945950-37-8|4-Methyl-7H-pyrrolo[2,3-d]pyrimidine| Ambeed

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Quality Control of [ 945950-37-8 ] Purity: 97% SDS Specification

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Product Details of [ 945950-37-8 ]

CAS No. :	945950-37-8
Formula :	C₇H₇N₃
M.W :	133.15
SMILES Code :	CC1=C2C(NC=C2)=NC=N1
MDL No. :	MFCD13619883
InChI Key :	QWIAHMVNMONKCU-UHFFFAOYSA-N
Pubchem ID :	51341959

Safety of [ 945950-37-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H320-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 945950-37-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	9
Fraction Csp3	0.14
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	38.85
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	41.57 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.4
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	1.06
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.27
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.	0.51
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	2.03
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.0
Solubility	1.33 mg/ml ; 0.01 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.	-1.52
Solubility	3.98 mg/ml ; 0.0299 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	-2.89
Solubility	0.171 mg/ml ; 0.00129 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.	-6.36 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	1.0
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)	1.25

Application In Synthesis of [ 945950-37-8 ]

* 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 [ 945950-37-8 ]

[ 945950-37-8 ] Synthesis Path-Downstream 1~35

1
4-chloro-1H-pyrrolo[2,3-d]pyrimidine [ No CAS ]
iron(III) acetylacetonate [ No CAS ]
[ 945950-37-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With magnesium chloride; In tetrahydrofuran; at 20℃; for 8h;	Example 31; [(1S,2S,4R)-2-Hydroxy-4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl]methyl sulfamate (Compound I-46); Step a: 4-Methyl-7H-pyrrolo[2,3-d]pyrimidine; A 3.00 M solution of magnesium chloride in THF (13.0 mL, 39.0 mmol) was added dropwise to a stirred solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.50 g, 16.3 mmol) and ferric acetylacetonate (700. mg 1.98 mmol) in THF (30.0 mL) under an atmosphere of argon. The resulting reaction mixture was stirred at rt for 8 h. The mixture was poured onto a mixture of ice (100 mL) and ammonium chloride (1.00 g) and the mixture was extracted with chloroform. Volatiles were removed in vacuo, and C-18 column chromatography eluting with a gradient of 0 to 60% AcCN in water with 0.1% AA afforded the title compound (1.50 g, 69%). LC/MS: Rt=0.94 min, ES+ 134 (AA standard).

References: [1]Patent: US2007/191293,2007,A1 .Location in patent: Page/Page column 62.

2
[ 918523-58-7 ]
[ 945950-37-8 ]
[ 1195071-58-9 ]

Yield	Reaction Conditions	Operation in experiment
		To <strong>[945950-37-8]4-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (42, 0.192 g, 1.44 mmol), propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (9, 0.456 g, 1.73 mmol), potassium hydroxide (0.263 g, 4.69 mmol) and 1.0 mL of methanol were added to provide a solution. The reaction was allowed to stir at room temperature for 30 hours, then quenched with water and adjusted to pH~5 with acetic acid and sodium bicarbonate and extracted with ethyl acetate and saturated sodium chloride. The organic layer was washed with water and brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluding with ethyl acetate and hexane with 4% acetic acid. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as an off-white solid (P-0055, 215 mg). 1H-NMR(dmso-d6) showed it contains about >80% of the desired compound, used in the next step without further purification. MS(ESI) [M+H-]+=397.1.

References: [1]Patent: US2009/286783,2009,A1 .Location in patent: Page/Page column 64.

3
[ 75-16-1 ]
[ 3680-69-1 ]
[ 945950-37-8 ]

Yield	Reaction Conditions	Operation in experiment
84.2%		Step 1: 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 150 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5.72 g of Pd(bppf)Cl2 were added to 1.5 L of tetrahydrofuran, stirred at room temperature for 0.5 hour, and then cooled down to below 0 C. To the resulting mixture was slowly added dropwise 850 mL of methylmagnesium bromide (3M dissolved in ether). After the addition was completed, the temperature was raised to 6065 C., and the resulting mixture reacted under reflux for 2 hours. Then, the temperature was lowered to below 0 C., and the reaction was quenched by slowly adding dropwise concentrated hydrochloric acid. After the addition was completed, 650 mL of purified water was added to the resulting mixture and stirred for 15 minutes, the phases were separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with NaHCO3 and then suction-filtered, the filter cake was washed with 455 mL of purified water, and the filtrate was collected and extracted three times with 1.05 L of ethyl acetate, and then the organic phase was concentrated to obtain 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (109.5 g, 84.2%). 1H-NMR (500 MHz, DMSO-d6): delta=12.00 (bs, 1H), 8.61 (s, 1H), 7.47 (d, J=3.6 Hz, 1H), 6.62 (d, J=3.5 Hz, 1H), 2.64 (d, J=1.6 Hz, 3H); MS (ES): 134.07 (M+H+).
	(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In diethyl ether; toluene; at 20 - 60℃;Inert atmosphere;	Into a round bottom flask the catalyst PdCl2(dppf), under an atmosphere of nitrogen, was placed with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene was added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) was added dropwise. The solution turned from orange to yellow, and was slowly heated to 60 C. and stirred for 3 hrs at 60 C. and then overnight at room temperature. The resulting dark orange reaction mixture was quenched with 1 N hydrochloric acid and adjusted to pH~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluding with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (42, 202 mg). 1H-NMR(dmso-d6) was consistent with the desired compound. MS(ESI) [M+H+]+=134.3.
		Step 1a-Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (15)To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (9, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) is added under an atmosphere of nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) is added slowly. The reaction is heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid is added and the pH is adjusted to 7-8 with the addition of saturated sodium bicarbonate. This is extracted 3× with ethyl acetate. The combined organic layer is washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a tan solid (15). MS (ESI) [M+H+]+=134. This is reacted similarly to steps 2 and 3 of Scheme 4 to provide the desired compound 16.

		Step 1 - Preparation of 4-methyl-7H-pyrrolo[2,3-d]pyrimidine (7):[0215] Into a round bottom flask the catalyst [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1 : 1 complex with dichloromethane (70.0 mg, 0.09 mmol), is placed under nitrogen with 15 mL of toluene along with a stir bar. A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 1.47 g, 9.57 mmol) in 15 mL of toluene is added at room temperature. After stirring for 10 minutes, methylmagnesium bromide (17.00 mL, 3.00 M in ether, 51.00 mmol) is added dropwise. The solution is slowly heated to 60 C and stirred for 3 hrs at 60 C, then overnight at room temperature. The resulting dark orange reaction mixture is quenched with 1 N hydrochloric acid and adjusted to pH ~5, then extracted with ethyl acetate and water saturated with sodium chloride. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound as a yellow solid (8, 202 mg). 1H-NMR(dmso-d6) is consistent with the desired compound. MS(ESI)[M+H+]+ = 134.3.
		To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (17, 5.03 g, 32.8 mmol) in 100 mL of toluene, [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane (0.627 g, 0.328 mmol) was added under nitrogen. After stirring for 10 minutes, methylmagnesium bromide (62.9 mL, 3.00 M in ether, 189 mmol) was added slowly. The reaction was heated at 55 C. overnight, then cooled to -70 to -80 C. and quenched by adding ammonium chloride dropwise. Then 1N hydrochloric acid was added and the pH was adjusted to 7-8 with addition of saturated sodium bicarbonate. This was extracted 3× with ethyl acetate. The combined organic layer was washed with saturated ammonium chloride and brine, then dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and dichloromethane, then methanol and dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a tan solid (18). MS (ESI) [M+H?]?=134.

References: [1]Patent: US2019/23712,2019,A1 .Location in patent: Paragraph 0241-0243.
[2]Journal of Organic Chemistry,2019.
[3]Patent: US2009/286783,2009,A1 .Location in patent: Page/Page column 64.
[4]Patent: US2011/263595,2011,A1 .Location in patent: Page/Page column 80.
[5]Patent: WO2011/63159,2011,A1 .Location in patent: Page/Page column 182.
[6]Patent: US9096593,2015,B2 .Location in patent: Page/Page column 93.

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[ 945950-37-8 ]
[ 1415220-34-6 ]