JP6906227B2 - Halogen bond donor / organic base complex compound and acid base complex catalyst - Google Patents

Description

The present invention relates to a halogen bond donor / organic base complex compound and an acid-base complex catalyst containing the same.

Since biopolymers containing optically active amino acids and sugars as basic constituent units construct a highly asymmetric space in the human body, pharmaceutical products using these biopolymers as receptors also have optical activity. Must be. The method of synthesizing such an optically active substance is called an asymmetric synthesis method, and even among the asymmetric synthesis methods, a catalytic infinite amount of optically active substances can be synthesized from a small amount of asymmetric sources. The asymmetric synthesis method has become extremely important.

Currently, various catalytic asymmetric syntheses using organocatalysts have been achieved. As a kind of organic molecular catalyst, an acid-base composite catalyst incorporating a hydrogen bond donor site and an organic base site is used in order to exhibit high catalytic activity. As a pioneering example, an example of an asymmetric Michael reaction using a hydrogen bond donor / organic base composite catalyst is described in Non-Patent Document 1 below. Further, an example of an asymmetric Mannich reaction using a hydrogen bond donor / organic base composite catalyst is described in Non-Patent Document 2 below.

Okino, T .; Hoashi, Y .; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. Zhijin, L .; Chen, X .; Wei, Z .; Zhiqiang, D .; Jianlin, H .; Yi, P. Chin. J. Chem. 2012, 60, 2333.

In the technique of Non-Patent Document 1, thiourea is incorporated in the catalyst, and in the technique of Non-Patent Document 2, a hydroxyl group is incorporated. Thiourea, hydroxyl groups, etc. can smoothly activate reaction substrates that have Lewis basic sites as acidic functional groups, but on the other hand, many substrates that can be activated due to their hardness are highly hard, and are within the scope of their application. Is limited.

Therefore, in view of the above problems, an object of the present invention is to create a new acid-base composite catalyst in which a halogen-bonded donor, which is an organic Lewis acid having strong softness, is introduced. By creating such a catalyst, it becomes possible to activate a soft substrate, which was difficult to activate with an existing catalyst, and it becomes possible to synthesize a new drug candidate compound or the like.

As a result of diligent studies on the above-mentioned problems, the present inventors have conducted a novel halogen by condensing an optically active diamine derived from a syncona alkaloid with 2,3,4,5-tetrafluoro-6-iodobenzoic acid. We have succeeded in creating a binding donor / organic base complex compound. Furthermore, as an example of utilizing the novel compound as a catalyst, we have succeeded in producing a Mannich product from malononitrile and N-Boc imine, and have completed the present invention.

That is, the composite compound and catalyst (organocatalysis, acid-base composite catalyst) created in the present invention are represented by the following formula (1).

It has four patterns of stereochemistry derived from cinchonine alkaloids (cinchonine, cinchonidine, quinine, quinidine), and R ¹ is hydrogen, a methoxy group, a hydroxyl group, or the like. R ² is a vinyl group, an alkyl group, or the like.

As described above, according to the present invention, the soft Lewis acidity of the halogen bond donor site enables activation of a soft substrate that was difficult to activate with an existing catalyst, and thus this catalyst has not been pioneered so far. It can be used in the reaction. Cinchona addition to the adjustment of the reaction field by selection of alkaloids, by the introduction of the electronic effect of adjustment and further hydrogen bond donor by changing the R ¹ substituent, flexible catalyst according to the reaction of interest using Can be provided.

Hereinafter, embodiments of the present invention will be described with reference to the drawings. However, the present invention can be implemented in many different modes and is not limited to the embodiments shown below.

(Embodiment 1)
The compound and catalyst according to the present embodiment are characterized by being represented by the above chemical formula (1).

The compound and catalyst according to the present embodiment have four patterns of stereochemistry derived from cinchonine alkaloids (cinchonine, cinchonidine, quinine, quinidine), and R ¹ is hydrogen, a methoxy group, a hydroxyl group, or the like. R ² is a vinyl group, an alkyl group, or the like.

It is considered that the catalyst according to the present embodiment can be used for various reactions, and although it is not limited, it can be suitably used for the Mannich reaction.

(Manufacturing of compounds and catalysts)

First, diisopropyl azodicarboxylate, triphenylphosphine, and diphenylphosphoryl azide are allowed to act on the syncona alkaloid represented by the following formula (2). Subsequently, by adding triphenylphosphine and water in this order, a cincona alkaloid derivative represented by the following formula (3) in which a hydroxyl group is converted into an amino group can be obtained.

Next, with respect to the cincona alkaloid derivative represented by the above formula (3), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 2,3,4 in the presence of 1-hydroxybenzotriazole. By allowing 5-tetrafluoro-6-iodobenzoic acid to act, the compound and catalyst shown in (1) above can be obtained.

As described above, according to this embodiment, it is possible to provide a catalyst that gives a high asymmetric yield with a wide range of substrates in, for example, the Mannich reaction.

Hereinafter, the catalyst of the above embodiment was actually prepared, and its effect was confirmed. This will be described below.

(Example)
In this example, a compound represented by the following formula (4) and a catalyst were prepared and used as a catalyst for the Mannich reaction.

(Synthesis of compounds and catalysts)
The above formula (4) was synthesized according to the following reaction formula (5).

First, according to the above reaction formula (5), quinidine (1.00 g, 3.08 mmol) and triphenylphosphine (1.10 g, 4.19 mmol) are dissolved in anhydrous THF (15 ml), and the mixture is placed in an ice bath and ice-cooled. Diisopropyl azodicarboxylate (0.760 mL, 3.83 mmol) is added thereto. Subsequently, diphenylphosphoryl azide (0.810 mL, 3.73 mmol) dissolved in anhydrous THF (7 ml) is slowly added, and the mixture is stirred at room temperature for 18 hours under an argon atmosphere, excluding the ice bath. Further, the temperature is raised to 50 degrees and the mixture is stirred for 2 hours. Then, triphenylphosphine (1.20 g, 4.36 mmol) is added, and the mixture is stirred at 50 ° C. for 2 hours (Note: foaming). The reaction mixture is cooled to room temperature, distilled water (0.350 mL) is added, and the mixture is stirred at room temperature for 14 hours. Then, dichloromethane is added to dilute, and 1N aqueous hydrochloric acid solution is slowly added until the pH becomes 2. The aqueous phase is washed 3 times with dichloromethane, followed by the addition of 10% aqueous sodium hydroxide solution to a pH of 10. The aqueous phase is extracted 3 times with dichloromethane, the organic phase is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent 1: 1: 0.03 n-hexane / ethyl acetate / triethylamine) to obtain a white solid quinidine derivative in a yield of 77%.

Next, in addition to the quinidine derivative (33 mg, 0.100 mmol) obtained above, 2,3,4,5-tetrafluoro-6-iodobenzoic acid (32 mg, 0.100 mmol), 1- (3-dimethylamino). (Propyl) -3-ethylcarbodiimide hydrochloride (20 mg, 0.100 mmol) and 1-hydroxybenzotriazole (0.6 mg, 0.003 mmol) are dissolved in anhydrous dichloromethane (1 ml), and the mixture is stirred at room temperature for 8 hours under an argon atmosphere. .. Dichloromethane and distilled water are added to dilute the mixture, and the mixture is further stirred for 2 hours. The organic phase is dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developing solvent 1: 1: 0.03 n-hexane / ethyl acetate / triethylamine) and represented by the above formula (4), 2,3,4,5-tellafluoro-6. -Iodo-N-((R)-(6-methoxyquinolin-4-yl) ((1S, 2R, 4S, 5R) -5-vinylquinuclidein-2-yl) methyl) 75% white solid of benzamide (A) Was obtained in the yield of.
Device data of (A):
^{1 1} H NMR (400 MHz, CDCl ₃ , 50 ° C): δ 8.75 (d, J = 4.6 Hz, 1H), 8.04 (d, J = 9.4 Hz, 1H), 7.58 ( br, 1H), 7.52 (br, 1H), 7.47 (d, J = 4.6Hz, 1H), 7.39 (dd, J = 9.4, 2.5Hz, 1H), 5. 97 (ddd, J = 17.4, 11.0, 6.2Hz, 1H), 5.20-5.10 (m, 2H), 3.98 (s, 3H), 3.10-2.87 (M, 5H), 2.37-2.31 (m, 1H), 1.61-1.44 (m, 4H), 1.11-1.05 (m, 1H); HRMS (ESI ⁺ ) calcd for C ₂₇ H ₂₅ F ₄ IN ₃ O ₂ [M + H] ⁺ 626.0922: found 626.0916.

(Synthesis of Mannich products)
Next, 0.7 mg of the obtained compound (4) was used as a catalyst to carry out an asymmetric Mannich reaction between malononitrile and N-Boc imine.

The above catalyst (4) and 26.4 mg of malononitrile were added to a reaction vessel, dissolved in 2 mL of anhydrous chloroform, and cooled to −50 ° C. under an argon atmosphere. 41.1 mg of tert-butyl (E) -benzylide carbamate was added, and the mixture was stirred at −50 ° C. for 32 hours. As a result, the reaction proceeded 93% and the Mannich product had an enantioselectivity of 98%. From this result, the usefulness of the catalyst of the present invention could be confirmed. Further, when the reaction was carried out using tert-butyl (E)-(2-bromovenzylide) carbamate as a substrate, the reaction proceeded 91% and the target product was 93% ee. Further, when the reaction was carried out using tert-butyl (E)-(2-methoxybenzylide) carbamate as a substrate, the reaction proceeded by 80% and the target product was 96% ee.

As described above, it was confirmed that the effect of this catalyst can be confirmed by this example, and that a catalyst that gives a high asymmetric yield in a wide range of substrates can be provided.

The "halogen bond donor / organic base composite compound having both a halogen bond donor site and an organic base site" according to the present invention is useful as an organic molecular catalyst (acid-base composite catalyst), and the present invention has industrial applicability. There is.

Claims (2)

A halogen-bonded donor / organic base complex compound represented by the following formula (1).

^{(R 1} is hydrogen, .R ² is a methoxy group, and hydroxyl group, a vinyl group, an alkyl group.) An acid-base composite catalyst comprising a halogen-bonded donor / organic-base complex compound represented by the following formula (1).

^{(R 1} is hydrogen, .R ² is a methoxy group, and hydroxyl group, a vinyl group, an alkyl group.)