[ CAS No. 21896-59-3 ] {[proInfo.proName]}

Name: 21896-59-3|N-(2-Chloroethyl)methanesulfonamide|98%
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Product Details of [ 21896-59-3 ]

CAS No. :	21896-59-3	MDL No. :	MFCD00129996
Formula :	C₃H₈ClNO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HLEGMLHPZDVLQL-UHFFFAOYSA-N
M.W :	157.62	Pubchem ID :	89092
Synonyms :

Calculated chemistry of [ 21896-59-3 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.1
TPSA :	54.55 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.32 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.73
Log Po/w (XLOGP3) :	-0.08
Log Po/w (WLOGP) :	0.86
Log Po/w (MLOGP) :	-0.5
Log Po/w (SILICOS-IT) :	0.0
Consensus Log Po/w :	0.2

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.57
Solubility :	42.5 mg/ml ; 0.27 mol/l
Class :	Very soluble
Log S (Ali) :	-0.61
Solubility :	38.4 mg/ml ; 0.243 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.66
Solubility :	3.47 mg/ml ; 0.022 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.42

Safety of [ 21896-59-3 ]

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

Application In Synthesis of [ 21896-59-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 21896-59-3 ]
Downstream synthetic route of [ 21896-59-3 ]

[ 21896-59-3 ] Synthesis Path-Upstream 1~1

1
[ 21896-59-3 ]
[ 5908-62-3 ]

Reference： [1] Organic Letters, 2003, vol. 5, # 22, p. 4175 - 4177

[ 21896-59-3 ] Synthesis Path-Downstream 1~22

1
[ 151-56-4 ]
[ 124-63-0 ]
[ 21896-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol

Reference： [1]Current Patent Assignee: G HOLDINGS INC - US2288178, 1939, A

2
[ 21896-59-3 ]
[ 153628-84-3 ]
5-[4-(2-(methylsulphonamido)ethyl)piperazino]pyrrolo[1,2-a]thieno[3,2-e]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With sodium hydrogencarbonate In ethanol for 6h; Heating;

Reference： [1]Prunier; Besret; Dauphin; Lancelot; Bureau; Rault [Pharmaceutical Sciences, 1997, vol. 3, # 5-6, p. 311 - 314]

3
[ 21896-59-3 ]
5-(piperidin-3-ylmethyloxy)pyrrolo[1,2-a]thieno[3,2-e]pyrazine [ No CAS ]
5-[(N-(2-(methylsulphonamido)ethyl)piperidin-3-yl)-methyloxy]pyrrolo[1,2-a]thieno[3,2-e]pyrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In N,N-dimethyl-formamide for 3h; Heating;

Reference： [1]Prunier; Besret; Dauphin; Lancelot; Bureau; Rault [Pharmaceutical Sciences, 1997, vol. 3, # 5-6, p. 311 - 314]

4
[ 21896-59-3 ]
5-(2-piperidin-4-yl-ethoxy)-1-thia-4,8a-diaza-as-indacene [ No CAS ]
N-(2-{4-[2-(1-thia-4,8a-diaza-as-indacen-5-yloxy)-ethyl]-piperidin-1-yl}-ethyl)-methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In ethanol Heating;

Reference： [1]Prunier; Besret; Dauphin; Lancelot; Bureau; Rault [Pharmaceutical Sciences, 1997, vol. 3, # 5-6, p. 311 - 314]

5
[ 21896-59-3 ]
[ 7144-05-0 ]
[ 152820-99-0 ]

Yield	Reaction Conditions	Operation in experiment
49%	In acetonitrile at 0 - 20℃;

Reference： [1]Lopez-Rodriguez, Maria L.; Benhamu, Bellinda; Viso, Alma; Morcillo, M.Jose; Murcia, Marta; Orensanz, Luis; Alfaro, M.Jose; Martin, M.Isabel [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2271 - 2281]

Yield	Reaction Conditions	Operation in experiment
95.5%		21 EXAMPLE 21 Then, to the mixture were added 300 g. of a 10 % aqueous sodium hydroxide solution and 112.1 g. of methanesulfonylamide at 20°+-2°C. over 3 hours while adjusting pH to 7 to 8.5, and the mixture was maintained for 1 hour under the same condition. After the reaction was completed, the separated aqueous layer was reextracted with 100 g. of chloroform, then combined chloroform layer was freed from chloroform by distillation to obtain 150.6 g. of 2-chloroethylmethanesulfonylamide. The over-all yield was 95.5 %.
85%		2 EXAMPLE 2 The organic layer which remained was transferred into a distillation vessel, subjected therein to vacuum distillation to expel ethylene dichloride by vaporization, and then further distilled under a vacuum degree of 3 torr at a temperature of 141° to 143° C., to obtain N-(2-chloroethyl) methanesulfonamide in a yield of 85.0% based on methanesulfonyl chloride. The purity of the produced N-(2-chloroethyl) methanesulfonamide, on analysis by gas chromatography, was found to be 99.9%. This product was devoid of color.
	2-Chlorethylamin*HCl, Methansulfonylchlorid, NaOH;

H2NCH2CH2OH*HCl (IV)/(CH3)2CHO, 1)SO2Cl2/C6H5Cl/C2H4Cl2 <50-100grad/3-6h>(-->ClCH2CH2NH2 (II) 2)CH3SO2Cl/NaOH;

7
[ 21896-59-3 ]
1-[(piperidin-4-yl)methyloxycarbonyl]naphthalene hydrochloride [ No CAS ]
naphthalene-1-carboxylic acid 1-(2-methanesulfonylamino-ethyl)-piperidin-4-ylmethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetone for 24h; Heating;

Reference： [1]Diouf, Ousmane; Depreux, Patrick; Chavatte, Philippe; Poupaert, Jacques Henri [European Journal of Medicinal Chemistry, 2000, vol. 35, # 7-8, p. 699 - 706]

8
[ 21896-59-3 ]
N-(piperidin-4-ylmethyl)naphth-1-ylcarboxamide hydrochloride [ No CAS ]
naphthalene-1-carboxylic acid [1-(2-methanesulfonylamino-ethyl)-piperidin-4-ylmethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetone Heating;

Reference： [1]Diouf, Ousmane; Depreux, Patrick; Chavatte, Philippe; Poupaert, Jacques Henri [European Journal of Medicinal Chemistry, 2000, vol. 35, # 7-8, p. 699 - 706]

9
[ 21896-59-3 ]
[ 5908-62-3 ]

Reference： [1]Organic Letters,2003,vol. 5,p. 4175 - 4177

10
[ 870-24-6 ]
[ 124-63-0 ]
[ 21896-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In acetonitrile at 5 - 20℃;
	With 4-methyl-morpholine In dichloromethane at -25 - 20℃; for 1.5h; Inert atmosphere; Industrial scale;

Reference： [1]Lee, Jaemoon; Zhong, Yong-Li; Reamer, Robert A.; Askin, David [Organic Letters, 2003, vol. 5, # 22, p. 4175 - 4177]
[2]Kowalczyk, Bruce A.; Robinson III, James; Gardner, John O. [Organic Process Research and Development, 2001, vol. 5, # 2, p. 116 - 121]

11
[ 21896-59-3 ]
[ 574-66-3 ]
C₁₆H₁₈N₂SO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide

Reference： [1]Gaul, Micheal D.; Xu, Guozhang; Kirkpatrick, Jennifer; Ott, Heidi; Baumann, Christian A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 17, p. 4861 - 4865]

12
[ 107-06-2 ]
[ 21896-59-3 ]

Yield	Reaction Conditions	Operation in experiment
92%		1 EXAMPLE 1 Then, the reaction solution remaining after the separation of ethylene dichloride was subjected to vacuum distillation in a thin-film distillation vessel under a vacuum of 1 torr at a temperature of 160° C., to obtain 684 g of N-(2-chloroethyl) methanesulfonamide. This amount of the product represents 92% of the theoretical yield based on the methanesulfonyl chloride consumed in the reaction. The purity of the produced N-(2-chloroethyl) methanesulfonamide, on analysis by liquid chromatography, was found to be 99.9%. This product was colorless and transparent.
		22 EXAMPLE 22 230 g. of 1,2-dichloroethane were added to the solution and then treated in the same manner as described in Example 3 to obtain 149 g. of 2-chloroethylmethanesulfonylamide.

Reference： [1]Current Patent Assignee: NIPPON SHOKUBAI CO LTD - US5210299, 1993, A
[2]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US3956385, 1976, A

Yield	Reaction Conditions	Operation in experiment
97%		8 EXAMPLE 8 Thereafter, the aqueous sodium hydroxide solution and the methanesulfonyl chloride were each added seven times in the same manner as described above, except that the amounts were each reduced each time to one half that of the preceding addition. After the reaction was completed, the reaction solution was separated into the aqueous and dichloroethane layers, and the organic layer was distilled to recover 1,2-dichloroethane, and then further distilled to obtain 152.8 g. of 2-chloroethylmethanesulfonylamide (b.p. 148° - 150°C./4 mmHg) in 97 % of yield.

14
[ 689-98-5 ]
[ 21896-59-3 ]

Yield	Reaction Conditions	Operation in experiment
93.6%		24 EXAMPLE 24 EXAMPLE 24 124 g. of the aqueous solution of 2-chloroethyl-amine obtained in Example 18 was treated in the same manner as described in Example 7 to obtain the aqueous solution containing no sulfur dioxide. The solution thus obtained was subjected to condensation reaction as described in Example 3 to obtain 2-chloroethylmethanesulfonylamide in 93.6 % of yield.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US3956385, 1976, A

15
[ 21896-59-3 ]
[ 56891-60-2 ]
[ 56891-61-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate In methanol; water	1.D D. D. Preparation of 4-Acetamino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline A mixture of 57.6g of 4-acetamino-3-methyl-N-ethylaniline, 52g of βmethanesulfonamidoethyl chloride, 27.7g of sodium hydrogen carbonate, 70g of water and 70ml of methanol were refluxed for 5 hours, and thereafter the methanol was distilled out under reduced pressure. Water was added to the reaction system and an oily product separated out. This oily product was poured into ethyl acetate and cooled to obtain white 4-acetamino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline. Yield: 64g; M.P.: 104° -105° C; Elemental Analysis: Found -- C: 53.57% H: 7.44%; N: 13.36%; Calc'd -- C: 53.65%; H: 7.40%; N: 13.41%.

Reference： [1]Current Patent Assignee: SANKO CHEMICAL CO.,LTD. - US4009205, 1977, A

16
[ 21896-59-3 ]
[ 56891-62-4 ]
[ 92-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sulfuric acid In methanol; water	2.D D. A mixture of 7g of 4-(N-p-toluenesulfonyl)amino-3-methyl-N-ethylaniline, 4g of β-methanesulfonamidoethyl chloride, 2.1g of sodium hydrogen carbonate, 16g of water and 30ml of methanol were refluxed for 5 hours, and then 16g of sulfuric acid were added thereto and the entire reaction system was again refluxed. Next, the reaction solution was condensed to half the original volume and 300ml of isopropyl alcohol were added thereto to separate crystals. The crystals were filtered out and dried to obtain 1.5g of 4-amino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline. sesquisulfate. H2 O. M.P.: 128°-130° C.

Reference： [1]Current Patent Assignee: SANKO CHEMICAL CO.,LTD. - US4009205, 1977, A

17
[ 21896-59-3 ]
[ 959762-97-1 ]
[ 959764-73-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine With sodium hydrogensulfide In water; N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: N-(2-chloroethyl)-methanesulfonamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 110℃; for 14h;	329 Example 329 Production of N-{2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-m ethanesulfonamide (compound 329): Partially purified 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (94.7 mg) obtained in Step 5 of Example 314 was dissolved in N,N-dimethylformamide (3 mL), sodium hydrosulfide (29.9 mg) and water (100 μL) were added, and this was stirred at room temperature for 10 minutes. Water was added to the reaction solution, and this was extracted using ethyl acetate. This ethyl acetate solution was washed with water, 1 N hydrochloric acid, water, and brine successively, and then dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (6 mL), and then N-(2-chloroethyl)methanesulfonamide (58.8 mg) and N,N-diisopropylethylamine (86.7 μL) were added and stirred at 110 °C for 14 hours. The reaction solution was cooled to room temperature, and then diluted with ethyl acetate. This ethyl acetate solution was washed with water and brine successively, and then dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (developing solvent; methylene chloride:methanol = 9:1), and thus, N-{2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-m ethanesulfonamide (compound 329) (58.1 mg) was obtained. Physicochemical properties of N-{2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-m ethanesulfonamide (compound 329): ESI (LC/MS positive mode) m/z=451/453 (M+H+). 1H-NMR (400 MHz, in dimethylsulfoxide-d6) chemical shifts δ: 2.93 (3H, s), 3.25-3.27 (4H, s), 5.04 (4H, d, J=4.1 Hz), 6.59 (1H, s), 6.86 (2H, brs), 7.27-7.30 (1H, m), 7.32 (1H, d, J=6.4 Hz), 7.34 (1H, d, J=7.8 Hz), 7.44 (1H, s), 7.49 (1H, m).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; Chugai Pharmaceutical (in: Roche) - EP2036895, 2009, A1 Location in patent: Page/Page column 141

18
[ 21896-59-3 ]
[ 110383-93-2 ]

Yield	Reaction Conditions	Operation in experiment
1.61 kg	With sodium iodide In butanone for 2h; Reflux; Inert atmosphere; Industrial scale;

Reference： [1]Kowalczyk, Bruce A.; Robinson III, James; Gardner, John O. [Organic Process Research and Development, 2001, vol. 5, # 2, p. 116 - 121]

19
[ 21896-59-3 ]
[ 959762-95-9 ]
[ 959764-54-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 70℃; for 2.5h;	22 General procedure: To the solution of 4-amino-6-{7-chloro-3-oxatricyclo[7.3.1.05,13]trideca-1(13),5,7,9,11-pentaen-8-yl}-1,3,5-triazine-2-thiol (17, 399 mg, 1.21 mmol) and N-(2-chloroethyl)methanesulfonamide (381 mg, 2.41 mmol) in N,N-dimethylformamide (20 mL) was added N-ethyldiisopropylamine (631 μL, 3.14 mmol) at room temperature. The resulting mixture was stirred for 2.5 h at 70 °C. After cooling to room temperature, the mixture was extracted between ethylacetate and water. The organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated by evaporation and the resulting residue was purified by preparative HPLC to give the title compound (383 mg, 86%) as a white solid. 1H NMR (270 MHz, DMSO-d6) δ: 2.84 (3H, s), 3.16 (2H, t, J = 6.6 Hz), 3.24-3.28 (2H, m), 5.04 (2H, br s), 5.05 (2H, br s), 7.21 (1H, br s), 7.34 (1H, d, J = 6.8 Hz), 7.42 (1H, d, J = 8.3 Hz), 7.45 (1H, s), 7.52 (1H, dd, J = 8.3, 6.8 Hz), 7.78 (1H, br s), 7.83 (1H, br s). MS (ESI+) m/z: 452, 454 [M+H]+. HRMS (ESI+) m/z: [M+H]+ calcd for C18H1935ClN5O3S2, 452.06124; found, 452.06032, [M+H]+ calcd for C18H1937ClN5O3S2, 454.05828; found, 454.05725.

Reference： [1]Suda, Atsushi; Kawasaki, Ken-Ichi; Komiyama, Susumu; Isshiki, Yoshiaki; Yoon, Dong-Oh; Kim, Sung-Jin; Na, Young-Jun; Hasegawa, Kiyoshi; Fukami, Takaaki A.; Sato, Shigeo; Miura, Takaaki; Ono, Naomi; Yamazaki, Toshikazu; Saitoh, Ryoichi; Shimma, Nobuo; Shiratori, Yasuhiko; Tsukuda, Takuo [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 2, p. 892 - 905]

20
[ 21896-59-3 ]
3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol [ No CAS ]
N-(2-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;	243 A mixture of N-(2-chloroethyl)methanesulfonamide (146 mg, 0.93 mmol), 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (200 mg, 0.77 mmol), Cs2CO3 (376 mg, 1.16 mmol) and DMF (6 mL) was stirred at room temperature for 16 hours, and then treated with water (10 mL). The mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried, concentrated to dryness, and the residue purified using FCC to give the title compound (165 mg, 56%). MS (CI): mass calcd. for O21H21FN4O3S, 380.13; m/z found, 381.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.08 (s, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.44-5.26 (m, 1H), 4.78 (s, 2H), 4.10 (t, J=4.9 Hz, 2H), 3.84-3.69 (m, 1H), 3.60-3.49 (m, 2H), 3.05 (s, 3H), 2.42-2.27 (m, 2H), 2.22-2.01 (m, 3H), 1.94-1.80 (m, 1H).
56%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	243 N-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide A mixture of N-(2-chloroethyl)methanesulfonamide (146 mg, 0.93 mmol), 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (200 mg, 0.77 mmol), Cs2CO3 (376 mg, 1.16 mmol) and DMF (6 mL) was stirred at room temperature for 16 hours, and then treated with water (10 mL). The mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried, concentrated to dryness, and the residue purified using FCC to give the title compound (165 mg, 56%). MS (Cl): mass calcd. for C21H21FN4O3S, 380.13; m/z found, 381.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 8.08 (s, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.44-5.26 (m, 1H), 4.78 (s, 2H), 4.10 (t, J=4.9 Hz, 2H), 3.84-3.69 (m, 1H), 3.60-3.49 (m, 2H), 3.05 (s, 3H), 2.42-2.27 (m, 2H), 2.22-2.01 (m, 3H), 1.94-1.80 (m, 1H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2014/221310, 2014, A1 Location in patent: Paragraph 0674; 0675
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2015/252008, 2015, A1 Location in patent: Paragraph 0680; 0681

21
[ 21896-59-3 ]
N-(2-((3-(3-amino-4-methoxyphenyl)-6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl)amino)ethyl)acetamide [ No CAS ]
N-(2-((6-chloro-3-(4-methoxy-3-((2-(methylsulfonamido)ethyl)amino)phenyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)amino)ethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium carbonate In toluene at 90℃;

Reference： [1]Mejdrová, Ivana; Chalupská, Dominika; Kögler, Martin; Šála, Michal; Plačková, Pavla; Baumlová, Adriana; Hřebabecký, Hubert; Procházková, Eliška; Dejmek, Milan; Guillon, Rémi; Strunin, Dmytro; Weber, Jan; Lee, Gary; Birkus, Gabriel; Mertlíková-Kaiserová, Helena; Boura, Evzen; Nencka, Radim [Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3767 - 3793]

22
[ 21896-59-3 ]
tert-butyl ((1S)-1-((3R)-1-(1-cyclopropyl-6-fluoro-4-hydroxy-8-methyl-2-oxo-1,2-dihydroquinolin-7-yl)pyrrolidin-3-yl)ethyl)carbamate [ No CAS ]
C₂₇H₃₉FN₄O₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 18-crown-6 ether; potassium carbonate In N,N-dimethyl acetamide at 40℃; Sealed tube;	66 Example 66: W-(2-((7-((R)-3-((S 1 -aminoethyl)pyrrolidin-1 -yl)-1 -cyclopropyl-6-fluoro-8- methyl-2-oxo-1 ,2-dihydroquinolin-4-yl)oxy)ethyl)methanesulfonamide A sealed vial charged with tert-butyl ((S)-1 -((R)-1 -(1 -cyclopropyl-6-fluoro-4-hydroxy-8- methyl-2-oxo-1 ,2-dihydroquinolin-7-yl)pyrrolidin-3-yl)ethyl)carbamate (25.4 mg, 0.057 mmol), /V-(2-chloroethyl)methanesulfonamide (9.44 mg, 0.060 mmol), potassium carbonate (15.76 mg, 0.1 14 mmol) and 18-crown-6 (60.3 mg, 0.228 mmol) in DMA (190 μΙ) was heated at 40 °C overnight. The reaction was poured into brine and extracted with ethyl acetate. The organic phase was collected, dried (MgS04), filtered and concentrated. The crude material was diluted with dichloromethane (1 mL), treated with trifluoroacetic acid (1 mL) and aged for 30 minutes. The reaction was concentrated under reduced pressure and purified by prep HPLC (46.6% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (bs, 2H), 7.57 (d, J = 13.6 Hz, 1 H), 7.45 (t, J = 6.2 Hz, 1 H), 5.81 (s, 1 H), 4.08 (t, J = 5.0 Hz, 2H), 3.54 - 3.22 (m, 8H), 2.95 (s, 3H), 2.44 (s, 3H), 2.38 (m, 1 H), 2.09 (m, 1 H), 1 .80 - 1 .67 (m, 1 H), 1 .26 (d, J = 6.5 Hz, 3H), 1 .08 (m, 2H), 0.35 (m, 2H) LC/MS calc'd for C22H32FN4O4S [M+H]+ 467.6, found 467.2

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2016/20836, 2016, A1 Location in patent: Page/Page column 146

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Ghs Precautionary Statements

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

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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. 21896-59-3 ] {[proInfo.proName]}

Quality Control of [ 21896-59-3 ]

Related Doc. of [ 21896-59-3 ]

Product Details of [ 21896-59-3 ]

Calculated chemistry of [ 21896-59-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 21896-59-3 ]

Application In Synthesis of [ 21896-59-3 ]

[ 21896-59-3 ] Synthesis Path-Upstream 1~1

[ 21896-59-3 ] Synthesis Path-Downstream 1~22

Related Functional Groups of [ 21896-59-3 ]

Aliphatic Chain Hydrocarbons

Amines

Sulfamides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 21896-59-3 ]