144657-66-9|tert-Butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate| Ambeed

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Quality Control of [ 144657-66-9 ] Purity: 97% SDS Specification

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Product Details of [ 144657-66-9 ]

CAS No. :	144657-66-9
Formula :	C₁₃H₁₄N₂O₃
M.W :	246.26
SMILES Code :	CC(C)(C)OC(=O)N1C=C(C=O)C2=CC=CN=C12
MDL No. :	MFCD11045434
InChI Key :	GFZQRKMUXOECFL-UHFFFAOYSA-N
Pubchem ID :	11806939

Safety of [ 144657-66-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H317
Precautionary Statements:	P280

Computational Chemistry of [ 144657-66-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	9
Fraction Csp3	0.31
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	67.32
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	61.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.33
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	2.0
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.63
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.	1.55
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	1.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.05

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.73
Solubility	0.456 mg/ml ; 0.00185 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.	-2.91
Solubility	0.302 mg/ml ; 0.00123 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	-2.94
Solubility	0.283 mg/ml ; 0.00115 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	Yes
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.	-6.38 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)	2.23

Application In Synthesis of [ 144657-66-9 ]

* 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 [ 144657-66-9 ]

[ 144657-66-9 ] Synthesis Path-Downstream 1~35

1
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[ 24424-99-5 ]
[ 144657-66-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine;dmap; In dichloromethane; at 20℃;	A round-bottom flask was charged with Int-15 (6.6 g, 45 mmol), (BoC)2O (10.7 g, 50 mmol), 4-dimethylaminopyridine (55 mg, 0.45 mmol), triethylamine (13 g, 130 mmol), and DCM (50 mL). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified by flash column chromatography to afford product Int-16 (9.8 g, 89%).
82%	With dmap; In acetonitrile; at 20℃; for 6.5h;	To a suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (304 mg, 2.08 mmol; commerciallyavailable from, for example, Enamine) and di-tett-butyl dicarbonate (0.580 mL, 2.50 mmol) inacetonitrile (5 mL) was added DMAP (28 mg, 0.23 mmol) and the reaction mixture stirred at rt under nitrogen for 6.5 h before being left to stand overnight. The reaction mixture was concentrated in vacuo to give a brown solid which was dissolved in dichloromethane (3 mL) and loaded onto a 25 g SNAP silica cartridge and purified by flash chromatography eluting with a gradient of 3O-5O% ethylacetate in cyclohexane. The required fractions were combined and concentrated in vacuo before the residue was dissolved in dichloromethane (6 mL), transferred to a tarred vial, concentrated under a stream of nitrogen and dried in vacuo to give a white solid; ter1butyl 3-formyl-1H-pyrrolo[2,3- b]pyridine-1-carboxylate (420.7 mg, 1.71 mmol, 82 % yield).LCMS (2 mm high pH) Rt = 0.97 mi m/z= 247 for [MH]
	With dmap; triethylamine; In acetonitrile; at 0 - 20℃; for 18.0h;	To an acetonitrile solution (0.2 M) of lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1 eq.) was added triethylamine (1.05 eq.), DMAP (0.3 eq.) and di-tert-butyl carbonate (1.2 eq.) at 0 0C. The resulting mixture was allowed to warm slowly to RT over 18 h. The resulting mixture was then diluted with water and extracted with EtOAc. The combined organic extracts were washed further with sat. aq. NH4Cl, sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered.

0.779 g

With dmap; In acetonitrile; at 20℃;

General procedure: To a solution of an appropriate indole, azaindole or alternative heterocycles (1.0 eq) and di-ferf-butyl dicarbonate (1eq. to 2 eq., more in particular 1.2 eq) in acetonitrile was added DMAP (0.1 to 0.5 eq. more in particular 0.1 eq). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution. The phases were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with a saturated ammonium chloride solution, water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The BOC-protected compound was used in the next step without further purification.

References: [1]Patent: WO2011/23081,2011,A1 .Location in patent: Page/Page column 55.
[2]Patent: WO2017/37116,2017,A1 .Location in patent: Page/Page column 143.
[3]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[4]Patent: WO2011/20193,2011,A1 .Location in patent: Page/Page column 36.
[5]Patent: WO2013/45516,2013,A1 .Location in patent: Page/Page column 129; 197.

2
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[ 144657-67-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium tetrahydroborate; In methanol; at 20℃; for 4.0h;	A mixture of l-(fer?-butyloxycarbonyl)-3-formyl-7-azaindole (Int-16, 9.8 g, 40 mmol) and sodium borohydride (1.7 g, 44 mmol) in methanol (50 mL) were stirred at rt for 4 h. TLC showed the reaction was complete. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, brine, dried, concentrated, and purified by flash column chromatography to afford alcohol Int-17 (8.4 g, 85%).
47%	With sodium tetrahydroborate; ethanol; at 0 - 20℃; for 1.25h;Inert atmosphere;	A solution of <strong>[144657-66-9]tert-butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate</strong> (420 mg, 1.71 mmol) in ethanol (10 mL) was cooled to 0 C with stirring under nitrogen before sodium borohydride (126.6 mg, 3.35 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 1.25 h.An aqueous solution of hydrochloric acid (2 M, 4 drops) was added, followed immediately by a saturated solution of sodium bicarbonate (1 mL). The reaction mixture was concentrated in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The phases were separated and the aqueous phase further extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, filtered through a cartridgecontaining a hydrophobic frit and the solvent evaporated in vacuo. The residue was dissolved in a1:1 mixture of dichloromethane/methanol (10 mL), concentrated under a stream of nitrogen, anddried in vacuoto give a white solid which was dissolved in dichloromethane (5 mL) and loaded ontoa 25 g SNAP silica cartridge which was purified by flash chromatography, eluting wih a gradient ofSO-100% ethyl acetate in cyclohexane. The required fractions were concentrated in vacuo beforebeing dissolved in a 1:1 mixture of dichloromethane/methanol (10 mL), transferrred to a tarred vial,concentrated under a stream of nitrogen and dried in vacuo to give a white solid; tert-butyl 3- (hydroxymethyl)-1 H-pyrrolo[2,3-b] pyrid me- 1-carboxylate (199.7 mg, 0.80 mmol, 47 % yield).LCMS (2 mm formic) Rt = 0.72 mi m/z= 249 for [MH]
44%	With sodium tetrahydroborate; In ethanol; at 20℃; for 4.0h;	To a solution of <strong>[144657-66-9]1-(tert-butoxycarbonyl)-3-formyl-7-azaindole</strong> (2.5g, 10.2 mmol) in 16 mL EtOH was added NaBH4 (115mg, 3.05 mmol). The reaction was stirred at ambient temperature for 4h, concentrated and triturated with IN NaOH. The basic solution was extracted with ether and ethylacetate. The organics were washed with water and brine, then dried over Na2S04, filtered and concentrated. The filtrate was concentrated and purified by silica gel chromatography (50% ethylacetate/hexanes) to give tert-butyl 3-(hydroxymethyl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (44%). LCMS [M-tert-Bu]+ = 191.1.

To a 10:1 (v/v) MeOH: THF solution (0.2 M) of tert-butyl 3-formyl-l//-pyrrolo[2,3- 6]pyridine-l-carboxylate (1 eq.) from the previous step was added sodium borohydride (2 eq.) at 0 0C. After 3 h of stirring at 0 0C, the mixture was carefully quenched with sat. aq. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained via column chromatography (SiO2, CH2Cl2 -> 9:1 (v/v) CH2Cl2: MeOH) afforded the title compound as a pale yellow solid.

References: [1]Patent: WO2011/23081,2011,A1 .Location in patent: Page/Page column 55.
[2]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[3]Patent: WO2017/37116,2017,A1 .Location in patent: Page/Page column 143; 144.
[4]Patent: WO2013/176970,2013,A1 .Location in patent: Page/Page column 58.
[5]Patent: WO2011/20193,2011,A1 .Location in patent: Page/Page column 36.

3
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References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[2]Patent: WO2011/23081,2011,A1 .

4
[ 5654-92-2 ]
[ 144657-66-9 ]

References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.

5
[ 144657-66-9 ]
[ 144657-68-1 ]

References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[2]Patent: WO2011/23081,2011,A1 .
[3]Patent: WO2013/176970,2013,A1 .

6
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[ 144657-69-2 ]

References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.

7
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References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.

8
[ 144657-66-9 ]
[ 144657-73-8 ]

References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[2]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.
[3]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.

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[ 134235-82-8 ]

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[ 144657-72-7 ]

References: [1]Canadian Journal of Chemistry,1992,vol. 70,p. 1531 - 1536.

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[ 144657-66-9 ]
[ 1266728-59-9 ]

References: [1]Patent: WO2011/20193,2011,A1 .

13
[ 144657-66-9 ]
tert-butyl (cis-1,3')-3'-[[1-(tert-butoxycarbonyl)-1H-pyrrolo[2,3-b ]pyridin-3-yl]methyl}(cyclopropyl)amino]carbonyl}-5,6-difluoro-1'H,3H-spiro[2-benzofuran-1,4'piperidine]-1'-carboxylate [ No CAS ]

References: [1]Patent: WO2011/20193,2011,A1 .

14
[ 144657-66-9 ]
(cis-1,3')-N-cyclopropyl-5,6-difluoro-N-(1H-pyrrolo[2,3-b ]pyridine-3-ylmethyl)-3H-spiro[2-benzofuran-1,4'-piperidine]-3'-carboxamide [ No CAS ]

References: [1]Patent: WO2011/20193,2011,A1 .

15
[ 144657-66-9 ]
1-(2-methoxy-5-chlorophenyl)-3-[1-(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1H-indol-4-yl]urea hydrochloride [ No CAS ]

References: [1]Patent: WO2011/23081,2011,A1 .

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[ 1268390-78-8 ]

References: [1]Patent: WO2011/23081,2011,A1 .

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[ 1268390-79-9 ]

References: [1]Patent: WO2011/23081,2011,A1 .

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[ 1268390-80-2 ]

References: [1]Patent: WO2011/23081,2011,A1 .

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[ 1268390-81-3 ]

References: [1]Patent: WO2011/23081,2011,A1 .

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[ 104-15-4 ]
[ 144657-66-9 ]
[ 1443528-04-8 ]