[ CAS No. 304897-49-2 ] {[proInfo.proName]}

Name: 304897-49-2|tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate|96%
Brand: Ambeed
SKU: A976208
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Quality Control of [ 304897-49-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 304897-49-2 ]

Product Details of [ 304897-49-2 ]

CAS No. :	304897-49-2	MDL No. :	MFCD06797795
Formula :	C₁₆H₂₅N₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZTYRRWNDQSVOCL-UHFFFAOYSA-N
M.W :	291.39	Pubchem ID :	12045001
Synonyms :

Calculated chemistry of [ 304897-49-2 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.56
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	92.3
TPSA :	58.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.84 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.08
Log Po/w (XLOGP3) :	1.74
Log Po/w (WLOGP) :	1.42
Log Po/w (MLOGP) :	1.62
Log Po/w (SILICOS-IT) :	1.33
Consensus Log Po/w :	1.84

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.62
Solubility :	0.692 mg/ml ; 0.00238 mol/l
Class :	Soluble
Log S (Ali) :	-2.59
Solubility :	0.746 mg/ml ; 0.00256 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.12
Solubility :	0.223 mg/ml ; 0.000764 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.27

Safety of [ 304897-49-2 ]

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

Application In Synthesis of [ 304897-49-2 ]

* 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 [ 304897-49-2 ]
Downstream synthetic route of [ 304897-49-2 ]

[ 304897-49-2 ] Synthesis Path-Upstream 1~4

1
[ 130636-61-2 ]
[ 304897-49-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen In ethyl acetate for 2 h;	Example 2 Synthesis of Compound 5 tert-Butyl 4-[4-(cis-4,7,10,13,16,19-docosahexenoyl)amino]benzyl-1-piperazinecarboxylate (5). To compound 3 (0.68 g, 2.1 mmol) in ethyl acetate (100 mL) was added 10percent Pd/C (0.1 g), and the reaction mixture was hydrogenated for 2 h under a pressure of 60 lb/inch². The product was filtered, and solvent was removed in vacuo to afford amine 4 (0.6 g, 97percent yield). Without further purification, to amine 4 (0.6 g, 2.06 mmol) dissolved in acetonitrile (90 mL) was added cis-4,7,10,13,16,19-docosahexenoic acid (DHA, 0.67 g, 2.0 mmol), 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.94 g, 2.5 mmol), and N,N-diisopropylethylamine (2.1 mL). The reaction mixture was stirred overnight. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with ethyl acetate to afford 5 as an oil (0.91 g, 73percent yield). ¹H NMR (DMSO-d6): 9.84 (s, 1H, NH), 7.53-7.51 (d, 2H, J=8.80 Hz, Ar-H), 7.19-7.17 (d, 2H, J=8.40 Hz, Ar-H), 5.35-5.31 (m, 12H, CH=CH), 3.40 (s, 2H, CH₂), 3.29 (brs, 4H, 2CH₂), 2.83-2.75 (m, 10H, 5CH₂), 2.35 (brs, 4H, 2CH₂), 2.27 (t, 4H, J=4.80 Hz, 2CH₂), 2.04-2.00 (m, 2H, CH₂), 1.38 (s, 9H, 3*CH₃), 0.91 (t, 3H, J=7.20 Hz, CH₃). Anal. (C₃₈H₅₅N₃O₃.4.1H₂O) C, H, N
90.2%	With ammonium chloride; zinc In tetrahydrofuran; water at 20℃; for 12 h;	A solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (1.100 g, 3.423 mmol), ammonium chloride (0.915 g, 17.114 mmol) and Zn dust (1.119 g, 17.114 mmol) in tetrahydrofuran (20 mL) / water (20 mL) was stirred at the room temperature for 12 hr. The reaction mixture was filtered to remove solids. Then, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The title compound was used without further purification (tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate, 0.900 g, 90.2 percent, yellow solid).
81%	With tin(II) chloride dihdyrate In ethyl acetate at 20℃;	To a solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate derivatives (1 mmol) (compound (ST) with suitable substitution) in ethyl acetate (O.12M ml), tin(ii) chloride dihydrate (5 mmol) was added and the resulting mixture was left stirring at RT overnight.Then, saturated aqueous solution of sodium bicarbonate (20 mL) was addedand vigorously stirred for 1 hour. Solids were removed by filtration throught a celite pad and the organic layer of the filtrate was separated and washed with water (20 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the following compounds of Formula (X).

72%	With hydrogen In ethyl acetate for 2 h;	ferf-Butyt 4-(4-nitrobenzyl)piperazine-1-carboxylate (I92) (0.500 g, 1.56 mmol), ethyl acetate (100 mL) and 10percent Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60percent ethyl acetate/petroleum benzine 40-60 °C) to give the title compound (193) (327 mg, 72percent yield) as a white solid; ¹H N R (400 MHz, CDCI₃) δ 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]⁺
72%	With palladium 10% on activated carbon; hydrogen In ethyl acetate for 2 h;	terf-Butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (192) (0.500 g, 1.58 mmol), ethyl acetate (100 mL) and 10percent Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60percent ethyl acetate/petroleum benzine 40-60 °C) to give the title compound {193) (327 mg, 72percent yield) as a white solid; ¹H N R (400 Hz, CDCI₃) δ 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]⁺.
67%	at 30℃;	A solution of 4-(4-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 8.77 mmol) was hydrogenated on an H-Cube apparatus with a 5percent Pd/C cartridge under the following conditions: flow rate=1 mL/min, heating column temperature=30° C., H₂pressure=40 bar. The material was passed through the column twice more in order to complete the reaction. Solvents were evaporated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 25-50percent EtOAc-hexane afforded the title compound (1.70 g, 67percent) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₅N₃O₂, 292.2 (M+H), found 292.1.

Reference： [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 19, p. 5592 - 5599
[2] Patent: US2004/34033, 2004, A1, . Location in patent: Page/Page column 12; Sheet 1
[3] Patent: WO2017/18803, 2017, A1, . Location in patent: Paragraph 1492; 1493; 1494
[4] Patent: WO2016/146220, 2016, A1, . Location in patent: Page/Page column 26; 27
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 4, p. 1499 - 1518
[6] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 120; 121
[7] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 123
[8] Patent: US2007/249649, 2007, A1, . Location in patent: Page/Page column 116
[9] Archiv der Pharmazie, 2000, vol. 333, # 8, p. 267 - 274
[10] Patent: US2003/69299, 2003, A1,
[11] Patent: US2007/167435, 2007, A1, . Location in patent: Page/Page column 47

2
[ 100-11-8 ]
[ 304897-49-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 19, p. 5592 - 5599
[2] Patent: WO2012/110773, 2012, A1,
[3] Patent: WO2014/27199, 2014, A1,
[4] Patent: WO2016/146220, 2016, A1,
[5] Patent: WO2017/18803, 2017, A1,
[6] Journal of Medicinal Chemistry, 2018, vol. 61, # 4, p. 1499 - 1518

3
[ 57260-71-6 ]
[ 304897-49-2 ]

4
[ 58198-49-5 ]
[ 304897-49-2 ]

Reference： [1] Archiv der Pharmazie, 2000, vol. 333, # 8, p. 267 - 274

[ 304897-49-2 ] Synthesis Path-Downstream 1~70

1
[ 530-62-1 ]
[ 304897-49-2 ]
(2S,4R)-4-Amino-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid ethyl ester [ No CAS ]
(2S,4R)-4-{3-[4-(4-tert-Butoxycarbonyl-piperazin-1-ylmethyl)-phenyl]-ureido}-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Archiv der Pharmazie,2000,vol. 333,p. 267 - 274

2
[ 130636-61-2 ]
[ 304897-49-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 2h;	Example 2 Synthesis of Compound 5 tert-Butyl 4-[4-(cis-4,7,10,13,16,19-docosahexenoyl)amino]benzyl-1-piperazinecarboxylate (5). To compound 3 (0.68 g, 2.1 mmol) in ethyl acetate (100 mL) was added 10% Pd/C (0.1 g), and the reaction mixture was hydrogenated for 2 h under a pressure of 60 lb/inch2. The product was filtered, and solvent was removed in vacuo to afford amine 4 (0.6 g, 97% yield). Without further purification, to amine 4 (0.6 g, 2.06 mmol) dissolved in acetonitrile (90 mL) was added cis-4,7,10,13,16,19-docosahexenoic acid (DHA, 0.67 g, 2.0 mmol), 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.94 g, 2.5 mmol), and N,N-diisopropylethylamine (2.1 mL). The reaction mixture was stirred overnight. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with ethyl acetate to afford 5 as an oil (0.91 g, 73% yield). 1H NMR (DMSO-d6): 9.84 (s, 1H, NH), 7.53-7.51 (d, 2H, J=8.80 Hz, Ar-H), 7.19-7.17 (d, 2H, J=8.40 Hz, Ar-H), 5.35-5.31 (m, 12H, CH=CH), 3.40 (s, 2H, CH2), 3.29 (brs, 4H, 2CH2), 2.83-2.75 (m, 10H, 5CH2), 2.35 (brs, 4H, 2CH2), 2.27 (t, 4H, J=4.80 Hz, 2CH2), 2.04-2.00 (m, 2H, CH2), 1.38 (s, 9H, 3*CH3), 0.91 (t, 3H, J=7.20 Hz, CH3). Anal. (C38H55N3O3.4.1H2O) C, H, N
90.2%	With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃; for 12h;	A solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (1.100 g, 3.423 mmol), ammonium chloride (0.915 g, 17.114 mmol) and Zn dust (1.119 g, 17.114 mmol) in tetrahydrofuran (20 mL) / water (20 mL) was stirred at the room temperature for 12 hr. The reaction mixture was filtered to remove solids. Then, water was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The title compound was used without further purification (tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate, 0.900 g, 90.2 %, yellow solid).
81%	With tin(II) chloride dihdyrate; In ethyl acetate; at 20℃;	To a solution of tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate derivatives (1 mmol) (compound (ST) with suitable substitution) in ethyl acetate (O.12M ml), tin(ii) chloride dihydrate (5 mmol) was added and the resulting mixture was left stirring at RT overnight.Then, saturated aqueous solution of sodium bicarbonate (20 mL) was addedand vigorously stirred for 1 hour. Solids were removed by filtration throught a celite pad and the organic layer of the filtrate was separated and washed with water (20 mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the following compounds of Formula (X).

72%	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 2585.81 Torr; for 2h;	ferf-Butyt 4-(4-nitrobenzyl)piperazine-1-carboxylate (I92) (0.500 g, 1.56 mmol), ethyl acetate (100 mL) and 10% Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60 C) to give the title compound (193) (327 mg, 72% yield) as a white solid; 1H N R (400 MHz, CDCI3) delta 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]+
72%	With palladium 10% on activated carbon; hydrogen; In ethyl acetate; under 2585.81 Torr; for 2h;	terf-Butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (192) (0.500 g, 1.58 mmol), ethyl acetate (100 mL) and 10% Pd/C (150 mg) were agitated under a hydrogen atmosphere at 50 psi. After two hours the mixture was filtered through celite and concentrated. The residue was chromatographed (12 g silica cartridge, 0-60% ethyl acetate/petroleum benzine 40-60 C) to give the title compound {193) (327 mg, 72% yield) as a white solid; 1H N R (400 Hz, CDCI3) delta 7.11 - 7.05 (m, 2H), 6.67 - 6.61 (m, 2H), 3.62 (s, 2H), 3.43 - 3.37 (m, 6H), 2.40 - 2.30 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 1.80 min; m/z 292.1 [M+H]+.
67%	With hydrogen;5%-palladium/activated carbon; at 30℃; under 30003.0 Torr;	A solution of 4-(4-nitro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (2.82 g, 8.77 mmol) was hydrogenated on an H-Cube apparatus with a 5% Pd/C cartridge under the following conditions: flow rate=1 mL/min, heating column temperature=30 C., H2 pressure=40 bar. The material was passed through the column twice more in order to complete the reaction. Solvents were evaporated in vacuo. Purification of the residue on a 50-g Isolute SPE column on a FlashMaster system with 25-50% EtOAc-hexane afforded the title compound (1.70 g, 67%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C16H25N3O2, 292.2 (M+H), found 292.1.
	aluminum nickel; In methanol; ethyl acetate;	b. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline Prepared analogously to Example Id by catalytic hydrogenation of 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raney nickel in ethyl acetate/methanol (1:1). Melting point: 106-107 C. Rf value: 0.6 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1)
	With hydrogen;50percent Raney Nickel (Ra-Ni) (aqueous slurry); In tetrahydrofuran; ethanol; under 2068.65 Torr; for 16h;	To a solution of compound 78 (35 g, 110 mmol) in a mixture of THF (300 mL)-EtOH (100 mL) was added 50% Raney Nickel (12 g, aqueous slurry), and the mixture was placed on a Parr Shaker and hydrogenated at P0=40 Psi for 16 h. The spent catalyst was filtered off, and the filtrate was concentrated in vacuo. The resultant residue was purified using flash column chromatography on silica gel, eluting with CH2Cl2-MeOH (25:1) to provide compound 79 as a light yellow solid (24.1 g).

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599
[2]Patent: US2004/34033,2004,A1 .Location in patent: Page/Page column 12; Sheet 1
[3]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1492; 1493; 1494
[4]Patent: WO2016/146220,2016,A1 .Location in patent: Page/Page column 26; 27
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518
[6]Patent: WO2012/110773,2012,A1 .Location in patent: Page/Page column 120; 121
[7]Patent: WO2014/27199,2014,A1 .Location in patent: Page/Page column 123
[8]Patent: US2007/249649,2007,A1 .Location in patent: Page/Page column 116
[9]Archiv der Pharmazie,2000,vol. 333,p. 267 - 274
[10]Patent: US2003/69299,2003,A1
[11]Patent: US2007/167435,2007,A1 .Location in patent: Page/Page column 47
[12]Journal of Medicinal Chemistry,2019,vol. 62,p. 2083 - 2098

3
[ 6217-54-5 ]
[ 304897-49-2 ]
[ 656233-40-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile;	Example 2 Synthesis of Compound 5 tert-Butyl 4-[4-(cis-4,7,10,13,16,19-docosahexenoyl)amino]benzyl-1-piperazinecarboxylate (5). To compound 3 (0.68 g, 2.1 mmol) in ethyl acetate (100 mL) was added 10% Pd/C (0.1 g), and the reaction mixture was hydrogenated for 2 h under a pressure of 60 lb/inch2. The product was filtered, and solvent was removed in vacuo to afford amine 4 (0.6 g, 97% yield). Without further purification, to amine 4 (0.6 g, 2.06 mmol) dissolved in acetonitrile (90 mL) was added cis-4,7,10,13,16,19-docosahexenoic acid (DHA, 0.67 g, 2.0 mmol), 2-(1-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.94 g, 2.5 mmol), and N,N-diisopropylethylamine (2.1 mL). The reaction mixture was stirred overnight. Solvent was removed in vacuo, and the product was purified by column chromatography, eluding with ethyl acetate to afford 5 as an oil (0.91 g, 73% yield). 1H NMR (DMSO-d6): 9.84 (s, 1H, NH), 7.53-7.51 (d, 2H, J=8.80 Hz, Ar-H), 7.19-7.17 (d, 2H, J=8.40 Hz, Ar-H), 5.35-5.31 (m, 12H, CH=CH), 3.40 (s, 2H, CH2), 3.29 (brs, 4H, 2CH2), 2.83-2.75 (m, 10H, 5CH2), 2.35 (brs, 4H, 2CH2), 2.27 (t, 4H, J=4.80 Hz, 2CH2), 2.04-2.00 (m, 2H, CH2), 1.38 (s, 9H, 3*CH3), 0.91 (t, 3H, J=7.20 Hz, CH3). Anal. (C38H55N3O3.4.1H2O) C, H, N

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599
[2]Patent: US2004/34033,2004,A1 .Location in patent: Page/Page column 12; Sheet 1

4
[ 100-11-8 ]
[ 304897-49-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599
[2]Patent: WO2012/110773,2012,A1
[3]Patent: WO2014/27199,2014,A1
[4]Patent: WO2016/146220,2016,A1
[5]Patent: WO2017/18803,2017,A1
[6]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518
[7]Journal of Medicinal Chemistry,2019,vol. 62,p. 2083 - 2098

5
[ 304897-49-2 ]
[ 656233-41-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599

6
[ 304897-49-2 ]
[ 656233-43-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2005,vol. 13,p. 5592 - 5599

7
[ 57260-71-6 ]
[ 304897-49-2 ]

8
[ 58198-49-5 ]
[ 304897-49-2 ]

Reference： [1]Archiv der Pharmazie,2000,vol. 333,p. 267 - 274

9
[ 100-11-8 ]
dipotassium-salt of/the/ (+-)-3-<naphthyl-(2)>-adipic acid [ No CAS ]
[ 304897-49-2 ]

Reference： [1]Archiv der Pharmazie,2000,vol. 333,p. 267 - 274

10
[ 304897-49-2 ]
(2S,4R)-4-{3-[4-(4-tert-Butoxycarbonyl-piperazin-1-ylmethyl)-phenyl]-ureido}-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid [ No CAS ]

Reference： [1]Archiv der Pharmazie,2000,vol. 333,p. 267 - 274

Yield	Reaction Conditions	Operation in experiment
		The following compounds are prepared analogously to Example VII: ... 4-(4-benzyl-piperidino-methyl)-aniline 4-(4-ethoxycarbonyl-piperidino-methyl)-aniline 4-(dimethylamino-methyl)-aniline 4-(di-n-propylamino-methyl)-aniline 4-(4-tert.butoxycarbonyl-piperazino-methyl)-aniline 3-(dimethylamino-methyl)-aniline 4-(2-diethylamino-ethyl)-aniline 4-(2-morpholino-ethyl)-aniline ...

12
[ 304897-49-2 ]
[ 14394-70-8 ]
[ 936092-59-0 ]

Yield	Reaction Conditions	Operation in experiment
		[0238] A mixture of 2-chloiO-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4- amino-benzyl)-piperazine-l-carboxylic acid fe/t-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70 C for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ~10. The resulting aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)+.

Reference： [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 134

13
[ 936092-35-2 ]
[ 304897-49-2 ]
[ 1332719-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 160℃; for 0.333333h;Microwave irradiation;	[0328] A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(4-amino-benzyl)-piperazine- 1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 0C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% EtOAc/hexanes) to afford the Boc-protected precursor. To a solution of the precursor in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (13 mg, 9%).[0329] 1H NMR (500 MHz, DMSO-d6): delta 2.11 (s, 3H), 2.30-2.40 (m, 4H), 2.83 (t, J= 4.8 Hz5 4H), 3.37 (s, 2H), 3.75 (s, 3H), 7.08 (d, J= 8.6 Hz, 2H), 7.29 (d, J= 8.6 Hz, IH), 7.43 (dd, J= 8.6, 2.2 Hz, IH), 7.47 (d, J= 2.2 Hz, IH), 7.59 (d, J= 8.6 Hz, 2H), 7.91 (s, IH), 8.37 (s, IH), 8.99 (s, IH). MS (ES+): m/z 439 (M+H)+.

Reference： [1]Patent: WO2007/53452,2007,A1 .Location in patent: Page/Page column 166

14
[ 5470-18-8 ]
[ 304897-49-2 ]
[ 943637-26-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 4h;	To a mixture of 2-chloro-3-nitropyridine (6.3 g, 40 mmol) in toluene (100 mL) was added compound 79 (11.6 g, 40 mmol), followed by solid K2CO3 (11 g, 80 mmol), and the resulting reaction was heated to 110 C. and allowed to stir at this temperature for 16 h. BINAP (500 mg, 2% mol) and Pd(OAc)2 (180 mg, 2% mol) were then added to the reaction mixture and the reaction was allowed to stir for an additional 4 h at 110 C. The reaction mixture was cooled to room temperature, then EtOAc (250 mL) and water (200 mL) were added, and the resulting solution was filtered through Celite to remove any insoluble material. The filtrate was separated and the aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel, eluting with EtOAc-Hexane (1:1) to provide compound 80 as a red solid (24.1 g).

Reference： [1]Patent: US2007/167435,2007,A1 .Location in patent: Page/Page column 48

15
[ 1092950-22-5 ]
[ 304897-49-2 ]
[ 1092950-24-7 ]

Yield	Reaction Conditions	Operation in experiment
		4-(4-Carboxy-phenyl)-thiazole-2-carboxylic acid, (100 mg, 0.4 mmol) was combined with HATU (304 mg, 0.8 mmol). This mixture was dissolved in 3 mL of DMF and DIEA (1.0 mmol, 0.17 mL) was added to the solution. Reaction mixture was stirred at room temperature for 30 minutes. To this was added 4-(4-amino-benzyl)-piperazine-l- carboxylic acid tert-butyl ester (233.1 mg, 0.8 mmol). Reaction mixture was heated at 6O0C overnight. The crude was purified using reverse phase HPLC to give the desired product.

Reference： [1]Patent: WO2008/154601,2008,A1 .Location in patent: Page/Page column 45

16
[ 1142945-86-5 ]
[ 304897-49-2 ]
tert-butyl 4-(4-(4-(4-methylthiophen-2-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 125℃; for 2.03333h;	A mixture of 9 (0.25 g, 0.62 mmol), tert-butyl 4-(4-aminobenzyl)piperazine-l- carboxylate (0.22 g, 0.76 mmol), Pd2(dba)3 (57 mg, 0.06 mmol), Xantphos (72 mg, 0.12 mmol) and Cs2CO3 (0.61 g, 1.88 mmol) in anhydrous DMF (25 mL) was degassed with argon for 2 min and then heated at 125 0C for 2 h. After cooling to room temperature, the solvent was removed by rotovap. The crude product was then purified by silica gel column with 10% CH3OH/CHC13 as an eluent to yield a yellow solid (90 mg, 22%).[0327] 1H NMR (500 MHz, DMSO-J6): delta 1.41 (s, 9H), 2.31 (s, 3H), 2.33 (s, 3H), 2.90-3.05 (m, 2H), 3.20-3.40 (m, 4H), 3.90-4.10 (m, 2H), 4.25-4.35 (m, 2H), 7.26 (d, J = 4.0 Hz, IH), 7.36 (d, J = 8.5 Hz, 2H), 7.48 (s, IH), 7.56 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 4.1 Hz, IH), 7.95- 8.10 (m, 5H), 9.88 (s, IH), 10.94 (br s, IH)

Reference： [1]Patent: WO2009/49028,2009,A1 .Location in patent: Page/Page column 135

17
[ 304897-49-2 ]
[ 1393901-47-7 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

18
[ 304897-49-2 ]
[ 1393901-48-8 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

19
[ 304897-49-2 ]
[ 1393901-49-9 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

20
[ 304897-49-2 ]
[ 1393901-50-2 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

21
[ 304897-49-2 ]
[ 1393900-63-4 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

22
[ 304897-49-2 ]
[ 1393900-74-7 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

23
[ 304897-49-2 ]
[ 1393901-81-9 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

24
[ 304897-49-2 ]
[ 1393901-82-0 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

25
[ 304897-49-2 ]
[ 1393900-75-8 ]

Reference： [1]Patent: WO2012/110773,2012,A1
[2]Patent: WO2014/27199,2014,A1

26
[ 3932-97-6 ]
[ 304897-49-2 ]
[ 1393901-46-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1 :1 dichloroethane: ferf-butanol was cooled to 0 C under nitrogen. A 1.0 M solution of zinc(ll) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0 "C. ferf'Butyl 4-(4-aminobenzyl)piperazine-1 -carboxylate (193) (0.667 g, 2.29 mmol) in 1 : 1 dichloroethane: ferf-butanol (20 mL) was added dropwise over thirty minutes, followed by triethylamine (0.351 mL, 2.52 mmol) in 1 :1 dichloroethane: ferf-butanol ( 0 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40- 60 C) to give a residue which was triturated with petroleum benzine 40-60 C to give the title compound (194) (0.976 g, 90%) as an off white solid; H NMR (400 MHz, d4- MeOD) delta 8.68 (d, J = 0.6 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.30 (s, 2H), 3.27 - 3.00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C: 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M-H]
90%		2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1 : 1 dichioroethane: fe/f-butanol was cooled to 0 C under nitrogen. A 1.0 M solution of zinc(ll) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0 C. iert-Butyl 4-(4-aminobenzyi)piperazine-1-carboxylate (193) (0.667 g, 2.29 mmol) in 1 : 1 dichioroethane: ferf-butanol (20 mL) vv'as added dropwise over thirty minutes, followed by triethyiamine (0.351 mL, 2.52 mmol) in 1 :1 dichioroethane: ferf-butanol (10 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40- 60 C) to give a residue which was triturated with petroleum benzine 40-60 C to give the title compound {194) (0.976 g, 90%) as an off white solid; 1H NMR (400 MHz, dr MeOD) delta 8.68 (d, J = 0.6 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.30 (s, 2H), 3.27 - 3,00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C: 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M-H]

Reference： [1]Patent: WO2012/110773,2012,A1 .Location in patent: Page/Page column 120; 121
[2]Patent: WO2014/27199,2014,A1 .Location in patent: Page/Page column 123

27
[ 304897-49-2 ]
[ 36802-47-8 ]
[ 1425383-94-3 ]

Yield	Reaction Conditions	Operation in experiment
0.62 g	In 1-methyl-pyrrolidin-2-one; at 0℃; for 2h;	d: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin- 1 -yl)methyl)phenylamino)-2-chloro- 6-methylpyrimidine-5-carboxylate Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.5 g, 2.1 mmol) and tert-butyl 4-(4-aminobenzyl)piperazine-l-carboxylate (0.6 g, 2.06 mmol) were dissolved in NMP and stirred at 0C for 2 hour. The reaction mixture was poured onto water and extracted with EtOAc. The organic layer was washed with water, dried over a2S04 and evaporated under vacuum to get the desired compound (0.62 g). XH NMR (400 MHz, CDC13): delta 10.58 (s, 1H), 7.58 (d, J = 6.4 Hz, 2H), 7.31 (d, J = 6.4 Hz, 2H), 4.45 (q, J = 6.8 Hz, 2H), 3.56 (s, 2H), 3.41 (m, 4H), 2.69 (s, 3H), 2.47 (m, 4H), 1.45 (s, 9H), 1.43 (t, J = 6.8 Hz, 3H); MS m/z 490.0 (M+l).

Reference： [1]Patent: WO2013/28818,2013,A1 .Location in patent: Page/Page column 47; 48

28
[ 586-76-5 ]
[ 304897-49-2 ]
tert-Butyl 4-(4-(4-bromobenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;	Step 1. Preparation of tert-Butyl 4-(4-(4-bromobenzamido)benzyl)piperazine-1-carboxylate (3) 4-Bromobenzoic acid (1, 685.0 mg, 3.4 mmol) and HATU (1298.1 mg, 3.4 mmol) are partially dissolved in DMF (10 mL) at rt. DIEA (560 muL, 3.4 mmol) is added to this mixture to give a pale yellow solution. After stirring at rt for 30 min, <strong>[304897-49-2]tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate</strong> (2, 992.9 mg, 3.4 mmol) is added and the resulting reaction mixture is heated at 60 C. for 20 h, allowed to cool to rt, and poured into water (100 mL). This mixture is extracted with Et2O (3*150 mL). The combined organic extracts are evaporated to dryness to give a white solid, which is washed with water (50 mL) and dried in vacuo. This material is used in the next synthetic step without further purification. HPLC: tR 1.67 min (method 1). LC-MS m/z calcd for C23H2879BrN3O3 ([M]+), 473. found, 474 ([M+H]+). 1H NMR (CD3OD): delta 1.46 (s, 9H), 2.96 (m, 4H), 3.59 (m, 4H), 4.05 (br s, 2H), 7.46 (m, 2H), 7.69 (m, 2H), 7.78 (m, 2H), 7.85 (m, 2H).

Reference： [1]Patent: US9125904,2015,B1

29
[ 1092789-65-5 ]
[ 304897-49-2 ]
tert-butyl 4-(4-(3-(benzyloxy)-4-chlorobenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 283 - 288

30
[ 3438-16-2 ]
[ 304897-49-2 ]
tert-butyl 4-(4-(5-chloro-2-methoxybenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 283 - 288

31
[ 3438-16-2 ]
[ 304897-49-2 ]
5-chloro-2-methoxy-N-(4-(piperazin-1-ylmethyl)phenyl)benzamide [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 283 - 288

32
[ 6280-89-3 ]
[ 304897-49-2 ]
tert-butyl 4-(4-(2-chloro-5-methoxybenzamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 283 - 288

33
4-chloro-6-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)pyrimidine-5-carbonitrile [ No CAS ]
[ 304897-49-2 ]
C₂₅H₂₄FN₇O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%		Compound 10 A mixture intermiediate 1 (100 mg, 0.33 mmol), tert-butyl 4-(4-aminobenzyl)piperazine-l- carboxylate (96 mg, 0.33 mmol),, and DIPEA (0.15 ml, 0.82 mmol) in DMSO (5 ml) was stirred at room temperature for 30 min. After checking the TLC, the mixture was added to water (100ml). After cooled with ice-bath, the solids were collected by filtration, washed by water. After air-drying at room temperature overnight, the solids were suspended into DCM/MeOH (10/1, 5 mL) and 1 ml of TFA was added. The mixture was stirred at room temperature for overnight. After concentrated, the residue was dissolved into DCM/MeOH (8/2, 15 ml) and sat. Sodium bicarbonate solution was added to pH about 7. The organic was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 0-15% MeOH in DCM) to give the desired product as light yellow solids (15 mg, 10% yield). 1H MR (400 MHz, DMSO-d6) delta 11.48 (br, 1H), 10.06 (s, 1H), 8.90 (m, 2H), 8.28 (m, 1H), 7.48 (m, 2H), 7.29 (m, 2H), 7.13 (m, 1H), 6.94 (m, 1H), 6.23 (s, 1H), 3.53 (m, 2H), 3.09 (m, 4H), 2.54 (m, 4H), 2.40 (m, 3H); ESI-MS: calcd for C25H24FN70 457, found 458 (MH+). HPLC: retention time: 13.75 min. purity: 91%.

Reference： [1]Patent: WO2016/138527,2016,A1 .Location in patent: Page/Page column 63

34
[ 2905-21-7 ]
[ 304897-49-2 ]
C₂₂H₂₈FN₃O₄S [ No CAS ]

Reference： [1]Patent: WO2016/146220,2016,A1 .Location in patent: Page/Page column 27; 29

35
[ 304897-49-2 ]
[ 433-97-6 ]
C₂₄H₂₈F₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		In a round bottomed flask under nitrogen atmosphere commercially available benzoic acid (1.1 mmol) or sulphonyl chloride was suspended in 75 ml of anhydrous DCM. Then HOBt (1.4 mmol) and EDO HCI (1.1 mmol) were added and the resulting mixture stirred at room temperature for 2 hours. Then a solution of intermediates (X) (compounds of examples 4-6 of Table 2) (1.1 mmol) in 75 ml of dry DCM was addedand the mixture stirred at 40 00 upon completion. The reaction mixture was left to cool to room temperature, washed with a saturated aqueous solution of NH4CI, then aqueous HCI 0.5M, aqueous NaOH 1 M and finally with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over sodium sulphate, filtered and evaporated under vacuum. The resulting crude product was purified by flashchromatography on silica gel, eluting with a gradient from cyclohexane/AcOEt 1/1 to100% AcOEt. The collected fractions were evaporated to give the compounds of examples 7-10,14.

Reference： [1]Patent: WO2016/146220,2016,A1 .Location in patent: Page/Page column 27; 28

36
[ 98-98-6 ]
[ 304897-49-2 ]
C₂₂H₂₈N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		Commercially available benzoic acid (1.3 mmol) was suspended in toluene (0.01 M), thionyl chloride (12 mmol) was added and the mixture was heated at 110 00for lh. Volatiles were evaporated and the residue was added to a solution of the intermediate of formula (X) (compounds of examples 4-6 of Table 2)(1 mmol) in pyridine (40 mmol) and the resulting mixture stirred for 1 h at rt. Pyridine was evaporated, then NaOMe (2 mmol) and MeOH were added. After 30 minutes solvent was evaporated and DCM and water were added. The separated organic phase was concentrated and the residue was purified by flash chromatography eluting with DCM/MeOH to give the compounds of examples 11,12,13.

Reference： [1]Patent: WO2016/146220,2016,A1 .Location in patent: Page/Page column 27; 28; 29

37
[ 123-75-1 ]
[ 530-62-1 ]
[ 304897-49-2 ]
C₂₁H₃₂N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%		3 Intermediates of formula (X) (compounds of examples 4-6 of Table 2) (1 mmol) andCDI (1 mmol) were dissolved in acetonitrile (Ratio: 1.000, 0.04M) and DCM (Ratio:0.5, 0.04M) . After 2 hours at rt solvents were evaporated, residue dissolved in DMF(Ratio: 0.5, 0.04M) and corresponding amine (1 mmol) was added and the mixture leftat 60 o upon completion. The reaction was then poured in water and extracted withAcOEt (3x); organic phases were collected, washed with water, dried and evaporatedto give the title urea (compound of example 15).

Reference： [1]Patent: WO2016/146220,2016,A1 .Location in patent: Page/Page column 28; 29

38
[ 594-44-5 ]
[ 304897-49-2 ]
tert-butyl 4-(4-(ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.5%	With pyridine; In dichloromethane; at 20℃; for 12h;	solution of <strong>[304897-49-2]tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate</strong> (0.900 g, 3.089mmol), pyridine (0.299 mL, 3.706 mmol) and ethanesulfonyl chloride (0.477 g, 3.706 mmol) in dichloromethane (30 mL) was stirred at the room temperature for 12 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give tert-butyl 4-(4-(ethylsulfonamido)benzyl)piperazine-1-carboxylate as yellow solid (0.800 g, 67.5 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1495; 1496; 1497

39
[ 304897-49-2 ]
tert-butyl 4-(4-(N-((5-(methoxycarbonyl)pyridin-2-yl)methyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/18803,2017,A1

40
[ 304897-49-2 ]
tert-butyl4-(3-(N-((5-(methoxycarbonyl)pyridin-2-yl)methyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/18803,2017,A1

41
[ 304897-49-2 ]
tert-butyl 4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/18803,2017,A1

42
[ 5334-40-7 ]
[ 304897-49-2 ]
C₂₀H₂₆N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

43
[ 304897-49-2 ]
tert-butyl 4-(4-(4-amino-1H-pyrazole-3-carboxamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

44
[ 304897-49-2 ]
N-(4-(piperazin-1-ylmethyl)phenyl)-4-(thieno[2,3-d]pyrimidin-4-ylamino)-1H-pyrazole-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

45
[ 304897-49-2 ]
C₂₁H₂₃N₉O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1499 - 1518

46
[ 1046490-81-6 ]
[ 304897-49-2 ]
C₂₆H₃₅N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		To a solution of 2,4-dihydroxy-5-isopropyl-benzenecarbodithioic acid (3.20 g, 14.0 mmol) in DMF (50 mL) was added sodium 2-chloroacetate (2.61 g, 22.4 mmol) and sodium carbonate (4.45 g, 42.0 mmol), and the solution degassed by bubbling nitrogen through the solution. The mixture was stirred at room temperature for 3 h, then a solution of tert-butyl 4-(4-aminobenzyl)piperazine-l-carboxylate (4.08 g, 14.0 mmol) in DMF (10 mL) was added. The resulting mixture was stirred at 80 C for 3 h. The reaction mixture was poured into ice water, and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried with sodium sulfate, and the solvent removed in vacuo to give 3A (5.20 g, 10.7 mmol, 76% yield).
76%		To a solution of 2,4-dihydroxy-5-isopropyl-benzenecarbodithioic acid (3.20 g, 14.0 mmol) in DMF (50 mL) was added sodium 2-chloroacetate (2.61 g, 22.4 mmol) and sodium carbonate (4.45 g, 42.0 mmol), and the solution degassed by bubbling nitrogen through the solution. The mixture was stirred at room temperature for 3 h, then a solution of tert-butyl 4-(4-aminobenzyl)piperazine-l-carboxylate (4.08 g, 14.0 mmol) in DMF (10 mL) was added. The resulting mixture was stirred at 80 C for 3 h. The reaction mixture was poured into ice water, and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried with sodium sulfate, and the solvent removed in vacuo to give 3A (5.20 g, 10.7 mmol, 76% yield).

Reference： [1]Patent: WO2018/112176,2018,A1 .Location in patent: Paragraph 00366
[2]Patent: WO2019/118830,2019,A1 .Location in patent: Paragraph 0343; 0345

47
[ 304897-49-2 ]
C₂₇H₃₃N₃O₅S [ No CAS ]

Reference： [1]Patent: WO2018/112176,2018,A1
[2]Patent: WO2019/118830,2019,A1

48
[ 304897-49-2 ]
C₂₇H₃₅N₅O₅ [ No CAS ]

Reference： [1]Patent: WO2018/112176,2018,A1
[2]Patent: WO2019/118830,2019,A1

49
[ 304897-49-2 ]
C₂₂H₂₇N₅O₃*(x)ClH [ No CAS ]