Structure of 260371-16-2
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CAS No. : | 260371-16-2 |
Formula : | C15H10FNO2 |
M.W : | 255.24 |
SMILES Code : | N#CC1=CC=C(C(C2=CC=C(F)C=C2)=O)C(CO)=C1 |
MDL No. : | MFCD08741682 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302+H312+H332-H315-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* 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 |
---|---|---|
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: |
Tags: 260371-16-2 synthesis path| 260371-16-2 SDS| 260371-16-2 COA| 260371-16-2 purity| 260371-16-2 application| 260371-16-2 NMR| 260371-16-2 COA| 260371-16-2 structure
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