CN111533662A - Synthesis method of citalopram intermediate - Google Patents
Synthesis method of citalopram intermediate Download PDFInfo
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- CN111533662A CN111533662A CN202010263399.8A CN202010263399A CN111533662A CN 111533662 A CN111533662 A CN 111533662A CN 202010263399 A CN202010263399 A CN 202010263399A CN 111533662 A CN111533662 A CN 111533662A
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Abstract
The invention provides a preparation method of citalopram intermediate 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile. The method has the advantages of cheap and easily obtained raw materials, short reaction steps, high yield, simple post-treatment, easy operation and the like, reduces the cost, has certain technical advantages, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method of a citalopram intermediate 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile. The information provided is only intended to assist the reader in understanding. Neither the information provided nor the references cited are admissions of prior art for the invention. Each reference cited is incorporated herein in its entirety and can be used for any purpose.
Background
Citalopram (Citalopram) was developed by LUNDBECK, denmark as a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) that selectively inhibits the 5-HT transporter, blocks the reuptake of 5-HT by the presynaptic membrane, prolongs and increases the effects of 5-HT, and thus produces antidepressant effects.
4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile is an important intermediate for preparing citalopram bulk drug, and the synthetic route thereof is reported at home and abroad, and is summarized as follows:
bogeso et al (US4650884) use 5-cyanophthalide as starting material, and perform Grignard reaction with p-fluorophenyl magnesium bromide and 3, 3-dimethylaminopropyl magnesium chloride twice, and then hydrolyze to obtain 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile according to the following synthetic route:
the method has short route, but the starting raw materials are expensive and not easy to obtain, and the synthesis pollution is large. In addition, the reaction needs twice lattice reagents, and the reaction is harsh; in addition, the used format reagent is not a common reagent and is expensive; and secondly, the reaction selectivity is poor, the yield is low, and the finishing cost is high.
Similar methods have been reported in other documents and patents, mainly aiming at solving the problem of 5-cyanophthalide as a starting material, and mainly differing in that the substituent at the 5-position is different, and the cyano group is constructed by coupling or amide dehydration or the like at a later stage.
The document (J.Am.chem.Soc.2016,138,3294-3297) reports a novel process for the synthesis of 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile by the following route:
the method comprises the steps of constructing a cyano group by oxidizing m-xylene which is cheap and is used as a starting material, converting methyl into hydroxymethyl through 3 steps of reaction, and reacting with ketone under the action of tert-butyl lithium to generate a target intermediate. The intermediate uses a class of solvents of carbon tetrachloride and heavy metal of silver nitrate, the final step uses extremely dangerous tert-butyl lithium, the yield is low, the intermediate is purified by column chromatography, the total cost is high, and the method is not beneficial to industrial production.
Aiming at the defects of the process route, the invention provides a synthetic route of a citalopram intermediate 4- (4- (dimethylamine group) -1- (4-fluorophenyl group) -1-hydroxybutyl group) -3- (hydroxymethyl) benzonitrile and a preparation method thereof. The method has the advantages of short route, easily obtained raw materials, low cost, simple and convenient operation, convenient separation and purification in each step, high yield and good product quality, and can be used for large-scale industrial preparation of citalopram intermediate and raw material medicines.
Disclosure of Invention
The application provides a synthetic route of a citalopram intermediate 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile and a preparation method thereof, and the compound can be applied to preparation of citalopram bulk drugs.
The invention provides a method for preparing a citalopram intermediate VI, which comprises the following steps:
wherein, in the process of the step (1), the compound of the formula I and dimethylamine or hydrochloride thereof react at 0-150 ℃ to prepare the compound of the formula II under the condition of solvent or no solvent;
wherein in the process of the step (2), the compound of the formula III reacts with the compound of the formula II under the action of a metal reagent in an aprotic organic solvent at a temperature of between 78 ℃ below zero and 30 ℃ under the protection of inert gas to prepare a compound of the formula IV;
wherein in the process of the step (3), the compound shown in the formula IV reacts with a reducing agent in an organic solvent at the temperature of-20-100 ℃ to prepare a compound shown in the formula V;
wherein, in the process of the step (4), under the protection of inert gas at 50-200 ℃, the compound of the formula V and metal cyanide react in a solvent under the action of an organic phosphine ligand and a transition metal catalyst to prepare the compound of the formula VI.
In some embodiments, during step (1), a compound of formula I and dimethylamine, or its hydrochloride salt, are reacted at 60 ℃ to 100 ℃ with or without a solvent to produce a compound of formula II, wherein the solvent is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N-dimethylformamide, N-diethylacetamide, N-methylpyrrolidone, or dimethylsulphoxide; the equivalent of dimethylamine or hydrochloride thereof is 1.0-5.0 equivalents.
In some embodiments, during step (1), under the action of a base, the compound of formula I and dimethylamine or the hydrochloride thereof react at 0 ℃ to 150 ℃ under the action of a solvent or no solvent to prepare the compound of formula II, wherein the base is selected from potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine or pyridine, and the using equivalent of the base is 1.0 to 5.0.
In some embodiments, during step (2), the compound of formula IV is prepared by reacting a compound of formula III with a compound of formula II in an aprotic organic solvent under the influence of a metal reagent at-78 ℃ to 0 ℃ under nitrogen atmosphere, wherein the aprotic organic solvent is selected from tetrahydrofuran or dimethyltetrahydrofuran; the metal reagent is selected from n-butyl lithium, isopropyl magnesium bromide or isopropyl magnesium chloride.
In some embodiments, the compound of formula IV is reacted with a reducing agent in tetrahydrofuran at-20 ℃ to 80 ℃ during step (3) to produce the compound of formula V; preferably, the reducing agent is selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, lithium aluminum hydride, sodium borohydride/I2Sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride, sodium borohydride/trifluoroacetic acid or sodium borohydride/sulfuric acid; more preferably, the reducing agent is selected from sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride or sodium borohydride/sulfuric acid.
In some embodiments, the compound of formula V is reacted with a metal cyanide under the action of an organophosphine ligand and a transition metal catalyst in a solvent at 70 ℃ to 150 ℃ under the protection of nitrogen gas during step (4) to produce the compound of formula VI, wherein the compound of formula V is reacted with the metal cyanide under the action of the organophosphine ligand and the transition metal catalyst in a solvent at 50 ℃ to 200 ℃ under the protection of an inert gas during step (4) to produce the compound of formula VI.
In some embodiments, during step (4), the compound of formula V is reacted with a metal cyanide under the action of an organophosphine ligand and a transition metal catalyst in a solvent at 50 ℃ to 200 ℃ under inert gas to produce the compound of formula VI, wherein the metal cyanide is zinc cyanide or cuprous cyanide.
In other embodiments, during step (4), reacting a compound of formula V with a metal cyanide in a solvent under an inert gas atmosphere at 50 ℃ to 200 ℃ under the action of an organophosphine ligand and a transition metal catalyst to produce a compound of formula VI, wherein the organophosphine ligand is selected from 1,1' -bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl, or triphenylphosphine; the transition metal catalyst is selected from bis (triphenylphosphine) nickel chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
The present invention also provides another process for the preparation of a citalopram intermediate comprising the steps of:
wherein in the process of the step (1), the compound shown in the formula III reacts with sodium borohydride/boron trifluoride ethyl ether, sodium borohydride/zinc chloride or sodium borohydride/sulfuric acid in tetrahydrofuran at the temperature of-20-80 ℃ to prepare a compound shown in the formula VII;
wherein in the process of the step (2), under the protection of nitrogen gas and at-78-0 ℃, a compound of formula VII in tetrahydrofuran or 2-methyltetrahydrofuran reacts with a compound of formula II under the action of n-butyl lithium, isopropyl magnesium bromide or isopropyl magnesium chloride to prepare a compound of formula V;
in the process of the step (3), under the protection of nitrogen and at 70-150 ℃, reacting a compound shown in a formula V with metal cyanide in a solvent under the action of an organic phosphine ligand and a transition metal catalyst to prepare a compound shown in a formula VI, wherein the solvent is selected from one or more of water, ethanol, isopropanol, acetonitrile, dioxane, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; the metal cyanide is zinc cyanide or cuprous cyanide; the organophosphorus ligand is selected from 1,1' -bis (diphenylphosphino) ferrocene, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl or triphenylphosphine; the transition metal catalyst is selected from bis (triphenylphosphine) nickel chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
By means of the scheme, compared with the prior art, the invention has the following advantages: the invention provides a preparation method of a citalopram intermediate 4- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile, which can be used for citalopram raw material medicines. The method has the advantages of short synthetic route, cheap and easily-obtained raw materials, simple overall process and strong operability, and is suitable for industrial production.
Detailed Description
The preparation process described in the present invention is further illustrated by the following examples, which include, but are not limited to.
The following examples are intended only to illustrate specific embodiments of the present invention, so as to enable those skilled in the art to more fully understand the present invention, but not to limit the present invention in any way. In the embodiments of the present invention, technical means or methods which are not specifically described are conventional in the art.
The chemicals used in the following examples are all commercially available chemicals.
In an exemplary embodiment of the invention, the synthetic route for formula VI is as follows:
(1) route one
(2) Route two
In the above synthetic routes, those skilled in the art can also make changes to the above synthetic routes, such as changing specific reaction conditions or making adjustments to the synthetic route of one or more steps, etc., as needed, and such changes are within the scope of the present application without departing from the spirit of the present invention.
EXAMPLE 14 Synthesis of- (dimethylamino) -1- (4-fluorophenyl) butan-1-one hydrochloride
To a 250mL three-necked flask were added 4-chloro-1- (4-fluorophenyl) butan-1-one (20.1g,0.1 mmol), dimethylamine (40% in water, 20mL) and ethanol (100mL) in that order. The reaction is refluxed for 16h, cooled to room temperature and then concentrated under reduced pressure, and then water is added and ethyl acetate is extracted. The organic phase is washed once more with water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was dissolved in acetone, hydrogen chloride gas was introduced, stirred for 1h and filtered under suction to give the hydrochloride of formula II (21.3g, 86.9%).
EXAMPLE 24 Synthesis of (dimethylamino) -1- (4-fluorophenyl) butan-1-one
To a 250mL three-necked flask were added 4-chloro-1- (4-fluorophenyl) butan-1-one (20.1g,0.1 mmol), dimethylamine hydrochloride (16.3g,0.2mol), potassium carbonate (27.6g,0.2mol), and DMF (100mL) in that order. Reacting at 80 ℃ for 16h, cooling to room temperature, adding saturated saline, and extracting with ethyl acetate. The organic phase was washed once more with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. Dissolving the crude product in acetone, introducing hydrogen chloride gas, stirring for 1h, and performing suction filtration to obtain the hydrochloride of the formula II. The hydrochloride salt of formula II was dissolved in water, extracted with aqueous sodium bicarbonate until no gas was formed, EA extracted, dried and concentrated until use (20.5g, 83.4%).
EXAMPLE 35 Synthesis of chloro-2- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) benzoic acid
N-butyllithium (2.5M/hexane, 0.11mol,44.0mL) was carefully added dropwise to 5-chloro-2-bromobenzoic acid (11.8g,0.05mol) in anhydrous THF (100mL) at-78 ℃ under nitrogen. After 1h of incubation, a solution of 4- (dimethylamino) -1- (4-fluorophenyl) butan-1-one (10.5g,0.05mol) in THF (20mL) was added dropwise. After the reaction was completed, the temperature was raised to-60 ℃ for reaction for 2 hours, and then saturated ammonium chloride (100mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with dichloromethane to give a white solid (15.3g, 83.5%).
EXAMPLE 45 Synthesis of chloro-2- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) benzoic acid
Isopropyl magnesium bromide (2.9M/2-methyltetrahydrofuran, 0.11mol, 37.9mL) was carefully added dropwise to 5-chloro-2-bromobenzoic acid (11.8g,0.05mol) in anhydrous 2-methyltetrahydrofuran (100mL) at-78 ℃ under nitrogen. After 1h of incubation, a solution of 4- (dimethylamino) -1- (4-fluorophenyl) butan-1-one (10.5g,0.05mol) in 2-methyltetrahydrofuran (20mL) was added dropwise. After the reaction was completed, the temperature was raised to-40 ℃ for 2 hours, and saturated ammonium chloride (100mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with dichloromethane to give a white solid (14.8g, 80.9%).
Example Synthesis of 51- (4-chloro-2- (hydroxymethyl) phenyl) -4- (dimethylamino) -1- (4-fluorophenyl) butan-1-ol
Add sodium borohydride (1.24g,32.8mmol) portionwise to a solution of 5-chloro-2- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) benzoic acid (10.00g,27.3mmol) in THF (60 mL). The temperature is reduced to 0 ℃, then boron trifluoride ethyl ether solution (5.3mL,32.8mmol) is added dropwise, and the solution is added within 1 h. The reaction solution was warmed to 25 ℃ and stirred for 16 h. Cooled to 0 ℃, aqueous sodium hydroxide (1N,44mL) was carefully added dropwise and stirred for 3 h. Then extracting with ethyl acetate, washing with water, drying and concentrating. The product was used directly in the next reaction without further purification.
EXAMPLE 64 Synthesis of (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile
1- (4-chloro-2- (hydroxymethyl) phenyl) -4- (dimethylamino) -1- (4-fluorophenyl) butan-1-ol (9.6g,27.3 mmol), zinc cyanide (9.6g,81.9mmol) and 1,1' -bis (diphenylphosphino) ferrocene (1.5g,2.7mmol) were placed in a dry three-necked flask, nitrogen was purged three times and anhydrous DMF (50mL) was added. Pd (dppf) C1 was added under a stream of nitrogen2·CH2Cl2(1.1g,1.4 mmol). Then the reaction bottle is placed in an oil bath at 130 ℃ for reaction for 36 hours, then the reaction bottle is moved to room temperature for cooling, and water is added for quenching reaction. The mixture was filtered through celite and extracted with ethyl acetate. The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate, concentrated and the crude product slurried with n-heptane/ethyl acetate to give a pale yellow solid (7.7g, 82% over two steps).
EXAMPLE synthesis of 74- (4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxybutyl) -3- (hydroxymethyl) benzonitrile
1- (4-chloro-2- (hydroxymethyl) phenyl) -4- (dimethylamino) -1- (4-fluorophenyl) butan-1-ol (3.5g,10.0 mmol), zinc cyanide (3.5g,30.0mmol) and triphenylphosphine (526mg,2.0mmol) were placed in a dry three-necked flask and nitrogen was purged three times and anhydrous DMF (20mL) was added. Tetratriphenylphosphine palladium (1.2g,1.0mmol) was added under a nitrogen stream. Then the reaction bottle is placed in an oil bath at 150 ℃ for reaction for 36 hours, then the reaction bottle is moved to room temperature for cooling, and water is added for quenching reaction. The mixture was filtered through celite and extracted with ethyl acetate. The organic phases were combined and washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a pale yellow solid (1.6g, 47%).
EXAMPLE 8 Synthesis of (2-bromo-5-chlorophenyl) methanol
To a solution of 5-chloro-2-bromobenzoic acid (23.5g,0.10mol) in THF (100mL) was added sodium borohydride (4.6g,0.12mol) in portions. The temperature is reduced to 0 ℃, then boron trifluoride ethyl ether solution (19.4mL,0.12mol) is added dropwise, and the dropwise addition is finished within 1 h. The reaction solution was warmed to 25 ℃ and stirred for 16 h. Cooled to 0 ℃, aqueous sodium hydroxide (1N, 160mL) was carefully added dropwise and stirred for 3 h. Then extracted with ethyl acetate, washed once with water, dried and concentrated. The product was not further purified and used directly in the next reaction.
Example 91 Synthesis of- (4-chloro-2- (hydroxymethyl) phenyl) -4- (dimethylamino) -1- (4-fluorophenyl) butan-1-ol
To (2-bromo-5-chlorophenyl) methanol (22.1g,0.10mol) in dry THF (150mL) at-78 deg.C under nitrogen was added n-butyllithium (2.5M/hexane, 0.22mol,88.0mL) carefully dropwise. After 1h of incubation, a solution of 4- (dimethylamino) -1- (4-fluorophenyl) butan-1-one (20.9g,0.10mol) in THF (50mL) was added dropwise. After the addition was completed, the reaction was allowed to warm to-60 ℃ for 2 hours, and then quenched by the addition of saturated ammonium chloride (100 mL). Concentrating to remove most of organic solvent, extracting with ethyl acetate, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating. The crude product was slurried with n-heptane/ethyl acetate to give a pale yellow solid (29.9g, 85.0%).
The above-mentioned embodiments are merely exemplary embodiments for fully illustrating the present invention, and the scope of the present invention is not limited to the above-mentioned embodiments, but defined by the contents of the claims. All matters disclosed in the specification including the abstract and all methods and steps disclosed herein may be combined in any combination, except combinations where the features and/or steps are mutually exclusive. Each feature disclosed in this specification, including the abstract, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features. Those skilled in the art should also realize that such equivalent substitutions and alterations can be made without departing from the spirit and scope of the present invention. Such modifications are also intended to be within the scope of the present invention. Each reference cited in this application is incorporated herein in its entirety.
Claims (10)
1. A process for the preparation of a citalopram intermediate characterized in that: the method comprises the following steps:
wherein, in the process of the step (1), the compound of the formula I and dimethylamine or hydrochloride thereof react at 0-150 ℃ to prepare the compound of the formula II under the condition of solvent or no solvent;
wherein in the process of the step (2), the compound of the formula III reacts with the compound of the formula II under the action of a metal reagent in an aprotic organic solvent at a temperature of between 78 ℃ below zero and 30 ℃ under the protection of inert gas to prepare a compound of the formula IV;
wherein in the process of the step (3), the compound of the formula IV reacts with a reducing agent in an organic solvent at the temperature of-20-100 ℃ to prepare a compound of the formula V;
wherein, in the process of the step (4), under the protection of inert gas at 50-200 ℃, the compound of the formula V and metal cyanide react in a solvent under the action of an organic phosphine ligand and a transition metal catalyst to prepare the compound of the formula VI.
2. The process of claim 1, wherein the solvent in step (1) is selected from one or more of water, methanol, ethanol, isopropanol, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, acetone, N-dimethylformamide, N-diethylacetamide, N-methylpyrrolidone, or dimethylsulfoxide; the equivalent weight of the dimethylamine or the hydrochloride thereof is 1.0-5.0 equivalent weight; the reaction temperature is 60-100 ℃.
3. The method of claim 1, wherein the compound of formula I in step (1) is reacted with dimethylamine or hydrochloride thereof under the action of a base to prepare a compound of formula II, wherein the base is selected from potassium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine or pyridine, and the using equivalent of the base is 1.0-5.0.
4. The method of claim 1, wherein the inert gas in step (2) is nitrogen; the aprotic organic solvent is selected from tetrahydrofuran or dimethyltetrahydrofuran; the metal reagent is selected from n-butyl lithium, isopropyl magnesium bromide or isopropyl magnesium chloride; the reaction temperature is-78-0 ℃.
5. The process of claim 1, wherein the organic solvent in step (3) is selected from the group consisting of tetrahydrofuran; the reaction temperature is-20 ℃ to 80 ℃.
6. The process of claim 1, wherein the reducing agent in step (3) is selected from borane dimethyl sulfide complex, borane tetrahydrofuran complex, lithium aluminum hydride, sodium borohydride/l2Sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride, sodium borohydride/trifluoroacetic acid or sodium borohydride/sulfuric acid; preferably, the reducing agent is selected from sodium borohydride/boron trifluoride etherate, sodium borohydride/zinc chloride or sodium borohydride/sulfuric acid.
7. The method of claim 1, wherein the reaction temperature in step (4) is 70 ℃ to 150 ℃; the inert gas is nitrogen; the solvent is one or more selected from water, ethanol, isopropanol, acetonitrile, dioxane, glycol dimethyl ether, toluene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
8. The process of claim 1 wherein the metal cyanide in step (4) is zinc cyanide or cuprous cyanide.
9. The process of claim 1, wherein the organophosphorus ligand in step (4) is selected from 1,1' -bis (diphenylphosphino) ferrocene, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl or triphenylphosphine; the transition metal catalyst is selected from bis (triphenylphosphine) nickel chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
10. A process for the preparation of a citalopram intermediate characterized in that: the method comprises the following steps:
wherein in the process of the step (1), the compound shown in the formula III reacts with sodium borohydride/boron trifluoride ethyl ether, sodium borohydride/zinc chloride or sodium borohydride/sulfuric acid in tetrahydrofuran at the temperature of-20-80 ℃ to prepare a compound shown in the formula VII;
wherein in the process of the step (2), under the protection of nitrogen gas at-78-0 ℃, a compound of formula VII in tetrahydrofuran or 2-methyltetrahydrofuran reacts with a compound of formula II under the action of n-butyl lithium, isopropyl magnesium bromide or isopropyl magnesium chloride to prepare a compound of formula V;
in the process of the step (3), under the protection of nitrogen and at 70-150 ℃, reacting a compound shown in a formula V with metal cyanide in a solvent under the action of an organic phosphine ligand and a transition metal catalyst to prepare a compound shown in a formula VI, wherein the solvent is selected from one or more of water, ethanol, isopropanol, acetonitrile, dioxane, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; the metal cyanide is zinc cyanide or cuprous cyanide; the organophosphorus ligand is selected from 1,1' -bis (diphenylphosphino) ferrocene, 2-dicyclohexyl phosphorus-2, 4, 6-triisopropyl biphenyl or triphenylphosphine; the transition metal catalyst is selected from bis (triphenylphosphine) nickel chloride, tetratriphenylphosphine palladium, tris (dibenzylideneacetone) dipalladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
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| WO2001002383A2 (en) * | 1999-07-06 | 2001-01-11 | Lundbeck Pharmaceuticals Italy S.P.A. | Process for the synthesis of citalopram |
| CN1359382A (en) * | 1999-04-14 | 2002-07-17 | H·隆德贝克有限公司 | Method for preparing citalopram |
| CN1688565A (en) * | 2002-01-25 | 2005-10-26 | 埃斯特维化学股份有限公司 | Method of obtaining citalopram |
| CN104072390A (en) * | 2014-03-11 | 2014-10-01 | 江苏奥赛康药业股份有限公司 | Escitalopram compound and preparation method thereof |
| JP2019119710A (en) * | 2018-01-05 | 2019-07-22 | 株式会社トクヤマ | Process for producing hydrobromide of diol compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1359382A (en) * | 1999-04-14 | 2002-07-17 | H·隆德贝克有限公司 | Method for preparing citalopram |
| WO2001002383A2 (en) * | 1999-07-06 | 2001-01-11 | Lundbeck Pharmaceuticals Italy S.P.A. | Process for the synthesis of citalopram |
| CN1688565A (en) * | 2002-01-25 | 2005-10-26 | 埃斯特维化学股份有限公司 | Method of obtaining citalopram |
| CN104072390A (en) * | 2014-03-11 | 2014-10-01 | 江苏奥赛康药业股份有限公司 | Escitalopram compound and preparation method thereof |
| JP2019119710A (en) * | 2018-01-05 | 2019-07-22 | 株式会社トクヤマ | Process for producing hydrobromide of diol compound |
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| WO2022151968A1 (en) * | 2021-01-14 | 2022-07-21 | 浙江华海药业股份有限公司 | Method for purifying key intermediates of citalopram |
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