JP4617457B2 - Method for producing racemic octahydrobisisoquinoline, method for producing optically active octahydrobisisoquinoline and optically active octahydrobisisoquinoline - Google Patents

Description

  The present invention relates to a method for producing racemic octahydrobisisoquinoline, a method for producing optically active octahydrobisisoquinoline, and an optically active octahydrobisisoquinoline.

  Conventionally, it is known that dihydroisoquinoline is dimerized using zinc, chlorotrimethylsilane (TMSCl) and 1,2-dibromoethane as catalysts to obtain octahydrobisisoquinoline (see Non-Patent Document 1).

  In the conventional reaction, a racemic form and a meso form of octahydrobisisoquinoline are produced in a ratio of about 1: 1, but a method for selectively synthesizing the racemic form is not known.

Mark C. Elliott, Eve Williams and Sian T. Howard: The Royal Society of Chemistry Journal of Chemical Society, Perkin Trans 2 2002, P.201-203

  In view of the above-described circumstances, the present invention provides a method for preferentially synthesizing a racemate of octahydrobisisoquinoline, a method for optically resolving it to obtain (+)-or (-)-octahydrobisisoquinoline, and a method obtained thereby It is an object of the present invention to provide (+)-or (-)-octahydrobisisoquinoline obtained.

  The first aspect of the present invention for solving the above-mentioned problems is characterized in that when dihydroisoquinoline is dimerized to obtain octahydrobisisoquinoline, a racemic octahydrobisisoquinoline is obtained by using a niobium salt as a reaction accelerator. In the production method of racemic octahydrobisisoquinoline.

  According to a second aspect of the present invention, there is provided a method for producing racemic octahydrobisisoquinoline according to the first aspect, wherein a reducing agent for reducing the niobium is used together with the niobium salt.

  According to a third aspect of the present invention, in the second aspect, the reducing agent is at least one selected from the group consisting of zinc, magnesium, iron, lithium aluminum hydride, and sodium borohydride. A method for producing racemic octahydrobisisoquinoline.

  According to a fourth aspect of the present invention, (+)-and (-)-octahydrobisisoquinoline is obtained by optical resolution of racemic octahydrobisisoquinoline obtained by the method of any one of the first to third aspects. It is in a method for producing optically active octahydrobisisoquinoline characterized in that at least one is obtained.

  According to a fifth aspect of the present invention, in the fourth aspect, the optical resolution is performed by (d)-and (l) -camphorsulfonic acid, (d)-and (l) -mandelic acid, optically active carboxylic acid and The present invention relates to a method for producing optically active octahydrobisisoquinoline, which is carried out using at least one selected from the group consisting of optically active phosphonic acids.

  A sixth aspect of the present invention is an optically active octahydrobisisoquinoline that functions as a catalyst for asymmetric coupling and is composed of (+)-octahydrobisisoquinoline.

  A seventh aspect of the present invention is an optically active octahydrobisisoquinoline that functions as a catalyst for asymmetric coupling and is composed of (−)-octahydrobisisoquinoline.

  According to the present invention, when dihydroisoquinoline is dimerized to obtain racemic octahydrobisisoquinoline, racemic octahydrobisisoquinoline can be preferentially synthesized by using niobium salt as a reaction accelerator, By optical resolution of the resulting racemic octahydrobisisoquinoline, at least one of (+)-and (-)-octahydrobisisoquinoline can be obtained, and the obtained (+)-or (-) -Octahydrobisisoquinoline can be used as a promoter for asymmetric coupling, for example, by forming a complex with a metal.

  Racemic octahydrobisisoquinoline of the present invention (official name: rac-1,1'2,2'3,3'4,4'-octahydro-1,1'-bisisoquinoline, hereinafter also abbreviated as "rac-OHBI") In the production method of dihydroisoquinoline (official name: 3,4-dihydroisoquinoline) to obtain octahydrobisisoquinoline (OHBI), a niobium salt is used as a reaction accelerator. By using a niobium salt as a reaction accelerator, a racemic octahydrobisisoquinoline can be selectively produced. For example, a high proportion of racemic: meso = 6.4: 1 to 14: 1 The body can be produced (the following reaction formula (1)). In addition, the overall yield of octahydrobisisoquinoline in which the racemic body and the meso body are mixed is also improved as compared with the conventional method such as Non-Patent Document 1.

  Examples of niobium salts include niobium chloride, niobium bromide, niobium iodide, and niobium chloride is particularly preferable. Further, any compound having an oxidation number of niobium of −1 to +5 may be used, but the compound having +5 is particularly preferable. The amount of niobium salt added is not particularly limited, but is preferably 0.5 mol or more, more preferably 1.0 to 2.0 mol, per 1 mol of dihydroisoquinoline.

  You may use the reducing agent which reduces the said niobium with a niobium salt. Examples of the reducing agent include at least one selected from the group consisting of zinc, magnesium, iron, lithium aluminum hydride, and sodium borohydride. In particular, zinc is preferable because it is inexpensive. The addition amount of the reducing agent is not particularly limited, but is preferably 1.0 mol or more, more preferably 1.2 to 2.0 mol, with respect to 1 mol of dihydroisoquinoline.

  Examples of the reaction solvent include methanol, ethanol, ethylene glycol, isopropanol, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and mixed solvents thereof. Particularly, THF-DME (10: 1) A mixed solvent is preferable.

  The reaction time and temperature are not particularly limited, but the reaction time is preferably 3 to 5 hours, and the reaction temperature is preferably 20 to 30 ° C.

  Examples of the reaction terminator include sodium hydroxide and potassium hydroxide.

  Only the racemic octahydrobisisoquinoline can be isolated from the octahydrobisisoquinoline thus obtained by a known method.

  The raw material dihydroisoquinoline can be obtained by a known method. For example, it is produced from 1,2,3,4-tetrahydroisoquinoline by the following reaction.

  In the method for producing (+)-and (−)-octahydrobisisoquinoline of the present invention, the racemic octahydrobisisoquinoline obtained by the above production method is further optically resolved (the following reaction formula (2)).

  The optical resolution can be performed using, for example, an optical rotatory acid. Examples of the optical rotatory acid include (d)-and (l) -camphorsulfonic acid ((d)-and-(l) -CSA), (d)-and (l) -mandelic acid, optically active carboxylic acid, And at least one selected from the group consisting of optically active phosphonic acids can be used, and camphorsulfonic acid is particularly preferable. When the d-form acid is used, (+)-octahydrobisisoquinoline can be produced, and when the d-form acid is used, (-)-octahydrobisisoquinoline can be produced. Conditions for this optical division may be performed by a conventionally known method and are not particularly limited. An example of the optical resolution will be specifically described. When (d) -CSA is added to racemic octahydrobisisoquinoline, (+)-octahydrobisisoquinoline is produced as crystals, and this precipitate was obtained by filtration. Treat the solid with alkali. Moreover, (-)-octahydrobisisoquinoline can be obtained by adding (l) -CSA to the solid obtained from the filtrate at the time of filtration. The d-form or l-form optical rotatory acid may be added in the reverse order.

  The optically active (+)-octahydrobisisoquinoline and optically active (−)-octahydrobisisoquinoline thus obtained function as, for example, a catalyst for asymmetric coupling.

  Moreover, (+)-octahydrobisisoquinoline or (-)-octahydrobisisoquinoline can form a metal compound and a metal-diamine complex, respectively.

  A metal compound is not specifically limited, A copper salt, vanadium salt, etc. can be mentioned, It is especially preferable that it is a copper salt. Examples of the copper salt include copper chloride, copper bromide, copper iodide, copper trifluoromethanesulfonate, and the like. These metal compounds may be used alone or in combination. The content ratio of (+)-or (-)-octahydrobisisoquinoline and the metal compound is not particularly limited, but the metal compound is preferably 1 with respect to 1 mole of (+)-or (-)-octahydrobisisoquinoline. ˜2 mol, more preferably 1 mol is used. A metal-diamine complex is synthesized by mixing such a metal compound with (+)-octahydrobisisoquinoline or (-)-octahydrobisisoquinoline in an appropriate solvent such as dichloromethane or acetonitrile. can do.

  This metal-diamine complex can be suitably used as a catalyst in an asymmetric coupling method of a naphthol derivative in which a naphthol derivative is oxidatively asymmetrically coupled. The amount of the metal-diamine complex used in the asymmetric coupling reaction of the naphthol derivative is not particularly limited. For example, the amount of metal in the metal-diamine complex is the same as the metal catalyst used in the normal coupling reaction. The amount may be used. Specifically, it is preferable to use 0.01 mol or more of metal-diamine complex with respect to 1 mol of naphthol derivative.

  As shown in the following reaction formula (3), when (R) -OHBI and a metal compound are used as a catalyst, a 2-naphthol derivative can be asymmetrically coupled to obtain (R) -isomer. On the other hand, when (S) -OHBI and a metal compound are used as a catalyst, (S) -isomer can be obtained by asymmetric coupling of 2-naphthol derivatives as shown in the following reaction formula (4). .

(In the formula, A represents -COOR, -COR, -CONR ₂ and R represents an alkyl group. Preferably, R is an alkyl group having 1 to 5 carbon atoms.)

(In the formula, A represents -COOR, -COR, -CONR ₂ and R represents an alkyl group. Preferably, R is an alkyl group having 1 to 5 carbon atoms.)

  Examples of the reaction solvent for the asymmetric coupling reaction include acetonitrile, dichloromethane, methanol, ether, benzene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), tetrahydrofuran and the like.

  The reaction time and temperature are not particularly limited, but the reaction time is preferably 24 hours or more, and the reaction temperature is preferably 0 to 25 ° C.

  Example 1 Synthesis of racemic 1,1′2,2′3,3′4,4′-octahydro-1,1′-bisisoquinoline (rac-OHBI)

  1,2-Dimethoxyethane (15 ml) was added to niobium pentachloride (6.2 g, 15.2 mmol) in a 500 ml eggplant flask, and then zinc (1.5 g, 22.8 mmol) was added at 0 ° C. for 30 minutes. Stir. Thereafter, tetrahydrofuran (115 ml) was added, and a solution of 3,4-dihydroisoquinoline (2.0 g, 15.2 mmol) in tetrahydrofuran (20 ml) was added, followed by stirring at room temperature for 3 hours. The reaction was stopped by adding 10% aqueous sodium hydroxide at 0 ° C. and stirring at room temperature. After filtration through celite, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and a solid was precipitated using a mixed solvent of hexane / ethyl acetate (1/8) and collected by filtration to obtain a yellow solid (1.0 g, yield 50%, rac-OHBI).

  Example 2 (+)-(1S, 1'S) -1,1'2,2'3,3'4,4'-octahydro-1,1'-bisisoquinoline ((+)-(1S , 1'S) -OHBI) and (-)-(1R, 1'R) -1,1'2,2'3,3'4,4'-octahydro-1,1'-bisisoquinoline ((- )-(1R, 1'R) -OHBI)

  After adding rac-OHBI (2.65 g, 10.0 mmol) obtained in Example 1 and dichloromethane (20 ml) to a 100 ml eggplant flask, (d) -camphorsulfonic acid (4.66 g, 20.0 mmol) was added. In addition, the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent, white crystals were obtained by recrystallization from a mixed solvent of diisopropyl ether and ethanol and filtration. The obtained crystal was recrystallized twice under the above conditions. The obtained crystals are dissolved in a mixed solvent of water, methanol and diethyl ether, 10% sodium hydroxide is added at 0 ° C., and the mixture is stirred and extracted with ethyl acetate. The organic layer is washed with saturated brine and sulfuric acid. Dried with magnesium. The solvent was distilled off to obtain a white solid (775 mg, yield 29%,> 99% ee, (1S, 1 ′S) -OHBI).

  Evaporate the solvent from the recrystallized mother liquor, dissolve in a mixed solvent of water, methanol, and diethyl ether. Add 10% sodium hydroxide at 0 ° C, stir, and extract with ethyl acetate to saturate the organic layer. Washed with brine and dried over magnesium sulfate. The solvent was distilled off to obtain a yellow solid (1.83 g, yield 69%, 40% ee, (1R, 1′R) -OHBI). The obtained solid was put into a 50 ml eggplant flask, dichloromethane (14 ml) was added, (l) -camphorsulfonic acid (3.22 g, 13.8 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent, the crystals were recrystallized with a mixed solvent of diisopropyl ether and ethanol and collected by filtration to obtain white crystals. The obtained crystal was recrystallized twice under the above conditions. The obtained crystals are dissolved in a mixed solvent of water, methanol and diethyl ether, 10% sodium hydroxide is added at 0 ° C., and the mixture is stirred and extracted with ethyl acetate. The organic layer is washed with saturated brine and sulfuric acid. Dried with magnesium. The solvent was distilled off to obtain a white solid (810 mg, yield 31%,> 99% ee, (1R, 1′R) -OHBI).

HPLC measurement conditions for measuring ¹ H-NMR, ¹³ C-NMR, melting point, specific optical rotation, and optical purity of the obtained (1S, 1 ′S) -OHBI and (1R, 1′R) -OHBI Is shown below.

Spectral Data
¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.60 (2H, d, J = 15.2 Hz), 2.80 (2H, dt, J = 3.2,11.5 Hz), 2.88-2.96 (2H, m), 3.18 (2H , ddd, J = 2.4,5.2,11.5Hz), 4.68 (2H, s), 7.10 (2H, d, J = 7.2Hz,), 7.15 (2H, t, J = 7.2Hz), 7.21 (2H, t , J = 7.6Hz), 7.36 (2H, d, J = 7.6Hz)
¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 30.4, 42.8, 60.1, 125.1, 126.0, 126.2, 129.3, 136.6, 137.3
mp113-114 ℃
(1S, 1'S) [α] _D ²² , + 254.8 (c1.07, CHCl ₃ )> 99% ee
(1R, 1'R) [α] _D ²² , -251.0 (c1.02, CHCl ₃ )> 99% ee
* HPCL condition; Column: DAICEL CHIRALCEL OD (manufactured by Daicel Chemical Industries), mobile phase: Hexane / iPrOH = 9/1, flow rate: 0.5mL / min, Rt: 17.7min (1S, 1'S), 27.5min (1R, 1 'R)

  (Application Example 1) Synthesis of metal-diamine complex

  (1R, 1′R) -OHBI (50 mg, 0.19 mmol) obtained in Example 2 was weighed into a 25 ml eggplant flask, dichloromethane (2 ml) was added, and then copper (I) chloride (18.7 mg, 0.19 mmol) was added and stirred at room temperature for 30 minutes. This solution was blue to green. Hexane (10 ml) was added to this solution to precipitate a solid, which was collected by filtration to obtain a blue solid (53 mg, yield 77%, copper-((1R, 1′R) -OHBI) complex).

  When the melting point of the obtained blue solid was measured, it changed from blue to yellow at around 90 ° C. and melted at 101 to 102 ° C.

  (Application Example 2) Asymmetric coupling reaction of 2-naphthols

  The copper-((1R, 1′R) -OHBI) complex (9.0 mg, 10 mol% as a 1: 1 complex) obtained in Application Example 1 was weighed into a reaction test tube, and acetonitrile (2.5 ml) was measured. ) And methyl 3-hydroxy-2-naphthoate (50 mg, 0.25 mmol) was added at 0 ° C. After stirring at 0 ° C. for 48 hours in an oxygen atmosphere, the reaction was stopped with 1N hydrochloric acid. Extraction with ethyl acetate was performed, and the resulting organic layer was washed with saturated brine and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (silica gel, hexane-ethyl acetate) to obtain a yellow solid (31.9 mg, yield 63%, 47% ee, (R) -isomer).

The ¹ H-NMR and HPLC measurement conditions of the product are shown below.

Spectral Data
¹ H-NMR (CDCl ₃ , 400 MHz) d: 4.05 (6H, s), 7.14-7.16 (2H, m) 7.32-7.35 (4H, m) 7.90-7.93 (2H, m) 8.68 (2H, s) , 10.7 (2H, s)
* HPLC conditions; Column: DAICEL CHIRALPAC AD (manufactured by Daicel Chemical Industries), mobile phase: Hexane / iPrOH = 9/1, flow rate: 1.0 ml / min, Rt: 9.4 min (S), 15.5 min (R)

  This will lead to the development of functional compounds in the chemical industry and the creation of new seed molecules for medical and agrochemicals in the medical and agrochemical industry.

Claims (5)

Racemic octahydro-1,1 characterized by obtaining racemic octahydro-1,1′-bisisoquinoline by using niobium salt as a reaction accelerator when dihydroisoquinoline is dimerized to obtain octahydrobisisoquinoline. Method for producing '-bisisoquinoline . The method for producing racemic octahydro-1,1'-bisisoquinoline according to claim 1, wherein a reducing agent that reduces the niobium is used together with the niobium salt. The racemic octahydro-1,1'- according to claim 2, wherein the reducing agent is at least one selected from the group consisting of zinc, magnesium, iron, lithium aluminum hydride, and sodium borohydride. A method for producing bisisoquinoline . When dihydroisoquinoline is dimerized to obtain octahydrobisisoquinoline, racemic octahydro-1,1'-bisisoquinoline is obtained by using niobium salt as a reaction accelerator, and the racemic octahydro-1,1'- A method for producing optically active octahydro- 1,1'-bisisoquinoline , wherein at least one of (+)-and (-)- octahydro-1,1'-bisisoquinoline is obtained by optical resolution of bisisoquinoline . 5. The optical resolution according to claim 4, wherein the optical resolution is selected from the group consisting of (d)-and (l) -camphorsulfonic acid, (d)-and (l) -mandelic acid, optically active carboxylic acid and optically active phosphonic acid. A process for producing optically active octahydro-1,1′-bisisoquinoline , characterized in that it is carried out using at least one of the above.