KR100476584B1 - Chiral Pyrrolidinyl(bisphosphinodiamide) Derivative Useful for Asymmetric Allylic Substitution Reaction - Google Patents

Abstract

The present invention relates to a chiral pyrrolidinyl (bisphosphinodiamide) derivative bonded to a polymer represented by the following formula (1), a method for preparing the same, and a use thereof. The following compound is asymmetric allyl substitution reaction through palladium and chelation reaction ( It can be used as a chiral catalyst for asymmetric allylic substitution reaction) to produce compounds with high optical purity in high yield, and can be easily recovered after the reaction.

Formula 1

(In the above formula, Ⓟ are all as described in the specification, and the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

Description

Chiral Pyrrolidinyl (bisphosphinodiamide) Derivative Useful for Asymmetric Allylic Substitution Reaction}

The present invention relates to chiral pyrrolidinyl (bisphosphinodiamide) derivatives, and more particularly, chiral pyrrolidinyl (bisphosphino) used as a chiral ligand in the asymmetric allyl substitution reaction for preparing a compound having optical activity. Diamide) derivatives and their use.

Chiral compounds are steadily increasing in demand in the pharmaceutical, agrochemical and fragrance industries.

In the pharmaceutical sector, more attention is focused on the US Food and Drug Administration (FDA) 's policy on chiral drugs. In other words, in case of new drug candidates, the product that induces optically pure chiral products rather than racemates and that previously sold as racemic mixtures proves that one enantiomer has excellent efficacy or fewer side effects. Policy to allow new drugs; When new drug candidates have asymmetric chiral centers in their molecules, the demand for chiral technology is exploding due to the policy that separate racemates and individual enantiomers and test their physiological activity. Growing.

Conventional methods for producing chiral products can be broadly divided into two; One is to prepare using enantiomerically pure starting materials derived from natural sources; The other is a method of optical resolution of racemates. Natural sources, however, have the problem of being limited to compounds found in nature so that only certain structures and orientations can be easily obtained (e.g., sugars in the D-form and amino acids in the L-form). Optical splitting also requires a separate optical splitting reagent, a very difficult method of separating the mixture, and most of all, if there is no special use of the isomer remaining after the splitting, at least 50% of the racemate has a disadvantage.

In order to solve this problem, various methods for obtaining a desired chiral compound using a chiral catalyst have recently been developed.

In view of the technical aspects and industrial use of the reaction products, one of the most successful methods is to use (bisphosphinodiamide) -palladium derivatives derived from chiral diamine, as shown above. It is a method using asymmetric allyl substitution reaction.

Through this reaction, various kinds of optically pure compounds can be obtained through carbon-carbon and carbon-hetero atom (eg, nitrogen, oxygen, sulfur) bond formation reactions. [References: (a) BM Trost, DL Van Vranken, C. Bingel, J. Am. Chem. Soc . 1992 , 114 , 9327 (b) BM Trost, RC Bunt, J. Am. Chem. Soc . 1994 , 116 , 4089 (c) BM Trost, MG Organ, GA O'Doherty, J. Am. Chem. Soc . 1995 , 117 , 9662 (d) BM Trost, SR Pulley, J. Am. Chem. Soc . 1995 , 117 , 10143 (e) BM Trost, GR Cook, Tetrahedron Lett . 1996 , 37 , 7485 (f) BM Trost, RC Lemoine, Tetrahedron Lett . 1996 , 37 , 9161 (g) BM Trost, AC Krueger, RC Bunt, J. Zambrano, J. Am. Chem. Soc . 1996 , 118 , 6520 (h) BM Trost, R. Madsen, SG Guile, AEH Elia, Angew. Chemie. Int. Ed. Engl . 1996 , 35 , 1569 (i) BM Trost, R. Radinov, EM Grenzer, J. Am. Chem. Soc . 1997 , 119 , 7879 (j) BM Trost, X. Ariza, Angew. Chemie. Int. Ed. Engl . 1997 , 36 , 2635.

Accordingly, many chiral phosphine catalysts have been developed for asymmetric allyl substitution reactions. However, in most conventionally known cases, the turnover number of the catalyst and the chiral phosphine ligand and the palladium metal itself are expensive. The use of this reaction was limited.

In addition, attempts have been made to reduce costs by using chiral phosphine-palladium repeatedly using a heterogeneous catalytic system. Recently, chiral phosphine derivatives bound to several polymers have been researched and developed. In most cases, however, the activity and enantioselectivity of the catalysts were significantly lower than those of homogeneous catalytic systems, which were of no practical value. [(a) Y. Uozumi, K. Shibatomi, J. Am. Chem. Soc . 2001 , 123 , 2919 (b) K. Hallman, E. Macedo, K. Nordstrom, C. Moberg, Tetrahedron: Asymmetry 1999 , 10 , 4037 (c) Y. Uozumi, H. Danjo, T. Hayashi, Tetrahedron Lett . 1998 , 39 , 8303 (d) MA Anson, AR Mirza, L. Tonks, JMJ Williams, Tetrahedron Lett . 1999 , 40 , 7147 (e) BFG Johnson, SA Raynor, DS Shephard, T. Mashmeyer, T. Mashmeyer, JM Thomas, G. Sankar, S. Bromley, R. Oldroyd, L. Gladden, MD Mantle, Chem. Commun . 1999 , 1167]

Accordingly, the present inventors have tried to develop a chiral catalyst that exhibits high activity and optical selectivity in asymmetric allyl substitution reactions. As a result, the phosphine- which is a metal complex of a chiral pyrrolidinyl (bisphosphinodiamide) derivative represented by Chemical Formula 1 The palladium derivatives were able to prepare optically pure compounds with high yields, and showed that the method for preparing chiral pyrrolidinyl (bisphosphinodiamide) derivatives was simple and economical, as well as performing asymmetric allyl substitution reactions. And it was confirmed that the present invention by confirming the excellent optical selectivity.

It is an object of the present invention to provide a chiral pyrrolidinyl (bisphosphinodiamide) derivative represented by formula (1) useful for preparing optically pure compounds.

Still another object of the present invention is to provide a method for preparing a chiral pyrrolidinyl (bisphosphadiamide) derivative, which is simple in production and can be produced in high yield.

Yet another object of the present invention is to provide the use of chiral pyrrolidinyl (bisphosphamiamido) derivatives useful as catalysts for asymmetric allyl substitution reactions.

In order to achieve the above object, the present inventors provide a novel chiral pyrrolidinyl (bisphosphinodiamide) derivative represented by the formula (1), a preparation method and a use thereof.

In the above formula,

Ⓟ represents all polymers that are insoluble in organic solvents,

At this time, the hydrogen atom (1) and the hydrogen atom (2) are in the position of a trans with each other, the compound of Formula 1 includes all the enantiomers represented by the following formula (1a) and 1b.

Preferably, the

Ⓟ is styrene and 1,4-divinylbenzene insoluble in solvent or 1,1 '-[1,4-butanedinylbis (oxy)] bis [4-ethenylbenzene] (1,1'-[ 1,4-butanediylbis (oxy)] bis [4-ethenylbenzene]).

The chiral diphosphine compound of the formula (1) preferably includes both enantiomers represented by the following formulas (1a) and (1b).

(Wherein ⓟ is as defined in formula 1)

(Wherein ⓟ is as defined in formula 1)

The present invention also provides a method for preparing a polymer chiral pyrrolidinyl (bisphosphinodiamide) derivative of the general formula (1).

Specifically, as shown in Scheme 1 below, the compound of Formula 2 is reacted with a polymer including a substituent of Formula 3 to prepare a compound of Formula 1.

(Wherein ⓟ is as defined in formula 1, Z is a halogen group as leaving group, and hydrogen atom 1 and hydrogen atom 2 are in trans position with each other.)

The compound of Formula 3 includes a leaving group in the terminal group of the polymer, and is bonded through a substitution reaction with the amine of the compound of Formula 2. Specifically, the compound of formula 3 is activated by binding to a nucleophile (aminodimethylpyridine) to which a leaving group present at the end is added, and then to the amine of formula (2).

Suitable organic solvents for the reaction may be used alone or in combination with common ones such as benzene, toluene, chlorobenzene, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl acetate and acetonitrile.

In addition, the substitution reaction of the present invention is preferably carried out for 1 to 24 hours at a reaction temperature of 0 ~ 70 ℃, preferably 0 ~ 25 ℃.

In particular, after completion of the substitution reaction, the unreacted compound of Chemical Formula 3 remains in an activated state as the leaving group of the end group is released, which may cause another side reaction, thereby necessarily performing END-CAPPING. The END-CAPPING reaction can use a general method used in this field, for example, methanol, ethanol, t-butanol, iso-propanol compound, including methyl, ethyl, t-butyl, or iso-propyl group, etc. Use In a preferred embodiment of the invention, it is carried out using methanol.

The chiral pyrrolidinyl (bisphosphinodiamide) compounds of formula (2) of the present invention are as shown in Scheme 2 below:

1) Mesylation of a compound of Formula 4 by reaction with an azide compound;

2) hydrogenating the obtained azide compound of formula 5 under a palladium catalyst;

3) reacting the obtained amine compound of formula 6 with an aryl compound of formula 7; And

4) The obtained compound of formula 8 is treated with Lewis acid to prepare a chiral pyrrolidinyl (bisphosphinodiamide) compound of formula 2.

In step 1, 3,4-bis-methanesulfonyloxy-pyrrolidine-1-carboxylic acid t-butyl ester of the general formula (4) (3,4-Bis-methanesulfonyloxy-pyrrolidine-1) as a starting material is shown in Scheme 3 below. -carboxylic acid tert-butyl ester) is reacted with an azide compound to give the 3,4-diazido-pyrrolidine-1-carboxylic acid t-butyl ester of formula (3,4-Diazido-pyrrolidine-1-carboxylic acid tert-butyl ester) is prepared.

As the azide compound used above, one used in the azidolation reaction can be used. In the present invention, sodium azide was used.

The reaction is carried out at 70 to 120 ° C. for 10 to 36 hours in an organic solvent.

At this time, the organic solvent that can be used may be used alone or in combination of common ones such as benzene, toluene, chlorobenzene, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl acetate and acetonitrile, dimethylformamide, and the like. .

In addition, 3,4-bis-methanesulfonyloxy-pyrrolidine-1-carboxylic acid t-butyl ester of the general formula (4) used as a starting material in Scheme 4 may be prepared from tartaric acid according to a known method [U. Nagel, Angew. Chem. Int. Ed. Engl . 1984 , 23 , 435.

(In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

In addition, the compound of Formula 4 is represented by (3S, 4S ) -bis-methanesulfonyloxy-pyrrolidine-1-carboxylic acid t-butyl ester of the formula (4a ) and (3R, 4R ) -bis-methanesulphate represented by 4b. It includes all enantiomers of the fonyloxy-pyrrolidine-1-carboxylic acid t-butylester.

The azide compound of formula 5 prepared by Scheme 3 is also represented by ( 3R, 4R ) -diazo-pyrrolidine-1-carboxylic acid t-butylester represented by the following formula 5a and ( 3S, 4S ) -represented by 5b- Diazo-pyrrolidine-1-carboxylic acid t-butylester enantiomer.

(In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

In step 2, the compound of formula 5 is hydrogenated in the presence of a palladium-carbon (Pd-C) catalyst as shown in Scheme 4 below to give 3,4-diamino-pyrrolidine-1-carboxylic acid t-butylester (3,4-Diamino-pyrrolidine-1-carboxylic acid tert-butyl ester) was prepared.

The hydrogenation is carried out for 10 to 36 hours under hydrogen pressure of 10 to 60 psi.

At this time, the solvent that can be used may be used singly or in combination with a common one, such as ethyl acetate, methanol, ethanol or dimethylformamide.

3,4-Diamino-pyrrolidine-1-carboxylic acid t-butyl ester of Chemical Formula 6 prepared by Scheme 4 is represented by the following Chemical Formula 6a: ( 3R , 4R) -diamino-py include pyrrolidine-1-carboxylic acid t- butyl ester enantiomer-diamino-pyrrolidine-1-carboxylic acid t- butyl ester and (3 S, 4 S) represented by 6b.

(In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

In step 3, as shown in Scheme 5, an amine compound of formula 6 is reacted with a compound of formula 7, dicyclohexylcarbaiimide (DCC) and 4-aminoaminopyridine (DMAP) N-tert-butoxycarbonyl-3,4-bis (2-diphenylphosphinobenzoyl) diaminopyrrolidine (N-tert-Butoxycarbonyl-3,4-bis (2-diarylphosphinobenzoyl) diaminopyrrolidine) Prepare the compound.

The reaction is carried out for 12 to 36 hours at low temperature, 0 ℃ or less in an organic solvent.

At this time, the organic solvent that can be used may be used singly or in combination with common ones such as benzene, toluene, chlorobenzene, diethyl ether, tetrahydrofuran, dioxane, dichloromethane, chloroform, ethyl acetate and acetonitrile.

N-tert-butoxycarbonyl-3,4-bis (2-diphenylphosphinobenzoyl) diaminopyrrolidine compound of Formula 8 obtained by Scheme 5 above is represented by the following Formula 8a ( 3R, 4R ) -N-tert-butoxycarbonyl-3,4-bis (2-diphenylphosphinobenzoyl) diaminopyrrolidine and ( 3S, 4S ) -N-tert- butoxycarbonyl represented by the following formula (8b) All enantiomers of -3,4-bis (2-diphenylphosphinobenzoyl) diaminopyrrolidine are included.

(In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

In step 4, the N-tert-butoxycarbonyl-3,4-bis (2-diphenylphosphinobenzoyl) diaminopyrrolidine compound of Formula 8 is reacted with Lewis acid to reduce the chiral pyrroli compound of Formula 2 A dinylic (bisphosphinodiamide) compound is prepared.

(In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other.)

The compound of Formula 2 includes all of the enantiomers represented by the following Formulas 2a (R-) and 2b (S-).

Meanwhile, another reactant, which is used to prepare the compound of Formula 1 of the present invention, may be purchased and used in the market and may be prepared in various compound forms by introducing various kinds of functional groups.

Specifically, as shown in the following formula, the leaving group of Z includes a polymer end group.

(Wherein Z is a leaving group and ⓟ represents all polymers insoluble in the organic solvent.)

At this time, the leaving group is preferably a halogen element such as chlorine, iodine, bromine and so on to perform the substitution reaction with the amine of formula (2).

P is a polymer having a high degree of swelling in the organic solvent used for the catalytic reaction. In one embodiment of the present invention, polystyrene trityl chloride, JANDAJEL ^™ trityl chloride resin was used.

An example of the preparation method of Chemical Formula 1 will be described with reference to Scheme 1 below.

In the reaction, a compound of Formula 2 is used as a starting material, and JandaJEL trityl chloride resin is used as a compound of Formula 3 [Reference: (a) R. Manzotti, TS Reger, KD Janda, Tetrahedron Lett . 2000 , 41 , 8417 (b) PH Toy, KD Janda, Tetrahedron Lett . 1999, 40 , 6329], it is possible to obtain a chiral pyrrolidinyl (bisphosphinodiamide) derivative of the formula (2) of the tertiary amine structure usually through the SN1 reaction. This reference discloses copolymers of styrene with a compound of formula A or a compound of formula B. Formula A Formula B (n is 1 to 3)

The chiral pyrrolidinyl (bisphosphadiamide) derivative of the formula (1) obtained by the present invention can be used as a catalyst in the asymmetric allyl substitution reaction to prepare a compound having high optical purity with high yield. The chiral pyrrolidinyl (bisphosphadiamide) derivative forms a complex with the palladium catalyst to form a heterogeneous catalyst system.

According to a preferred embodiment of the present invention, the asymmetric allyl substitution reaction using the complex showed a high catalytic activity of at least 95% and excellent optical selectivity of at least 97% ee (see Tables 1 and 2). ).

In particular, since the chiral pyrrolidinyl (bisphosphadiamide) derivative of the present invention is insoluble in an organic solvent, after completion of the reaction, the chiral pyrrolidinyl derivative can be easily separated and recovered through filtration and can be reused.

Therefore, the chiral pyrrolidinyl (bisphosphinodiamide) derivative bound to the polymer of the present invention has been proved to be an appropriate chiral scaffold, and it can be seen that it can be useful for asymmetric allyl substitution as a chiral catalyst. have.

The present invention will be described in more detail with reference to the following Examples.

However, the above-mentioned objects and other objects below illustrate the present invention, and the content of the present invention is not limited by the embodiments.

Preparation Example 1 Preparation of Chiral Pyrrolidinyl (Bisphosphadiamide) Derivative 2: R-Isomer

Step 1) Azido Reaction

Formula 4b (30 g, 83.47 mmol) was dissolved in dimethylformamide (250 ml) and sodium azide (32.56 g, 500.8 mmol) was added. After slowly raising the reaction temperature to 90 ° C., the temperature was fixed and reacted by stirring for 24 hours. After completion of the reaction, the obtained reaction was extracted with diethyl ether, and then washed with water and brine. Then, dried over anhydrous sodium sulfate, excess solvent was removed under reduced pressure, and the product was separated by column chromatography (developing solvent, ethyl acetate: hexane = 1: 4) to give compound 5a (16.47 g, 77.9%) as a yellow oil. The desired compound (5a) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 3.41 (t, J = 4.5, 13.2 Hz, 2H 6H), 3.37-3.46 (m, 2H), 3.64-3.71 (m, 2H) , 3.97 (t, J = 2.8 Hz 2H)

¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 28.52, 48.53, 48.88, 63.47, 64.20, 80.33, 153.95; IR (KBr pellet) 744, 912, 1166, 1256, 1406, 1644, 2104, 3440 cm ^-1 .

Step 2) Reduction

Formula 5a (11.72 g, 46.28 mmol) obtained in the above step was dissolved in methanol (300 mL), and then 10% Pd-C (7.93 g) was added to the reaction and reacted under a pressure of 50 psi. After the completion of the reaction, the reaction product was filtered using a carrier, and the solvent was removed under reduced pressure to obtain the title compound (6a) (9.31 g, 100%) as a dark brown solid. The following reaction was carried out without further purification.

Step 3) Condensation Reaction

Dissolve (2-diphenylphosphino) benzoic acid (DPPBA) in dried dichloromethane (350 mL), add dicyclohexylcarbaiimide, 4-aminodimethylpyridine, 4-dimethylaminopyridine, and the above step. The compound of formula 6a (8.91 g, 44.27 mmol) obtained in was dissolved in dichloromethane (50 mL) and slowly added dropwise at 0 ° C. Subsequently, the mixture was stirred at room temperature for 24 hours, and the dicyclohexyl urea produced after the reaction was terminated was first filtered off and then extracted with distilled water and ethyl acetate. Dried over anhydrous sodium sulfate and filtered. The excess solvent was removed under reduced pressure and the product was separated by column chromatography (developing solvent, ethyl acetate: dichloromethane = 1: 5), followed by complete dicyclohexylurea with methanol, dichloromethane and diethyl ether. The obtained compound was obtained to give the title compound 8a (23.87 g, 69.5%) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.44 (s, 9H), 2.67 (t, J = 10.1 Hz, 1H), 2.94 (t, J = 10.1 Hz, 1H), 3.63 (t, J = 8.6 Hz , 1H), 3.75 (t, J = 7.9 Hz, 1H), 4.07-4.17 (m, 1H), 4.33-4.44 (m, 1H), 6.66 (d, J = 6.7 Hz, 1H), 6.90 (d, J = 3.8 Hz, 2H), 7.15-7.31 (m, 26H), 7.55-7.61 (m, 2H)

IR (KBr pellet) 698, 746, 880, 1028, 1090, 1136, 1170, 1254, 1322, 1366, 1408, 1432, 1458, 1478, 1524, 1584, 1646, 1696, 2976, 3052, 3298 cm ^-1 .

Step 4) Removal of t-butoxycarbonyl Group

Compound of formula 8a obtained in the step (7.00 g, 9.02 mmol) was dissolved in dried dichloromethane (150 mL), and BF ₃ · Et ₂ O was slowly added dropwise at 0 ^° C., and the temperature was raised to room temperature, followed by stirring for 1 hour. After completion of the reaction, saturated sodium bicarbonate (sodium bicarbonate) was added to adjust the pH to 7, and the methanol was added to remove the slurry, which was extracted with dichloromethane and washed with water and brine. Then, dried over anhydrous sodium sulfate, filtered, and the excess solvent was removed under reduced pressure, and the product was separated using column chromatography (developing solvent, 10% methanol: dichloromethane) to give the title compound 2a as a white solid (6.00 g, 98.2%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.78-2.83 (m, 2H), 3.21-3.37 (m, 2H), 4.11 (d, J = 3.9 Hz, 2H), 5.16 (bs, 1H), 6.81- 6.85 (m, 2H), 7.13-7.27 (m, 24H), 7.57-7.60 (m, 2H), 7.69 (d, J = 4.4 Hz, 2H)

¹³ C NMR (75.5 MHz, (CD ₃ ) ₂ SO) δ 49.54, 54.83, 127.75, 127.81, 128.47, 129.95, 133.17, 133.31, 133.43, 133.58, 133.67, 136.40, 136.69, 137.95, 138.12, 140.90, 141.23.

IR (KBr pellet) 698, 746, 910, 1026, 1090, 1162, 1310, 1434, 1480, 1532, 1584, 1644, 3050, 3286 cm ^-1

Preparation Example 2 Preparation of Chiral Pyrrolidinyl (Bisphos Diamide) Derivative 2: S-Isomer

Using the compound of 4a as a starting material in the same manner as in Preparation Example 1 to prepare a compound of 2b.

The compound obtained at each step was subjected to NMR measurement, the result was the same as the prepared compound, except that the sign of the optical rotation (optical rotation) was reversed.

I. Preparation of Chiral Pyrrolidinyl (Bisphosphinodiamide) Derivatives Bonded to Polymers of Formula 1

Example 1 Preparation of Trityl Resin (crosslinked with 1% DVB; 100-200 mesh; ˜1.1 mmol Cl / g resin, Fluka Chemie AG)

Compound of Formula 2a prepared in Preparation Example 1 (230 mg, 0.34 mmol) was purified dichloromethane. After dissolving in (50 mL), triethylamine (71 μL, 0.51 mmol), trityl chloride polystyrene resin (2.00 g, 2.2 mmol) 4-aminodimethylpyridine (2.1 mg, 0.017 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 14 hours for reaction. After half-termination, the reaction product was filtered and then dichloromethane (160 mL), distilled water (150 mL), methanol (200 mL) was washed several times.

The resulting resin was dried under high vacuum in order to cap the terminal portion of the unreacted resin with -OCH ₃ , and then dichloromethane. (15 mL), methanol (15 mL), triethylamine (600 μL, 4.37 mmol) were added, and the mixture was stirred and filtered for 15 minutes. Then, dichloromethane again (50 mL), distilled water (150 mL), methanol (200 mL), dichloromethane (50 mL) After washing in order, the unreacted compound of formula 2a remaining in the polymer compound was extracted with tetrahydrofuran (THF) for 24 hours using a Soxhlet extractor. Subsequently, it dried for 24 hours under high vacuum, and obtained the target compound.

As a result of elemental analysis, the product contains 0.73% of nitrogen atoms, which means that 0.17 mmol of the chiral ligand of Formula 2a is bound per 1 g of the product.

IR (KBr pellet) 694, 742, 830, 1104, 1446, 1490, 1654, 2922, 3022, 3408 cm ^-1

Example 2 Polymer is JandaJEL ^TM Preparation of Intrityl Resin Compound

Compound of Formula 2a prepared in Preparation Example 1 (288.7 mg, 0.426 mmol) was purified on dichloromethane. After dissolving in (50 mL), triethylamine (89μL, 0.639), JandaJel trityl chloride resin (2.00 g, 1.42 mmol) 4-aminodimethylpyridine (2.6 mg, 0.0213 mmol) was added thereto, and stirred at room temperature for 14 hours for reaction. After completion of reaction, dichloromethane (160 mL), distilled water (150 mL), methanol (200 mL) was washed several times.

In order to cap the terminal group of the unreacted trityl chloride resin with -OCH ₃ , the resin was dried under high vacuum and again dichloromethane. (15 mL), methanol (15 mL), triethylamine (383 μL, 2.75 mmol) were added, and the mixture was stirred and filtered for 15 minutes. Then dichloromethane (50 mL), distilled water (150 mL), methanol (200 mL), dichloromethane (50 mL) After washing in order, it was extracted with tetrahydrofuran (THF) for 24 hours using a Soxhlet extractor as in Example 1 to remove the unreacted starting material of formula (2). After extraction, the obtained product was dried under high vacuum for 24 hours to obtain the target compound.

As a result of elemental analysis, the product contains 0.64% nitrogen atom, which means that 0.15 mmol of the chiral ligand of Formula 2a is bound per gram of product 1a.

IR (KBr pellet) 538, 696, 746, 830, 902, 1026, 1072, 1176, 1238, 1448, 1492, 1600, 1656, 2920, 3024, 3406 cm ^-1

Experimental Example 1 Catalytic Activity and Optical Selectivity of Chiral Pyrrolidinyl (Bisphosphinodiamide) Derivatives 1

In the present invention, in order to examine the catalytic effect of the chiral pyrrolidinyldiamide diphosphine derivative of the general formula (1), cis-1,4-bis (benzoyloxy) cyclopent-2-ene and dimethyl malonic acid are used as nucleophiles. Using ([η ³ -C ₃ H ₅ ) PdCl] ₂ as a catalytic amount, asymmetric allyl substitution reaction of Scheme 7 was carried out.

[(Η ³ -C ₃ H ₅ ) PdCl] ₂ (1.5 mg, 4 μmol) and the respective chiral compounds (22.1 mg, 24 μmol) prepared in Examples 1 and 2 were added to anhydrous tetrahydrofuran (2 mL). It was put under argon and stirred at room temperature for 1 hour. Separately add dimethyl malonic acid (25.1 mg, 0.19 mmol) and 95% sodium hydride (4.8 mg, 33.3 μmol) in tetrahydrofuran anhydride (1 mL) at 0 ^° C. to prepare dimethyl sodiomalonic acid directly Then further cis-1,4-bis (benzoxy) cyclopent-2-ene (50 mg, 0.16 mmol) was injected.

The chiral ligand and palladium complex with the polymer as a support were cooled to 0 ^° C., and a solution containing cis-1,4-bis (benzoxy) cyclopent-2-ene and dimethyl sodiomalonic acid was slowly added dropwise. After completion of the reaction, the chiral ligand and palladium complex having the polymer as a support were filtered and washed with dichloromethane. The solvent was removed under reduced pressure and then column chromatography (developing solvent, ethyl acetate: hexane = 1: 4) afforded the desired product.

Yield and optical purity of the products obtained in Experimental Example 1 and Experimental Example 2 were measured using chiral high performance liquid chromatography and the results are shown in Table 1 below.

Activity and Optical Selectivity of Chiral Ligands Based on the Polymers Prepared in Examples 1 and 2 1 order Ligand time yield(%) Optical selectivity (%) Absolute array One Example 1 15 hours 73 84 1 S , 4 R 2 Example 2 30 minutes 98 96 1 S , 4 R

All reactions were based on 0.2 mmol size of substrate at 0 ^o C [(η ³ -C ₃ H ₅ ) PdCl] ₂ : ligand: substrate: NaH (95%): dimethylmalonate = 0.025: 0.15: 1: 1.8: 1.5 The molar ratio was performed and the optical selectivity was determined via high performance liquid chromatography using a Chiralcel OJ column. [Separation conditions: ⁱ PrOH-hexane (15:85), flow rate = 1.0 mL min ⁻¹ ; 15.8 min (1 S , 4 R) , 21.5 min ( 1R, 4S )]

As shown in Table 1, the chiral compound of the present invention was found to exhibit high yield and excellent optical selectivity in the asymmetric allyl reaction.

Experimental Example 2 Catalytic Activity and Optical Selectivity of Chiral Pyrrolidinyl (Bisphosphinodiamide) Derivatives 2

In the present invention, [(η ³ -C ₃ H ₅ ) PdCl] using meso biscarbamate as a substrate to investigate the catalytic effect of the chiral pyrrolidinyl (bisphosphinodiamide) derivative of the formula (1) Asymmetric allyl substitution was carried out using ₂ as a catalytic amount, as shown in Scheme 8 below.

[(Η ³ -C ₃ H ₅ ) PdCl] ₂ (1.8 mg, 4.93 μmol) and each chiral compound (87.1 mg, 14.8 μmol) prepared in Examples 1 and 2 were added to anhydrous tetrahydrofuran (3 mL). It was put under argon and stirred at room temperature for 1 hour. Separately, meso biscarbamate (97.4 mg, 0.197 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), triethylamine (27.4 μL, 0.197 mmol) was added thereto, and the mixture was stirred for 20 minutes.

The chiral ligand and palladium complex with the polymer as support were cooled to 0 ^° C. and the meso biscarbamate solution was slowly added dropwise. At the end of the reaction, the catalyst was washed several times with anhydrous tetrahydrofuran (4 × 2 mL) using a syringe. The solvent was removed under reduced pressure followed by column chromatography (developing solvent, 10-20% ethyl acetate: hexane) to give oxazolidinone as a white solid.

Yield and optical purity of the products obtained in Experimental Example 1 and Experimental Example 2 were measured using chiral high performance liquid chromatography and the results are shown in Table 1 below.

Activity and Optical Selectivity of Chiral Ligands Based on Polymers Prepared in Examples 1 and 2 order Ligand time yield(%) Optical selectivity (%) Absolute array One Example 1 30 minutes 98 97.5 1 S , 4 R 2 Example 2 20 minutes 99 99 1 S , 4 R 3 ^a Example 2 20 minutes 99 98.2 1 S , 4 R 4 ^a Example 2 40 minutes 99 97.7 1 S , 4 R 5 ^a Example 2 1 hours 99 97.1 1 S , 4 R 6 ^a Example 2 3 hours 95 94.7 1 S , 4 R

All reactions were performed at 0 ^o C with [(η ³ -C ₃ H ₅ ) PdCl] ₂ : ligand: substrate: Et ₃ N = 0.025: 0.075: 1: 1 molar ratio based on 0.2 mmol of substrate. Determination via high performance liquid chromatography using a Chiralpak AD column. [Separation conditions: ⁱ PrOH-heptane (15:85), flow rate = 1.0 mL min ⁻¹ ; 24.4 min ( 1S, 4R) , 27.3 min ( 1R, 4S )] (a: The ligand used in the previous reaction was recovered by regeneration, and further (η ³ -C ₃ H ₅ ) PdCl] ₂ was added. The reaction proceeds without.)

In Table 2 and Table 1 in the previous experiment As can be seen, high catalytic activity (up to 99% yield) and excellent optical selectivity (up to 99%) in asymmetric allyl substitution reactions in heterogeneous catalyst systems using chiral pyrrolidinyl (bisphosphinodiamide) derivatives bound to the polymer of formula (1) % ee).

Experimental Example 3 Reuse of Chiral Pyrrolidinyl (bisphosphinodiamide) Derivatives

In order to determine the reuse efficiency of the chiral pyrrolidinyl (bisphosphinodiamide) compound of the present invention was carried out as follows.

After completion of the reaction in Experimental Example 1, the reaction solution was filtered to separate the chiral pyrrolidinyl (bisphosphinodiamide) compound used as a catalyst. After washing with anhydrous tetrahydrofuran, the asymmetric allyl reaction of Experimental Example 1 was again performed. As a result, the yield of the reaction product was about 95 to 99%, and the optical activity was confirmed to be 95 to 98%, indicating that the chiral pyrrolidinyl (bisphosphinodiamide) compound of the present invention can be reused. 2).

Since the chiral pyrrolidinyl (bisphosphinodiamide) derivatives are insoluble in organic solvents, they can be easily filtered, separated and recovered from the reaction solution after the reaction, as well as expensive [(η ³ -C ₃ H ₅ ) PdCl]. _Since it can be reused without adding ₂ , it can be usefully used as a chiral catalyst for asymmetric allyl substitution.

As described above, the chiral pyrrolidinyl (bisphosphinodiamide) derivative according to the present invention, as a catalyst for the asymmetric allyl substitution reaction, can not only synthesize a compound having high optical purity with high yield but also a simple manufacturing method. Not only is it economical, it can be recovered and reused by a simple treatment and can be usefully used.

Claims (7)

A chiral pyrrolidinyl (bisphosphinodiamide) compound represented by Formula 1 below: Formula 1 In the above formula, Ⓟ is a polystyrene or copolymer of styrene with a compound of formula A or a compound of formula B; Formula A Formula B (n is 1 to 3) At this time, the hydrogen atom 1 and the hydrogen atom 2 are in a trans position with each other. The compound of claim 1, wherein the chiral pyrrolidinyl (bisphosphinodiamide) compound is represented by the following Chemical Formulas 1a and 1b: Formula 1a (Wherein ⓟ is as defined in formula 1) Formula 1b (Wherein ⓟ is as defined in formula 1) Method of preparing a compound of Formula 1 prepared by reacting a compound of Formula 2 with a polymer including a substituent of Formula 3: Scheme 1 (Wherein ⓟ is as defined in Formula 1, Z is a leaving group as a leaving group) The method of claim 3, wherein the compound of Formula 2, 1) reacting the compound of formula 4 with an azide compound to azidize; 2) hydrogenating the obtained azide compound of formula 5 under a palladium catalyst; 3) reacting the obtained amine compound of formula 6 with an aryl compound of formula 7; And 4) A process according to claim 8, wherein the compound of formula 8 is prepared by treating with a Lewis acid. Scheme 2 (In the above formula, the hydrogen atom 1 and the hydrogen atom 2 are in trans position with each other). The compound according to claim 1, wherein the chiral pyrrolidinyl (bisphosphinodiamide) compound is used as a chiral catalyst for asymmetric allyl substitution. 6. The compound of claim 5, wherein said chiral catalyst further comprises palladium. The compound according to any one of claims 5 to 6, wherein the chiral catalyst is used after the filtration in an asymmetric reaction and then separated and reused.