723286-79-1|tert-Butyl 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate| Ambeed

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Quality Control of [ 723286-79-1 ] Purity: 97% SDS Specification

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Product Details of [ 723286-79-1 ]

CAS No. :	723286-79-1
Formula :	C₁₀H₁₆N₄O₂
M.W :	224.26
SMILES Code :	CC(C)(C)OC(=O)N1CCN2C=NN=C2C1
MDL No. :	MFCD10574958
InChI Key :	OKVLFQQWHATAHW-UHFFFAOYSA-N
Pubchem ID :	46738299

Safety of [ 723286-79-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 723286-79-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	5
Fraction Csp3	0.7
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	61.5
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	60.25 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.97
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	-0.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.5
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.	0.19
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	-0.16
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.47

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.17
Solubility	15.2 mg/ml ; 0.0677 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.	-0.66
Solubility	49.0 mg/ml ; 0.218 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	-1.11
Solubility	17.4 mg/ml ; 0.0774 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	No
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	Yes
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.	-7.77 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	0.0 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)	2.7

Application In Synthesis of [ 723286-79-1 ]

* 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 [ 723286-79-1 ]
Downstream synthetic route of [ 723286-79-1 ]

[ 723286-79-1 ] Synthesis Path-Upstream 1~4

1
[ 24424-99-5 ]
[ 723286-79-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine In dichloromethane at 25℃;	To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1.0 g, 6.23 mmol) in CH₂Cl₂(25 mL) were added Et₃N (2.17 mL, 15.57 mmol) and Boc₂O (1.52 mL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO₄(50 mL). The organic layer was dried (Na₂SO₄) and evaporated to dryness to afford compound A48-1 (1.29 g, 92percent).
92%	With triethylamine In dichloromethane at 20℃;	Procedure for step-1:To a solution of 5, 6, 7 , 8-tetrahydro- [ 1, 2 , 4 ] triazolo [ 4 , 3- ajpyrazine hydrochloride (1.0 g, 6.23 irunol) in CH₂CI₂ (25 itiL) were added Et₃N (2.17 mL, 15.57 mmol) and BoC₂O (1.52 itiL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO₄ (50 mL) . The organic layer was dried (Na₂SO₄) and evaporated to dryness to afford compound A48-1 (1.29 g, 92percent) .

References: [1] Patent: US2009/186899, 2009, A1, . Location in patent: Page/Page column 48.
[2] Patent: WO2009/90055, 2009, A1, . Location in patent: Page/Page column 140; 141.

2
[ 68774-77-6 ]
[ 24424-99-5 ]
[ 723286-79-1 ]

Yield	Reaction Conditions	Operation in experiment
22%	Stage #1: With platinum(IV) oxide; palladium 10% on activated carbon; hydrogen In methanol for 34 h; Stage #2: With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 3 h;	After dissolution compound obtained in Step 2 (8.10 g) and platinum oxide (IV) and 10percent palladium / carbon (2g, 50percent water content) in methanol (8 mL), under an atmosphere of hydrogen 50psi (Parr) 34 time and stirred. After filtering the reaction solution at Hyflo Super Cel, the oil obtained by concentrating the solvent was dissolved in dichloromethane (200 mL), N, N-diisopropylethylamine (10 mL) and di-tert-butylcarbonate (11 .4g) was added was stirred for 3 hours at room temperature. The reaction solution was extracted three times with chloroform after adding a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was concentrated after dried over sodium sulfate. The resulting residue to give the title compound purified by silica gel column chromatography (2.55g, 22percent).

References: [1] Patent: JP5851663, 2016, B1, . Location in patent: Paragraph 0302.

3
[ 24424-99-5 ]
[ 723286-79-1 ]

References: [1] Patent: WO2004/58266, 2004, A1, . Location in patent: Page/Page column 79-80.

4
[ 274-82-8 ]
[ 723286-79-1 ]

References: [1] Patent: WO2004/58266, 2004, A1, .

[ 723286-79-1 ] Synthesis Path-Downstream 1~15

1
[ 24424-99-5 ]
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine [ No CAS ]
[ 723286-79-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	To a solution of 9.70 g (76.2 mmol) of 5,6, 7,8-tetrahydro [1, 2,4] triazolo [4,3- AJPYRAZINE in 250 mL of dichloromethane was added sequentially 11.8 g (91.4 mmol) of N, N diisopropylethylamine and 18.3 g (83.8 mmol) of di-tert-butyl dicarbonate. The reaction was stirred at ambient temperature for 2 h. The reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was azeotroped with hexanes and the resultant solid triturated with a mixture of hexanes/ethyl acetate (95: 5) to afford the title compound. LC/MS 225. 1 (M+1).

References: [1]Patent: WO2004/58266,2004,A1 .Location in patent: Page/Page column 79-80.

2
[ 723286-79-1 ]
[ 723286-80-4 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-Bromosuccinimide; sodium hydrogencarbonate; In chloroform; at 0 - 20℃; for 2h;	The compound obtained in Step 3 (1 g) was dissolved in chloroform (20 mL), sodium bicarbonate (688 mg) and N- bromosuccinimide (873 mg) was added at 0 C., the-reaction solution was stirred for 2 hours at room temperature and extracted 3 times with chloroform after addition of water, the organic layer gave the title compound by the residue obtained, which was concentrated after drying over sodium sulfate and purified by silica gel column chromatography (693mg, 51%). LRMS (ESI) m / z 303 [M + H] +.
	With N-Bromosuccinimide; sodium hydrogencarbonate; In chloroform; at 0 - 20℃; for 16h;	To a solution of 9.01 g (40.0 mmol) of 7- (tert-butoxycarbonyl)-5, 6,7, 8- tetrahydro [1, 2,4] triazolo [4, 3-a] pyrazine in 150 mL chloroform was added 6.72 g (80.0 mmol) of sodium bicarbonate. The system was cooled to 0 C and 7.11 g (40.0 mmol) OF N- bromosuccinimide was added. The reaction was stirred at 0 C for 15 min and at ambient temperature for 16 h. The reaction was diluted with dichloromethane and washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography on a BIOTAGE system (silica gel, 4% methanol/ethyl acetate) to yield the title compound. LC/MS 303.0 and 305.0 (M+1).

References: [1]Patent: JP5851663,2016,B1 .Location in patent: Paragraph 0303.
[2]Patent: WO2004/58266,2004,A1 .Location in patent: Page/Page column 80.

3
[ 723286-79-1 ]
[ 109-94-4 ]
[ 1174069-03-4 ]

Yield	Reaction Conditions	Operation in experiment
83%		To a solution of compound A48-1 (1.29 g, 5.75 mmol) in dry THF (50 mL) was added a solution of 2.5 M n-BuLi in hexane (2.53 mL, 6.33 mmol) at -78 C. under argon. After 15 min ethyl formate (702 muL, 8.63 mmol) was added and the reaction mixture was stirred for 15 min at -78 C. Saturated aqueous NH4Cl (150 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layer was dried (Na2SO4) and evaporated to dryness to afford aldehyde A48-2 (1.21 g, 83%).
83%		Procedure for step-2 :To a solution of compound A48-1 (1.29 g, 5.75 mmol) in dry THF (50 mL) was added a solution of 2.5 M ?-BuLi in hexane (2.53 mL, 6.33 mmol) at -78 C under argon. After 15 min ethyl formate (702 muL, 8.63 mmol) was added and the reaction mixture was stirred for 15 min at -78 0C. <n="143"/>Saturated aqueous NH4Cl (150 mL) was added and the mixture was extracted with CH2CI2 (3 x 100 mL) . The combined organic layer was dried (Na2SO4) and evaporated to dryness to afford aldehyde A48-2 (1.21 g, 83%).

References: [1]Patent: US2009/186899,2009,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2009/90055,2009,A1 .Location in patent: Page/Page column 141; 142.

4
[ 24424-99-5 ]
5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride [ No CAS ]
[ 723286-79-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 25℃;	To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1.0 g, 6.23 mmol) in CH2Cl2 (25 mL) were added Et3N (2.17 mL, 15.57 mmol) and Boc2O (1.52 mL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO4 (50 mL). The organic layer was dried (Na2SO4) and evaporated to dryness to afford compound A48-1 (1.29 g, 92%).
92%	With triethylamine; In dichloromethane; at 20℃;	Procedure for step-1:To a solution of 5, 6, 7 , 8-tetrahydro- [ 1, 2 , 4 ] triazolo [ 4 , 3- ajpyrazine hydrochloride (1.0 g, 6.23 irunol) in CH2CI2 (25 itiL) were added Et3N (2.17 mL, 15.57 mmol) and BoC2O (1.52 itiL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO4 (50 mL) . The organic layer was dried (Na2SO4) and evaporated to dryness to afford compound A48-1 (1.29 g, 92%) .

References: [1]Patent: US2009/186899,2009,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2009/90055,2009,A1 .Location in patent: Page/Page column 140; 141.

5
[ 723286-79-1 ]
[ 1378367-44-2 ]
[ 1378365-54-8 ]

Yield	Reaction Conditions	Operation in experiment
6%		Example 102: 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 - carboximidamide hydrochlorideTo a solution of tert-butyl 5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (100 mg, 0.446 mmol) in dichloromethane (5 ml) was charged trifluoroacetic acid (1 .5 ml, 19.47 mmol) and the reaction was stirred at RT for 2 h. The reaction was concentrated in vacuo, the resulting oil was dissolved in DMF (1 .5 ml) and 4-(3-(tert-butyl)-4- isopropoxyphenyl)-2-chloropyrimidine (100 mg, 0.328 mmol) and DIPEA (0.229 ml, 1 .312 mmol) were added. The mixture was heated at 120C under microwave conditions for 80 min. After cooling the reaction mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted once more with ethyl acetate and the organic extracts were combined, washed four times with water/brine1 :1 , dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Si02, 0-10%, MeOH in DCM) to afford the title compound (8 mg, 6%) as a colourless gum.LCMS (Method F): RT = 1 .53 min, M+H+ = 393; 1H NMR (500 MHz, MeOH-d4): 8.50 (1 H,s), 8.41 (1 H, d), 8.16 (1 H, d), 7.98 (1 H, dd), 7.19 (1 H, d), 7.06 (1 H, d), 5.27 (2H, s), 4.83 (1 H, m), 4.42 (2H, t), 4.29 (2H, t), 1 .48 (9H, s), 1 .43 (6H, d).

References: [1]Patent: WO2012/69852,2012,A1 .Location in patent: Page/Page column 133-134.

6
[ 68774-77-6 ]
[ 24424-99-5 ]
[ 723286-79-1 ]

Yield	Reaction Conditions	Operation in experiment
22%		After dissolution compound obtained in Step 2 (8.10 g) and platinum oxide (IV) and 10% palladium / carbon (2g, 50% water content) in methanol (8 mL), under an atmosphere of hydrogen 50psi (Parr) 34 time and stirred. After filtering the reaction solution at Hyflo Super Cel, the oil obtained by concentrating the solvent was dissolved in dichloromethane (200 mL), N, N-diisopropylethylamine (10 mL) and di-tert-butylcarbonate (11 .4g) was added was stirred for 3 hours at room temperature. The reaction solution was extracted three times with chloroform after adding a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was concentrated after dried over sodium sulfate. The resulting residue to give the title compound purified by silica gel column chromatography (2.55g, 22%).

References: [1]Patent: JP5851663,2016,B1 .Location in patent: Paragraph 0302.

7
[ 723286-79-1 ]
4-((3-(4-isopropoxyphenyl)amino)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]

References: [1]Patent: JP5851663,2016,B1 .

8
[ 723286-79-1 ]
4-(3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-2-(trifluoromethyl)benzonitrile [ No CAS ]

References: [1]Patent: JP5851663,2016,B1 .

9
[ 723286-79-1 ]
[ 903130-08-5 ]