JP2015172025A - Method of preparing pharmaceutical by continuous flow multi-stage reaction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain optic active compounds efficiently by incorporating, into a multi-stage flow synthesis system, a column provided with a solid-phase synthesis device necessary for synthesizing optic active compounds to become pharmaceuticals or synthetic intermediate thereof and a column provided with a solid-phase synthesis device necessary for a functional group conversion.SOLUTION: In a multi-stage flow synthesis device as shown in the following figure, the above problem is solved by using a multi-stage synthesis device in which two kinds of flow synthesis columns such as a column A filled with chiral ligand and metal salt for obtaining an optic active compound, and a column B, which is necessary for a functional group conversion, filled with a solid-phase catalyst for performing hydrogenation reaction are connected in series according to the number of necessary processes to pass through reaction substrate.

Description

  The present invention is a method for obtaining a pharmaceutical product or an optically active compound as a synthesis intermediate thereof by connecting a plurality of continuous flow synthesizers connected in series and performing a multi-stage reaction from raw materials at once. It provides a method for providing the intermediate very simply and conveniently.

  As a basic technology for producing synthetic pharmaceuticals, bioactive substances for research, etc. using an organic synthetic method, a method of performing a batch reaction in a liquid phase is widely used. Conditions required for these organic syntheses include control of the reaction on an industrial scale level and construction of a manufacturing method with an emphasis on the process. In particular, in the production using a reaction kettle, it often happens that the results at the small scale are not reproduced at the scale-up. Also, waste that could not be ignored on a small scale may need to be dealt with when the scale is scaled up.

  As for the problem of waste, the reduction effect is remarkably improved by the development and utilization of catalysts with high TON and TOF due to the recent development of catalytic chemistry. In addition, reaction systems that generate almost no waste have been developed with the development of environmentally conscious research. Catalysts that support these technologies not only improve the activity of the catalyst, but also have a great deal of research on the foundation for supporting the catalyst. Development of solid catalysts that can react even in water by using a substrate that exhibits hydrophobicity and affinity for water as a base and supporting the catalyst on the substrate is proceeding (Non-Patent Document 1-2).

  As a synthesis method using a solid catalyst, a method in which a catalyst is fixed to a solid phase and reacted in a catalytic and continuous manner by a microreactor has attracted attention. By devising the flow path in the microreactor, a high-throughput screening system that sequentially reacts a large number of reaction substrates becomes possible (Non-patent Documents 3-5). As described above, the flow-type synthesis system is one of synthesis processes that have recently attracted attention as a technique for solving the drawbacks of batch synthesis on a large scale.

  In the flow synthesis system, a reaction field is provided on the liquid feed line, and the sample in the liquid feed is reacted little by little. Therefore, reaction temperature control is easier than batch reaction, which is a very effective means for carrying out precise organic synthesis. Moreover, since it is sufficient to control the temperature only in the reaction field, energy consumption tends to be reduced compared to batch synthesis. Furthermore, in batch synthesis, temperature control and stirring efficiency according to the reaction scale are required. These elements cannot be ignored because the local unevenness tends to occur as the reaction scale increases. Therefore, it becomes more difficult to reflect the experimental results obtained on a small scale with good reproducibility even on a large scale.

  On the other hand, in the flow synthesis system, even if the reaction scale changes, the liquid feed amount and the reaction field can be kept constant, so that the same conditions are maintained in the part contributing to the reaction. For this reason, most of the problems concerned in batch synthesis are solved. Furthermore, since the reaction catalyst is immobilized, the catalyst removal operation after the reaction is unnecessary, and it is not necessary to use a trapping agent or the like to remove the catalyst. Despite these many advantages, there are very few reports using the flow synthesis system.

  In recent years, many solid catalysts that can be used for flow synthesis and batch reactions have been developed. Especially, metal catalysts coordinated with natural products or synthetic chiral compounds, or enzymes are supported on a solid support for use in asymmetric synthesis. (Non-patent literature 1-2, Non-patent literature 6). In particular, the planar chiral ligands such as Box and Pybox are chemically stable, and show excellent asymmetric induction when a complex with a metal is used as a catalyst. Therefore, they have been introduced into carriers such as silica gel and polystyrene. (Non-patent document 6).

  The inventor has invented a PS-Pybox calcium complex introduced into a polystyrene resin, and uses it for asymmetric synthesis by a batch reaction using the same (Patent Document 1). In this invention, since the central metal is a calcium salt, the environmental load is small, and the calcium salt is insoluble in various organic solvents, so that elution of the metal can be avoided. Furthermore, the present inventor has developed a method for efficiently obtaining an optically active substance by immobilizing a PS-Pybox calcium complex and using it in a flow synthesis system to perform asymmetric synthesis (Patent Document 2).

The present inventor has invented a palladium / alumina hybrid catalyst [= Pd / (PSi-Al ₂ O ₃ )] supported on poly (methylphenyl) silane, and using a continuous flow reactor incorporating this catalyst in a column, Reduction of carbon-carbon double bonds and triple bonds under airflow is possible (Non-patent Documents 7-8). This reaction apparatus can reduce nitrobenzene to an amino group and deprotect a Cbz group, and can be applied to a reduction reaction using water as a solvent.

  When chemically synthesizing an optically active compound, it is possible to construct a compound having a more complex skeleton by appropriately using two synthesis methods. One is a method for constructing a carbon-carbon bond using a synthetic method having high stereoselectivity, and the other is a method for enabling functional group conversion in a regioselective and functional group selective manner. By combining these two methods, synthesis of an optically active compound having a more complicated structure can be achieved. However, a batch reaction method is generally used, and solid-phase synthesis is limited to DNA or peptide synthesis. The method using the flow synthesis system is merely an example used for the synthesis method of a compound having a simple structure that does not include asymmetric synthesis. In particular, there has been no report on a technique for continuously performing functional group conversion while achieving asymmetric synthesis to achieve multistage synthesis (Non-patent Document 9).

The present inventor has developed a method for efficiently obtaining an optically active substance by a flow synthesis system in which a PS-Pybox calcium complex is immobilized (Patent Document 2), and further, Pd / (PSi—Al ₂ O under a hydrogen stream. ₃ ) Development of methods for reducing carbon-carbon double bonds and triple bonds, reducing nitrobenzene to amino groups, and deprotecting Cbz groups by using a flow synthesis system with immobilized ( ₃ ) 7-8). By connecting these two flow synthesizers in series at appropriate positions, it was thought that synthesis of optically active complex compounds could be achieved at once, leading to the invention of a multi-stage flow synthesis system.

JP, 2013-185150, A. JP2013-184973A.

R. Akiyama, S .; Kobayashi, Chem. Rev. 2009, 109, 594-642. S. Kobayashi, H .; Miyamura, the Chemical Record, 2010, 10, 271-290. B. P. Mason, K .; E. Price, J.M. L. Steinbacher, A.M. R. Bogdan, D.M. T. T. et al. McQuade. Chem. Rev. 2007, 107, 2300-2318. C. Willes, P.M. Watts, Eur. J. et al. Org. Chem. 2008, 1655-1671. T. T. et al. Fukuyama, Md. T. T. et al. Rahman, M .; Sato, I. et al. Ryu. Synlett 2008, 151-163. X. Y. Mak, P .; Laurino, P.A. H. Seeberger. Bejlstein J.M. Org. Chem, 2009, 5, No. 19. H. Oyamada, R.A. Akiyama, H .; Hagio, T .; Naito, S .; Kobayashi, Chem. Commun. 2006, 4297-4299. H. Oyamada, T .; Naito, S .; Kobayashi, Beilstein J. et al. Org. Chem. 2011, 7, 735-739. T. T. et al. Tsubogo, T .; Ishiwata, S .; Kobayashi, Angew. Chem. Int. Ed. 2013, 52, 6590-6604.

  The problem to be solved by the present invention is to appropriately adopt a flow synthesis system having a solid phase asymmetric synthesizer necessary for the synthesis of pharmaceuticals and intermediates thereof, and a flow synthesis system having a solid phase synthesizer necessary for functional group conversion. It is to obtain a pharmaceutical product efficiently by connecting in series to various positions and continuously performing asymmetric synthesis and functional group conversion.

In order to solve the problems, the inventors have developed a flow synthesis system in which a PS-Pybox calcium complex essential for asymmetric synthesis is immobilized, a flow in which Pd / (PSi-Al ₂ O ₃ ) necessary for functional group transformation is immobilized. Each of the synthesis systems was invented, and two types of flow synthesizers were connected in series according to the number of steps required according to the synthesis step of the compound to be synthesized. This problem was achieved by allowing the reaction substrate required for synthesis to pass through this continuous multi-stage synthesizer.

  With the above, the invention relating to the method for producing a pharmaceutical by the continuous flow multi-stage reaction which is the subject has been made. That is, the configuration of the flow synthesis system serving as a means for solving the above-described problems is composed of two types of flow synthesis systems shown in FIG.

  Although not limited in the above (0017), the column C supporting the solid acid catalyst or the solid base catalyst as shown in FIG. (2) is connected to the flow synthesizer shown in FIG. (1). It is also possible to introduce into the flow path. In addition, the introduction position of the column C is not limited to a specific position in the flow path, and can be connected at an arbitrary position according to a desired synthesis plan. If the reaction does not proceed sufficiently with one column, a plurality of columns may be connected in succession.

  In the flow synthesizer described in the above (0017) and (0018), when it is necessary to remove water contained in the solvent, it is possible to introduce a drying column as shown in FIG.

In the flow synthesizer described in the above (0017), (0018), and (0019), a chiral asymmetric ligand applicable to a solid phase carrier such as a PyBox ligand is used for column A. . The metal species to be combined with these catalysts may be selected from palladium, calcium, scandium, barium, and copper, and the corresponding hydrate may be used. Preferably well being selected PS-Pybox ligand, calcium salts to be _{combined, CaCl 2, CaF 2, CaBr} 2, CaI 2, Ca (OTf) 2, or calcium salt of CaCO ₃ or their, And preferably CaCl ₂ or its dihydrate.

In the flow synthesizer described in the above (0017) to (0019), the column B uses a solid phase catalyst applicable as a solid phase carrier necessary for functional group conversion. For example, a catalyst in which palladium, ruthenium, platinum, or rhodium is supported on a solid phase can be mentioned, and a palladium / alumina hybrid catalyst [= Pd / (PSi—Al ₂ O ₃ )] is preferable.

  In the flow synthesizer described in (0017) to (0019) above, a solid phase acid catalyst or a solid phase base catalyst is used for column C. For example, an ion resin such as amberlite can be selected, and examples thereof include silica gels such as silica gel and alumina gel, and inorganic salts such as calcium chloride and potassium carbonate.

  In the flow synthesizer described in the above (0017) to (0019), a compound having an action of removing moisture contained in the solvent is used as the filler of the drying column. Examples include calcium chloride, molecular sieves, silica gels such as silica gel and alumina gel.

  In the flow synthesis system described in the above (0017) to (0019), an organic solvent can be used. As an example, but not limited to toluene can be used. It is not necessary to be anhydrous, but it is desirable to use a drying column as described in (0019), (0023) if necessary.

  In the flow synthesis system described in the above (0017) to (0019), it is desirable to use a system in which the reaction is appropriately selected from −20 ° C. to 150 ° C. and the temperature can be adjusted in a thermostatic bath. Further, any temperature can be set according to the number of reaction columns to be used, and an appropriate temperature setting is appropriately selected according to each reaction column.

  In the flow synthesis system described in the above (0017) to (0019), the amount of liquid fed per hour is not limited as long as the reaction proceeds efficiently. It depends on the inner diameter of the column incorporated in the flow path, the amount of celite, etc., and the particle size, and is appropriately selected.

  In the flow synthesis system described in the above (0017) to (0026), in order to stabilize the system, until the solvent system described in (0024) is stabilized at the liquid feeding amount described in (0026). Do. There is no standard for judging stabilization, but one standard is that the pressure is constant.

  As a specific example, the multi-stage flow synthesis system shown in FIG. (4) was designed as a method for stereoselectively obtaining a γ-amino acid derivative often found as a pharmaceutical skeleton. As a result, it was confirmed that an optically active γ-amino acid derivative was obtained by a series of continuous reactions.

Continuous flow multi-stage synthesizer Column A is a column packed with a solid phase carrier necessary for the synthesis of chiral compounds, column B is a column packed with a solid phase carrier necessary for functional group conversion, and if necessary a gas solution It is also possible to pass while mixing. In addition, the coupling | bonding order of the column of an apparatus is not limited to FIG. 1, You may couple | bond in the reverse order. Further, when the reaction is insufficient with one column, a plurality of columns may be connected in series. Acid / base catalyst flow reactor Various solid phase carriers used in column C are used for condensation reactions, hydrolysis reactions, cyclization reactions, etc. catalyzed by acids or bases, but are not limited to these reaction examples. And can be used for organic synthesis reactions that proceed with acids or bases. Flow synthesis drying column apparatus The position of introduction of the drying column is not limited to a specific position in the flow path, and can be connected to an arbitrary position according to a desired reaction plan. In addition, when drying with one column is not sufficient, a plurality of drying columns may be connected in succession. Schematic diagram of optically active γ-amino acid derivative synthesis by flow multi-step reaction. Flow1 is a nitroaldol reaction using a column packed with amino group-supported silica gel and calcium chloride. In the case of simultaneous Michael reaction and Flow3, a palladium / alumina hybrid catalyst [= Pd / (PSi-Al ₂ O ₃ )] is packed in a column, and a γ-amino acid derivative is synthesized through a cyclization reaction. Nitroalkane Synthesis Flow Reactor A glass column (φ1.0 cm × 30 cm) with a glass filter at both ends, (450 mg, 0.7 mmol / g) silica-amine catalyst (Fuji Silysia Chromatorex DM1020), and powder form 1.35 g of crushed anhydrous calcium chloride (> 95% made by Wako Pure Chemical Industries, Ltd.) is thoroughly mixed and filled (referred to as Column 1). Toluene is sent to this at a flow rate of 1.0 mL / min to prepare a catalyst in a slurry state. Asymmetric 1,4-addition reaction flow reactor Two glass columns (φ1.0 cm x 10 cm) were prepared. Celite (1.4 g), anhydrous calcium chloride (375 mg) and polymer-supported Pybox (0.85 mmol / g, 750 mg) is filled in two column tubes (referred to as Column 3 and Column 4 respectively). A column for drying (φ0.5 cm × 5 cm) is packed with activated molecular sieves 4A (500 mg) (referred to as Column 2). This is connected between Valve1 and Column3. Column 4 is connected in series with Column 3 and connected to Valve 2. A catalytic reduction flow reactor SUS column (φ1.0 cm × 10 cm) is used, and Celite (1.2 g) and Pd / (PMPSi-C) (4.8 g) are packed (referred to as Column 6). In addition, a column in which Celite (423 mg) is packed in a (φ1.0 cm × 10 cm) column tube is prepared (referred to as Column 5). Column5 is connected between Valve2 and Column6. Optically active γ-amino acid derivative synthesis flow multi-stage reaction apparatus The apparatuses shown in FIG. 8 are assembled by connecting the apparatuses shown in FIGS. A solution in which benzaldehyde (60 mmol), nitromethane (50 mmol), and toluene (<200 mL) are mixed is prepared in a receiver 1 (Reserver 1). A receiver 2 (Reserver 2) is prepared with a toluene solution of ethyl malonate (0.22M) and triethylamine (0.016M). Ethanol is prepared in the receiver 3 (Reserver 3). Flow synthetic decarboxylation device 9 g of Chromatorex ACD (COOH) is packed into a SUS column (φ10 mm × 200 mm) (referred to as Column 8). As a mixer for mixing the two liquids, a glass column (φ5 mm × 50 mm) packed with Celite (ca. 350 mg) is connected (referred to as Column 7). (S) -Rolipram synthesis continuous flow multi-stage reaction apparatus The apparatus from Flow 1 to Flow 3 is assembled with reference to FIG. (8), and Valve 3 is connected to the end of the Flow 3 flow path, and further shown in FIG. (9). Connect the Flow4 device to Valve3.

  Hereinafter, the present invention will be clarified using examples, but the present invention is not limited to these examples.

式（１）に示した反応（Ａｒ＝Ｐｈ）について、連続的フロー多段階反応を行うため、図（８）で説明される連続的フロー多段階反応装置の組み以下の操作により反応を行う。５０℃に加温したＣｏｌｕｍｎ１に受け器１（Ｒｅｓｅｒｖｅｒ１）より０．０５ｍＬ／ｍｉｎの流速で送液を開始する。はじめの１２時間は流路Ａで送液を行い、その後、Ｖａｌｖｅ１を流路Ｂに切り替え、Ｃｏｌｕｍｎ２への送液を開始する。同時に受け器２（Ｒｅｓｅｒｖｅｒ２）からもＣｏｌｕｍｎ２に０．０５ｍＬ／ｍｉｎの流速で送液を開始する。Ｃｏｌｕｍｎ３と４は０〜１０℃の温度範囲になるよう調整しておいた状態で送液する。この時、Ｃｏｌｕｍｎ２〜４の間の流速は０．１ｍＬ／ｍｉｎにする。Ｖａｌｖｅ２を流路Ｃにした状態で１時間送液を行った後、Ｖａｌｖｅ２を流路Ｄに切り替えて、Ｃｏｌｕｍｎ５への送液を開始する。同時に受け器３（Ｒｅｓｅｒｖｅｒ３）から流速０．１０ｍＬ／ｍｉｎでエタノールをＣｏｌｕｍｎ５へ送液して混合させ、流速０．２ｍＬ／ｍｉｎとする。８０℃に加熱させたＣｏｌｕｍｎ６に、水素ガスと共に導入して反応させる。送液開始から１８時間後、表（１）に示すように、いくつかのフラクションに分けながら回収を行い、溶媒を除去した後、ＮＭＲ分析とｐＴＬＣによる精製を行うことで、（３Ｒ，４Ｓ）−ｅｔｈｙｌ ４−（ｐｈｅｎｙｌ）−２−ｏｘｏｐｙｒｒｏｌｉｄｉｎｅ−３−ｃａｒｂｏｘｙｌａｔｅが光学純度９４％ｅｅで得られる^１Ｈ ＮＭＲ（ＣＤＣｌ_３，６００ＭＨｚ）δ：７．３２−７．１８（ｍ，５Ｈ），４．１９（ｑ，２Ｈ，Ｊ＝７．１Ｈｚ），４．０５（ｑ，１Ｈ，Ｊ＝８．７Ｈｚ），３．７７（ｔ，１Ｈ，Ｊ＝８．９），３．５１（ｄ，１Ｈ，Ｊ＝９．６Ｈｚ），３．３８（ｄｄ，１Ｈ，Ｊ＝９．６，８．３Ｈｚ），１．２３（ｔ，３Ｈ，Ｊ＝６，９Ｈｚ）．^１３Ｃ ＮＭＲ（ＣＤＣｌ_３，１２４．５１ＭＨｚ）δ：１７２．９，１６９．２，１３９．９，１２８．９，１２７．５，１２６．９，６１．７，５５．３，４７．７，４４．３，１４．１．ＨＰＬＣ Ｄａｉｃｅｌ Ｃｈｉｒａｌｃｅｌ ＡＤ３ ｘ ２，ｈｅｘａｎｅ／^ｉＰｒＯＨ＝９／１，ｆｌｏｗ ｒａｔｅ＝０．３５ｍＬ／ｍｉｎ，Ｄｅｔｅｃｔｉｏｎ ｗａｖｅｌｅｎｇｔｈ＝２２０ｎｍ：ｔ_Ｒ＝８３．９ｍｉｎ（ｍｉｎｏｒ），ｔ_Ｒ＝９４．１ｍｉｎ（ｍａｊｏｒ）．

Synthesis of optically active γ-amino acid derivatives using a continuous flow multistage reactor starting from aromatic aldehydes and nitromethane

For the reaction (Ar = Ph) represented by the formula (1), in order to perform a continuous flow multistage reaction, the reaction is performed by the following operations of the continuous flow multistage reaction apparatus illustrated in FIG. Liquid supply is started at a flow rate of 0.05 mL / min from the receiver 1 (Reserver 1) to Column 1 heated to 50 ° C. For the first 12 hours, liquid feeding is performed in the flow path A, and then Valve 1 is switched to the flow path B, and liquid feeding to Column 2 is started. At the same time, liquid feeding from the receiver 2 (Reserver 2) to the Column 2 is started at a flow rate of 0.05 mL / min. Columns 3 and 4 are fed in a state adjusted to be in the temperature range of 0 to 10 ° C. At this time, the flow rate between Columns 2 to 4 is 0.1 mL / min. After performing the liquid feeding for 1 hour in a state where the Valve 2 is set to the flow path C, the Valve 2 is switched to the flow path D, and the liquid feeding to the Column 5 is started. At the same time, ethanol is fed from the receiver 3 (Reserver 3) to the Column 5 at a flow rate of 0.10 mL / min and mixed to obtain a flow rate of 0.2 mL / min. It introduce | transduces and reacts with Column 6 heated to 80 degreeC with hydrogen gas. 18 hours after the start of liquid feeding, as shown in Table (1), recovery was performed while dividing into several fractions, and after removing the solvent, purification by NMR analysis and pTLC was performed (3R, 4S). ^1- H NMR (CDCl ₃ , 600 MHz) δ: 7.32-7.18 (m, 5H), wherein 4-ethyl-4-oxypyrrolidin-3-carboxylate is obtained with an optical purity of 94% ee. 19 (q, 2H, J = 7.1 Hz), 4.05 (q, 1H, J = 8.7 Hz), 3.77 (t, 1H, J = 8.9), 3.51 (d, 1H) , J = 9.6 Hz), 3.38 (dd, 1H, J = 9.6, 8.3 Hz), 1.23 (t, 3H, J = 6, 9 Hz). ¹³ C NMR (CDCl ₃ , 124.51 MHz) δ: 172.9, 169.2, 139.9, 128.9, 127.5, 126.9, 61.7, 55.3, 47.7, 44 .3, 14.1. HPLC Daicel Chiralcel AD3 x 2, hexane / ⁱ PrOH = 9/1, flow rate = 0.35 mL / min, Detection wavelength = 220 nm: t _R = 83.9 min (minor), t _R = 94.1 min (major).

上記（実施例１）の方法に従い、３−（ｃｙｃｌｏｐｅｎｔｙｌｏｘｙ）−４−ｍｅｔｈｏｘｙｂｅｎｚａｌｄｅｈｙｄｅとｍｅｔｈｙｌ ｍａｌｏｎａｔｅを用いて、図（８）に示すＦｌｏｗ１〜Ｆｌｏｗ３まで計１８時間、連続的にフロー多段階反応を行った後、送液を回収すると（３Ｒ，４Ｓ）−ｍｅｔｈｙｌ４−［３−（ｃｙｃｌｏｐｅｎｔｙｌｏｘｙ）−４−ｍｅｔｈｏｘｙｐｈｅｎｙｌ］−２−ｏｘｏｐｙｒｒｏｌｉｄｉｎｅ−３−ｃａｒｂｏｘｙｌａｔｅが得られる。ＨＰＬＣ Ｄａｉｃｅｌ Ｃｈｉｒａｌｃｅｌ ＯＪ３ ＋ Ｃｈｉｒａｌｐａｃ ＡＤ３，ｈｅｘａｎｅ／ＥｔＯＨ＝９／１，ｆｌｏｗ ｒａｔｅ＝０．５ｍＬ／ｍｉｎ，２５℃，Ｄｅｔｅｃｔｉｏｎ ｗａｖｅｌｅｎｇｔｈ＝２１０ｎｍ：ｔ_Ｒ＝８２．７ｍｉｎ（Ｒ），ｔ_Ｒ＝９３．９ｍｉｎ（Ｓ）．^１Ｈ ＮＭＲ（ＣＤＣｌ_３，５００ＭＨｚ）δ：６．８０（ｄ，１Ｈ，Ｊ＝８．５Ｈｚ），６．７５−６．７４（ｍ，２Ｈ），６．５８（ｂｓ，１Ｈ），４．７５−４．１（ｍ，１Ｈ），４．０３（ｑ，１Ｈ，Ｊ＝８．７Ｈｚ），３．８１（ｓ，３Ｈ），３．７８−３．７５（ｍ，４Ｈ），３．５２（ｄ，１Ｈ，Ｊ＝９．６Ｈｚ），３．３８（ｔ，１Ｈ，Ｊ＝９．１Ｈｚ），１．９４−１．７７（ｍ，６Ｈ），１．６３−１．５５（ｍ，２Ｈ）．^１３Ｃ ＮＭＲ（ＣＤＣｌ_３，１２５ＭＨｚ）δ：１７２．３，１６９．７，１４９．５，１４７．９，１３２．０，１１８．９，１１３．９，１１２．２，８０．５，５６．１，５５．３，５２．９，４７．７，４４．０，３２．８，２４．０．Synthesis of (S) -Rolipram precursor using a continuous flow multi-stage reactor

According to the method of the above (Example 1), the flow multistage reaction was continuously performed for 18 hours from Flow 1 to Flow 3 shown in FIG. 8 using 3- (cyclopropylene) -4-methylbenzaldehyde and methyl malonate. Thereafter, when the liquid feeding is recovered, (3R, 4S) -methyl4- [3- (cyclopropylene) -4-methylphenyl] -2-oxopyrrolidin-3-carboxylate is obtained. HPLC Daicel Chiralcel OJ3 + Chiralpac AD3, hexane / EtOH = 9/1, flow rate = 0.5 mL / min, 25 ° C., detection wavelength = 210 nm: t _R = 82.7 min (R), t _R = 93.9 min ( S). ¹ H NMR (CDCl ₃ , 500 MHz) δ: 6.80 (d, 1H, J = 8.5 Hz), 6.75-6.74 (m, 2H), 6.58 (bs, 1H), 4. 75-4.1 (m, 1H), 4.03 (q, 1H, J = 8.7 Hz), 3.81 (s, 3H), 3.78-3.75 (m, 4H), 3. 52 (d, 1H, J = 9.6 Hz), 3.38 (t, 1H, J = 9.1 Hz), 1.94-1.77 (m, 6H), 1.63-1.55 (m , 2H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ: 172.3, 169.7, 149.5, 147.9, 132.0, 118.9, 113.9, 112.2, 80.5, 56.1 , 55.3, 52.9, 47.7, 44.0, 32.8, 24.0.

２０ｍＬフラスコに（３Ｒ，４Ｓ）−ｍｅｔｈｙｌ４−［３−（ｃｙｃｌｏｐｅｎｔｙｌｏｘｙ）−４−ｍｅｔｈｏｘｙｐｈｅｎｙｌ］−２−ｏｘｏｐｙｒｒｏｌｉｄｉｎｅ−３−ｃａｒｂｏｘｙｌａｔｅ（６６．７ｍｇ、０．２ｍｍｏｌ）とＣｒｏｍａｔｏｒｅｘ ＡＣＤ（ＳＯ_３Ｈ、ｌｏａｄｉｎｇ ０．４ｍｍｏｌ／ｇ、５０ｍｇ、フジシリシア製）を入れる。その後、ｏ−キシレン（２ｍＬ）と水（０．２ｍＬ）を入れ１２０℃にて２４時間撹拌する。反応溶液を室温に戻した後、エタノールにて希釈し、Ｃｅｌｉｔｅと無水硫酸ナトリウムのパットにてろ過後、減圧下溶媒を留去する。ｐＴＬＣ（展開溶媒：酢酸エチル）にて単離精製を行うことで（Ｓ）−Ｒｏｌｉｐｒａｍが７７％で得られる。エナンチオ選択性は、ＨＰＬＣにて決定する。ＨＰＬＣ Ｄａｉｃｅｌ Ｃｈｉｒａｌｐａｃ ＡＤ３，ｈｅｘａｎｅ／ＥｔＯＨ＝９／１，ｆｌｏｗ ｒａｔｅ＝１．０ｍＬ／ｍｉｎ，２５℃，Ｄｅｔｅｃｔｉｏｎ ｗａｖｅｌｅｎｇｔｈ＝２２０ｎｍ：ｔ_Ｒ＝１５．２ｍｉｎ（Ｒ），ｔ_Ｒ＝２１．２ｍｉｎ（Ｓ）．^１Ｈ ＮＭＲ（ＣＤＣｌ_３，５００ＭＨｚ）δ：６．８０（ｄ，１Ｈ，Ｊ＝７．９Ｈｚ），６．７６−６．７３（ｍ，２Ｈ），６．４６（ｂｓ，１Ｈ），４．７６−４．７２（ｍ，１Ｈ），３．８０（ｓ，３Ｈ），３．７３（ｔ，１Ｈ，Ｊ＝８．８Ｈｚ），３．６３−３．５６（ｍ，１Ｈ），３．３６（ｄｄ，１Ｈ，Ｊ＝９．４，７．７Ｈｚ），２．６８（ｑ，１Ｈ，Ｊ＝８．５Ｈｚ），２．４５（ｑ，１Ｈ，Ｊ＝８．５Ｈｚ），１．９２−１．７７（ｍ，６Ｈ），１．６１−１．５６（ｍ，２Ｈ）．^１３Ｃ ＮＭＲ（ＣＤＣｌ_３，１２５ＭＨｚ）δ：１７７．７，１４９．１，１４７．９，１３４．５，１１８．８，１１３．８，１１２．１，８０．６，５６．１，４９．７，４０．０，３８．０，３２．８，２４．０．Synthesis of (S) -Rolipram by batch processing

In a 20 mL flask, (3R, 4S) -methyl4- [3- (cyclopropylene) -4-methylphenyl] -2-oxopyrrolidin-3-carboxylate (66.7 mg, 0.2 mmol) and Cromatorex ACD (SO ₃ H, loading 0. 0). 4 mmol / g, 50 mg, manufactured by Fuji Silysia). Thereafter, o-xylene (2 mL) and water (0.2 mL) are added and stirred at 120 ° C. for 24 hours. The reaction solution is returned to room temperature, diluted with ethanol, filtered through a pad of Celite and anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. By performing isolation and purification with pTLC (developing solvent: ethyl acetate), (S) -Rolipram is obtained at 77%. Enantioselectivity is determined by HPLC. HPLC Daicel Chiralpac AD3, hexane / EtOH = 9/1, flow rate = 1.0 mL / min, 25 ° C., detection wavelength = 220 nm: t _R = 15.2 min (R), t _R = 21.2 min (S). ¹ H NMR (CDCl ₃ , 500 MHz) δ: 6.80 (d, 1H, J = 7.9 Hz), 6.76-6.73 (m, 2H), 6.46 (bs, 1H), 4. 76-4.72 (m, 1H), 3.80 (s, 3H), 3.73 (t, 1H, J = 8.8 Hz), 3.63-3.56 (m, 1H), 3. 36 (dd, 1H, J = 9.4, 7.7 Hz), 2.68 (q, 1H, J = 8.5 Hz), 2.45 (q, 1H, J = 8.5 Hz), 1.92 -1.77 (m, 6H), 1.61-1.56 (m, 2H). ¹³ C NMR (CDCl ₃ , 125 MHz) δ: 177.7, 149.1, 147.9, 134.5, 118.8, 113.8, 112.1, 80.6, 56.1, 49.7 , 40.0, 38.0, 32.8, 24.0.

Synthesis of (S) -Rolipram Using Flow Synthesis System According to FIG. 9, the o-xylene solution containing the substrate is sent at 200 μL / min and water is sent at 15 μL / min using an HPLC pump. In order to mix the two liquids, the two liquids are introduced from the bottom of Column 7 and eluted from the top. Thereafter, the solution is introduced from the top of Column 8 and the reaction solution is collected from the bottom. Substrate (0.05 M, 8 mL) is introduced over 40 minutes, and then the reaction column is washed with o-xylene and water for 24 hours. The reaction column is kept at 132.5 ° C. Thereafter, water is removed by liquid separation, the solvent is distilled off, and isolation and purification is performed with pTLC (developing solvent: ethyl acetate), whereby (S) -Rolipram is obtained at 62%.

Synthesis of (S) -Rolipram Using Continuous Flow Multistage Reactor Referring to the above (Example 2), the reaction is performed using the continuous flow multistage reaction illustrated in FIG. According to the method of (Example 2), 3- (cyclopentyloxy) -4-methoxybenzaldehyde is subjected to flow multi-stage reaction continuously from Flow 1 to Flow 3 for a total of 18 hours, and then the solution is recovered (3R, 4S)- methyl 4- [3- (cyclopropylene) -4-methylphenyl] -2-oxopyrrolidin-3-Carboxylate is obtained (recovered at Receiver 4). According to the method of (Example 4), this is sent to a Flow 4 apparatus, reacted with Column 8 heated to 132.5 ° C., and then recovered and purified to obtain (S) -Rolipram.

  As described above, the present invention relates to a method for obtaining an optically active compound as a pharmaceutical or a synthetic intermediate thereof using a continuous flow multi-step synthesis system, and provides an efficient synthesis system required in pharmaceutical synthesis. It is something to offer. It is expected to be used for the manufacture of pharmaceuticals with complex solids.

Claims (4)

A plurality of columns used for asymmetric synthesis or functional group conversion are provided in series in the flow path shown in Fig. (1), and this is used for flow synthesis in which a substrate of two or more components is allowed to pass through. A method of obtaining a pharmaceutical product or an optically active compound as an intermediate thereof by continuously performing a plurality of reactions such as a functional group conversion reaction in multiple stages.
[Figure 1]
(However, column A is a column packed with a solid phase carrier necessary for the synthesis of a chiral compound, and column B is a column packed with a solid phase carrier necessary for functional group conversion, and is passed while mixing a gas solution if necessary. The binding order of each column is not limited to that shown in FIG. (1), and the columns may be combined in the reverse order. May be connected in series.)   In the flow synthesis including a plurality of steps, a multistage flow synthesizer in which a necessary number of asymmetric synthesis columns and a plurality of necessary number of functional group conversion columns are connected at appropriate positions are used. Method. In the flow synthesis including a plurality of processes, the acid catalyst or the base catalyst column shown in the following figure (2), or both columns are connected at appropriate positions according to the required reaction process. The method according to claim 1 or 2, wherein a flow synthesizer is used.
[Figure 2]
(However, various solid phase carriers used in column C are used in condensation reactions, hydrolysis reactions, cyclization reactions and the like catalyzed by acids or bases, but are not limited to these reaction examples. It can be used for organic synthesis reactions that proceed with a base, and if the reaction is insufficient with one column, a plurality of columns may be connected in series.) In the flow synthesis including a plurality of steps, a multi-stage in which the drying column shown in the following figure (3) is connected to an appropriate position according to a reaction step that is necessary according to a step that requires dehydration conditions. The method of Claims 1-3 using a flow synthesizer.
[Fig. 3]
(However, when water removal from the solvent is insufficient with one drying column, a plurality of dehydration columns may be connected in series.)

Images