Structure of 149968-10-5
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CAS No. : | 149968-10-5 |
Formula : | C20H16ClNO |
M.W : | 321.80 |
SMILES Code : | C=CC(C1=CC=CC(/C=C/C2=NC3=CC(Cl)=CC=C3C=C2)=C1)O |
MDL No. : | MFCD09833496 |
InChI Key : | PITUINHIXKJYJX-UXBLZVDNSA-N |
Pubchem ID : | 11782229 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 23 |
Num. arom. heavy atoms | 16 |
Fraction Csp3 | 0.05 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 97.39 |
TPSA ? Topological Polar Surface Area: Calculated from | 33.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 3.54 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 5.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 4.74 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 3.88 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 5.64 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 4.58 |
Log S (ESOL):? ESOL: Topological method implemented from | -5.29 |
Solubility | 0.00166 mg/ml ; 0.00000517 mol/l |
Class? Solubility class: Log S scale | Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from | -5.52 |
Solubility | 0.000976 mg/ml ; 0.00000303 mol/l |
Class? Solubility class: Log S scale | Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -6.82 |
Solubility | 0.0000486 mg/ml ; 0.000000151 mol/l |
Class? Solubility class: Log S scale | Poorly 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) | Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | Yes |
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 | -4.66 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 | 1.0 |
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) | 3.03 |
* 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 |
---|---|---|
85 - 86% | With tetrabutylammomium bromide; triethylamine;palladium diacetate; In toluene; at 80℃; for 6h;Product distribution / selectivity; | Example 1; 100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 25 gm of tetrabutylammonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm of Palladium acetate. The reaction mass is heated to 800C for 6 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 550C under vacuum to get 120 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.15%; Chemical assay (by HPLC) = 98.5%; Yield = 85% (by theory).; Example 2 (Recycling procedure); 100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in the above residue. To this 41.2 gm of triethylamine is added. The reaction mass is heated to 800C for 6 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 55C under vacuum to get 121 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.13%; Chemical assay (by HPLC) = 98.6%; Yield = 86% (by theory)The above example can be repeated up to a maximum of 5 batches without affecting the yield and quality parameters. |
83% | With Methyltriphenylphosphonium bromide; triethylamine;palladium diacetate; In toluene; at 80℃; for 22h;Product distribution / selectivity; | Example 4; 100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 35 gm of methyl triphenyl phosphonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm ofPalladium acetate. The reaction mass is heated to 800C for 22 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 550C under vacuum to get 117 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.19%;Chemical assay (by HPLC) = 98.24%; Yield = 83% (by theory) |
81.5% | With tetraphenylphosphonium bromide; triethylamine;palladium diacetate; In toluene; at 80℃; for 22h;Product distribution / selectivity; | Example 3; 100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 35 gm of tetraphenyl phosphonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm of EPO <DP n="7"/>Palladium acetate. The reaction mass is heated to 8O0C for 22 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 550C under vacuum to get 115 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.14%; Chemical assay (by HPLC) = 98.1%; Yield = 81.5% (by theory) |
With triethylamine;palladium diacetate; In tetrahydrofuran; toluene; for 24h;Heating / reflux;Product distribution / selectivity; | EXAMPLE 11 : PREPARATION OF 2-(3-(3-[2-(7-CHLORO-QUINOLIN^-YL)-VINYL]- PHENYL}-3-OXO-PROPYL)-BENZOIC ACID METHYL ESTER OF FORMULA XII:Toluene (500 ml), 3-[2-(7-chloro-quinolin-2-yl)-vinyl] benzaldehyde (50 g) were taken into a round bottom flask and stirred for about 10 minutes. The reaction mass was then cooled to 0 to -10 0C. Then Vinyl Magnesium bromide (1 M solution in THF) (230 ml) was added slowly at about 0 to -100C under nitrogen atmosphere. After the addition was complete, the reaction mass was maintained at 0 to -100C for about 2 hours. After the reaction was completed, the reaction mass was quenched with 10 % aqueous acetic acid solution (300 ml) below 10 0C . Toluene (250 ml) was then added to the reaction mass, and the temperature of the reaction mass was raised to 25-35 0C and stirred for about 30-45 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (150 ml). The combined organic layer was washed with 5 % aqueous sodium bicarbonate solution (250 ml) followed by washing with water (2X400 ml). The organic layer was distilled azeotropically to remove the traces of water until the reaction volume was 400 ml and then cooled to 25-35 0C. Methyl 2-iodo benzoate (22.4 ml), THF (25 ml) and triethylamine (65.1 ml) was added to the residual organic layer. Palladium acetate (0.25 g) was added and the reaction mass was heated to reflux and maintained under reflux for about 24 hrs. After the reaction was completed, EPO <DP n="33"/>the reaction mass was filtered under hot condition and washed the filtered bed with toluene (100 ml). The combined filtrate was washed with water (2 X250 ml) under hot condition (60-70 0C). The toluene layer was Distill off completely under vacuum below 600C. Then toluene (75 ml) was added to the reaction mass and heated to 70-80 0C to get the clear dissolution. The solution was then cooled to about 25-35 0C and maintained for about 2 hours. Then the reaction mass was further cooled to 0-5 0C and stirred for about 4 hours. The separated solid was filtered and washed with chilled toluene (25 ml) and finally washed with hexanes (100 ml). The wet compound was dried at 50-550C under vacuum to afford 45 g of the title compound. | |
With triethylamine;palladium diacetate; In acetonitrile; for 6h;Heating / reflux; | Example 2: Synthesis of methyl 2-[3-[(E)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl]-3-oxopropyl]benzoate; The crude slurry of example 1 in acetonitrile was treated with methyl 2-iodobenzoate (44.6 g, 0.17 mol), triethylamine (35.6 mL, 0.254 mol) and palladium acetate (0.36 g, 1.7 mmol). The mixture was degassed and heated at reflux under nitrogen for 6 hours. Then, the hot solution was filtered through cellulose (Solka Floc) to remove any precipitated palladium. When the filtrate cooled to ambient temperature, the desired title product crystallized from solution. After one hour at ambient temperature, the suspension was filtered. The filter cake was washed consecutively with 130 mL acetonitrile, 100 mL acetonitrile/water (1:1), 100 mL water and finally 150 mL acetonitrile. After drying, the title product was obtained as a pale-yellow solid (53 g, 69% referring to the benzaldehyde of Example 1). 1H NMR complies with EP 0 480 717 B (example 16, step 3). | |
With triethylamine;palladium diacetate; In toluene; at 100℃;Reflux; | In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, methyl 2- iodobenzoate( 105.6 g, 0.40 moles), triethyl amine (78 g, 0.77 moles) and palladium acetate(0.48 g, 0.007 moles) was added in a solution of [E]-l-[3-[2-(7- chloro-2-quinolinyl)- ethenyl]-phenyl]-2-propen-l-ol in toluene (obtained from example 2). Reflux the reaction mass for 24 to 30 hrs at 100 0C (+/-5 0C). Filter the salt/catalyst and filtrate washed with water and 10%sodium chloride solution. Recover the solvent under vacuum and product was crystallized in methanol, toluene, acetonitrile or mixture thereof. Filter the product and wash with methanol, toluene, acetonitrile or mixture thereof. Dry the material 40- 45 0C for 4 - 6 hrs to obtain pure Methyl-[E]-2-[3-[3-[2-(7- chloro-2-quinolinyl)-ethenyl]-phenyl] -3-oxo- propyl]-benzoate ( 1 10 g, HPLC purity 99%) | |
With triethylamine;palladium diacetate; In acetonitrile; at 80 - 85℃; for 12 - 15h; | EXAMPLE 10: Preparation of MethyI-[E]-2-[3-[3-[2-(7-Chloro-2-quinolinyI) ethenyl] phenyI]-3-oxopropyl]benzoate (VI) To a 1.01t/4 neck round bottom flask fitted with a mechanical stirrer, thermometer pocket and calcium chloride drying tube under nitrogen gas atmosphere, were successively charged crude 1-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-l-ol (II) (125 g, 92.5 % pure), acetonitrile, methyl-2-iodobenzoate (100 g, 0.38 mol) and triethylamine (112 mL ) and the mixture was stirred for 15 min. Palladium acetate (1.0 g) wasthen added and the mixture was slowly heated to reflux at 80 to 85 C and progress of the reaction was monitored by TLC. After the reaction was(12-15 hr), fresh acetonitrile was added to the reaction mixture and the hot solution was filtered through hyflow bed to remove the palladium salts and then allowed to stir at 20 to 25 C for 8 hr by which time most of the product had precipitated out. The solid was filtered and successively washed with cold (5 to 10 C) acetonitrile (125 mL), mixture of water and acetonitrile (125 mL +125 mL each), slurry washed with cold acetonitrile (125 mL) and finally with hexanes ( 125 mL) and dried at 55 to 60 C to afford crude keto ester (VI) as a brownish colored powder. Yield = 111.2 g ( 69.6% on 100 % basis); Purity (HPLC ) =97.21%; Assay (HPLC ) = 94.34 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In tetrahydrofuran; hexane; toluene; | Step 1 1-(3-(2-(7-Chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0 C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0 C., the reaction was quenched by the slow addition of saturated NH4 Cl solution (150 ml), followed by H2 O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2 O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110-112 C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g. | |
With acetic acid; In tetrahydrofuran; hexane; toluene; | Step 1 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0 C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0 C., the reaction was quenched by the slow addition of saturated NH4 Cl solution (150 mL), followed by H2 O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2 O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110-112 C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g. | |
With acetic acid; In tetrahydrofuran; hexane; toluene; | Step 1 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0 C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0 C., the reaction was quenched by the slow addition of saturated NH4 Cl solution (150 ml), followed by H2 O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2 O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110-112 C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g. |
With acetic acid; In tetrahydrofuran; hexane; toluene; | Step 1 1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-2-propen-1-ol To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0 C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0 C., the reaction was quenched by the slow addition of saturated NH4 Cl solution (150 ml), followed by H2 O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2 O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110-112 C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium chloride;palladium diacetate; In hexane; ethyl acetate; N,N-dimethyl-formamide; toluene; | Step 2 Methyl 2-(3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-oxopropyl)benzoate A degassed suspension of the product of Step 1 (50.3 g, 156 mmol), n-Bu4 NCl (86.0 g, 312 mmol), LiOAc.2H2 O (41.2 g, 390 mmol), LiCl (6.84 g, 156 mmol), Pd(OAc)2 (1.00 g, 4.7 mmol), and methyl 2-iodobenzoate (41.00 g, 156 mmol) in DMF (300 mL) was stirred for 3 hours at 90 C. The dark red solution was then cooled to r.t. and poured into 2 L of ice cold H2 O. The product was extracted with hot EtOAc, dried over Na2 SO4, filtered and concentrated to dryness. It was dissolved in 600 ml of hot toluene and filtered through a small silica pad (1 L). The title product was finally recrystallized from EtOAc:hexane 1:1 (1.2 L). The title product was finally recrystallized from EtOAc:hexane 1:1 (1.2 L). Recrystallization of the mother liquors in EtOAc:hexane 1:3 (400 mL) afforded a second crop of the title compound. 1 H NMR (CDCl3): delta3.40 (4H, s), 3.92 (3H, s), 7.25-7.52 (6H, m), 7.63 (1H, d), 7.70-7.82 (3H, m), 7.95 (2H, d) 8.05 (1H, br s), 8.11 (1H, d), 8.29 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
This was then assembled using Method K, with the alcohol from Example 80, Step 1, and the thiol from Example 138, Step 7 to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 114 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-((4-hydroxy-4-methylpentyl)thio)propyl)phenyl)-2-methylpropanoic acid 2-(2-iodophenyl)acetic acid was first esterified with 2-(trimethylsilyl)ethanol. Double alkylation (LDA/MeI) gave 2-(trimethylsilyl)ethyl 2-(2-iodophenyl)-2-methylpropanoate. This was then coupled to the alcohol from Example 80, Step 1, using Method K. The thiol was that of Example 138, Step 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 92 3-((1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-(3-(2-hydroxy-2-propyl)phenyl)propyl)thio)-2(S)-ethylpropanoic acid From methyl 3-iodobenzoate, the alcohol from Example 80, Step 1, and the thiol from Example 32, Step 10, this compound was prepared by Method K, using the silylation-THP-desilylation protection sequence of Method G. | ||
EXAMPLE 92 3-((1-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(3-(2-hydroxy-2-propyl)phenyl)propyl)thio)-2(S)-ethylpropanoic acid From methyl 3-iodobenzoate, the alcohol from Example 80, Step 1, and the thiol from Example 32, Step 10, this compound was prepared by Method K, using the silylation-THP-desilylation protection sequence of Method G. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 11 : PREPARATION OF 2-(3-(3-[2-(7-CHLORO-QUINOLIN^-YL)-VINYL]- PHENYL}-3-OXO-PROPYL)-BENZOIC ACID METHYL ESTER OF FORMULA XII:Toluene (500 ml), 3-[2-(7-chloro-quinolin-2-yl)-vinyl] benzaldehyde (50 g) were taken into a round bottom flask and stirred for about 10 minutes. The reaction mass was then cooled to 0 to -10 0C. Then Vinyl Magnesium bromide (1 M solution in THF) (230 ml) was added slowly at about 0 to -100C under nitrogen atmosphere. After the addition was complete, the reaction mass was maintained at 0 to -100C for about 2 hours. After the reaction was completed, the reaction mass was quenched with 10 % aqueous acetic acid solution (300 ml) below 10 0C . Toluene (250 ml) was then added to the reaction mass, and the temperature of the reaction mass was raised to 25-35 0C and stirred for about 30-45 minutes. The organic layer was separated and the aqueous layer was extracted with toluene (150 ml). The combined organic layer was washed with 5 % aqueous sodium bicarbonate solution (250 ml) followed by washing with water (2X400 ml). The organic layer was distilled azeotropically to remove the traces of water until the reaction volume was 400 ml and then cooled to 25-35 0C. Methyl 2-iodo benzoate (22.4 ml), THF (25 ml) and triethylamine (65.1 ml) was added to the residual organic layer. Palladium acetate (0.25 g) was added and the reaction mass was heated to reflux and maintained under reflux for about 24 hrs. After the reaction was completed, EPO <DP n="33"/>the reaction mass was filtered under hot condition and washed the filtered bed with toluene (100 ml). The combined filtrate was washed with water (2 X250 ml) under hot condition (60-70 0C). The toluene layer was Distill off completely under vacuum below 600C. Then toluene (75 ml) was added to the reaction mass and heated to 70-80 0C to get the clear dissolution. The solution was then cooled to about 25-35 0C and maintained for about 2 hours. Then the reaction mass was further cooled to 0-5 0C and stirred for about 4 hours. The separated solid was filtered and washed with chilled toluene (25 ml) and finally washed with hexanes (100 ml). The wet compound was dried at 50-550C under vacuum to afford 45 g of the title compound. | ||
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, (400 g, 0.40 moles) vinyl magnesium bromide (I M solution in THF) was added in a solution of [E]-3-[2- (7- chloro-2-quinolinyl) ethenyl]-Benzaldehyde (100 g, 0.34 moles) in toluene (700 ml) and tetrahydrofuran (200 ml) at -40 0C (+/-5 0C). Stir the reaction mass for 2-4 hrs at -40 0C (+/-5 0C) and quench the reaction mass in 10% ammonium chloride solution ( 1 ltr). Organic layer washed with water then with 10%sodium chloride solution. Recover the solvent under vacuum to get moisture content NMT 0.05% and proceed to next stage immediately | ||
EXAMPLE 9: Preparation of [E]-l-[3-[2-(7-ChIoro-2-quinolinyI)ethenyl]phenyl]-2-propen-l-ol (II): To a cooled (-10 to 0 C) and stirred suspension of [E]-3-2-(7-Chloro-2-quinolinyl)ethenyl]benzaldehyde (I) (lOOg, 0.34 mol) in tetrahydrofuran (300 mL) and toluene (1000 mL) in a 3.0 lt/4 neck round bottomed flask fitted with a mechanical stirrer, thermometer pocket and calcium chloride drying tube under nitrogen gas atmosphere, vinylmagnesium bromide (500 g, , approx. 1.0 molar solution in THF) was added drop wise60 minutes keeping the temperature to -10 to 0 C. The reaction mixture was stirred at -15 to + 20 C and progress of the reaction was monitored by TLC. After the reaction was(approx 2 hours), ammonium acetate (600 mL, 10% aqueous solution) was added to reaction mixture and the reaction mixture was stirred for 30 minutes. The toluene layer was separated and the aqueous layer was extracted with toluene (2 x 1000 mL), the toluene layers were combined, washed with water (2x1000 mL), driedsodium sulfate and evaporated under vacuum at 55 to 60 C to afford crude residue of [E]-l-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-2-propen-l-ol (II) which is used as such in the next stage. Yield 126 g. Purity (HPLC) =92.5 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In tetrahydrofuran; ethylbenzene; at -15℃; | A flask was charged with monoaldehyde, (£)-3-(2-(7-chloroquinolin-2- yl)vinyl)benzaldehyde III, (94.7 g), ethylbenzene (500 mL) and THF (200 mL), and stirred. The mixture was cooled to -15C. Vinyl magnesium chloride (1.6 M in THF, 232 mL) was slowly charged via additional funnel. Quench solution preparation: A flask was charged with Ammonium acetate (74.6 g), water (530 mL), solka flock (16.7g), ethylbenzene (60mL) and THF (20mL) and cooled to 5C. The batch was added into the quench solution. After quenching, the batch was warmed up and agitated at room temp. The batch was filtered, rinsed with ethylbenzene/THF and phase cut. The organic phase was washed with water. Solvent was removed under reduced pressure at ~50C. The batch was concentrated and slowly cooled to room temp and agitated for 15h. The crystalline product was collected by filtration, rinsed with ethylbenzene and dried under vacuum with nitrogen sweep to yield vinyl alcohol IV (94.94 g, 91% yield from the monoaldehyde III, (£)-3-(2-(7-chloroquinolin-2-yl)vinyl)benzaldehyde). 1NMR (500MHz, CDCl3) delta 8.10 (d, J= 8.5 Hz, IH), 8.08 (d, J= 2.0 Hz, IH), 7.71 (od, J= 16.2 Hz IH), 7.70 (d, J= 8.6 Hz, IH), 7.68 (m, IH), 7.64 (d, J= 8.5 Hz, IH), 7.55 (m, IH), 7.45 (dd, J= 8.6, 2.0 Hz, IH), 7.40 (t, J= 7.5 Hz, IH), 7.38 (od, J= 16.2 Hz, IH), 7.36 (om, IH), 6.09 (ddd, J= 17.1, 10.4, 5.9 Hz, IH), 5.41 (dt, J= 17.1, 1.3 Hz IH), 5.28 (brm, IH), 5.25 (m, IH) 2.23 (s, IH). 13C NMR (125MHz, CDCl3) delta 156.8, 148.6, 143.2, 140.1, 136.6, 136.1, 135.6, 135.0, 129.0, 128.8, 128.6, 128.2, 127.1, 126.85, 126.79, 125.7, 125.1, 1 19.6, 115.5, 75.2. |
Example 1: Synthesis of 1-[(E)-3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl]-2-propen-1-ol; A suspension of (E)-3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (50 g, 0.17 mol, commercially available from Unibest Industrial Ltd., Ningbo, China) in 400 mL toluene was degassed at 0 C. A 1.6 M solution of vinylmagnesium chloride in THF (115 mL, 0.18 mol) was added dropwise over 30 minutes while keeping the internal temperature at <10 C. After stirring for 1 hour at 0-5 C, the reaction mixture was quenched by slow addition of 400 mL aqueous ammonium acetate solution (10 %). The two-phase mixture thus obtained was stirred for 1 hour to ensure the solvolysis of the magnesium salts. The separated organic layer was washed two times with 500 mL water and concentrated in vacuum to a volume of 75 mL. Then, again 75 mL acetonitrile were added and the mixture was concentrated in vacuum to 75 mL. After repetition of the last procedure, the resulting slurry was directly used in the next step. |
Tags: 149968-10-5 synthesis path| 149968-10-5 SDS| 149968-10-5 COA| 149968-10-5 purity| 149968-10-5 application| 149968-10-5 NMR| 149968-10-5 COA| 149968-10-5 structure
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