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Chemical Structure| 64837-49-6 Chemical Structure| 64837-49-6

Structure of 64837-49-6

Chemical Structure| 64837-49-6

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Product Details of [ 64837-49-6 ]

CAS No. :64837-49-6
Formula : C5H5ClN2O2S
M.W : 192.62
SMILES Code : ClC1=NN=C(S1)C(=O)OCC
MDL No. :MFCD11112114
InChI Key :YQWCUJDSRXQJRN-UHFFFAOYSA-N
Pubchem ID :12348753

Safety of [ 64837-49-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 64837-49-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 5
Fraction Csp3 0.4
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 41.01
TPSA ?

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

80.32 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.98
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

1.88
Log Po/w (WLOGP)?

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

1.37
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.

0.25
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

2.46
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.59

Water Solubility

Log S (ESOL):?

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

-2.36
Solubility 0.847 mg/ml ; 0.0044 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.

-3.19
Solubility 0.125 mg/ml ; 0.000647 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

-2.02
Solubility 1.83 mg/ml ; 0.00951 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

No
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.

-6.14 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)

2.89

Application In Synthesis of [ 64837-49-6 ]

* 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 [ 64837-49-6 ]

[ 64837-49-6 ] Synthesis Path-Downstream   1~15

  • 1
  • [ 623-73-4 ]
  • [ 463-71-8 ]
  • [ 6702-95-0 ]
  • [ 64837-49-6 ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; at 0 - 20℃; Ethyl diazoacetate (1, 10 g, 87.6 mmol) was taken up in acetonitrile (50 mL) and the resultant mixture cooled to 0 C. Thiophosgene (3.4 mL, 43.8 mmo.) was added to the mixture dropwise and the mixture was then stirred at room temperature for 20 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated from the reaction mixture under reduced pressure. The resultant crude product was purified by column chromatography using 10% EtOAc-hexane to afford ethyl 5-chloro-l ,3,4-thiadiazole-2-carboxylate (2, 3, 4 g, 25%). NMR (400 MHz, CDCI3): delta 4.57 (q, 2H), 1.42 (t, 3H).
  • 2
  • [ 623-73-4 ]
  • [ 463-71-8 ]
  • [ 64837-49-6 ]
  • 3
  • [ 64837-49-6 ]
  • [ 64837-52-1 ]
  • 4
  • C9H5ClNO(1-)*Na(1+) [ No CAS ]
  • [ 64837-49-6 ]
  • [ 664324-71-4 ]
YieldReaction ConditionsOperation in experiment
In DMF (N,N-dimethyl-formamide); at 70 - 80℃; for 18.0h; Synthesis of 5-(7-Chloro-quinolin-4-yloxy)-[1,3,4]thiadiazole-2-carboxylic Acid Ethyl Ester [CHEMMOL-00141] [0176] NaH (0.022 mg, 0.5 mmol) was added in portions to a solution of 7-chloro-4-hydroxyquinoline (0.093 mg, 0.5 mmol) in DMF (6 ml) at room temperature and the mixture stirred at room temperature for 20 min. 2-Chloro-[1,3,4]thiadiazole derivative (0.097 mg, 0.5 mmol) was then added in one portion and the mixture heated at 70-80 C. (oil bath temperature) for 18 h. The reaction mixture was allowed to cool to room temperature and water (15-30 ml) was added. The precipitate was separated by filtration, washed several times with cold water, then with Et2O and dried to afford the product (0.081 mg, 47% yield).
  • 5
  • C9H6ClN2(1-)*Na(1+) [ No CAS ]
  • [ 64837-49-6 ]
  • [ 664324-73-6 ]
YieldReaction ConditionsOperation in experiment
In DMF (N,N-dimethyl-formamide); at 80℃; for 18.0h; Synthesis of 5-Chloro-[1,3,4]thiadiazole-2-carboxylic Acid (7-chloro-quinolin-4-yl)-amide [CHEMMOL-00146] [0186] NaH (0.023 g, 0.58 mmol) was added in portions to a solution of 4-amino-7-chloro-quinoline (0.1 g, 0.56 mmol) in DMF (6 ml) at room temperature and the mixture was stirred for 20 min. 5-Chloro-[1,3,4]thiadiazole derivative (0.108 g, 0.56 mmol) was then added in one portion and the mixture heated at 80 C. (oil bath temperature) for 18 h. The reaction mixture was allowed to cool to room temperature and water (15 ml) was added. The precipitate was separated by filtration, washed with Et2O and dried to afford the product (0.08 g, 60% yield).
  • 6
  • [ 64837-49-6 ]
  • [ 912669-58-0 ]
YieldReaction ConditionsOperation in experiment
75% With sodium borohydrid; In methanol; Preparation 39 Synthesis of (5-chloro-1,3,4-thiadiazol-2-yl)methanol To a solution of <strong>[64837-49-6]ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate</strong> (0.51 g, 2.60 mmol) in anhydrous methanol (5.00 mL) was added sodium borohydride (0.30 g, 7.99 mmol) at 0 C. The reaction mixture was stirred at ambient temperature for 16 h, diluted with acetic acid (3.00 mL) and extracted with ethyl acetate (2*150 mL). The combined organics was washed with aqueous saturated sodium bicarbonate (3*25.0 mL) and aqueous saturated sodium chloride (2*25.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (0.30 g, 75%) as a light yellow semi-solid: 1H NMR (300 MHz, CDCl3) delta 5.04 (s, 2H), 2.80 (br, 1H); MS (ES+) 151.1 (M+1), 153.1 (M+1).
75% With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 16.0h; To a a solution of <strong>[64837-49-6]ethyl 5-chloro-1 ,3,4-thiadiazole-2-carboxylate</strong> (0.51 g, 2.60 mmol) in anhydrous methanol (5.00 mL) was added sodium borohydride (0.30 g, 7.99 mmol) at 0 0C. The reaction mixture was stirred at ambient temperature for 16 h, diluted with acetic acid (3.00 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organics was washed with aqueous saturated sodium bicarbonate (3 x 25.0 mL) and aqueous saturated sodium chloride (2 x 25.0 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (0.30 g, 75%) as a light yellow semi-solid: 1H NMR (300 MHz, CDCI3) delta 5.04 (s, 2H), 2.80 (br, 1 H); MS (ES+) 151.1 (M + 1), 153.1 (M + 1).
  • 7
  • [ 122833-04-9 ]
  • [ 64837-49-6 ]
  • [ 1313036-60-0 ]
YieldReaction ConditionsOperation in experiment
25% With toluene-4-sulfonic acid; In Isopropyl acetate; at 80℃; Ethyl 5-chloro-l ,3,4-thiadiazole-2 -carboxylate (3, 3 g, 15.7 mmol), 2-methoxy-4-(4-methyl piperazin-l -yl)aniline (4, 3.4 g, 15.7 mmol) and p-TSA (3 g, 15.7 mmol) were taken up in IPA (25 mL) and the resultant mixture was stirred at 80 C overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated from the reaction mixture under reduced pressure, and the resultant residue was basified using aq. NaHC03 solution and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resultant crude product was purified by columnchromatography using 5% MeOH-DCM to afford ethyl 5-((2-methoxy-4-(4-methylpiperazin-l - yl)phenyl)amino)-l ,3,4-thiadiazole-2-carboxylate (5, 1 .5 g, 25%). NMR (400 MHz, CDC13): delta 7.90 (bs, 1 H), 7.43 (d, 1 H), 6.59-6.55 (m, 2H), 4.50 (q, 2H), 3.90 (s, 3H), 3.25-3.22 (m, 4H), 2.65- l .60 (m, 4H), 2.40 (s, 3H), 1.42 (t, 3H).
  • 8
  • [ 109-01-3 ]
  • [ 64837-49-6 ]
  • [ 1542223-12-0 ]
YieldReaction ConditionsOperation in experiment
73% With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 3.0h; Step 1. General procedure for preparation of Intermediate 8. 8 A solution of ethyl 5-chloro-l,3,4-thiadiazole-2-carboxylate (60 g, 0.313 mol), K2CO3 (130 g, 0.94 mol) and methyl piperazine in DMF (300 mL) was stirred at 40 C for 3 h. TLC Rf 0.5 (petroleum ether/EtOAc, 10/1) showed the reaction was complete. The reaction mixture was poured into water and extracted with. CH2CI2. The organic layer was washed with water, dried over Na2S04, and concentrated to give Intermediate 8 (58.5 g, 73%) as a yellow solid. 1H NMR (400 MHz, CDCI3) delta 1.35-1.47 (m, 3H), 2.34 (s, 3H), 2.47-2.60 (m, 4H), 3.60-3.71 (m, 4H), 4.37-4.47 (m, 2H), 5.30 (s, 1H).
73% With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 3.0h; A solution of compound 7A (60 g, 0.313 mol), K2C03 (130 g, 0.94 mol), and methyl piperazine in DMF (300 mL) was stirred at 40 C for 3 h. The reaction mixture was poured into water and extracted with CH2C12. The organic layer was washed with water, dried over Na2S04, and concentrated to give compound 7B (58.5 g, 73%) as a yellow solid. 1H NMR (400 MHz, CDC13) delta 4.37-4.47 (m, 2H), 3.60-3.71 (m, 4H), 2.47-2.60 (m, 4H), 2.34 (s, 3H), 1.35- 1.47 (m, 3H).
  • 9
  • [ 7146-68-1 ]
  • [ 64837-49-6 ]
  • [ 1562692-97-0 ]
YieldReaction ConditionsOperation in experiment
44% With toluene-4-sulfonic acid; In ethanol;Reflux; [0192] Step 3. A mixture of Compound 6-D (4.1 g, 0.015 mol), Compound 6-E (2.33 g, 0.0 13 mol) and p-toluenesulfonic acid (2.85 g, 0.0 15 mol) in ethanol (70 mL) was refluxed overnight. Monitoring by thin layer chromatography (petrol ether: ethyl acetate=2: 1 and Rf at 0.5) showed the reaction was complete. The mixture was partitioned between saturated aqueous NaHCO3 (100 mL) and ethyl acetate (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried and concentrated. The residue was recrystallized with ethyl acetate to give Compound 6-F (2.8 g, 44%) as light brown solid.?H NMR (400 MHz, MeOH) oe 1.37-1.41 (m, 3H), 4.40-4.48 (m, 2H), 7.42-7.47 (m, 2H), 7.78-7.87 (m, 4H).
  • 10
  • [ 627-19-0 ]
  • [ 64837-49-6 ]
  • ethyl 5-pent-1-ynyl-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.95 g With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 20℃; for 7.5h;Inert atmosphere; Reference Production Example 2 (0648) 5-Chloro-1,3,4-thiadiazole-2-carboxylic acid ethyl ester (1.00 g, 5.19 mmol), 1-pentyne (530 mg, 7.79 mmol), triethylamine (2.9 mL, 20.8 mmol), copper iodide (20 mg, 0.10 mmol) and dichlorobis(triphenylphosphine)palladium (73 mg, 0.10 mmol) were added, and the mixture was stirred at room temperature for 7 hours and 30 minutes, under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with aqueous ammonia, 1.5% hydrochloric acid and saturated saline water, and then dried over anhydrous sodium sulfate. The residue was applied to a silica gel column chromatography to obtain 0.95 g of ethyl 5-pent-1-ynyl-1,3,4-thiadiazole-2-carboxylate represented by the following formula. 1H-NMR(CDCl3, TMS)delta(ppm) :1.07(t, 3H), 1.46(t, 3H), 1.70(m, 2H), 2.51(t, 2H), 4.52(q, 2H)
  • 11
  • 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine hydrochloride [ No CAS ]
  • [ 64837-49-6 ]
  • ethyl 5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; To a stirred solution of <strong>[64837-49-6]ethyl 5-chloro-1 ,3,4-thiadiazole-2-carboxylate</strong> (0.25 g, 1 .29mmol) in dry DMF (2.5 mL), K2C03 (0.54 g, 3.89 mmol) and Intermediate 30 (0.59 g,1 .93 mmol) were added at rt. The reaction mixture was stirred overnight at 80 C. It was then concentrated under vacuum. EtOAc (10 mL) was added and the resulting solution was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash chromatography to afford thetitle compound. Yield: 51% (0.26 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 67.15 (d, J= 7.60 Hz, IH), 6.75 (d, J= 7.60 Hz, IH), 6.71 (s, IH), 4.50 (t, J= 8.80 Hz,2H), 4.33 (q, J = 6.80 Hz, 2H), 3.54 (t, J= 5.20 Hz, 4H), 3.43-3.41 (m, IH), 3.13 (t, J=8.40 Hz, 2H), 2.45-2.32 (m, 4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H),Rt. 2.88mm, 95.7% (Max). HPLC: (Method A) Rt2.8lmin, 96.5% (Max).
0.26 g With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; To a stirred solution of <strong>[64837-49-6]ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate</strong> (0.25 g, 1.29 mmol) in dry DMF (2.5 mL), K2CO3 (0.54 g, 3.89 mmol) and Example 8 (0.59 g, 1.93 mmol) were added at rt. The reaction mixture was stirred overnight at 80 C It was then concentrated under vacuum. EtOAc (10 mL) was added and the resulting solution was washed with water (10 mL), brine(10 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash chromatography to afford the title compound. Yield: 51% (0.26 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 7.15 (d, J = 7.60 Hz, 1H), 6.75 (d, J = 7.60 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.80 Hz, 2H), 4.33 (q, J = 6.80 Hz, 2H), 3.54 (t, J= 5.20 Hz, 4H), 3.43-3.41 (m, 1H), 3.13 (t, J= 8.40Hz, 2H), 2.45-2.32 (m, 4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2(M+H), Rt. 2.88min, 95.7% (Max). HPLC: (Method A) Rt 2.81min, 96.5% (Max).
  • 12
  • 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine dihydrochloride [ No CAS ]
  • [ 64837-49-6 ]
  • ethyl 5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
51% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; To a stirred solution of <strong>[64837-49-6]ethyl 5-chloro-1 ,3,4-thiadiazole-2-carboxylate</strong> (0.25 g, 1 .29 mmol) in dry DMF (2.5 mL), K2C03 (0.54 g, 3.89 mmol) and Intermediate 13 (0.59 g, 1.93 mmol)were added at rt. The reaction mixture was stirred overnight at 80 C. It was then concentrated under vacuum. EtOAc (10 mL) was added and the resulting solution waswashed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated.The crude product was purified by flash chromatography to afford the title compound.Yield: 51% (0.26 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 6 7.15 (d, J = 7.60 Hz,IH), 6.75 (d, J = 7.60 Hz, IH), 6.71 (5, IH), 4.50 (t, J = 8.80 Hz, 2H), 4.33 (q, J = 6.80 Hz,2H), 3.54 (t, J = 5.20 Hz, 4H), 3.43-3.41 (m, IH), 3.13 (t, J = 8.40 Hz, 2H), 2.45-2.32 (m,4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H), Rt. 2.88mm, 95.7% (Max). HPLC:(Method A) Rt 2.81 mm, 96.5% (Max).
51% With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; To a stirred solution of <strong>[64837-49-6]ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate</strong> (0.25 g, 1.29 mmol) in dry DMF (2.5 mL), K2CO3 (0.54 g, 3.89 mmol) and Intermediate 13 (0.59 g, 1.93 mmol) were added at rt. The reaction mixture was stirred overnight at 80 C. It was then concentrated under vacuum. EtOAc (10 mL) was added and the resulting solution was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04 and concentrated. The crude product was purified by flash chromatography to afford the title compound. Yield: 51 % (0.26 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 7.15 (d, J = 7.60 Hz, 1 H), 6.75 (d, J = 7.60 Hz, 1 H), 6.71 (s, 1 H), 4.50 (t, J = 8.80 Hz, 2H), 4.33 (q, J = 6.80 Hz, 2H), 3.54 (t, J = 5.20 Hz, 4H), 3.43-3.41 (m, 1 H), 3.13 (t, J = 8.40 Hz, 2H), 2.45-2.32 (m, 4H), 1.31 -1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H), Rt. 2.88min, 95.7% (Max). HPLC: (Method A) Rt 2.81 min, 96.5% (Max).
  • 13
  • 6-(1-(piperazin-1-yl)ethyl)quinoxaline hydrochloride [ No CAS ]
  • [ 64837-49-6 ]
  • ethyl 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With triethylamine; In N,N-dimethyl-formamide; at 0 - 100℃; To a stirred solution of Intermediate 2 (2.62 g, 9.40 mmol) in dry DMF (25 mL), TEA (2.8 mL, 20.15 mmol) and <strong>[64837-49-6]ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate</strong> (1.2 g, 6.71 mmol) were added at 0 C. The reaction mixture was stirred at 100 C overnight. The reaction mixture was concentrated under vacuum. The resulting crude mixture was dissolved inDCM (35 mL), washed with water (20 mL) and dried over Na2SO4. After evaporation of thesolvent, the resulting product was triturated in Et20 (2 x 4 mL), affording the titlecompound. Yield: 50% (1.3 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.93 (d, J= 6.0 Hz, 2H), 8.09 (d, J = 8.8 Hz, IH), 8.01 (5, IH), 7.91 (d, J = 8.8 Hz, IH), 4.33 (q, J =7.2 Hz, 2H), 3.85 (t, J = 6.0 Hz, IH), 3.58 (5, 4H), 2.70-2.58 (m, 2H), 2.58-2.50 (m, 2H),1.44 (d, J = 6.4 Hz, 3H), 1.29 (t, J = 6.80 Hz, 3H). LCMS: (Method A) 399.2 (M+H), Rt.2.22 mm, 96.96% (Max). HPLC: (Method A) Rt 2.27 mm, 96.97% (Max).
  • 14
  • 6-(1-(piperazin-1-yl) ethyl)quinoxaline hydrochloride [ No CAS ]
  • [ 64837-49-6 ]
  • ethyl 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With triethylamine; In N,N-dimethyl-formamide; at 0 - 100℃; To a stirred solution of Intermediate 2 (2.62 g, 9.40 mmol) in dry DMF (25 mL), TEA (2.8 mL, 20.15 mmol) and <strong>[64837-49-6]ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate</strong> (1.2 g, 6.71 mmol) were added at 0 C. The reaction mixture was stirred at 100 C overnight. The reaction mixture was concentrated under vacuum. The resulting crude mixture was dissolved in DCM (35 mL), washed with water (20 mL) and dried over Na2SO4. After evaporation of the solvent, the resulting product was triturated in Et20 (2 x 4 mL), affording the title compound. Yield: 50% (1.3 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 8.93 (d, J = 6.0 Hz, 2H), 8.09 (d, J = 8.8 Hz, 1 H), 8.01 (s, 1 H), 7.91 (d, J = 8.8 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2H), 3.85 (t, J = 6.0 Hz, 1 H), 3.58 (s, 4H), 2.70-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.44 (d, J = 6.4 Hz, 3H), 1.29 (t, J = 6.80 Hz, 3H). LCMS: (Method A) 399.2 (M+H), Rt. 2.22 min, 96.96% (Max). HPLC: (Method A) Rt 2.27 min, 96.97% (Max).
  • 15
  • [ 33216-53-4 ]
  • [ 64837-49-6 ]
  • ethyl 5-((3,5-dichloropyridin-4-yl)thio)-1,3,4-thiadiazole-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 2.0h;Inert atmosphere; A mixture of <strong>[64837-49-6]ethyl 5-chloro-1 ,3,4-thiadiazole-2-carboxylate</strong> (2.31 g, 12.00 mmol) and 3,5-dichloropyridine-4-thiol (2.484 g, 13.80 mmol) in DMF (48 mL) was treated with K2CO3 (3.65 g, 26.4 mmol). The reaction mixture was stirred at 65QC for 2 h. The reaction was cooled to room temperature, quenched with H2O, and extracted with EA. The combined organic extracts were washed with H2O and brine, dried over Na2SO4. The solvent was removed and the residue was purified by flash column (Hex:EA = 5:1 ) to afford 2.776 g (69%) of ethyl 5-((3,5-dichloropyridin-4-yl)thio)-1 ,3,4-thiadiazole-2- carboxylate as a yellow solid. 0.25 (Hex:EA = 4:1 ); HRMS (ESI) (m/z) [MH]+calcd for C10H8CI2N3O2S2, 335.9435, found 335.9205.
 

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