2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine,2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine

Cat.NO.:A155605,A1477072,A155605,A1477072 Purity:97%,98%,97%,98%

Product Details of [ 1003845-08-6 ]

CAS No. :	1003845-08-6
Formula :	C₁₀H₁₄BClN₂O₂
M.W :	240.49
SMILES Code :	CC1(C)OB(OC1(C)C)C1=CN=C(Cl)N=C1
MDL No. :	MFCD11856048
InChI Key :	VLAPDEKXZLRRKV-UHFFFAOYSA-N
Pubchem ID :	51341943

Safety of [ 1003845-08-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 1003845-08-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.6
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	63.52
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	44.24 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	2.15
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.43
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	1.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.08

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.9
Solubility	0.305 mg/ml ; 0.00127 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.	-2.71
Solubility	0.468 mg/ml ; 0.00194 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	-3.87
Solubility	0.0321 mg/ml ; 0.000134 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	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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.24 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)	2.87

Application In Synthesis of [ 1003845-08-6 ]

* 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.

Upstream synthesis route of [ 1003845-08-6 ]
Downstream synthetic route of [ 1003845-08-6 ]

[ 1003845-08-6 ] Synthesis Path-Upstream 1~3

1
[ 76-09-5 ]
[ 1003845-06-4 ]
[ 1003845-08-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With magnesium sulfate In toluene at 20℃; for 15 h;	34). Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium \r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 ⁰C over 45 min and stirred at -78 ⁰C for 1 hour. The mixture is warmed to -20 ⁰C, then added aq. hydrogen chloride (1M, 20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO₄ (18.15 mmol, 2.2 g) in toluene (10 mL) is <n=”192″/>stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2- chloro-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]\ Retention time 1.75 min (condition A).
100%	With magnesium sulfate In toluene at 20℃; for 15 h;	Example 14; 1) Synthesis of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 mL) in toluene (16 mL) and THF (4 mL) is added n-butyl lithium in hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78° C. over 45 min and stirred at -78° C. for 1 hour. The mixture is warmed to -20° C., then added aqueous 1 M HCl (20 mL). The mixture is warmed to room temperature. The precipitate is collected and washed with hexane to give a colorless powder (808 mg, 51percent). A mixture of the powder (3.63 mmol, 575 mg), pinacol (3.81 mmol, 450 mg) and MgSO4 (18.15 mmol, 2.2 g) in toluene (10 mL) is stirred at room temperature for 15 hour. The mixture is filtrated and the solution is concentrated under reduced pressure. The resultant solid is washed with water to give 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (875 mg, quant); ESI-MS m/z: 159 [M+1-pinacol]+, Retention time 1.75 min (condition A).

References:

[1] Patent: WO2008/9435, 2008, A1, . Location in patent: Page/Page column 189-190.

[2] Patent: US2009/118287, 2009, A1, . Location in patent: Page/Page column 67-68.

2
[ 61676-62-8 ]
[ 32779-36-5 ]
[ 1003845-08-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at -78 – 20℃; for 5 h;	Synthesis of Intermediate 1-1 (0337) 1.93 g (10 mmol) of 5-bromo-2-chloropyrimidine was dissolved in 200 mL of THF, and then, at a temperature of −78° C., 4 mL (2.5M in hexane) of normal butyllithium was added thereto. At the same temperature about one hour thereafter, 2.0 mL (10 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added thereto. At room temperature, the result was stirred for about 5 hours, and then, water was added thereto and a washing process was performed three times thereon using diethylether (100 mL). A washed diethylether layer was dried by using MgSO₄, and then, dried under reduced pressure, thereby obtaining a product. The product was separation-purified by silica gel column chromatography, thus preparing 1.56 g (Yield 65percent) of Intermediate 1-1.

References:

[1] Patent: US2017/179408, 2017, A1, . Location in patent: Paragraph 0336-0337.

[2] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0023.

3
[ 1195-66-0 ]
[ 32779-36-5 ]
[ 1003845-08-6 ]

References:

[1] Patent: CN104788482, 2016, B, . Location in patent: Paragraph 0018.

[ 1003845-08-6 ] Synthesis Path-Downstream 1~2

1
[ 1003845-08-6 ]
[ 31560-06-2 ]
(1S,4S)-5-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-2-oxa-5-azabicyclo[2.2.1]heptane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triethylamine; In ethanol; at 80℃; for 4h;	2-chloropyrimidine-5-boronic acid (52.3 mmol, 8.53 g), thiomorpholine (52.3 mmol, 5.3 ml) and TEA (52.3 mmol, 7.3 ml) were dissolved in EtOH (100 ml) and heated at 80°C for 4h. The solvent was removed in vacuo and the resulting solid triturated with Et20 yielding the title compound (8.64 g, 74percent). The title compound was prepared from (15′,45)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1 : 1) (406 mg, 2.99 mmol) and 2-chloro-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidine (650 mg, 2.70 mmol) by the Method E (580 mg, 70 percent). 1H NMR (500 MHz, CDC13) delta ppm 8.59 (s, 2H), 5.11 (s, 1H), 4.71 (s, 1H), 3.92 – 3.83 (m,2H), 3.66 – 3.53 (m, 2H), 2.02 – 1.89 (m, 2H), 1.32 (s, 12H).

References: [1]Patent: WO2015/86526,2015,A1 .Location in patent: Page/Page column 128; 129.

2
[ 88675-24-5 ]
[ 1003845-08-6 ]
2′-bromo-6′,8′-dihydrospiro[chroman-4,9′-pyrido[3′,2′:4,5]imidazo[2,1-c][1,4]oxazine] [ No CAS ]
5-(6’H,8’H-spiro[chromane-4,9′-pyrido[3′,2′:4,5]imidazo[2,1-c][1,4]oxazin]-2′-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		In a 4 mL vial was mixed the 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (61 mg, 0.25 mmol), tetrahydrofuran-3 -amine (22 mg, 0.25 mmol) and TEA (46 uL, 0.36 mmol) in EtOH (0.3 mL). The reaction was heated to 95 °C for 2 h before being cooled and concentrated. To the crude residue was added the 2′-bromo-6’H,8’H-spiro[chromane-4,9′-pyrido[3′,2′:4,5]imidazo[2,l-c][l,4]oxazine] (39 mg, 0.10 mmol, Preparation 86), Pd2(dba)3 (9.6 mg, 0.010 mmol), l,3,5,7-Tetramethyl-2,4,8-trioxa-6- phospha-adamantane (6.1 mg, 0.020 mmol) and CS2CO3 (74.8 mg, 0.25 mmol). THF (1 mL) and H20 (0.25 mL) were added, and the reaction was stirred at 60 °C for 18 h before being cooled to rt and concentrated. The residue was dissolved in 1 : 1 MeOH/DMSO and purified by reverse phase chromatography using a gradient of MeCN (A) and 0.1percent TFA in H20 (B) at a flow rate of 50 mL/min (0- 0.5 min 5percent A, 0.5-8.5 min linear gradient 05-100percent A, 8.7-10.7 min 100percent A, 10.7-11 min linear gradient 100-05percent A) to yield the title compound. (39 mg, 33percent); LC/MS (Table 1, method ai) Rt = 0.61 min; MS 111 ~ 457 (M+H)+. (TNF IC50= B).

References: [1]Patent: WO2016/168641,2016,A1 .Location in patent: Page/Page column 308; 309.

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