[ CAS No. 141412-60-4 ] {[proInfo.proName]}

Name: 141412-60-4|1,4-Difluoro-2-methyl-5-nitrobenzene|97%
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SKU: A130408
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Quality Control of [ 141412-60-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 141412-60-4 ]

SDS Specification

Alternatived Products of [ 141412-60-4 ]

Product Details of [ 141412-60-4 ]

CAS No. :	141412-60-4	MDL No. :	MFCD06200905
Formula :	C₇H₅F₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ABWWQMGGJXKGBL-UHFFFAOYSA-N
M.W :	173.12	Pubchem ID :	230658
Synonyms :

Calculated chemistry of [ 141412-60-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.15
TPSA :	45.82 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) :	-5.71 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	2.32
Log Po/w (WLOGP) :	3.02
Log Po/w (MLOGP) :	2.06
Log Po/w (SILICOS-IT) :	0.98
Consensus Log Po/w :	1.99

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.68
Solubility :	0.363 mg/ml ; 0.00209 mol/l
Class :	Soluble
Log S (Ali) :	-2.92
Solubility :	0.208 mg/ml ; 0.0012 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.72
Solubility :	0.33 mg/ml ; 0.00191 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.76

Safety of [ 141412-60-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 141412-60-4 ]

* 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 [ 141412-60-4 ]
Downstream synthetic route of [ 141412-60-4 ]

[ 141412-60-4 ] Synthesis Path-Upstream 1~3

1
[ 452-67-5 ]
[ 141412-60-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With KNO₃ In conc. H₂ SO₄	2,5-Difluoro-4-nitrotoluene. To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H₂ SO₄ (5.0 mL) at 0° C., KNO₃ (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28° C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na₂ SO₄ and evaporated to afford 0.555 g (91percent) of the title compound as a light red oil; ¹ H NMR (CDCl₃): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J₁ =8.1 Hz, J₂ =6.0 Hz), 7.734 (dd, 1H, J₁ =8.4 Hz, J₂ =6.3 Hz).

Reference： [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 12, p. 2321 - 2327
[2] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5838 - 5842
[3] Patent: US5631373, 1997, A,
[4] Patent: WO2008/119720, 2008, A1, . Location in patent: Page/Page column 54

2
[ 141412-60-4 ]
[ 116465-48-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 12, p. 2321 - 2327

3
[ 14447-18-8 ]
[ 141412-60-4 ]
[ 1071974-01-0 ]

Reference： [1] Patent: EP2133332, 2009, A1, . Location in patent: Page/Page column 28

[ 141412-60-4 ] Synthesis Path-Downstream 1~72

1
[ 452-67-5 ]
[ 141412-60-4 ]

Yield	Reaction Conditions	Operation in experiment
0.555 g (91%)	With KNO3; In conc. H2 SO4;	2,5-Difluoro-4-nitrotoluene. To a stirred solution of 2,5-difluorotoluene (0.544 g, 4.25 mmol, Aldrich, used as received) in conc. H2 SO4 (5.0 mL) at 0 C., KNO3 (0.430 g, 4.25 mmol) was added in one portion. The resulting pale yellow solution was warmed to 28 C. and stirred at that temperature overnight. It was then poured into ice (25 g) and extracted with ethyl acetate (40 mL). The extract was dried over Na2 SO4 and evaporated to afford 0.555 g (91%) of the title compound as a light red oil; 1 H NMR (CDCl3): 2.369 (d, 3H, J=1.8 Hz), 7.127 (dd, 1H, J1 =8.1 Hz, J2 =6.0 Hz), 7.734 (dd, 1H, J1 =8.4 Hz, J2 =6.3 Hz).
	With sulfuric acid; potassium nitrate; at 20 - 30℃; for 0.25h;	A solution of 2,5-difluorotoluene (10g) in concentrated sulphuric acid (50ml) at 20-30C was treated portionwise with potassium nitrate (7.9g). After 15min, the mixture was poured onto ice and extracted with hexane:diethyl ether (1 :1 ), washed with water, dried, and evaporated to give the title compound (8.9g).

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327
[2]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[3]Patent: US5631373,1997,A
[4]Patent: WO2008/119720,2008,A1 .Location in patent: Page/Page column 54

2
[ 141412-60-4 ]
[ 116465-48-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

3
[ 6000-44-8 ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)glycine sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.134 g (18%)	In water; ethyl acetate; N,N-dimethyl-formamide;	N-(4-Fluoro-5-methyl-2-nitrophenyl)glycine sodium salt. To a stirred solution of <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (0.550 g. 3.18 mmol) in DMF (5.0 mL) was added dropwise a solution of sodium glycinate (0.308 g, 3.18 mmol, Aldrich, used as received) in water (1.0 mL). The resulting suspension was stirred at 28 C. overnight. The solid was filtered and dried under vacuum to give 0.168 g (23%) of crude product. It was purified as follows. 0.150 g material was boiled in ethyl acetate (5.0 mL) and filtered while hot to give 0.134 g (18%) of the pure (1 H NMR) title compound as a yellow powder. 1 H NMR (DMSO-d6): 2.213 (s, 3H), 3.428 (d, 2H, J=3.9 Hz), 6.765 (d, 1H, J=6.9 Hz), 7.700 (d, 1H, J=10.5 Hz), 8.728 (s, 1H).

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842
[2]Patent: US5631373,1997,A

4
[ 141412-60-4 ]
[ 170099-04-4 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842

5
[ 141412-60-4 ]
7-Fluoro-1,4-dihydro-6-methyl-5-nitroquinoxaline-2,3-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5838 - 5842

6
[ 141412-60-4 ]
2,5-difluoro-4-nitrobenzoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

7
[ 141412-60-4 ]
[ 141412-61-5 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

8
[ 141412-60-4 ]
[ 141412-63-7 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

9
[ 141412-60-4 ]
[ 7498-31-9 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

10
[ 141412-60-4 ]
[ 141412-62-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

11
[ 141412-60-4 ]
[ 141412-84-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

12
[ 141412-60-4 ]
[ 141412-69-3 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

13
[ 141412-60-4 ]
[ 141412-83-1 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

14
[ 141412-60-4 ]
[ 141412-68-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 2321 - 2327

15
[ 87120-72-7 ]
[ 141412-60-4 ]
[ 932374-58-8 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h;	1 ,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 mL) was treated under argon at room temperature with 1 ,1-dimethylethyl 4-amino-1- piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70 (?80) 0C for 38h. The mixture was concentrated under vacuum, treated with water and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under vacuum to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether 6 CV) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H = 298.07, main fragment (molecule has lost its tert-butyl group)
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h;	1 ,4-Difluoro-2-methyl-5-nitrobenzene (D30, 1.5 mol, 260 mg) in dimethylformamide (10 ml.) was treated under argon at room temperature with 1 ,1-dimethylethyl 4-amino-1- piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70-80 0C for 38h. The mixture was concentrated under reduced pressure, treated with water and extracted twice with ether. Organics were combined, dried over MgSO4 and concentrated under reduced pressure to give a red- brown residue which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H-'Bu = 298.07, main fragment.
64%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 38.0h;	Description 11; . 1,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1- piperidine-carboxylate (D11); .1 ,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 ml.) was treated under argon at room temperature with commercially available 1 ,1- dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 mul_, 1 eq) then stirred at 70-80 0C for 38h. The mixture was concentrated under reduced pressure, treated with water and extracted twice with ether. The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H-'Bu = 298.07, main fragment.

Reference： [1]ACS Medicinal Chemistry Letters,2010,vol. 1,p. 244 - 248
[2]Patent: WO2007/36718,2007,A2 .Location in patent: Page/Page column 55
[3]Patent: WO2008/119720,2008,A1 .Location in patent: Page/Page column 54
[4]Patent: WO2008/119721,2008,A1 .Location in patent: Page/Page column 56

16
1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[trans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 24.0h;	Description 95. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1 -[trans-lambda -methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine (D95); <n="91"/>To a solution of 1 ,4-difluoro-2-methyl-5-nitrobenzene (2.6 eq., 2.19mmol, 380 mg) in dry dimethylformamide (12 ml), diisopropylethylamine (2eq., 1.68 mmol, 0.29 ml) and 1- [frans-1-methyl-4-(methyloxy)cyclohexyl]-4-piperidinamine (D59, 1eq., 0.841 mmol, 190 mgs) were added at room temperature and the mixture was refluxed at 8O0C for 24 hours. The crude mixture was then cooled to room temperature and the crude was poured onto water (50 ml) and basified with 2M NaOH to pH 10. The aqueous solution was extracted with EtOAc (3x) and the organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude product. The crude product was passed through an SCX cartridge and then purified by chromatography (MeOH-N H3- dichloromethane) on silica column afford the title compound, 125 mgs, 40%, M+ + H = 380.

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 89-90

17
1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[trans-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.5%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 16.0h;	Description 103. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1-[frans-1-methyl-4- (propyloxy)cyclohexyl]-4-piperidinamine (D103); A stirred mixture of 1 ,4-difluoro-2-methyl-5-nitrobenzene (170mg, 0.98mmole), 1-[frans-1- methyl-4-(propoxy)cyclohexyl]-4-piperidinamine (D76 free base, 250mg, 0.98mmole) and diisopropylethylamine (0.2ml, 1.17mmole) in dimethylformamide (20ml) was heated at 8O0C overnight under an argon atmosphere. The mixture was washed with sat. NaHCC>3 solution then extracted with dichloromethane. The organic phase was eluted through an <n="96"/>SCX cartridge, washed with methanol and the compound was collected by elution with 2M NH3 in MeOH. The solvent was removed under vacuum to leave the title compound as an orange solid (313mg, 78.5%). MH+ = 408.

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 94-95

18
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine dihydrochloride [ No CAS ]
[ 141412-60-4 ]
1-[trans-4-(ethyloxy)-1-methylcyclohexyl]-N-(4-fluoro-5-methyl-2-nitrophenyl)-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 16.0h;	Description 97. 1 -[frans-4-(Ethyloxy)-1 -methylcyclohexyl]-lambda/-(4-fluoro-5-methyl-2- nitrophenyl)-4-piperidinamine (D97); A stirred suspension of 1-[frans-4-(ethyloxy)-1-methylcyclohexyl]-4-piperidinamine (D68 free base, 160mg, 0.67mmole) in dimethylformamide (3ml) at room temperature under argon was treated with diisopropylethylamine (0.18ml, LOmmole) followed by 2,5-difluoro- 4-nitrotoluene (147mg, 0.85mmole) and heated at 8O0C for 16hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with dichloromethane. The extract was dried (Na2SO4), concentrated under vacuum and the residue chromatographed on silica gel (1Og) eluting with 0-10% methanol/dichloromethane. The title compound crystallised from MeOH as an orange solid (107mg, 41 %). MH+ 394. 1H NMR D(CDCI3, 400 MHz): 0.93 (3H, s), 1.21 (3H, t), 1.42-1.72 (8H, m), 1.80-1.90 (2H, m), 2.02-2.12 (2H, m), 2.28-2.40 (2H, m), 2.29 (3H, s), 2.90-3.00 (2H, m), 3.35-3.43 (1 H, m), 3.43-3.53 (3H, m), 6.64 (1 H, d), 7.82 (1 H, d), 8.05 (1 H, d).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 91

19
1-(trans-4-ethoxycyclohexyl)piperidin-4-amine [ No CAS ]
[ 141412-60-4 ]
1-[trans-4-(ethyloxy)cyclohexyl]-N-(4-fluoro-5-methyl-2-nitrophenyl)-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;	Description 21. 1 -[frans-4-(Ethyloxy)cyclohexyl]-lambda/-(4-fluoro-5-methyl-2-nitrophenyl)- 4-piperidinamine (D21); A stirred mixture of <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (168mg, 0.972mmole), diisopropylethylamine (1.5eqs, 0.21 ml, 1.21 mmole) and 1-(frans-4- ethoxycyclohexyl)piperidin-4-amine (D20, 183mg, 0.810mmole) in dimethylformamide (3ml) was heated at 8O0C over one weekend. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with dichloromethane. The extract was dried (Na2SO4) and concentrated under vacuum. The residue was chromatographed on silica gel (2Og) eluting with 0-10% methanol/dichloromethane to afford the title compound as an orange solid (90mg, 29%). 1H NMR D(CDCI3, 400 MHz): 1.17-1.40 (7H including 4H, m and 3H, t), 1.58-1.72 (2H, m), 1.85-2.00 (2H, m), 2.02-2.17 (4H, m), 2.30 (3H, s), 2.30-2.50 (3H, m), 2.82-2.92 (2H, <n="57"/>m), 3.12-3.22 (1 H, m), 3.47-3.57 (3H including 1 H,m and 2H, q), 6.63 (1 H, d), 7.82 (1 H, d), 8.06 (1 H, d).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 55-56

20
1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 70℃; for 18.0h;Product distribution / selectivity;	Description 35. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1 -[frans~4-(propyloxy- cyclohexyl]-4-piperidinamine (D35); A stirred solution of 1-[frans-4-(propyloxy)cyclohexyl]-4-piperidinamine (D26, 250mg, I .Ommole) and diisopropylethylamine (0.43ml, 2.4mmole) in dimethylformamide (4ml) at room temperature under argon was treated with <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (208mg, 1.2mmole) and heated at 7O0C for 18h. The resulting solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (20ml) and extracted with dichloromethane (25ml). The extract was dried, concentrated under vacuum to ~4ml and loaded onto a SCX cartridge (5g), which was eluted with dichloromethane followed by <n="64"/>methanol to remove non-basic contaminants, then with 2M NH3/methanol to remove the product. The product solution was concentrated under vacuum and the residue crystallised from methanol to afford the title compound as a dark orange solid (190mg, 48%). 1H NMR D(CDCI3, 400 MHz): 0.91 (3H, t), 1.18-1.38 (4H, m), 1.50-1.72 (4H, m), 1.88-1.98 (2H, m), 2.00-2.15 (4H, m), 2.25-2.38 (1 H, m), 2.30 (3H, s), 2.38-2.50 (2H, m), 2.83-2.93 (2H, m), 3.10-3.22 (1 H, m), 3.41 (2H, t), 3.45-3.58 (1 H, m), 6.63 (1 H, d), 7.82 (1 H, d), 8.06 (1 H, d).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 62-63

21
1-[cis-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[cis-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 200℃; for 0.333333h;Microwave irradiation;	Description 101. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1 -[c/s-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine (D101)); A microwave vessel was charged with <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (0.254g), 1-[c/'s-1- methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine (D1 19, 0.2g), dimethylformamide (3ml) <n="95"/>and diisopropylethylamine (1.0ml) and heated at 2000C for 20 minutes in a microwave reactor. The cooled reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution then the solvent was removed and the residue was chromatographed on silica gel eluted with 0-5% dichloromethane - methanolic ammonia to give the title as a yellow orange solid (0.274g). MH+ = 408, 409.

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 93-94

22
1-[cis-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-chloro-5-methyl-2-nitrophenyl)-1-[cis-1-methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 200℃; for 0.333333h;Microwave irradiation;	Description 105. lambda/-(4-Chloro-5-methyl-2-nitrophenyl)-1 -[c/s-1 -methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine (D105); A microwave vessel was charged with 2-chloro-5-fluoro-4-nitrotoluene (0.22g), 1 -[c/s-1 - methyl-4-(propyloxy)cyclohexyl]-4-piperidinamine (D1 19, 0.254g), dimethylformamide (3ml) and diisopropylethylamine (1.0ml) and heated at 2000C for 20 minutes in a microwave reactor. The cooled reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution then the solvent was removed and the residue was chromatographed on silica gel eluted with 0-5% dichloromethane - methanolic ammonia to give the title as a yellow solid (0.18g). MH+ = 424, 426.

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 95

23
cis/trans-1-(4-methoxycyclohexyl)-4-piperidinamine dihydrochloride [ No CAS ]
[ 141412-60-4 ]
cis-N-(4-fluoro-5-methyl-2-nitrophenyl)-1-(4-methoxycyclohexyl)-4-piperidinamine [ No CAS ]
trans-N-(4-fluoro-5-methyl-2-nitrophenyl)-1-(4-methoxycyclohexyl)-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 18.0h;	Description 8. cis and frans-lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1-(4- methoxycyclohexyl)-4-piperidinamine (Ddeltaa, D8b); A stirred solution of <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (0.7g) in dimethylformamide (15ml) at room temperature under argon was treated with diisopropylethylamine (2.0ml) and 1-[4- (methoxy)cyclohexyl]-4-piperidinamine dihydrochloride (D7, cis:trans mixture, 0.85g) and heated at 8O0C for 18h. The cooled reaction was diluted with ethyl acetate and washed three times with water then dried, evaporated and chromatographed on Biotage KP-NH (NH-silica column eluting with 0-25% ethyl acetate/hexane) to give the separate cis (D8a, 370mg) and trans (D8b, 180mg) isomers of the title compound.

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 48

24
cis/trans-1-[4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[cis-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-[trans-4-(propyloxy)cyclohexyl]-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 24.0h;Product distribution / selectivity;	Description 33. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1-[c/s-4-(propyloxy)cyclohexyl]- 4-piperidinamine (D33); A stirred solution of <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (0.95g, 5.5mmole) in dimethylformamide (12ml) at room temperature under argon was treated with diisopropylethylamine (3.0ml, 17mmole) and c/s/frans-1 -[4-(propyloxy)cyclohexyl]-4-piperidinamine dihydrochloride (D28, ~3:1 cis:trans mixture, 1.5g, 4.8mmole) and heated at 8O0C for 24h. The resulting solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (40ml) and extracted with dichloromethane (40ml). The extract was dried, concentrated under vacuum to ~5ml and loaded onto a SCX cartridge (10g), which was eluted with dichloromethane followed by methanol to remove non-basic contaminants, <n="63"/>then with 2M NH3/methanol to remove the product. The product solution was concentrated under vacuum and the residue chromatographed on NH-silica column (10Og) eluting with 0-20% ethyl acetate/hexane to obtain the title compound as the fastest eluting isomer. This was obtained as an orange solid (0.675g, 36%). 1H NMR D(CDCI3, 400 MHz): 0.94 (3H, t), 1.34-1.44 (2H, m), 1.53-1.80 (8H, m), 1.92-2.02 (2H, m), 2.02-2.12 (2H, m), 2.29 (3H, s), 2.30-2.40 (1 H, m), 2.40-2.50 (2H, m), 2.82-2.92 (2H, m), 3.35 (2H, t), 3.45-3.55 (2H, m), 6.64 (1 H, d), 7.82 (1 H, d), 8.06 (1 H, d). Latter fractions afforded some of the trans isomer (190mg, >90% purity).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 61-62

25
1-{trans-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinamine dihydrochloride [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-{trans-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 20.0h;	Description 93. lambda/-(4-Fluoro-5-methyl-2-nitrophenyl)-1 -{frans-4-[(1 methylethyl)oxy]cyclohexyl}-4-piperidinamine (D93); A stirred suspension of 1-{frans-4-[(1-methylethyl)oxy]cyclohexyl}-4-piperidinamine dihydrochloride (D44, 250mg, O.deltaOmmole) in dimethylformamide (4ml) at room temperature under argon was treated with diisopropylethylamine (0.62ml, 3.5mmole) followed by <strong>[141412-60-4]2,5-difluoro-4-nitrotoluene</strong> (173mg, LOmmole) and heated at 8O0C for 20hrs. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution (25ml) and extracted with EtOAc (25ml). The extract was dried (Na2SO4), concentrated under vacuum and the residue chromatographed on silica gel (2Og) eluting with 0-10% methanol/dichloromethane to afford the title compound as an orange solid (220mg, 70%). MH+ 394. <n="90"/>1H NMR D(CDCI3, 400 MHz): 1.14 (6H, d), 1.20-1.38 (4H, m), 1.60-1.72 (2H, m), 1.89- 1.96 (2H, m), 2.00-2.12 (4H, m), 2.29 (3H, s), 2.30-2.50 (3H, m), 2.83-2.93 (2H, m), 3.20- 3.30 (1 H, m), 3.47-3.59 (1 H, m), 3.66-3.76 (1 H, m), 6.63 (1 H, d), 7.82 (1 H, d), 8.06 (1 H, d).

Reference： [1]Patent: WO2007/107566,2007,A1 .Location in patent: Page/Page column 88-89

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; potassium nitrate; at 20 - 30℃; for 0.25h;	A solution of 2,5-dinitrotoluene (10g) in concentrated sulphuric acid (50ml) at 20-30C was treated portionwise with potassium nitrate (7.9g). After 15min more poured onto ice and extracted with hexane:diethyl ether (1 :1 ), washed with water, dried, and evaporated to give the subtitle compound (8.9g).

27
1-(cis-3-propoxycyclohexyl)-4-piperidinamine [ No CAS ]
[ 141412-60-4 ]
N-(4-fluoro-5-methyl-2-nitrophenyl)-1-(cis-3-propoxycyclohexyl)-4-piperidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 200℃; for 0.166667h;microwave reactor;	A stirred solution of 1-(cis-3-propoxycyclohexyl)-4-piperidinamine (D9, 150mg, 0.63mmole) in N,N-dimethylformamide (4ml) under argon was treated with diisopropylethylamine (0.23ml, 1.3mmole) and <strong>[141412-60-4]2,5-difluoro-4-methyl-1-nitrobenzene</strong> (D35,138mg, O.deltaOmmole) then heated at 2000C in a microwave reactor for 10 minutes. The solution was concentrated under vacuum and the residue treated with 10% Na2CC>3 solution and extracted with dichloromethane. The extract was dried (Na2SO4) and concentrated under vacuum. The residue was chromatographed on silica gel (1 Og) eluting with 0-10% methanol/dichloromethane to afford the title compound as a dark yellow oil (150mg, 61%). MH+ 394.

Reference： [1]Patent: WO2008/119715,2008,A1 .Location in patent: Page/Page column 56

28
[ 14447-18-8 ]
[ 141412-60-4 ]
[ 1071974-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24.0h;	A suspension of <strong>[141412-60-4]1,4-difluoro-2-methyl-5-nitrobenzene</strong> (1.00 g), cyanoacetic acid benzyl ester (1.01 g) and potassium carbonate (1.76 g) in N,N-dimethylformamide (20.0 mL) was stirred at 60C for 1 day. To this reaction mixture was added 1 mol/L hydrochloric acid (25.4 mL), and this mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. This residue was washed with ethanol to give the title compound (1.54 g).

Reference： [1]Patent: EP2133332,2009,A1 .Location in patent: Page/Page column 28

29
[ 141412-60-4 ]
[ 1299488-20-2 ]

Reference： [1]Patent: WO2011/51282,2011,A1

30
[ 141412-60-4 ]
[ 1260640-04-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide;dibenzoyl peroxide; In chlorobenzene; for 4.5h;Reflux;	1 ,4-Difluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6ml_) and N-bromosuccinimide (1.54g) added followed by benzoyl peroxide (0.2g). The reaction mixture was stirred at reflux for 2.5 hours then additional benzoyl peroxide (0.2g) and N-bromosuccinimide (1.54g) were added. The reaction was refluxed for 2 hours then was cooled to room temperature, quenched with water and extracted with dichloromethane (3x). The combined organics were dried and concentrated under reduced pressure. The oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure to yield the title compound (3.21 g). 1H NM (CDCI3, 400 MHz): delta 7.82 (dd, 1 H), 7.40 (dd, 1 H), 4.46 (s, 2H)

Reference： [1]Patent: WO2011/51282,2011,A1 .Location in patent: Page/Page column 51

31
[ 141412-60-4 ]
[ 1299488-21-3 ]

Reference： [1]Patent: WO2011/51282,2011,A1

32
[ 141412-60-4 ]
[ 1299488-22-4 ]

Reference： [1]Patent: WO2011/51282,2011,A1

33
[ 141412-60-4 ]
[ 1299488-25-7 ]

Reference： [1]Patent: WO2011/51282,2011,A1

34
[ 141412-60-4 ]
[ 1299488-24-6 ]

Reference： [1]Patent: WO2011/51282,2011,A1

35
[ 141412-60-4 ]
[ 1299488-23-5 ]

Reference： [1]Patent: WO2011/51282,2011,A1

36
[ 67-56-1 ]
[ 141412-60-4 ]
1-fluoro-4-methoxy-2-methyl-5-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydride; In tetrahydrofuran; at 60℃; for 12.0h;	To a suspension of NaH (200 mg, 5 mmol) in THF (10 mL) was added MeOH (203 muL, 5 mmol) dropwise and the mixture was stirred for 30 min.1,4-Difluoro-2- methyl-5-nitrobenzene (865 mg, 5 mmol) was added and the mixture was heated to 60oC for 12 h. The contents were poured into H2O and extracted with EA. The organic phase was washed with diluted NaOH, then H2O, and brine. The organic phase was dried (Na2SO4), filtered, and the solvent was removed in vacuo. The resulting residue was purified by chromatography (EA/hexanes) to provide 640 mg (68%) of Intermediate 39A. LCMS [m/z] calculated for C8H8FNO: 185.1; found 186.4 [M+H]+, tR=4.2 min (Method 4).

Reference： [1]Patent: WO2018/45246,2018,A1 .Location in patent: Paragraph 322

37
[ 141412-60-4 ]
5-fluoro-2-methoxy-4-methylaniline [ No CAS ]

Reference： [1]Patent: WO2018/45246,2018,A1

38
[ 141412-60-4 ]
[ 932374-53-3 ]

Reference： [1]Patent: WO2008/119720,2008,A1
[2]Patent: WO2008/119721,2008,A1

39
[ 141412-60-4 ]
1,1-dimethylethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidine-carboxylate [ No CAS ]

Reference： [1]Patent: WO2008/119720,2008,A1

40
[ 141412-60-4 ]
[ 932374-49-7 ]

Reference： [1]Patent: WO2008/119720,2008,A1

41
[ 141412-60-4 ]
5-fluoro-6-methyl-1-(1-{cis-3-[(methyloxy)methyl]cyclobutyl}-4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
5-fluoro-6-methyl-1-(1-{trans-3-[(methyloxy)methyl]cyclobutyl}-4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2008/119720,2008,A1

42
[ 141412-60-4 ]
1-(1-{cis-3-[(ethoxy)methyl]cyclobutyl}-4-piperidinyl)-5-fluoro-6-methyl-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
1-(1-{trans-3-[(ethoxy)methyl]cyclobutyl}-4-piperidinyl)-5-fluoro-6-methyl-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2008/119720,2008,A1

43
[ 141412-60-4 ]
5-fluoro-6-methyl-1-(1-{cis-3-[(methyloxy)methyl]cyclobutyl}-4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2008/119720,2008,A1

44
[ 141412-60-4 ]
1-(1-{cis-3-[(ethoxy)methyl]cyclobutyl}-4-piperidinyl)-5-fluoro-6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2008/119720,2008,A1

45
[ 141412-60-4 ]
[ 1065652-80-3 ]

Reference： [1]Patent: WO2008/119721,2008,A1

46
[ 141412-60-4 ]
5-fluoro-6-methyl-1-[1-(cis-4-[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

47
[ 141412-60-4 ]
5-fluoro-6-methyl-1-[1-(trans-4-[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

48
[ 141412-60-4 ]
cis-1-[4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]-4-[2-(methyloxy)ethyl]oxy}cyclohexanecarbonitrile [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

49
[ 141412-60-4 ]
trans-4-[2-(ethyloxy)ethyl]oxy}-1-[4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinyl]cyclohexanecarbonitrile [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

50
[ 141412-60-4 ]
5-fluoro-6-methyl-1-[1-(cis-4-[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

51
[ 141412-60-4 ]
5-fluoro-6-methyl-1-[1-(trans-4-[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2008/119721,2008,A1

52
[ 141412-60-4 ]
5-fluoro-6-methyl-1-{1-[cis-4-(methyloxy)cyclohexyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]