WO2016167361A1 - METHOD FOR PRODUCING ORGANIC COMPOUND SUBSTANTIALLY FREE OF Pd, AND NOVEL METHOD FOR REMOVING Pd FROM ORGANIC COMPOUND USING HYDROGEN GAS - Google Patents
METHOD FOR PRODUCING ORGANIC COMPOUND SUBSTANTIALLY FREE OF Pd, AND NOVEL METHOD FOR REMOVING Pd FROM ORGANIC COMPOUND USING HYDROGEN GAS Download PDFInfo
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- WO2016167361A1 WO2016167361A1 PCT/JP2016/062160 JP2016062160W WO2016167361A1 WO 2016167361 A1 WO2016167361 A1 WO 2016167361A1 JP 2016062160 W JP2016062160 W JP 2016062160W WO 2016167361 A1 WO2016167361 A1 WO 2016167361A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
- C07B63/02—Purification; Separation; Stabilisation; Use of additives by treatment giving rise to a chemical modification
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/09—Diamines
- C07C211/10—Diaminoethanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to a novel method for producing an organic compound substantially free of Pd.
- the present invention also relates to a novel method for removing Pd from organic compounds.
- Types of organic synthesis reactions include heterogeneous hydrogenation reactions using Pd catalysts such as Pd / C (nitro group reduction, debenzylation, dephenethylation, etc.), Suzuki-Miyaura coupling reaction, Pd Many examples such as homogeneous Suzuki-Miyaura coupling reaction and Negishi coupling reaction using Pd catalyst such as (PPh 3 ) 4 have been reported.
- Non-patent Document 1 the allowable amount of residual metals in pharmaceuticals is shown as a guideline, and it is necessary to remove residual Pd from organic compounds that are active pharmaceutical ingredients.
- Methods for removing Pd include distillation, removal to the filtrate by crystallization, removal by column purification using silica gel, etc., removal using adsorbents such as thiol, thiourea, carboxylic acid, and sulfonic acid. Removal using additives such as n-Bu 3 P / lactic acid, N-acetylcysteine, L-cysteine, and ethylenediamine (Patent Documents 1 and 2, and Non-Patent Documents 2 to 4) are known.
- an organic compound substantially free of Pd can be produced by stirring a solution containing an organic compound and Pd in a hydrogen gas atmosphere, and completed the present invention. It came to do.
- the present invention relates to the following ⁇ 1> to ⁇ 9>.
- ⁇ 1> substantially free of Pd including a step of stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere.
- a method for producing an organic compound ⁇ 2>
- ⁇ 3> The production method according to ⁇ 1> or ⁇ 2>, wherein the hydrogen gas pressure in the step of stirring in the hydrogen gas atmosphere is from atmospheric pressure to 100 psig.
- ⁇ 4> The production method according to any one of ⁇ 1> to ⁇ 3>, wherein the temperature in the step of stirring in the hydrogen gas atmosphere is 0 to 120 ° C.
- ⁇ 5> The production method according to any one of ⁇ 1> to ⁇ 4>, wherein the organic compound is a compound that is not decomposed by a combination of Pd and hydrogen gas.
- ⁇ 6> The production method according to any one of ⁇ 1> to ⁇ 5>, wherein the organic compound is a compound containing a nitrogen atom.
- ⁇ 7> The production method according to any one of ⁇ 1> to ⁇ 6>, wherein the organic compound is a compound containing at least one of a monocyclic ring and a heterocyclic ring.
- the organic compound is (R)-( ⁇ )-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) Ethyl] amino] -1-phenylethanol monohydrochloride, 3-chloro-4- ⁇ 4- [5- (3- ⁇ [glycyl (methyl) amino] methyl ⁇ phenyl) pyrimidin-2-yl] piperazine-1- Yl ⁇ benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidine -3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6
- residual Pd can be effectively removed by including a process using hydrogen gas that is industrially inexpensive and environmentally friendly. Organic compounds containing no can be easily produced. In addition, since the Pd catalyst is expensive, the removed residual Pd can be recovered and reused as a catalyst.
- the present invention facilitates removal of Pd by including a step of stirring a solution containing an organic compound and Pd in a hydrogen gas atmosphere, an organic compound substantially free of Pd can be obtained. It is preferable to include a step of removing Pd by filtration after the stirring.
- substantially free of Pd means that the concentration of Pd contained in an organic compound is 25 ppm or less in principle when measured by inductively coupled plasma optical emission spectrometry (ICP-AES). It means that when strict management such as drug substance of pharmaceutical is necessary, Pd is not detected or it is 10 ppm or less.
- the present invention stirs a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere, and then filters the residual Pd by filtration or the like. Can be removed.
- the organic compound obtained by synthesis using a Pd catalyst includes, for example, an organic compound (hydrogen adduct) obtained by isolation, purification, etc. after a hydrogenation reaction. Isolation includes crystallization, distillation and the like, and a certain amount of Pd can be removed by isolation.
- the organic compound containing Pd is dissolved in a solvent to form a solution, and the solution is stirred in a hydrogen gas atmosphere, and preferably filtered.
- Pd can be removed.
- the inside of the system is preferably replaced with an inert gas and then replaced with hydrogen gas.
- the inert gas include nitrogen gas and argon gas.
- the substitution with the inert gas is preferably 3 times or more, and more preferably 5 times or more.
- the replacement with hydrogen gas is preferably performed 3 times or more, more preferably 5 times or more.
- the concentration of hydrogen gas used is preferably 99.9% or more.
- the hydrogen gas pressure in the step of stirring the solution in a hydrogen gas atmosphere is preferably from atmospheric pressure to 100 psig, and the higher the hydrogen gas pressure, the more preferable from the viewpoint of Pd removal efficiency.
- a pressure-resistant container capable of high airtightness is used.
- the temperature in the step of stirring the solution in a hydrogen gas atmosphere is preferably from 0 to 120 ° C., and more preferably from a point of view of Pd removal efficiency.
- the pH of the solution in the step of stirring the solution under a hydrogen gas atmosphere is not particularly limited.
- the stirring time in the step of stirring the solution under a hydrogen gas atmosphere is preferably 1 to 48 hours, and more preferably longer from the viewpoint of Pd removal efficiency.
- a magnetic stirrer In the step of stirring the solution in a hydrogen gas atmosphere, a magnetic stirrer, a mechanical stirrer, a stirring blade, or the like can be used.
- the solvent of the solution only needs to dissolve the organic compound.
- water, methanol, ethanol, tetrahydrofuran (THF) or a mixed solvent thereof can be used.
- the production method according to the present invention targets an organic compound in which Pd remains in the compound by using a Pd catalyst such as Pd / C in the synthesis of the organic compound.
- a Pd catalyst such as Pd / C in the synthesis of the organic compound.
- the organic compound is preferably a compound that does not decompose due to the combination of Pd and hydrogen gas.
- an organic compound having a weak coordination ability or interaction with Pd is preferred.
- the compound containing a nitrogen atom can also be used preferably as an organic compound, and the compound containing at least any one of a monocyclic ring and a heterocyclic ring can also be used preferably.
- the compound containing a nitrogen atom is preferably an aliphatic compound containing nitrogen or an aromatic compound containing nitrogen, and may contain a nitrogen atom in a chain part such as an amine or an amide. May be included.
- the “nitrogen-containing heterocycle” is a heterocycle containing at least one nitrogen atom, and specifically includes the following.
- monocyclic saturated heterocycle those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc .; (B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like; (2) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl,
- Nonanyl and the like those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like; (4) condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahyzolobenzoimidazolyl, quinolyl, tetrahydro Quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquino
- preferable organic compounds include the following compounds.
- (R)-( ⁇ )-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenyl Ethanol monohydrochloride, 3-chloro-4- ⁇ 4- [5- (3- ⁇ [glycyl (methyl) amino] methyl ⁇ phenyl) pyrimidin-2-yl] piperazin-1-yl ⁇ benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidin-3-yl] -1, 6-dihydrodipyrolo [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline
- the concentration of the organic compound in the solvent is not particularly specified, but it is sufficient that the organic compound is dissolved in the solvent.
- Pd can be taken out using centrifugation, distillation or the like.
- the extracted Pd may be reused as a Pd catalyst by a known method.
- Pd contained in the organic compound can be identified by inductively coupled plasma optical emission spectrometry (ICP-AES).
- ICP-AES inductively coupled plasma optical emission spectrometry
- the organic compound which is the target compound can be isolated by distillation, drying under reduced pressure, crystallization / filtration, or the like.
- the raw materials and solvents to be used may be used after appropriately degassing, dehydrating, purifying and the like. Deaeration, dehydration, and purification can be performed by known methods.
- the present invention also relates to a method for removing Pd from an organic compound, wherein the solution containing the organic compound and Pd is stirred in a hydrogen gas atmosphere. That is, Pd is removed from an organic compound, characterized in that a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound is stirred in a hydrogen gas atmosphere. Also related to how to do. It is preferable to carry out filtration after stirring, and Pd can be taken out by centrifugation, distillation or the like instead of filtration. Preferred conditions, specific examples and the like in the method are the same as the preferred conditions and specific examples and the like in the method for producing an organic compound substantially free of Pd described above.
- Example 2 is a product name manufactured by N.E. Chemcat Co., Ltd .: 10% Pd / C (K)
- Example 4 is a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 10 % Pd / C (M)
- Example 5 is a product name manufactured by N.E. Chemcat Co., Ltd .: 20% Pd (OH) 2 / C, and in other examples, a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 5 % Pd / C (PH) was used as is without pretreatment.
- the water content of each Pd / C is about 50%.
- the Pd content contained in the synthesized organic compound was determined by measurement by inductively coupled plasma emission spectroscopy (ICP-AES) (trade name: ICPE-9000) manufactured by Shimadzu Corporation.
- ICP-AES inductively coupled plasma emission spectroscopy
- Example 1 (R)-(-)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride 2R, 1R-2-- synthesized based on the method of Example 1 of Japanese Patent Publication No. 06-6565 Methoxy-5- [2- (1-methylbenzylamino) propyl] benzenesulfonamide Hydrochloride 2 g, methanol 45 mL, 5% Pd / C 0.86 g were added, nitrogen substitution was performed three times, and hydrogen substitution was performed twice. did. The mixture was stirred for 3 hours at an external temperature of 70 ° C. under hydrogen gas pressure (80 psig).
- Example 4 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid 9-hydroxy-9 synthesized according to the method described in Organic Process Research & Development, 2012, 16, 654-663 -[3- (Tetrahydropyran-2-yloxy) prop-1-in-1-yl] -9H-fluorene-2-carboxylic acid 500 mg was dissolved in 10 mL of methanol, 10% Pd / C 80 mg was added, and hydrogen gas atmosphere Stirring under. After completion of the reaction, the mixture was stirred overnight in an air atmosphere, and the catalyst was filtered and washed with 5.5 mL of methanol.
- the Pd concentration of the solution was 6.6 ppm.
- this solution was replaced with nitrogen three times and then replaced with hydrogen twice, and then stirred for 5 hours in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.). After stirring, the mixture was filtered and the Pd concentration was measured. As a result, Pd was not detected (crystal conversion: Pd not detected, Pd removal rate 100%).
- the Pd concentration in the solution at this time was 0.19 ppm (crystal conversion: 30.9 ppm, removal rate: 99.5%). Subsequently, the external temperature was raised to 120 ° C., stirred under hydrogen gas pressure (80 psig) for 24 hours, and filtered to measure the Pd concentration in the solution. As a result, the Pd concentration was 0.08 ppm (crystal conversion: 12.1 ppm, (Removal rate: 99.8%).
- Example 6 1 g of pyridine 5% Pd / C was suspended in 50 mL of methanol, 1.01 mL of pyridine (manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure), and stirred in air for 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 25.4 ppm. Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (pyridine conversion: Pd not detected, Pd removal rate 100%).
- Example 7 2-picoline 5% Pd / C (1 g) is suspended in 50 mL of methanol, 1.23 mL of 2-picoline (manufactured by Tokyo Chemical Industry Co., Ltd.) is added, and the mixture is stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure) and stirred in air for 48 hours. did. Thereafter, Pd / C was removed by filtration. At this time, the Pd concentration of the solution was 6.81 ppm. Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (2-picoline conversion: Pd not detected, Pd removal rate: 100%).
- Example 8 2,6-lutidine 5% Pd / C (1 g) was suspended in 50 mL of methanol, 1.45 mL of 2,6-lutidine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure). For 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 2.79 ppm. Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was 0.03 ppm (2,6-lutidine conversion: 0.80 ppm, Pd removal rate 98.9%).
- Example 9 1 g of ethylenediamine 5% Pd / C was suspended in 50 mL of methanol, 0.84 mL of ethylenediamine (manufactured by Wako) was added, and the mixture was stirred under a hydrogen gas atmosphere (atmospheric pressure) for 1 hour, and stirred in air for 24 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 12.3 ppm. Next, the obtained filtrate was purged with nitrogen three times and twice with hydrogen, then stirred under hydrogen gas pressure (80 psig) at 100 ° C. for 6 hours, and filtered to measure Pd concentration. (Pd removal rate 100%).
- residual Pd can be effectively removed by a process using hydrogen gas, which is industrially inexpensive and environmentally friendly, and an organic compound substantially free of Pd is easily produced. be able to. Further, the removed residual Pd can be recovered and reused as a new catalyst.
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Abstract
The purpose of the present invention is to provide a novel method for producing an organic compound substantially free of Pd in an inexpensive and simple manner. The present invention pertains to a method for producing an organic compound substantially free of Pd, the method including a step for stirring, in a hydrogen gas atmosphere, a solution that includes an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound.
Description
本発明は、Ｐｄを実質的に含まない有機化合物を製造する新規な方法に関する。また、有機化合物からＰｄを除去する新規な方法に関する。
The present invention relates to a novel method for producing an organic compound substantially free of Pd. The present invention also relates to a novel method for removing Pd from organic compounds.
遷移金属の１種であるパラジウム（Ｐｄ）は、医薬品や医薬品中間体を含むファインケミカル分野の有機合成反応における触媒として非常に有用であり、工業的にも多く用いられている。
有機合成反応の種類としては、Ｐｄ／Ｃ等のＰｄ触媒を用いた不均一系の水素添加反応（ニトロ基の還元、脱ベンジル化、脱フェネチル化等）、鈴木－宮浦カップリング反応や、Ｐｄ（ＰＰｈ３）４等のＰｄ触媒を用いた均一系の鈴木－宮浦カップリング反応、根岸カップリング反応など、多くの例が報告されている。 Palladium (Pd), which is one of transition metals, is very useful as a catalyst in organic synthesis reactions in the fine chemical field including pharmaceuticals and pharmaceutical intermediates, and is widely used industrially.
Types of organic synthesis reactions include heterogeneous hydrogenation reactions using Pd catalysts such as Pd / C (nitro group reduction, debenzylation, dephenethylation, etc.), Suzuki-Miyaura coupling reaction, Pd Many examples such as homogeneous Suzuki-Miyaura coupling reaction and Negishi coupling reaction using Pd catalyst such as (PPh 3 ) 4 have been reported.
有機合成反応の種類としては、Ｐｄ／Ｃ等のＰｄ触媒を用いた不均一系の水素添加反応（ニトロ基の還元、脱ベンジル化、脱フェネチル化等）、鈴木－宮浦カップリング反応や、Ｐｄ（ＰＰｈ３）４等のＰｄ触媒を用いた均一系の鈴木－宮浦カップリング反応、根岸カップリング反応など、多くの例が報告されている。 Palladium (Pd), which is one of transition metals, is very useful as a catalyst in organic synthesis reactions in the fine chemical field including pharmaceuticals and pharmaceutical intermediates, and is widely used industrially.
Types of organic synthesis reactions include heterogeneous hydrogenation reactions using Pd catalysts such as Pd / C (nitro group reduction, debenzylation, dephenethylation, etc.), Suzuki-Miyaura coupling reaction, Pd Many examples such as homogeneous Suzuki-Miyaura coupling reaction and Negishi coupling reaction using Pd catalyst such as (PPh 3 ) 4 have been reported.
一方、医薬品中の残留金属の許容量がガイドラインとして示されており、医療品原薬である有機化合物中から残留Ｐｄを除去する必要がある（非特許文献１）。
Ｐｄの除去方法としては、蒸留による除去、結晶化による濾液への除去、シリカゲルなどを用いたカラム精製による除去、チオール系やチオウレア系、カルボン酸系、スルホン酸系などの吸着剤を用いた除去、ｎ－Ｂｕ３Ｐ／乳酸やＮ－アセチルシステイン、Ｌ－システイン、エチレンジアミンなどの添加物を用いた除去（特許文献１及び２、並びに非特許文献２～４）などが知られている。 On the other hand, the allowable amount of residual metals in pharmaceuticals is shown as a guideline, and it is necessary to remove residual Pd from organic compounds that are active pharmaceutical ingredients (Non-patent Document 1).
Methods for removing Pd include distillation, removal to the filtrate by crystallization, removal by column purification using silica gel, etc., removal using adsorbents such as thiol, thiourea, carboxylic acid, and sulfonic acid. Removal using additives such as n-Bu 3 P / lactic acid, N-acetylcysteine, L-cysteine, and ethylenediamine (Patent Documents 1 and 2, and Non-Patent Documents 2 to 4) are known.
Ｐｄの除去方法としては、蒸留による除去、結晶化による濾液への除去、シリカゲルなどを用いたカラム精製による除去、チオール系やチオウレア系、カルボン酸系、スルホン酸系などの吸着剤を用いた除去、ｎ－Ｂｕ３Ｐ／乳酸やＮ－アセチルシステイン、Ｌ－システイン、エチレンジアミンなどの添加物を用いた除去（特許文献１及び２、並びに非特許文献２～４）などが知られている。 On the other hand, the allowable amount of residual metals in pharmaceuticals is shown as a guideline, and it is necessary to remove residual Pd from organic compounds that are active pharmaceutical ingredients (Non-patent Document 1).
Methods for removing Pd include distillation, removal to the filtrate by crystallization, removal by column purification using silica gel, etc., removal using adsorbents such as thiol, thiourea, carboxylic acid, and sulfonic acid. Removal using additives such as n-Bu 3 P / lactic acid, N-acetylcysteine, L-cysteine, and ethylenediamine (Patent Documents 1 and 2, and Non-Patent Documents 2 to 4) are known.
従来のＰｄの除去方法では、Ｐｄの除去効率が低い、吸着ロスによって収率が低下する、再現性に乏しい等、Ｐｄを効果的に除去することができなかった。また、添加剤や吸着剤を使用することによりＰｄの除去効率を高くできても、当該添加剤や吸着剤が高価であったり、添加剤や吸着剤自身が不純物として有機化合物中に残留することがあり、低コストかつ簡便な方法によるＰｄの効果的な除去方法の開発が求められていた。
そこで本発明は、低コストかつ簡便な方法により、実質的にＰｄを含まない有機化合物の新規な製造方法を提供することを課題とする。 In the conventional Pd removal method, Pd could not be removed effectively, such as low Pd removal efficiency, reduced yield due to adsorption loss, and poor reproducibility. Even if the removal efficiency of Pd can be increased by using an additive or adsorbent, the additive or adsorbent is expensive or the additive or adsorbent itself remains in the organic compound as an impurity. Therefore, development of an effective method for removing Pd by a low-cost and simple method has been demanded.
Then, this invention makes it a subject to provide the novel manufacturing method of the organic compound which does not contain Pd substantially by a low-cost and simple method.
そこで本発明は、低コストかつ簡便な方法により、実質的にＰｄを含まない有機化合物の新規な製造方法を提供することを課題とする。 In the conventional Pd removal method, Pd could not be removed effectively, such as low Pd removal efficiency, reduced yield due to adsorption loss, and poor reproducibility. Even if the removal efficiency of Pd can be increased by using an additive or adsorbent, the additive or adsorbent is expensive or the additive or adsorbent itself remains in the organic compound as an impurity. Therefore, development of an effective method for removing Pd by a low-cost and simple method has been demanded.
Then, this invention makes it a subject to provide the novel manufacturing method of the organic compound which does not contain Pd substantially by a low-cost and simple method.
本発明者らは、鋭意研鑽を積んだ結果、有機化合物とＰｄを含む溶液を水素ガス雰囲気下で攪拌することにより、実質的にＰｄを含まない有機化合物を製造できることを見出し、本発明を完成するに至った。
As a result of intensive studies, the present inventors have found that an organic compound substantially free of Pd can be produced by stirring a solution containing an organic compound and Pd in a hydrogen gas atmosphere, and completed the present invention. It came to do.
すなわち、本発明は下記＜１＞～＜９＞に関するものである。
＜１＞Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する工程を含む、実質的にＰｄを含まない有機化合物の製造方法。
＜２＞前記水素ガス雰囲気下で撹拌する工程に次いで、濾過により前記残留Ｐｄを取り除く工程を含む、前記＜１＞に記載の製造方法。
＜３＞前記水素ガス雰囲気下で撹拌する工程における水素ガス圧が大気圧～１００ｐｓｉｇである、前記＜１＞又は＜２＞に記載の製造方法。
＜４＞前記水素ガス雰囲気下で撹拌する工程における温度が０～１２０℃である、前記＜１＞～＜３＞のいずれか１に記載の製造方法。
＜５＞前記有機化合物がＰｄと水素ガスの組み合わせにより分解が起こらない化合物である、前記＜１＞～＜４＞のいずれか１に記載の製造方法。
＜６＞前記有機化合物が窒素原子を含む化合物である、前記＜１＞～＜５＞のいずれか１に記載の製造方法。
＜７＞前記有機化合物が単素環及び複素環の少なくともいずれか一方を含む化合物である、前記＜１＞～＜６＞のいずれか１に記載の製造方法。
＜８＞前記有機化合物が、（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩、３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩、９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン、ピリジン、２－ピコリン、２，６－ルチジン、またはエチレンジアミンである、前記＜１＞～＜４＞のいずれか１に記載の製造方法。
＜９＞Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する、有機化合物からＰｄを除去する方法。 That is, the present invention relates to the following <1> to <9>.
<1> substantially free of Pd, including a step of stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere. A method for producing an organic compound.
<2> The production method according to <1>, further including a step of removing the residual Pd by filtration after the step of stirring in the hydrogen gas atmosphere.
<3> The production method according to <1> or <2>, wherein the hydrogen gas pressure in the step of stirring in the hydrogen gas atmosphere is from atmospheric pressure to 100 psig.
<4> The production method according to any one of <1> to <3>, wherein the temperature in the step of stirring in the hydrogen gas atmosphere is 0 to 120 ° C.
<5> The production method according to any one of <1> to <4>, wherein the organic compound is a compound that is not decomposed by a combination of Pd and hydrogen gas.
<6> The production method according to any one of <1> to <5>, wherein the organic compound is a compound containing a nitrogen atom.
<7> The production method according to any one of <1> to <6>, wherein the organic compound is a compound containing at least one of a monocyclic ring and a heterocyclic ring.
<8> The organic compound is (R)-(−)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) Ethyl] amino] -1-phenylethanol monohydrochloride, 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazine-1- Yl} benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidine -3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6-lutidine, or ethylenediamine, <1 > ~ <4> The method according to any one.
<9> A method for removing Pd from an organic compound, comprising stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere.
＜１＞Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する工程を含む、実質的にＰｄを含まない有機化合物の製造方法。
＜２＞前記水素ガス雰囲気下で撹拌する工程に次いで、濾過により前記残留Ｐｄを取り除く工程を含む、前記＜１＞に記載の製造方法。
＜３＞前記水素ガス雰囲気下で撹拌する工程における水素ガス圧が大気圧～１００ｐｓｉｇである、前記＜１＞又は＜２＞に記載の製造方法。
＜４＞前記水素ガス雰囲気下で撹拌する工程における温度が０～１２０℃である、前記＜１＞～＜３＞のいずれか１に記載の製造方法。
＜５＞前記有機化合物がＰｄと水素ガスの組み合わせにより分解が起こらない化合物である、前記＜１＞～＜４＞のいずれか１に記載の製造方法。
＜６＞前記有機化合物が窒素原子を含む化合物である、前記＜１＞～＜５＞のいずれか１に記載の製造方法。
＜７＞前記有機化合物が単素環及び複素環の少なくともいずれか一方を含む化合物である、前記＜１＞～＜６＞のいずれか１に記載の製造方法。
＜８＞前記有機化合物が、（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩、３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩、９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン、ピリジン、２－ピコリン、２，６－ルチジン、またはエチレンジアミンである、前記＜１＞～＜４＞のいずれか１に記載の製造方法。
＜９＞Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する、有機化合物からＰｄを除去する方法。 That is, the present invention relates to the following <1> to <9>.
<1> substantially free of Pd, including a step of stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere. A method for producing an organic compound.
<2> The production method according to <1>, further including a step of removing the residual Pd by filtration after the step of stirring in the hydrogen gas atmosphere.
<3> The production method according to <1> or <2>, wherein the hydrogen gas pressure in the step of stirring in the hydrogen gas atmosphere is from atmospheric pressure to 100 psig.
<4> The production method according to any one of <1> to <3>, wherein the temperature in the step of stirring in the hydrogen gas atmosphere is 0 to 120 ° C.
<5> The production method according to any one of <1> to <4>, wherein the organic compound is a compound that is not decomposed by a combination of Pd and hydrogen gas.
<6> The production method according to any one of <1> to <5>, wherein the organic compound is a compound containing a nitrogen atom.
<7> The production method according to any one of <1> to <6>, wherein the organic compound is a compound containing at least one of a monocyclic ring and a heterocyclic ring.
<8> The organic compound is (R)-(−)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) Ethyl] amino] -1-phenylethanol monohydrochloride, 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazine-1- Yl} benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidine -3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6-lutidine, or ethylenediamine, <1 > ~ <4> The method according to any one.
<9> A method for removing Pd from an organic compound, comprising stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere.
本発明に係る有機化合物の製造方法によれば、工業的に安価であり環境にも優しい水素ガスを用いた工程を含むことにより、残留Ｐｄを効果的に除去することができ、実質的にＰｄを含まない有機化合物を簡便に製造することができる。
また、Ｐｄ触媒は高価であることから、除去された残留Ｐｄを回収し、触媒として再利用することも可能である。 According to the method for producing an organic compound according to the present invention, residual Pd can be effectively removed by including a process using hydrogen gas that is industrially inexpensive and environmentally friendly. Organic compounds containing no can be easily produced.
In addition, since the Pd catalyst is expensive, the removed residual Pd can be recovered and reused as a catalyst.
また、Ｐｄ触媒は高価であることから、除去された残留Ｐｄを回収し、触媒として再利用することも可能である。 According to the method for producing an organic compound according to the present invention, residual Pd can be effectively removed by including a process using hydrogen gas that is industrially inexpensive and environmentally friendly. Organic compounds containing no can be easily produced.
In addition, since the Pd catalyst is expensive, the removed residual Pd can be recovered and reused as a catalyst.
以下、本発明を詳細に説明するが、本発明は以下の実施形態に限定されるものではなく、本発明の要旨を逸脱しない範囲において、任意に変形して実施することができる。
本明細書において、単に“ｐｐｍ”と記載した場合には“重量ｐｐｍ”を意味する。また、数値範囲を示す「～」とは、その前後に記載された数値を下限値及び上限値として含む意味で使用される。 Hereinafter, the present invention will be described in detail, but the present invention is not limited to the following embodiments, and can be arbitrarily modified without departing from the gist of the present invention.
In the present specification, when “ppm” is simply described, it means “weight ppm”. In addition, “to” indicating a numerical range is used in the sense of including the numerical values described before and after the numerical value as a lower limit value and an upper limit value.
本明細書において、単に“ｐｐｍ”と記載した場合には“重量ｐｐｍ”を意味する。また、数値範囲を示す「～」とは、その前後に記載された数値を下限値及び上限値として含む意味で使用される。 Hereinafter, the present invention will be described in detail, but the present invention is not limited to the following embodiments, and can be arbitrarily modified without departing from the gist of the present invention.
In the present specification, when “ppm” is simply described, it means “weight ppm”. In addition, “to” indicating a numerical range is used in the sense of including the numerical values described before and after the numerical value as a lower limit value and an upper limit value.
本発明は有機化合物及びＰｄを含む溶液を水素ガス雰囲気下で攪拌する工程を含むことによりＰｄを取り除きやすくなることから、実質的にＰｄを含まない有機化合物を得ることができる。前記攪拌の後に濾過によりＰｄを取り除く工程を含むことが好ましい。なお、本明細書において「実質的にＰｄを含まない」とは、誘導結合プラズマ発光分光分析法（ＩＣＰ－ＡＥＳ）にて測定した場合に、原則有機化合物中に含まれるＰｄ濃度が２５ｐｐｍ以下であることを意味し、医薬品の原薬等厳格な管理が必要な場合はＰｄが未検出であるか、１０ｐｐｍ以下であることを意味する。
Since the present invention facilitates removal of Pd by including a step of stirring a solution containing an organic compound and Pd in a hydrogen gas atmosphere, an organic compound substantially free of Pd can be obtained. It is preferable to include a step of removing Pd by filtration after the stirring. In this specification, “substantially free of Pd” means that the concentration of Pd contained in an organic compound is 25 ppm or less in principle when measured by inductively coupled plasma optical emission spectrometry (ICP-AES). It means that when strict management such as drug substance of pharmaceutical is necessary, Pd is not detected or it is 10 ppm or less.
すなわち本発明は、Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を、水素ガス雰囲気下で攪拌し、次いで濾過等により前記残留Ｐｄを取り除くことができる。
Ｐｄ触媒を用いて合成して得られた有機化合物とは、例えば水素添加反応後、単離、精製等により得られた有機化合物（水素付加物）等が挙げられる。単離には晶析、蒸留等が挙げられ、単離により一定量のＰｄを除去することができる。 That is, the present invention stirs a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere, and then filters the residual Pd by filtration or the like. Can be removed.
The organic compound obtained by synthesis using a Pd catalyst includes, for example, an organic compound (hydrogen adduct) obtained by isolation, purification, etc. after a hydrogenation reaction. Isolation includes crystallization, distillation and the like, and a certain amount of Pd can be removed by isolation.
Ｐｄ触媒を用いて合成して得られた有機化合物とは、例えば水素添加反応後、単離、精製等により得られた有機化合物（水素付加物）等が挙げられる。単離には晶析、蒸留等が挙げられ、単離により一定量のＰｄを除去することができる。 That is, the present invention stirs a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound in a hydrogen gas atmosphere, and then filters the residual Pd by filtration or the like. Can be removed.
The organic compound obtained by synthesis using a Pd catalyst includes, for example, an organic compound (hydrogen adduct) obtained by isolation, purification, etc. after a hydrogenation reaction. Isolation includes crystallization, distillation and the like, and a certain amount of Pd can be removed by isolation.
しかしながら、Ｐｄ／Ｃ等のＰｄ触媒を用いて合成された前記有機化合物中には前記単離では除去しきれていない残留Ｐｄが存在する。この残留Ｐｄは有機化合物に配位または相互に作用し、残留していると考えられる。これに対し、水素にはＰｄと有機化合物との配位能または相互作用を弱める作用があることから、有機化合物及びＰｄ（残留Ｐｄ）を含む溶液を水素ガス雰囲気下で攪拌することによりＰｄを分離や析出させ、さらには、濾過等にて当該Ｐｄを除去できるものと考えられる。
However, in the organic compound synthesized using a Pd catalyst such as Pd / C, there is residual Pd that cannot be removed by the isolation. This residual Pd is considered to be coordinated or interact with the organic compound and remain. On the other hand, since hydrogen has an action of weakening the coordination ability or interaction between Pd and an organic compound, Pd is reduced by stirring a solution containing the organic compound and Pd (residual Pd) in a hydrogen gas atmosphere. It is considered that the Pd can be removed by separation or precipitation, and further by filtration or the like.
有機化合物及びＰｄを含む溶液を水素ガス雰囲気下で攪拌する工程においては、Ｐｄを含む有機化合物を溶媒に溶解させて溶液とし、当該溶液を水素ガス雰囲気下で攪拌後、好ましくは濾過を実施することにより、Ｐｄを除去することができる。
水素ガス雰囲気下にするにあたり、系内を不活性ガスで置換し、次いで水素ガスで置換することが好ましい。不活性ガスとしては窒素ガス、アルゴンガス等が挙げられる。不活性ガスでの置換は３回以上が好ましく、５回以上がより好ましい。次いで行われる水素ガスでの置換は３回以上が好ましく、５回以上がより好ましい。
なお、使用する水素ガスの濃度は９９．９％以上が好ましい。 In the step of stirring the solution containing an organic compound and Pd in a hydrogen gas atmosphere, the organic compound containing Pd is dissolved in a solvent to form a solution, and the solution is stirred in a hydrogen gas atmosphere, and preferably filtered. Thus, Pd can be removed.
In the hydrogen gas atmosphere, the inside of the system is preferably replaced with an inert gas and then replaced with hydrogen gas. Examples of the inert gas include nitrogen gas and argon gas. The substitution with the inert gas is preferably 3 times or more, and more preferably 5 times or more. Next, the replacement with hydrogen gas is preferably performed 3 times or more, more preferably 5 times or more.
The concentration of hydrogen gas used is preferably 99.9% or more.
水素ガス雰囲気下にするにあたり、系内を不活性ガスで置換し、次いで水素ガスで置換することが好ましい。不活性ガスとしては窒素ガス、アルゴンガス等が挙げられる。不活性ガスでの置換は３回以上が好ましく、５回以上がより好ましい。次いで行われる水素ガスでの置換は３回以上が好ましく、５回以上がより好ましい。
なお、使用する水素ガスの濃度は９９．９％以上が好ましい。 In the step of stirring the solution containing an organic compound and Pd in a hydrogen gas atmosphere, the organic compound containing Pd is dissolved in a solvent to form a solution, and the solution is stirred in a hydrogen gas atmosphere, and preferably filtered. Thus, Pd can be removed.
In the hydrogen gas atmosphere, the inside of the system is preferably replaced with an inert gas and then replaced with hydrogen gas. Examples of the inert gas include nitrogen gas and argon gas. The substitution with the inert gas is preferably 3 times or more, and more preferably 5 times or more. Next, the replacement with hydrogen gas is preferably performed 3 times or more, more preferably 5 times or more.
The concentration of hydrogen gas used is preferably 99.9% or more.
溶液を水素ガス雰囲気下で攪拌する工程における水素ガス圧は、大気圧～１００ｐｓｉｇが好ましく、Ｐｄ除去効率の点から水素ガス圧が高いほどより好ましい。大気圧よりも高い水素ガス圧にする場合には、高気密が可能な耐圧容器を用いる。
The hydrogen gas pressure in the step of stirring the solution in a hydrogen gas atmosphere is preferably from atmospheric pressure to 100 psig, and the higher the hydrogen gas pressure, the more preferable from the viewpoint of Pd removal efficiency. When the hydrogen gas pressure is higher than the atmospheric pressure, a pressure-resistant container capable of high airtightness is used.
溶液を水素ガス雰囲気下で攪拌する工程における温度は、０～１２０℃が好ましく、Ｐｄ除去効率の点から高温ほどより好ましい。
溶液を水素ガス雰囲気下で攪拌する工程における溶液のｐＨは特に制限されない。
溶液を水素ガス雰囲気下で攪拌する工程における攪拌時間は、１～４８時間が好ましく、Ｐｄ除去効率の点から長い方がより好ましい。 The temperature in the step of stirring the solution in a hydrogen gas atmosphere is preferably from 0 to 120 ° C., and more preferably from a point of view of Pd removal efficiency.
The pH of the solution in the step of stirring the solution under a hydrogen gas atmosphere is not particularly limited.
The stirring time in the step of stirring the solution under a hydrogen gas atmosphere is preferably 1 to 48 hours, and more preferably longer from the viewpoint of Pd removal efficiency.
溶液を水素ガス雰囲気下で攪拌する工程における溶液のｐＨは特に制限されない。
溶液を水素ガス雰囲気下で攪拌する工程における攪拌時間は、１～４８時間が好ましく、Ｐｄ除去効率の点から長い方がより好ましい。 The temperature in the step of stirring the solution in a hydrogen gas atmosphere is preferably from 0 to 120 ° C., and more preferably from a point of view of Pd removal efficiency.
The pH of the solution in the step of stirring the solution under a hydrogen gas atmosphere is not particularly limited.
The stirring time in the step of stirring the solution under a hydrogen gas atmosphere is preferably 1 to 48 hours, and more preferably longer from the viewpoint of Pd removal efficiency.
溶液を水素ガス雰囲気下で攪拌する工程における攪拌はマグネティックスターラー、メカニカルスターラー、撹拌翼等を用いることができる。
In the step of stirring the solution in a hydrogen gas atmosphere, a magnetic stirrer, a mechanical stirrer, a stirring blade, or the like can be used.
溶液の溶媒は有機化合物を溶解させることができればよい。例えば水、メタノール、エタノール、テトラヒドロフラン（ＴＨＦ）やこれらの混合溶媒を用いることができる。
The solvent of the solution only needs to dissolve the organic compound. For example, water, methanol, ethanol, tetrahydrofuran (THF) or a mixed solvent thereof can be used.
本発明に係る製造方法では、有機化合物の合成にあたってＰｄ／Ｃ等のＰｄ触媒を用いること等により、当該化合物内にＰｄが残留している有機化合物を対象とする。
残留Ｐｄを含む有機化合物を水素ガス雰囲気下で攪拌することにより実質的にＰｄを含まない有機化合物を得ることから、有機化合物はＰｄと水素ガスの組み合わせにより分解が起こらない化合物であることが好ましい。
また、残留Ｐｄと有機化合物との配位能または相互作用の強さがＰｄ除去に影響していると考えられることから、Ｐｄと配位能または相互作用が弱い有機化合物の方が好ましい。
また、有機化合物として窒素原子を含む化合物も好ましく用いることができ、単素環及び複素環の少なくともいずれか一方を含む化合物も好ましく用いることができる。 The production method according to the present invention targets an organic compound in which Pd remains in the compound by using a Pd catalyst such as Pd / C in the synthesis of the organic compound.
Since an organic compound substantially free of Pd is obtained by stirring the organic compound containing residual Pd in a hydrogen gas atmosphere, the organic compound is preferably a compound that does not decompose due to the combination of Pd and hydrogen gas. .
In addition, since the coordination ability or interaction strength between the residual Pd and the organic compound is considered to influence Pd removal, an organic compound having a weak coordination ability or interaction with Pd is preferred.
Moreover, the compound containing a nitrogen atom can also be used preferably as an organic compound, and the compound containing at least any one of a monocyclic ring and a heterocyclic ring can also be used preferably.
残留Ｐｄを含む有機化合物を水素ガス雰囲気下で攪拌することにより実質的にＰｄを含まない有機化合物を得ることから、有機化合物はＰｄと水素ガスの組み合わせにより分解が起こらない化合物であることが好ましい。
また、残留Ｐｄと有機化合物との配位能または相互作用の強さがＰｄ除去に影響していると考えられることから、Ｐｄと配位能または相互作用が弱い有機化合物の方が好ましい。
また、有機化合物として窒素原子を含む化合物も好ましく用いることができ、単素環及び複素環の少なくともいずれか一方を含む化合物も好ましく用いることができる。 The production method according to the present invention targets an organic compound in which Pd remains in the compound by using a Pd catalyst such as Pd / C in the synthesis of the organic compound.
Since an organic compound substantially free of Pd is obtained by stirring the organic compound containing residual Pd in a hydrogen gas atmosphere, the organic compound is preferably a compound that does not decompose due to the combination of Pd and hydrogen gas. .
In addition, since the coordination ability or interaction strength between the residual Pd and the organic compound is considered to influence Pd removal, an organic compound having a weak coordination ability or interaction with Pd is preferred.
Moreover, the compound containing a nitrogen atom can also be used preferably as an organic compound, and the compound containing at least any one of a monocyclic ring and a heterocyclic ring can also be used preferably.
窒素原子を含む化合物は、窒素を含む脂肪族化合物、又は、窒素を含む芳香族化合物が好ましく、アミン、アミド等鎖状部分に窒素原子を含んでいてもよく、又、含窒素へテロ環を含んでいてもよい。
「含窒素へテロ環」とは窒素原子を少なくとも１つ含有するヘテロ環であり、具体的には以下が挙げられる。
（１）単環式飽和へテロ環
（ａ）１～４個の窒素原子を含むもの、例えば、アゼパニル、ジアゼパニル、アジリジニル、アゼチジニル、ピロリジニル、イミダゾリジニル、ピペリジル、ピラゾリジニル、ピペラジニル、アゾカニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チオモルホリニル、チアゾリジニル、イソチアゾリジニル、オキサゾリジニル、モルホリニル等；
（２）単環式不飽和へテロ環基
（ａ）１～４個の窒素原子を含むもの、例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ジヒドロピリジル、テトラヒドロピリジ二ル、ピリミジニル、ピラジニル、ピリダジニル、トリアゾリル、テトラゾリル、トリアジニル、ジヒドロトリアジニル、アゼピニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チアゾリル、イソチアゾリル、チアジアゾリル、ジヒドロチアジニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、オキサジニル等；
（３）縮合多環式飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、キヌクリジニル、７－アザビシクロ［２．２．１］ヘプチル、３－アザビシクロ［３．２．２］ノナニル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、トリチアジアザインデニル、ジオキソロイミダゾリジニル等；
（４）縮合多環式不飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、インドリル、イソインドリル、インドリニル、インドリジニル、ベンゾイミダゾリル、ジヒドロベンゾイミダゾリル、テトラヒゾロベンゾイミダゾリル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、インダゾリル、イミダゾピリジル、ベンゾトリアゾリル、テトラゾロピリダジニル、カルバゾリル、アクリジニル、キノキサリニル、ジヒドロキノキサリニル、テトラヒドロキノキサリニル、フタラジニル、ジヒドロインダゾリル、ベンゾピリミジニル、ナフチリジニル、キナゾリニル、シンノリニル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、ベンゾチアゾリル、ジヒドロベンゾチアゾリル、ベンゾチアジアゾリル、イミダゾチアゾリル、イミダゾチアジアゾリル、ベンゾオキサゾリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾオキサジニル、ベンゾオキサジアゾリル、ベンゾイソチアゾリル、ベンゾイソオキサゾリル等 The compound containing a nitrogen atom is preferably an aliphatic compound containing nitrogen or an aromatic compound containing nitrogen, and may contain a nitrogen atom in a chain part such as an amine or an amide. May be included.
The “nitrogen-containing heterocycle” is a heterocycle containing at least one nitrogen atom, and specifically includes the following.
(1) monocyclic saturated heterocycle (a) those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc .;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like;
(2) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like;
(3) Fused polycyclic saturated heterocyclic group (a) One containing 1 to 5 nitrogen atoms, for example, quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2. 2] Nonanyl and the like;
(B) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like;
(4) condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahyzolobenzoimidazolyl, quinolyl, tetrahydro Quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazo Ril, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, etc .;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, for example benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzooxadiazolyl, benzisothiazolyl, benzoisoxazolyl, etc.
「含窒素へテロ環」とは窒素原子を少なくとも１つ含有するヘテロ環であり、具体的には以下が挙げられる。
（１）単環式飽和へテロ環
（ａ）１～４個の窒素原子を含むもの、例えば、アゼパニル、ジアゼパニル、アジリジニル、アゼチジニル、ピロリジニル、イミダゾリジニル、ピペリジル、ピラゾリジニル、ピペラジニル、アゾカニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チオモルホリニル、チアゾリジニル、イソチアゾリジニル、オキサゾリジニル、モルホリニル等；
（２）単環式不飽和へテロ環基
（ａ）１～４個の窒素原子を含むもの、例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ジヒドロピリジル、テトラヒドロピリジ二ル、ピリミジニル、ピラジニル、ピリダジニル、トリアゾリル、テトラゾリル、トリアジニル、ジヒドロトリアジニル、アゼピニル等；
（ｂ）１～３個の窒素原子、ならびに１～２個の硫黄原子および／または１～２個の酸素原子を含むもの、例えば、チアゾリル、イソチアゾリル、チアジアゾリル、ジヒドロチアジニル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、オキサジニル等；
（３）縮合多環式飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、キヌクリジニル、７－アザビシクロ［２．２．１］ヘプチル、３－アザビシクロ［３．２．２］ノナニル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、トリチアジアザインデニル、ジオキソロイミダゾリジニル等；
（４）縮合多環式不飽和へテロ環基
（ａ）１～５個の窒素原子を含むもの、例えば、インドリル、イソインドリル、インドリニル、インドリジニル、ベンゾイミダゾリル、ジヒドロベンゾイミダゾリル、テトラヒゾロベンゾイミダゾリル、キノリル、テトラヒドロキノリル、イソキノリル、テトラヒドロイソキノリル、インダゾリル、イミダゾピリジル、ベンゾトリアゾリル、テトラゾロピリダジニル、カルバゾリル、アクリジニル、キノキサリニル、ジヒドロキノキサリニル、テトラヒドロキノキサリニル、フタラジニル、ジヒドロインダゾリル、ベンゾピリミジニル、ナフチリジニル、キナゾリニル、シンノリニル等；
（ｂ）１～４個の窒素原子、ならびに１～３個の硫黄原子および／または１～３個の酸素原子を含むもの、例えば、ベンゾチアゾリル、ジヒドロベンゾチアゾリル、ベンゾチアジアゾリル、イミダゾチアゾリル、イミダゾチアジアゾリル、ベンゾオキサゾリル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾオキサジニル、ベンゾオキサジアゾリル、ベンゾイソチアゾリル、ベンゾイソオキサゾリル等 The compound containing a nitrogen atom is preferably an aliphatic compound containing nitrogen or an aromatic compound containing nitrogen, and may contain a nitrogen atom in a chain part such as an amine or an amide. May be included.
The “nitrogen-containing heterocycle” is a heterocycle containing at least one nitrogen atom, and specifically includes the following.
(1) monocyclic saturated heterocycle (a) those containing 1 to 4 nitrogen atoms, such as azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, etc .;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl and the like;
(2) monocyclic unsaturated heterocyclic group (a) containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl and the like;
(B) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and / or 1 to 2 oxygen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, Oxazinyl and the like;
(3) Fused polycyclic saturated heterocyclic group (a) One containing 1 to 5 nitrogen atoms, for example, quinuclidinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2. 2] Nonanyl and the like;
(B) those containing 1 to 4 nitrogen atoms, and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, such as trithiadiazaindenyl, dioxoleumidazolidinyl and the like;
(4) condensed polycyclic unsaturated heterocyclic group (a) containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, dihydrobenzimidazolyl, tetrahyzolobenzoimidazolyl, quinolyl, tetrahydro Quinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazo Ril, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, etc .;
(B) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and / or 1 to 3 oxygen atoms, for example benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothia Zolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, benzooxadiazolyl, benzisothiazolyl, benzoisoxazolyl, etc.
好ましい有機化合物として、具体的には以下の化合物が挙げられる。
（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩、３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩、９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン、ピリジン、２－ピコリン、２，６－ルチジン、エチレンジアミン。 Specific examples of preferable organic compounds include the following compounds.
(R)-(−)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenyl Ethanol monohydrochloride, 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl} benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidin-3-yl] -1, 6-dihydrodipyrolo [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6-lutidine, ethylenediamine.
（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩、３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩、９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン、ピリジン、２－ピコリン、２，６－ルチジン、エチレンジアミン。 Specific examples of preferable organic compounds include the following compounds.
(R)-(−)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenyl Ethanol monohydrochloride, 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl} benzoic acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidin-3-yl] -1, 6-dihydrodipyrolo [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6-lutidine, ethylenediamine.
溶媒中の有機化合物濃度は通常特に規定はないが、有機化合物が溶媒に溶解していればよい。
The concentration of the organic compound in the solvent is not particularly specified, but it is sufficient that the organic compound is dissolved in the solvent.
有機化合物及びＰｄを含む溶液を水素ガス雰囲気下で攪拌する工程に次いで、濾過によりＰｄを取り出す工程を含むことが好ましい。濾過に代えて、遠心分離、蒸留等を用いてＰｄを取り出すこともできる。
取り出されたＰｄは、公知の方法によりＰｄ触媒として再利用してもよい。 It is preferable to include a step of removing Pd by filtration after the step of stirring the solution containing the organic compound and Pd in a hydrogen gas atmosphere. Instead of filtration, Pd can be taken out using centrifugation, distillation or the like.
The extracted Pd may be reused as a Pd catalyst by a known method.
取り出されたＰｄは、公知の方法によりＰｄ触媒として再利用してもよい。 It is preferable to include a step of removing Pd by filtration after the step of stirring the solution containing the organic compound and Pd in a hydrogen gas atmosphere. Instead of filtration, Pd can be taken out using centrifugation, distillation or the like.
The extracted Pd may be reused as a Pd catalyst by a known method.
有機化合物に含まれるＰｄは、誘導結合プラズマ発光分光分析法（ＩＣＰ－ＡＥＳ）により同定することができる。
なお、Ｐｄを除去した後、目的化合物である有機化合物は、蒸留、減圧乾燥、晶析・濾過等により単離することができる。また、目的化合物の収率向上のため、用いる原料や溶媒を、適宜脱気や脱水、精製等してから用いてもよい。脱気や脱水、精製は、公知の方法により行うことができる。 Pd contained in the organic compound can be identified by inductively coupled plasma optical emission spectrometry (ICP-AES).
In addition, after removing Pd, the organic compound which is the target compound can be isolated by distillation, drying under reduced pressure, crystallization / filtration, or the like. In addition, in order to improve the yield of the target compound, the raw materials and solvents to be used may be used after appropriately degassing, dehydrating, purifying and the like. Deaeration, dehydration, and purification can be performed by known methods.
なお、Ｐｄを除去した後、目的化合物である有機化合物は、蒸留、減圧乾燥、晶析・濾過等により単離することができる。また、目的化合物の収率向上のため、用いる原料や溶媒を、適宜脱気や脱水、精製等してから用いてもよい。脱気や脱水、精製は、公知の方法により行うことができる。 Pd contained in the organic compound can be identified by inductively coupled plasma optical emission spectrometry (ICP-AES).
In addition, after removing Pd, the organic compound which is the target compound can be isolated by distillation, drying under reduced pressure, crystallization / filtration, or the like. In addition, in order to improve the yield of the target compound, the raw materials and solvents to be used may be used after appropriately degassing, dehydrating, purifying and the like. Deaeration, dehydration, and purification can be performed by known methods.
本発明は、有機化合物及びＰｄを含む溶液を水素ガス雰囲気下で攪拌することを特徴とする、有機化合物からＰｄを除去する方法にも関する。すなわち、Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌することを特徴とする、有機化合物からＰｄを除去する方法にも関する。
攪拌後に濾過を実施することが好ましく、濾過に代えて、遠心分離、蒸留等を用いてＰｄを取り出すこともできる。
当該方法における好ましい条件、具体例等は先述したＰｄを実質的に含まない有機化合物の製造方法における好ましい条件、具体例等とそれぞれ同様である。 The present invention also relates to a method for removing Pd from an organic compound, wherein the solution containing the organic compound and Pd is stirred in a hydrogen gas atmosphere. That is, Pd is removed from an organic compound, characterized in that a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound is stirred in a hydrogen gas atmosphere. Also related to how to do.
It is preferable to carry out filtration after stirring, and Pd can be taken out by centrifugation, distillation or the like instead of filtration.
Preferred conditions, specific examples and the like in the method are the same as the preferred conditions and specific examples and the like in the method for producing an organic compound substantially free of Pd described above.
攪拌後に濾過を実施することが好ましく、濾過に代えて、遠心分離、蒸留等を用いてＰｄを取り出すこともできる。
当該方法における好ましい条件、具体例等は先述したＰｄを実質的に含まない有機化合物の製造方法における好ましい条件、具体例等とそれぞれ同様である。 The present invention also relates to a method for removing Pd from an organic compound, wherein the solution containing the organic compound and Pd is stirred in a hydrogen gas atmosphere. That is, Pd is removed from an organic compound, characterized in that a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound is stirred in a hydrogen gas atmosphere. Also related to how to do.
It is preferable to carry out filtration after stirring, and Pd can be taken out by centrifugation, distillation or the like instead of filtration.
Preferred conditions, specific examples and the like in the method are the same as the preferred conditions and specific examples and the like in the method for producing an organic compound substantially free of Pd described above.
以下に実施例を挙げ、本発明を具体的に説明するが、本発明はこれらに限定されない。
＜市販試薬＞
本実施例において使用するＰｄ／Ｃは、実施例２はエヌ・イーケムキャット株式会社製の商品名：１０％ Ｐｄ／Ｃ（Ｋ）、実施例４は川研ファインケミカル株式会社製の商品名：１０％ Ｐｄ／Ｃ（Ｍ）、実施例５はエヌ・イーケムキャット株式会社製の商品名：２０％ Ｐｄ（ＯＨ）２／Ｃ、その他の実施例においては川研ファインケミカル株式会社製の商品名：５％ Ｐｄ／Ｃ（ＰＨ）を、前処理を施すことなくそのまま用いた。なお、それぞれのＰｄ／Ｃの含水率は約５０％である。
＜評価方法＞
本実施例において、合成した有機化合物中に含まれるＰｄ含有量は株式会社島津製作所社製の誘導結合プラズマ発光分光分析法（ＩＣＰ－ＡＥＳ）（商品名：ＩＣＰＥ－９０００）による測定によって求めた。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these.
<Commercially available reagents>
As for Pd / C used in this example, Example 2 is a product name manufactured by N.E. Chemcat Co., Ltd .: 10% Pd / C (K), Example 4 is a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 10 % Pd / C (M), Example 5 is a product name manufactured by N.E. Chemcat Co., Ltd .: 20% Pd (OH) 2 / C, and in other examples, a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 5 % Pd / C (PH) was used as is without pretreatment. The water content of each Pd / C is about 50%.
<Evaluation method>
In this example, the Pd content contained in the synthesized organic compound was determined by measurement by inductively coupled plasma emission spectroscopy (ICP-AES) (trade name: ICPE-9000) manufactured by Shimadzu Corporation.
＜市販試薬＞
本実施例において使用するＰｄ／Ｃは、実施例２はエヌ・イーケムキャット株式会社製の商品名：１０％ Ｐｄ／Ｃ（Ｋ）、実施例４は川研ファインケミカル株式会社製の商品名：１０％ Ｐｄ／Ｃ（Ｍ）、実施例５はエヌ・イーケムキャット株式会社製の商品名：２０％ Ｐｄ（ＯＨ）２／Ｃ、その他の実施例においては川研ファインケミカル株式会社製の商品名：５％ Ｐｄ／Ｃ（ＰＨ）を、前処理を施すことなくそのまま用いた。なお、それぞれのＰｄ／Ｃの含水率は約５０％である。
＜評価方法＞
本実施例において、合成した有機化合物中に含まれるＰｄ含有量は株式会社島津製作所社製の誘導結合プラズマ発光分光分析法（ＩＣＰ－ＡＥＳ）（商品名：ＩＣＰＥ－９０００）による測定によって求めた。 EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these.
<Commercially available reagents>
As for Pd / C used in this example, Example 2 is a product name manufactured by N.E. Chemcat Co., Ltd .: 10% Pd / C (K), Example 4 is a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 10 % Pd / C (M), Example 5 is a product name manufactured by N.E. Chemcat Co., Ltd .: 20% Pd (OH) 2 / C, and in other examples, a product name manufactured by Kawaken Fine Chemical Co., Ltd .: 5 % Pd / C (PH) was used as is without pretreatment. The water content of each Pd / C is about 50%.
<Evaluation method>
In this example, the Pd content contained in the synthesized organic compound was determined by measurement by inductively coupled plasma emission spectroscopy (ICP-AES) (trade name: ICPE-9000) manufactured by Shimadzu Corporation.
＜実施例１＞
（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩
日本国特公平０６－６５６５号公報の実施例１の方法に基づき合成した２Ｒ，１Ｒ－２－メトキシ－５－［２－（１－メチルベンジルアミノ）プロピル］ベンゼンスルホンアミド 塩酸塩２ｇ、メタノール４５ｍＬ、５％ Ｐｄ／Ｃ０．８６ｇを加え、窒素置換を３回実施後、水素置換を２回実施した。水素ガス加圧下（８０ｐｓｉｇ）外温７０℃にて３時間撹拌した。５０℃以下まで冷却し、空気下終夜撹拌した。撹拌後の溶液を濾過し、水１８ｍＬにて洗浄した。得られた溶液のＰｄ濃度は８２．０ｐｐｍであった。
次に、得られた溶液を水素ガス雰囲気下（大気圧、２０～３０℃）５時間撹拌後、ろ過を実施し、Ｐｄ濃度を測定したところ、Ｐｄ未検出（結晶換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。その濾液を濃縮し、溶媒を完全に留去し、析出した結晶を乾燥し、Ｐｄ濃度を測定したところ４．１ｐｐｍであった。 <Example 1>
(R)-(-)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride 2R, 1R-2-- synthesized based on the method of Example 1 of Japanese Patent Publication No. 06-6565 Methoxy-5- [2- (1-methylbenzylamino) propyl] benzenesulfonamide Hydrochloride 2 g, methanol 45 mL, 5% Pd / C 0.86 g were added, nitrogen substitution was performed three times, and hydrogen substitution was performed twice. did. The mixture was stirred for 3 hours at an external temperature of 70 ° C. under hydrogen gas pressure (80 psig). It cooled to 50 degrees C or less, and stirred under air all night. The stirred solution was filtered and washed with 18 mL of water. The Pd concentration of the obtained solution was 82.0 ppm.
Next, the obtained solution was stirred in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.) for 5 hours, followed by filtration and measurement of Pd concentration. As a result, Pd was not detected (crystal conversion: Pd not detected, Pd The removal rate was 100%. The filtrate was concentrated, the solvent was completely distilled off, the precipitated crystals were dried, and the Pd concentration was measured and found to be 4.1 ppm.
（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩
日本国特公平０６－６５６５号公報の実施例１の方法に基づき合成した２Ｒ，１Ｒ－２－メトキシ－５－［２－（１－メチルベンジルアミノ）プロピル］ベンゼンスルホンアミド 塩酸塩２ｇ、メタノール４５ｍＬ、５％ Ｐｄ／Ｃ０．８６ｇを加え、窒素置換を３回実施後、水素置換を２回実施した。水素ガス加圧下（８０ｐｓｉｇ）外温７０℃にて３時間撹拌した。５０℃以下まで冷却し、空気下終夜撹拌した。撹拌後の溶液を濾過し、水１８ｍＬにて洗浄した。得られた溶液のＰｄ濃度は８２．０ｐｐｍであった。
次に、得られた溶液を水素ガス雰囲気下（大気圧、２０～３０℃）５時間撹拌後、ろ過を実施し、Ｐｄ濃度を測定したところ、Ｐｄ未検出（結晶換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。その濾液を濃縮し、溶媒を完全に留去し、析出した結晶を乾燥し、Ｐｄ濃度を測定したところ４．１ｐｐｍであった。 <Example 1>
(R)-(-)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride 2R, 1R-2-- synthesized based on the method of Example 1 of Japanese Patent Publication No. 06-6565 Methoxy-5- [2- (1-methylbenzylamino) propyl] benzenesulfonamide Hydrochloride 2 g, methanol 45 mL, 5% Pd / C 0.86 g were added, nitrogen substitution was performed three times, and hydrogen substitution was performed twice. did. The mixture was stirred for 3 hours at an external temperature of 70 ° C. under hydrogen gas pressure (80 psig). It cooled to 50 degrees C or less, and stirred under air all night. The stirred solution was filtered and washed with 18 mL of water. The Pd concentration of the obtained solution was 82.0 ppm.
Next, the obtained solution was stirred in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.) for 5 hours, followed by filtration and measurement of Pd concentration. As a result, Pd was not detected (crystal conversion: Pd not detected, Pd The removal rate was 100%. The filtrate was concentrated, the solvent was completely distilled off, the precipitated crystals were dried, and the Pd concentration was measured and found to be 4.1 ppm.
＜実施例２＞
（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩
日本国特許第３８００２２０号公報の参考例２に記載の方法に従い合成した（Ｒ）－２－［［２－（４－ニトロフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩５０ｇ、メタノール２５０ｍＬ、１０％ Ｐｄ／Ｃ２ｇを１Ｌオートクレーブに仕込み、次いで撹拌下、窒素置換（５回）、次いで水素置換（５回）を実施した。その後、内温５～２５℃、水素ガス加圧下（４３ｐｓｉｇ）で４時間撹拌し、反応を行った。次いで、反応液を開放系で内温２３℃にて撹拌した。
触媒をろ過後、メタノールで洗浄後、残量８３ｍＬまで減圧濃縮し、残渣に酢酸エチル３７ｍＬを３５℃で１時間かけて滴下した。（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩を種結晶として５０ｍｇ加え、２時間撹拌した。次いで、酢酸エチル３３０ｍＬを加えた後、内温２０℃で撹拌した。結晶を濾過後、酢酸エチルで洗浄し、５０℃で減圧乾燥することにより、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩４０ｇを得た（収率８８．２％）。得られた結晶中のＰｄ濃度は５８．８ｐｐｍであった。
得られた（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩５ｇをメタノール４０ｍＬ、水０．１ｍＬに溶解し、オートクレーブに仕込んだ。窒素置換（７回）、水素置換（７回）後、水素ガス加圧下（５０ｐｓｉｇ）２５℃で８時間撹拌した。
撹拌開始後から３時間経過後及び８時間経過後に各々サンプリングを実施し、それぞれの溶液についてＰｄ濃度を測定したところ、撹拌開始から３時間経過後のＰｄ濃度は０．３６ｐｐｍ（結晶換算：４．５ｐｐｍ、Ｐｄ除去率９２％）であり、撹拌開始から８時間経過後のＰｄ濃度は０．１９ｐｐｍ（結晶換算：２．３ｐｐｍ、Ｐｄ除去率９６％）であった。 <Example 2>
(R) -2-[[2- (4-Aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride (R) — synthesized according to the method described in Reference Example 2 of Japanese Patent No. 3800220 2-[[2- (4-Nitrophenyl) ethyl] amino] -1-phenylethanol Monohydrochloride (50 g), methanol (250 mL), 10% Pd / C (2 g) were charged into a 1 L autoclave, and then purged with nitrogen (5 times). Then, hydrogen substitution (5 times) was performed. Thereafter, the reaction was carried out by stirring for 4 hours under an internal temperature of 5 to 25 ° C. under hydrogen gas pressure (43 psig). Subsequently, the reaction solution was stirred at an internal temperature of 23 ° C. in an open system.
The catalyst was filtered, washed with methanol, and concentrated under reduced pressure to a residual amount of 83 mL. To the residue, 37 mL of ethyl acetate was added dropwise at 35 ° C. over 1 hour. 50 mg of (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride as a seed crystal was added and stirred for 2 hours. Next, 330 mL of ethyl acetate was added, followed by stirring at an internal temperature of 20 ° C. The crystals are filtered, washed with ethyl acetate, and dried under reduced pressure at 50 ° C. to give 40 g of (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride. Obtained (yield 88.2%). The Pd concentration in the obtained crystal was 58.8 ppm.
5 g of the obtained (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride was dissolved in 40 mL of methanol and 0.1 mL of water, and charged into an autoclave. After nitrogen substitution (7 times) and hydrogen substitution (7 times), the mixture was stirred at 25 ° C. under hydrogen gas pressure (50 psig) for 8 hours.
Sampling was performed after 3 hours and 8 hours from the start of stirring, and the Pd concentration was measured for each solution. The Pd concentration after 3 hours from the start of stirring was 0.36 ppm (crystal conversion: 4. The Pd concentration after 8 hours from the start of stirring was 0.19 ppm (crystal conversion: 2.3 ppm, Pd removal rate 96%).
（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩
日本国特許第３８００２２０号公報の参考例２に記載の方法に従い合成した（Ｒ）－２－［［２－（４－ニトロフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩５０ｇ、メタノール２５０ｍＬ、１０％ Ｐｄ／Ｃ２ｇを１Ｌオートクレーブに仕込み、次いで撹拌下、窒素置換（５回）、次いで水素置換（５回）を実施した。その後、内温５～２５℃、水素ガス加圧下（４３ｐｓｉｇ）で４時間撹拌し、反応を行った。次いで、反応液を開放系で内温２３℃にて撹拌した。
触媒をろ過後、メタノールで洗浄後、残量８３ｍＬまで減圧濃縮し、残渣に酢酸エチル３７ｍＬを３５℃で１時間かけて滴下した。（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩を種結晶として５０ｍｇ加え、２時間撹拌した。次いで、酢酸エチル３３０ｍＬを加えた後、内温２０℃で撹拌した。結晶を濾過後、酢酸エチルで洗浄し、５０℃で減圧乾燥することにより、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩４０ｇを得た（収率８８．２％）。得られた結晶中のＰｄ濃度は５８．８ｐｐｍであった。
得られた（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩５ｇをメタノール４０ｍＬ、水０．１ｍＬに溶解し、オートクレーブに仕込んだ。窒素置換（７回）、水素置換（７回）後、水素ガス加圧下（５０ｐｓｉｇ）２５℃で８時間撹拌した。
撹拌開始後から３時間経過後及び８時間経過後に各々サンプリングを実施し、それぞれの溶液についてＰｄ濃度を測定したところ、撹拌開始から３時間経過後のＰｄ濃度は０．３６ｐｐｍ（結晶換算：４．５ｐｐｍ、Ｐｄ除去率９２％）であり、撹拌開始から８時間経過後のＰｄ濃度は０．１９ｐｐｍ（結晶換算：２．３ｐｐｍ、Ｐｄ除去率９６％）であった。 <Example 2>
(R) -2-[[2- (4-Aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride (R) — synthesized according to the method described in Reference Example 2 of Japanese Patent No. 3800220 2-[[2- (4-Nitrophenyl) ethyl] amino] -1-phenylethanol Monohydrochloride (50 g), methanol (250 mL), 10% Pd / C (2 g) were charged into a 1 L autoclave, and then purged with nitrogen (5 times). Then, hydrogen substitution (5 times) was performed. Thereafter, the reaction was carried out by stirring for 4 hours under an internal temperature of 5 to 25 ° C. under hydrogen gas pressure (43 psig). Subsequently, the reaction solution was stirred at an internal temperature of 23 ° C. in an open system.
The catalyst was filtered, washed with methanol, and concentrated under reduced pressure to a residual amount of 83 mL. To the residue, 37 mL of ethyl acetate was added dropwise at 35 ° C. over 1 hour. 50 mg of (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride as a seed crystal was added and stirred for 2 hours. Next, 330 mL of ethyl acetate was added, followed by stirring at an internal temperature of 20 ° C. The crystals are filtered, washed with ethyl acetate, and dried under reduced pressure at 50 ° C. to give 40 g of (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride. Obtained (yield 88.2%). The Pd concentration in the obtained crystal was 58.8 ppm.
5 g of the obtained (R) -2-[[2- (4-aminophenyl) ethyl] amino] -1-phenylethanol monohydrochloride was dissolved in 40 mL of methanol and 0.1 mL of water, and charged into an autoclave. After nitrogen substitution (7 times) and hydrogen substitution (7 times), the mixture was stirred at 25 ° C. under hydrogen gas pressure (50 psig) for 8 hours.
Sampling was performed after 3 hours and 8 hours from the start of stirring, and the Pd concentration was measured for each solution. The Pd concentration after 3 hours from the start of stirring was 0.36 ppm (crystal conversion: 4. The Pd concentration after 8 hours from the start of stirring was 0.19 ppm (crystal conversion: 2.3 ppm, Pd removal rate 96%).
＜実施例３＞
３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩
国際公開第２０１１／０３４０７８号の実施例２６３に記載の方法に従い合成した３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩２５０ｍｇにテトラヒドロフラン（ＴＨＦ）５０ｍＬ、メタノール５０ｍＬを加え溶解後、不溶物を濾過した。この時の溶液のＰｄ濃度は２１．１ｐｐｍであった。
次にこの溶液を窒素置換を３回実施後、水素置換を２回実施し、その後、水素ガス雰囲気下（大気圧、２０～３０℃）、終夜撹拌した。撹拌後、溶液を濾過してＰｄ濃度を測定したところ、０．０７ｐｐｍ（結晶換算：２３．４ｐｐｍ、Ｐｄ除去率９９．７％）であった。 <Example 3>
3-Chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl} benzoic acid monohydrochloride International Publication No. 2011/034078 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl synthesized according to the method described in Example 263 } To 250 mg of benzoic acid monohydrochloride, 50 mL of tetrahydrofuran (THF) and 50 mL of methanol were added and dissolved, and insoluble matter was filtered off. The Pd concentration of the solution at this time was 21.1 ppm.
Next, this solution was purged with nitrogen three times and then purged with hydrogen twice, and then stirred overnight in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.). After stirring, the solution was filtered and the Pd concentration was measured and found to be 0.07 ppm (crystal conversion: 23.4 ppm, Pd removal rate 99.7%).
３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩
国際公開第２０１１／０３４０７８号の実施例２６３に記載の方法に従い合成した３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩２５０ｍｇにテトラヒドロフラン（ＴＨＦ）５０ｍＬ、メタノール５０ｍＬを加え溶解後、不溶物を濾過した。この時の溶液のＰｄ濃度は２１．１ｐｐｍであった。
次にこの溶液を窒素置換を３回実施後、水素置換を２回実施し、その後、水素ガス雰囲気下（大気圧、２０～３０℃）、終夜撹拌した。撹拌後、溶液を濾過してＰｄ濃度を測定したところ、０．０７ｐｐｍ（結晶換算：２３．４ｐｐｍ、Ｐｄ除去率９９．７％）であった。 <Example 3>
3-Chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl} benzoic acid monohydrochloride International Publication No. 2011/034078 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl synthesized according to the method described in Example 263 } To 250 mg of benzoic acid monohydrochloride, 50 mL of tetrahydrofuran (THF) and 50 mL of methanol were added and dissolved, and insoluble matter was filtered off. The Pd concentration of the solution at this time was 21.1 ppm.
Next, this solution was purged with nitrogen three times and then purged with hydrogen twice, and then stirred overnight in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.). After stirring, the solution was filtered and the Pd concentration was measured and found to be 0.07 ppm (crystal conversion: 23.4 ppm, Pd removal rate 99.7%).
＜実施例４＞
９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸
Ｏｒｇａｎｉｃ Ｐｒｏｃｅｓｓ Ｒｅｓｅａｒｃｈ＆Ｄｅｖｅｌｏｐｍｅｎｔ，２０１２，１６，６５４－６６３記載の方法に従い合成した９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロプ－１－イン－１－イル］－９Ｈ－フルオレン－２－カルボン酸５００ｍｇをメタノール１０ｍＬに溶解し、１０％ Ｐｄ／Ｃ８０ｍｇを加え、水素ガス雰囲気下撹拌した。反応終了後、空気雰囲気下終夜撹拌し、触媒を濾過しメタノール５．５ｍＬで洗浄した。この時の溶液のＰｄ濃度は６．６ｐｐｍであった。
次に、この溶液を窒素置換３回実施後、水素置換２回実施し、その後、水素ガス雰囲気下（大気圧、２０～３０℃）、５時間撹拌した。撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ未検出（結晶換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。 <Example 4>
9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid 9-hydroxy-9 synthesized according to the method described in Organic Process Research & Development, 2012, 16, 654-663 -[3- (Tetrahydropyran-2-yloxy) prop-1-in-1-yl] -9H-fluorene-2-carboxylic acid 500 mg was dissolved in 10 mL of methanol, 10% Pd / C 80 mg was added, and hydrogen gas atmosphere Stirring under. After completion of the reaction, the mixture was stirred overnight in an air atmosphere, and the catalyst was filtered and washed with 5.5 mL of methanol. At this time, the Pd concentration of the solution was 6.6 ppm.
Next, this solution was replaced with nitrogen three times and then replaced with hydrogen twice, and then stirred for 5 hours in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.). After stirring, the mixture was filtered and the Pd concentration was measured. As a result, Pd was not detected (crystal conversion: Pd not detected, Pd removal rate 100%).
９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸
Ｏｒｇａｎｉｃ Ｐｒｏｃｅｓｓ Ｒｅｓｅａｒｃｈ＆Ｄｅｖｅｌｏｐｍｅｎｔ，２０１２，１６，６５４－６６３記載の方法に従い合成した９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロプ－１－イン－１－イル］－９Ｈ－フルオレン－２－カルボン酸５００ｍｇをメタノール１０ｍＬに溶解し、１０％ Ｐｄ／Ｃ８０ｍｇを加え、水素ガス雰囲気下撹拌した。反応終了後、空気雰囲気下終夜撹拌し、触媒を濾過しメタノール５．５ｍＬで洗浄した。この時の溶液のＰｄ濃度は６．６ｐｐｍであった。
次に、この溶液を窒素置換３回実施後、水素置換２回実施し、その後、水素ガス雰囲気下（大気圧、２０～３０℃）、５時間撹拌した。撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ未検出（結晶換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。 <Example 4>
9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid 9-hydroxy-9 synthesized according to the method described in Organic Process Research & Development, 2012, 16, 654-663 -[3- (Tetrahydropyran-2-yloxy) prop-1-in-1-yl] -9H-fluorene-2-carboxylic acid 500 mg was dissolved in 10 mL of methanol, 10% Pd / C 80 mg was added, and hydrogen gas atmosphere Stirring under. After completion of the reaction, the mixture was stirred overnight in an air atmosphere, and the catalyst was filtered and washed with 5.5 mL of methanol. At this time, the Pd concentration of the solution was 6.6 ppm.
Next, this solution was replaced with nitrogen three times and then replaced with hydrogen twice, and then stirred for 5 hours in a hydrogen gas atmosphere (atmospheric pressure, 20 to 30 ° C.). After stirring, the mixture was filtered and the Pd concentration was measured. As a result, Pd was not detected (crystal conversion: Pd not detected, Pd removal rate 100%).
＜実施例５＞
１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン
国際公開第２０１０／１１９８７５号の製造例６に記載の方法に従い合成した１－［（３Ｒ，４Ｒ）－１－ベンジル－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン１０ｇにエタノール２０ｍＬ、常水３０ｍＬを加え溶解し、６Ｎ塩酸を９．５ｍＬ、２０％ Ｐｄ（ＯＨ）２／Ｃを１ｇ加えた。窒素置換３回実施後、水素置換３回実施し、水素ガス加圧下（３０ｐｓｉｇ）、室温にて１９時間撹拌後、空気中でさらに３時間撹拌した。その後触媒を濾過し、得られた濾液に水酸化ナトリウム水溶液を用いてｐＨ１３に調整した。析出した結晶を濾取し、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジンの結晶を得た。この時の結晶１２５ｍｇをメタノール２５ｍＬに溶解させた水溶液のＰｄ濃度は３６．９ｐｐｍであった。
次に、当該溶液を窒素置換３回、水素置換２回実施後、外温１００℃、水素ガス加圧下（８０ｐｓｉｇ）にて２４時間撹拌した。この時の溶液中のＰｄ濃度は０．１９ｐｐｍ（結晶換算：３０．９ｐｐｍ、除去率：９９．５％）であった。引き続き外温を１２０℃まで加温し、水素ガス加圧下（８０ｐｓｉｇ）２４時間攪拌後、濾過して溶液中のＰｄ濃度を測定したところ、Ｐｄ濃度は０．０８ｐｐｍ（結晶換算：１２．１ｐｐｍ、除去率：９９．８％）であった。 <Example 5>
1-[(3R, 4R) -4-methylpiperidin-3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine International Publication No. 2010/119875 1-[(3R, 4R) -1-benzyl-4-methylpiperidin-3-yl] -1,6-dihydrodipyrolo [2,3-b: 2 ′, synthesized according to the method described in Preparation Example 6 3 mL of 3′-d] pyridine was dissolved by adding 20 mL of ethanol and 30 mL of normal water, and 9.5 mL of 6N hydrochloric acid and 1 g of 20% Pd (OH) 2 / C were added. After performing nitrogen substitution three times, hydrogen substitution three times, hydrogen gas pressurization (30 psig), stirring at room temperature for 19 hours, and further stirring in air for 3 hours. Thereafter, the catalyst was filtered, and the obtained filtrate was adjusted to pH 13 using an aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, and 1-[(3R, 4R) -4-methylpiperidin-3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine Crystal was obtained. The Pd concentration of an aqueous solution in which 125 mg of crystals at this time was dissolved in 25 mL of methanol was 36.9 ppm.
Next, the solution was subjected to nitrogen substitution three times and hydrogen substitution twice, and then stirred for 24 hours at an external temperature of 100 ° C. under hydrogen gas pressure (80 psig). The Pd concentration in the solution at this time was 0.19 ppm (crystal conversion: 30.9 ppm, removal rate: 99.5%). Subsequently, the external temperature was raised to 120 ° C., stirred under hydrogen gas pressure (80 psig) for 24 hours, and filtered to measure the Pd concentration in the solution. As a result, the Pd concentration was 0.08 ppm (crystal conversion: 12.1 ppm, (Removal rate: 99.8%).
１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン
国際公開第２０１０／１１９８７５号の製造例６に記載の方法に従い合成した１－［（３Ｒ，４Ｒ）－１－ベンジル－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン１０ｇにエタノール２０ｍＬ、常水３０ｍＬを加え溶解し、６Ｎ塩酸を９．５ｍＬ、２０％ Ｐｄ（ＯＨ）２／Ｃを１ｇ加えた。窒素置換３回実施後、水素置換３回実施し、水素ガス加圧下（３０ｐｓｉｇ）、室温にて１９時間撹拌後、空気中でさらに３時間撹拌した。その後触媒を濾過し、得られた濾液に水酸化ナトリウム水溶液を用いてｐＨ１３に調整した。析出した結晶を濾取し、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジンの結晶を得た。この時の結晶１２５ｍｇをメタノール２５ｍＬに溶解させた水溶液のＰｄ濃度は３６．９ｐｐｍであった。
次に、当該溶液を窒素置換３回、水素置換２回実施後、外温１００℃、水素ガス加圧下（８０ｐｓｉｇ）にて２４時間撹拌した。この時の溶液中のＰｄ濃度は０．１９ｐｐｍ（結晶換算：３０．９ｐｐｍ、除去率：９９．５％）であった。引き続き外温を１２０℃まで加温し、水素ガス加圧下（８０ｐｓｉｇ）２４時間攪拌後、濾過して溶液中のＰｄ濃度を測定したところ、Ｐｄ濃度は０．０８ｐｐｍ（結晶換算：１２．１ｐｐｍ、除去率：９９．８％）であった。 <Example 5>
1-[(3R, 4R) -4-methylpiperidin-3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine International Publication No. 2010/119875 1-[(3R, 4R) -1-benzyl-4-methylpiperidin-3-yl] -1,6-dihydrodipyrolo [2,3-b: 2 ′, synthesized according to the method described in Preparation Example 6 3 mL of 3′-d] pyridine was dissolved by adding 20 mL of ethanol and 30 mL of normal water, and 9.5 mL of 6N hydrochloric acid and 1 g of 20% Pd (OH) 2 / C were added. After performing nitrogen substitution three times, hydrogen substitution three times, hydrogen gas pressurization (30 psig), stirring at room temperature for 19 hours, and further stirring in air for 3 hours. Thereafter, the catalyst was filtered, and the obtained filtrate was adjusted to pH 13 using an aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, and 1-[(3R, 4R) -4-methylpiperidin-3-yl] -1,6-dihydrodipyrroro [2,3-b: 2 ′, 3′-d] pyridine Crystal was obtained. The Pd concentration of an aqueous solution in which 125 mg of crystals at this time was dissolved in 25 mL of methanol was 36.9 ppm.
Next, the solution was subjected to nitrogen substitution three times and hydrogen substitution twice, and then stirred for 24 hours at an external temperature of 100 ° C. under hydrogen gas pressure (80 psig). The Pd concentration in the solution at this time was 0.19 ppm (crystal conversion: 30.9 ppm, removal rate: 99.5%). Subsequently, the external temperature was raised to 120 ° C., stirred under hydrogen gas pressure (80 psig) for 24 hours, and filtered to measure the Pd concentration in the solution. As a result, the Pd concentration was 0.08 ppm (crystal conversion: 12.1 ppm, (Removal rate: 99.8%).
＜実施例６＞
ピリジン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、ピリジン（関東化学社製）を１．０１ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は２５．４ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は未検出（ピリジン換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。 <Example 6>
1 g of pyridine 5% Pd / C was suspended in 50 mL of methanol, 1.01 mL of pyridine (manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure), and stirred in air for 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 25.4 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (pyridine conversion: Pd not detected, Pd removal rate 100%).
ピリジン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、ピリジン（関東化学社製）を１．０１ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は２５．４ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は未検出（ピリジン換算：Ｐｄ未検出、Ｐｄ除去率１００％）であった。 <Example 6>
1 g of pyridine 5% Pd / C was suspended in 50 mL of methanol, 1.01 mL of pyridine (manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure), and stirred in air for 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 25.4 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (pyridine conversion: Pd not detected, Pd removal rate 100%).
＜実施例７＞
２－ピコリン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、２－ピコリン（東京化成社製）を１．２３ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は６．８１ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は未検出（２－ピコリン換算：Ｐｄ未検出、Ｐｄ除去率：１００％）であった。 <Example 7>
2-picoline 5% Pd / C (1 g) is suspended in 50 mL of methanol, 1.23 mL of 2-picoline (manufactured by Tokyo Chemical Industry Co., Ltd.) is added, and the mixture is stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure) and stirred in air for 48 hours. did. Thereafter, Pd / C was removed by filtration. At this time, the Pd concentration of the solution was 6.81 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (2-picoline conversion: Pd not detected, Pd removal rate: 100%).
２－ピコリン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、２－ピコリン（東京化成社製）を１．２３ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は６．８１ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は未検出（２－ピコリン換算：Ｐｄ未検出、Ｐｄ除去率：１００％）であった。 <Example 7>
2-picoline 5% Pd / C (1 g) is suspended in 50 mL of methanol, 1.23 mL of 2-picoline (manufactured by Tokyo Chemical Industry Co., Ltd.) is added, and the mixture is stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure) and stirred in air for 48 hours. did. Thereafter, Pd / C was removed by filtration. At this time, the Pd concentration of the solution was 6.81 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was not detected (2-picoline conversion: Pd not detected, Pd removal rate: 100%).
＜実施例８＞
２，６－ルチジン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、２，６－ルチジン（東京化成社製）を１．４５ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は２．７９ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は０．０３ｐｐｍ（２，６－ルチジン換算：０．８０ｐｐｍ、Ｐｄ除去率９８．９％）であった。 <Example 8>
2,6-lutidine 5% Pd / C (1 g) was suspended in 50 mL of methanol, 1.45 mL of 2,6-lutidine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure). For 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 2.79 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was 0.03 ppm (2,6-lutidine conversion: 0.80 ppm, Pd removal rate 98.9%).
２，６－ルチジン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、２，６－ルチジン（東京化成社製）を１．４５ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で４８時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は２．７９ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス雰囲気下（大気圧）、５０℃にて２４時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は０．０３ｐｐｍ（２，６－ルチジン換算：０．８０ｐｐｍ、Ｐｄ除去率９８．９％）であった。 <Example 8>
2,6-lutidine 5% Pd / C (1 g) was suspended in 50 mL of methanol, 1.45 mL of 2,6-lutidine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere (atmospheric pressure). For 48 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 2.79 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, followed by stirring in a hydrogen gas atmosphere (atmospheric pressure) at 50 ° C. for 24 hours, followed by filtration to measure the Pd concentration. Was 0.03 ppm (2,6-lutidine conversion: 0.80 ppm, Pd removal rate 98.9%).
＜実施例９＞
エチレンジアミン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、エチレンジアミン（和光社製）を０．８４ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で２４時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は１２．３ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス加圧下（８０ｐｓｉｇ）、１００℃にて６時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ未検出（Ｐｄ除去率１００％）であった。 <Example 9>
1 g of ethylenediamine 5% Pd / C was suspended in 50 mL of methanol, 0.84 mL of ethylenediamine (manufactured by Wako) was added, and the mixture was stirred under a hydrogen gas atmosphere (atmospheric pressure) for 1 hour, and stirred in air for 24 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 12.3 ppm.
Next, the obtained filtrate was purged with nitrogen three times and twice with hydrogen, then stirred under hydrogen gas pressure (80 psig) at 100 ° C. for 6 hours, and filtered to measure Pd concentration. (Pd removal rate 100%).
エチレンジアミン
５％ Ｐｄ／Ｃ１ｇをメタノール５０ｍＬに懸濁し、エチレンジアミン（和光社製）を０．８４ｍＬ加えて水素ガス雰囲気下（大気圧）で１時間撹拌し、空気中で２４時間撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は１２．３ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス加圧下（８０ｐｓｉｇ）、１００℃にて６時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ未検出（Ｐｄ除去率１００％）であった。 <Example 9>
1 g of ethylenediamine 5% Pd / C was suspended in 50 mL of methanol, 0.84 mL of ethylenediamine (manufactured by Wako) was added, and the mixture was stirred under a hydrogen gas atmosphere (atmospheric pressure) for 1 hour, and stirred in air for 24 hours. Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 12.3 ppm.
Next, the obtained filtrate was purged with nitrogen three times and twice with hydrogen, then stirred under hydrogen gas pressure (80 psig) at 100 ° C. for 6 hours, and filtered to measure Pd concentration. (Pd removal rate 100%).
＜参考例１＞
Ｌ－システイン
５％ Ｐｄ／Ｃ１ｇを常水４０ｍＬ、メタノール１０ｍＬに懸濁し、Ｌ－システイン（東京化成社製）を０．３ｇ加えて水素ガス雰囲気下で１時間撹拌後、空気中で終夜撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は１１３．１ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス加圧下（８０ｐｓｉｇ）、８０℃にて１６時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は１０５．０ｐｐｍ（Ｐｄ除去率７．２％）であった。 <Reference Example 1>
1 g of L-cysteine 5% Pd / C was suspended in 40 mL of normal water and 10 mL of methanol, 0.3 g of L-cysteine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere and then stirred overnight in air. . Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 113.1 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, and after stirring for 16 hours at 80 ° C. under hydrogen gas pressurization (80 psig), filtration was performed and Pd concentration was measured. It was 105.0 ppm (Pd removal rate 7.2%).
Ｌ－システイン
５％ Ｐｄ／Ｃ１ｇを常水４０ｍＬ、メタノール１０ｍＬに懸濁し、Ｌ－システイン（東京化成社製）を０．３ｇ加えて水素ガス雰囲気下で１時間撹拌後、空気中で終夜撹拌した。その後Ｐｄ／Ｃを濾過により取り除いた。この時の溶液のＰｄ濃度は１１３．１ｐｐｍであった。
次に、得られた濾液を窒素置換３回、水素置換２回実施後、水素ガス加圧下（８０ｐｓｉｇ）、８０℃にて１６時間撹拌後、濾過してＰｄ濃度を測定したところ、Ｐｄ濃度は１０５．０ｐｐｍ（Ｐｄ除去率７．２％）であった。 <Reference Example 1>
1 g of L-cysteine 5% Pd / C was suspended in 40 mL of normal water and 10 mL of methanol, 0.3 g of L-cysteine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred for 1 hour in a hydrogen gas atmosphere and then stirred overnight in air. . Thereafter, Pd / C was removed by filtration. The Pd concentration of the solution at this time was 113.1 ppm.
Next, the obtained filtrate was subjected to nitrogen substitution 3 times and hydrogen substitution 2 times, and after stirring for 16 hours at 80 ° C. under hydrogen gas pressurization (80 psig), filtration was performed and Pd concentration was measured. It was 105.0 ppm (Pd removal rate 7.2%).
本発明を詳細に、また特定の実施態様を参照して説明したが、本発明の精神と範囲を逸脱することなく様々な変更や修正を加えることができることは当業者にとって明らかである。本出願は２０１５年４月１７日出願の日本特許出願（特願２０１５－０８５１１２）に基づくものであり、その内容はここに参照として取り込まれる。
Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention. This application is based on a Japanese patent application filed on April 17, 2015 (Japanese Patent Application No. 2015-085112), the contents of which are incorporated herein by reference.
本発明によれば、工業的に安価であり環境にも優しい、水素ガスを用いた工程により残留Ｐｄを効果的に除去することができ、実質的にＰｄを含まない有機化合物を簡便に製造することができる。
また、除去された残留Ｐｄを回収し、新たな触媒として再利用することができる。 According to the present invention, residual Pd can be effectively removed by a process using hydrogen gas, which is industrially inexpensive and environmentally friendly, and an organic compound substantially free of Pd is easily produced. be able to.
Further, the removed residual Pd can be recovered and reused as a new catalyst.
また、除去された残留Ｐｄを回収し、新たな触媒として再利用することができる。 According to the present invention, residual Pd can be effectively removed by a process using hydrogen gas, which is industrially inexpensive and environmentally friendly, and an organic compound substantially free of Pd is easily produced. be able to.
Further, the removed residual Pd can be recovered and reused as a new catalyst.
Claims (9)
- Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する工程を含む、実質的にＰｄを含まない有機化合物の製造方法。 An organic compound substantially free of Pd, comprising a step of stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound under a hydrogen gas atmosphere. Production method.
- 前記水素ガス雰囲気下で撹拌する工程に次いで、濾過により前記残留Ｐｄを取り除く工程を含む、請求項１に記載の製造方法。 The manufacturing method according to claim 1, further comprising a step of removing the residual Pd by filtration after the step of stirring in the hydrogen gas atmosphere.
- 前記水素ガス雰囲気下で撹拌する工程における水素ガス圧が大気圧～１００ｐｓｉｇである、請求項１又は２に記載の製造方法。 The method according to claim 1 or 2, wherein the hydrogen gas pressure in the step of stirring in the hydrogen gas atmosphere is from atmospheric pressure to 100 psig.
- 前記水素ガス雰囲気下で撹拌する工程における温度が０～１２０℃である、請求項１～３のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 3, wherein a temperature in the step of stirring in the hydrogen gas atmosphere is 0 to 120 ° C.
- 前記有機化合物がＰｄと水素ガスの組み合わせにより分解が起こらない化合物である、請求項１～４のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 4, wherein the organic compound is a compound that is not decomposed by a combination of Pd and hydrogen gas.
- 前記有機化合物が窒素原子を含む化合物である、請求項１～５のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 5, wherein the organic compound is a compound containing a nitrogen atom.
- 前記有機化合物が単素環及び複素環の少なくともいずれか一方を含む化合物である、請求項１～６のいずれか１項に記載の製造方法。 The production method according to any one of claims 1 to 6, wherein the organic compound is a compound containing at least one of a monocyclic ring and a heterocyclic ring.
- 前記有機化合物が、（Ｒ）－（－）－５－（２－アミノプロピル）－２－メトキシベンゼンスルホンアミド 塩酸塩、（Ｒ）－２－［［２－（４－アミノフェニル）エチル］アミノ］－１－フェニルエタノール 一塩酸塩、３－クロロ－４－｛４－［５－（３－｛［グリシル（メチル）アミノ］メチル｝フェニル）ピリミジン－２－イル］ピペラジン－１－イル｝安息香酸 一塩酸塩、９－ヒドロキシ－９－［３－（テトラヒドロピラン－２－イルオキシ）プロピル］－９Ｈ－フルオレン－２－カルボン酸、１－［（３Ｒ，４Ｒ）－４－メチルピペリジン－３－イル］－１，６－ジヒドロジピロロ［２，３－ｂ：２’，３’－ｄ］ピリジン、ピリジン、２－ピコリン、２，６－ルチジン、またはエチレンジアミンである、請求項１～４のいずれか１項に記載の製造方法。 The organic compound is (R)-(−)-5- (2-aminopropyl) -2-methoxybenzenesulfonamide hydrochloride, (R) -2-[[2- (4-aminophenyl) ethyl] amino ] -1-Phenylethanol monohydrochloride, 3-chloro-4- {4- [5- (3-{[glycyl (methyl) amino] methyl} phenyl) pyrimidin-2-yl] piperazin-1-yl} benzoic acid Acid monohydrochloride, 9-hydroxy-9- [3- (tetrahydropyran-2-yloxy) propyl] -9H-fluorene-2-carboxylic acid, 1-[(3R, 4R) -4-methylpiperidine-3- Yl] -1,6-dihydrodipyrrolo [2,3-b: 2 ′, 3′-d] pyridine, pyridine, 2-picoline, 2,6-lutidine, or ethylenediamine. No The method according to Re preceding paragraph.
- Ｐｄ触媒を用いて合成して得られた有機化合物と、前記有機化合物中に残留する残留Ｐｄとを含む溶液を水素ガス雰囲気下で撹拌する、有機化合物からＰｄを除去する方法。 A method of removing Pd from an organic compound by stirring a solution containing an organic compound obtained by synthesis using a Pd catalyst and residual Pd remaining in the organic compound under a hydrogen gas atmosphere.
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| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50111011A (en) * | 1974-02-19 | 1975-09-01 | ||
| JPS55134137A (en) * | 1979-04-05 | 1980-10-18 | Ube Ind Ltd | Palladium recovering method |
| JP2004520322A (en) * | 2000-12-27 | 2004-07-08 | ロディア・ポリアミド・インターミーディエッツ | Method for producing carboxylic acid by carbonylation using palladium |
| JP2013202533A (en) * | 2012-03-28 | 2013-10-07 | Ube Industries Ltd | Method for recovering palladium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS50111011A (en) * | 1974-02-19 | 1975-09-01 | ||
| JPS55134137A (en) * | 1979-04-05 | 1980-10-18 | Ube Ind Ltd | Palladium recovering method |
| JP2004520322A (en) * | 2000-12-27 | 2004-07-08 | ロディア・ポリアミド・インターミーディエッツ | Method for producing carboxylic acid by carbonylation using palladium |
| JP2013202533A (en) * | 2012-03-28 | 2013-10-07 | Ube Industries Ltd | Method for recovering palladium |
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| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
| CN113816864B (en) * | 2020-06-18 | 2024-03-29 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenethylamine |
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