JP5165951B2 - (±) -Trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine production method - Google Patents

Description

  The present invention relates to a method for producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine. More specifically, the present invention relates to (±) -trans-4- (4-fluoro) by borane reduction of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. The present invention relates to a method for producing phenyl) -3-hydroxymethylpiperidine.

(±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is a useful synthetic intermediate for paroxetine hydrochloride used as an antidepressant.
(±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is obtained by, for example, converting (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one to lithium. It is known to be produced by reduction with aluminum hydride (LAH) (see Patent Documents 1 and 2).

  However, LAH is expensive and difficult to handle because it is ignitable. Therefore, it is desired industrially to reduce without using LAH.

  On the other hand, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethyl-N-methylpiperidine, another synthetic intermediate of paroxetine hydrochloride, is (±) -trans-4- (4-fluoro It is known that it is produced by borane reduction of (phenyl) -3-methoxycarbonyl-N-methylpiperidine-2,6-dione (see Patent Document 3). Here, borane is produced in the reaction system from boron trifluoride-ether complex and sodium borohydride.

  In this method, after the reduction, the reaction solution is acidified to decompose the amine borane complex, the produced boric acid compound (derived from boron trifluoride-ether complex and sodium borohydride) is filtered, and the resulting acidic aqueous solution is used. The basic product is extracted with an organic solvent, and a poor solvent is added to the organic layer to crystallize the target product.

Japanese Patent No. 3446468 Japanese Patent Laid-Open No. 10-291975 Japanese National Patent Publication No. 8-507540

  The boric acid compound is considered to be boric acid, sodium borate, metaboric acid, borofluoride, and the like and hydrolysates thereof. When the above method is applied to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, the boric acid compound is sufficiently precipitated even if the reaction solution is acidified after borane reduction. Without being dissolved in the aqueous layer. When this aqueous layer was made basic, the target product and the boric acid compound were precipitated at the same time, and it was difficult to isolate and purify the target product with high purity even by operations such as extraction and filtration.

  An object of the present invention is to provide a method capable of producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine with high purity and high yield.

  As a result of investigations to solve the above problems, the present inventors have determined that (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is boron trifluoride-ether. By adding mineral acid and potassium salt to the reaction solution after reduction using the complex and sodium borohydride to adjust the pH to a certain range, and then adjusting the pH of the acidic solution after filtration to a certain range. (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was found to be obtained with good purity and high yield.

  Furthermore, the corrosion of the glass lining (GL) reaction vessel is suppressed by containing a potassium salt in the acidic solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine. I found.

That is, the present invention is as follows.
[1] Reduction of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one with boron trifluoride-ether complex and sodium borohydride to obtain a reaction solution Then, a mineral acid and potassium salt are added to the obtained reaction solution to adjust the pH to 0.5 to 4.0, and the precipitate is removed to obtain an acidic solution. A method for producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine, wherein the pH is adjusted to 11.0 to 12.5.
[2] The production method according to the above [1], wherein the potassium salt is at least one selected from the group consisting of potassium chloride, potassium bromide and potassium iodide.
[3] The production method according to the above [1] or [2], wherein the mineral acid is hydrochloric acid.
[4] The pH adjustment of the acidic solution is performed by adding the acidic solution and the alkali to the solvent containing water while maintaining the pH in the system at 11.0 to 12.5. [1] The production method according to any one of [3].
[5] Reduction involves adding sodium borohydride to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one in the presence of boron trifluoride-ether complex The production method according to any one of the above [1] to [4], which is performed by:
[6] A cis isomer or a cis isomer-trans isomer mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is treated with a base to convert the cis isomer into a trans isomer. The method according to any one of [1] to [5] above, wherein the obtained (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is reduced. .

The present invention also includes:
[7] Reduction of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one with boron trifluoride-ether complex and sodium borohydride, then obtained Mineral acid and potassium salt are added to the reaction solution to adjust the pH to 0.5 to 4.0, and boron trifluoride-ether complex and boric acid compound derived from sodium borohydride are precipitated in the form of salt. And then the pH of the resulting acidic solution is adjusted to 11.0-12.5 to crystallize (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine A process for producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine,
[8] The production method of the above-mentioned [7], wherein the potassium salt is selected from potassium chloride, potassium bromide and potassium iodide.
[9] The production method according to the above [7] or [8], wherein the mineral acid is hydrochloric acid.
[10] The pH adjustment of the acidic solution is performed by adding the acidic solution and an alkali while maintaining the pH in the system at 11.0 to 12.5 in a solvent containing water. 7]-[9] The manufacturing method as described in any one.
[11] Reduction involves adding sodium borohydride to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one in the presence of boron trifluoride-ether complex The production method according to any one of the above [7] to [10], which is performed by:
[12] A cis isomer or a cis isomer-trans isomer mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is treated with a base to convert the cis isomer into a trans isomer. Any one of the above [7] to [11], wherein the obtained (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is reduced without isolation. The manufacturing method as described in.

  According to the present invention, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine can be easily and industrially produced with high purity and good yield. The resulting (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is useful as an intermediate in the synthesis of paroxetine hydrochloride used as an antidepressant.

The present invention is described in detail below.
First, (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one as a raw material of the present invention is produced according to various methods, for example, the method described in Patent Document 2. can do. This document discloses that a cis form of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is converted (isomerized) into a trans form by treatment with a base. Has been.

  That is, a cis or cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is used as a raw material and treated with a base to obtain its trans The body is manufactured. This isomerization reaction is usually performed in an organic solvent. Here, the kind and amount of the organic solvent and the base, and other reaction conditions can be appropriately selected.

  For example, examples of the base include C1-C6 alkali metal alkoxides such as sodium methoxide. The amount of the base used is generally 0.01 to 0.1 mol, preferably 0.01 to 0.03 mol, more preferably 0.02 to 1 mol per 1 mol of the cis isomer or cis isomer-trans isomer mixture. 0.03 mol.

  Examples of the organic solvent include aromatic hydrocarbon solvents such as toluene, xylene, and benzene; aliphatic hydrocarbon solvents such as hexane and heptane. In view of the subsequent reaction processing operation, aromatic hydrocarbon solvents. Is preferred. The usage-amount of an organic solvent is 0.5-2.5L normally with respect to 1 mol of the said cis-isomer or cis-isomer-trans mixture, Preferably it is 0.5-1.0L.

  In the isomerization reaction, a cis isomer or cis isomer-trans isomer mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is usually 40 ° C. or higher, preferably in an organic solvent. After heating to 60 to 114 ° C., a base is added, and heating is usually performed at 80 to 114 ° C., preferably 96 to 114 ° C., usually 0.5 to 48 hours, preferably 1 to 2 hours. The base may be added at room temperature.

  After the isomerization reaction, the reaction solution is cooled, and this cooling is preferably performed by slow cooling for 1 minute, preferably at 2 ° C. or less, more preferably at 1 ° C. or less. Usually, when the temperature of a solution falls to 10-96 degreeC, a trans body will begin to crystallize and crystallization will be completed at 0-10 degreeC. Cooling is preferably performed by allowing the reaction solution to cool to room temperature and then cooling with ice.

  Further, the crystallization of the trans isomer may be performed by swing cooling in which the reaction solution is repeatedly cooled and heated, thereby further improving the slurry property of the reaction solution. In swing cooling, for example, the reaction solution is first stirred at 96 to 98 ° C. for about 30 minutes, and then cooled to about 80 ° C. at a cooling rate of about 5 ° C. per hour. Next, after stirring at about 80 ° C. for about 30 minutes, the temperature is raised to about 90 ° C., and stirring is performed at the same temperature for about 30 minutes. It is then cooled to about 40 ° C. at a cooling rate of about 8 ° C. per hour. Next, after stirring at about 40 ° C. for about 30 minutes, the temperature is raised to about 60 ° C., and stirring is performed at the same temperature for about 30 minutes. Then, it can be carried out by cooling to 2 ° C. at a cooling rate of about 10 ° C. per hour.

  In addition, (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one obtained by the isomerization reaction is isolated and purified by filtration as necessary. However, it is convenient and preferable to subject the reaction mixture to the next reduction reaction as it is.

  The (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one thus obtained is then reduced using boron trifluoride-ether complex and sodium borohydride. As a result, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is produced. Here, boron trifluoride-ether complex and sodium borohydride generate borane in the system, which becomes a reducing agent. The reduction with this boron trifluoride-ether complex and sodium borohydride, unlike LAH, is inexpensive and safe to handle.

  The boron trifluoride-ether complex used in the present invention includes boron trifluoride-tetrahydrofuran (THF) complex, boron trifluoride-dimethyl ether complex, boron trifluoride-diethyl ether complex, boron trifluoride-di Examples thereof include a butyl ether complex, and among them, boron trifluoride-THF complex is preferable from the viewpoints of easy handling and economy. The amount of boron trifluoride-ether complex used is usually 2.67 to 4.0 times per mole of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. The mole is preferably 3.16 to 3.5 times mole. When the amount of boron trifluoride-ether complex used is less than 2.67 times mol, the reduction reaction rate decreases, and conversely, when it exceeds 4.0 times mol, it is economically disadvantageous.

  The form of sodium borohydride used in the present invention is not particularly limited, and may be, for example, a powder form, a caplet type, or the like. The amount of sodium borohydride used is usually 2.0 to 3.0 times mol, preferably 1 mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. Is 2.37 to 2.63 moles. When the amount of sodium borohydride used is less than 2.0 times mol, the reduction reaction rate decreases. Conversely, when the amount exceeds 3.0 times mol, it is economically disadvantageous, and excessive hydrogenation. With sodium boron, a part of the trans form of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is isomerized to the cis form over time.

  The reduction reaction is usually performed in an organic solvent. Examples of the organic solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), t-butyl methyl ether (MTBE), dioxane and diethylene glycol dimethyl ether; hydrocarbon solvents such as toluene, cyclohexane, heptane and hexane; and mixtures thereof Among them, THF is preferable from the viewpoint of easy handling. The amount of the organic solvent to be used is generally 1.2 to 2.0 L, preferably 1 to 1 mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. 3 to 1.8 L. As described above, after the isomerization reaction of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, the reaction mixture is directly subjected to the reduction reaction without isolation and purification. When provided, the organic solvent is added to the reaction mixture (including the solvent used in the isomerization reaction).

  The reduction reaction is performed by adding sodium borohydride to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one in the presence of boron trifluoride-ether complex. Is preferred. When a boron trifluoride-ether complex is added to a mixture of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one and sodium borohydride, There is a possibility that a part of the trans isomer isomerizes to a cis isomer with time due to alkali. In the reduction reaction, for example, an amount of about 1% by weight of the boron trifluoride-ether complex used is first converted to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. For example, by adding sodium borohydride and the remaining boron trifluoride-ether complex, respectively. In addition, sodium borohydride and boron trifluoride-ether complex are usually added at 0 to 70 ° C, preferably 20 to 50 ° C.

The temperature of the reduction reaction is usually 20 to 80 ° C, preferably 30 to 55 ° C.
The time for the reduction reaction is the amount of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, boron trifluoride-ether complex, sodium borohydride and the amount of organic solvent used. Depending on the type of boron trifluoride-ether complex and organic solvent, it is usually 1 to 18 hours, preferably 2 to 10 hours.

  The lower alcohol is then added. Examples of the lower alcohol include methanol, ethanol, isopropanol and the like, and methanol is preferable from the viewpoint of post-treatment. The amount of the lower alcohol used may be 0.1 to 1 mol with respect to 1 mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. The lower alcohol is preferably added dropwise. The addition temperature of the lower alcohol is preferably 0 to 10 ° C.

  After the above reduction reaction, mineral acid and potassium salt are added to the reaction solution, and most of the boric acid compound derived from boron trifluoride-ether complex and sodium borohydride is deposited in the form of salt and removed. To do.

  The addition of the mineral acid and potassium salt is performed so that the pH of the reaction solution is 0.5 to 4.0, preferably 0.5 to 2.3, more preferably 1.0 to 2.0.

  Examples of the mineral acid used in the present invention include hydrochloric acid, hydrobromic acid, sulfuric acid and the like, and among them, hydrochloric acid is preferable from the viewpoint of economy. In the case of hydrochloric acid, the amount used is preferably 1.0 to 1.3 mol per mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, More preferably, it is 1.05-1.1 mol. If the amount of hydrochloric acid used is less than 1.0 mol, the solubility of the target product in water decreases. Conversely, if it exceeds 1.3 mol, the vessel used for the treatment with hydrochloric acid and potassium salt will corrode quickly. Become. The mineral acid is preferably used in the form of an aqueous solution. For example, in the case of hydrochloric acid, the concentration is preferably 1 to 36% by weight, more preferably 2 to 5% by weight.

  Examples of the potassium salt used in the present invention include potassium chloride, potassium bromide, potassium iodide and the like. These potassium salts may be used alone or in combination of two or more. Of these, potassium chloride is preferred from the viewpoint of economy. The amount of potassium salt used is preferably 2 to 5 mol, more preferably 3 to 4 mol per mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. Mol or 2 to 3 mol. When the amount of the potassium salt used is less than 2 mol, the salt of the boric acid compound does not precipitate, and the load on the amount of inorganic salt dissolved in water during crystallization (crystallization) described later increases. On the other hand, when the amount exceeds 5 mol, an excessive potassium salt increases the load on the amount of inorganic salt dissolved in water during crystallization (crystallization) described later. In addition, it is preferable to use potassium salt in the form of aqueous solution, The density | concentration becomes like this. Preferably it is 5-25 weight%, More preferably, it is 12-18 weight%.

  By adding the potassium salt, it becomes possible to remarkably suppress the corrosion of the reaction vessel made of glass lining (GL).

  The treatment with the mineral acid and the potassium salt is performed as follows, for example. First, the reaction solution after reduction is added to mineral acid (preferably an aqueous solution), or mineral acid (preferably aqueous solution) is added to the reaction solution, and excess borane (boron trifluoride-ether complex and hydrogenation) is added. Quenched by reaction with sodium boron. This quenching is performed until the borane disappears, but it is preferably 1 to 10 hours, more preferably 3 to 7 hours.

  Then, a potassium salt (preferably an aqueous solution) is added to the quenched reaction solution to precipitate the boric acid compound in the form of a salt. Or when quenching, you may use the mineral acid aqueous solution which added potassium salt.

  The addition of the mineral acid and potassium salt is preferably performed at 0 ° C to 50 ° C, more preferably 10 to 40 ° C.

  Then, if necessary, the organic solvent in the reaction solution is distilled off. When this organic solvent is a toluene / THF mixed solvent, by heating to about 68 ° C., the toluene / THF mixed solvent azeotropes with water, and almost all the toluene / THF mixed solvent is distilled off at about 96 ° C. be able to.

  In addition, you may implement distillation of an organic solvent under reduced pressure, and can reduce distillation temperature by this. In this case, corrosion of the glass lining (GL) reaction vessel can be more significantly suppressed.

  Thereafter, it is preferably cooled to around 5 ° C. at a rate of 2 to 25 ° C./hour, more preferably 10 to 15 ° C./hour, and preferably stirred at 0 to 5 ° C., more preferably 0 to 2 ° C. for about one night. As a result, most of the boric acid compound can be precipitated in the form of a salt. Next, the precipitated salt of the boric acid compound is filtered and washed. Filtration is preferably performed at 0-5 ° C, more preferably 0-2 ° C. For washing, water is preferably used, but washing with water containing the mineral acid and potassium salt used in the above treatment (1-2% by weight of the amount used) is more preferred. The amount of the washing water used is preferably 100 to 300 g, more preferably 100 g relative to 100 g of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one that is the raw material. 150-250 g.

  Some acidic boric acid compounds (including salt forms) still remain in the acidic solution obtained by filtration. In the present invention, the pH of the acidic solution is adjusted to 11.0 to 12.5, preferably 11.5 to 12.0, and (±) -trans-4- (4-fluorophenyl) -3-hydroxy Methylpiperidine is crystallized (crystallized) and separated from the remaining boric acid compound. If the pH is less than 11.0, the target product does not crystallize (crystallize) and remains dissolved in the acidic solution. Conversely, if the pH exceeds 12.5, impurities (boron) together with the target product. Acid compounds, organic impurities, etc.) crystallize (crystallize), and the purity of the target product (crystals) obtained decreases.

  This crystallization (crystallization) is preferably performed using an alkali. Examples of the alkali include sodium hydroxide and sodium carbonate. Among them, sodium hydroxide is preferable from the viewpoint of economy. The amount of alkali used is preferably 1 to 3 mol, more preferably 1.2 to 1 mol per mol of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. 2.2 moles. When the amount of alkali used is less than 1 mol, the pH of the acidic solution is below the above range, and conversely when it exceeds 3 mol, the pH of the acidic solution exceeds the above range. From the viewpoint of promoting crystallization (crystallization), the alkali is preferably used in the form of an aqueous solution, and its concentration is preferably 1 to 48% by weight, more preferably 14 to 35% by weight.

The pH adjustment with alkali is preferably performed as follows, for example.
First, water is added to the crystallization vessel. The amount of water is preferably 100 to 350 g, more preferably 150 to 300 g based on 100 g of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. Further, an organic solvent such as toluene may be added, and the amount thereof is preferably equal to or less than that of water, and (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one. It is 150 to 250 ml for 100 g. Next, an acidic solution and an alkali (preferably an aqueous solution) are added to the crystallization vessel while maintaining the pH in the system in the range of 11.0 to 12.5. This addition is preferably performed at 5-35 ° C, more preferably at 10-30 ° C.

  The method for adding the acidic solution and the alkali (preferably an aqueous solution) is not particularly limited as long as the pH in the system is maintained in the range of 11.0 to 12.5, but it is preferable to add in small portions, Dropping is particularly preferred. Further, the addition of the acidic solution and the alkali (preferably an aqueous solution) may be performed simultaneously or alternately, but is preferably performed simultaneously. The acid solution and the alkali (preferably an aqueous solution) may be added continuously or intermittently, but intermittent addition is preferable.

  Further, a small amount of seed crystals may be added during the addition of the acidic solution and alkali, and it may be added when 5 to 10% by weight of the acidic solution is added.

  After completion of the addition, aging is performed to complete crystallization (crystallization). The aging is usually performed at 5 to 35 ° C., preferably 10 to 30 ° C., and usually 1 to 12 hours, preferably 1 to 6 hours. Alternatively, this ripening can be carried out by a so-called temperature swing method in which the temperature is raised or lowered, whereby granular crystals with better filterability can be obtained. The temperature swing method can be carried out, for example, by cooling the acidic solution to which alkali has been added to about 10 ° C., raising the temperature to about 48 ° C., and then cooling to about 10 ° C. The precipitated crystals are collected by filtration, washed with an organic solvent such as toluene or water, and dried.

  The (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine thus obtained contains almost no boric acid compound and has a high purity (preferably 98 to 100%, especially Preferably it is 99 to 100%), and the yield is also high (preferably 88 to 97%, particularly preferably 90 to 97%).

  In the filtrate, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine may remain about 5% by weight of the theoretical yield. In this case, the pH of the filtrate is adjusted to 12-13 with caustic, and (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is extracted and separated into the organic layer (toluene layer). (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine hydrochloride by isolating and separating the aqueous layer by adding water and hydrochloric acid to the resulting organic layer Can be recovered and reused as an aqueous solution.

  Further, the separation of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine from the boric acid compound by the above-described series of treatments is a simple method and is very useful for industrial production. Is suitable.

  Therefore, such a method for producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is very useful for the synthesis of paroxetine hydrochloride, which is an antidepressant.

  According to the present invention, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is purified using an inexpensive boron trifluoride-ether complex and sodium borohydride as a reducing agent. It can be manufactured with good yield. In addition, by containing a potassium salt in an acidic solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine, corrosion of a reaction vessel made of glass lining (GL) can be suppressed. It becomes possible.

  Next, the present invention will be described in more detail based on examples, but it goes without saying that the present invention is not limited to the examples.

A cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one was produced according to the method described in Patent Document 2. The conditions for HPLC analysis are as follows.
(HPLC conditions)
Detector: UV 210nm
Column: TSK-GEL ODS-80TM (4.6 mmφ × 15 cm)
Column temperature: 40 ° C
Mobile phase: 12 mM sodium 1-heptanesulfonate, 32 mM KH ₂ PO ₄ / phosphate buffer, pH 3.0 / acetonitrile = 80/20
Flow rate: 1 mL / min

The corrosion of the glass lining (GL) reaction vessel was measured under the following conditions.
A reaction solution of a cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one of about 4 molar scale was used, and the reaction solution (liquid phase part) was used. A test piece (weighed in advance) obtained from a GL product manufacturer was placed, stirred, washed and dried after a certain time, the weight of the test piece was measured, and the weight loss (mg) was calculated.
The annual corrosion rate was obtained by the following formula.
Annual corrosion rate (mm / year) = 1.59 × weight loss (mg) / test time (h)

Example 1
Under a nitrogen atmosphere, 200 ml of toluene and 100 g (0.398 mol) of a cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one were added to Kolben, Heated to 100 ° C. To this solution, 0.43 g (8 mmol) of sodium methoxide was added and heated to reflux for 30 minutes. The reaction solution was cooled to 96 ° C., a part of the reaction solution was collected, nitrogen was passed through or heated and dried, and toluene was distilled off. The mixture was aged at 96 ° C. for 1 hour and cooled to 80 ° C. over about 1 hour. After aging at 80 ° C. for 1 hour, it was cooled to 20 ° C. at a rate of about 10 ° C./hour. Stir at about 20 ° C. overnight, then warm and stir at 40 ° C. for 1 hour. The mixture was cooled to 2 ° C. over 4 hours and stirred for 1 hour. A part of the precipitated crystals was collected, and it was confirmed by HPLC analysis that the cis form was isomerized to the trans form.

  To the reaction solution obtained above, 1.66 g (0.012 mol) of boron trifluoride-THF complex was added at 2 ° C., and then 300 ml of THF was added. Further, 185.53 g (1.321 mol) of boron trifluoride-THF complex was added dropwise at about 20 ° C. Subsequently, a suspension of 37.64 g (0.995 mol) of sodium borohydride in THF (100 ml) was added dropwise at 35 ° C. over 6 hours. The mixture was heated to 74 ° C. and stirred for 3 hours. The reaction solution was cooled to about 10 ° C., and 3.83 g of methanol was added dropwise over 30 minutes.

  To another Kolben, 406 g of water, 44.09 g (0.423 mol) of 35 wt% hydrochloric acid and 79.05 g (1.060 mol) of potassium chloride were added and mixed, and 7.9 g (1.5 wt%) was added. Extracted. The previous reaction solution was added to the remaining solution at 25 ° C. over 2 hours to adjust the pH to 1.5. It heated until internal temperature was set to 96 degreeC, and methanol, THF, and toluene were distilled off. Subsequently, it cooled to 5 degreeC over 6 hours, filtered after stirring at 0-5 degreeC overnight. The filtration residue was washed with an aqueous solution of 200 g by adding water to the previously extracted aqueous solution of hydrochloric acid and potassium chloride (177 g when the filtration residue was dried).

  Further, another Kolben was charged with 300 ml of water and 200 ml of toluene, and the filtrate ((±) -trans-4- (4-fluorophenyl) -3-hydroxy was maintained while maintaining the pH at 11.2 to 11.5. Methyl piperidine hydrochloride acidic solution) and 30% by weight sodium hydroxide aqueous solution 106 g (0.795 mol) were simultaneously added dropwise at 12 ° C. During the addition, when about 10% by weight of each solution was added, about 1 mg of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine seed crystal was added. The time required for dropping was 6.5 hours. After completion of the dropwise addition, the mixture was stirred at about 10 ° C. for 3 hours, and the precipitated crystals were collected by filtration and washed twice with 100 ml of toluene and then with 100 ml of water. Drying at 80 ° C. under reduced pressure gave 77.8 g of crystals. The yield was 93.4%. HPLC purity: 99.7%.

Example 2
Under a nitrogen atmosphere, 160 ml of toluene and 80 g (0.318 mol) of a cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one were added to the reaction vessel, The mixture was heated to 111 ° C., and 20 ml of toluene was distilled off. An additional 20 ml of toluene was added, 0.34 g (6.3 mmol) of sodium methoxide was added to the solution, and the mixture was heated to reflux for 30 minutes. The reaction solution was cooled to 97 ° C., a part of the reaction solution was collected, dried by heating, toluene was distilled off, and 10 mg of the obtained crystals were inoculated as seed crystals into the reaction solution. The mixture was aged at 96 to 97 ° C. for 30 minutes and cooled to 80 ° C. over about 2 hours. After maintaining at 80 ° C. for 30 minutes, the mixture was heated to 90 ° C. and aged at the same temperature for 30 minutes. Subsequently, it cooled to 40 degreeC over 5 hours. The mixture was further heated to 60 ° C. and kept for 30 minutes, and then cooled to 2 ° C. over 6 hours. A part of the precipitated crystals was collected, and it was confirmed by HPLC analysis that the isomerization rate from the cis form to the trans form was 99.5%.

  After adding 1.3 g (0.0094 mol) of boron trifluoride-THF complex at 2 ° C. to the reaction solution obtained above, the mixture was heated to 30 ° C. and 240 ml of THF was added. Further, 147 g (1.047 mol) of boron trifluoride-THF complex and a suspension of 30.1 g (0.796 mol) of sodium borohydride in THF (80 ml) were added dropwise at 32-35 ° C., respectively. (Drip time 3 hours). After stirring for 30 minutes, the mixture was heated to 70 ° C and stirred at 70 to 74 ° C for 3 hours. The reaction solution was cooled to 10 ° C., and 3.1 g of methanol was added dropwise.

  In another reaction vessel, 325 ml of water, 35.4 g (0.400 mol) of 35 wt% hydrochloric acid and 63.3 g (0.849 mol) of potassium chloride were added and mixed to obtain 6.4 g (1.5 wt%). Extracted. The reaction solution obtained by adding the previous methanol to the remaining solution was added dropwise at about 20 ° C. over 50 minutes (the obtained solution is referred to as hydrolyzed solution). The container in which the reaction solution containing the previous methanol was added was washed with 20 ml of toluene, and this washing solution was added to the hydrolyzed solution. The hydrolyzed solution was heated to 55 ° C. and kept for 30 minutes, and then heated to 80 ° C. to distill off the solvent. Subsequently, it concentrated at 75-83 degreeC and the pressure reduction degree 53.3-73.3kPa (total distillation amount 755 ml). 80 ml of water was added to the resulting concentrate, and the mixture was kept at 80 ° C. for 30 minutes. Subsequently, it cooled to 5 degreeC over 3 hours, and filtered after stirring at 2-5 degreeC for 30 minutes. The filtration residue was washed with a solution obtained by mixing 154 ml of water and 6.4 g of an aqueous solution of hydrochloric acid and potassium chloride extracted earlier, and the resulting washing was mixed with the filtrate to obtain (±) -trans-4- ( An aqueous hydrochloric acid solution of 4-fluorophenyl) -3-hydroxymethylpiperidine was obtained.

  Further, 216 ml of water and 160 ml of toluene were charged into another reaction vessel, and hydrochloric acid of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine obtained above was added to this solution at 20-21 ° C. A 42 g portion of the aqueous solution and 3 ml of a 26 wt% aqueous sodium hydroxide solution were poured together while maintaining the pH in the system at 11.2 to 12.5. The time required for co-injection was 30 minutes. After co-injection, 10 mg of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine seed crystals were added and stirred for 30 minutes. Thereafter, at 20 to 22 ° C., the remaining (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine in 557 g of hydrochloric acid and 43 ml of 26% by weight sodium hydroxide in the same manner as above were used. While maintaining the pH in the system at 11.2 to 12.5, the solution was injected together. The time required for co-injection was 3 hours. After completion of the co-injection, the mixture was stirred at about 20 ° C. for 1 hour, and the precipitated crystals were collected by filtration and washed three times with 80 ml of toluene cooled to 4 to 5 ° C. and then with 80 ml of water to obtain wet crystals. The wet crystals were dried at 40-80 ° C. under reduced pressure to obtain 58.95 g of crystals. The yield was 88.5%. The HPLC purity was 99.7%.

Example 3
Under a nitrogen atmosphere, 530 g of toluene and 306 g (1.22 mol) of a cis-trans mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one were added to the reaction vessel, Heated to 110 ° C. To this solution, 0.7 g (13 mmol) of sodium methoxide was added and heated to reflux for 30 minutes. The reaction solution was cooled to 97 ° C., a part of the reaction solution was collected, dried by heating, toluene was distilled off, and the seed crystal obtained was inoculated into the reaction solution. The mixture was aged at 97 to 98 ° C for 30 minutes and cooled to 80 ° C over about 2 hours. After incubating at 80 ° C. for 30 minutes, the mixture was heated to 90 ° C. and aged at the same temperature for 30 minutes. Subsequently, it cooled to 2 degreeC over 8 hours. A part of the precipitated crystals was collected, and it was confirmed by HPLC analysis that the isomerization ratio from the cis form to the trans form was 99%.

  After adding 5 g (0.036 mol) of boron trifluoride-THF complex to the reaction solution obtained above at 0 to 10 ° C., 816 g of THF was added. Further, 562 g (4.00 mol) of boron trifluoride-THF complex and a suspension of 115 g (3.04 mol) of sodium borohydride in THF (272 g) were added dropwise at 30 to 40 ° C. (dropping). 3 hours). After stirring for 30 minutes, the mixture was heated to 70 ° C and stirred at 70 to 74 ° C for 3 hours. The reaction solution was cooled to 10 ° C., and 12 g of methanol was added dropwise.

  In a separate reaction vessel, 1224 g of water, 133 g (1.28 mol) of 35% by weight hydrochloric acid and 238 g (3.19 mol) of potassium chloride were added and mixed. The solution was added dropwise over a period of time (the obtained solution was called hydrolyzed solution). The container in which the reaction solution containing the previous methanol was added was washed with 60 ml of toluene, and this washing solution was added to the hydrolyzed solution. The hydrolyzed solution was heated to 55 ° C. and kept for 30 minutes, and then heated to 80 ° C. to distill off the solvent. Then, it concentrated at 83 degreeC and the pressure reduction degree 56kPa (total distillation amount 2300 ml). 306 g of water was added to the obtained concentrate, and the mixture was kept at 80 ° C. for 30 minutes. Subsequently, it cooled to 5 degreeC over 4 hours, filtered after stirring at 0-5 degreeC for 30 minutes. The filtration residue was washed with a solution obtained by mixing 588 g of water, 4 g (0.0536 mol) of potassium chloride and 4 g (0.0384 mol) of 35% by weight hydrochloric acid, and the resulting washing was mixed with the filtrate. As a result, 2350 g of an aqueous hydrochloric acid solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was obtained at a concentration of 10.4% by weight.

  The obtained hydrochloric acid aqueous solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was divided, and each was crystallized by the following method.

  1) A reaction vessel was charged with 275 ml of water and 204 ml of toluene, and this solution was charged with 20 g of an aqueous hydrochloric acid solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine obtained above at 20 ° C. While maintaining a pH of 12 in the system, 12 g of a 26% by weight aqueous sodium hydroxide solution was co-injected. The time required for co-injection was 30 minutes. After co-injection, 0.05 g of seed crystal of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was added and stirred for 30 minutes. Thereafter, at 20 ° C., an aqueous hydrochloric acid solution (743 g) of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine and 125 g of 26% by weight aqueous sodium hydroxide solution were added to the system in the same manner as described above. While maintaining the pH at 12, the solution was added in parallel. The time required for co-injection was 3 hours. After completion of the co-injection, the mixture was stirred at 20 ° C. for 1 hour, and the precipitated crystals were collected by filtration and washed three times with 102 ml of toluene cooled to 5 ° C. and then with 102 ml of water. The obtained wet crystals had a solid content of 57%. According to HPLC analysis, the wet crystals contained (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine and toluene. It was included at a weight ratio of 1: 0.25. The XRD of this wet crystal shows a different pattern from that after drying. From various instrumental analysis, this wet crystal was found to be (±) -trans-4- (4-fluorophenyl) -3-hydroxy solvated with toluene. It is considered to be a crystal of methylpiperidine. The wet crystals were dried at 40 to 80 ° C. under reduced pressure to obtain 77.6 g of crystals. The yield was 91.3%. The HPLC purity was 99.7%.

2) A reaction vessel was charged with 275 ml of water and 204 ml of toluene, and this solution was charged with 20 g of an aqueous hydrochloric acid solution of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine obtained above at 20 ° C. While maintaining a pH of 12 in the system, 13 g of a 26% by weight aqueous sodium hydroxide solution was injected together. The time required for co-injection was 30 minutes. After co-injection, 0.05 g of seed crystal of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was added and stirred for 30 minutes. Thereafter, at 20 ° C., a further hydrochloric acid aqueous solution (743 g) of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine and 130 g of 26% by weight sodium hydroxide aqueous solution were added in the same manner as above. While maintaining the pH at 12, the solution was added in parallel. The time required for co-injection was 3 hours. After completion of the co-injection, the temperature was raised to 48 ° C. while adding a 26 wt% aqueous sodium hydroxide solution dropwise so that the pH in the system was maintained at 11.5-12. After cooling to 10 ° C., the precipitated crystals were collected by filtration and washed three times with 102 ml of toluene cooled to 5 ° C. and then with 102 ml of water. The solid content of the obtained wet crystal was 82%. According to HPLC analysis, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine and toluene contained in the wet crystal The weight ratio was 1: 0.04. The wet crystals were dried at 40-80 ° C. under reduced pressure to obtain 79.1 g of crystals. The yield was 93.1%. The HPLC purity was 99.8%.
The obtained crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine had an aspect ratio as shown in the micrograph of FIG. It is a cubic crystal having a ratio (aspect ratio / aspect ratio) of about 1, and has excellent filterability and purity.

Example 4
Using 1061 kg of a cis isomer-trans isomer mixture of (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, the reaction was carried out under the same conditions as in Example 2, and the precipitated crystals were collected by filtration. Washing and drying yield crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine. Further, the filtrate and the washing solution are combined, and while stirring, 410 kg of a 26 wt% sodium hydroxide aqueous solution is added to adjust the pH to 12.3, and the toluene layer is separated. To the aqueous layer after separation, 1061 L of toluene is further added, followed by separation and extraction, and combined with the previously obtained toluene layer. The resulting toluene layer contains (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine corresponding to 5% by weight of the theoretical yield. By adding 531 kg of water to the toluene layer, separating the solution with 35% by weight hydrochloric acid at a pH of 7.5, and isolating the aqueous layer, (±) -trans-4- (4-fluorophenyl) -3 -Hydroxymethylpiperidine hydrochloride can be recovered as an aqueous solution.

Measurement of Glass Lining (GL) Corrosion Rate For the GL test piece tested at 96 ° C. for 24 hours using the reaction solution obtained under the same conditions as in Example 1, the annual corrosion rate was 0.19 mm / year. .
For the GL test piece tested at 96 ° C. for 24 hours using the reaction solution obtained under the same conditions as in Example 1 except that potassium chloride was not used, the annual corrosion rate was 1.52 mm / year. It was.
The GL test piece tested at 78-83 ° C. for 15 days using the reaction solution obtained under the same conditions as in Example 3 (however, the reaction solution was changed every 5 days) had an annual corrosion rate of 0. 04 mm / year.
From the above, it can be seen that GL corrosion could be remarkably suppressed by using potassium chloride.

  According to the production method of the present invention, (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine can be easily and industrially produced with high purity and good yield. The resulting (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine is useful as an intermediate in the synthesis of paroxetine hydrochloride used as an antidepressant.

FIG. 1 is an XRD pattern of a crystal of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine produced by the method of Japanese Patent Application Laid-Open No. 2001-114764. FIG. 2 is an XRD pattern of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine crystals produced by the same method as in Example 2. FIG. 3 shows crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine prepared by the same method as in Example 1 and obtained by washing with toluene and then with water. This is an XRD pattern. FIG. 4 shows the crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine prepared by the same method as in Example 1 and obtained by washing with toluene and water before drying. FIG. FIG. 5 is a photomicrograph of crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine produced by the same method as in Example 1. FIG. 6 is a photomicrograph of crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine produced by the method of Japanese Patent Application Laid-Open No. 2001-117464. FIG. 7 is a photomicrograph of crystals of (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine produced by the same method as in Example 3, 2). FIG. 8 is a 0.1 mm scale corresponding to the micrographs of FIGS.

Claims (6)

  Reduction of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one with boron trifluoride-ether complex and sodium borohydride to obtain a reaction solution, Mineral acid and potassium salt are added to the resulting reaction solution to adjust the pH to 0.5 to 4.0, the precipitate is removed to obtain an acidic solution, and then the pH of the resulting acidic solution is adjusted to 11. A method for producing (±) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine, which is adjusted to 0.0 to 12.5.   The production method according to claim 1, wherein the potassium salt is at least one selected from the group consisting of potassium chloride, potassium bromide and potassium iodide.   The production method according to claim 1 or 2, wherein the mineral acid is hydrochloric acid.   PH adjustment of an acidic solution is performed by adding the said acidic solution and an alkali, maintaining pH in a system at 11.0-12.5 in the solvent containing water. The manufacturing method of any one of these.   The reduction is performed by adding sodium borohydride to (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one in the presence of boron trifluoride-ether complex. The manufacturing method of any one of Claims 1-4.   (±) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one cis isomer or cis isomer-trans isomer mixture is treated with a base to convert the cis isomer to the trans isomer, resulting in 6. The production method according to claim 1, wherein (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one is reduced.