105486-72-4|Ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate| Ambeed

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Quality Control of [ 105486-72-4 ] Purity: 95% SDS Specification

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Product Details of [ 105486-72-4 ]

CAS No. :	105486-72-4
Formula :	C₇H₉BrN₂O₂
M.W :	233.06
SMILES Code :	CCOC(=O)C1=C(Br)N(C)N=C1
MDL No. :	MFCD13189831
InChI Key :	OMQVPOJHVUMCGK-UHFFFAOYSA-N
Pubchem ID :	53302113

Safety of [ 105486-72-4 ]

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

Computational Chemistry of [ 105486-72-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	5
Fraction Csp3	0.43
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	47.28
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	44.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.16
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	1.48
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.36
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.	1.09
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	1.18
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.45

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.33
Solubility	1.1 mg/ml ; 0.0047 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.01
Solubility	2.26 mg/ml ; 0.00969 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	-2.14
Solubility	1.7 mg/ml ; 0.00728 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	Yes
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.	-6.67 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)	2.02

Application In Synthesis of [ 105486-72-4 ]

* 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 [ 105486-72-4 ]

[ 105486-72-4 ] Synthesis Path-Downstream 1~35

1
[ 105486-72-4 ]
[ 54367-67-8 ]

Yield	Reaction Conditions	Operation in experiment
92%		Step 2. Synthesis of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid A suspension of <strong>[105486-72-4]ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate</strong> (8.00 g, 34.3 mmol) in tetrahydrofuran (60 mL), water (20 mL) and ethanol (20 mL) was treated with lithium hydroxide monohydrate (3.17 g, 75.5 mmol) and stirred for 4 hours at room temperature. Removal of solvents under reduced pressure provided a white solid residue, which was diluted with water (50 mL), washed with diethyl ether (50 mL) and adjusted to pH 2.5 with aqueous 6 N hydrochloric acid. The thick suspension was extracted with 2-methyltetrahydrofuran (2*125 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the product as an off-white solid. Yield: 6.49 g, 31.7 mmol, 92%. LCMS m/z 205.2 (M+1). 1H NMR (500 MHz, DMSO-d6) delta 3.86 (s, 3H), 7.91 (s, 1H), 12.64 (br s, 1H).
91.05%	With water; sodium hydroxide; In methanol; at 25℃; for 3h;	[0939] to a solution of compound 163b (600 mg, 2.57 mmol) in MeOH (10 ml) and H2O (10 ml) was added NaOH (514 mg, 12.85 mmol). The mixture was stirred at 25 C for 3h. The reaction mixture was concentrated and added 20 ml of water, the mixture was extracted with mtbe (10 ml x 2), the aqueous layer was acidified by in HCl to ph ~ 2-3 at 0 C, and extracted with EtOAc (20 ml x 2), the organic phase was dried over Na2SO4, concentrated to give a residue. Compound 163d (480 mg, yield: 91.05%) was obtained as a white solid. 1H NMR (400mhz, DMSO-d6) delta 12.65 (s, 1h), 8.13 (s, 1h), 3.82 (s, 3h).
		Step 2. (5-Bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)-methanone; To a solution of <strong>[105486-72-4]5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester</strong> (6.9 g, 29.6 mmol) in CH3OH (25 mL) and water (25 mL) was added LiOH (0.78 g, 32.6 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl (3 mL). The resulting mixture was then extracted with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid, which was used without further purification.

References: [1]Patent: US2012/214791,2012,A1 .Location in patent: Page/Page column 23.
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.
[3]Patent: WO2018/64119,2018,A1 .Location in patent: Paragraph 0939.
[4]Patent: US2006/223852,2006,A1 .Location in patent: Page/Page column 10.

2
[ 31037-02-2 ]
[ 105486-72-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20 - 65℃; for 3.5h;	Intermediate 1: (5-Bromo-1-methyl-1H-pyrazol-4-yl)-(octahydro-quinolin-1-yl)methanone; Step 1. ; 5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester; To a mixture of t-butyl nitrite (29.5 mL, 221.5 mmol), cupric bromide (39.7 g, 177.5 mmol), and acetonitrile was added 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (25 g, 148 mmol) in portions over 30 minutes. The reaction mixture was stirred at ambient temperature for 2 h, then at 65 C. for 1 h. The mixture was then poured into 6N HCl (400 mL) and extracted with dichloromethane. After concentration in vacuo, the crude residue was purified by flash chromatography with a gradient of 0-20% ethyl acetate/hexanes to give 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (28 g, 81%).
68%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 60℃; for 2h;Inert atmosphere;	5-Amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.0 g, 29.6 mmol) was added portionwise to a mixture of tert-butyl nitrite (4.57 g, 44.3 mmol) and copper (II) bromide (7.92 g, 35.5 mmol) in acetonitrile (20 mL). The mixture was heated to 60C for 2 h. The resulting mixture was poured into 6M HCl (200 mL) and extracted with dichloromethane (3 x 250 mL). The combined organics was dried on magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (SiO2, 0% to 50% ethyl acetate in hexanes) to afford 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester as an off-white solid (4.7 g, 68%). 1H NMR (CDCl3) : 7.93 (s, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H).
66%	With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 65℃; for 24h;	Step 1. Synthesis of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate Copper(II) bromide (99%, 20.0 g, 88.6 mmol) and tert-butyl nitrite (90%, 14.1 mL, 107 mmol) were combined in acetonitrile (65 mL) and heated to 65 C. Ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10.0 g, 59.1 mmol) was slowly added portion-wise {Caution: gas evolution!} and the reaction was maintained at 65 C. for 24 hours. The mixture was cooled to room temperature, poured into aqueous hydrochloric acid (3 N, 600 mL), diluted with ethyl acetate (300 mL) and stirred for 10 minutes. The aqueous layer was extracted with ethyl acetate (150 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 5% to 100% ethyl acetate in heptane, with a 5-minute hold at 32%), affording the product as a pale yellow solid. Yield: 9.10 g, 39.0 mmol, 66%. LCMS m/z 233.3 (M+1). 1H NMR (500 MHz, CDCl3) delta 1.36 (t, J=7.1 Hz, 3H), 3.92 (s, 3H), 4.32 (q, J=7.1 Hz, 2H), 7.93 (s, 1H).

References: [1]Patent: US2006/223852,2006,A1 .Location in patent: Page/Page column 10.
[2]Patent: WO2013/189904,2013,A1 .Location in patent: Page/Page column 49.
[3]Patent: US2012/214791,2012,A1 .Location in patent: Page/Page column 23.
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

3
[ 105486-72-4 ]
[ 1394034-59-3 ]

References: [1]Patent: US2012/214791,2012,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

4
[ 105486-72-4 ]
[ 1394034-60-6 ]

References: [1]Patent: US2012/214791,2012,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

5
[ 105486-72-4 ]
4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-amine trifluoroacetate salt [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

6
[ 105486-72-4 ]
[ 1394034-63-9 ]

References: [1]Patent: US2012/214791,2012,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

7
[ 105486-72-4 ]
[ 1394034-64-0 ]

References: [1]Patent: US2012/214791,2012,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

8
[ 105486-72-4 ]
[ 1394034-65-1 ]

References: [1]Patent: US2012/214791,2012,A1 .
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1001 - 1018.

9
[ 105486-72-4 ]
[ 1394034-69-5 ]