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WO2008013248A1 - Procédé de production de (±)-trans-4-(4- fluorophényl)-3-hydroxyméthylpipéridine - Google Patents

Procédé de production de (±)-trans-4-(4- fluorophényl)-3-hydroxyméthylpipéridine Download PDF

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Publication number
WO2008013248A1
WO2008013248A1 PCT/JP2007/064723 JP2007064723W WO2008013248A1 WO 2008013248 A1 WO2008013248 A1 WO 2008013248A1 JP 2007064723 W JP2007064723 W JP 2007064723W WO 2008013248 A1 WO2008013248 A1 WO 2008013248A1
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trans
fluorophenyl
solution
hydroxymethylpiperidine
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Japanese (ja)
Inventor
Seiji Yamada
Koh Kawami
Ken Ishihara
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Sumitomo Chemical Co Ltd
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Sumitomo Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a method for producing ( ⁇ ) -trans-4- (4-fluorophenyl) _3-hydroxy'bimethylbiperidine.
  • 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.
  • ( ⁇ ) -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.
  • LAH lithium aluminum hydride
  • 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.
  • 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.
  • 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.
  • the present inventors have found that ( ⁇ ) -trans-4- (4-fluorophenyl) -1-3-methoxycarbonylpiperidine-6-one is converted to boron trifluoride-one ether.
  • 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].
  • 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 ⁇ 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
  • (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • this cooling is preferably carried out by allowing the reaction solution to cool to room temperature and then cooling with ice.
  • 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.
  • 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.
  • boron trifluoride-ether complex examples 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.
  • TH F boron trifluoride-tetrahydrofuran
  • boron trifluoride-dimethyl 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.
  • organic solvents examples 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration is preferably 1 to 36% by weight, more preferably 2 to 5% by weight.
  • 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.
  • 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.
  • 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.
  • a mineral acid preferably an aqueous solution
  • borane boron trifluoride monoether
  • 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.
  • the organic solvent in the reaction solution is distilled off.
  • 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.
  • the boric acid compound is precipitated in the form of salt.
  • 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.
  • 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.
  • the pH of this acidic solution is 11.0 to 12.5, preferably 11.
  • 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.
  • 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.
  • pH adjustment with alkali is preferably performed as follows.
  • 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.
  • an organic solvent such as toluene may be added, and the amount thereof is preferably not more than the same volume as water.
  • an acidic solution and an alkali 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 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.
  • the addition of the acidic solution and the alkali 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.
  • 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.
  • ripen and complete crystallization 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.
  • 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.
  • 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.
  • the annual corrosion rate was calculated by the following formula.
  • 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.
  • 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%.
  • 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.
  • 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%).
  • 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)
  • 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.
  • 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.
  • the reaction solution was cooled to 10 ° C, and 12 g of methanol was added dropwise.
  • 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).
  • 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%.
  • 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 resulting toluene layer contains (soil) -trans-4- (4-fluorophenyl) -3-hydroxymethylpiperidine equivalent to 5% by weight of the theoretical yield.
  • 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.
  • 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)
  • ( ⁇ ) -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.

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Abstract

L'invention concerne un procédé destiné à produire (±)-trans-4-(4-fluorophényl)- 3-hydroxyméthylpipéridine, qui consiste à réduire (±)-trans-4-(4-fluorophényl)-3-méthoxycarbonylpipéridine-6-one avec un composé éther de trifluorure de bore et du borohydrure de sodium afin de produire une solution de réaction, à ajouter un acide minéral et un sel de potassium à la solution de réaction, à ajuster la valeur de pH de la solution pour qu'elle soit comprise entre 0,5 et 4,0, à éliminer tout précipité de la solution afin de produire une solution acide, puis à ajuster la valeur de pH de la solution acide pour qu'elle soit comprise entre 11,0 et 12,5.
PCT/JP2007/064723 2006-07-24 2007-07-20 Procédé de production de (±)-trans-4-(4- fluorophényl)-3-hydroxyméthylpipéridine Ceased WO2008013248A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
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JPH08507540A (ja) * 1993-03-13 1996-08-13 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー アクリル−ピペリジンカルビノールの製造方法
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