63894-67-7|4-(2-Chlorothieno[2,3-d]pyrimidin-4-yl)morpholine| Ambeed

CAS No. :	63894-67-7
Formula :	C₁₀H₁₀ClN₃OS
M.W :	255.72
SMILES Code :	ClC1=NC(N2CCOCC2)=C(C=CS3)C3=N1
MDL No. :	MFCD15144569
InChI Key :	YPVVQAPITTYKRL-UHFFFAOYSA-N
Pubchem ID :	13038189

Safety of [ 63894-67-7 ]

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

Computational Chemistry of [ 63894-67-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	9
Fraction Csp3	0.4
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	68.15
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	66.49 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.57
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	2.6
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.8
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.	1.03
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	3.19
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.41
Solubility	0.0986 mg/ml ; 0.000386 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.	-3.65
Solubility	0.0578 mg/ml ; 0.000226 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	-3.4
Solubility	0.101 mg/ml ; 0.000394 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	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.	-6.01 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<0.0
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)	2.56

Application In Synthesis of [ 63894-67-7 ]

* 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 [ 63894-67-7 ]

[ 63894-67-7 ] Synthesis Path-Downstream 1~54

2
[ 63894-67-7 ]
2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-sulfinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 32 2-(lH-indazol-4-yl)-4-mophiholino-6-(propylsulfonyl)thieno[2,3-d]pyrimidine 105[00357] 500 mg of 2-chloro-4-morpholinothieno[2.3-<5(lpyrimidine was cooled to -78C in 50 mL of THF before adding 1.3 eq of a 2.5M solution of nBuLi in hexanes. The <n="159"/>reaction was stirred at -78C for 30 minutes before warming to -40C for several minutes to allow for complete formation of the Lithium anion. The reaction was then re-cooled to -78C and sulfur dioxide gas was bubbled in via cannula to the reaction solution for 2 minutes. The reaction was cooled to 0C and quenched with water. The aqueous was extracted with ethyl acetate to remove any 2-cMoro-4-mophiholinothieno[2,3-^pyrirnidine. The aqueous layer was then lyophilized and purified via reverse phase HPLC to afford 180 mg of pure 2-chloro-4-mophiholinotWeno[2,3-d]pyrimidme-6-sulfinic acid.[00358] To 90 mg of 2-cMoro-4-morpholinothieno[23-^pyri?iidine-6-sulfmic acid in 1.5 mL of DMF was added 1.05 eq of NaH (60% oil dispersion). The reaction was stirred at room temperature for 30 minutes prior to addition of 1.05 eq of iodopropane, whereupon the temperature was raised to 500C and the reaction was complete in 30 minutes. The reaction was cooled to room temperature and then extracted into Ethyl Acetate with a saturated bicarbonate solution two times. The organic layer was dried with MgSO4, filtered and concentrated to dryness. The crude chloride was subjected to Procedure A to give 27.6 mg of 105. MS (Ql) 444.1 (M)+.

References: [1]Patent: WO2007/127183,2007,A1 .Location in patent: Page/Page column 157-158.

3
[ 110-91-8 ]
[ 18740-39-1 ]
[ 63894-67-7 ]

Yield	Reaction Conditions	Operation in experiment
88.4%		A 5 L reaction vial equipped with a mechanical stirrer, internal temperature probe, and a nitrogen bubbler was charged with 2,4-dichlorothieno[2,3-d]pyrimidine (91 g.) and methanol (1.5 L). Next, morpholine (85.1 g.) was added and the reaction mixture was stirred at ambient temperature for 1-2 hours. An aliquot was taken and diluted with DCM/ ACN and analyzed by LC/MS to confirm consumption of the starting material. The reaction flask was then charged with water (3.0 L) at a rate that maintains an internal temperature below 25 C. A solid was collected by vacuum filtration and rinsed with water (500 mL). The washed solid was dried in a vacuum oven at 66 C for 24 hours to afford 2- chloro-4-morpholinotMeno[2,3-<i]pyrimidme as an off white solid (100.3 g., 88.4%). This intermediate may also be prepared by General Procedure D-2. 1H NMR (400 MHz, DMSO- d6) delta 3.736 (t, J= 4.8 Hz, 4H), delta 3.897 (t, J= 5.2 Hz, 4H), delta 7.658 (d, J= 6.4Hz, IH), delta 7.682 (t, J= 6.4Hz, 4H). LCMS (ESI pos) m/e 257 (M+l).
86.1%	at 20℃; for 1.5h;	2,4-Dichlorothieno[2,3-d]pyrimidine (13, 2.8 g, 0.014 mol) was dissolved in 20 mL CH3OH. 2.8 mL morpholine was added slowly at room temperature. Stirred for 1.5 h. The product was filtered off and dry to afford 3.1 g 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine (14). Yield: 86.1%. 1H NMR (400 MHz, DMSO) delta 7.70 (s, 1H, Ar-H), 7.69-7.65 (m, 1H, Ar-H), 3.96-3.86 (m, 4H, OCH2), 3.75 (d, J=4.4 Hz, 4H, NCH2). ESI-MS [M+H] m/z: 256.1.
86.1%	In methanol; at 20℃; for 0.5h;Cooling with ice;	1 g of 2,4-dichlorothieno [2,3-d] pyrimidine was dissolved in 20 mL of methanol, 1 mL of morpholine was added dropwise to the ice bath,Gradually rose to room temperature, reaction 0.5h, precipitation of solid, filter,A white solid,4- (2-chlorothieno [2,3-d] pyrimidin-4-yl) morpholine in a yield of 86.1%.

80%	In methanol; at 20℃; for 1h;Cooling with ice;	A mixture of 1.07 g (0.005 mol) of intermediate IIlbWas placed in 20 mL of methanol,Ice bath1 mL of morpholine was slowly added dropwise,After completion of the dropwise addition,Room temperature reaction lh,After reaction, the reaction solution was added to 100mL of ice water. A large amount of yellow solid was precipitated. The filter cake was washed with 200mL water and dried at 50 C for 5 hours to obtain 1.02g of yellow solid. The yield was 80%.
	at 20℃; for 3h;	The title compound (3.82 g, 76%) was prepared by a known methods using 2,4-dichlorothieno[2,3- d]pyrimidine (4.00 g, 19.50 mmol) and morpholine( 3.75 mL, 42.91 mmol). 1H MR (DMSO- d6): d 3.72 (t, J=4.6 Hz, 4H), 3.88(t, J= 5.0 Hz, 4H), 7.60-7.70 (m, 2H).

References: [1]Patent: WO2008/73785,2008,A2 .Location in patent: Page/Page column 170.
[2]European Journal of Medicinal Chemistry,2015,vol. 93,p. 64 - 73.
[3]Patent: CN106831812,2017,A .Location in patent: Paragraph 0094; 0095; 0096.
[4]Journal of Medicinal Chemistry,2011,vol. 54,p. 7815 - 7833.
[5]Patent: CN103980287,2016,B .Location in patent: Paragraph 0148; 0153; 0154.
[6]Patent: WO2019/113523,2019,A1 .Location in patent: Paragraph 0217.
[7]Molecules,2019,vol. 24.

4
[ 68-12-2 ]
[ 63894-67-7 ]
[ 955978-98-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of 2-chloro-4-mophiholinothieno[2,3-<f]pyrirnidine (1.75g,6.85mmol) in dry THF (4OmL) at -780C was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3mL, 1.2eq.). After stirring for 1 h, dry DMF (796 muL, 1.5eq.) was added. The reaction mixture was stirred for 1 h at -78 0C and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 2-chloro-4-mophiholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.50 g) MS (Ql) 284 (M+).
1.5 g		To a suspension of <strong>[63894-67-7]2-chloro-4-morpholinothieno[2,3-d]pyrimidine</strong> 38 (1.75 g, 6.85 mmol) in dry THF (40 mL) at -78 C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 muL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at -78 C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate which was collected by filtration and air-dried to yield <strong>[63894-67-7]2-chloro-4-morpholinothieno[2,3-d]pyrimidine</strong>-6-carbaldehyde 33 (1.50 g)

References: [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7815 - 7833.
[2]Patent: WO2008/73785,2008,A2 .Location in patent: Page/Page column 150.
[3]Patent: JP5658565,2015,B2 .Location in patent: Paragraph 0338-0339.

5
[ 67-64-1 ]
[ 63894-67-7 ]
[ 956391-88-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[63894-67-7]2-chloro-4-morpholinothieno[2,3-d]pyrimidine</strong> (GeneralProcedure D-2, 1.0 eq) dissolved in THF (0.15M) at -78 C was added solution of n- butyllithium (1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at -78 C for 30 minutes. Acetone (4.0 eq) was added and reaction mixture was allowed to warm up to -40 C and stirred for 1 h. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol. MS(Ql) SH (M+).

References: [1]Patent: WO2008/73785,2008,A2 .Location in patent: Page/Page column 198.

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[ 402960-38-7 ]
[ 63894-67-7 ]
[ 1033737-58-4 ]