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Structure of 23784-96-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 23784-96-5 |
Formula : | C5H4Cl2S |
M.W : | 167.06 |
SMILES Code : | ClCC1=CC=C(Cl)S1 |
MDL No. : | MFCD00009764 |
InChI Key : | MQTKXCOGYOYAMW-UHFFFAOYSA-N |
Pubchem ID : | 583079 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314-H290 |
Precautionary Statements: | P501-P260-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338-P310-P406-P405 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 39.09 |
TPSA ? Topological Polar Surface Area: Calculated from |
28.24 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.16 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.99 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.99 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
4.15 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.96 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.16 |
Solubility | 0.117 mg/ml ; 0.000698 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.25 |
Solubility | 0.0946 mg/ml ; 0.000566 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.3 |
Solubility | 0.0845 mg/ml ; 0.000506 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.2 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.43 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium; In hydrogenchloride; methanol; | a 2-[(5-Chloro-2-thenyl)thio]ethylamine STR204 3.41 g (30 mmol) of cysteamine hydrochloride are introduced under a current of nitrogen into a solution of 1.38 g (60 mmol) of sodium in 100 ml of methanol. 5.01 g (30 mmol) of 5-chloro-2-(chloromethyl)thiophene are added after 10 minutes, stirring at room temperature. The solvent is distilled off under vacuum after one hour and the residue is dissolved in 5% hydrochloric acid and extracted with ether. After alkalization with sodium hydroxide solution, the aqueous phase is extracted by shaking with methylene chloride and the organic phase is washed with water, dehydrated over sodium sulphate and concentrated by evaporation under vacuum. The oily amine base left as residue is converted into the hydrochloride by reaction with ethanolic hydrochloric acid and recrystallized from ethanol/water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL; In acetonitrile; at 120℃; for 0.333333h;microwave irradiation; | Preparation of final compound 13-2; Compound 14-1 (31 mg, 0.1 mmol), 2-chloro-5-(chloromethyl) thiophene (0.2 mmol), and PS-TBD (100 mg, 0.3 mmol) were suspended in CH3CN (2 ml). The reaction was heated in the microwave at 120 0C for 20 minutes. The resin was filtered off, and the filtrate was concentrated under vacuum. The resulting crude was purified by HPLC yielding 0.029 g of the purified final compound 13-2 (65 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With C15H20N3Pol; In acetonitrile; at 120℃; for 0.333333h;microwave irradiation; | Final compound 13-1 (31 mg, 0.1 mmol), 2-chloro-5-(chloromethyl) thiophene (0.2 mmol), and PS-TBD (100 mg, 0.3 mmol) were suspended in CH3CN (2 ml). The reaction was heated in the microwave at 120 0C for 20 minutes. The resin was filtered off, and the filtrate was concentrated under vacuum. The resulting crude was purified by HPLC yielding 0.027 g of the purified final compound 12-2 (69 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL; In acetonitrile; at 120℃; for 0.333333h;Microwave irradiation; | m) Preparation of final compound 10-1 1; Intermediate compound I-9 (28 mg, 0.1 mmol), <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.2 mmol) and PS-TBD (103 mg, 0.3mmol) were suspended in CH3CN (2 ml). The reac- <n="43"/>tion was heated in the microwave at 120 0C for 20 minutes. The resin was filtered off, and the filtrate was concentrated under vacuum. The resulting crude was purified by HPLC yielding 0.031 g of the purified final compound 10-11 (75 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 21h; | To a stirred solution of ethyl 9H-O-carboline-3-carboxylate (300 mg, 1.25 mmol) in DMF (3 mL) under a nitrogen atmosphere was added NaH (50.0 mg, 60% in mineral oil, 1.25 mmol) portionwise, followed by 2-chloro-5-(chloromethyl)-thiophene (151 μL, 1.25 mmol). The stirring was continued for 21 hours at ambient temperature, water (50 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give a solid that was dissolved in methanol (25 mL). To the resulting solution, H2NOH (25 mL, 50 wt. % solution in H2O, 0.38 mol) was added. The suspension was stirred for 4 days at ambient temperature. The mixture was then filtered, and the solid was boiled in methanol (25 mL). After filtration, the desired product (0.26 g, 58%) was obtained. 1H NMR (400 MHz, DMSO-d6): 11.28 (1H, s), 9.15 (1H, s), 9.01 (1H, s), 8.81 (1H, s), 8.44 (1H, d, J=8 Hz), 6.94-7.92 (5H, m), 5.99 (2H, s). HRMS (M+H)+ found: 358.0417. Calcd for C17H13N3O2SCl: 358.0417. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 11H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). | |
22% | A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). | |
In 1,4-dioxane; methanol; chloroform; mineral oil; | 1-[(5-CHLORO-2-THIENYL)METHYL]-2H-INDOLE-2,3-DIONE A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H) 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). |
In 1,4-dioxane; methanol; chloroform; mineral oil; | 1-[(5-CHLORO-2-THIENYL)METHYL]-2H-INDOLE-2,3-DIONE: A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. Age reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). | |
In 1,4-dioxane; methanol; chloroform; mineral oil; | 1-[(5-CHLORO-2-THIENYL)METHYL]-2H-INDOLE-2,3-DIONE: A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). | |
In 1,4-dioxane; methanol; chloroform; mineral oil; | 1-[(5-CHLORO-2-THIENYL)METHYL]-2H-INDOLE-2,3-DIONE: A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 C. under argon. The mixture was allowed to stir for 5 minutes and then <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e (0.12 mL, 1.02 mmol) in dioxane (10 mL) was added dropwise to the resulting mixture. The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22%). 1H NMR (400 MHz): δ 7.62 (d, J=7.4, 1H), 7.56 (t, J=7.8, 1H), 7.14 (t, J=7.7, 1H), 6.94 (d, J=8.0, 1H), 6.90 (d, J=3.2, 1H), 6.78 (d, J=3.7, 1H), 4.90 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In N-methyl-acetamide; water; ethyl acetate; Petroleum ether; | B. 2-Hydroxymethyl-4-[3-(5-chlorothiophen-2-ylmethylsulfanyl)propylsulfanyl]-3-methyl-pyridine 6.9 g (26 mmol) of [4-(3-mercaptopropylsulfanyl)-3-methylpyridin-2-yl]methanol hydrochloride and 4.4 g (26 mmol) of 2-chloro-5-chloromethylthiophene are stirred in 100 ml of dimethylformamide for two hours together with 14 g (132 mmol) of sodium carbonate. The mixture is diluted with 100 ml of water and extracted three times with 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel using ethyl acetate/petroleum ether/triethylamine=8/2/0.3. 5.9 g (63%) of the title compound are obtained as a crystalline solid, which is used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
350 mg (41%) | With potassium tert-butylate; In N,N-dimethyl-formamide; | EXAMPLE 17 1-((5-Chloro-2-thienyl)methyl)-3-(5-ethoxycarbonyl-2-furyl)indazole: 600 mg (2.3 mmol) of 3-(5-ethoxycarbonyl-2-furyl)indazole together with 265 mg (2.4 mmol) of potassium tert-butoxide were initially charged in 10 ml of DMF, 430 mg (2.6 mmol) of <strong>[23784-96-5]2-chloro-5-(chloromethyl)thiophen</strong>e in 1 ml of DMF were added dropwise and the mixture was stirred at RT for 2 h. Customary work-up gave 350 mg (41%) of the title compound. m.p.: 124-126 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 104 2-(4-Chlorophenylimino)-3-(5-chloro-2-thenyl)-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 2-[N-(4-chlorophenyl)-N-(5-chloro-2-thenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one The reaction procedure of Example 11 was followed except that 2.536 g (8.75 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 154 mg of lithium hydride, 1.462 g of 5-chloro-2-thenyl chloride and 40 ml of DMF were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform). As a result, 2.643 of 2-(4-chlorophenylimino)-3-(5-chloro-2-thenyl)-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ethanol) was obtained as a low polarity substance, and 263 mg of 2-[N-(4-chlorophenyl)-N-(5-chloro-2-thenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ethyl acetate and diisopropyl ether) was obtained as a high polarity substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; | STR478 3.2 g (0.03 mol) of 2-amino-5-methylpyridine are dissolved in 100 ml of acetonitrile, and 5 g (0.03 mol) of 2-chloro-5-chloromethylthiophene are added. The mixture is stirred for 8 hours at 60 C. and for 18 hours at room temperature. The solid which has formed is filtered off with suction and dried. 1.6 g (20% of theory) of N-(5-chlorothien-2-yl-methyl)-5-methyl-2-iminopyridine hydrochloride of melting point 208 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thiourea; In methanol; | Step 1. Preparation of S-(5-chloro-2-thienylmethyl)-isothiouronium chloride. <strong>[23784-96-5]2-Chloro-5-(chloromethyl)thiophene</strong> (14.5 g, 87 mmol) and thiourea (6.6 g, 87 mol) were dissolved in methanol (30 mL) and heated to reflux for 16 hours. The reaction was cooled to room temperature and a precipitate formed. Ether (150 mL) was added to complete the precipitation of compound. The crystals were isolated by filtration and washed with ether (100 mL). After drying in vacuo, 19.0 g (90%) of pure S-(5-chloro-2-thienylmethyl)-isothiouronium chloride were obtained: 1 H NMR (CD3 OD) δ=4.83p (s, 2H), 6.87p (d, 1H, J=3.8 Hz), 6.96p (d, 1H, J=3.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,2-dimethoxyethane; water; | EXAMPLE 1 Preparation of N-[4-chloro-2-fluoro-5-(5-chloro-2-thenyloxy)phenyl]-1,2-piperidinedicarboximide (Compound No. 1) 0.83 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,2-piperidinedicarboximide was stirred together with 1.40 g of potassium carbonate, 10 ml of dimethoxyethane and 0.42 g of 5-chloro-2-thenyl chloride at 60 to 65 C. for 5 hours. After letting the reaction mixture stand to cool, water was added thereto to precipitate out crystals, followed by filtering off the crystals and washing them with water to thus obtain crude crystals. The crystals were purified with ether to obtain 0.70 g of the title compound. M.P.=135~137 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.6% | With hydrogenchloride; formaldehyd; concentrated aqueous hydrochloric acid; | 1. Preparation of 5-chloro-2-chloromethyl thiophene In a 250 ml round-bottom flask equipped with a mechanical stirrer and an ice/salt bath, were mixed concentrated aqueous hydrochloric acid (40 ml) and 2-chlorothiophene (40 g, 0.34 mol). This mixture was cooled to 0 C. and a stream of gaseous HCl was introduced under the surface of the mixture. A 40% aqueous solution formaldehyde (40 ml) was added dropwise, and the temperature was maintained at 3-8 C. When the addition was complete, stirring was continued for 20 minutes, while HCl gas was continuously passed through the reaction mixture. The resulting mixture was poured on 120 ml ice/water. An oil was separated and the aqueous solution was extracted with ether (2*100 ml). The combined organic extracts were washed with water (2*100 ml) and were dried over anhydrous potassium carbonate. The solvents were stripped and the residue was distilled in vacuo, to collect 33.1 g, 58.6% yield, of a colorless liquid, with a b.p. of 50-53 C. at 0.35 torr. NMR: (CDCl3) 6.7 (m,2H), 4.6 (5,2H). |
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