[ CAS No. 112559-81-6 ] {[proInfo.proName]}

Name: 112559-81-6|4-(4-(4-Nitrophenyl)-1-piperazinyl)phenol|97%
Brand: Ambeed
SKU: A188498
Price: 13.0 USD
Availability: InStock
Rating: 91 (27 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

2D 3D

Structure of 112559-81-6 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 112559-81-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 112559-81-6 ]

SDS Specification

Alternatived Products of [ 112559-81-6 ]

Product Details of [ 112559-81-6 ]

CAS No. :	112559-81-6	MDL No. :	MFCD08460988
Formula :	C₁₆H₁₇N₃O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BNHYDULILNJFFY-UHFFFAOYSA-N
M.W :	299.32	Pubchem ID :	11381017
Synonyms :

Calculated chemistry of [ 112559-81-6 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	93.78
TPSA :	72.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.92 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.88
Log Po/w (XLOGP3) :	3.11
Log Po/w (WLOGP) :	1.87
Log Po/w (MLOGP) :	1.43
Log Po/w (SILICOS-IT) :	-0.14
Consensus Log Po/w :	1.63

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.86
Solubility :	0.0412 mg/ml ; 0.000138 mol/l
Class :	Soluble
Log S (Ali) :	-4.3
Solubility :	0.0149 mg/ml ; 0.0000499 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-3.49
Solubility :	0.0966 mg/ml ; 0.000323 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.28

Safety of [ 112559-81-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 112559-81-6 ]

* 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 [ 112559-81-6 ]
Downstream synthetic route of [ 112559-81-6 ]

[ 112559-81-6 ] Synthesis Path-Upstream 1~12

1
[ 112559-81-6 ]
[ 74853-08-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hypophosphite In 2-methoxy-ethanol; water at 70 - 80℃; for 2 - 2.5 h;	Under nitrogen, 430 g (1.34 mol) N-(4-Hydroxyphenyl)-N'-(4'-nitrophenyl)-piperazine are suspended in 2.8 liters methoxyethanol at 20° - 25° C. After the addition of 52 g palladium ((5percent on charcoal, 50percent water wet) (Degussa Typ E1049)) the suspension is degassed (3 times) and heated to 70° - 75° C. A solution of 497 g sodium hypophosphite monohydrate in 1.12 liters water is slowly added over 2 -2.5 hours at 70° - 75° C. (After addition of about 10 ml the evolution of hydrogenation starts and the temperature has to be kept at 75° - 80° C; towards the end of the addition external heating is needed). After complete addition, the reaction mixture is stirred at 70° - 75° C and the reaction is followed by TLC (silicagel, n-hexane/ethylacetate 1/2). After complete conversion (30 - 45 minutes, color turns from brown-yellow to grey) the suspension is cooled to 25° - 30° C and diluted with 2.4 liters water. The pH is adjusted to <=2 by the addition of about 400 ml concentrated HCl (about 10 minutes) at 25° to 30° C and stirred at this temperature for about 15 minutes. The catalyst is filtered off and washed with 600 ml water. The combined filtrates are warmed to 35° to 40° C and the pH is adjusted to 7.1 +/- 1 at 35° to 40° C by the addition of about 760 ml concentrated sodium hydroxide (slightly exothermic). The resulting suspension is cooled to 20° - 25° C and stirred at that temperature for 30 minutes. The product is filtered off under nitrogen (about 40 minutes) and washed twice with 1.6 liters water, followed by 400 ml water/methanol (1:1) and 800 ml methanol. The product is dried under vacuum at 50° C (slight stream of nitrogen) to constant weight. [] Yield317 g (88percent)Assay (HPLC)99.7percent pure by area

Reference： [1] Patent: EP1230231, 2005, B1, . Location in patent: Page/Page column 4
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[3] Patent: CN108003118, 2018, A, . Location in patent: Paragraph 0030

2
[ 56621-48-8 ]
[ 100-00-5 ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 120 - 125℃; for 5 - 7 h;	Under nitrogen, 420 g (2.36 mol) N-(4-Hydroxyphenyl)-piperazine, 520.6 g (3.30 mol) 1-chloro-4-nitrobenzene and 457.5 g (3.54 mol) N,N-Diisopropylethylamine (Huenig's Base) are suspended in 1260 ml N-Methylpyrrolidone and heated to 120° - 125°C. The clear solution is stirred at 120° - 125°C and the reaction is followed by HPLC. After complete reaction (5 - 7 hours) the solution is cooled to 75° - 80° C and 6.3 liters of isopropanol are added over a period of about 30 minutes to the reaction mixture while keeping the temperature at 75° - 80° C (slight heating is necessary). Towards the end of the addition the product starts to precipitate (yellow crystals). The suspension is cooled to 20° - 25° C and stirred overnight at this temperature. Afterwards the suspension is cooled to -10° to -5° C and stirred for 30 minutes. The product is filtered off, washed with 1.7 liters isopropanol, followed by 5 x 840 ml warm (35° - 40° C) water. The product is dried under vacuum at 50° C (slight stream of nitrogen) to constant weight. [] Yield96percentAssay (HPLC)93percent pure vs. standard

Reference： [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3635 - 3649
[2] Patent: EP1230231, 2005, B1, . Location in patent: Page/Page column 4
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7363 - 7374
[4] Patent: WO2018/45106, 2018, A1, . Location in patent: Paragraph 00131
[5] Patent: WO2018/45104, 2018, A1, . Location in patent: Paragraph 00156

3
[ 100-00-5 ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
25 kg	With triethylamine In dimethyl sulfoxide at 100 - 110℃; Inert atmosphere	The proportion of the parts: 180 parts by mass of dimethyl sulfoxide (DMSO), 35 parts by mass of p-hydroxyphenyl piperazine hydrobromide, 0.4 mol of triethylamine, and 35 parts by mass of p-chloronitrobenzene;In a 1000 L enamel reactor, under the protection of nitrogen, 180.0 kg of dimethyl sulfoxide (DMSO) was added. After stirring, 35.0 kg of p-hydroxyphenyl piperazine hydrobromide and 40.0 kg of triethylamine were added in sequence. 35.0 kg of p-chloronitrobenzene, then slowly warmed to 100-110 ° C, after 15-20 h of reaction, analyzed by TLC dot plate, the volume ratio of the developing solvent was ethyl acetate: methanol = 4:1, the amount was 5 ml, Under UV light, observation was carried out at a wavelength of 254 nm until the starting material p-hydroxyphenyl piperazine hydrobromide was absent. Cool down to 20-25 ° C, add tap water 500.0 kg, stir crystallization, then cool to 0-5 ° C filtration, then wash with 50-60 ° C hot water, rinse with 10.0 kg of isopropanol, wet at 70 ° C- 80 ° C, vacuum -0.08mPa to -0.09mPaDrying under reduced pressure, the product was 25.0 kg.

Reference： [1] Patent: CN108003118, 2018, A, . Location in patent: Paragraph 0029

4
[ 56621-48-8 ]
[ 350-46-9 ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate In N,N-dimethyl acetamide; water	(a) A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76percent) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0° C. (intermediate 9).

Reference： [1] Patent: US4791111, 1988, A,

5
[ 74852-61-2 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 18, p. 3359 - 3363

6
[ 586-78-7 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 18, p. 3359 - 3363
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[3] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659

7
[ 153466-15-0 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659

8
[ 6269-89-2 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659

9
[ 67455-41-8 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659

10
[ 38212-30-5 ]
[ 112559-81-6 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 18, p. 3359 - 3363

11
[ 104-94-9 ]
[ 112559-81-6 ]

Reference： [1] Patent: CN108003118, 2018, A,

12
[ 84145-43-7 ]
[ 112559-81-6 ]

Reference： [1] Patent: CN108003118, 2018, A,

[ 112559-81-6 ] Synthesis Path-Downstream 1~75

1
[ 112559-81-6 ]
[ 74853-08-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hypophosphite;5%-palladium/activated carbon; In 2-methoxy-ethanol; water; at 70 - 80℃; for 2 - 2.5h;	Under nitrogen, 430 g (1.34 mol) <strong>[112559-81-6]N-(4-Hydroxyphenyl)-N'-(4'-nitrophenyl)-piperazine</strong> are suspended in 2.8 liters methoxyethanol at 20 - 25 C. After the addition of 52 g palladium ((5% on charcoal, 50% water wet) (Degussa Typ E1049)) the suspension is degassed (3 times) and heated to 70 - 75 C. A solution of 497 g sodium hypophosphite monohydrate in 1.12 liters water is slowly added over 2 -2.5 hours at 70 - 75 C. (After addition of about 10 ml the evolution of hydrogenation starts and the temperature has to be kept at 75 - 80 C; towards the end of the addition external heating is needed). After complete addition, the reaction mixture is stirred at 70 - 75 C and the reaction is followed by TLC (silicagel, n-hexane/ethylacetate 1/2). After complete conversion (30 - 45 minutes, color turns from brown-yellow to grey) the suspension is cooled to 25 - 30 C and diluted with 2.4 liters water. The pH is adjusted to ?2 by the addition of about 400 ml concentrated HCl (about 10 minutes) at 25 to 30 C and stirred at this temperature for about 15 minutes. The catalyst is filtered off and washed with 600 ml water. The combined filtrates are warmed to 35 to 40 C and the pH is adjusted to 7.1 +/- 1 at 35 to 40 C by the addition of about 760 ml concentrated sodium hydroxide (slightly exothermic). The resulting suspension is cooled to 20 - 25 C and stirred at that temperature for 30 minutes. The product is filtered off under nitrogen (about 40 minutes) and washed twice with 1.6 liters water, followed by 400 ml water/methanol (1:1) and 800 ml methanol. The product is dried under vacuum at 50 C (slight stream of nitrogen) to constant weight. [] Yield317 g (88%)Assay (HPLC)99.7% pure by area
	With hydrogen; In methanol; ethyl acetate; at 35 - 40℃; under 2250.23 Torr;Large scale;	Proportioning parts: 400 parts by mass of methanol, 250 parts by mass of ethyl acetate, 25 parts by mass of 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)-piperazine, active nickel (AMC-1000) ) 5 parts by mass;In a 1000 L autoclave, under a nitrogen atmosphere, 400.0 kg of methanol and 250.0 kg of ethyl acetate were added. After stirring, 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)- After piperazine 25.0 kg, and then nitrogen substitution three times, 5.0 kg of activated nickel (AMC-1000) was added, the reaction kettle was sealed, replaced with nitrogen three times, and after three hydrogen substitutions,Hydrogenation pressure to 0.3MPa slowly warmed to 35 C -40 C, after 10-15h reaction, using TLC point plate analysis, the volume ratio of the developing agent is ethyl acetate: methanol = 4:1, the amount is 5ml, in the UV lamp The reaction was observed at a wavelength of 254 nm until no starting material, 1-(4-hydroxyphenyl)-4-(4-nitrophenyl)-piperazine. Nitrogen replacement three times, transfer to the desolvation kettle, decompose the mixed solvent under reduced pressure, add 250.0 kg of water, stir and cool to 0-5 C, adjust pH=2 with 10% hydrochloric acid aqueous solution, filter, and use 10% ammonia water for the filtrate. Adjust pH=7, filter, and obtain 50.0 kg of wet crude. The mother liquor is collected and collected separately.

Reference： [1]Patent: EP1230231,2005,B1 .Location in patent: Page/Page column 4
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[3]Patent: CN108003118,2018,A .Location in patent: Paragraph 0030

2
[ 153466-15-0 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

3
[ 74852-61-2 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

4
[ 104-92-7 ]
Pd((PAnPh₂)2Cl₂ [ No CAS ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

5
[ 38212-30-5 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363

6
[ 586-78-7 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 3359 - 3363
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[3]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

7
[ 100-25-4 ]
Me₃SiCH₂Mg halide [ No CAS ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

8
[ 67455-41-8 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

9
[ 6269-89-2 ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

10
[ 100-00-5 ]
dipotassium-salt of bis-<4-hydroxy-phenyl>-ether [ No CAS ]
[ 112559-81-6 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659
[2]Tetrahedron Letters,1999,vol. 40,p. 5655 - 5659

11
[ 56621-48-8 ]
[ 100-00-5 ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120 - 125℃; for 5 - 7h;	Under nitrogen, 420 g (2.36 mol) N-(4-Hydroxyphenyl)-piperazine, 520.6 g (3.30 mol) 1-chloro-4-nitrobenzene and 457.5 g (3.54 mol) N,N-Diisopropylethylamine (Huenig's Base) are suspended in 1260 ml N-Methylpyrrolidone and heated to 120 - 125C. The clear solution is stirred at 120 - 125C and the reaction is followed by HPLC. After complete reaction (5 - 7 hours) the solution is cooled to 75 - 80 C and 6.3 liters of isopropanol are added over a period of about 30 minutes to the reaction mixture while keeping the temperature at 75 - 80 C (slight heating is necessary). Towards the end of the addition the product starts to precipitate (yellow crystals). The suspension is cooled to 20 - 25 C and stirred overnight at this temperature. Afterwards the suspension is cooled to -10 to -5 C and stirred for 30 minutes. The product is filtered off, washed with 1.7 liters isopropanol, followed by 5 x 840 ml warm (35 - 40 C) water. The product is dried under vacuum at 50 C (slight stream of nitrogen) to constant weight. [] Yield96%Assay (HPLC)93% pure vs. standard
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;	1001311 FIG. 6A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-fungal compounds, which was used to produce Compounds lia4id. Generally, reagents and conditions for synthesis of compounds according to FIG. 6A included: a) NMP, DIPEA, 4- chloronitrobenzene; h) x,w-dihaloaikane. K2C03, acetone or Cs2CO3, DMF; c) imidazole or 1.2,4-triazole, Cs2CO3, DMF; d) Pd/C, H2, EtOAc/MeOH; e) S-(2-naphthyimethyi-2- pyridyithioimidate hydrobromide, CH3CN/F:tOl-I.
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one;	FIG. 7A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-parasitic compounds, which was used to produce Compounds lla-lld. Generally, reagents and conditions for synthesis of compounds according to FIG. 7A included: a) NMP, DIPEA, 4- chloronitrobenzene; b) alpha,omega-dihaloalkane, K2C0 , acetone or Cs2C0 , DMF; c) imidazole or 1 ,2,4-triazole, Cs2C03, DMF; d) Pd/C, H2, EtOAc/MeOH; e) ,S-(2-naphthylmethyI-2- pyridylthioimidate hydrobromide, CH3CN/EtOH.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 3635 - 3649
[2]Patent: EP1230231,2005,B1 .Location in patent: Page/Page column 4
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374
[4]Patent: WO2018/45106,2018,A1 .Location in patent: Paragraph 00131
[5]Patent: WO2018/45104,2018,A1 .Location in patent: Paragraph 00156
[6]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

12
[ 112559-81-6 ]
(2S-cis)-1-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-4-(4-nitrophenyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In 1,3-dimethyl-2-imidazolidinone; dichloromethane; water;	a) A mixture of intermediate 8 (0.048 mol) in 1,3-dimethyl-2-imidazolidinone (200 ml) was stirred under N2 flow for 15 minutes. NaOH (3 ml; 50%) was added. The mixture was stirred for 30 minutes. <strong>[112559-81-6]4-[4-(4-nitrophenyl)-1-piperazinyl]phenol</strong> (0.04 mol) and then NaOH (2.4 g; solid) were added. The mixture was stirred at 70 C. mol under N2 flow for 9 hours and at room temperature overnight, then poured out into H2O and stirred for 1 hour. The precipitate was filtered off and dissolved in CH2Cl2. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/EtOAc/hexane 48/2/30/20). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from EtOAc. The precipitate was filtered off and dried, yielding 9 g of (2S-cis)-1-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-4-(4-nitrophenyl)piperazine (interm. 19).

Reference： [1]Patent: US6387906,2002,B1

13
[ 171764-50-4 ]
[ 62018-65-9 ]
[ 112559-81-6 ]
cis-1-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-nitrophenyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6.69 parts (38.5%)	With potassium hydroxide; In methanol; hexane; N,N-dimethyl-formamide;	(a) A mixture of 9.0 parts of <strong>[112559-81-6]4-[4-(4-nitrophenyl)-1-piperazinyl]phenol</strong>, 13.6 parts of cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester), 6.0 parts of potassium hydroxide and 90 parts of N,N-dimethylformamide was stirred overnight at 70 C. under nitrogen atmosphere. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, ethyl acetate, hexane and methanol (500:300:200:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis-1-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy]-phenyl]-4-(4-nitrophenyl)piperazine; mp. 169.8 C. (intermediate 7).
6.69 parts (38.5%)	With potassium hydroxide; In methanol; hexane; N,N-dimethyl-formamide;	(b) A mixture of 9.0 parts of <strong>[112559-81-6]4-[4-(4-nitrophenyl)-1-piperazinyl]phenol</strong>, 13.6 parts of cis-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol methanesulfonate(ester), 6.0 parts of potassium hydroxide and 90 parts of N,N-dimethylformamide was stirred overnight at 70 C. under nitrogen atmosphere. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by column chromatography over silica gel using a mixture of trichloromethane, ethyl acetate, hexane and methanol (500:300:200:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis-1-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-(4-nitrophenyl)piperazine: mp. 169.8 C. (intermediate 10).

Reference： [1]Patent: US4916134,1990,A
[2]Patent: US4791111,1988,A

14
[ 132507-95-0 ]
[ 112559-81-6 ]
[ 128063-69-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide;	(i) 2-(2,4-Dichlorophenyl)-3-(4-[4-(4-nitrophenyl)piperazin-1-yl]phenoxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol A stirred mixture of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (40 g, 0.11 mmole), 4-(4-[4-nitrophenyl]piperazin-1-yl)phenol (see EP-0228125) (35 g, 0.12 mmole) and cesium carbonate (100 g, 0.3 mmole) in DMF (500 ml) was heated at 120 for 18 hours. The mixture was cooled, diluted with methylene chloride (500 ml) and the insoluble inorganic material removed by filtration. The filtrate was concentrated under reduced pressure and the residue partitioned between methylene chloride (800 ml) and water (200 ml). The organic phase was separated, washed with water (200 ml) and dried over magnesium sulphate. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel eluding with methylene chloride (90):methanol (1):0.88 ammonia solution (0.1) to yield, after collection and evaporation of appropriate fractions, the title compounds as a viscous oil, (26.6 g, 46%), which was used directly in the next stage.
	With caesium carbonate; In N,N-dimethyl-formamide;	(i) 2-(2,4-Dichlorophenyl)-3-(4-[4-(4-nitrophenyl)piperazin-1-yl]phenoxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol A stirred mixture of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (40 g, 0.11 mmole), 4-(4-[4-nitrophenyl]piperazin-1-yl)phenol (see EP-0228125) (35 g, 0.12 mmole) and cesium carbonate (100 g, 0.3 mmole) in DMF (500 ml) was heated at 120 for 18 hours. The mixture was cooled, diluted with methylene chloride (500 ml) and the insoluble inorganic material removed by filtration. The filtrate was concentrated under reduced pressure and the residue partitioned between methylene chloride (800 ml) and water (200 ml). The organic phase was separated, washed with water (200 ml) and dried over magnesium sulphate. After concentration under reduced pressure, the residue was purified by flash chromatography on silica gel eluding with methylene chloride (90):methanol (1):0.88 ammonia solution (0.1) to yield, after collection and evaporation of appropriate fractions, the title compound as a viscous oil, (26.6 g, 46%), which was used directly in the next stage.

Reference： [1]Patent: US5023258,1991,A
[2]Patent: EP352946,1990,A1

15
[ 86386-76-7 ]
[ 112559-81-6 ]
[ 128063-72-9 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide;	(i) 2-(2,4-Difluorophenyl)-3-(4-[4-(4-nitrophenyl)piperazin-1-yl]phenoxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol A mixture of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (3.3 g, 13.9 mmole), 4-(4-[4-nitrophenyl]piperazin-1-yl)phenol (3.0 g, 10 mmole) and cesium carbonate (4.8 g, 14.7 mmole) in DMF (20 ml) was heated at 80 overnight. After cooling, the solvent was removed by concentration under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried over magnesium sulphate. The solution was concentrated under reduced pressure and purified by flash chromatography on silica gel eluding with ethyl acetate (10):hexane (1) to yield, after collection and evaporation of appropriate fractions, the desired product, m.p. 187-189 (0.9 g, 17%). Analysis %: Found: C,59.77; H,4.80; N,15.11; Calculated for C27 H26 F2 N6 O4.0.25 CH3 COOC2 H5: C,60.16; H,5.01; N,15.04.
	With caesium carbonate; In N,N-dimethyl-formamide;	(i) 2-(2,4-Difluorophenyl)-3-(4-[4-(4-nitrophenyl)piperazin-1-yl]phenoxy)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol A mixture of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (3.3 g, 13.9 mmole), 4-(4-[4-nitrophenyl]piperazin-1-yl)phenol (3.0 g, 10 mmole) and cesium carbonate (4.8 g, 14.7 mmole) in DMF (20 ml) was heated at 80 overnight. After cooling, the solvent was removed by concentration under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried over magnesium sulphate. The solution was concentrated under reduced pressure and purified by flash chromatography on silica gel eluding with ethyl acetate (10):hexane (1) to yield, after collection and evaporation of appropriate fractions, the desired product, m.p. 187-189 (0.9 g, 17%).

Reference： [1]Patent: US5023258,1991,A
[2]Patent: EP352946,1990,A1

16
[ 56621-48-8 ]
[ 350-46-9 ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
114.4 parts (76%)	With potassium carbonate; In N,N-dimethyl acetamide; water;	(a) A mixture of 91.7 parts of 4-(1-piperazinyl)phenol, 71.0 parts of 1-fluoro-4-nitrobenzene, 60.0 parts of potassium carbonate and 450 parts of N,N-dimethylacetamide was stirred over weekend at room temperature. Water was added and after standing for 5 hours, the product was filtered off. It was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 114.4 parts (76%) of 4-[4-(4-nitrophenyl)-1-piperazinyl]phenol; mp. 260.0 C. (intermediate 9).

Reference： [1]Patent: US4791111,1988,A

17
[ 75-36-5 ]
[ 112559-81-6 ]
acetic acid 4-[4-(4-nitro-phenyl)-piperazin-1-yl]-phenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 10 - 20℃;	To a stirred suspension of 4-[4-(4-nitro-phenyl)-piperazin-l-yl]-phenol (5Og), triethylamine (34.34g) in dichloromethane (500ml), acetyl chloride (16.Og) was added slowly at 10 . The temperature of the resulting mixture was raised to ambient temperature and stirred for 4-5 hours. After completion of reaction (monitored by TLC), the reaction mixture was washed with water (250ml) and brine (250ml). Organic layer was separated and evaporated to obtain 50g of title compound having purity of 98.0% by HPLC.

Reference： [1]Patent: WO2009/141837,2009,A2 .Location in patent: Page/Page column 17

18
[ 107-30-2 ]
[ 112559-81-6 ]
[ 1246819-65-7 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	To a mixture of 10 (263.4 mg, 0.88 mmol) and diisopropylamine (DIPEA) (170.6 mg, 1.32 mmol) in CH2C12 (12 mL) was added slowly chloromethyl methyl ether (77.9 mg, 0.97 mmol) at room temperature. The reaction was stirred for 16 h, and then quenched by the addition of saturated aqueous ammonium chloride (10 mL). The resulting solution was extracted with more CH202, dried (Na2S04), filtered, and concentrated to yield the crude product, which was purified by column chromatography (neat CH2C12? 100:1 CH2Cl2-Acetone) to afford 11 (250.8 mg, 83%) as a yellow amorphous solid: 1H NMR (400 MHz, CDC13, deltaEta) 8.20 - 8.08 (m, 2H), 7.07 - 6.97 (m, 2H), 6.97 - 6.82 (m, 4H), 5.13 (s, 2H), 3.62 - 3. 1 (m, 4H), 3.48 (s, 3H), 3.30 - 3.18 (m, 4H); 13C NMR (100 MHz, CDC13, 5C) 154.99, 151.98, 146.31, 138.84, 126.18, 118.59, 117.58, 113.04, 95.28, 56.13, 50.42, 47.43. MALDI-MS: 344.2 (M+H+), 366.2 (M+Na+).

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374
[2]Patent: WO2013/36866,2013,A1 .Location in patent: Paragraph 0235

19
[ 154003-23-3 ]
[ 112559-81-6 ]
C₂₉H₂₈Cl₂N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

20
[ 154003-21-1 ]
[ 112559-81-6 ]
C₂₉H₂₈Cl₂N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

21
[ 112559-81-6 ]
[ 1329503-19-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374
[2]Patent: WO2013/36866,2013,A1

22
[ 112559-81-6 ]
[ 1339803-88-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374
[2]Patent: WO2013/36866,2013,A1

23
[ 112559-81-6 ]
C₂₉H₃₀Cl₂N₆O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

24
[ 112559-81-6 ]
C₂₉H₃₀Cl₂N₆O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

25
[ 112559-81-6 ]
C₃₆H₃₄Cl₂N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

26
[ 112559-81-6 ]
C₃₀H₃₂Cl₂N₈O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

27
[ 112559-81-6 ]
C₃₆H₃₄Cl₂N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

28
[ 112559-81-6 ]
C₃₀H₃₂Cl₂N₈O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374

29
[ 112559-81-6 ]
[ 1246815-17-7 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7363 - 7374
[2]Patent: WO2013/36866,2013,A1

30
2RS,4RS-toluene-4-sulfonic acid (2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)methyl-1,3-dioxolan-4-yl)methyl ester [ No CAS ]
[ 112559-81-6 ]
1-(4-((2-((1H-1,2,4-triazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl)methoxy)phenyl)-4-(4-nitrophenyl)piperazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 3635 - 3649

31
[ 100-00-5 ]
1-(4-hydroxyphenyl)piperazine hydrobromide [ No CAS ]
[ 112559-81-6 ]

Yield	Reaction Conditions	Operation in experiment
25 kg	With triethylamine; In dimethyl sulfoxide; at 100 - 110℃;Inert atmosphere;	The proportion of the parts: 180 parts by mass of dimethyl sulfoxide (DMSO), 35 parts by mass of p-hydroxyphenyl piperazine hydrobromide, 0.4 mol of triethylamine, and 35 parts by mass of p-chloronitrobenzene;In a 1000 L enamel reactor, under the protection of nitrogen, 180.0 kg of dimethyl sulfoxide (DMSO) was added. After stirring, 35.0 kg of p-hydroxyphenyl piperazine hydrobromide and 40.0 kg of triethylamine were added in sequence. 35.0 kg of p-chloronitrobenzene, then slowly warmed to 100-110 C, after 15-20 h of reaction, analyzed by TLC dot plate, the volume ratio of the developing solvent was ethyl acetate: methanol = 4:1, the amount was 5 ml, Under UV light, observation was carried out at a wavelength of 254 nm until the starting material p-hydroxyphenyl piperazine hydrobromide was absent. Cool down to 20-25 C, add tap water 500.0 kg, stir crystallization, then cool to 0-5 C filtration, then wash with 50-60 C hot water, rinse with 10.0 kg of isopropanol, wet at 70 C- 80 C, vacuum -0.08mPa to -0.09mPaDrying under reduced pressure, the product was 25.0 kg.

Reference： [1]Patent: CN108003118,2018,A .Location in patent: Paragraph 0029

32
[ 104-94-9 ]
[ 112559-81-6 ]

Reference： [1]Patent: CN108003118,2018,A

33
[ 84145-43-7 ]
[ 112559-81-6 ]

Reference： [1]Patent: CN108003118,2018,A

34
((3S,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate [ No CAS ]
[ 112559-81-6 ]
1-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)-4-(4-nitrophenyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		General procedure: Cs2CO3 (10 equiv.) and the requisitelinker (1 equiv.) were diluted in anhydrous DMSO and stirred for30 min at room temperature before addition of the des-triazole THFregion in DMSO. The mixture was heated to 90 C and stirred for12 h. The reaction was quenched with water and extracted usingEtOAc (2x) and DCM (2x). For 17 and 18, the water layer wasacidified to pH= 2 to ensure complete extraction of the carboxylicacid into the organic phase. The organic layers were combined,dried over Na2SO4, filtered and concentrated. The crude analoguewas purified by column chromatography (SiO2, 10-30% Acetone inHexanes).
67%		CS2CO3 (445 mg, 1.26 mmol, 10 equiv.) and 4-(4-(4-nitrophenyl)piperazin-l-yl)phenol (38 mg, 0.126 mmol, 1 equiv.) were diluted in anhydrous DMSO (10 mL) and stirred for 30 minutes at room temperature before the addition of P8 (45 mg, 0.126 mmol, 1 equiv.). The reaction was heated to 90 C and stirred overnight. The next day, the reaction was quenched with water and extracted using EtOAc (3x). The organic layers were combined, dried over Na2S04, filtered and concentrated. The crude was purified by column chromatography (Si02, 10-30% Acetone in Hexanes). The fractions containing product were collected and dried by rotary evaportation. Orange oil. (Yield = 40 mg, 67% ). 1HNMR (500 MHz, CDCI3) delta 8.21 - 8.19 (m, 2H), 7.65 - 7.51 (m, 1H), 6.98 - 6.80 (m, 8H), 4.29 - 4.26 (m, 1H), 4.19 - 4.10 (m, 1H), 4.00 - 3.94 (m, 2H), 3.87 - 3.72 (m, 1H), 3.63 - 3.60 (m, 4H), 3.28 - 3.26 (m, 4H), 2.98 - 2.95 (m, 1H), 2.66 - 2.52 (m, 2H), 2.07 - 1.95 (m, 1H), 1.65 (s, 1H), 1.58 (s, 2H). 1 CNMR (126 MHz, CDCI3) delta 154.79, 145.38, 130.16, 127.72, 127.64, 126.99, 125.98, 118.68, 115.38, 115.33, 113.38, 112.92, 104.36, 104.15, 82.81, 70.19, 70.08, 69.90, 60.31, 50.47, 47.29, 42.03, 39.53, 28.37. DART-HRMS: m/z [M+H]+ cald. for [C28H3oF2N304]+, 510.2126; found 510.2205. IR (solid) vmax: 2932, 2850, 1596, 1509, 1322, 1229, 1115, 1038, 944, 826, 754. Purity = 95.6%.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 320 - 332
[2]Patent: WO2019/40363,2019,A1 .Location in patent: Paragraph 0195; 0202; 0203; 0212

35
[ 112559-81-6 ]
4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)aniline [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

36
[ 112559-81-6 ]
phenyl (4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

37
[ 112559-81-6 ]
N-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)hydrazinecarboxamide [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

38
[ 112559-81-6 ]
N-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-3-hydroxybenzamide [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

39
[ 112559-81-6 ]
N-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)nicotinamide [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

40
[ 112559-81-6 ]
3-acetyl-N-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5- methyltetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Patent: WO2019/40363,2019,A1

41
((2R,4S)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate [ No CAS ]
[ 112559-81-6 ]
1-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4-(4-nitrophenyl)piperazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

42
((2S,4S)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate [ No CAS ]
[ 112559-81-6 ]
1-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)-4-(4-nitrophenyl)piperazine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

43
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)picolinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

44
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)nicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

45
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)isonicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

46
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

47
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-naphthamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

48
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)picolinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

49
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)nicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

50
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)isonicotinamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

51
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

52
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-3-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

53
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

54
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

55
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-3-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

56
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

57
[ 112559-81-6 ]
3-chloro-N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

58
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-3-methoxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

59
[ 112559-81-6 ]
3-acetyl-N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

60
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)furan-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

61
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)thiophene-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

62
[ 112559-81-6 ]
phenyl (4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

63
[ 112559-81-6 ]
phenyl (4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

64
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)hydrazine carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

65
[ 112559-81-6 ]
N-(4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)hydrazine carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

66
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

67
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

68
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

69
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

70
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

71
[ 112559-81-6 ]
C₄₁H₃₉Cl₂N₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

72
[ 112559-81-6 ]
4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)aniline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

73
[ 112559-81-6 ]
4-(4-(4-(((2S,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)aniline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

74
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)benzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

75
[ 112559-81-6 ]
N-(4-(4-(4-(((2R,4R)-2-(2,4-dichlorophenyl)-2-methyl-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-naphthamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3873 - 3885

Same Skeleton Products

Related Products

Historical Records

Pharmaceutical Intermediates of
[ 112559-81-6 ]

Posaconazole Related Intermediates

[ 74853-08-0 ]

1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine

[ 159811-30-0 ]

((3R,5R)-5-((1H-1,2,4-Triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate

[ 105-53-3 ]

Diethyl malonate

[ 184177-81-9 ]

Phenyl (4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenyl)carbamate

[ 122263-03-0 ]

2-Acetoxy-2',4'-difluoroacetophenone

Related Functional Groups of
[ 112559-81-6 ]

Aryls

[ 761440-26-0 ]

1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine

Similarity: 0.85

[ 92952-81-3 ]

4-((3-Hydroxypropyl)amino)-3-nitrophenol

Similarity: 0.84

[ 5521-38-0 ]

2-(4-(4-Nitrophenyl)piperazin-1-yl)ethanol

Similarity: 0.82

[ 54054-85-2 ]

1-(3-Nitrophenyl)piperazine

Similarity: 0.80

[ 56621-48-8 ]

4-(Piperazin-1-yl)phenol

Similarity: 0.76

Nitroes

[ 761440-26-0 ]

1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine

Similarity: 0.85

[ 92952-81-3 ]

4-((3-Hydroxypropyl)amino)-3-nitrophenol

Similarity: 0.84

[ 5521-38-0 ]

2-(4-(4-Nitrophenyl)piperazin-1-yl)ethanol

Similarity: 0.82

[ 54054-85-2 ]

1-(3-Nitrophenyl)piperazine

Similarity: 0.80

[ 23491-48-7 ]

5-(4-Methylpiperazin-1-yl)-2-nitroaniline

Similarity: 0.76

Related Parent Nucleus of
[ 112559-81-6 ]

Aliphatic Heterocycles

[ 761440-26-0 ]

1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine

Similarity: 0.85

[ 5521-38-0 ]

2-(4-(4-Nitrophenyl)piperazin-1-yl)ethanol

Similarity: 0.82

[ 74853-08-0 ]

1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine

Similarity: 0.76

[ 23491-48-7 ]

5-(4-Methylpiperazin-1-yl)-2-nitroaniline

Similarity: 0.76

[ 5367-58-8 ]

5-Nitro-2-(piperidin-1-yl)aniline

Similarity: 0.71

Piperazines

[ 761440-26-0 ]

1-(3-Methoxy-4-nitrophenyl)-4-methylpiperazine

Similarity: 0.85

[ 5521-38-0 ]

2-(4-(4-Nitrophenyl)piperazin-1-yl)ethanol

Similarity: 0.82

[ 54054-85-2 ]

1-(3-Nitrophenyl)piperazine

Similarity: 0.80

[ 74853-08-0 ]

1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine

Similarity: 0.76

[ 56621-48-8 ]

4-(Piperazin-1-yl)phenol

Similarity: 0.76

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 112559-81-6 ] {[proInfo.proName]}

Quality Control of [ 112559-81-6 ]

Related Doc. of [ 112559-81-6 ]

Product Details of [ 112559-81-6 ]

Calculated chemistry of [ 112559-81-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 112559-81-6 ]

Application In Synthesis of [ 112559-81-6 ]

[ 112559-81-6 ] Synthesis Path-Upstream 1~12

[ 112559-81-6 ] Synthesis Path-Downstream 1~75

Pharmaceutical Intermediates of [ 112559-81-6 ]

Posaconazole Related Intermediates

Related Functional Groups of [ 112559-81-6 ]

Aryls

Nitroes

Related Parent Nucleus of [ 112559-81-6 ]

Aliphatic Heterocycles

Piperazines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Pharmaceutical Intermediates of
[ 112559-81-6 ]

Related Functional Groups of
[ 112559-81-6 ]

Related Parent Nucleus of
[ 112559-81-6 ]