[ CAS No. 1169563-99-8 ] {[proInfo.proName]}

Name: 1169563-99-8|tert-Butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate|95%
Brand: Ambeed
SKU: A152203
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Quality Control of [ 1169563-99-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1169563-99-8 ]

CAS No. :	1169563-99-8	MDL No. :	MFCD16618570
Formula :	C₁₃H₂₂N₄O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RPOLHXPGLRUGBT-UHFFFAOYSA-N
M.W :	266.34	Pubchem ID :	49761279
Synonyms :

Calculated chemistry of [ 1169563-99-8 ] Expand+

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.69
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	77.63
TPSA :	84.24 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.99
Log Po/w (XLOGP3) :	1.33
Log Po/w (WLOGP) :	1.73
Log Po/w (MLOGP) :	1.3
Log Po/w (SILICOS-IT) :	1.02
Consensus Log Po/w :	1.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.26
Solubility :	1.46 mg/ml ; 0.0055 mol/l
Class :	Soluble
Log S (Ali) :	-2.7
Solubility :	0.531 mg/ml ; 0.00199 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.27
Solubility :	1.42 mg/ml ; 0.00535 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.63

Safety of [ 1169563-99-8 ]

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 [ 1169563-99-8 ]

* 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 [ 1169563-99-8 ]
Downstream synthetic route of [ 1169563-99-8 ]

[ 1169563-99-8 ] Synthesis Path-Upstream 1~2

1
[ 660406-84-8 ]
[ 1169563-99-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine hydrate In ethanol at 80℃; for 20 h;	A 5 mL conical reaction vial was charged with tert-butyl 4-(2- cyanoacetyl)piperidine-l-carboxylate (348 mg, 1.379 mmol), hydrazine monohydrate (329.4 μL, 6.896 mmol) and EtOH (4 mL). The reaction vessel was sealed and heated to 80⁰C for 20 hours. The volatiles were removed to afford tert-butyl 4-(5-amino-lH-pyrazol-3- yl)piperidine-l-carboxylate as a foam (367 mg. 99percent).
6.2 g	With hydrazine hydrate; acetic acid In isopropyl alcohol at 85℃;	Example 17 - Preparation of Compound 14 The synthesis of Compound 14 followed the procedure of General Procedure 3 following: Intermediate 3 Compound 14 To a solution of tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate) (Intermediate 3, 7.0 g, 27.6 mmol, 1.0 eq) in isopropanol (210 mL) was added hydrazine monohydrate (1.65 mL, 33.2 mmol, 1.2 eq) dropwise, followed by the addition of acetic acid (1.65 mL, 27.6 mmol, 1.0 eq). The reaction mixture was stirred at 85°C for 4-5 hours. After completion, the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh), eluting with 10-15percent methanol in dichloromethane to yield tert-butyl 4-(5-amino-1H- pyrazol-3-yl)piperidine-1-carboxylate (Compound 14, 6.2 g, yield: 84percent) m/z 266.17. ¹H NMR (DMSO-d₆, 400 MHz) δ 5.182 (1H, s), 3.935-3.965 (2H, d), 3.172 (2H, s), 2.791 (1H, m), 1.747-1.802 (2H, d), 1.424(9H, s), 1.361-1.402 (2H, d), 1.341- 1.351(1H, d) ppm.

Reference： [1] Patent: WO2009/111279, 2009, A1, . Location in patent: Page/Page column 87
[2] Patent: WO2011/45344, 2011, A1, . Location in patent: Page/Page column 88-89
[3] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 6, p. 677 - 682
[4] Patent: WO2016/138532, 2016, A1, . Location in patent: Paragraph 0252

2
[ 124443-68-1 ]
[ 1169563-99-8 ]

Reference： [1] Patent: WO2016/138532, 2016, A1,

[ 1169563-99-8 ] Synthesis Path-Downstream 1~58

1
[ 660406-84-8 ]
[ 1169563-99-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine hydrate; In ethanol; at 80℃; for 20h;	A 5 mL conical reaction vial was charged with tert-butyl 4-(2- cyanoacetyl)piperidine-l-carboxylate (348 mg, 1.379 mmol), hydrazine monohydrate (329.4 muL, 6.896 mmol) and EtOH (4 mL). The reaction vessel was sealed and heated to 800C for 20 hours. The volatiles were removed to afford tert-butyl 4-(5-amino-lH-pyrazol-3- yl)piperidine-l-carboxylate as a foam (367 mg. 99%).
	With ethanol; hydrazine hydrate; for 3h;Reflux;	To 1 g (3.96 mmol) of <strong>[660406-84-8]tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate</strong> obtained following procedure A2 diluted in 10 ml of ethanol, are added 992 mg (19.82 mmol) of hydrazine hydrate. The solution is refluxed for 3h, and the solvent is concentrated to yield 1 g of tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate. 1H-NMR: deltaEta pm 400 MHz, CDC13: 5.47 (1H, s, CH^), 4.12-4.23 (2H, m, CH2), 3.19 (2H, si, NH2), 2.78-2.86 (2H, m, CH2), 2.68-2.75 (1H, m, CH), 1.89-1.94 (2H, m, CH2), 1.53-1.64 (2H, m, CH2), 1.49 (9H, s, 3CH3).
6.2 g	With hydrazine hydrate; acetic acid; In isopropyl alcohol; at 85℃;	Example 17 - Preparation of Compound 14 The synthesis of Compound 14 followed the procedure of General Procedure 3 following: Intermediate 3 Compound 14 To a solution of <strong>[660406-84-8]tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate</strong>) (Intermediate 3, 7.0 g, 27.6 mmol, 1.0 eq) in isopropanol (210 mL) was added hydrazine monohydrate (1.65 mL, 33.2 mmol, 1.2 eq) dropwise, followed by the addition of acetic acid (1.65 mL, 27.6 mmol, 1.0 eq). The reaction mixture was stirred at 85C for 4-5 hours. After completion, the reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (60-120 mesh), eluting with 10-15% methanol in dichloromethane to yield tert-butyl 4-(5-amino-1H- pyrazol-3-yl)piperidine-1-carboxylate (Compound 14, 6.2 g, yield: 84%) m/z 266.17. 1H NMR (DMSO-d6, 400 MHz) delta 5.182 (1H, s), 3.935-3.965 (2H, d), 3.172 (2H, s), 2.791 (1H, m), 1.747-1.802 (2H, d), 1.424(9H, s), 1.361-1.402 (2H, d), 1.341- 1.351(1H, d) ppm.

Reference： [1]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2011/45344,2011,A1 .Location in patent: Page/Page column 88-89
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682
[4]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0252

2
[ 1169563-99-8 ]
[ 1142197-14-5 ]
tert-butyl 4-(5-amino-1-(5-cyclopropylpyridin-2-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In dimethyl sulfoxide; at 130.0℃; for 15h;Inert atmosphere; sealed tube;	A mixture of tert-butyl 4-(5-amino-lH-pyrazol-3-yl)piperidine-l-carboxylate (300 mg, 1.126 ramol), <strong>[1142197-14-5]2-bromo-5-cyclopropylpyridine</strong> (234mg, 1.183mmol), copper(I) iodide (21.45mg, 0.1 13mmol), (lS,2S)-NN2-dime ylcyclohexane-l,2-diamine (16.02 mg, 0.113 mmol), and cesium carbonate (734mg, 2.253 mmol), DMSO (3 rnL), was purged with N2 for 30 min. The mixture was heated to 130 C in a sealed tube for 15 h. The mixture was cooled to rt. and water (30 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (MgS04) and concentrated in vacuo. The residue was purified by silica gel chromatography, eiuting with a solvent gradient of 0 to 40 % EtOAc in hexanes to give the product as a white solid. 1H NMR (400 MHz, CDC13) delta 8.03 (m, 1H), 7.74 (m, 1H), 7.32 (m, 1H), 5.88 (bs, 2H), 5.26 (s, 1H), 4.10 (m, 2H), 2.79 (m, 2H), 2.67 (m, 1H), 1.88-1.79 (ra, 3H), 1.61-1.54 (m, 2H), 1.42 (s, 9H), 1.20(t, J- 7.2 Hz, 1H), 0.94 (m, 2H), 0.63 (m, 2H).

Reference： [1]Patent: WO2012/129258,2012,A1 .Location in patent: Page/Page column 171; 172
[2]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

3
[ 660406-84-8 ]
[ 1169563-99-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrazine hydrate; In isopropyl alcohol; at 80℃;	A solution of ieri-butyl 4-(2-cyanoacetyl) piperidine-l-carboxylate (40 g, 158 mmol) and hydrazine monohydrate (39.6 mL, 792 mmol) in 2-propanol (500 mL) was added heated to 80 C overnight. The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in dichloromethane (1 L). The solution was washed sequentially with water (500 mL) and saturated aqueous sodium chloride solution (500 mL). The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide a pale yellow oil (35 g, 83%). LCMS (ESI): [MH]+ = 267.2. NMR (400 MHz, DMSO-d6): delta 11.14 (br s, 1 H), 5.15 (s, 1 H), 4.41 (br s, 2 H), 3.93 - 3.90 (m, 2 H), 2.76 - 2.74 (m, 2 H), 2.65 - 2.55 (m, 1 H), 1.78 - 1.74 (m, 2 H), 1.39 - 1.36 (m, 11 H).

Reference： [1]Patent: WO2014/111496,2014,A1 .Location in patent: Page/Page column 153; 154
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8182 - 8199

4
[ 1169563-99-8 ]
4-hydroxy-3-(piperidin-4-yl)-4-(trifluoromethyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-b]pyridine-6-one hydrochloride [ No CAS ]

Reference： [1]eLife,2018,vol. 7

5
[ 1169563-99-8 ]
3-(piperidin-4-yl)-1H-pyrazol-5-amine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride; In 1,4-dioxane; ethyl acetate; at 20℃; for 3.0h;Cooling with ice;	4- (5-amino -1H- pyrazol-3-yl) piperidine-1-carboxylic acid tert- butyl (compound described in WO2011 / 045344 pamphlet, 13.5 g, 50.7 mmol) ethyl acetate (60 mL) to the solution under cooling with ice, it was added dropwise hydrochloric acid (4M in dioxane, 31.7mL, 127mmol), followed by stirring at room temperature for 3 hours.After stirring for 10 minutes by adding ethyl acetate (40 mL) to the reaction solution, and collected by filtration and the resulting precipitate to give the title compound (12.5 g, yield: 100%) was obtained.

Reference： [1]Patent: EP2862861,2015,A1 .Location in patent: Paragraph 0244; 0245; 0246
[2]Patent: JP2015/113323,2015,A .Location in patent: Paragraph 0201 - 0203

6
[ 1169563-99-8 ]
[ 1401222-41-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

7
[ 1169563-99-8 ]
[ 1401219-64-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

8
[ 1169563-99-8 ]
[ 1401219-67-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

9
[ 1169563-99-8 ]
[ 1401219-71-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

10
[ 1169563-99-8 ]
[ 1401219-87-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

11
[ 1169563-99-8 ]
C₂₆H₃₀N₈O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

12
[ 1169563-99-8 ]
[ 1401219-70-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

13
[ 1169563-99-8 ]
C₂₅H₂₉N₉O₃ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

14
[ 1169563-99-8 ]
[ 1401219-86-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

15
[ 1169563-99-8 ]
[ 1401220-92-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

16
[ 3510-66-5 ]
[ 1169563-99-8 ]
C₁₉H₂₇N₅O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

17
[ 1169563-99-8 ]
[ 150010-20-1 ]
C₁₈H₂₆N₆O₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 677 - 682

18
[ 1169563-99-8 ]
3-{1-[2-(trifluoromethyl)pyrimidin-5-yl]piperidin-4-yl}-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

19
[ 1169563-99-8 ]
5-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]-N,N-dimethyl-2-(trifluoromethyl)benzamide [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

20
[ 1169563-99-8 ]
3-[1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl]-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

21
[ 1169563-99-8 ]
3-[1-(5-bromopyridin-2-yl)piperidin-4-yl]-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

22
[ 1169563-99-8 ]
3-{1-[2,6-di(propan-2-yl)pyrimidin-4-yl]piperidin-4-yl}-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

23
[ 1169563-99-8 ]
3-[1-(6-chloropyridazin-3-yl)piperidin-4-yl]-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

24
[ 1169563-99-8 ]
5-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]pyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

25
[ 1169563-99-8 ]
5-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]-3-fluoropyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

26
[ 1169563-99-8 ]
5-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

27
[ 1169563-99-8 ]
6-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]-2-methylpyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

28
[ 1169563-99-8 ]
6-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]pyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

29
[ 1169563-99-8 ]
3-{1-[6-(trifluoromethyl)pyridin-3-yl]piperidin-4-yl}-1H-pyrazol-5-amine [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

30
[ 1169563-99-8 ]
6-[4-(5-amino-1H-pyrazol-3-yl)piperidin-1-yl]-4-methylpyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

31
[ 1169563-99-8 ]
6-{4-[4-hydroxy-6-oxo-4-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-3-yl]piperidin-1-yl}pyridine-2-carbonitrile [ No CAS ]

Reference： [1]Patent: JP2015/113323,2015,A

32
[ 7283-96-7 ]
[ 1169563-99-8 ]
tert-butyl 4-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)piperidine-1-carboxylate [ No CAS ]