1408334-75-7|2-(4-Iodo-1H-pyrazol-1-yl)ethanol| Ambeed

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Quality Control of [ 1408334-75-7 ] Purity: 98% SDS Specification

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Product Details of [ 1408334-75-7 ]

CAS No. :	1408334-75-7
Formula :	C₅H₇IN₂O
M.W :	238.03
SMILES Code :	IC1=CN(CCO)N=C1
MDL No. :	MFCD16619492
InChI Key :	BQTYRYUORKTCJO-UHFFFAOYSA-N
Pubchem ID :	57886737

Safety of [ 1408334-75-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 1408334-75-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.4
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	42.17
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.05 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.52
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.13
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.48
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.46
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.03
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.73

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.68
Solubility	5.01 mg/ml ; 0.021 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.49
Solubility	77.9 mg/ml ; 0.327 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.6
Solubility	5.97 mg/ml ; 0.0251 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.66 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.12

Application In Synthesis of [ 1408334-75-7 ]

* 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.

Downstream synthetic route of [ 1408334-75-7 ]

[ 1408334-75-7 ] Synthesis Path-Downstream 1~35

1
[ 1408334-75-7 ]
[ 1546324-71-3 ]

References: [1]Patent: WO2014/37750,2014,A1 .

2
[ 1408334-75-7 ]
[ 1578246-29-3 ]

References: [1]Patent: WO2014/37750,2014,A1 .

3
[ 1408334-75-7 ]
[ 879488-19-4 ]

References: [1]Patent: WO2014/37750,2014,A1 .

4
[ 1408334-75-7 ]
[ 1578246-31-7 ]

References: [1]Patent: WO2014/37750,2014,A1 .

5
[ 1408334-75-7 ]
[ 98-59-9 ]
[ 1578246-28-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	Preparation 58: 2-(4-iodo-1 H-pyrazol-1 -yl)ethyl 4-methylbenzenesulfonate 2-(4-lodo-1 H-pyrazol-1 -yl)ethanol (Preparation 57, 535 mg, 2.248 mmol) in DCM (1 1 ml_) was treated with triethylamine (1 .55 ml_, 1 1 .14 mmol) at 0C. Tosyl chloride (857 mg, 4.50 mmol) was added at 0C and the mixture was allowed to warm to room temperature for 18 hours. The organic layer was washed with water, HCI 1 M and water (twice). The organic layers were dried, concentrated and purified by silica gel column chromatography eluting with 0 to 30% EtOAc in cyclohexane to give the title compound (817 mg, 93%). 1 H NMR (500 MHz, CDCI3): delta 7.64 (d, J = 8.4 Hz, 2H), 7.40 (s, 1 H), 7.39 (s, 1 H), 7.32 (d, J = 8.4 Hz, 2H), 4.38 - 4.34 (m, 4H), 2.47 (s, 3H). LCMS (ESI) Rt = 2.26 minutes MS m/z 393 [M+H]+

References: [1]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 00145-00147.

6
[ 1408334-75-7 ]
[ 58479-61-1 ]
[ 1578246-34-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 18h;	1-(2-(tert-butyldiphenylsilyloxy)ethyl)-4-iodo-1H-pyrazole A solution of 2-(4-iodo-1 H-pyrazol-1 -yl)ethanol (Preparation 57) (1 .01 g, 4.24 mmol) in DMF (21 ml_) was treated with imidazole (410 mg, 6.03 mmol) followed by tert- butylchlorodiphenylsilane (1 .321 ml_, 5.09 mmol) and the mixture was stirred to room temperature for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in cyclohexane to give the title compound (2.25 g, quant). 1 H NMR (500 MHz, CDCI3): delta 7.56 (s, 1 H), 7.54 - 7.50 (m, 5H), 7.47 - 7.35 (m, 6H), 4.26 (t, J = 5.2 Hz, 2H), 3.96 - 3.91 (m, 2H), 1 .03 (s, 9H). LCMS (ESI) Rt = 1 .98 minutes MS m/z 498 [M+Na]+

References: [1]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 00164-00166.

7
[ 3469-69-0 ]
[ 540-51-2 ]
[ 1408334-75-7 ]

Yield	Reaction Conditions	Operation in experiment
64%		Preparation 57: 2-(4-iodo-1 H-pyrazol-1 -yl)ethanol A solution of 4-iodo-1 H-pyrazole (4.50 g, 23.20 mmol) in DMF (45 mL) was treated with sodium hydride (60% w/w, 1 .42 g, 35.5 mmol) at 0C and stirred at room temperature. After 1 hour the resulting mixture was treated with 2-bromoethanol (2.5 mL, 35.2 mmol) at 0C. The resulting mixture was heated to 65 C for 3 days. The reaction quenched with brine/EtOAc and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water, brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 50% EtOAc in cyclohexane to give the title compound (3.55 g, 64%). 1 H NMR (500 MHz, CDCI3): delta 7.55 (s, 1 H), 7.52 (s, 1 H), 4.32 - 4.22 (m, 2H), 4.04 - 3.95 (m, 2H), 2.79 - 2.68 (br m, 1 H). LCMS (ESI) Rt = 1 .50 minutes MS m/z 238 [M+H]+

References: [1]Patent: WO2014/37750,2014,A1 .Location in patent: Paragraph 00142-00144.

8
[ 96-49-1 ]
[ 3469-69-0 ]
[ 1408334-75-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	In N,N-dimethyl-formamide; at 125℃; for 24h;	a. 2-(4-Iodo-pyrazol-1-yl)-ethanol (Intermediate Aa) A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 C. for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC using 30-70% EtOAc in DCM to give the title compound (9.36 g, 53%). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53%	In N,N-dimethyl-formamide; at 125℃; for 24h;	A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC, using 30-70% EtOAc in DCM, to give the title compound (9.36 g, 53%). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53%	In N,N-dimethyl-formamide; at 125℃; for 24h;	A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC using 30-70% EtOAc in DCM to give the title compound (9.36 g, 53%). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].

53%

In N,N-dimethyl-formamide; at 125℃; for 24h;

A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylenecarbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 C for 24 h.The cooled solution was concentrated under vacuum to leave a brown oil. Theresidue was purified by FCC, using 30-70% EtOAc in DCM, to give the titlecompound (9.36 g, 53%).

References: [1]Patent: US2014/364411,2014,A1 .Location in patent: Paragraph 0423; 0424.
[2]Patent: WO2014/194956,2014,A1 .Location in patent: Page/Page column 42.
[3]Patent: WO2014/195400,2014,A1 .Location in patent: Page/Page column 92.
[4]Patent: KR2016/16973,2016,A .Location in patent: Paragraph 0221-0223.

9
[ 1408334-75-7 ]
[ 82560-12-1 ]
2-(5-amino-3-tert-butyl-[1,4']bipyrazolyl-1'-yl)-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Inert atmosphere; Reflux;	b. 2-(5-Amino-3-tert-butyl-[1,4']bipyrazolyl-1'-yl)-ethanol (Intermediate Gb) A solution of Intermediate Ga (9.36 g, 39.3 mmol) in xylene (40 mL) was purged with argon for 30 min. In a separate flask, a mixture of 3-tert-butyl-1H-pyrazole-5-amine (5.75 g, 41.3 mmol), copper iodide (375 mg, 1.97 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (1.12 g, 7.87 mmol) and potassium carbonate (11.4 g, 82.6 mmol) was de-gassed and purged with argon three times. The xylene solution was then added, via cannula to the flask and the resultant brown solution was heated at reflux for 3 h. The cooled solution was diluted with EtOAc (40 mL) and washed with saturated aqueous ammonia solution/water (1:1, 40 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organics were washed with water (40 mL) and brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a solid. This was purified by FCC, using 4-7.5% MeOH in DCM to afford the title compound (6.01 g, 61%). LCMS (Method 1): Rt 1.84 min, m/z 250 [MH+].
61%	With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Inert atmosphere; Reflux;	A solution of Intermediate 6a (9.36 g, 39.3 mmol) in xylene (40 mL) was purged with Argon for 30 min. In a separate flask, a mixture of 3-tert- butyl-lH-pyrazole-5-amine (5.75 g, 41.3 mmol), copper iodide (375 mg, 1.97 mmol), trans-N,N-dimethylcyclohexane- l ,2-diamine (1.12 g, 7.87 mmol) and potassium carbonate (1 1.4 g, 82.6 mmol) was de-gassed and purged with Argon three times. The xylene solution was then added, via cannula to the flask and the resultant brown solution was heated at reflux for 3 h. The cooled solution was diluted with EtOAc (40 mL) and washed with saturated aqueous ammonia solution/water (1 : 1 , 40 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organics were washed with water (40 mL) and brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a solid. This was purified by FCC, using 4-7.5% MeOH in DCM, to afford the title compound (6.01 g, 61 %). LCMS (Method 3): Rt 1.84 min, m/z 250 [MH+].
61%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Inert atmosphere; Reflux;	A solution of Intermediate Ga (9.36 g, 39.3 mmol) in xylene (40 mL) was purged with argon for 30 min. In a separate flask, a mixture of 3-tert-butyl-lH- pyrazole-5-amine (5.75 g, 41.3 mmol), copper iodide (375 mg, 1.97 mmol), trans- N,N-dimethylcyclohexane-l ,2-diamine (1.12 g, 7.87 mmol) and potassium carbonate (1 1.4 g, 82.6 mmol) was de-gassed and purged with argon three times. The xylene solution was then added, via cannula to the flask and the resultant brown solution was heated at reflux for 3 h. The cooled solution was diluted with EtOAc (40 mL) and washed with saturated aqueous ammonia solution/water (1 : 1 , 40 mL). The aqueous layer was extracted with EtOAc (40 mL) and the combined organics were washed with water (40 mL) and brine (40 mL), dried (Na2S04), filtered and concentrated in vacuo to afford a solid. This was purified by FCC, using 4-7.5% MeOH in DCM to afford the title compound (6.01 g, 61 %). LCMS (Method 1): Rt 1.84 min, m/z 250 [MH+].

61%

With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In 5,5-dimethyl-1,3-cyclohexadiene; for 3h;Inert atmosphere; Reflux;

A solution of Intermediate 6a (9.36 g, 39.3 mmol) in xylene (40 mL)was purged with Argon for 30 min. In a separate flask, a mixture of 3-tertbutyl-lH-pyrazole-5-amine (5.75 g, 4 1.3 mmol), copper iodide (375 mg, 1.97mmol), trans-N,N-dimethylcyclohexane-l,2-diamine ( 1.12 g, 7.87 mmol) andpotassium carbonate ( 11.4 g, 82.6 mmol) was de-gassed and purged with Argon three times. The xylene solution was then added, via cannula to theflask and the resultant brown solution was heated at reflux for 3 h. The cooledsolution was diluted with EtOAc (40 mL) and washed with saturated aqueousammonia solution/water ( 1:1, 40 mL). The aqueous layer was extracted withEtOAc (40 mL) and the combined organics were washed with water (40 mL)and brine (40 mL), dried (Na2SO4), filtered and concentrated in vacuo toafford a solid. This was purified by FCC, using 4-7.5% MeOH in DCM, toafford the title compound (6.01 g, 61%).

References: [1]Patent: US2014/364411,2014,A1 .Location in patent: Paragraph 0477; 0478.
[2]Patent: WO2014/194956,2014,A1 .Location in patent: Page/Page column 42-43.
[3]Patent: WO2014/195400,2014,A1 .Location in patent: Page/Page column 104; 105.
[4]Patent: KR2016/16973,2016,A .Location in patent: Paragraph 0224-0226.

10
[ 1408334-75-7 ]
1-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-3-[1'-(2-hydroxy-ethyl)-3-isopropyl-1'H-[1,4']bipyrazolyl-5-yl]-urea [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

11
[ 1408334-75-7 ]
[ 1443246-38-5 ]

References: [1]Patent: US2014/364411,2014,A1 .
[2]Patent: WO2014/195400,2014,A1 .

12
[ 1408334-75-7 ]
[3-tert-butyl-1'-(2-hydroxy-ethyl)-1'H-[1,4']bipyrazolyl-5-yl]-carbamic acid 2,2,2-trichloroethyl ester [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .
[2]Patent: WO2014/194956,2014,A1 .
[3]Patent: WO2014/195400,2014,A1 .
[4]Patent: KR2016/16973,2016,A .

13
[ 1408334-75-7 ]
[ 1443246-37-4 ]

References: [1]Patent: US2014/364411,2014,A1 .
[2]Patent: WO2014/195400,2014,A1 .

14
[ 1408334-75-7 ]
1-[3-tert-butyl-1'-(2-hydroxy-ethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-{4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-cyclohexyl}-urea [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

15
[ 1408334-75-7 ]
methanesulfonic acid 2-[3-tert-butyl-5-(3-{4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]cyclohexyl}ureido)-[1,4']bipyrazolyl-1'-yl]ethyl ester [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

16
[ 1408334-75-7 ]
1-[3-tert-butyl-1'-(2-dimethylaminoethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-{4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]cyclohexyl}urea [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

17
[ 1408334-75-7 ]
1-[1'-(2-dimethylaminoethyl)-3-isopropyl-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethylpiperidin-1-yl)-[1,2,4]triazolo[4,3a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}urea formate salt [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

18
[ 1408334-75-7 ]
methanesulfonic acid 2-[5-(3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-3-isopropyl-[1,4']bipyrazolyl-1'-yl]-ethyl ester [ No CAS ]

References: [1]Patent: US2014/364411,2014,A1 .

19
[ 1408334-75-7 ]
[ 56367-24-9 ]
2-(5-amino-3-isopropyl-[1,4']bipyrazolyl-1'-yl)-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 5,5-dimethyl-1,3-cyclohexadiene; at 110℃; for 18h;Inert atmosphere;	b. 2-(5-Amino-3-isopropyl-[1,4']bipyrazolyl-1'-yl)-ethanol (Intermediate Ab) A mixture of 5-isopropyl-2H-pyrazol-3-ylamine (550 mg, 4.4 mmol), Intermediate Aa (1.0 g, 4.2 mmol), copper (I) iodide (40 mg, 0.21 mmol), (1S,2S)-N.N'-dimethyl cyclohexane-1,2-diamine (119 mg, 0.84 mmol) and potassium carbonate (1.22 g, 8.8 mmol) in Xylene (5 mL) was de-gassed and flushed with argon (3*). The reaction mixture was heated at 110 C. for 18 h. The mixture was poured onto a SCX-2 and eluted with MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure to afford a brown gum. The residue obtained was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (0.25 g, 25%). LCMS (Method 3): Rt 1.43 min, m/z 236 [MH+].
25%	With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 5,5-dimethyl-1,3-cyclohexadiene; at 110℃; for 18h;Inert atmosphere;	A mixture of 5-isopropyl-2H-pyrazol-3-ylamine (550 mg, 4.4 mmol), Intermediate Aa (1.0 g, 4.2 mmol), copper (I) iodide (40 mg, 0.21 mmol), (1 S,2S)- N.N'-dimethyl cyclohexane-l ,2-diamine (1 19 mg, 0.84 mmol) and potassium carbonate (1.22 g, 8.8 mmol) in Xylene (5 mL) was de-gassed and flushed with argon (3x). The reaction mixture was heated at 1 10C for 18 h. The mixture was poured onto a SCX-2 and eluted with MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure to afford a brown gum. The residue obtained was purified by FCC, using 0-10% MeOH in DCM to afford the title compound (0.25 g, 25%). LCMS (Method 3): Rt 1.43 min, m/z 236 [MH+].

References: [1]Patent: US2014/364411,2014,A1 .Location in patent: Paragraph 0425; 0426.
[2]Patent: WO2014/195400,2014,A1 .Location in patent: Page/Page column 92.

20
[ 1408334-75-7 ]
1-[3-tert-butyl-1'-(2-dimethylaminoethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-1-methylpyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea formate salt [ No CAS ]

References: [1]Patent: WO2014/194956,2014,A1 .

21
[ 1408334-75-7 ]
1-[3-tert-butyl-1'-(2-hydroxyethyl)-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-(2,6-dichlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydronaphthalen-1-yl}-urea [ No CAS ]