KR100340760B1 - Stereoselective process for preparing (R)-(-)-muscone - Google Patents

Abstract

The present invention provides 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphepine (I), 4- (R, R-2,5-diphenylpyrrolidine) -(R) -dynaphthodioxaphosphine (II) is reacted with copper (II) triplate to form a complex with copper, which is used as a chiral catalyst to form dimethylzinc with 2-cyclopentadecenon and 1,4 - and by addition reaction with an optical purity and high yield (R) - (-) - a non-scones (l -muscone) to provide a process for producing a stereoselective.

Description

Stereoselective process for preparing (R)-(-)-muscone}

The present invention relates to a stereoselective method for preparing l -muscon optically active material. More specifically, 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine of the following formula (I) which is a novel compound, 4- (R of the following formula (II) , R-2,5-diphenylpyrrolidine)-(R) -dynaphthodioxaphosphine and its preparation method and (E) -2-cyclopentadeceen-1-one using a catalytic amount thereof as a chiral ligand The present invention relates to a method for stereoselectively preparing (R)-(-)-muscon (A) having an optical activity by stereoselectively reducing a.

(Formula A)

Musk has the effect of strong heart, soothing, central nervous excitement, and is used in Korea as medicinal raw material such as wowang cheongsimwon and Ki Eung Hwan and has been relying on total imports, but since October 1996, CITES As a result of the entry into force, domestic imports are virtually banned, and the development of alternative materials is one of the urgent tasks of the domestic industry (Pharmaceutical Newspaper '97 .6.26).

At present, some pharmaceutical companies have synthesized l -muscon in musk as a substitute for musk, and has been proved to be equivalent in musk and drug expression, and has been replaced by Woowang Cheongsimwon. -It is not easy to introduce the carbon-position methyl group in three-dimensionally selective, so it is essential to study the mass production industrialization process of l -muscon with pure optical activity of more than 95% enantiomer excess.

(Formula A)

Meanwhile, dl-free scones in place despite the racemate and commercial production by economical way on a commercial scale can not be separated optically active by the material structure, the chemical method l, etc. Drug-available to only a non-scones pure and therefore stereoselective l -Research on manufacturing muscons has emerged as an important task.

Conventional l -muscon synthesis method with optical activity is full of l -muscon due to the drawbacks such as the use of starting materials that are too complex or unsatisfactory in chemical and optical purity, as shown in the following scheme. It was not applied to industrialized commercial production.

Iii) Asymmetric conjugate addition of CH ₃ Li; Schematic of the matter disclosed in JCS Perkin I, 1193 (1992) is as follows.

Ii) Diastereoselective cyclopropanation of enoens; Schematic of what is disclosed in JACS , 107, 8256 (1985) is as follows.

As described above, the method of synthesizing l -muscon using a chiral ligand or a stereoselective reaction by introducing an appropriate stereoprotective functional group includes a process that is difficult to apply industrially while using an expensive reaction reagent. do. On the other hand, the reaction is unsatisfactory for commercialization when the synthesis route is long and the optical activity is less than 85% enantiomer access. Therefore, the intermediate and l -muscon separation and purification processes are required. Except for its value in terms of value, it is an uneconomical synthesis that is not suitable for commercialization.

On the other hand, several studies such as a method of producing (R)-(-)-muscon having optical activity by obtaining (E) -2-cyclopentadeceen-1-one by asymmetric organic reduction reaction are in progress. In particular, it is reported that the use of amino alcohol chiral auxiliaries having a bonane skeleton shows good results. However, the synthesis of (R)-(-)-muscon by this chiral group is difficult to commercialize due to the disadvantage that the reaction takes a long time and the chiral group needs to be used in excess of 1 equivalent.

Accordingly, the technical problem of the present invention is to provide a novel chiral ligand compound which makes it possible to synthesize (R)-(-)-muscone in high optical purity, high yield by the use of a catalytic amount (5-30 mol%) and It is to provide a method for stereoselectively preparing (R)-(-)-muscon using such a chiral ligand compound.

Thus, the present invention provides 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine (I), 4- (R, R-2,5-diphenylpyrrolidine It is to provide a method for synthesizing (R)-(-)-muscone using)-(R) -dynaphthodioxaphosphine (II) as a chiral ligand.

This is 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphope (I), 4- (R, R-2,5-diphenylpyrrolidine)-( R) -Dynaphthodioxaphosphine (II) is reacted with copper (II) triplate to form a complex with copper, which is used as a chiral catalyst to add dimethyl zinc to 2-cyclopentadedecenone and 1,4-addition. By reaction to stereoselectively prepare (R)-(-)-muscone with high optical purity and high yield.

(Scheme 1)

The chiral ligand used at this time makes it possible to synthesize (R)-(-)-muscon with high optical purity and high yield by the use of a catalytic amount (5 to 30 mol%).

According to the present invention, 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine of the following formula (I) which is a new chiral ligand compound and 4- of the following formula (II) (R, R-2,5-diphenylpyrrolidine)-(R) -dynaphthodioxaphosphine is provided.

4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphope (I) according to the present invention has (R) -1,1'-by-2 having optical activity Reacting with phosphorus trichloride using naphthol as a starting material to form 4-chloro- (R) -dynaphthodioxaphosphope, which in turn is cis- in the presence of a base such as n-butyllithium, sodium hydride, sodium alkoxide It can be prepared by reacting with 2,6-dimethylpiperidine.

(Scheme 2)

In addition, 4- (R, R-2,6-diphenylpyrrolidine)-(R) -dynaphthodioxaphosphope (II) is 4-chloro- (R) -dynaphthodioxaphosphine synthesized above. Can be prepared by reacting with R, R-2,5-diphenylpyrrolidine in the presence of a base such as n-butyllithium, sodium hydride, sodium alkoxide.

(Scheme 3)

In this reaction, R, R-2,5-diphenylpyrrolidine used as a reactant in the reaction is trans-dibenzoyl ethylene as a starting material and reduced to tin chloride, hydrochloric acid to 1,4-diphenylbutane-1 , 4-dione is used to reduce the ketone with (-)-DIP-chloride to form S, S-diphenylbutane-1,4-diol with a chiral structure. After allyl-R, R-2,5-diphenylpyrrolidine was used, triphenylphosphinedium chloride was used to obtain the resulting compound (R, R) -2,5-diphenylpyrrolidine. (J. Michael Chong et al ., Tetrahedron; Asymmetry , 6 , 409-418 (1995)).

(Scheme 4)

4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine (I), 4- (R, R-2,5-diphenylpyrroli, which is the novel compound Dine)-(R) -dynaphthodioxaphosphope (II) is preferably used as a chiral catalyst, in which case the amount of (R)-(-)-muscone is increased by the use of a catalytic amount (eg 0.1 equivalent). It is possible to synthesize with optical purity and high yield.

4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphope (I), 4- (R, R-2,5-diphenylpyrrolidine) of the present invention A method for synthesizing (R)-(-)-muscone using-(R) -dynaphthodioxaphosphine (II) as a chiral catalyst is as follows.

First 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine (I), 4- (R, R-2,5-diphenylpyrrolidine)-( R) -Dynaphthodioxaphosphine (II) is reacted with copper (II) triflate to form a complex with copper, which is used as a chiral catalyst, and dimethyl zinc is reacted with 2-cyclopentadedecenone and 1,4-addition. (R)-(-)-muscone is obtained with high optical purity and high yield.

This is represented by the chemical reaction formula.

Hereinafter, the present invention will be described in detail with reference to Examples.

(Example 1)

1 g of (R) -1,1'-bi-2-naphthol dissolved in an appropriate amount of toluene was added to the reaction vessel, followed by adding 4 mL of excess phosphorus trichloride under argon and boiling for 12 hours. After cooling to room temperature, toluene and phosphorus trichloride were removed under reduced pressure to obtain 1.27 g (100%) of 4-chloro- (R) -dynaphthodioxaphosphine.

(Example 2)

A 3 mL solution of 68 μL of cis-2,6-dimethylpiperidine (THF) was cooled to −78 ° C. under argon, followed by the addition of 200 μL of n-BuLi (2.5 M hexane solution) for 1 hour. After stirring, a solution of 3 mL of 4-chloro- (R) -dynaphthodioxaphosphope 176 mg of tetrahydrofuran (THF) was added thereto, and then slowly heated up to room temperature and stirred for 12 hours. Remove

The concentrated solution was purified by chromatography (silica column, solvent: ethyl ester / hexane = 1/20) 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine 110 mg (50%) was obtained.

1 H NMR (ppm): 7.84-7.94 (m, 4H), 7.17-7.50 (m, 8H), 3.78-3.91 (m, 1H), 3.35-3.43 (m, 1H), 1.77-1.83 (m, 2H) , 1.44-1.67 (m, 4H), 1.23-1.25 (d, 3H), 1.10-1.12 (d, 3H).

(Example 3)

A 3 mL solution of 127 mg of tetrahydrofuran (THF) of R, R-diphenylpyrrolidine was cooled to −78 ° C. under argon, followed by addition of 250 μL of n-BuLi (2.5M hexane solution) and stirred for 1 hour. Then, 4-chloro- (R) -dynaphthodioxaphosphopine 205 mg of tetrahydrofuran (THF) 3 mL solution was added thereto, and slowly heated to room temperature, stirred for 12 hours, and then the solvent was removed under reduced pressure. The concentrated solution was purified by chromatography (silica column, solvent: ethyl ester / hexane = 1/20) 4- (R, R-2,5-diphenylpyrrolidine)-(R) -dynaphthodioxafoss 100 mg (30%) of pepin were obtained.

1 H NMR (ppm): 7.12-7.94 (m, 22H), 5.04-5.11 (m, 2H), 2.34-2.41 (m, 2H), 1.68-1.75 (m, 2H).

(Example 4)

Under argon, a solution of 10 mg of Cu (OTf) ₂ and chiral ligand [I (21.4 mg), II (27.7 mg)] in toluene was stirred at room temperature for 1 hour. The solution is cooled to −20 ° C. and 1 mL of (E) -2-cyclopentadesen-1-one (111 mg) and dimethyl zinc (2 M toluene solution) are added. After 2 hours, 1 N hydrochloric acid was poured out and extracted with diethyl ether. Chromatography (silica column, solvent: ethyl ester / hexane = 1/20) gave R-(-)-muscon (95%, 90% ee) with optical activity.

1 H NMR (ppm): 0.94 (d, 3H), 1.14-1.48 (m, 20H), 1.78-1.95 (m, 2H), 2.18 (dd, 1H), 2.36-2.50 (m, 3H).

The effect of the present invention is to provide a novel chiral ligand compound that enables the synthesis of (R)-(-)-muscones in high optical purity, high yield with the use of a catalytic amount (5-30 mol%) and such chiral ligands. It is to provide a method for stereoselectively preparing (R)-(-)-muscon using a compound.

Claims (5)

4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine (I), 4- (R, R-2,5-diphenylpyrrolidine)-(R ) -Dynaphthodioxaphosphine (II) is reacted with copper (II) triflate to form a complex with copper, which is used as a chiral catalyst to react dimethyl zinc with 2-cyclopentadedecenone and 1,4-addition. Stereoselective preparation of (R)-(-)-muscon with high optical purity and high yield According to claim 1, wherein the chiral ligand is a stereoselective method for producing (R)-(-)-muscon, characterized in that the catalytic amount (5 to 30 mol%) is used. The method of claim 1, wherein the 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine (I) has optical activity (R) -1,1'- Bi-2-naphthol is used as a starting material and reacted with phosphorus trichloride to form 4-chloro- (R) -dynaphthodioxaphosphine, which is then present in bases such as n-butyllithium, sodium hydride and sodium alkoxide. Method for stereoselective preparation of (R)-(-)-muscone, which is prepared by reacting with cis-2,6-dimethylpiperidine under The method of claim 1, wherein 4- (R, R-2,6-diphenylpyrrolidine)-(R) -dynaphthodioxaphosphine (II) is 4-chloro- (R) -dynaphthodie (R)-(-)-characterized in that oxaphosphine is reacted with R, R-2,5-diphenylpyrrolidine in the presence of a base such as n-butyllithium, sodium hydride, sodium alkoxide Stereoselective Manufacturing Method of Muscon The novel chiral ligand compound 4- (cis-2,6-dimethylpiperidine)-(R) -dynaphthodioxaphosphine of formula (I) and 4- (R, R-2,5-diphenylpyrrolidine)-(R) -dynaphthodioxaphosphine