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CAS No. : | 82104-74-3 | MDL No. : | MFCD01072882 |
Formula : | C9H5NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XEEGWTLAFIZLSF-UHFFFAOYSA-N |
M.W : | 159.14 | Pubchem ID : | 821218 |
Synonyms : |
|
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 : | 50.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.9 cm/s |
Log Po/w (iLOGP) : | 1.4 |
Log Po/w (XLOGP3) : | 0.52 |
Log Po/w (WLOGP) : | 1.08 |
Log Po/w (MLOGP) : | 0.89 |
Log Po/w (SILICOS-IT) : | 2.12 |
Consensus Log Po/w : | 1.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.52 |
Solubility : | 4.76 mg/ml ; 0.0299 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.14 |
Solubility : | 11.5 mg/ml ; 0.072 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.65 |
Solubility : | 0.355 mg/ml ; 0.00223 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.86 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280 | UN#: | N/A |
Hazard Statements: | H302+H312+H332 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
86% | Stage #2: at -6 - -2℃; |
A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000ml methylene dichloride at-6 to-2 C and worked up according to the method of Example 1, resulting in a thick semi-solid. This is triturated with 500ml of isopropyl alcohol (IPA) and cooled to0-5 C to provide 5-cyano-1- (4-fluorophenyl)-1, 3-dihydroisobenzofuran (2b) as a solid. This solid is filtered and washed with cold 50ml of IPA. Yield: 130-140g HPLC purity: 99.32percent |
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 |
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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 |
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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 |
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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 |
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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 |
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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 |
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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. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium tetrahydroborate; magnesium; In tetrahydrofuran; ethanol; water; ethyl acetate; | Example 1 (4-Cyano-2-hydroxymethylphenyl)(4-fluorophenyl)methanol A solution of 4-fluorophenylmagnesium bromide, prepared from 4-fluorobromobenzene (605 g, 3.45 mole) and magnesium turnings (107 g, 4.4 mole) in dry THF (1200 mL), is added dropwise to a suspension of 5-cyanophthalid (500 g, 3.14 mole) in dry THF (3000 mL). The temperature is kept below 5° C. After the addition is complete, the reaction mixture is stirred the night over at room temperature. Ethanol (4500 mL) is added to the reaction mixture and NaBH4 (238 g, 6.30 mole) is added to the mixture in portions of 50 grams and is stirred the night over at room temperature. About 2/3 of the solvents is removed in vacuo and water (4000 mL) is added to the reaction mixture. The resulting solution is extracted with EtOAc (2*500 mL). Evaporation of the solvents leaves a crude title compound (780 g) as an oil which is deemed pure enough for further reaction. A pure sample is obtained after column chromatography on silica gel using EtOAc/n-Heptane (1/1) as eluent. The title compound is obtained as crystals after evaporation of the eluent. DSC onset: 116.5° C. 1H NMR (DMSO-db, 500 MHz): 4.42 (1H, dd J=13 Hz, J=5 Hz), 4.53 (1H, dd J=13 Hz, J=5 Hz), 5.45 (1H, t J=5 Hz), 5.98 (1H, d J=3 Hz), 6.14 (1H, d J=3 Hz), 7.15 (2H, J=10 Hz), 7.35 (2H, m), 7.74 (1H, d J=8.5 Hz), 7.77 (1H, d J=8.5 Hz), 7.83 (1H, s). Anal. calcd. for C15H12N1F1O2; C, 70.02; H, 4.71; N, 5.45. Found C, 70.01; H, 4.71; N, 5.51. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With thionyl chloride; at 80℃; for 6h;Heating / reflux;Product distribution / selectivity; | Example 2: synthesis of cyanophthalide starting from 5-hydroxamyl phthalide; Hydroxylamine HC1 (8.86 g, 0.1275 mole), triethylamine (12.9 g, 0.1275 mole) and tetrahydrofuran (30 ml) are introduced into a flask. The system is brought to 10°C. A solution of 5-chlorocarbonyl phthalide (100 ml corresponding to approximately 11 g of 5-chlorocarbonyl phthalide 0.056 mole) is added dropwise over a period of 1 hour. The whole is left under agitation for 1 hour and is then evaporated under vacuum. The appearance of a solid is observed and 5-hydroxamyl phthalide 10 g (molar yield 92percent Ppercent=99.16percent) is filtered off. 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s 7.98(1H,s), 9.30 (1H,s), 11.52(1H,s) 2 g of 5-hydroxamyl phthalide (0.01 mole) are introduced into a flask to which thionyl chloride (15 ml) is added, and the whole is heated under reflux (80°C) to give, after 6 hours, a light yellow solution. Toluene (20 ml) is introduced. The whole is evaporated under vacuum to leave a residue which is taken up with toluene (20 ml). The whole is heated under reflux and precipitation is awaited. Filtration is carried out to give 5-cyanophthalide 1.5 g (molar yield 91 percent) (purity HPLC (Apercent) 99percent). 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s), 7.98(1H,s); Example 3: one-pot synthesis of cyanophthalide starting from 5-carboxyphthalide; There are introduced into a flask in an inert nitrogen atmosphere: 5-carboxyphthalide (50 g, 0.2806 mole), thionyl chloride (125 ml, 1.71 mole), and dimethylformamide (0.5 ml). The system is heated under reflux (60°C) for 3 hours. The system is returned to ambient temperature. The system is evaporated under vacuum to leave a residue, and toluene (3 x 100 ml) is introduced; a solid is obtained which is taken up with tetrahydrofuran (500 ml). A solution containing 5-chlorocarbonyl phthalide (purity HPLC (Apercent) 98percent) 50 g (titrated in solution, molar yield 91 percent) is obtained. An aqueous hydroxylamine solution (18 ml, 12.5 g, 0.378 mole) is introduced into a flask. The system is brought to 10°C. A chlorocarbonyl phthalide solution (100 ml corresponding to approximately 11 g of chlorocarbonyl phthalide 0.056 mole) is introduced (period of introduction 1 hour). The appearance of a solid is observed during the dropwise addition. The whole is left under agitation overnight and then filtered. The solid is washed with water (100 ml) and 5-hydroxamyl phthalide 10.5 g (molar yield 92percent Ppercent=99.percent) is obtained. 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s), 7.98(1H,s),9.30 (1H,s), 11.52(1H,s) 2 g of 5-hydroxamyl phthalide (0.01 mole) are introduced into a flask to which thionyl chloride (15 ml) is added and the whole is heated under reflux (80°C) to give, after 6 hours, a light yellow solution. Toluene (20 ml) is introduced. The whole is evaporated under vacuum to leave a residue which is taken up with toluene (20 ml). The whole is heated under reflux and precipitation is awaited. Filtration is carried out and cyanophthalide 1.5 g (molar yield 91 percent) (purity HPLC (Apercent) 99percent) is obtained. 1HNMR (DMSO-d6 400MHz) 5.45(2H,s), 7.87(1Hs), 7.91(1H,s), 7.98(1H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; dmap; acetic anhydride; diisobutylaluminium hydride; In dichloromethane; toluene; | a) 5-Cyano-1,3-dihydro-2-benzofuran-1-yl acetate To a stirred solution of 1-oxo-1,3-dihydro-2-benzofuran-5-carbonitrile (1.0 g, 6.28 mmol) in dry dichloromethane (50 mL) at -78° C. under nitrogen was added 1M DIBAL-H in toluene (7.54 mL, 7.54 mmol). After stirring for 4 h 4-dimethylaminopyridine (850 mg, 6.9 mmol) and pyridine (1.52 mL, 18.9 mmol) were added; acetic anhydride (2.36 mL, 25.1 mmol) was then added dropwise and the reaction stirred at -78° C. for 12 h. The reaction mixture was neutralised with aqueous ammonium chloride and extracted with dichloromethane, dried (MgSO4), filtered and the solvent removed in vacuo. The title compound was obtained as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
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Example 1 Synthesis of 4-[3-[1, 3]-dioxolan-2-yl-1-(4-fluorophenyl)-1-hydroxypropyl]-3-hydroxymethylbenzonitrile To a suspension of <strong>[82104-74-3]1-oxo-1,3-dihydro-isobenzofuran-5-carbonitrile</strong> 5 (15 g) in THF (50 mL, anhydrous) at 5-10° C. under argon was added 4-fluorophenylmagnsium bromide in ethyl ether (50 ml, 2 m). The reaction mixture was warmed to room temperature and stirred for 5 h. At that time, a second Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxolane (25 g) with Mg powder in THF was added at room temperature. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was then quenched at 0° C. with aqueous ammonium chloride. The organic phase was separated and washed with water (50 mL), and concentrated to give a crude product. It was purified by flash chromatography (EtOAc:Hexane 1:1) to give 17 g of the titled product 5. 1H NMR (CDCl3, 6): delta 1.54-1.66 (m, 1H), 1.75-1.88 (m, 1H), 2.18-2.30 (m, 1H), 2.36-2.47 (m, 1H), 356 (broad s, 1H), 3.80-4.00 (m, 4H), 4.10-4.17 (d, J=8 Hz, 1H), 4.22-4.30 (d, J=8 HZ, 1H), 4.86 (t, J=3 Hz, 1H), 5.50 (broad s, 1H), 6.8-7.10 (m, 2H), 7.16-7.26 (m, 2H), 7.50-7.70 (m, 3H). 13C NMR (CDCl3, 6): delta 27.2, 35.8, 63.1, 64.9, 77.8, 103.4, 111.4, 114.7, 115.0, 118.3, 127.1, 127.6, 127.3, 131.1, 134.7, 141.1, 149.7, 159.9, 163.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-Cyano-1 -oxo-2-benzofuran (75.0 g, 0.47 mol) is added to in situ prepared Ghgnard solution of methylmagnesium iodide (470.5 g, 2.83 mol) in tetrahydrofuran at -300C and stirred for one hour at -300C. The reaction mixture is quenched with ammonium chloride solution and aqueous layer is extracted with ethyl acetate. Combined organic layers are washed with demineralized water (1x40 ml_) followed by brine (1x30 ml_) and finally dried over sodium sulphate. Removal of ethyl acetate under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 80:20) to give 3-hydroxymethyl-4-(1 -hydroxy- 1 -methylethyl)benzonitrile. |
Yield | Reaction Conditions | Operation in experiment |
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86% | A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000ml methylene dichloride at-6 to-2 C and worked up according to the method of Example 1, resulting in a thick semi-solid. This is triturated with 500ml of isopropyl alcohol (IPA) and cooled to0-5 C to provide 5-cyano-1- (4-fluorophenyl)-1, 3-dihydroisobenzofuran (2b) as a solid. This solid is filtered and washed with cold 50ml of IPA. Yield: 130-140g HPLC purity: 99.32percent | |
A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000 ml toluene at-6to-2 C and worked-up as explained in Example 4 to provide a thick semi-solid. This is triturated with 500mi of isopropyl alcohol (IPA) and cooled to0-5 C to provide 2b as a solid. The solid is filtered and washed with 50ml of cold IPA. Dry weight :105-110g Purity by HPLC: 97.5percent |
Yield | Reaction Conditions | Operation in experiment |
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A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4-fluoro bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry300moi tetrahydrofuran, is added to a suspension of 100g 5-cyanophthalide (0.628 moles) in1000ml methylene dichloride at-6to-2 C. After the reaction is completed, the reaction mass is quenched with100ml 20percent aqueous ammonium chloride solution. The organic layer is separated and diluted with100ml of methanol. Slowly, 12g of sodium borohydride (0.324moles) added over a period of one hour at below25 C, and the same temperature is maintained for 4-6 hours. The mixture is then cooled to 5-10 C, maintained for 2 hours and then the precipitated solid is filtered. The solid is washed with cold water and dried under vacuum below40 C to provide pure4-cyano-2-hydroxymethylphenyl- (4-fluorophenyl) methanol (5b). Yield: 115-120g HPLC purity: 99.2percent |
Yield | Reaction Conditions | Operation in experiment |
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86.2% | With hydroxylamine; In ethanol; water; at 20℃; for 63h;Heating / reflux; | Cyanoethylation of piperizine: A solution of 5-cyanophthalide (1 g, 6.28 mmol) and hydroxylamine (50percent in water, 0.77 cm3, 0.83 g, 12.6 mmol, 2 eq) in EtOH (50 cm3) was stirred at room temperature for 60 hours and then under reflux for 3 hours. After cooling to room temperature and standing overnight, the solid formed was collected by filtration and dried in high vacuum line to give the product N'-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-carboximidamide (1.04 g, 86.2percent) as a white solid, mp 223-226° C. (decomposed). Reaction of 4-chlorobenzonitrile to give the product 4-chloro-N'-hydroxybenzimidamide: |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; dichloromethane; at -78 - 20℃; for 16h; | 20.0 g (125.6 mmol) of 5-cyanophthalimide was dissolved in 200 mi of anhydrous dichloromethane. The solution was cooled to -780C, and 188 mi of 4-methoxyphenylmagnesium bromide (1 M in THF, 188 mmol) was added drop wise. The mixture was raised to room temperature and stirred for 16 hrs, followed by addition of a saturated ammonium chloride solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, thereby yielding a yellow compound, represented by Formula 3. The compound thus obtained was used in the next reaction without further purification.[194][195] 1H NMR(400 MHz, CDCl3) : 3.89(s, 3H), 4.60(4 J=6.0 Hz, 2H), 695(4 J=7.2 Hz, 2H), 7.48(4 J=7.6 Hz, IH), 7.65(4 J=7.6 Hz, IH), 7.75(4 J=7.2 Hz, 2H), 7.86(s, IH). |
Yield | Reaction Conditions | Operation in experiment |
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50 gm of 5-Cyano phthalide was stirred in 150 ml of THF at -5 °C. 227 gm of l-(4-fluorophenyl) magnesium bromide solution obtained in above step a) was added to the above solution and stirred for about 15 minutes at -5 0C. 324 gm of l-[3-(dimethylamino) propyl] magnesium chloride solution obtained in step b) was added slowly to the reaction mass at -5 0C and then stirred for about 30 minutes at room temperature. The reaction mixture was quenched into cold water (650 ml). Reaction mass pH was adjusted to about 2.0 with 36percent aqueous hydrochloric acid (94 ml) and washed the reaction mixture with toluene (2 X 150 ml). The aqueous layer was separated, toluene (300 ml) was added and pH was adjusted to about 7.5 with aqueous ammonia (45 ml) . The organic layer was separated and aqueous layer was extracted with toluene (1 X 200 ml; 1 X 100 ml). Total organic layer was washed with water (1 X 250 ml) followed by saturated aqueous sodium chloride solution (1 X 250 ml). The final organic layer was distilled completely under vacuum to get the residue of 70 gm. | ||
50 gm of 5-Cyano phthalide was stirred in 150 ml of THF at -5C. 227 gm of 1-(4-fluorophenyl)magnesium bromide solution obtained in above step a) was added to the above solution and stirred for about 15 minutes at -5C. 324 gm of 1-[3-(dimethylamino) propyl]magnesium chloride solution obtained in step b) was added slowly to the reaction mass at -5 C. and then stirred for about 30 minutes at room temperature.The reaction mixture was quenched into cold water (650 ml).Reaction mass pH was adjusted to about 2.0 with 36percent aqueous hydrochloric acid (94 ml) and washed the reaction mixture with toluene (2*150 ml).The aqueous layer was separated, toluene (300 ml) was added and pH was adjusted to about 7.5 with aqueous ammonia (45 ml).The organic layer was separated and aqueous layer was extracted with toluene (1*200 ml; 1*100 ml).Total organic layer was washed with water (1*250 ml) followed by saturated aqueous sodium chloride solution (1*250 ml).The final organic layer was distilled completely under vacuum to get the residue of 70 gm. |
Yield | Reaction Conditions | Operation in experiment |
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A solution of 4-fluorophenyl magnesium bromide, prepared from 4-fluoro-1-bromobenzene (71.6 g) and magnesium (11.3 g) in THF (100 mL), is added to a suspension of 5-cyanophthalide (50 g) in dichloromethane (150 mL) at 5 to -5 C. and stirred at that temperature for 30 minutes. After the completion of the reaction, a solution of 3-N,N-dimethylaminopropyl magnesium chloride, prepared by reacting 3-N,N-dimethylaminopropyl chloride (65%, 173.6 g) in toluene (200 mL) with magnesium (22.6 g) in THF (75 mL), is added at 5 to -5 C. After completion of the reaction, the reaction is quenched with aqueous ammonium chloride (5%, 250 mL). The mass is filtered and the solid is washed with toluene (50 mL). Water (250 mL) is added to the filtrate. The filtrate is treated with aqueous HBr (47%, 38 mL) at 25-35 C. and stirred for 2 hours. The solid is collected by filtration, washed with water (2×50 mL) and toluene (2×50 mL), and dried at 60-70 C. for 6 hours. (Yield: 110 g). | ||
102.1 g | To a 2000 mL four-necked flask equipped with a stirring blade and a thermometer and purged with argon, 150 mL of THF and 60 g (377.0 mmol) of 5-cyanophthalide (1) are added and stirred at 0 to 15 C. 4-magnesium bromidefluorobenzene was added dropwise within a temperature range of 0 to 15 C. over a dropping time of 3 hours. After the dropping, the mixture was stirred for 1 hour, and a Grignard reagent of 3-magnesium chloride-N, N-dimethyl-1-propanamine was added dropwise within a dropping time of 3 hours within a temperature range of 0 to 15 C. After dropping, the mixture was stirred for 1 hour, and 18 mL of distilled water was added dropwise within a temperature range of 0 to 15 C. Thereafter, 100 g of acetic acid and 220 mL of distilled water were mixed to prepare an aqueous acetic acid solution, and the aqueous acetic acid solution was added dropwise within a temperature range of 0 to 30 C. After the dropping, the solution was concentrated under reduced pressure in the temperature range of 40 to 60 C. to concentrate THF. Distilled water (360 mL), toluene (480 mL) and 25% aqueous ammonia (50 g) are added to the concentrated residue, and the mixture is stirred at 60 C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and 90 mL of toluene was added to the aqueous layer, followed by stirring at 60 C. for 30 minutes. After stirring, the organic layer and the aqueous layer are separated, and the obtained two organic layers are mixed. 90 mL of distilled water was added to the mixed organic layer, and the mixture was stirred at 60-80 C. for 30 minutes. After stirring, the organic layer and the aqueous layer were separated, and the resulting organic layer was concentrated under reduced pressure at an external temperature of 60 C. Add 360 mL of diethyl ether to the concentrated residue, stir at 25 C. to homogenize the solution, add 360 mL of distilled water and 19.1 g (113.1 mmol) of 48% hydrobromic acid at a temperature near room temperature, and stir for 30 minutes. Then, precipitation of crystals was confirmed. After confirming the precipitation of crystals, 41.3 g (245.1 mmol) of 48% hydrobromic acid was added at a temperature close to room temperature, followed by concentration under reduced pressure, and diethyl ether was concentrated. After concentration in diethyl ether, the precipitated crystals were filtered off under reduced pressure, and the filtered crystals were washed with 120 mL of distilled water and 120 mL of diethyl ether. The obtained white crystals were dried under reduced pressure at 30-50 C. for 12 hours to obtain white crystals.4- [4- (Dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile102.1 g (241.3 mmol) of hydrobromide was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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A solution of 4-fluorophenyl magnesium bromide (prepared from 153.3g 4- flouro bromobenzene, 25.3g magnesium turnings and Iodine (0.05gm) in dry 300ml tetrahydrofuran), was added to a suspension of lOOg 5-cyanophthalide in 900ml dichloromethane at -4 to -2°C. After the completion of the reaction a solution of 3- (N,N-dimethylamino)propyl magnesium chloride in toluene/THF mixture [generated in situ by reacting 175g 3-(N,N-dimethylamino)propyl chloride in 350ml toluene with 41.6gm magnesium turnings, 6.0 gin 4-bromofluorobenzene and Iodine in dry tetrahydrofuran] was added between 0 to -50C. The reaction mass was stirred for 3-4 hours. After completion of the reaction, the reaction mass was quenched with 20percent aqueous ammonium chloride solution. The organic layer was separated and washed with water. Organic layer was then extracted with 20percent acetic acid. The aqueous acid extract was cooled and pH was adjusted to 8.5 to 9.0 using liquor ammonia, and extracted with toluene 3 x 600ml. The toluene layer was washed with water, dried and then treated with carbon. Reaction mixture was filtered and subjected to salt formation to get Diol acid addition salts. |
Yield | Reaction Conditions | Operation in experiment |
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A suspension of R-24 (l.Og, 6.28 mmol) and NaOH (1M aqueous solution, 6.28 mL, 6.28 mmol) in THF (10 mL) is stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is then suspended in DMF (25 mL) and iodoethane (0.53 mL, 6.59 mmol) is added. The reaction mixture is then stirred at 80 °C for 0.5 hour and then cooled to 0 °C and saturated aqueous NH4C1 is added. The product is extracted into EtOAc and the organics are washed with water and brine and dried with Na2S04, filtered and concentrated in vacuo to give R-25 (1.20 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Fluorophenyl magnesium bromide (86mL 1.1M solution in THF, 94mmol) was added dropwise to 5-cyano-3H-isobenzofuran-l-one (15g, 94mmol) in 150mL THF at 0-5°C to give solution A. 4-Fluorophenyl magnesium bromide (188mL 1.0M solution in THF, 180mmol) was added dropwise to 4-fluorothiophenol (24.2g, 188mmol) in lOOmL THF at 0-5°C. 155mL of the resulting solution was added to solution A from above at 0-5°C. The reaction mixture was stirred at room temperature overnight and cooled to 0-5°C. N-(Dimethyl)-propyl-l- magnesiumchloride (79mL 1.2M solution in THF, 94mmol) was added. 100 mL saturated aqueous ammonium chloride was added. The mixture was filtrated and the two phases were separated. The aqueous phase was extracted with lOOmL ethyl acetate and 50mL toluene. The combined organic phases were extracted with 2 x IN H2SO4 (aq). The organic phase was concentrated in vacuo and toluene and isopropyl acetate were added. The organic phase was extracted with 2 x IN H2SO4 (aq). The combined H2SO4 phases were basified with concentrated aqueous ammonia and extracted with toluene. 2N HCl (aq) (40mL) was added to the organic phase at room temperature. The mixture was stirred at room temperature overnight. A solid was formed. The solid was reprecipitated from 50mL isopropyl acetate. The solid was washed with diethyl ether to give the intermediate of general structure III. The intermediate III Rl=cyano, R2=4-(4-fluoro-phenylsulfanyl)-phenyl was ring-closed analogously to the method described for example 1. (l-(3-dimethylamino-propyl)-l- naphthalen-l-yl-l,3-dihydro-isobenzofuran-5-carbonitrile). The title compound was isolated as the oxalate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.2 g | Grignard Reaction Mixture: To a stirred solution/suspension of 5-cyanophthalide (15 g, 94.2 mmol), THF (250 mL), and magnesium bromide di ethyl etherate (6.08 g, 23.6 mmol) under nitrogen and with mechanical stirring at 0 °C was added dropwise a solution of 4- fluorophenylmagnesium bromide in THF ( 0.85 M) until less than 5 percent of the 5- cyanophthalide remained (ca. 120 mL). In a separate flask, to a stirred suspension of sodium hydride (5.65 g, 236 mmol) in THF (50 mL) was added dropwise a solution of 4-fluorothiophenol (24.2 g, 188 mmol) in THF (50 mL) with cooling using a water bath. After the exothermic addition was complete, the resultant solution was stirred for 1 h at 25 °C. This solution was then added dropwise to the Grignard Reaction Mixture at 0 °C, and was allowed to stir at 25 °C overnight. The mixture was cooled to 10-15 °C, and water (200 mL) was added dropwise. Sodium borohydride (1.78 g, 47.1 mmol) was added neat in 5 portions, and the mixture was stirred at 25 °C until analysis by HPLC indicated that the reduction was complete. The pH of the mixture was adjusted to 3-5 by the addition of aqueous hydrochloric acid (4 M). The organic phase was then separated by decantation due to the thickness of the aqueous phase. The aqueous phase was extracted with isopropyl acetate (200 mL) and the organic phases were combined and evaporated under reduced pressure. The residue was dissolved in isopropyl acetate (200 mL) and was washed with water (100 mL) and an aqueous solution of sodium hydroxide (1.0 M, 100 mL). The organic phase was dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give an oil (48 g). HPLC analysis indicated a purity of 46 percent. This oil was dissolved by heating in toluene (140 mL) at reflux, and then was allowed to cool to 25 °C over 1 h. The solid formed was removed by filtration, washed with toluene (2 x 20 mL) and dried under vacuum (40 °C) to give 21.2 g (purity 98.9 percent by HPLC) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Oxone; 2-iodo-3,4,5,6-tetramethylbenzoic acid; In water; acetonitrile; at 30℃; for 8h;Green chemistry; | General procedure: In a typical experiment, a round bottom flask containing 4?6mL of acetonitrile/water mixture (1:1) was charged with 0.5?1.0mmol of the diol, 5molpercent of TetMe-IA, and oxone (2equiv). The resulting mixture was stirred at rt for benzylic diols and at 45°C for aliphatic diols. At the end of the reaction, as judged from TLC analysis, little water was added to dissolve the inorganic salts, and the organic matter was extracted with EtOAc at least two times. The combined extract was dried over anhydrous Na2SO4, concentrated in vacuo to obtain the crude product, which was subjected to silica-gel column chromatography using ethyl acetate/pet ether to isolate the pure product. |
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
[ 89877-62-3 ]
3-Oxo-1,3-dihydroisobenzofuran-5-carbonitrile
Similarity: 0.90
[ 72985-23-0 ]
6-Methylisobenzofuran-1(3H)-one
Similarity: 0.83
[ 23405-32-5 ]
Methyl 1-oxo-1,3-dihydroisobenzofuran-5-carboxylate
Similarity: 0.83
[ 54120-64-8 ]
5-Methylisobenzofuran-1(3H)-one
Similarity: 0.83
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