369638-68-6|tert-Butyl (5-methylpyrazin-2-yl)carbamate| Ambeed

Structure of 369638-68-6

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Quality Control of [ 369638-68-6 ] Purity: 95% SDS Specification

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Product Details of [ 369638-68-6 ]

CAS No. :	369638-68-6
Formula :	C₁₀H₁₅N₃O₂
M.W :	209.25
SMILES Code :	O=C(OC(C)(C)C)NC1=NC=C(C)N=C1
MDL No. :	MFCD09907674
InChI Key :	FGAZCKUQQRDXOX-UHFFFAOYSA-N
Pubchem ID :	22046506

Safety of [ 369638-68-6 ]

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

Computational Chemistry of [ 369638-68-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	57.24
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.11 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.06
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	1.08
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.94
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.	0.41
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	1.1
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.32

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.85
Solubility	2.96 mg/ml ; 0.0141 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.	-2.02
Solubility	2.01 mg/ml ; 0.00959 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.0
Solubility	0.211 mg/ml ; 0.00101 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.	-6.81 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)	2.63

Application In Synthesis of [ 369638-68-6 ]

* 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 [ 369638-68-6 ]

[ 369638-68-6 ] Synthesis Path-Downstream 1~35

1
[ 5521-55-1 ]
[ 75-65-0 ]
[ 369638-68-6 ]

Yield	Reaction Conditions	Operation in experiment
72.7%	With diphenyl phosphoryl azide; triethylamine; In toluene; for 8.0h;Reflux;	5-Methylpyrazin-2-carboxylic acid (13.81 g, 0.1 mol), tert-butanol (95 mL, 1 mol), triethylamine (27.9 mL, 0.2 mol) and diphenylphosphoryl azide (30.27 g, 0.11 mol) were mixed in 300 mL toluene, heated to reflux and reacted for 8 hours, and chromatographed on a silica gel column (petroleum ether - petroleum ether:ethyl acetate=20:1) to obtain a light yellow solid 15.2 g, at a yield of 72.7%.
70%	With diphenyl phosphoryl azide; triethylamine; In toluene; for 6.0h;Reflux;	A. tert-butyl 5-methylpyrazin-2-ylcarbamate; To a solution of 5-methylpyrazine-2-carboxylic acid (500 mg, 3.62 mmol) in toluene (12 mL) were added DPPA (0.85 mL, 3.98 mmol), TEA (1.01 mL, 7.24 mmol) and te/t-butanol (3.4 mL, 36.2 mmol). The reaction mixture was refluxed for 6 hours after which, it was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSC^, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (10% Ethyl acetate/Hexane) as a solvent to afford title compound (530 mg, 70% yield).1H NMR (600 MHz, CDC13) delta 9.15 (s, 1H), 8.08 (s, 1H), 7.61 (s, 1H), 2.50 (s, 3H), 1.55 (s, 9H). MS m/z : 210 [M+l].
70%	With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; at 100℃; for 3.0h;Product distribution / selectivity;	Step 1: To a solution of 2-methylpyrazine-5-carboxylic acid (10 g, 72.4 mmol) and TEA (20 mL, 108 mmol) in t-butanol (156 mL) and dioxanes (100 mL) was added diphenyl phosphorylazide (23.4 mL, 108 mmol) and the resulting solution was warmed at 100 C. for 3 hours and then cooled to room temperature overnight. The crude reaction mixture was concentrated in vacuo. Purification by chromatography (silica 0-15% ethyl acetate/hexanes) following trituration of impure fractions with ether afforded (5-methyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (10.6 g, 70%): 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.56 (s, 9H) 2.51 (s, 3H) 8.02 (br. s., 1H) 8.07-8.14 (m, 1H) 9.18 (d, J=1.13 Hz, 1H).

63%	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; at 82℃;Inert atmosphere;	To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-methylpyrazine-2-carboxylic acid (1.0 eq), tert-butanol (3.5 vols) and di-isopropylethylamine (1.5 eq) under a nitrogen atmosphere. The mixture was heated to 82 C., then diphenylphosphorylazide (1.0 eq) was added over a time period of 5-14 hours, maintaining the temperature of the reaction mixture at approximately 82 C. The reaction mixture was stirred for at least 1.5 hours, and then cooled to approximately 60 C. A solution of 4% w/w sodium hydroxide (1.75 eq) was added over a period of 2 hours. The mixture was cooled to 15 C. over at least 5 hours then held at 15 C. for 3 hours. The batch was then filtered, and the solid slurry washed with water (2 vols). The batch was again slurry washed with water (2 vols). After drying at 55-60 C. overnight, the desired product was obtained as a solid (corrected yield 56-63%). 1H NMR delta (400 MHz CDCl3): 9.18 (s, 1H), 8.17 (bs, 1H), 8.11 (s, 1H), 2.51 (s, 3H), 1.56 (s, 9H)
	With diphenyl phosphoryl azide; In 1,4-dioxane; for 12.0h;Reflux;	Intermediate: te/t-butyl 5-methylpyrazin-2-ylcarbamate (29a) (29a)To a stirred solution of 5-methyl-2-carboxylic acid (138 g, 1.0 mol) in dioxane (1 L) was added te/t-BuOH (100 mL) and diphenylphosphoryazide (330 g) and the reaction mixture was heated at reflux for 12 hours. The reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography (ethyl acetate/hexanes), then recrystalized from ether to provide te/t-butyl 5-methylpyrazin-2- ylcarbamate (29a).
	With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; at 100℃; for 3.0h;	(1) 175 g of 5-methyl-2-pyrazinecarboxylic acid was suspended in 1 L of dioxane, then 1 L of t-butanol, 175 mL of triethylamine, and 287 mL of diphenyl azidophosphate were sequentially added to the suspension, and the reaction solution was heated to 100C. The obtained reaction solution was stirred at the same temperature for 3 hours and then cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was poured onto a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous phase was extracted with ethyl acetate. The obtained extraction liquid was washed with a saturated aqueous solution of ammonium chloride and dried, and then the solvent was distilled off under reduced pressure. The obtained crude product was crystallized from acetonitrile, to obtain 158 g of the following Compound [1-1]. [Show Image] The spectral data of the compound represented by the above Formula [1-1] is presented below. 1H-NMR (CDCl3) delta: 9.15 (1H, s), 8.70 (1H, s), 7.41 (1H, brs), 2.51 (3H, s), 1.55 (9H, s). mass: 210 (M+1)+.
	With diphenyl phosphoryl azide; triethylamine; In 1,4-dioxane; at 95℃; for 3.0h;	Step 1. tert-butyl 5-methylpyrazin-2-ylcarbamate To solution 5-methylpyrazine-2-carboxylic acid (2.5 g, 18.1 mmol), tert-butanol (6.92 mL, 72.4 mmol), Et3N (3.78 mL, 27.1 mmol) in 1,4-dioxane (12.5 mL) at 95 C. was dropwise added diphenylphosphoryl azide (DPPA, 3.23 mL, 18.1 mmol), and the reaction was heated at 95 C. for 1.5 h, followed by a 2nd portion of DPPA (1 mL, 5.6 mmol) and heated for additional 1.5 h. The reaction mixture was cooled down, concentrated and the residue was diluted with EtOAc (50 mL), washed with water (30 mL), 3 M NaOH (30 mL), sat. NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by flashed chromatography on silica gel eluting with gradient EtOAc/CH2Cl2 (0-20%) to afford tert-butyl 5-methylpyrazin-2-ylcarbamate as white solid. LCMS (m/z): 210.1 (MH+), 0.69 min; 1H NMR (400 MHz, CDCl3) delta ppm 9.17 (s, 1H), 8.09 (s, 1H), 7.75 (br. s., 1H), 2.51 (s, 3H), 1.56 (s, 9H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3751 - 3754.
[2]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.
[3]Patent: EP2781508,2014,A1 .Location in patent: Paragraph 0153.
[4]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1203 - 1208.
[5]Patent: WO2011/90738,2011,A2 .Location in patent: Page/Page column 45.
[6]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 37.
[7]Patent: US2010/210841,2010,A1 .Location in patent: Page/Page column 19.
[8]Patent: WO2010/13161,2010,A1 .Location in patent: Page/Page column 44.
[9]Patent: EP1754706,2007,A1 .Location in patent: Page/Page column 32.
[10]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 136; 137; 138.

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[ 369638-68-6 ]
[ 369638-69-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 4.0h;Product distribution / selectivity;	Step 2: To a solution of <strong>[369638-68-6](5-methyl-pyrazin-2-yl)-carbamic acid tert-butyl ester</strong> (from above and from example 21, step 1, 12.9 g, 61.6 mmol) and AIBN (10.1 g, 61 mmol) in CCl4 (100 mL) was added NBS (11 g, 61.6 mmol) and the reaction mixture was stirred at 100 C. for 4 h. The reaction mixture was filtered, washed with CH2Cl2 and concentrated in vacuo. Purification by chromatography (silica, 4:5:1 CH2Cl2:hexanes:ethyl acetate) with repurification of mixed fractions by chromatography (silica, 4:5:1 CH2Cl2:hexanes:ethyl acetate) afforded a total of (5-bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (13.6 g, 77%): 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.57 (s, 9H) 4.55 (s, 2H) 8.15 (s, 1H) 8.34 (d, J=1.51 Hz, 1H) 9.28 (d, J=1.51 Hz, 1H).
75%	With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 4.0h;	B. tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate; To a solution <strong>[369638-68-6]tert-butyl 5-methylpyrazin-2-ylcarbamate</strong> (500 mg, 2.39 mmol) in CC (8.0 niL) were added NBS(446 mg, 2.51 mmol) and AIBN (117 mg, 0.72 mmol). The reaction mixture was stirred for 4 hours at 80 C after which, it was partitioned between CH2CI2 and water. The organic layer was separated and the aqueous layer was extracted with CH2CI2. The combined organic extracts were washed with brine, dried over MgS04, celite filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography using (10% Ethyl acetate/Hexane) as a solvent to afford title compound (520 mg, 75% yield). 1H NMR (600 MHz, CDC13) delta 9.29 (s, 1H), 8.95 (s, 1H), 8.37 (s, 1H), 4.38 (s, 2H), 1.57 (s, 9H). MS m/z : 288 [M+l].
	With N-Bromosuccinimide; sodium hydrogencarbonate; In tetrachloromethane; at 80℃; for 12.0h;	Intermediate: te/t-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate (29b)BocHNgammaN.(29b)To a solution of te/t-butyl 5-methylpyrazin-2-ylcarbamate (29a) (100 g, 0.48 mol) inCCU (40 mL) was added NaHCO,? followed by AZ-bromosuccinimide (130 g, 0.57 mol). The resulting mixture was heated to reflux at 800C for 12 hours then cooled to room temperature. The reaction mixture was filtered through Cehte and the filtrate was concentrated in vacuo. The crude product was chromatographed (SiO?; 5 % EtOAc in CHCI3) to give tert-buty 5-{bromomethyi)pyrazm-2-y.carbamate (29b).

With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 85℃; for 4.0h;Inert atmosphere;

Step 2. tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate:_A solution of [369638-68-6]tert-butyl 5-methylpyrazin-2-ylcarbamate (2.79 g, 13.33 mmol), NBS (2.61 g, 14.67 mmol) and AlBN (0.219 g, 1.33 mmol) in CCl4 (45 mL) was purged with Argon, then the solution was heated with 85 C. oil bath for 4 h. The reaction mixture was cooled to room temperature, concentrated and the residue was redissolved in EtOAc (?50 mL), washed with dilute aqueous NaOH twice (10 mL 1 N NaOH diluted in 20 mL H2O), brine (30 mL), dried (Na2SO4) and concentrated. The residue was further purified by flash chromatography on silica gel eluted with gradient EtOAc/CH2Cl2 (0-30%) and tert-butyl 5-(bromomethyl)pyrazin-2-ylcarbamate was obtained in off-white solid. LCMS (m/z): 288.1/290.1 (MH+), 0.82 min; 1H NMR (400 MHz, CDCl3) delta ppm 9.26 (s, 1H), 8.32 (d, J=1.2 Hz, 1H), 7.62 (br. s., 1H), 4.56 (s, 2H), 1.56 (s, 9H).

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 4136 - 4142.
[2]Patent: US2012/149718,2012,A1 .Location in patent: Page/Page column 38.
[3]Patent: WO2011/90738,2011,A2 .Location in patent: Page/Page column 45-46.
[4]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1203 - 1208.
[5]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3751 - 3754.
[6]Patent: WO2010/13161,2010,A1 .Location in patent: Page/Page column 44-45.
[7]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 136; 137; 138.

3
[ 369638-68-6 ]
[ 874476-55-8 ]