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CAS No. : | 82104-74-3 |
Formula : | C9H5NO2 |
M.W : | 159.14 |
SMILES Code : | N#CC1=CC2=C(C(OC2)=O)C=C1 |
MDL No. : | MFCD01072882 |
InChI Key : | XEEGWTLAFIZLSF-UHFFFAOYSA-N |
Pubchem ID : | 821218 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302+H312+H332 |
Precautionary Statements: | P280 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.11 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 40.48 |
TPSA ? Topological Polar Surface Area: Calculated from | 50.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.4 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 0.52 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.08 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.89 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.2 |
Log S (ESOL):? ESOL: Topological method implemented from | -1.52 |
Solubility | 4.76 mg/ml ; 0.0299 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (Ali)? Ali: Topological method implemented from | -1.14 |
Solubility | 11.5 mg/ml ; 0.072 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.65 |
Solubility | 0.355 mg/ml ; 0.00223 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) | No |
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 | -6.9 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 | 0.0 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) | 1.86 |
* 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 |
---|---|---|
In tetrahydrofuran; water; at -10 - -5℃; for 3h; | To a suspension of 95 G OF 5-CYANOPHTHALIDE in 710 ml of tetrahydrofuran, previously cooled at -10°C, 384 g of a 20percent solution of 4- fluorophenylmagnesium bromide in tetrahydrofuran obtained in PREPARATION I ("Grignard solution") are dropped thereinto, in two hours at A temperature not higher than-5°C, then, in the same conditions, in THREE TIMES, 230 g, 115 G and 49 g of Grignard solution are dropped thereinto. When the reaction is over, 675 ML of A 15percent aqueous solution of ammonium chloride are added in about one hour, maintaining the TEMPERATURE LOWER THAN 0°C. The phases are separated, the aqueous one is extracted with 285 ml of tetrahydrofuran and the organic phase is collected. The organic phase (950 ml), containing a theoretical quantity of 150 g of 3-HYDROXYMETHYL-4- (4-FLUOROBENZOYL) BENZONITRILE, referred to the starting 5-cyanophthalide, and about 14-16percent OF 3-HYDROXYMETHYL-4-[BIS (4- fluorophenyl) hydroxymethyl] benzonitrile, is cooled at 0=5°C, under nitrogen atmosphere. A solution of 23.3 g of NaBH4,230 ml of water and 1 ml of 30percent NaOH is added to the mixture dropwise, in 30 minutes and at a temperature not higher than 15°C. At the end of the addition a control by HPLC [COLUMN : DEVELOSIL C18 4.6 x 250 mm, 5 U ; DETECTOR: UV 240 nm; FLOW : 1.5 ML/MIN ; GRADIENT : A: aq. NH4H2PO4 + H3P04-pH = 2.85/B : CH3CN/H20 = 9/1 (v/v)] detects the disappearance of 3-hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile. The temperature is kept to 25°C, the aqueous phase is eliminated and tetrahydrofuran is evaporated under vacuum at 50°C. 100 ml of ethyl acetate are added to the residue and the solvent is evaporated under vacuum at 50°C, then other 350 ml of ethyl acetate are added. The phases are separated, the organic phase is collected and the aqueous phase is extracted with 230 ml of ethyl acetate. The phases are separated, the aqueous phase is discarded and the organic phases are collected obtaining 720 ml of A solution in ethyl acetate containing 150 G of 3-hydroxymethyl-4- [ (4- fluorophenyl) hydroxymethyl] benzonitrile and the same quantity of 3- hydroxymethyl-4- [bis(4-fluorophenyl)hydroxymethyl]benzonitrile contained into the starting solution. To this solution, 930 ml of 60percent H3PO4 are added at 25°C and the biphasic mixture water/ethyl acetate (81-82°C) IS HEATED AT REFLUX for 2 hours. A control by HPLC (see above) shows the disappearance of 3- hydroxymethyl-4 4-FLUOROPHENYL) HYDROXYMETHYLLBENZONITRILE AND of 3- hydroxymethyl-4- [bis(4-fluorophenyl)hydroxymethyl] benzonitrile contained in the starting solution. In the mixture thus obtained, containing the 1- (4- fluorophenyl)-1, 3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE AND ABOUT 14No.16percent of 1, 1-bis (4-FLUOROPHENYL)-1, 3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE, 750 ml of water are dropped thereinto, then the phases are separated. The organic phase is collected and the aqueous one is extracted with 600 ml of ethyl acetate. After separation of the phases, the organic phases are collected and the aqueous one is extracted with additional 450 mi of ethyl acetate. The aqueous phase is discarded and the collected organic phases are washed with 750 ml of water containing NaCI. The organic phase is decolorized with 4.6 g of activated charcoal and, after 30 minute- stirring at 25°C and subsequent filtration on CELITE layer, the filtrate is concentrated under vacuum at 50°C until an oily residue, that is treated with 150 ml of isopropanol. The solution is concentrate under vacuum at 50°C until a light yellow residue is obtained, which is treated with additional 150 ml of isopropanol. The suspension thus obtained is let under stirring for 30 minutes at 25°C, then for 15 hours at 0-5°C, and finally it is filtered. After washing on the filter with 2 x 30 ml of isopropanol, the product is dried under vacuum at 50°C to give 94 g of 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile with a 65.8percent yield evaluated on the starting 5-cyanophthalide, with a purity (HPLC) = 98. 2. 98. 5percent and with a 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile content lower than 0.5percent. H-NMR and 13C-NMR product data are indicated in Figure 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In toluene; at 0 - 80℃; for 10h; | In a 500 mL three-necked flask, add 5-cyanophthalide 5.00 g (0.031 mol, 1.0 eq), add 50 mL of toluene, and stir. And the temperature was lowered to 0-5 ° C, and 4-fluorophenylmagnesium bromide (1 mol/L) (31 mL, 1.0 eq) was slowly added dropwise. After the completion of the dropwise addition, the reaction was stirred at 0-5 ° C for 5 h, and then the reaction solution was further stirred. 4-Fluorophenylmagnesium bromide (1mol/L) (47mL, 1.5eq) was slowly added dropwise, and the temperature was raised to 80 ° C to continue the reaction for 5 hours. After the reaction was completed, the temperature was lowered to room temperature, and the reaction solution was poured into 200 mL of ice water. Add acetic acid to the reaction solution to adjust Ph=6-7, stir for 5 mins, add ammonia water to adjust Ph=8-9, add dichloromethane extraction (100 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate by suction filtration. The crude product was purified by column chromatography, and the developing solvent was petroleum ether: ethyl acetate = 10:1By 5:1, the product fraction was concentrated to give 9.2 g of a white solid, which was the escital oxalic acid process impurity (formula II), yield 84percent. |
64.18% | In tetrahydrofuran; at 0 - 20℃; for 17h;Inert atmosphere; | At room temperature, formula (I) (4.24 g, 26.64 mmol, 1.00 equiv.) was suspended in dry tetrahydrofuran (42 mL) the reaction mixture was purged with nitrogen for 4 times, the reaction mixture was cooled to 0 deg. C, the Grignard reagent of formula (V) (53.3 mL, 1.0 mol / L in anhydrous tetrahydrofuran, 53.3 mmol) was added dropwise to the reaction mixture and the reaction mixture was stirred at 0 ° C under nitrogen for 1 h. The reaction mixture was warmed to room temperature and the reaction was continued for 16 h under nitrogen. Reaction post-treatment: Samples were quenched with saturated NH4Cl solution, and the tetrahydrofuran layer was analyzed by HPLC. The reaction mixture was cooled to 0 deg. C, a saturated NH4Cl solution (50 mL) was added dropwise to the reaction mixture, about 20 min dropwise addition, reaction was quenched. The reaction mixture was warmed to room temperature, filtered, the tetrahydrofuran layer was separated from the filtrate, the aqueous phase was extracted with EtOAc (2 x 100 mL), the combined organic phases were washed with saturated brine, the organic phase was separated by liquid separation, the organic solvent was removed by concentration under reduced pressure to give the crude product as an orange oil (9.01 g), chromatography on silica gel, elution with cyclohexane (250 mL), followed by elution with dichloromethane (250 mL) and eluted with dichloromethane: methanol (250: 1, 2.5 L), collecting the target components, and concentrated under reduced pressure by a rotary evaporator to obtain a white solid (6.22 g, yield: 64.18percent, purity: 97.33percent). |
In tetrahydrofuran; at 25 - 35℃; | (a) Synthesis To A suspension of 20 g of 5-CYANOPHTHALIDE in 150 ml of tetrahydrofuran, under nitrogen FLOW, AT 25°C, 422.6 g of the 20percent solution of 4-fluorophenylmagnesium bromide obtained in PREPARATION I are added and a rise in temperature of the mixture to about 35°C is observed. The mixture is kept under stirring until, by a HPLC control [COLUMN: DEVELOSIL C18 4.6 x 250 mm, 5 P ; DETECTOR: UV 240 nm; FLOW : 1.5 ML/MIN ; GRADIENT : A: aq. NH4H2PO4 + H3PO4-PH = 2.85/B : CH3CN/H2O = 9/1 (v/v) ], the disappearance of 5-cyanophthalide is observed. When the reaction is over, 200 ml of a 15percent aqueous solution of ammonium chloride are added, maintaining the temperature not higher than 30°C, then the phases are separated and the organic one is concentrated under vacuum to obtain 52 g of a yellow oil, the raw 3-HYDROXYMETHYL-4- [BIS- (4- fluorophenyl) hydroxymethyl] benzonitrile, with a purity of 92.12percent. (b) Purification In a 250-ML FLASK, 20 g of raw 3-hydroxymethyl-4- [bis (4- fluorophenyl) hydroxymethyl] benzonitrile obtained in the preceding synthesis and 100 ml of ethyl acetate are charged. The mixture is stirred until a solution is obtained, wherein 30 ml of silica gel 60 are added, then the solvent is evaporated under vacuum until a dry powder is obtained. Separately, a 5-cm diameter column is prepared with 300 ml of silica gel 60 (particles 0 0. 063-0. 200 mm) for GRAVIMETRIC column, using A mixture heane/ethyl acetate 9/1 (V/V) as eluent. The product previously adsorbed on silica gel 60 is charged into the column prepared as described and is eluted with the mixture itself. The fractions containing the product are collected and concentrated under vacuum at 50'C with ROTAVAPORX (the solution is getting foaming, so that during the concentration must be taken the due precautions). The oily residue obtained is TREATED WITH 100 MI dichloromethane and the solution is concentrated to give 11. 6 g of 3- hydroxymethyl-4- [bis(4-fluorophenyl)hydroxymethyl]benzonitrile as white crystals with M. P. = 66. 4. 72. 3°C AND PURITY (HPLC) = 97. 35percent. H-NMR and C-NMR PRODUCT DATA ARE INDICATED in Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | 1048g of a 10percent solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran are added to a suspension of 60.Og of 5-cyanophthalide in 390ml of 1 ,2-dimethoxyethane at -100C within three hours. After stirring for 30 minutes at -100C, the cold reaction mixture is poured into 1L of aqueous NH4CI (18Og in 1000ml of water, 200C) in about 5 minutes. The layers are separated and the aqueous layer is extracted with 300ml of tetrahydrofuran. The organic layers are combined and volatiles are removed under reduced pressure at 45°C. The residue is dissolved in a mixture of 100OmL of CH2CI2 and 200ml of water containing 2.5g of sodium carbonate (pH of 9). The layers are separated and the organic phase is dried with 4Og of sodium carbonate. The dry CH2CI2 solution is treated with 6g of charcoal, stirred for 10 minutes and the charcoal is removed by filtration. The filter cake is washed with 5OmL of CH2CI2. Filtrate and washing liquid are combined and the solvent is removed under reduced pressure. 30OmL of diisopropylether are added to the residue. After stirring for 1 hour at 22°C the crystal suspension is cooled to 0°C and stirred for another two hours, then cooled to -100C and stirred for 14 hours. The product is isolated by filtration and washed with 4OmL of chilled diisopropylether, 8OmL of a 1 :1 mixture of diisopropylether/cyclohexane and 8OmL of cyclohexane. After drying for 3 hours at 50°C in vacuo 83.0 g (86.2 percent of theory, purity (HPLC): 99.8 areapercent) white, crystalline powder of the title compound are obtained (mp. 85°C).1H-NMR (CDCI3, 300MHz): delta 3.01 (t, J = 6.30, 0.8 H, OH), 3.66 (s, 0.2 H, OH), 4.66 (d, J = 6.11 Hz, 1.6 H, CH2-O), 5.33 (m, CH2-O, 0.4 H, lactol-isomer), 7.03 - 7.93 (m, 7 H, ArH) | |
85% | In tetrahydrofuran; at 0 - 5℃; for 5h; | In a 100 mL three-necked flask, add 5-cyanophthalide 5.00g (0.031 mol, 1.0 eq), add 50 mL of tetrahydrofuran, stir and cool to 0-5 ° C. 4-fluorophenylmagnesium bromide (1 mol/L) (31 mL, 1.0 eq) was slowly added dropwise. After the completion of the dropwise addition, the reaction was maintained at 0-5 ° C for 5 h. After the reaction is completed, the reaction solution is poured into 100 mL of ice water, and acetic acid is added dropwise to the reaction solution to adjust Ph=6-7, and stirred for 5 mins. Add ammonia water to adjust Ph=8-9, add dichloromethane extraction (50mLx3), The organic phase was combined, dried over anhydrous sodium sulfate and concentrated by suction filtered, and then purified and purified by column chromatography. The solvent was petroleum ether: ethyl acetate = 5:1 to 3:1, and the product fraction was concentrated to give 6.8 g. a white solid, which is the escitalopram oxalate process impurity (formula II), yield 85percent. |
A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4- fluorol bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, was added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000ml methylene dichloride at-6 to-2°C. After the reaction was completed, the reaction mass was quenched with 100ml 20percent aqueous ammonium chloride solution. The organic layer was separated and diluted with 100ml of methanol. Slowly, 12g of sodium borohydride (0. 324moles) was added over a period of one hour at below 25°C, and the same temperature was maintained for 4-6 hours. The mixture was then cooled to 5-10°C, maintained for 2 hours and then the precipitated boron complex VB solid was filtered. The solid was washed with chilled dichloromethane and dried under vacuum below 40°C to provide pure boron complex. Weight: 115-120g HPLC purity: 98-99percent |
In tetrahydrofuran; toluene; at -4 - -2℃;Product distribution / selectivity; | Example-1 a) Process for the preparation of citalopram (by single Grignard method) : A solution of 4-fluorophenyl magnesium bromide, prepared from 153.33g 4-flour bromobenzene (0.876 moles) and 25.33g magnesium turnings (1.055 moles) and Iodine (0.05g.) in 300mi of dry tetrahydrofuran was added to a suspension of 100g 5- cyanophthalide (0.628 moles) in 900moi dry toluene at-4 to-2°C. After the reaction was completed, the reaction mass was quenched with 100moi 20percent aqueous ammonium chloride solution. Toluene layer was separated and diluted with 100ml of methanol. 12g Sodium borohydride (0. 324moles) was added over a period of one hour at 10-15°C and the same temperature was maintained for additional one hour. The reaction mass was quenched with 200moi ice water and the toluene layer was separated. Toluene layer was washed with water (200ml) and then 10g of paratoluene sulphonic acid was added to toluene layer. The reaction mixture was heated to 80-85°C and the temperature was maintained for additional 3 hours. After the completion of the reaction toluene layer was washed with aq. Sodium hydroxide solution (200ml), water (200moi) and dried over anhydrous sodium sulfate. The toluene solution was then added to a solution of 21grams of sodium hydride dissolved in 400ml of dimethyl sulfoxide and 500 ml toluene under nitrogen atmosphere at 20-25°C. To the resulting solution a solution of 3-N, N,- dimethylaminopropylchloride (53g) in 200 ml of toluene was added quickly at 20-25°C. The reaction mixture was stirred for 3 hrs at the same temperature. After completion the reaction the mixture was poured into ice water and the toluene layer was separated. The aqueous layer was extracted again with toluene. The combined toluene phase was extracted with 200moi 20percent aqueous acetic acid (40ml acetic acid and 160ml water). The aq. acid extract was cooled to 5-10°C and the pH was adjusted to basic using liquor ammonia (85ml) at 5-10°C and extracted with toluene 3x300m1. The toluene layer was washed with water and dried over anhydrous sodium sulphate. The toluene layer was treated with carbon (10g) and filtered. The filtrate toluene is subjected to salt formation as per following methods.; Example-2) Process for the preparation of citalopram (by double Grignard method): A solution of 4-fluorophenyl magnesium bromides prepared from 153. 33g 4-flour bromobenzene (0.876 moles) and 25.33g magnesium turnings (1. 055 moles) and iodine (0.05gm) in dry 300mi tetrahydrofuran was added to a suspension of 100g 5- cyanophthalide (0.628 moles) in 900ml dry methylene dichloride at-4 to-2°C. After the completion of the reaction a solution of 3-N, N dimethylaminopropyl magnesiumchloride in toluen/THF mixture [generated in situ by reacting 175g 3-N, N dimethylamiopropyl chloride (1. 446mole) in 350ml toluene with 41. 6gm magnesium turnings (9. 733moles) and iodine (0. 05g) in dry 75ml tetrahydrofuran and dibromoethane] was added between 0- 5°C. The reaction mass was then maintained at-5 to 0°C for 3-4 hours. After completion of the reaction, the reaction mass was quenched with 200ml 20percent aqueous ammonium chloride solution. The toluene layer was separated and washed with 200ml water. Methylene dichloride and THF was distilled. 189g sulphuric acid and 60ml of water was added to the toluene layer and heated to 85-90°C. The same temperature was maintained for additional 4-5 hours. After completion of the reaction the reaction mass was diluted with 200ml water and the pH was adjusted to basic with liquor ammonia below 10-15°C. The toluene layer was separated, washed with 200moi water and extracted with 400ml 20percent acetic acid (80mi acetic acid and 320ml water). The aq. acid extract was cooled to 5- 10°C and the pH was adjusted to 8.5 to 9.0 using liquor ammonia (85ml) at 5-10°C and extracted with toluene 3x600m1. The toluene layer was washed with water, dried over anhydrous sodium sulphate. The dried toluene layer was treated with carbon (10g) and filtered. The filtrate toluene was subjected to salt formation in accordance with the following methods: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With lithium hydroxide; In methanol; water; for 5h; | In a 100 mL three-necked flask, 5.00 g (0.031 mol, 1.0 eq) of 5-cyanophthalide,Then successively add 40mL of methanol and 10mL of water,Finally, 1.13 g of LiOH (0.047 mol, 1.5 eq)The reaction was stirred for 5h, the reaction was completed, concentrated under reduced pressure,The concentrate was added to 50mL of dichloromethane and water 10mL at room temperature under stirring with 1N HCl solution was adjusted system pH = 4-6, suction filtered to give a white solid, removed and dried to give the product 4-cyano-2-hydroxymethyl benzoic acid(Formula III) 4.86 g, yield 87.3percent. |
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.25h; | 1-Oxo-1,3-dihydroisobenzofuran-5-carbonitrile (1.56 g, 9.78 mmol) obtained from in Example 4-(4) was suspended in tetrahydrofuran (15 ml), and an aqueous solution of sodium hydroxide (1.008N; 9.70 ml, 9.78 mmol) was added thereto. The mixture was stirred at room temperature for 15 minutes and the solvent was distilled off under reduced pressure. The residue was dried using a vacuum pump to give an amorphous solid. The solid was dissolved in N,N-dimethylformamide (30 ml), and 4-methoxybenzyl chloride (1.53 g, 9.78 mmol) was added thereto, and then the mixture was stirred at 80°C for 5 minutes. After the mixture was cooled to 0°C, a saturated aqueous solution of ammonium chloride was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was dissolved in dichloromethane (50 ml), and tetrazole (1.40 g, 20 mmol) and bis(allyloxy)(diisopropylamino)phosphine (Tetrahedron Lett., 30, 4219 (1989); 3.43 g, 14 mmol) were added thereto at 0°C, and then the resulting mixture was stirred at the same temperature for 5 minutes. The mixture was warmed to room temperature and stirred for 20 minutes, and then methanol (0.5 ml) was added thereto. The mixture was stirred for 10 minutes and cooled to 0°C, and tert-butyl hydroperoxide (80percent di-tert-butyl peroxide solution; Merck; 2.7 g, 24 mmol) was added thereto, and then the reaction mixture was warmed to room temperature followed by stirring 20 minutes. A saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium thiosulfate were added to the reaction mixture, and the resulting mixture was stirred for 10 minutes and partitioned between ethyl acetate and water. The organic layers were combined and the solvent was distilled off under reduced pressure to give a residue. The residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate : hexane = 2 : 3) to afford a mixture of a solid and an oily material. The mixture was washed with a mixed solvent of ethyl acetate-hexane, and the washings were concentrated to give a residue. The residue was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate : hexane = 2 : 3) to afford the title compound (1.18 g, 26percent yield) as a colorless oil. NMR spectrum (400 MHz, CDCl3) delta ppm: 3.82 (3H, s), 4.58-4.62 (4H, m), 5.29 (2H, dd, J=10, 1 Hz), 5.29 (2H, s), 5.39 (2H, dd, J=17, 1 Hz), 5.53 (2H, d, J=7 Hz), 5.96 (2H, ddt, J=17, 10, 5 Hz), 6.92 (2H, d, J=9 Hz), 7.37 (2H, d, J=9 Hz), 7.65 (1H, dd, J=8, 2 Hz), 8.00 (1H, br s), 8.09 (1H, d, J=8 Hz) IR spectrum nu max CHCl3 cm-1: 2237, 1721, 1613, 1516, 1266, 1031, 990 Mass spectrum m/z (FAB): 458 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; SULFAMIDE; In sulfolane; water; | Example 1 5-Cyanophthalid 5-Carboxyphthalid (50 g, 0.28 mole) and sulfamide (31 g, 0.32 mole) were suspended in sulfolane (150 mL). Thionylchloride (41 g, 0.34 mole) was added and the temperature was raised to 130-140° C. for 2 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool to 90° C. and water (150 mL) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (250 mL). The title compound was crystallized from acetic acid.Yield: 34.5 g, 77percent. DSC onset: 203° C. Purity: 98.5percent (hplc, peak area). 1H NMR (DMSO-d6, 500 MHz): 5.48 (2H, s), 8.03 (2H, s), 8.22 (1H, s). 13C NMR (DMSO-d6, 125 MHz): 70.0, 116.1, 188.0, 126.0, 127.5, 129.0, 132.8, 147.7, 169.3. | |
With thionyl chloride; SULFAMIDE; In sulfolane; water; | Example 2 5-Cyanophthalid Wet 5-carboxyphthalid (14 kg, approx. 6.3 kg dry, 35 mole) was suspended in sulfolane (23.5 kg). The water was removed by azeotropic distillation with toluene. Sulfamide (3.9 kg, 41 mole) and thionyl chloride (5.8 kg, 48 mole were added and the temperature was raised to 135-140° C. for 5 hours. At about 90° C. gas evolution took place. The mixture was allowed to cool to 90° C. and water (21.3 kg) was added. The temperature was held at 85-90° C. for 15 min and then the solution was cooled to 35° C. The crystals were filtered off and washed with water (14.2 kg). The title compound was crystallized from acetic acid. Yield: 3.8 kg, 68percent. Purity: 99.5percent (hplc, peak area). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-Oxo-1,3-dihydroisobenzofuran-5-carbaldehyde (2.01 g, 12.4 mmol) obtained from Example 4-(3) was suspended in tetrahydrofuran (50 ml), and after the suspension was cooled to 0°C, hydroxylamine hydrochloride (1.04 g, 14.9 mmol) in an aqueous solution of sodium hydroxide (1.0N; 14.8 ml, 14.8 mmol) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and then concentrated to one third of the volume under reduced pressure. To the concentrated solution was added water, and the product was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give crude 1-oxo-1,3-dihydroisobenzofuran-5-carbaldehyde oxime as a solid. The crude product was dissolved in tetrahydrofuran (50 ml), and the solution was cooled to 0°C, then triethylamine (3.04 g, 30 mmol) and anhydrous trifluoroacetic acid (3.13 g, 14.9 mmol) were added thereto. The resulting mixture was stirred at the same temperature for 30 minutes, and then warmed to room temperature followed by stirring for 30 minutes more. The reaction mixture was cooled again to 0°C, and a saturated aqueous solution of sodium hydrogen carbonate was added thereto. The reaction product was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous solution of sodium chloride. The extract was concentrated under reduced pressure to give a solid residue. The residue was subjected to chromatography on a silica gel (150 g) column (eluent; ethyl acetate : dichloromethane = 0 : 1 ~ 1 : 10) to afford the title compound (1.57 g, 79percent yield) as a solid (mp. 200-201°C). NMR spectrum (400 MHz, CDCl3) delta ppm: 5.40 (2H, s), 7.84 (1H, s), 7.85 (1H, d, J=9 Hz), 8.12 (1H, d, J=9 Hz) IR spectrum nu max KBr cm-1: 1760, 1055, 1003, 681 Mass spectrum m/z (EI): 159 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.9 g (75%) | In thionyl chloride; water; N,N-dimethyl-formamide; toluene; | Example 3 Preparation of 5-Cyanophthalide To a suspension of 4,4-dimethyl-2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline (23.1 g, 0.1 mol) in thionyl chloride (36 mL) is slowly added N,N-dimethylformamide (5 ml). The solution is heated at reflux for 1 hour and then allowed to cool to room temperature over 3 hours. Then toluene (150 mL) is added and the suspension is filtered and washed with toluene (2*50 mL). The wet crystals are taken into deionized water (150 mL) and the pH is adjusted to 8.0 with 25percent aqueous ammonia. The solid is filtered and washed with deionized water (2*50 mL) and dried at 60° C. under reduced pressure. Yield: 11.9 g (75percent) of an off-white product having a purity (HPLC, peak area)=92percent. An analytical pure sample is obtained by crystallisation from acetic acid or toluene. 1H NMR (DMSO d-6, 500 MHz): 5.48 (2H,s), 8.04 (2H,s+s), 8.22 (1H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; toluene; | Method A): 5-Cyanophthalid. Dry 5-carbamylphthalid (36 g, 0.2 mole) was suspended in toluene (600 mL) and thionyl-chloride (36 g, 0.3 mole) was added. DMF (2 mL) was added. The reaction mixture was heated at 75 ° C. for 6 hours. Toluene (100 mL) was removed by destillation and the remaining solution was cooled to room temperature. The crystals formed were filtered off and washed with toluene (150 mL) and water (100 mL). The product was recrystallized from toluene. Yield: 22 g, 80percent. DSC onset:203 ° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Example 3 A mixture of 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) and Cu(CN)2 (2.3 g, 0.02 mol) in NMP (60 mL) were stirred at 140° C. for 3hrs. Then solvent was removed by distilation under reduced pressure and the residue was refluxed in water (150 mL) for 10 minutes and allowed to cool to room temperature. Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.1 g) (HPLC 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine)palladium (0); In N,N-dimethyl-formamide; | Example 1 A mixture of Zn(CN)2 (2.4 g, 0.02 mol) and 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol,). Then the reaction was heated at 75° C. for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150 mL). Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.8 g) (HPLC 95percent). | |
With NaCN;tetrakis(triphenylphosphine)palladium (0); In N,N-dimethyl-formamide; | Example 2 A mixture of Zn(CN)2 (0.3 g, 0.00256 mol), NaCN (1 g, 0,02 mol) and 5-bromo-3H-isobenzofuran-1-one (4.2 g, 0.02 mol) in DMF (80 mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol). Then the reaction was heated at 75° C. for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150 mL). Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.7 g) (HPLC 94percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine)palladium (0); In N,N-dimethyl-formamide; | Example 4 A mixture of Zn(CN)2 (2.4 g, 0.02 mol) and 5-iodo-3H-isobenzofuran-1-one (5.24 g, 0.02 mol) in DMF (80 mL) were stirred at room temperature under an atmosphere of argon for 30 minutes. Then dissolved oxygen was removed by bubbling argon through the reaction mixture for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium (0) (1.2 g, 0.00096 mol). Then the reaction was heated at 75° C. for 3 hrs, and then the solvent was removed under reduce pressure and the residue poured into water (150 mL). Filtration and followed by drying in vacuo give the crude 5-cyano-3H-isobenzofuran-1-one (2.4 g) (HPLC 93percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With SULFAMIDE; In sulfolane; water; | Example 3 5-Cyanophthalid 5-Chlorocarbonylphthalid (24.3 g, 0.124 mole) was dissolved in sulfolane (51 g). Sulfamide (13.8 g 0.144 mole) was added and the temperature was raised to 135° C. for 3 hours. At about 90° C., gas evolution took place. The mixture was allowed to cool and water (100 g) was added. The temperature was held at 85-90° C. for 5 min and then the solution was cooled to 60° C. The crystals were filtered off and washed with water (60 g) and acetic acid (30 g). Then the title compound was dried in vacuo. Yield: 19 g, 96percent. Purity: 98.2percent (hplc, peak area). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroborane diethyl ether; In thionyl chloride; | Example 1 2-Chloromethyl-4-cyano-benzoyl chloride 1-Oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (25 g), boron trifluoride etherate (0.8ml), and benzyl triethyl ammonium chloride (0.72 g) were suspended in thionyl chloride (92 ml) and heated to reflux for 17 hours. Excess thionyl chloride was removed by distillation under nitrogen to give an internal temperature of 95° C., and heating to reflux was continued for another 24 hours. The product was purified by distillation under reduced pressure. Yield: 27.5 g, 92percent. Melting point 44 -44.5 C. 1H NMR (CDCl3, 400 MHz): 4.83 (2H, s), 7.74 (1H, dd, J=1, 8 Hz), 7.89 (1H, d, J=1 Hz), 8.25 (1H, d, J=8 Hz). 13C NMR (CDCl3, 100 MHz): 42.7, 116.8, 118.0, 132.2, 133.8, 134.0, 135.7, 140.0, 166.9. IR (KBr): v 3108, 3077, 2963, 2239, 1755, 1604, 1298, 1195, 1103, 944, 935, 840 cm-1. | |
With thionyl chloride; trifluoroborane diethyl ether; In 5,5-dimethyl-1,3-cyclohexadiene; | Example 2 2-Chloromethyl-4-cyano-benzoyl chloride 1-Oxo-1,3-dihydro-isobenzofuran-5-carbonitrile (80 g), boron trifluoride etherate (4,4 ml), benzyltriethyl ammonium chloride (9,2 g), and thionyl chloride (55 ml) were suspended in xylene (320 ml). The mixture was heated to reflux for 4 hours and volatiles were removed under reduced pressure. The product was purified by distillation under high vacuum. Yield: 78,2 g, 73percent. Melting point 44 -44.5° C. 1H NMR (CDCl3, 400 MHz): 4.83 (2H, s), 7.74 1H, dd, J=1, 8 Hz), 7.89 1H, d, J=1 Hz), 8.25 1H, d, J=8 Hz). 13C NMR (CDCl3, 100 MHz): 42.7, 116.8, 118.0, 132.2, 133.8, 134.0, 135.7, 140.0, 166.9. IR (KBr): v 3108, 3077, 2963, 2239, 1755, 1604, 1298, 1195, 1103, 944, 935, 840 cm-1. |
Tags: 82104-74-3 synthesis path| 82104-74-3 SDS| 82104-74-3 COA| 82104-74-3 purity| 82104-74-3 application| 82104-74-3 NMR| 82104-74-3 COA| 82104-74-3 structure
A400504 [89877-62-3]
3-Oxo-1,3-dihydroisobenzofuran-5-carbonitrile
Similarity: 0.90
A169917 [72985-23-0]
6-Methylisobenzofuran-1(3H)-one
Similarity: 0.83
A222724 [23405-32-5]
Methyl 1-oxo-1,3-dihydroisobenzofuran-5-carboxylate
Similarity: 0.83
A330073 [54120-64-8]
5-Methylisobenzofuran-1(3H)-one
Similarity: 0.83
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