[ 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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SDS Specification

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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 :	JLMQIJJJKPJVCE-UHFFFAOYSA-N
M.W :	257.28 g/mol	Pubchem ID :	68309269
Synonyms :

Calculated chemistry 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 1~32

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