56844-40-7|6-Bromothieno[2,3-d]pyrimidin-4(3H)-one| Ambeed

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Quality Control of [ 56844-40-7 ] Purity: 95% SDS Specification

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Product Details of [ 56844-40-7 ]

CAS No. :	56844-40-7
Formula :	C₆H₃BrN₂OS
M.W :	231.07
SMILES Code :	O=C1C(C=C(Br)S2)=C2NC=N1
MDL No. :	MFCD09746332
InChI Key :	WIURMUHBQYODCB-UHFFFAOYSA-N
Pubchem ID :	12217338

Safety of [ 56844-40-7 ]

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

Computational Chemistry of [ 56844-40-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	47.94
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	73.99 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.21
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	1.74
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.75
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.	1.27
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	3.51
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.9

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.97
Solubility	0.245 mg/ml ; 0.00106 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	0.284 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	-3.36
Solubility	0.0999 mg/ml ; 0.000433 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.	-6.47 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)	2.35

Application In Synthesis of [ 56844-40-7 ]

* 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 [ 56844-40-7 ]

[ 56844-40-7 ] Synthesis Path-Downstream 1~35

1
[ 14080-50-3 ]
[ 56844-40-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With bromine; acetic acid; at 80℃; for 1.0h;	6-Bromothieno[2,3-d]pyrimidin-4(3H)-one (3). Thieno[2,3-d]pyrimidin-4(3H)-one (2) (50.03 g, 329 mmol) was mixed with cone, acetic acid (600 mL), and bromine (30.0 mL, 93.0 g, 582 mmol) was added slowly before the mixture was heated at 80 C for 1 h. The reaction mixture was then cooled to rt. and filtered. The filtrate was washed with water and saturated aq NaHC03 solution. Drying gave 72.24 g (313 mmol, 95%) of 3 as a light brown solid, mp. 299 - 301 C (dec); 1H NMR (400 MHz, DMSO-d6) delta: 12.63 (s br, 1H), 8.14 (s, 1H), 7.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6) delta: 165.0, 156.0, 146.5, 125.6, 124.6, 110.3; IR (neat, cm 1): 3074, 1663, 1649, 1504, 755; HRMS (EI, 70 eV, m/z): 229.9146 (calcd C6H3Br79N2OS, 229.9144, M+).
92%	With bromine; acetic acid; at 20℃; for 4.0h;	[0119] To thieno[2,3-d]pyrimidin-4(3H)-one (5 g, 32.9 mmol, 1.0 equiv) in 50 mL acetic acid was added bromine (5 mL, 2.95 equiv, 97 mmol). The mixture stirred at r.t. for 4 h. The resulting solid was collected by filtration, washed with water, and dried in vacuo to give 6- bromothieno[2,3-d]pyrimidin-4(3H)-one (7.02 g, 92 % yield) as a tan solid. ]H NMR (400 MHz, DMSO- 6) delta ppm 12.61 (br. s., 1 H), 8.1 1 (d, J=3.52 Hz, 1 H), 7.47 - 7.56 (m, 1 H).
90%	With bromine; at 20℃; for 4.0h;	To the suspension of 5 (1g, 6.572 mmol) in acetic acid was added Br2 (1 mL, 19.517 mmol) at RT. After stirring for 4 h, the precipitate was filtered. The filter cake was neutralized by saturated NaHCO3 and washed with water repeatedly to afford 6 in 90% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO) delta 12.64 (s, 1H), 8.15 (d, J = 2.5 Hz, 1H), 7.56 (s, 1H).

87%	With bromine; acetic acid; at 80℃; for 3.0h;	Thieno[2,3-d]pyrimidin-4(3H)-one (2) (25.1 g, 165 mmol) was mixed with concd acetic acid (425 mL), and bromine (17.0 mL, 52.8 g, 330 mmol) was added slowly before the mixture was heated at 80 C for 3 h. The reaction mixture was then cooled to rt and filtered to remove insoluble components. The liquid fraction was diluted with ice and neutralised using a saturated aq NaHCO3 solution. The precipitated material was isolated by filtration and washed with water (6×100 mL). Drying gave 33.1 g (143 mmol, 87%) of 3 as a light brown solid, mp. 283-290 C (dec), (lit.40 301-304 C). A fraction of this material was purified before it was used in Suzuki coupling. The dry material was applied to the top of a packed silica gel plug and eluted with CH2Cl2, mp. 298-301 C; 1H NMR (400 MHz, DMSO-d6) delta: 12.63 (s br, 1H), 8.14 (s, 1H), 7.55 (s, 1H); 13C NMR (100 MHz, DMSO-d6) delta: 165.0, 156.0, 146.5, 125.6, 124.6, 110.3; IR (neat, cm-1): 3074, 1663, 1649, 1504, 755; HRMS (EI, 70 eV, m/z): 229.9146 (calcd C6H3Br79N2OS, 229.9144, M+). The 1H NMR spectrum corresponds with Ref. 41. 13C NMR spectroscopy data has not previously been reported.
56%	With bromine; potassium acetate; In acetic acid; at 0 - 20℃; for 24.0h;	[00113] To a stirred solution of thieno[2,3-d]pyrimidin-4(3H)-one (4.0 g, 12.33 mmol) and potassium acetate (17.25 g, 210.32 mmol) in acetic acid (100 mL) was added slowly bromine (2.7 mL, 52.57 mmol) at 0 C. The reaction mixture was stirred at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated, the residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 x 1000 mL).The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound 6-bromothieno[2,3-d]pyrimidin-4(3H)-one (3.4 g crude, 56% yield) as brown solid. [00114] Calculated (M+H): 230.91; Found (M+H): 231.0.
	With bromine; acetic acid; at 20℃; for 4.0h;	A suspension of 3flr-thieno[2,3-<fjpyrimidin-4-one (7.68g, 0.056mol) in glacial acetic acid (75ml) was treated with bromine (7.5ml) and stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, washed with water and dried in vacua to give 6-bTOmo-3No.-thieno[2,3-d]pyrimidin-4~one as a light brown solid (11.64g), which was used without further purification.
	With bromine; In dichloromethane; acetic acid;	EXAMPLE 15 6-Bromo-3,4-dihydrothieno[2,3-d]pyrimidin-4-one (Compound 6g) The product from Example 14 (0.75 g) was added to glacial acetic acid (10 ml) and heated with stirring until it dissolved. Bromine (0.75 ml) was then added and the mixture immediately set solid. More acetic acid was added and the mixture broken up. It was then heated at 80 C. for 61/2 hours, cooled and poured into ice-water. The solid was filtered and washed with water followed by dichloromethane and dried to give the title product, m.p. 304 C.
	With bromine; acetic acid; at 20℃; for 16.0h;	The mixture of 60.1 g 3H-thieno[2,3-djpyrimidin-4-one (0.395 mol), 605 mL acetic acidand 24 mL bromine (0.468 mol) was stirred at room temperature for 16 hours. The reactionmixture was monitored by LCMS. Further bromine was added in three portions (12 mE, 5 mE, 10 mE) until the conversion exceeded 95%. The precipitate was filtered off, washed with acetic acid (3x50 mE), diethyl ether (3x100 mL) and then air dried to give the product as a tan powder.
4.76 g	With bromine; acetic acid; at 80℃; for 5.0h;Inert atmosphere;	Under argon atmosphere, 2.50 mL of bromine was slowly added to 3.66 g of acetic acid solution (62.0 mL) of thieno [2,3-d] pyrimidin-4 (3H) -one with stirring and stirred at 80 C. for 5 hours, The temperature was returned to room temperature. The precipitated solid was separated by filter paper filtration, washed with acetic acid and water in this order, neutralized with saturated aqueous layer water, and then washed with water. After drying under reduced pressure, 4.76 g of the title compound was obtained as a brown solid.

References: [1]Patent: WO2015/959,2015,A1 .Location in patent: Page/Page column 48.
[2]Patent: WO2012/44993,2012,A1 .Location in patent: Page/Page column 44.
[3]Bioorganic and Medicinal Chemistry Letters,2020,vol. 30.
[4]Chemical Communications,2017,vol. 53,p. 4473 - 4476.
[5]Tetrahedron,2012,vol. 68,p. 9226 - 9233.
[6]MedChemComm,2015,vol. 6,p. 339 - 346.
[7]Journal of Medicinal Chemistry,2015,vol. 58,p. 5522 - 5537.
[8]Journal of Medicinal Chemistry,2014,vol. 57,p. 5764 - 5776.
[9]Patent: WO2017/100599,2017,A1 .Location in patent: Paragraph 00113-00114.
[10]Bulletin de la Societe Chimique de France,1975,p. 587 - 591.
[11]Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques,1968,vol. 267,p. 697 - 700.
[12]Patent: WO2004/111057,2004,A1 .Location in patent: Page 57.
[13]Patent: US6432964,2002,B1 .
[14]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 37.
[15]Journal of Medicinal Chemistry,2017,vol. 60,p. 2119 - 2134.
[16]Patent: JP2018/154587,2018,A .Location in patent: Paragraph 0080.

2
[ 56844-40-7 ]
[ 56844-12-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With trichlorophosphate; at 120℃; for 3.0h;	Compound 3 (32.7 g, 142 mmol) was mixed with POCl3 (100 mL) and heated at 120 C for 3 h. Then the mixture was quenched into 5 M aq NaOH (1 L) and ice. The pH was adjusted to 7 using a saturated aq NaHCO3 solution. The formed precipitate was isolated by filtration and washed with water (3×200 mL). Drying gave 31.0 g (124 mmol, 88%) of 4 as a brown solid, mp. 112-118 C. A fraction of this material was further purified: the dry material was applied to the top of a packed silica gel plug and eluted with CH2Cl2, mp. 114-118 C; Rf (CH2Cl2/MeOH, 98/2)=0.67; 1H NMR (400 MHz, DMSO-d6) delta: 8.95 (s, 1H), 7.89 (s, 1H); 13C NMR (100 MHz, DMSO-d6) delta: 168.9, 153.2, 152.5, 130.2, 122.9, 118.5; IR (neat, cm-1): 3082, 1508, 1411, 959, 832, 816, 760; HRMS (EI, 70 eV, m/z): 247.8813 (calcd C6H2Br79Cl35N2S, 247.8811, M+). The 1H NMR spectrum corresponds with Ref. 41. 13C NMR spectroscopic data and a reference melting point have not been identified.
72.7%	With trichlorophosphate; for 6.0h;Reflux;	[0121] 6-Bromothieno[2,3-d]pyrimidin-4(3H)-one (7.02 g, 30.4 mmol, 1.0 equiv) was taken up in 100 mL POCI3 and refluxed for 6 h. Upon completion, the reaction was concentrated in vacuo and the residue was taken up in 10 mL acetonitrile and heated to reflux for 10 min. The acetonitrile solution was then poured in a flask and cooled. The ppt was then filtered and washed with hexane to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine (5.51 g, 72.7 % yield) as a tan solid. NMR (400 MHz, CHLOROFORM-d) delta ppm 8.80 (s, 1 H), 7.47 (s, 1 H).
	With trichlorophosphate; for 6.0h;Heating / reflux;	6-Bromo-3No.-thieno[2,3-J]pyrirnidin-4-one (11.64g, 0.05mol) was added portion-wise to phosphoryl chloride (220ml) and the resulting mixture was heated under reflux for 6 hours. The excess phosphoryl chloride was then removed in vacua. The resulting residue was dissolved in dichloromethane (250ml) and washed with water (2xlOOml), followed by saturated sodium hydrogen carbonate solution (100ml). The organic layer was then dried (MgSCU) and the solvent was removed in vacuo to give 6-bromo-4-chlorothieno[2,3-d]pyrirnidine (9.06g) as a yellow solid, which was used without further purification.

With trichlorophosphate; at 120℃; for 2.5h;

6-Bromo-4-Chlorothieno[2,3-d]pyrimidine (4). Compound 3 (50.00 g, 216 mmol) was mixed with POCl3 (110 mL, 1180 mmol) and heated at 120 C for 2.5 h. Then the mixture was quenched into 5 M aq NaOH (900 mL) and ice. The formed precipitate was isolated by filtration and washed with water (3 x 200 mL). Drying gave 50.57 g (203 mmol, 94%) of 4 as a brown solid, mp. 113 - 114 C. A fraction of this material was further purified: the dry material was applied to the top of a packed silica gel plug and eluted with CH2C12, mp. 1 15 - 116 C; R/(CH2Cl2/MeOH, 98/2) = 0.67; 1H NMR (400 MHz, DMSO-d6) delta: 8.95 (s, 1H), 7.89 (s, 1H); 13C NMR (100 MHz, DMSC /6) delta: 168.9, 153.2, 152.5, 130.2, 122.9, 118.5; IR (neat, cm 1): 3082, 1508, 14011 , 959, 832, 816, 760; HRMS (EI, 70 eV, m z): 247.8813 (calcd C6H2Br79Cl35N2S, 247.881 1, M+).

References: [1]Chemical Communications,2017,vol. 53,p. 4473 - 4476.
[2]Tetrahedron,2012,vol. 68,p. 9226 - 9233.
[3]MedChemComm,2015,vol. 6,p. 339 - 346.
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 5522 - 5537.
[5]Patent: WO2012/44993,2012,A1 .Location in patent: Page/Page column 44-45.
[6]Journal of Medicinal Chemistry,2014,vol. 57,p. 5764 - 5776.
[7]Bulletin de la Societe Chimique de France,1975,p. 592 - 597.
[8]Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques,1968,vol. 267,p. 697 - 700.
[9]Patent: WO2004/111057,2004,A1 .Location in patent: Page 58.
[10]Patent: WO2015/959,2015,A1 .Location in patent: Page/Page column 48.
[11]Journal of Medicinal Chemistry,2017,vol. 60,p. 2119 - 2134.

3
[ 56844-40-7 ]
[ 56844-15-6 ]

References: [1]Bulletin de la Societe Chimique de France,1975,p. 592 - 597.
[2]Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques,1968,vol. 267,p. 697 - 700.

5
[ 4651-82-5 ]
[ 56844-40-7 ]

References: [1]Bulletin de la Societe Chimique de France,1975,p. 587 - 591.

6
[ 43028-71-3 ]
[ 56844-40-7 ]

References: [1]Bulletin de la Societe Chimique de France,1975,p. 587 - 591.

7
[ 56844-40-7 ]
[ 56844-31-6 ]

References: [1]Bulletin de la Societe Chimique de France,1975,p. 592 - 597.

8
[ 56844-40-7 ]
[ 56844-12-3 ]

Yield	Reaction Conditions	Operation in experiment
83%		Step B: Preparation of 6-bromo-4-chlorothieno[2,3-d]pyrimidine: To 6-bromothieno[2,3-d]pyrimidin-4-ol (3.0 g, 19.7 mmol) was added phosphorus oxychloride (5 mL). After heating to 80 C for 1.5 hours, the reaction mixture was poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product (4.06 g, 83%) as brown solid.

References: [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 434 - 438.
[2]Patent: EP2090575,2009,A1 .Location in patent: Page/Page column 60.

9
[ 56844-40-7 ]
[ 814918-95-1 ]

References: [1]Patent: WO2012/44993,2012,A1 .

10
[ 56844-40-7 ]
[ 885229-27-6 ]

References: [1]Patent: WO2012/44993,2012,A1 .

11
[ 56844-40-7 ]
[ 1370338-71-8 ]

References: [1]Patent: WO2012/44993,2012,A1 .

12
[ 56844-40-7 ]
[ 1370338-31-0 ]

References: [1]Patent: WO2012/44993,2012,A1 .

13
[ 56844-40-7 ]
[ 35970-79-7 ]