WO2008013248A1 - Process for production of (±)-trans-4-(4- fluorophenyl)-3-hydroxymethylpiperidine - Google Patents

Abstract

A process for producing (±)-trans-4-(4-fluorophenyl)- 3-hydroxymethylpiperidine, comprising reducing (±)-trans-4-(4-fluorophenyl)-3-methoxycarbonylpiperidin-6 -one with a boron trifluoride-ether complex and sodium borohydride to produce a reaction solution, adding a mineral acid and a potassium salt to the reaction solution, adjusting the pH value of the solution to 0.5 to 4.0, removing any precipitate from the solution to produce a acidic solution, and then adjusting the pH value of the acidic solution to 11.0 to 12.5.

Description

 Specification

(±) One-trans-4 One (4 One-fluorophenyl) One 3-Hydroxymethylpiperidine Production Method Technical Field

 The present invention relates to a method for producing (±) -trans-4- (4-fluorophenyl) _3-hydroxy'bimethylbiperidine.

 In more detail, the present invention relates to (±) —trans 1 4— (4—) by (1) 1 trans 1 4 1 (4 1 fluorophenyl) 1 3-methoxycarbonylpiperidin-6-one reduced by borane reduction. Fluorophenyl) relates to a process for producing 1-hydroxymethylpiperidine. Background art

 (±) —Trans 4- (4-Fluorophenyl) 1 3-hydroxymethylpiperidine is a useful synthetic intermediate for paroxetine hydrochloride used as an antidepressant.

 (±) -trans-one 4-one (4-one-fluorophenyl) -one 3-hydroxymethylpiperidine is, for example, (±) -trans-one 4-one (4-one-fluorophenyl) one 3 _methoxycarbonyl piperidine-one 6-one It is known that it is produced by reduction with lithium 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 L AH. On the other hand, it is another synthetic intermediate of paroxetine hydrochloride (Shi) —trans 1 4- (4 1 fluorophenyl) 1 3 -hydroxymethyl 1 N-methyl piperidine (soil) 1 trans 4 — (4 1 fluoro (Phenyl) _3-methoxycarbonyluro N-methylpiperidine 1,2,6-dione is known to be produced by reducing it with porane (see Patent Document 3). Here, poran is produced in the reaction system from boron trifluoride monoether complex and sodium borohydride. In this method, after the reduction, the reaction solution is acidified to decompose the amine-porane complex, and the resulting boric acid compound (from boron trifluoride monoether complex and sodium borohydride) is filtered, and the resulting acidic solution is obtained. The aqueous solution is made basic and extracted with an organic solvent, and a poor solvent is added to the organic layer to crystallize the desired product.

[Patent Document 1] Japanese Patent No. 3 4 4 6 4 6 8 [Patent Document 2] Japanese Patent Laid-Open No. 10-291975

 [Patent Document 3] Japanese National Patent Publication No. 8-507540 Disclosure of Invention

 The boric acid compound is considered to be boric acid, sodium borate, metaboric acid, borofluoride, etc. and their hydrolysates. When the above method is applied to (Trans) 1-Trans 4 4- (4-Fluorophenyl) -3-methoxycarbonylbiperidin 1-one, the boric acid compound can be analyzed even if the reaction solution is acidified after the reduction of polan. It remains 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) -13-hydroxymethylpiperidine with high purity and high yield. As a result of investigations to solve the above-mentioned problems, the present inventors have found that (±) -trans-4- (4-fluorophenyl) -1-3-methoxycarbonylpiperidine-6-one is converted to boron trifluoride-one ether. By adding mineral acid and potassium salt to the reaction solution after reduction using a 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. It was found that (±) -trans-4- (4-fluorophenyl) 1-3-hydroxymethylpiperidine can be obtained with high purity and high yield. That is, the present invention provides the following [1] to [6].

 [1] (Shi) One-Trans-One 4-One (4-Fluorophenyl) _ Reduction of 3-methoxycarbonylpiperidin-6-one with boron trifluoride-ether complex and sodium hydrogen hydride Then, a mineral acid and a 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. The pH of the obtained acidic solution is adjusted to 11.0 to 12.5. (Shi) One trans-4 one (4 one fluorophenyl) One 3-hydroxymethylpiperidine production method.

 [2] The production method according to [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 [1] or [2], wherein the mineral acid is hydrochloric acid.

[4]. The pH of the acidic solution is adjusted by adding the acidic solution and the alkali in a 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 is achieved by adding sodium borohydride to (±) —trans 4 1 (4 1 fluorophenyl) 1 3 -methoxycarbonylpiperidine 6 —one in the presence of boron trifluoride monoether complex. The manufacturing method according to any one of claims [1] to [4].

 [6]. (±)-4-(4 Monofluorophenyl) 1-Methoxycarbonylpiperidin-6-one cis-isomer or cis-one-trans-isomer mixture is treated with a base to convert the cis-isomer to trans. The production according to any one of [1] to [5], wherein (±) -trans-4-one (4-fluorophenyl) -1-3-methoxycarbonylpiperidin-6-one is reduced. Method. Brief Description of Drawings

FIG. 1 is an XRD pattern of (±) -trans-4-4 (4-fluorophenyl) -1-hydroxymethylpiperidine produced by the method of JP-A-2001-114764.

FIG. 2 is an XRD pattern of (±) -trans-4- (4-fluorophenyl) 13-hydroxymethylpiperidine crystals produced by the same method as in Example 2.

FIG. 3 is an XRD pattern of wet crystals of (Transformer) 4-trans (4-fluorophenyl) -3-hydroxymethylpiperidine prepared by the same method as in Example 1 before drying.

FIG. 4 is a micrograph of wet crystals of (±) -trans-4- (4-fluorophenyl) 13-hydroxymethylpiperidine prepared by the same method as in Example 1 before drying.

FIG. 5 is a photomicrograph of (Shi) 1-trans-4 1 (4-fluorophenyl)-. 3-hydroxymethylpiperidine crystals produced by the same method as in Example 1. FIG. 6 is a micrograph of (±) -trans-4-4 (4-fluorophenyl) -3-hydroxymethylpiperidine crystals produced by the method of JP-A-2001-114764.

FIG. 7 is a photomicrograph of (±) -trans-4- (4-fluorophenyl) _3-hydroxymethylpiperidine crystals produced by the same method as in Example 3, 2). From Fig. 7, the temperature ratio of the (±) -trans-4-1 (4-fluorophenyl) -13-hydroxymethylpiperidine crystal (vertical Ζ aspect ratio) is about 1 by temperature swing during crystallization. It can be seen that a cubic crystal is obtained.

Fig. 8 is a 0.1mm scale corresponding to the micrographs of Figs. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described in detail below. First, (trans) 1-trans-4-1- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one, which is a raw material of the present invention, can be obtained by various methods, for example, the method described in Patent Document 2, etc. Can be manufactured. This document discloses that the cis form of (±) 1 4 1 (4 1 fluorophenyl) 1 3 -methoxycarbonylpiperidin 1 6-one is converted (isomerized) into a trans form by treatment with a base. Has been. That is, by using (±) — 4 1 (4 1 fluorophenyl) 1 3 -methoxycarbonylpiperidin-6-one cis-form or cis-trans-form mixture as a raw material and treating this with a base The trans form is produced. This isomerization reaction is usually carried out 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 alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide. The amount of the base to be used is generally 0.1 to 0.1 mol, preferably 0.02 to 0.03 mol, relative to 1 mol of the cis isomer or cis isomer-trans isomer mixture. 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 treatment operation, aromatic hydrocarbons may be used. A solvent is preferred.

 The amount of the organic solvent to be used is generally 0.5 to 2.5 L, preferably 0.5 to 1.0 L, per 1 mol of the cis isomer or cis isomer-trans mixture. The isomerization reaction is carried out by using a cis-form or cis-one-trans mixture of (±) — 4 1 (4-fluorophenyl) 1 3 -methoxycarbo dirubiperidine 1 6-one in an organic solvent, usually 40 ° C or higher. Preferably, after heating to 60-1 14 ° C, base is added, usually 80-1 14 ° C, preferably 96-1 14 ° C, usually 0.5-4 8 It is carried out by heating for a time, 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 at 1 ° C. or less, preferably 2 ° C. or less, more preferably 1 ° C. or less. Usually, when the temperature of the solution falls to 10 to 96 ° C, the trans isomer starts to crystallize, and crystallization is completed at 0 to 10 ° C. Cooling is preferably carried out by allowing the reaction solution to cool to room temperature and then cooling with ice.

In addition, the crystallization of the trans isomer may be performed by swing cooling, in which the reaction solution is repeatedly cooled and heated. In this case, the slurry property of the reaction solution is further improved. Can be made. In swing cooling, for example, the reaction solution is stirred at 96 to 98 ° C for about 30 minutes, cooled to about 80 ° C at a cooling rate of about 5 ° C per hour, and about 80 ° C for about 30 minutes. Stir, heat up to about 90 ° C, stir at the same temperature for about 30 minutes, then cool to about 40 ° C at a cooling rate of about 8 per hour, and stir at about 40 ° C for about 30 minutes The temperature can be raised to about 60 ° C, stirred for about 30 minutes at the same temperature, and cooled to about 2 ° C at a cooling rate of about 10 ° C per hour. The isomers obtained by the above isomerization reaction are isolated and purified by filtering, if necessary, by trans-4-1- (4-fluorophenyl) -3-methoxycarbonylpiperidine-6_one. However, it is convenient and preferable to subject the reaction mixture to the next reduction reaction as it is. Next, the (±) -trans 4- (4-fluorophenyl) 1-methoxycarbonylpiperidin-6-one thus obtained was used with boron trifluoride-ether complex and sodium borohydride. (±) —trans 1 4 _ (4 -fluorophenyl) 1 3 -hydroxymethylpiberidine is produced by reduction. Here, boron trifluoride-ether complex and sodium borohydride generate borane in the system, which becomes the reducing agent. The reduction with this boron trifluoride-ether complex and sodium borohydride is inexpensive and safe to handle, unlike LAH. Examples of the boron trifluoride-ether complex used in the present invention include boron trifluoride-tetrahydrofuran (TH F) complex, boron trifluoride-dimethyl ether complex, boron trifluoride-jetyl ether complex, Examples thereof include boron fluoride-dibutyl ether complex, among which boron trifluoride-THF complex is preferable from the viewpoint of ease of handling and economy.

The amount of boron trifluoride-ether complex used is (±) -trans 4- (4-fluorophenyl) _ 3-methoxycarbonylpiperidin-6-one per mole, usually 2.6 6 7 ˜4.0 times mol, preferably 3.16 to 3.5 times mol. If the amount of boron trifluoride-ether complex used is less than 2.67 moles, the reduction reaction rate decreases. Conversely, if it exceeds 4.0 moles, 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 couplet type, or the like. The amount of sodium hydrogen hydride used is usually 2.0 to 3.0 times the amount of (±) -trans-4- (4-fluorophenyl) -1-3-methoxycarbonylpiperidine-6_one per mole. Mole, preferably 2.3 7-2.6 3 moles. If the amount of sodium borohydride used is less than 2.0-fold mol, the reduction reaction rate will decrease, In addition, if it exceeds 3.0 moles, it is economically disadvantageous, and due to excess sodium borohydride, (trans) 1 trans 1 4 1 (4-fluorophenyl) 1 3-methoxycarbonyl piperidine— Part of the 6-one trans isomer isomerizes to the cis isomer over time. The reduction reaction is usually performed in an organic solvent.

 Examples of organic solvents include ether solvents such as jetyl ether, tetrahydrofuran (TH F), t-butyl methyl ether (MT BE), dioxane, diethylene dimethyl dimethyl ether; toluene, cyclohexane, heptane, and the like. Hydrocarbon solvents such as xanthone; and mixed solvents thereof. Among them, THF is preferable from the viewpoint of easy handling.

 The amount of the organic solvent used is usually 1.2 to 2.0 L, preferably 1 to 1 trans 4- (4 monofluorophenyl) -3-methoxycarbonylpiperidine-6_one per mole. 1.3 to 1.8 L. As described above, after the isomerization reaction of (shi) -4- (4-fluorophenyl) 1-3-methoxycarbonylpiperidine-1-6-one, the reaction mixture is directly subjected to the reduction reaction without isolation / purification. If provided, the above organic solvent is added to the reaction mixture (including the solvent used in the isomerization reaction). The reduction reaction is carried out in the presence of boron trifluoride monoether complex by adding sodium borohydride to (Shi) -trans-4- (4-fluorophenyl) 1-3-methoxycarbonylpiperidin-6_one Is preferred. (±) —Trans—4— (4 monofluorophenyl) — 3-methoxycarbonylpiperidine 1 6 1-one and boron borohydride sodium complex add hydrogen triethyl monoether complex to form hydrogen Due to the alkali of sodium borohydride, a part of the trans isomer may be isomerized to the cis isomer over time.

 In the reduction reaction, for example, about 1% by weight of the boron trifluoride-ether complex to be used is added to (trans), trans, 4-1 (4, 1-fluorophenyl), 1-methoxycarbonylbiperidine, 1-one. Then, it is carried out by adding sodium borohydride and boron trifluoride monoether complex, respectively.

The sodium borohydride and the remaining boron trifluoride monoether complex are usually added at 0 to 70 ° C, preferably 20 to 50 ° C. The temperature of the reduction reaction is usually from 20 to 80 ° (: preferably from 30 to 55 ° C. The time of the reduction reaction is (±) —trans 4 1 (4-fluorophenyl) 1 3—Methoxycarbonyl piperidine 1_one, boron trifluoride monoether complex, sodium borohydride, organic solvent usage, boron trifluoride ether Although it depends on the type of ruthenium complex and organic solvent, it is usually 1 to 18 hours, preferably 2 to 10 hours. 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 as a salt and removed. To do. The addition of the mineral acid and potassium salt is carried out 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. Is called. Examples of the mineral acid used in the present invention include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. Among these, hydrochloric acid is preferable from the viewpoint of economy. In the case of hydrochloric acid, the amount used is preferably from 1.0 to 1.3 moles per mole of (±) -trans-4- (4-fluorophenyl) -1-3-methoxycarboxylpiperidin-1-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 will decrease, and 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 economical point of view. The amount of potassium salt used is preferably 2 to 5 moles, more preferably 2 to 4 moles per mole of (±) -trans-4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-1-6-one. Mol, more preferably 2 to 3 mol. When the amount of potassium salt used is less than 2 mol, the salt of 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 moles, the excess potassium salt increases the load on the amount of inorganic salt dissolved in water during crystallization (crystallization) described later. The potassium salt is preferably used in the form of an aqueous solution, and its concentration is preferably 5 to 25% by weight, more preferably 12 to 18% by weight.

By adding potassium salt, corrosion of the glass-lined (GL) reaction vessel can be remarkably suppressed. The treatment with mineral acid and potassium salt is performed, for example, as follows. First, the reduced reaction solution is added to a mineral acid (preferably an aqueous solution), or mineral acid (preferably an aqueous solution) is added to the reaction solution, and an excess of borane (boron trifluoride monoether) is added. It is formed by the reaction of the complex with sodium borohydride. This quenching is carried out until polan disappears, but it is preferably 1 to 10 hours, more preferably 3 to 7 hours. Next, 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. Alternatively, when quenching, an aqueous mineral acid solution to which a strong lithium salt is added may be used. The addition of the mineral acid and potassium salt is preferably carried out at 0 ° C. to 50 ° (:, 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 ZTHF mixed solvent, by heating to about 68 ° C, the toluene ZTHF mixed solvent azeotropes with water, and almost all the toluene / THF mixed solvent is distilled off at about 96 mm. Distilling off the organic solvent can be carried out by reducing the distillation temperature by reducing the pressure, in which case the corrosion of the glass lining (GL) can be further suppressed. Is cooled to around 5 ° C at a rate of 2-25 ° C / hour, more preferably 10-15 ° C / hour, preferably 0-5 ° (: more preferably about 1 at 0-2 ° C By stirring overnight, most of the boric acid compound is precipitated in the form of salt. Next, the precipitated salt of the boric acid compound is filtered and washed. Filtration is preferably performed at 0 to 5 ° (:, more preferably at 0 to 2 ° C. Water is used for washing. However, it is more preferable to wash with water containing the mineral acid and potassium salt used in the above treatment (1 to 2% by weight of the amount used), respectively. The amount is preferably 100 to 300 g, more preferably 150 to 250 g based on 100 g of (±) —trans 1 4- (4-fluorophenyl) 1 3 -methoxycarbonylpiperidin 1-one as the raw material. In the acidic solution obtained by filtration, some boric acid compounds (including salt forms) still remain, and in the present invention, the pH of this acidic solution is 11.0 to 12.5, preferably 11. Adjust from 5 to 12.0, (Shi) One transformer One 4 one (4—Frills 1-hydroxymethylpiperidine 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). Remains dissolved in acidic solution, conversely, 12.5 If it exceeds, impurities (boric acid ^: compounds, organic impurities, etc.) will crystallize (crystallize) together with the target product, and the purity of the resulting target product (crystals) will decrease. 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 moles, more preferably 1.2 to 1 mole of (4-) 1-trans (4-fluorophenyl) 1-methoxycarbonylpiperidin 1-one. ~ 2.2 moles. When the amount of alkali used is less than 1 mole, the pH of the acidic solution is below the above range, and conversely, when it exceeds 3 moles, the pH of the acidic solution is above the above range. The alkali is preferably used in the form of an aqueous solution from the viewpoint of promoting crystallization (crystallization), and its concentration is preferably 1 to 48% by weight, more preferably 14 to 35% by weight. It is. For example, pH adjustment with alkali is preferably performed as follows. First, add water to the crystallization vessel. The amount of water is preferably (10) 1-trans-4- (4-fluorophenyl) _3-hydroxymethylpiperidine with respect to 100 g, preferably 100-350 g, more preferably 15 0 to 300 g. Further, an organic solvent such as toluene may be added, and the amount thereof is preferably not more than the same volume as water. 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 to 35 ° C, more preferably 10 to 30 T :. The method of adding an acidic solution and an alkali (preferably an aqueous solution) is not particularly limited as long as the pH in the system is maintained within the range of 11.0-12.5, but it should be added in small portions. Is preferred, and dripping 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 addition may be either an acidic solution or an alkali (preferably an aqueous solution), either continuously or intermittently, but intermittently is preferred. 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 the addition is complete, ripen and complete 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. In addition, this ripening can be carried out by a so-called temperature swing method in which the temperature is raised or lowered, and in this case, 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 1 ° C., raising the temperature to about 48 ° C., and then cooling to about 10. The precipitated crystals can be collected by filtration, washed with an organic solvent such as toluene or water, and dried.

 Thus, the obtained (±) -trans-4 (4-fluorophenyl) -3-hydroxymethylpiperidine contains almost no boric acid compound and has a high purity (preferably 98 to 10). 0%, particularly preferably 9 9 to 100%) and high yields (preferably 88 to 9 7%, particularly preferably 90 to 9 7%). If (5) 1-trans-4- (4 monofluorophenyl) -3-hydroxymethylpiperidine remains in the filtrate at about 5% by weight of the theoretical yield, the pH should be reduced with caustic alkali. Adjust to 1 to 3 and extract (±) -trans 1 4- 1 (4-fu J Leoguchi phenyl) 1 3-hydroxymethylpiperidine into the organic layer (toluene layer) and separate it into organic layer (toluene layer) (±) -trans-4- (4-fluorophenyl) 1-3-hydroxymethylpiperidine hydrochloride is recovered as an aqueous solution by separating the aqueous layer by adding water and hydrochloric acid to the solution. Can do. In addition, separation of (trans) one-trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine from boric acid compounds by the series of treatments described above is a simple method and is very useful for industrial production. Is suitable. Therefore, such a method for producing (trans) 1-trans-4-1 (4-fluorophenyl) -13-hydroxymethylpiperidine is very useful for the synthesis of paroxetine hydrochloride, which is a depressant. According to the present invention, an inexpensive boron trifluoride monoether complex and sodium borohydride are used as a reducing agent, and (shi) —trans-4- (4 monofluorophenyl) 1 3-hydroxymethylpiperidine has a purity of It can be manufactured with good yield. In addition, the presence of a strong Ryum salt in an acidic solution of 1-trans-1, 4- (4-fluorophenyl) 1-3-hydroxymethylpiperidine suppresses the corrosion of the reaction vessel made by Dura Lining (GL). It becomes possible to do. Example

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) 13-methoxycarbonylpiperidin-6-one was produced according to the method described in Patent Document 2. The conditions for HPLC analysis are as follows.

 (H PLC condition)

Detector: UV 210 nm

Column: TSK— GEL ODS-80TM (4. 6mmd) xl 5 cm) Column temperature: 40 ° C

Mobile phase: 12 mM 1—sodium heptane sulfonate, 32 mM KH ₂ PO ₄ Z phosphate buffer, PH3.00 acetonitrile = 80Z20

Flow rate: 1 mLZm i n Glass Lining (GL) Material corrosion was measured under the following conditions.

 (±) 1 4- (4-Fluorophenyl) 1 3-methoxycarbonylbiperidin 1 6-one cis-trans mixture Using about 4 molar scale hydrolyzed solution, and from the GL product manufacturer in the liquid phase The obtained test piece (weighed in advance) was placed, stirred, washed and dried after a certain period of time, the weight of the test piece was measured, and the weight loss (mg) was calculated.

 The annual corrosion rate was calculated by the following formula.

 Annual corrosion rate (mm / year) = 1.59 X Weight loss (mg) / Test time (h) Example 1

Under a nitrogen atmosphere, add 200 ml of toluene and 100 g (0. 398 mol) of a cis-trans mixture of (±) — 4— (4-fluorophenyl) —3-methoxycarbonylpiperidin-6-one to Kolben. In addition, it was heated to about 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 bubbled or heated and dried to distill off toluene, and the obtained seed crystal was inoculated into the reaction solution. 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 HP LC 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 mono-THF complex was added at 2 ° C., and then THF 30 Om 1 was added. Further, 185.53 g (1.321 mol) of boron trifluoride mono-THF complex was added dropwise at about 20 ° C. Next, a suspension of 37.64 g (0.995 mol) of sodium borohydride in THF (10 Oml) was added dropwise at 35 ° C. over 6 hours. Heat to 74 ° C and stir for 3 hours Stir. The reaction solution was cooled to about 10 ° C, and 3.83 g of methanol was added dropwise over 30 minutes. In another Kolben, add 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 and mix, and then add 7.9 g (1. 5% by weight) was extracted. The previous reaction solution was added to the remaining solution at 25 ° C over 2 hours to adjust the pH to 1.5. Heating was performed until the internal temperature reached 96, and methanol, THF and toluene were distilled off. Next, the mixture was cooled to 5 ° C over 6 hours, stirred overnight at 0-5 ° C, and then filtered. 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 after drying the filtration residue). In yet another Kolben, 300 ml of water and 200 ml of toluene were added, and the pH was maintained at 11.2 to 11.5, while the filtrate ((±) —trans 1 4 1 (4 —fluorophenyl) 1 3— Hydroxymethylpiperidine hydrochloride acidic solution) and a 30 wt% aqueous solution of sodium hydroxide 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-4-1- (4-fluorophenyl) -13-hydroxymethylpiperidine seed crystals were added. The time required for dropping was 6.5 hours. After completion of the dropping, 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 to obtain wet crystals. The wet crystals were dried at 80 ° C under reduced pressure to obtain 77.8 g of crystals. The yield was 93.4%. HPLC purity: 99.7%. Example 2

 Under a nitrogen atmosphere, add 160 ml of toluene and 80 g (0.318 mol) of a cis-isomer mixture of (soil) -4- (4-fluorophenyl) -3-methoxycarbonylpiperidin-6-one 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, and a part of the reaction solution was collected, dried by heating, and toluene was distilled off. The mixture was aged at 96 to 97 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 40 degreeC over 5 hours.

The mixture was further heated to 60 ° C, 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 HP LC that the isomerization ratio from the cis form to the trans form was 99.5%. To the reaction solution obtained above, 1.3 g (0.094 mol) of boron trifluoride mono-THF complex was added to the reaction solution at 2 ° C., and the mixture was heated to 30 and 240 ml of THF was added. Boron trifluoride mono-THF complex 147g (1.047 mol) and sodium borohydride 30.1g (0.779 6 mol) suspended in THF 80m 1 at 32 to 35 ° C. The solution was added dropwise (drop time 3 hours). After stirring for 30 minutes, the mixture was heated to W ° 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 a separate reaction vessel, add 35.4 g (0.400 mol) of 35 wt% hydrochloric acid and 63.3 g (0.849 mol) of potassium chloride to 325 m 1 of water and mix to obtain 6.4 g (1.5 wt%). Extracted. The reaction solution obtained by adding methanol to the remaining solution was added dropwise at about 20 ° C. over 50 minutes (the resulting solution is referred to as a hydrolyzed solution). The container containing the reaction solution was washed with 20 ml of toluene, and this washing solution was added to the hydrolyzed solution. This 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 m 1) To the obtained concentrate, 80 ml of water was added and kept at 80 ° C. for 30 minutes. The mixture was cooled to 5 ° C over 3 hours, stirred at 2-5 ° C for 30 minutes, and then filtered. Wash the residue with a solution of 154 g of water and 6.4 g of the mixture of potassium chloride and hydrochloric acid mixed with the previous solution, and mix the resulting washing with the filtrate. An aqueous hydrochloric acid solution of 4- (4-fluorophenyl) -3-hydroxymethylpiperidine was obtained.

 Furthermore, 216m 1 of water and 160m 1 of toluene were charged into another reaction vessel, and this solution was obtained at 20-21 ° C at (Sat)-Trans-4- (4-Fluorophenyl)-

42 g of hydrochloric acid aqueous solution of 3-hydroxymethylpiperidine and 3 ml of 26 wt% sodium hydroxide aqueous solution were injected together while maintaining the pH in the system at 11.2 to 12.5. The time required for co-injection was 30 minutes. After completion of the co-injection, 10 mg of seed crystal of (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was added and stirred for 30 minutes. After that, at 20-22 ° C, the remaining (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine in 557 g of hydrochloric acid and 43 ml of 26 wt% sodium hydroxide in the same manner as above While maintaining the pH in the system at 11.2 to 12.5, the same was carried out at the same pH. The time required for co-injection was 3 hours. After completing the co-injection, the mixture was stirred at about 20 ° C for 1 hour, and the precipitated crystals were filtered and washed with 80 ml of toluene cooled to 4 to 5 ° C and then with 80 ml of water three times to obtain wet crystals. Wet crystals under reduced pressure,

The crystals were dried at 40 to 80 ° C. to obtain 58.95 g of crystals. The yield was 88.5%. The HP LC purity was 99.7%. Example 3

In a nitrogen atmosphere, 530 g of toluene and (Sat) -4- (4-Fluorophenyl) -3-methoxycarbonylbiperidine-6-one cis-isomer-trans mixture in a reaction vessel 306 g (1.22 mol) of the compound was added and 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, and toluene was distilled off. The mixture was aged at 97-98 ° C for 30 minutes and cooled to 80 ° C in 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. Then it was cooled to 2 ° C over 8 hours.

 A part of the precipitated crystals was collected, and it was confirmed by HPLC that the isomerization rate from the cis form to the trans form was 99%.

 To the reaction solution obtained above, boron trifluoride mono-THF complex 5 g (0.036 mol) was added to the reaction solution at 0 to 0 ° C., and then THF 816 g was added.

 A suspension of 562 g (4.00 mol) of boron trifluoride-THF complex and 115 g (3.04 mol) of sodium borohydride in 272 g of THF was added dropwise at 30 to 40 ° C (dropping 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 12 g of methanol was added dropwise. In a separate reaction vessel, add 1224 g of water, 133 g of 35% by weight hydrochloric acid (1.28 mol) and 238 g of lithium chloride (3.19 mol), mix, and add 10-20 of the reaction solution containing the previous methanol. The solution was added dropwise over 1 hour at ° C (the resulting solution was called hydrolyzed solution). The container containing the reaction solution was washed with toluene 60 ml, and this washing solution was added to the hydrolyzed solution. This 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 83 degreeC and the pressure reduction degree 56kPa. (Evaporation amount 2300 ml).

306 g of water was added to the resulting concentrate, kept at 80 ° C. for 30 minutes, cooled to 5 ° C. over 4 hours, stirred at 0-5 ° C. for 30 minutes, and then filtered. The residue was washed with a solution in which 588 _{g of} water, 4 _g (0.0536 mol) of potassium chloride and 4 _g (0.0384 mol) of 35% by weight hydrochloric acid were mixed, and the resulting washing was mixed with the filtrate.

 As a result, 2350 g of an aqueous hydrochloric acid solution of (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was obtained at a concentration of 10.4% by weight. The obtained hydrochloric acid aqueous solution of (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine was divided, and each was crystallized by the following method.

1) Charge the reaction vessel with 275 ml of water and 204 ml of toluene, and add 20 ml of this solution to the hydrochloric acid of (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine obtained above at 20 ° C. 40 g of aqueous solution and 12 g of 26 wt% sodium hydroxide aqueous solution were injected together while maintaining the pH of the system at 12. The time required for concurrent injection was 30 minutes. After completion of the co-injection, 0.05 g of (sat) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine seed crystal was added and stirred for 30 minutes. Then at 20 ° C, the remaining Rino (Shi)-Trans-4- (4-Fluorophenyl) -3-hydroxymethylpiperidine in aqueous hydrochloric acid (743g) and 26wt% sodium hydroxide 7 aqueous solution 125g. While keeping at 1 to 2, it was injected together. 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 filtered and washed three times with 102 ml of toluene cooled to 5 ° C and then with 102 ml of water. The resulting wet crystals had a solid fraction of 57%. According to HPLC analysis, the wet crystals contained (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine and toluene. , 1: contained in a weight ratio of 0.25. The XRD of this wet crystal shows a different pattern from that after drying. From various instrumental analyses, it was found that toluene was solvated in the crystal of (trans) 1-trans 4-4-1 (4-fluorophenyl) 1-3-hydroxymethylpiperidine It is believed that there is. The wet crystals were dried at 40-80 under reduced pressure to obtain 77.6 g of crystals. The yield was 91.3%. The HP LC purity was 99.7%.

2) Charge the reaction vessel with 275 ml of water and 204 ml of toluene, and add 20 ml of this solution to the aqueous solution of (sat) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine in hydrochloric acid at 20 ° C. 40 g and 26 g of a 26% by weight aqueous sodium hydroxide solution were added together while maintaining a pH of 12 in the system. The time required for concurrent injection was 30 minutes. After completion of the co-injection, 0.05 g of (sat) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine seed crystal was added and stirred for 30 minutes. After that, at 20 ° C, the remaining (soil)-卜 lance-4- (4-fluorophenyl) -3-hydroxymethylpiperidine aqueous hydrochloric acid solution (743g) and 26wt% sodium hydroxide aqueous solution 130g While maintaining the pH in the system at 12 in the same manner as described above, injection was carried out simultaneously. The time required for co-injection was 3 hours. After completion of the co-infusion, the solution was heated to 48 ° C while dropping 26 wt% aqueous sodium hydroxide solution so that the pH in the system was maintained at 11.5-12, cooled to 10 ° C, and then the deposited crystals were Filtered. This was washed 3 times with 102 ml of toluene cooled to 5 ° C and then with 102 ml of water. The solid content of the obtained wet crystals was 82%. According to HPLC analysis, (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine contained in the wet crystals The weight ratio of toluene 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 (shi) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine crystal was obtained by using the temperature swing method in the crystallization, as shown in the micrograph of FIG. Cubic crystals with a vertical Z aspect ratio of about 1 and excellent filterability and purity. Example 4

(Shi) -4- (4-Fluorophenyl) -3-methoxycarbonylpiperidin-6-one cis-isomer-trans mixture 1061 kg was used and the same conditions as in Example 2 The precipitate crystal is collected by filtration, washed and dried to obtain (trans) 1-trans 4- (4-fluorophenyl) 1 3-hydroxymethylpiperidine crystal. Further, combine the filtrate and the washing solution, add 410 kg of 26 wt% sodium hydroxide aqueous solution with stirring to pH 12.3, and separate toluene. Add 1061L of toluene to the separated aqueous layer, extract, and combine with the toluene layer obtained earlier. The resulting toluene layer contains (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine equivalent to 5% by weight of the theoretical yield. Add 531kg of water to this toluene layer, 35 weight. /. Separation with aqueous hydrochloric acid as pH 7.5 and isolation of the aqueous layer allows recovery as an aqueous solution of (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine hydrochloride can do. Glass Lining (GL) Measurement of Corrosion Rate A reaction solution obtained under the same conditions as in Example 1 was used and tested at 96 ° C. for 24 hours. For the GL test piece, the annual corrosion rate was 0.19 mm / year.

 A reaction solution obtained under the same conditions as in Example 1 except that potassium chloride was not used was tested for 24 hours at 96 ° C. For the GL test piece, the annual corrosion rate was 1.52 mm / year.

 The annual corrosion rate of the liquid phase GL test piece was 0.04 mm / year when the reaction solution obtained under the same conditions as in Example 3 was used for 15 days at 78 to 83 ° C. (Reaction solution is replaced every 5 days)

 From the above, GL corrosion can be remarkably suppressed by using potassium chloride. Industrial applicability

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

Claims

The scope of the claims 1. (±) One trans— 4— (4 One fluorophenyl) One 3-Methoxycarbonylpiperidin One 6-one with boron trifluoride-ether complex and borohydride 5 Reduce with sodium to obtain a reaction solution, and then add mineral acid and strong lithium salt to the resulting reaction solution to adjust the pH to 0.5 to 4.0 to remove the precipitate. To obtain an acidic solution, and then adjust the pH of the resulting acidic solution to 1 1.0 to 12.5, (±) —trans 4- (4-fluorophenyl) 1 3-hydroxymethylpiperidine Manufacturing method. 0  2. 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. ' 3. The production method according to claim 1 or 2, wherein the mineral acid is hydrochloric acid. Five  4. The pH adjustment of the acidic solution is performed by adding the acidic solution and the Al force in a solvent containing water while maintaining the pH in the system at 11.0 to 12.5. The manufacturing method in any one of 1-3. 0 5. Reduction is carried out in the presence of boron trifluoride-ether complex with (±) —trans-4 (4-fluorophenyl) _ 3-methoxycarbonylpiperidin 1 ′ 6-one with sodium borohydride The production method according to any one of claims 1 to 4, which is carried out by adding. 5 6. (±) —4 One (4-Fluorophenyl) _ 3-Methoxycarbonylpiberidin-6-one cis-isomer or cis-trans-mixture is treated with a base to convert the cis-isomer to trans. 6. The production method according to any one of claims 1 to 5, wherein (±) -trans-4-one (4-fluorophenyl) -1-3-methoxycarbonylpiperidin _ 6-one obtained is converted into a form. . 0