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Product Details of [ 28987-46-4 ]

CAS No. :	28987-46-4	MDL No. :	MFCD04115631
Formula :	C₉H₁₀FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SLRNETDLLJMLMR-UHFFFAOYSA-N
M.W :	199.18	Pubchem ID :	10631832
Synonyms :

Safety of [ 28987-46-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 28987-46-4 ]

* 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 [ 28987-46-4 ]
Downstream synthetic route of [ 28987-46-4 ]

[ 28987-46-4 ] Synthesis Path-Upstream 1~1

1
[ 28987-46-4 ]
[ 148583-65-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen In ethanol; water for 1 h; Sealed tube; Inert atmosphere	A round-bottom flask was charged with 4-fluoro-2-isopropoxy-l -nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10 percent Pd/C (50 percent in water, Degussa type E101; 10 g, 20wtpercent by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H₂ (x3) from a balloon filled with H₂. The reaction was stirred for 4 d using a H₂ filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98percent) as a brown liquid that was used without further purification. 1H NMR (300 MHz; ₆-DMSO) δ 6.67-6.72 (dd, 1H, J = 2.7Hz, 11Hz), 6.55-6.60 (dd, 1H, J = 6.0Hz, 8.7Hz), 6.43-6.49 (td, 1H, J = 2.7Hz, 8.4Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J = 6.0Hz); ¹⁹F NMR (282 MHz; ₆-DMSO) δ - 127.4 (sextet); m/z = 170 (M+H)⁺.
92%	at 20℃; for 2 h;	To a solution of 4-fluoro-2-isopropxy-1-nitrobenzene (3c,199 mg, 0.999 mmol) in anhydrous EtOH (10 mL) was added 10percentPd/C (11 mg, 0.010 mmol). The reaction mixture was stirred andbubbled with H2 at room temperature for 2 h. The solids werefiltered off and washed with DCM (25 mL). The filtrate and DCMwashing were combined and concentrated under reduced pressure.The residue was purified by Biotage® Isolera™ Four automatedflash chromatography (Biotage® SNAP cartridge KP-Sil 10 g, hexaneramping to EtOAc:hexane 1:4) to give 4c as a colorless oil(155 mg, 92percent).

Reference： [1] Patent: WO2013/152198, 2013, A1, . Location in patent: Paragraph 00588
[2] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 539 - 550
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 12, p. 1997 - 2009
[4] Patent: US6455528, 2002, B1,

[ 28987-46-4 ] Synthesis Path-Downstream 1~10

1
[ 446-35-5 ]
[ 683-60-3 ]
[ 28987-46-4 ]
[ 28987-50-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ammonia at -70℃; for 0.166667h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

Reference： [1]Kizner, T. A.; Shteingarts, V. D. [Journal of Organic Chemistry USSR (English Translation), 1985, vol. 21, # 11, p. 2173 - 2178][Zhurnal Organicheskoi Khimii, 1985, vol. 21, # 11, p. 2376 - 2382]

2
[ 446-35-5 ]
[ 6831-82-9 ]
[ 28987-46-4 ]
[ 28987-50-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ammonia at -70℃; for 0.166667h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

3
[ 446-36-6 ]
[ 75-26-3 ]
[ 28987-46-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate In N,N-dimethyl-formamide
95%	With potassium carbonate In N,N-dimethyl-formamide 1.) 22 deg C, 1 d, 2.) 60 deg C, 1 d;
95%	In N,N-dimethyl-formamide at 60℃; for 16h;

Reference： [1]Reitz, Allen B.; McDonnell, Mark E.; Baxter, Ellen W.; Codd, Ellen E.; Wu, Wu-Nan [Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 14, p. 1927 - 1930]
[2]Reitz, Allen B.; Baxter, Ellen W.; Codd, Ellen E.; Davis, Coralie B.; Jordan, Alfonzo D.; Maryanoff, Bruce E.; Maryanoff, Cynthia A.; McDonnell, Mark E.; Powell, Eugene T.; Renzi, Michael J.; Schott, Mary R.; Scott, Malcolm K.; Shank, Richard P.; Vaught, Jeffry L. [Journal of Medicinal Chemistry, 1998, vol. 41, # 12, p. 1997 - 2009]
[3]Mueller, Christiane; Bauer, Andreas; Bach, Thorsten [Angewandte Chemie - International Edition, 2009, vol. 48, # 36, p. 6640 - 6642][Angewandte Chemie, 2009, vol. 121, # 36, p. 6767 - 6769]

4
[ 28987-46-4 ]
[ 148583-65-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen; In ethanol; water; for 1h;Sealed tube; Inert atmosphere;	A round-bottom flask was charged with 4-fluoro-2-isopropoxy-l -nitrobenzene (49.3 g, 248 mmol), EtOH (600 mL), and 10 % Pd/C (50 % in water, Degussa type E101; 10 g, 20wt% by weight of the starting nitro compound). The flask was sealed with a rubber septum, degassed, and back-filled with H2 (x3) from a balloon filled with H2. The reaction was stirred for 4 d using a H2 filled balloon. The reaction mixture was filtered through a pad of celite, and the pad of celite was rinsed with MeOH. The filtrate was evaporated to dryness to provide 4-fluoro-2-isopropoxybenzenamine (41.0 g, 98%) as a brown liquid that was used without further purification. 1H NMR (300 MHz; 6-DMSO) delta 6.67-6.72 (dd, 1H, J = 2.7Hz, 11Hz), 6.55-6.60 (dd, 1H, J = 6.0Hz, 8.7Hz), 6.43-6.49 (td, 1H, J = 2.7Hz, 8.4Hz), 4.47-4.55 (m, 3H), 1.23-1.25 (d, 6H, J = 6.0Hz); 19F NMR (282 MHz; 6-DMSO) delta - 127.4 (sextet); m/z = 170 (M+H)+.
92%	With palladium 10% on activated carbon; hydrogen; at 20℃; for 2h;	To a solution of 4-fluoro-2-isopropxy-1-nitrobenzene (3c,199 mg, 0.999 mmol) in anhydrous EtOH (10 mL) was added 10%Pd/C (11 mg, 0.010 mmol). The reaction mixture was stirred andbubbled with H2 at room temperature for 2 h. The solids werefiltered off and washed with DCM (25 mL). The filtrate and DCMwashing were combined and concentrated under reduced pressure.The residue was purified by Biotage Isolera Four automatedflash chromatography (Biotage SNAP cartridge KP-Sil 10 g, hexaneramping to EtOAc:hexane 1:4) to give 4c as a colorless oil(155 mg, 92%).
		(2) Synthesis of 4-Fluoro-2-isopropoxyaniline By similar reaction and treatment to that in Example 40(2) using 4-fluoro-2-isopropoxynitrobenzene instead of 4-fluoro-2-methoxynitrobenzene, the title compound was obtained as a black oil. 1H-NMR(CDCl3)delta: 1.35(6H, d, J=5.9 Hz), 3.47(2H, br.s), 4.48(1H, septet, J=5.9 Hz), 6.44-6.65(3H, m). IR(KBr): 3460, 3373, 2980, 1614, 1589 cm-1; MS(EI): 169(M+);

Reference： [1]Patent: WO2013/152198,2013,A1 .Location in patent: Paragraph 00588
[2]European Journal of Medicinal Chemistry,2015,vol. 103,p. 539 - 550
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 1997 - 2009
[4]Patent: US6455528,2002,B1

5
[ 446-36-6 ]
[ 67-63-0 ]
[ 28987-46-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	5-Fluoro-2-nitrophenol (48 g) was dissolved in dry tetrahydrofuran (THF) (300 mL). TRIPHENYLPHOSPHINE (88 g) and 2-propanol (47 mL) were added, and the resulting mixture was cooled to 0 °C. DIISOPROPYLAZODICARBOXYLATE (66 ML) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred over night. The solvent was evaporated I71 VACUO and the resulting mixture was filtered THROUGH silica (heptane/ethyl acetate 1: 1). The solvent was evaporated in vacuo and the resulting mixture was recrystallised from heptane/ethyl acetate (1: 1). The organic phase was separated from the crystalline solid by filtration, the solvent was evaporated in vacuo, and the remaining product was purified by flash chromatography (silica gel, heptane/ethyl acetate 9: 1), yielding the title compound as colourless oil (47. 2 G, 78 %). LH NMR (DMSO-D6) : 1.30 (d, 6H), 4.85 (h, 1H), 6.93 (m, 1H), 7.34 (dd, 1H), 7.96 (dd, 1H).
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 0.5h;	84 4-Fluoro-2-isopropoxy-1-nitro-benzene was obtained using 5-fluoro-2-nitro- phenol and isopropanol under Mitsunobu reaction condition. The general procedure is described as follows: to a solution of 4-fluoro-2-isopropoxy-1-nitro-benzene (313 mg, 1.99 mmol), triphenylphosphine (783 mg, 2.98 mmol) and ispropanol (161 mg, 2.59 mmol) in 2 mL THF, was added diethyl azodicarboxylate (0.49 ml, 2.99 mmol) dropwise at 0 °C. The mixture was warmed to room temperature and stirred for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give 4-fluoro-2-isopropoxy-1-nitro-benzene.

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - WO2004/82677, 2004, A1 Location in patent: Page/Page column 108
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2005/35520, 2005, A1 Location in patent: Page/Page column 69-70

6
[ 28987-46-4 ]
[ 405-66-3 ]
[ 766519-29-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In dimethyl sulfoxide at 90℃;	4-FLUORO-2-ISOPROPOXY-L-NITROBENZENE (1.0 g) was dissolved in dry dimethylsulfoxide (25 mL). Potassium carbonate (1.4 g) and (4-fluorobenzyl)-(methyl)-amine (0.84 g) were added. The resulting mixture was heated to 90 °C over night. After cooling to room temperature, water (75 ML) was added, and the resulting mixture was extracted with ethyl acetate (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo to yield the title compound as slightly yellow solid (1. 6 g, 100 %). LC-MS (m/z) 319.1 ([M+H] +) ; RT = 3.43, (UV, ELSD) 85 %, 96 %. H NMR (DMSO-D6) : 1.21 (d, 6H), 3.18 (s, 3H), 4.71 (m, 1H), 4.73 (s, 2H), 6.26 (d, 1H), 6.41 (dd, 1H), 7.17 (m, 2H), 7.25 (m, 2H), 7.84 (d, 1H).

Reference： [1]Current Patent Assignee: H. LUNDBECK A/S - WO2004/82677, 2004, A1 Location in patent: Page/Page column 108

7
[ 75-30-9 ]
[ 446-36-6 ]
[ 28987-46-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate In acetone Reflux;	29 Preparation of 4-fluoro-2-isopropoxy-l-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (50.0 g, 318 mmol, 1 equiv), 2-iodopropane (96.0 mL, 955 mmol, 3 equiv), and K2CO3 (132.0 g, 955 mmol, 3 equiv) in acetone (1 L) was heated to reflux for ON. After cooling to RT, the solid was filtered-off and rinsed with DCM, then the filtrate was concentrated to dryness. The residue was taken in water, EtOAc, and IN NaOH. The layers were separated, and the organic layer was washed with IN NaOH lx. The organic layer was dried over Na2S04, filtered, and concentrated to dryness to provide 4-fluoro-2-isopropoxy-l -nitrobenzene (49.3 g, 78%) as a yellow-brown liquid that was used without further purification. 1H NMR (300 MHz; 6-DMSO) δ 7.91-7.96 (dd, 1H, J = 6.3Hz, 9.0Hz), 7.31-7.35 (dd, 1H, J = 2.4Hz, l lHz), 6.88-6.95 (m, 1H), 4.77-4.89 (hep, 1H, J = 6.0Hz), 1.27-1.29 (d, 6H, J = 6.0Hz); 19F NMR (282 MHz; 6-DMSO) δ -102.4 (sextet); m/z = 200 (M+H)+.
69%	With potassium carbonate In acetone at 70℃;
65%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3.5h;	29 A mixture of 5-fluoro-2-nitrophenol (91.0 g) , 2- iodopropane (103.4 g) , potassium carbonate (146 g) and N,N- dimethylformamide (600 mL) was stirred at 50°C for 3.5 h. The mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100 to 30/70, volume ratio) to give the title compound (75.4 g, 65%) as a yellow oil. 1H NMR (CDCl3) δ 1.42 (6H, d, J = 6.0 Hz), 4.63 (IH, spt, J = 6.1 Hz), 6.64-6.73 (IH, m) , 6.76 (IH, dd, J = 10.6, 2.5 Hz), 7.88 (IH, dd, J = 9.0, 6.0 Hz) .

64%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; Sealed tube;
	With potassium carbonate In acetone for 22h; Reflux;	20 4-fluoro-2-isopropoxy-1-nitrobenzene was prepared as follows:2-iodopropane (3.81 mL, 38.1 mmol) was added to a stirred mixture of potassium carbonate (6.60 g, 47.7 mmol) and 5-fluoro-2-nitrophenol (3 g, 19.1 mmol) in acetone (54 mL). The resulting red thick slurry was stirred at reflux for 22 hours. The reaction mixture to was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with a 1M aqueous solution of sodium hydroxide, water and brine, dried over magnesium sulfate and concentrated to afford crude 4-fluoro-2-isopropoxy-1-nitrobenzene (2.27 g, 59%) as a yellow liquid. This product was used in the next step without further purification.
13 g	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	8 Method 6 4-(4-Methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline A mixture of 18.0 g of 5-fluoro-2-nitrophenol, 29.0 g of caesium carbonate and 13.7 ml of 2-iodopropane in 119 ml of DMF is stirred at ambient temperature overnight. The mixture is concentrated under vacuum and the residue is taken up with 250 ml of water and extracted twice with 250 ml of ethyl acetate. The organic phases are washed twice with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, so as to obtain 17 g of crude product. The crude product is purified on 400 g of silica, elution being carried out with cyclohexane/ethyl acetate (95/5), so as to obtain 13.0 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in the form of a light yellow oil.
13.0 g	With caesium carbonate In N,N-dimethyl-formamide at 20℃;	III.8.6 A mixture of 18.0 g of 5-fluoro-2-nitrophenol, 29.0 g of caesium carbonate and 13.7 ml of 2-iodopropane in 1 19 ml of DMF is stirred at ambient temperature overnight. The mixture is concentrated under vacuum and the residue is taken up with 250 ml of water and extracted twice with 250 ml of ethyl acetate. The organic phases are washed twice with 200 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, so as to obtain 17 g of crude product. The crude product is purified on 400 g of silica, elution being carried out with cyclohexane/ethyl acetate (95/5), so as to obtain 13.0 g of 4-fluoro-1 -nitro-2-(propan-2-yloxy)benzene in the form of a light yellow oil.
	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 3h;
	With potassium carbonate In N,N-dimethyl-formamide at 50℃;	4.1 step 1; Preparation of 4-fluoro-2-isopropoxy-1-nitrobenzene 5-fluoro-2-nitrophenol (300 mg), isopropyl iodide (0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL) and reacted at 50° C. overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.
	With potassium carbonate In N,N-dimethyl-formamide at 50℃;	4.1 Step 1: Preparation of 4-fluoro-2-isopropoxy-1-nitrobenzene Step 1: Preparation of 4-fluoro-2-isopropoxy-1-nitrobenzene 5-fluoro-2-nitrophenol(300 mg), isopropyl iodide(0.50 mL) and potassium carbonate (500 mg) were dissolved in dimethylformamide (DMF, 3 mL) and reacted at 50°C overnight. The dimethylformamide of the reaction mixture was concentrated under reduced pressure, added with water and the organic layer was extracted with ethyl acetate. The organic layer was washed with brine, and the water was removed with sodium sulfate, and the solvent was removed under reduced pressure. The thus obtained compound was used in the subsequent reaction without further purification.

Reference： [1]Current Patent Assignee: RIGEL PHARMACEUTICALS INC - WO2013/152198, 2013, A1 Location in patent: Paragraph 00587
[2]Toth, Philipp M.; Lieber, Sonja; Scheer, Frithjof M.; Schumann, Tim; Schober, Yvonne; Nockher, Wolfgang A.; Adhikary, Till; Müller-Brüsselbach, Sabine; Müller, Rolf; Diederich, Wibke E. [ChemMedChem, 2016, vol. 11, # 5, p. 488 - 496]
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2009/125873, 2009, A1 Location in patent: Page/Page column 131-132
[4]Abdelhameed, Ahmed; Feng, Mei; Joice, April C.; Zywot, Emilia M.; Jin, Yiru; La Rosa, Chris; Liao, Xiaoping; Meeds, Heidi L.; Kim, Yena; Li, Junan; McElroy, Craig A.; Wang, Michael Zhuo; Werbovetz, Karl A. [ACS Infectious Diseases, 2021, vol. 7, # 7, p. 1901 - 1922]
[5]Current Patent Assignee: ASTRAZENECA PLC - US2010/105655, 2010, A1 Location in patent: Page/Page column 171
[6]Current Patent Assignee: SANOFI - US2013/261106, 2013, A1 Location in patent: Paragraph 0532
[7]Current Patent Assignee: SANOFI - WO2013/150036, 2013, A1 Location in patent: Page/Page column 102
[8]Park, Chi Hoon; Choe, Hyeonjeong; Jang, In-Young; Kwon, So Yeong; Latif, Muhammad; Lee, Heung Kyoung; Lee, Hyeon Ji; Yang, Eun Hye; Yun, Jeong In; Chae, Chong Hak; Cho, Sung Yun; Choi, Sang Un; Ha, Jae Du; Jung, Heejung; Kim, Hyoung Rae; Kim, Pilho; Lee, Chong Ock; Yun, Chang-Soo; Lee, Kwangho [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 22, p. 6192 - 6196]
[9]Current Patent Assignee: PINOTBIO - US2015/152069, 2015, A1 Location in patent: Paragraph 0197; 0198
[10]Current Patent Assignee: PINOTBIO - EP2883875, 2015, A1 Location in patent: Paragraph 0076

8
[ 889939-92-8 ]
[ 28987-46-4 ]
[ 1462950-83-9 ]

Yield	Reaction Conditions	Operation in experiment
1.15 g	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110.0℃; for 6.0h;	Method 9 4-[3-(2-Methoxyethyl)-4-methylpiperazin-1-yl]-2-(propan-2-yloxy)aniline 974 mg of N,N-diisopropylethylamine and 724 mg of <strong>[889939-92-8]2-(1-methylpiperazin-2-yl)ethanol</strong> are added to a suspension of 1 g of 4-fluoro-1-nitro-2-(propan-2-yloxy)benzene in 10 ml of acetonitrile. The reaction medium is microwave-heated at 110 C. for 6 hours and then concentrated to dryness under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (90/10). 1.15 g of 2-{1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]piperazin-2-yl}ethanol are obtained in the form of a yellow oil.
1.15 g	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110.0℃; for 6.0h;Microwave irradiation;	974 mg of Nu,Nu-diisopropylethylamine and 724 mg of 2-(1 -methylpiperazin-2-yl)ethanol are added to a suspension of 1 g of 4-fluoro-1 -nitro-2-(propan-2-yloxy)benzene in 10 ml of acetonitrile. The reaction medium is microwave-heated at 1 10C for 6 hours and then concentrated to dryness under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 microns), elution being carried out with a mixture of dichloromethane and methanol (100/0) to (90/10). 1 .15 g of 2-{1 -methyl-4-[4-nitro-3- (propan-2-yloxy)phenyl]piperazin-2-yl}ethanol are obtained in the form of a yellow oil.

Reference： [1]Patent: US2013/261106,2013,A1 .Location in patent: Paragraph 0540
[2]Patent: WO2013/150036,2013,A1 .Location in patent: Page/Page column 104

9
[ 28987-46-4 ]
[ 1280594-97-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 20 °C 2: palladium 10% on activated carbon; hydrazine hydrate / ethanol / 0.75 h / 80 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / dimethyl sulfoxide / 20 °C 2: palladium 10% on activated carbon; hydrazine hydrate / ethanol / 0.75 h / 80 °C

Reference： [1]Current Patent Assignee: SANOFI - US2013/261106, 2013, A1
[2]Current Patent Assignee: SANOFI - WO2013/150036, 2013, A1

10
[ 28987-46-4 ]
[ 107017-73-2 ]
C₁₈H₂₆N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of potassium tert-butoxide (1? 5eq) was added to a solution of (1-hydroxymethylcyclopropyl) -tert-butoxycarbonylamino in tetrahydrofuran [THF] at room temperature. After stirring for 30 min, 4-fluoro-2-isopropyl Oxy-1-nitrobenzene (1.3 eq) and heated to 50 C overnight. After completion of the reaction, the reaction solution was cooled, poured into water and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and then poured onto the column. PE [petroleum ether]: EA [ethyl acetate] Volume ratio) = 5: 1 to obtain compound 4-3.

Reference： [1]Patent: CN107216319,2017,A .Location in patent: Paragraph 0071; 0072

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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. 28987-46-4 ] {[proInfo.proName]}

Quality Control of [ 28987-46-4 ]

Related Doc. of [ 28987-46-4 ]

Product Details of [ 28987-46-4 ]

Safety of [ 28987-46-4 ]

Application In Synthesis of [ 28987-46-4 ]

[ 28987-46-4 ] Synthesis Path-Upstream 1~1

[ 28987-46-4 ] Synthesis Path-Downstream 1~10

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry