4 ]
[ 1303974-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: palladium on activated charcoal; hydrogen / acetic acid / 60 °C / 2585.81 Torr 2.1: triethylamine / methanol / 0 - 20 °C / Inert atmosphere 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 3.2: 1 h / -60 °C
	Multi-step reaction with 2 steps 1.1: Rh/Al<SUB>2</SUB>O<SUB>3</SUB>; sulfuric acid; hydrogen / methanol / 26 h / 80 °C / 7500.75 Torr / Inert atmosphere 1.2: 3 h / 20 °C 2.1: Dess-Martin periodane / dichloromethane / 3.25 h / 20 °C

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Hauke, Tobias J.; Wein, Thomas; Höfner, Georg; Wanner, Klaus T. [Journal of Medicinal Chemistry, 2018, vol. 61, # 22, p. 10310 - 10332]

6
[ 27828-71-3 ]
1-(tert-butyl) 3-methyl 5-oxopiperidine-1,3-dicarboxylate [ No CAS ]

Reference： [1]Patent: WO2015/164508,2015,A1

7
[ 1095010-44-8 ]
[ 1303974-96-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / methanol / 0 - 20 °C / Inert atmosphere 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -60 °C / Inert atmosphere 2.2: 1 h / -60 °C

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1

8
[ 1303974-96-0 ]
[ 1255666-86-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2: sodium hydroxide; water / methanol / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: ethanaminium,N-(difluoro-λ⁴-sulfanylidene)-N-ethyl-,tetrafluoroborate; triethylamine tris(hydrogen fluoride) / 1,2-dichloro-ethane / 2.5 h / Reflux 2: sodium hydroxide; water / methanol / 2 h / 70 °C

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2016/221948, 2016, A1

9
[ 1303974-96-0 ]
[ 1821111-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 0 - 20 °C / Inert atmosphere 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 1 h / -70 °C / Inert atmosphere 3.2: 1 h / -60 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1

10
[ 1303974-96-0 ]
[ 1821111-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1.02 h / -78 °C / Inert atmosphere 2.2: -78 - 0 °C
	Multi-step reaction with 4 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 0 - 20 °C / Inert atmosphere 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 1 h / -70 °C / Inert atmosphere 3.2: 1 h / -60 °C / Inert atmosphere 4.1: acetic acid / 2 h / 125 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1

11
[ 1303974-96-0 ]
[ 1821111-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1.02 h / -78 °C / Inert atmosphere 2.2: -78 - 0 °C 3.1: hydrogenchloride / ethyl acetate / 3 h / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 0 - 20 °C / Inert atmosphere 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 1 h / -70 °C / Inert atmosphere 3.2: 1 h / -60 °C / Inert atmosphere 4.1: acetic acid / 2 h / 125 °C / Inert atmosphere 5.1: hydrogenchloride / ethyl acetate / 3 h / 0 - 20 °C / Inert atmosphere 6.1: triethylamine / dichloromethane / 3 h / 0 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1

12
[ 1303974-96-0 ]
[ 1821111-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / tetrahydrofuran / 1.02 h / -78 °C / Inert atmosphere 2.2: -78 - 0 °C 3.1: hydrogenchloride / ethyl acetate / 3 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: diethylamino-sulfur trifluoride / dichloromethane / -20 °C / Inert atmosphere 2.1: sodium hydroxide; water / methanol / 0 - 20 °C / Inert atmosphere 3.1: diisopropylamine; n-butyllithium / tetrahydrofuran / 1 h / -70 °C / Inert atmosphere 3.2: 1 h / -60 °C / Inert atmosphere 4.1: acetic acid / 2 h / 125 °C / Inert atmosphere 5.1: hydrogenchloride / ethyl acetate / 3 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1
[2]Current Patent Assignee: DART NEUROSCIENCE LLC - WO2015/164508, 2015, A1

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Code	Phrase
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P230	Keep wetted
P231	Handle under inert gas.
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P322
P330	Rinse mouth.
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P337	If eye irritation persists:
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P342	If experiencing respiratory symptoms:
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P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
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P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
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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
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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.
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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.
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P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
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P401
P402	Store in a dry place.
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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. 1303974-96-0 ]

Quality Control of [ 1303974-96-0 ]

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Water Solubility

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Application In Synthesis of [ 1303974-96-0 ]

[ 1303974-96-0 ] Synthesis Path-Downstream 1~12

Related Functional Groups of [ 1303974-96-0 ]

Ketones

Esters

Amides

Related Parent Nucleus of [ 1303974-96-0 ]

Piperidines

Precautionary Statements-General

Prevention

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[ 1303974-96-0 ]

Related Parent Nucleus of
[ 1303974-96-0 ]