JPH0655748B2 - Asymmetric bisphosphine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to (+) or (−)-trans-4,5-bis [bis (4-methoxy-3,5-dimethylphenyl) phosphinomethyl] -2. , 2-dimethyl-1,3 dioxolane.

This asymmetric bisphosphine is a catalyst for the asymmetric hydrogenation reaction in the production of optically active α-benzylsuccinic acid half ester derivatives and β-benzyl-γ-butyrolactone derivatives useful as intermediates for pharmaceuticals such as optically active lignans. There is a use as a rank.

[Prior Art] General Formula: (Wherein, A _r represents an aryl group, * represents an asymmetric carbon) formula obtained by selective reduction of optically active α- benzyl succinate half ester derivatives and ester moiety of this compound is shown in: (Wherein, A _r represents an aryl group, * represents an asymmetric carbon) important synthetic intermediate of an optically active lignans showing an optically active β- benzyl -γ- butyrolactone derivatives physiological activity such as anticancer action represented by However, asymmetric hydrogenation reaction catalyzed by a complex of an asymmetric bisphosphine ligand and a transition metal has been used to obtain this compound.

That is, a method of converting an α-benzylidene succinic acid half ester derivative obtained by the Stobbe reaction into an optically active α-benzyl succinic acid half ester derivative by an asymmetric hydrogenation reaction using a BPPM-rhodium complex catalyst.
(Heterocycles, Vol.12,515 (1979)).

The method using this asymmetric hydrogenation reaction is another method for obtaining the above-mentioned intermediate, for example, a multistep asymmetric synthesis using L-glutamic acid as a starting material (Tetrahedron Letters, 4687 (1978)), or α-benzylsuccinic acid. Method for optical resolution of acid half-festel ((Tetrahedron Letters, Vol.26, 3997 (1985)), etc., which has a shorter process, and can be mass-produced because the target intermediate can be obtained in high yield. Is expected.

As described above, the BPPM-rhodium complex described above is regarded as a promising catalyst for mass production of the intermediate.

[Problems to be Solved by the Invention] However, in the case of the conventional asymmetric hydrogenation reaction catalyzed by a rhodium complex having a BPPM as a ligand, an optical yield of 7
8% e. e. It is only about the level, and has not reached the level that is satisfactory in actual operation. In order to make this method practical, it is necessary to develop hydrogenation catalysts showing higher optical yields and activities, especially asymmetric catalytic ligands which are the main factors for them.

Therefore, the present inventor aims to develop a catalytic ligand for an asymmetric hydrogenation reaction when producing an optically active α-benzylsuccinic acid derivative, and relates to an asymmetric bisphosphine compound having a 1,3-dioxolane skeleton. As a result of various studies, when a novel asymmetric bisphosphine having a specific chemical formula is used as the catalyst ligand, D which has been well known as an asymmetric bisphosphine having a 1,3-dioxolane skeleton has been conventionally known.
Not only does it show a significantly higher optical yield than IOP, but it also
The present invention has been completed by discovering that the optical yield is higher than that of PPMs.

An object of the present invention is to provide the above novel asymmetric bisphosphine.

[Means for Solving the Problems] The present invention has the general formula; (In the formula, * represents an asymmetric carbon) or (+) or (-)-trans-4,5-bis [bis (4-methoxy-3,5-dimethylphenyl)]
Phosphinomethyl] -2,2-dimethyl-1,3-dioxolane is an asymmetric bisphosphine.

(+) Or (-)-trans-4,5-bis [bis (4
-Methoxy-3,5-dimethylphenyl) phosphinomethyl] -2,2-dimethyl-1,3-dioxolane (hereinafter referred to as (+) or (-)-asymmetric bisphosphine)
In the above formula, the skeletons other than the four phosphino groups are respectively represented by the following formula: It is a symmetric asymmetric molecule shown in.

The novel asymmetric bisphosphines of the present invention are obtained from L-(+)-and D-(-)-diethyl tartrate by known methods (-) and (+)-trans-4,5-bis (tosyloxy). Methyl) -2,2-dimethyl-1,3-dioxolane and bis (4-methoxy-3,5
-Dimethylphenyl) phosphine is obtained by treating lithium phosphide obtained by treating normal butyl lithium with it at a low temperature.

When the novel asymmetric bisphosphine of the present invention is used, for example, as a catalyst for hydrogenation reaction, it is used as a rhodium cation complex or a rhodium neutral complex using the asymmetric bisphosphine as a ligand.

Then, these rhodium complexes have the following characteristics in the asymmetric hydrogenation reaction when producing an optically active α-benzylsuccinic acid half ester derivative.

87% e. e. The above high optical yield is given.

The amount of catalyst used is 0.2 mol% with respect to the substrate, and room temperature,
The reduction proceeds almost completely under normal pressure.

Both the cation complex and the neutral complex show almost the same optical yield and activity.

[Effects of the Invention] The novel asymmetric bisphosphine of the present invention can be a useful catalyst ligand in industrially producing optically active α-benzylsuccinic acid hafester derivative and β-benzyl-γ-butyrolactone derivative. .

[Example] The novel asymmetric bisphosphine of the present invention is produced, for example, by the following production examples.

Production Example 1 Production of (+)-asymmetric bisphosphine 1- (1), Synthesis of 4-methoxy-3,5-dimethylbromobenzene 4-Bromo-2,6-dimethylphenol 20 g (9
25 g (198 mmol) of dimethylsulfate and 3.3 g of 50% tetrabutylammonium bromide aqueous solution were dissolved in 100 ml of benzene and stirred at room temperature for 4 hours.
21 g of 8% aqueous sodium hydroxide solution was added dropwise. After the dropwise addition, stirring was continued at room temperature for 1 hour, and then the mixture was heated under reflux for 1.5 hours to complete the reaction. After cooling to room temperature, 50 ml of water was added and the separated benzene layer was further added with 50 ml of water and saturated saline solution 1
Wash with 00 ml. After the benzene layer was dried over magnesium sulfate, benzene was distilled off under reduced pressure to give a yellow liquid 20.8.
5 g was obtained. This was confirmed to be 4-methoxy-3,5-dimethylbromobenzene (I) by NMR and the like. The yield of this compound (I) was 97%.

Synthesis of 1- (2) bis (4-methoxy-3,5-dimethylphenyl) phosphine oxide 9.67 g (45 mmol) of compound (I) obtained in the previous step
Was treated with 1.12 g (46 mmol) of magnesium powder in tetrahydrofuran (30 ml) to prepare the Grignard reagent, which was then dibutyl phosphite 2.9.
1 g (15 mmol) of tetrahydrofuran (25 ml)
The solution was added dropwise, stirred at room temperature for 1 hour, and then heated under reflux for 2 hours. After cooling to room temperature, the gray residue obtained by distilling off tetrahydrofuran under reduced pressure was dissolved in ether, and 50 ml of 10% hydrochloric acid was slowly added dropwise to this under hydrolysis with ice to hydrolyze. The ether layer was separated, and the aqueous layer was further extracted with ether (50 ml twice), combined with the above ether layer, washed with 50 ml of saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After the ether was distilled off under reduced pressure, the obtained yellow oily matter was purified by silica gel chromatography (developing solvent; ethyl acetate: ethanol = 10: 1) to obtain 2.96 g of a viscous colorless oily matter. This was confirmed to be bis (4-methoxy-3,5-dimethylphenyl) phosphine oxide (II) by NMR and the like. The yield of this compound (II) was 62%.

Synthesis of 1- (3) bis (4-methoxy-3,5-dimethylphenyl) phosphine Compound (III) 1. obtained in the previous step under an argon gas atmosphere.
3.39 g (25.0 mmol) of trichlorosilane was added to 60 g (5.0 mmol) of a toluene solution (18 ml), and the mixture was heated and stirred in an oil bath at 80 to 90 ° C for 12 hours. Then, 20 ml of degassed 25% aqueous sodium hydroxide solution was slowly added dropwise under ice cooling. After the dropping, stirring was continued at room temperature until the produced white solid was completely dissolved and the toluene layer became transparent. The toluene layer was separated, the aqueous layer was extracted with 50 ml of degassed benzene, and this was combined with the previous toluene layer and washed with 50 ml of degassed water, and then washed with degassed saturated saline solution, followed by argon. It was dried over anhydrous magnesium sulfate under a gas atmosphere. The solvent was distilled off under reduced pressure, and the resulting pale yellow oily substance was distilled under reduced pressure to give 901 mg of a colorless transparent oily substance.
Got This was confirmed to be bis (4-methoxy-3,5-dimethylphenyl) phosphine (III) by NMR and the like.

The boiling point was 210 to 215 ° C. (bath temperature) / 2 Torr, and the yield was 59%.

Synthesis of 1- (4) (+)-asymmetric bisphosphine Compound (III) 1. obtained in the previous step under an argon gas atmosphere.
50 g (4.96 mmol) of tetrahydrofuran (1
5 ml) solution was cooled to -30 to -35 ° C, and normal butyllithium (1.59M) hexane solution) 3.1 with stirring.
ml (4.96 mmol) was added dropwise. The obtained red solution was stirred at the same temperature for 10 minutes, and then (-)-trans-4.5-bis (tosyloxymethime) -2,2-
A solution of 701 mg (1.49 mmol) of dimethyl-1,3-dioxolane in tetrahydrofuran (10 ml) was added dropwise. After stirring overnight at the same temperature, the generated insoluble matter was suction-filtered with Celite, and the filtrate was concentrated under reduced pressure. The obtained pale yellow oily substance was separated by silica gel chromatography using toluene-5% ethyl acetate as a developing solvent to produce a white solid 736.
to obtain mg. The following data confirmed that this was a (+)-asymmetric bisphosphine. The yield at this time was 68%.

The physical properties and analysis results of this product are shown below.

Physical property value: Melting point 128 to 129 ° C. (recrystallized with ethanol) Degree of optics ▲ [α] ²¹ _D ▼ + 14.4 ° (C =
1.08, benzene) Elemental analysis (C ₄₃ H ₅₆ O ₆ P ₂ ) CH Calculated value 70.67 7.72 Measured value 70.81 7.62 Production Example 2 (-)-Production of asymmetric bisphosphine By the same operation as the step 1- (4) of Production Example 1, (+)-
Trans-4.5-bis (tosyloxymethyl) -2,2
A white solid was obtained from dimethyl-1,3-dioxolane in a yield of 45%. It was confirmed from the data below that this was a (-)-asymmetric bisphosphine. The physical properties and analysis results of this product are shown below.

Physical property value: Melting point 128.5-129.5 ° C (recrystallized from ethanol) Degree of illuminance ▲ [α] ²⁷ _D ▼ = -14.4 ° (C = 1.0
2, Benzene) Elemental analysis (C ₄₃ H ₅₆ O ₆ P ₂ ) CH Calculated value 70.67 7.72 Measured value 70.35 7.63 Use example 1, asymmetric hydrogenation reaction catalyzed by rhodium cation complex Synthesis of 1- (1) Rhodium Cation Complex Under an argon gas atmosphere, 125 mg (0.171 mmol) of (+)-asymmetric bisphosphine obtained in Production Example 1 and chloro (1,5-dichlorooctadiene) rhodium (I ) And dimer [Rh (COD) C1] ₂ 42 mg (0.085 mmol) were added with 13 ml of methanol and stirred at room temperature for 30 minutes.
Then add 3.76 g of sodium borofluoride to this
A solution of (34.2 mmol) in water (10 ml) was slowly added dropwise. After the dropping, the reaction liquid became homogeneous temporarily and then a yellow solid was deposited. After further stirring for 1 hour, the reaction suspension was ice-cooled, 70 ml of water was added thereto, and the mixture was stirred.
The precipitated yellow solid was collected by suction filtration using a glass filter and washed with water. After drying under reduced pressure, 170 mg of a yellow solid was obtained.

The analysis results of this product are shown below.

Elemental analysis (C ₅₁ H ₆₈ BF ₄ O ₆ P ₂ Rh) Calculated value C = 59.54 H = 6.66 Measured value C = 58.85 H = 6.32 1- (2) Asymmetric hydrogenation reaction Is performed according to the following formula.

(Wherein, _{A r} represents an aryl group, * represents an asymmetric carbon) Sutobbe eggplant flask with 50ml three-way cock (Stob
BE) 1 mmol synthesized α- benzylidene succinic acid monomethyl ester derivative (IV) by reaction, triethylamine 101 mg (1 mmol), the Use Example 1- (1) rhodium was adjusted with cation complex 2.1 mg (2 × 10 ^{- (3} mmol) was weighed, 2 ml of methanol was added as a solvent,
After sufficiently replacing the inside of the system with hydrogen, the reaction was carried out at a hydrogen pressure of 1 atm and a temperature of 30 ° C. for 40 hours. After confirming completion of the reaction by NMR, methanol was distilled off under reduced pressure, and 0.5 ml of 0.5 N aqueous sodium hydroxide solution was added to the residue under ice cooling and the mixture was stirred. Then, 4 ml of methylene chloride was added to this, the catalyst was extracted and removed, and the aqueous layer was washed with 0.4N of 6N hydrochloric acid.
Acidified with ml. After extraction with 60 ml of ether and drying over magnesium sulfate, the ether was distilled off under reduced pressure to obtain α-bedylsuccinic acid monomethyl ester derivative (V).
The yield was almost quantitative.

The optical yield of this compound (V) was determined by the following method.

Compound (V) (0.5 mmol) was dissolved in methylene chloride (1.5 ml), and dicyclohexylcarbodiimide 1 was stirred with ice cooling.
After adding 03 mg (0.5 mmol) (DCC) and stirring at the same temperature for 15 minutes, 44 mg (0.5 mmol) of morpholine was added and stirred at room temperature for 1 hour. Methylene chloride was distilled off under reduced pressure, and then 10 ml of acetic acid ester was added. The insoluble matter was filtered off by suction with a glass filter, and the filtrate was concentrated under reduced pressure to obtain an amide compound. This is analyzed by HPLC (column; Ch
iralcel OC Daicel Chemical Industries, Ltd., developing solvent;
The optical yield was determined by analysis with isopropanol: normal hexane = 1: 1). The results are shown in Table 1.

Use Example 2 Asymmetric hydrogenation reaction catalyzed by a rhodium neutral complex 3.5 mg (4.8 × 10 ⁻³ mmol) of the asymmetric bisphosphine obtained in Production Example 1 [Rh (CO
D) Cl] ₂ 1.0 mg (2 × 10 ⁻³ mmol) was weighed and added with 1 ml of degassed methanol under an argon atmosphere, stirred for 30 minutes and made uniform to prepare a yellow rhodium neutral complex solution. . The reaction is performed according to the following formula.

(In the formula, Ar is * Represents an asymmetric carbon) In an argon gas atmosphere, in a 50 ml round-bottomed flask equipped with a three-way cock, 528 mg (2 mmol) of the compound (VI) represented by the above formula and 202 mg (2 mmol) of triethylamine were weighed, and degassed methanol was added. After the solution was dissolved and the neutral complex solution prepared above was added thereto and the system was sufficiently replaced with hydrogen, the reaction was carried out at a hydrogen pressure of 1 atm and a temperature of 30 ° C. for 40 hours.

Next, the same procedure as in Use Example 1 was carried out to perform purification by NMR.
After further confirming the completion of the reaction, the same operation as in Use Example 1 was performed to obtain an amide, and the optical yield was determined by HPLC. The optical yield of this product is 93.6% e. e. And the degree of light application was −27.3 ° (C = 2.02, methanol).

Use Example 3 Asymmetric hydrogenation reaction using a complex having (-)-asymmetric bisphosphine as a ligand as a catalyst Further, the (-)-asymmetric bisphosphine obtained in Production Example 2 was synthesized as a ligand. The asymmetric hydrogenation reaction catalyzed by the rhodium cation complex and the rhodium neutral complex was carried out under the same conditions as in Use Examples 1 and 2 above. As a result, an α-benzylsuccinic acid derivative having a positive degree of light rotation was given (+)-
It was confirmed that the same optical yield and activity as those of the asymmetric bisphosphine complex were exhibited.

Comparative Example Rhodium cation complex [Rh (COD) (−)-DIOP] ⁺ BF ⁻ using a conventional asymmetric bisphosphine as a ligand.
_{Using 4} as a catalyst, the reaction of the following formula was carried out in the same manner as in Use Example 1.

(In the formula, _Ar is (-)-DIOP is , * Represents an asymmetric carbon.) As a result, the conversion rate is 100% and the optical yield is 56.3% e.
e. Met. The degree of light application was -17.2 ° (C = 2.04, methanol).

As described above, the rhodium complex having the (+) or (−)-asymmetric bisphosphine as a ligand of the present invention is used in the asymmetric hydrogenation reaction in producing an optically active α-benzylsuccinic acid monomethyl ester derivative, 87% e. e. The above high optical yield can be provided. Further, the amount of the catalyst is 0.2 mol% with respect to the substrate, and the reduction proceeds almost completely at room temperature and atmospheric pressure, and almost the same optical yield and activity are obtained with both the cation complex and the neutral complex. To be

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication C07C 67/303 69/612 9279-4H C07F 15/00 B 9155-4H

Claims (1)

[Claims] 1. A general formula (In the formula, * represents an asymmetric carbon) or (+) or (-)-trans-4,5-bis [bis (4-methoxy-3,5-dimethylphenyl)]
An asymmetric bisphosphine which is phosphinomethyl] -2,2-dimethyl-1,3-dioxolane.