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Chemical Structure| 18740-39-1 Chemical Structure| 18740-39-1
Chemical Structure| 18740-39-1

2,4-Dichlorothieno[2,3-d]pyrimidine

CAS No.: 18740-39-1

4.5 *For Research Use Only !

Cat. No.: A319798 Purity: 98%

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Product Details of [ 18740-39-1 ]

CAS No. :18740-39-1
Formula : C6H2Cl2N2S
M.W : 205.06
SMILES Code : ClC1=NC2=C(C(=N1)Cl)C=CS2
MDL No. :MFCD09743991
InChI Key :HRXNGIQKOWQHCX-UHFFFAOYSA-N
Pubchem ID :12217324

Safety of [ 18740-39-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H317-H319
Precautionary Statements:P280-P305+P351+P338

Calculated chemistry of [ 18740-39-1 ] 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 0.0
Molar Refractivity 47.44
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

54.02 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.22
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.48
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.0
Log Po/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.

1.85
Log Po/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

3.97
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.9

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.91
Solubility 0.0253 mg/ml ; 0.000123 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.

-4.3
Solubility 0.0104 mg/ml ; 0.0000505 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

-3.83
Solubility 0.03 mg/ml ; 0.000146 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.

-5.08 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)

2.37

Application In Synthesis of [ 18740-39-1 ]

* 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 [ 18740-39-1 ]

[ 18740-39-1 ] Synthesis Path-Downstream   1~29

  • 1
  • [ 18740-39-1 ]
  • [ 124-41-4 ]
  • [ 18740-40-4 ]
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  • [ 139-02-6 ]
  • [ 56844-19-0 ]
  • 4
  • [ 18740-39-1 ]
  • [ 18740-44-8 ]
  • 5
  • [ 18740-39-1 ]
  • 4-chloro-thieno[2,3-<i>d</i>]pyrimidin-2-ylamine [ No CAS ]
  • 7
  • [ 18740-39-1 ]
  • [ 56844-22-5 ]
YieldReaction ConditionsOperation in experiment
63% With ammonium hydroxide; In ethanol; at 20℃; for 48h; <strong>[18740-39-1]2,4-dichlorothieno[2,3-d]pyrimidine</strong> (51 g, 250 mmol),28percent aqueous ammonia (94g, 750mmol a flask containing 500mL of ethanol,The reaction was stirred for 48 hours with stirring at room temperature.TLC monitors the reaction endpoint.The precipitated solid was filtered, and the ethanol was rinsed.Drying gave Compound 22-1 (29 g, yield 63percent).
  • 8
  • [ 18740-38-0 ]
  • [ 18740-39-1 ]
YieldReaction ConditionsOperation in experiment
56% With trichlorophosphate; In N,N-dimethyl-formamide; at 115℃; for 8h; Thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (12) (2.5 g, 0.012 mol) and a drop of DMF were added to 20 mL POCl3. Heated to 115 C for 8 h. After cooling to room temperature, the reactant was added to 500 g ice-water mixture slowly. The product was filtered off and dissolved in CH2Cl2. The insoluble was filtered off and the filtrate was distilled under reduced pressure to afford 1.7g 2,4-dichlorothieno[2,3-d]pyrimidine (13). Yield: 56.0 %, 1H NMR (400 MHz, DMSO) delta 8.16 (d, J=3.4 Hz, 1H, Ar-H), 7.62 (d, J=3.4 Hz, 1H, Ar-H). ESI-MS m/z: 205.1.
56% With N,N-dimethyl-formamide; trichlorophosphate; at 115℃; for 5h; To 1 g of dry thieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione was added 10 g of phosphorus oxychloride,Add 1 drop of DMF catalyst, heating to 115 , the reaction 5h, the reaction is completed, the reaction slowly added to the crushed ice,While stirring vigorously,A brown solid,Filter, filter residue dissolved in 50mL of dichloromethane, to the solution by adding 1g activated carbon and 2g silica gel,Heated to 45 reflux decolorization 1h, while the hot filter, remove the solvent,Pale yellow solid,2,4-dichlorothieno [2,3-d] pyrimidine in a yield of 56.0%.
56% With N,N-dimethyl-aniline; trichlorophosphate; In acetonitrile; at 0 - 85℃; for 24h; Thieno[2,3-d] pyrimidine-2,4 (1H, 3H) -dione (IX-2) (5.0 g, 29.7 mmol)And 3 mL of N, N-dimethylaniline were dissolved in 30 mL of acetonitrile,It was cooled to 0 C.16 mL of phosphorus oxychloride is kept at the reaction temperature not higher than 25 C.I am dripping slowly. The reaction mixture was heated and stirred at 80-85 C. for 24 hours.The reaction solution was cooled to 15 C.,Was slowly added to 70 mL of ice water.The obtained slurry was collected by filtration,And washed with cold water (20 mL).After drying, column chromatography (elution solvent: hexane: dichloroMethane = 1: 2)3.41 g (yield 56%) of the dichloro compound (IIa-2) was obtained as gray crystals.
49% 3 g (0.018 mol) of the intermediate lib was placed in a 100 mL three-necked flask,30 mL (0.329 mol) of phosphorus oxychloride was slowly added dropwise,After 30 min addition, 2 drops of DMF were added to the reaction mixture and the reaction was heated to reflux for 8 h. The reaction was poured into 1000 g of ice water with stirring, and a large amount of orange-colored solid was precipitated. The filter cake was washed with a large amount of water and dried at 45 C for 24 hours to obtain 1.8 g of an orange solid in a yield of 49%.
41% With trichlorophosphate; at 106℃; for 3h;Inert atmosphere; Under a nitrogen streamThieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione (8.4 g, 50.0 mmol) and phosphoryl chlorideL), which was stirred for 3 hours at 106 C. After completion of the reaction, the organic layer was separated using ethyl acetateWater was removed using MgSO4. The solvent of the organic layer was removed, and the residue was purified by column chromatography to obtain the target compound2,4-dichlorothieno [2,3-d] pyrimidine (4.2 g, 20.5 mmol, yield 41%).
40% With trichlorophosphate; at 116℃; for 3h; A mixture of thieno[2,3-phiyrimidine-2,4(l//,3//)-dione (100 mg, 0.59 mmol) and phosphonyl chloride (2 mL, 21.5 mmol) was heated at 1 16 0C for 3 h. Upon completion of the reaction, the reaction mixture was poured into ice and extract with ethyl acetate 3 times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by column chromatography, eluting with Hexanes/Ethyl Acetate (9: 1) afforded the product as a white solid (48.1 mg, 40%): 1H NMR (DMSO, 300 MHz) delta 7.6 (d, J = 6.3 Hz, IH), 8.13(d, J = 5.7 Hz, IH).
35.5% With N,N-dimethyl-aniline; trichlorophosphate; for 16h;Reflux; A total of 0.8 mL N,N-dimethylaniline was added to 3.0 g of thieno[2,3-d]pyrimidine-2,4-(1H,3H)-dione 6a in 20 mL POCl3. The mixture was then heated under reflux for 16 h. Excess POCl3 was removed in vacuo, and the resulting residue was treated with ice water to yield a precipitate. The solid was collected by filtration, washed with water and dried over a funnel to afford solid 7a (1.3 g, yield 35.5%). 1H NMR (400 MHz, CDCl3): delta 7.62 (d, J = 6.4 Hz, 1H), 7.43 (d, J = 6.4 Hz, 1H).
With trichlorophosphate; at 200℃; for 2.3h; EXAMPLE 402,4-Dichlorothieno[2,3-d]pyrimidine; The dione of Example 39 (2.6 g) was placed into a pressure vessel with phosphorus oxychloride (15 mL). The mixture was heated at 200 0C for 2.3 hours and then cooled to room temperature and concentrated under reduced pressure. Residual phosphorus oxychloride was azeotroped . twice with toluene (30 mL) under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The resulting layers were separated and the organic layer was filtered through anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 1.06 g of the title compound: MS (ESI+) for C6H2N2CI2S m/z205.0 (M+H)+. 1H NMR (400 MHz, CDCI3) delta 7.42 (d,1 H), 7.61 (d,1 H).
With N,N-dimethyl-aniline; trichlorophosphate; In toluene; at 100℃; for 3h; To a solution of 1H-thieno[2,3-d]pyrimidine-2,4-dione (62) (92.8 mg, 0.552 mmol) in toluene (1 mL) were added N,N-dimethylaniline (0.140 mL, 1.10 mmol) and phosphoryl chloride (0.280 mL, 3.00 mmol). The reaction mixture was warmed to 100 C and stirred for 3 h. After cooling to room temperature, H2O was added to the reaction mixture and the mixture was extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2,4-dichlorothieno[2,3-d]pyrimidine (63). This compound was used for the next reaction without further purification.To a solution of 63 in DMF (4 mL) was added ethyl 2-(4-aminophenyl)acetate (95.2 mg, 0.531 mmol) and the reaction mixture was stirred at 65 C for 2.5 h. After cooling, H2O was added to the reaction mixture and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed (EtOAc/hexane = 0% to 100%) to give the title compound (85.9 mg, 0.247 mmol, 45%) as a colorless solid. 1H NMR (CDCl 3) delta: 1.28 (3H, t, J = 7.4 Hz), 3.64 (2H, s), 4.18 (2H, q, J = 7.4 Hz), 7.03 (1H, d, J = 5.7 Hz), 7.21 (1H, s), 7.29 (1H, d, J = 5.7 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.6 Hz).

  • 9
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  • [ 18740-39-1 ]
  • 10
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  • [ 109-89-7 ]
  • [ 56844-23-6 ]
  • 11
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  • [ 62-53-3 ]
  • [ 56844-26-9 ]
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  • [ 76872-43-0 ]
  • 13
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  • [ 62-53-3 ]
  • [ 134372-89-7 ]
  • 14
  • [ 18740-39-1 ]
  • [ 95-53-4 ]
  • [ 1027594-22-4 ]
  • 15
  • [ 18740-39-1 ]
  • [ 100-61-8 ]
  • [ 134372-88-6 ]
YieldReaction ConditionsOperation in experiment
With trichlorophosphate; In N,N-dimethyl-aniline; for 3h; General procedure: 2,4-Dihydroxythieno[3,2-d]pyrimidine (M1) (3.38 g, 0.020 mol) was added to the reaction flask.Phosphorus oxychloride (11.6 ml, 0.127 mol) was added.N,N-dimethylaniline (7.44 ml, 0.058 mol) was added dropwise with stirring at room temperature for 3 hours under reflux.Stop heating,Pour into 100ml of ice water.Precipitating a brownish black solid,Filtering,dry,Column chromatography (petroleum ether - ethyl acetate = 3: 1) to give a pale yellow solid 2.10g,The yield was 51.2percent.
  • 18
  • [ 18740-39-1 ]
  • 4-(N-methylphenylamino)-2-<(2-methylphenyl)amino>thieno<2,3-d>pyrimidine [ No CAS ]
  • 19
  • [ 18740-39-1 ]
  • N2,N4-Dimethyl-N2,N4-diphenyl-thieno[2,3-d]pyrimidine-2,4-diamine [ No CAS ]
  • 20
  • [ 18740-39-1 ]
  • 2-(2-Methylphenylamino)-4-(phenylamino)thieno[2,3-d]-pyrimidine hydrochloride [ No CAS ]
  • 21
  • [ 18740-39-1 ]
  • 2-(4-Fluoro-2-methylphenylamino)-4-(N-methylphenylamino)thieno-[2,3-d]pyrimidine hydrochloride [ No CAS ]
  • 22
  • [ 18740-39-1 ]
  • [ 79041-55-7 ]
  • 23
  • [ 18740-39-1 ]
  • 1,5-Dihydro-imidazo[1,2-a]thieno[2,3-d]pyrimidin-2-one [ No CAS ]
  • 24
  • [ 18740-39-1 ]
  • [ 14080-56-9 ]
  • 25
  • [ 18740-39-1 ]
  • [ 56844-24-7 ]
  • 27
  • [ 18740-39-1 ]
  • [ 902765-99-5 ]
  • [ 902765-98-4 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; EXAMPLE 41 4-[4-(1 ,1 '-biphenyl-4-ylcarbonyl) piperazin-1 -yl]-2-chlorothieno[2,3d]pyrimidine; To a mixture of <strong>[18740-39-1]2,4-dichlorothieno[2,3-d]pyrimidine</strong> (Example 40, 0.4 g) in THF/DMF (20/8 mL) was added diisopropylethylamine (0.44mL) and (1,1'-biphenyl-4-yl)piperazine trifluoroacetate (0.780 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. EPO <DP n="95"/>"The resulting crude mixture was stirred in hot MeOH to remove impurities and the remaining solid was collected and dried to give 0.34 g of the title compound: MS (ESI+) for C23H19CIN4O1S1 m/z 435.25 (M+H)+.1H NMR (400 MHz, CDCI3). delta 3.6 to 4.2 (m, 8H) 7.3 to 7.67 (m.11 H). To a mixture of the pyrimidine of Example 40 (0.4 g) in THF/DMF (20/8 ml_) was added diisopropylethylamine (0.44 ml_) and the TFA salt of Example 15 (0.780 g). The mixture was stirred overnight at room temperature. The mixture was then partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed four times with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting crude mixture was stirred in hot methanol to remove impurities and the remaining solid was collected and dried to give 0.34 g of the title compound: MS (ESI+) for C23H19CIN4OS m/z 435.25 (M+H)+. 1H NMR (400 MHz, CDCI3). delta 3.6-4.2 (m, 8H) 7.3-7.67 (m, 11H).
  • 28
  • [ 18740-39-1 ]
  • [ 100-61-8 ]
  • 2,4-Bis(N-methylphenylamino)thieno(2,3-d)pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; chloroform; EXAMPLE 8 2,4-Bis(N-methylphenylamino)thieno(2,3-d)pyrimidine 2,4-Dichlorothieno[2,3-d]pyrimidine (2 g, 0.00975 mol) and N-methylaniline (5 ml) were heated in an oil bath at 150° for 2 hours. The reaction mixture was dissolved in chloroform (200 ml) and extracted with 2N hydrochloric acid (3*100 ml). The chloroform solution was then washed with sodium carbonate solution, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by chromatography using dichloromethane as eluant. The solid obtained was recrystallized from ether/petroleum ether (b.p. 40°-60°) to give the title compound, (1.2 g) m.p. 85°-87°.
In dichloromethane; chloroform; Example 8 2,4-Bis(N-methylphenylamino)thieno(2,3-d)pyrimidine 2,4-Dichlorothieno[2,3-d]pyrimidine (2 g, 0.00975 mol) and N-methylaniline (5 ml) were heated in an oil bath at 150° for 2 hours. The reaction mixture was dissolved in chloroform (200 ml) and extracted with 2N hydrochloric acid (3x100 ml). The chloroform solution was then washed with sodium carbonate solution, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by chromatography using dichloromethane as eluant. The solid obtained was recrystallized from ether/petroleum ether (b.p. 40-60°) to give the title compound, (1.2 g) m.p. 85-87°.
  • 29
  • [ 18740-39-1 ]
  • [ 142-04-1 ]
  • [ 134372-89-7 ]
YieldReaction ConditionsOperation in experiment
With aniline; In diethyl ether; ethanol; (b) 2-Chloro-4-(phenylamino)thieno[2,3-d]pyrimidine 2,4-Dichlorothieno[2,3-d]pyrimidine (3.2 g, 0.0156 mol) and aniline (2.9 g, 0.0311 mol) in ethanol were stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was treated with diethyl ether to give a solid, aniline hydrochloride. The filtrate was evaporated under reduced pressure to give the product as a solid, (3.74 g). Recrystallization (0.7 g) from methanol gave a pure sample of the title compound, (0.53 g), m.p. 149°-151°.
With aniline; In diethyl ether; ethanol; (b) 2-Chloro-4-(phenylamino)thieno[2,3-d]pyrimidine 2,4-Dichlorothieno[2,3-d]pyrimidine (3.2 g, 0.0156 mol) and aniline (2.9 g, 0.0311 mol) in ethanol were stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was treated with diethyl ether to give a solid, aniline hydrochloride. The filtrate was evaporated under reduced pressure to give the product as a solid, (3.74 g). Recrystallization (0.7 g) from methanol gave a pure sample of the title compound, (0.53 g), m.p. 149-151°.
 

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Technical Information

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