KR100340761B1 - Resolution method for preparing l-muscone stereoselectively - Google Patents

Abstract

In the present invention, dl -muscon ketal compound (III) is made by reacting pentitol derivatives with 3-methylcyclopentadecan-1-one (II), and then hydrolyzed to separate l -muscon (I). In the method, a dl -muscon ketal compound (III) is collected under normal phase chromatography conditions and then hydrolyzed to provide a method for stereoselectively separating l -muscon (I).

(Scheme 1)

In formula, R <_1> represents the functional group of the following structural formula.

Description

Solution method for preparing l-muscone stereoselectively}

The present invention relates to a method for separating and purifying l -muscon optically active material. Still more particularly, dl - no scones la by reacting tray tolyl derivative in racemic dl - no scones using a back column chromatography to form a ketal according to the method of separating the optically active substance, the type of column and eluted number of The present invention relates to a method for stereoselectively separating and purifying high purity l -muscon optically active substance in high yield through selection.

Musk has the effect of strong heart, soothing, central nervous excitement, so it is used in Korea as a pharmaceutical ingredient such as wowang cheongsimwon and Ki Eung Hwan and has been relying on total imports, but since October 1996, CITES (Protection Agreement on International Trade in Endangered Animals) 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).

Currently, some pharmaceutical companies have synthesized l -muscon in natural musk as a substitute for musk, and has been proved to be equivalent in musk and drug expression, and has been replaced by Wu Hwang Cheongsimwon, but as shown in Structural Formula (1) below, -It is not easy to introduce the carbon-position methyl group in three-dimensionally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.

(Equation 1)

Until now, the synthesis of dl -muscon as a racemate has been published for many economic and reasonable processes [ Angew. Chem. 69 , 397 (1957); Tetrahedron Letters , 2257 (1979); Tetrahedron Letters , 32 , 565 (1991)], through cyclopentadecanone as α, β-unsaturated Cyclopentadec-2-enone as α, β-unsaturated Cyclopentadec-2-enone Carbon position methylation is known to be the most effective synthesis method (Scheme 2).

(Scheme 2)

However, even though commercial production of dl -muscon racemate by the economical method by the synthesis process of Scheme 2, it is not possible to optically separate by chemical method due to the material structure, and only l -muscon is used purely in medicine. It is possible, and therefore, the study of the method for producing stereoselective l -muscon has emerged as an important task.

Conventional optically active l -muscon synthesis method has focused mainly on stereoselective methylation methods from an academic point of view. As shown in Scheme 2, the synthesis process is too complicated, chemical or optical purity is not satisfactory, and difficult to obtain starting materials. There was a flaw, such as the use of l -muscon, which could not be applied to the industrialized commercial production of muscon.

Viii) Asymmetric conjugate addition of CH3Li; J.C.S. Schematic of what is disclosed in Perkin I, 1193 (1992) is as follows.

(Scheme 2-1)

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

(Scheme 2-2)

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.

Meanwhile, Korean Patent Publication No. 226,622 discloses ketal by reacting with 1,4-di-O-benzyl-2,3-D-thritol in dl -muscon racemate, followed by reverse phase chromatography (column C _18). , 85% of mobile phase acetonitrile-water mixture), but this material has very low solubility in polar organic solvents, so it has a low sample loading and a long run time, making it practical for commercial use. There was a hard disadvantage.

The technical problem to be achieved by the present invention is to react with 1,4-di-O-benzyl-2,3-D-thritol in dl -muscon racemate already known to form a ketal and then in reverse phase chromatography conditions. to separate only non-scones in stereoselective tablet-conducted when the material is low sample loading amount of run time increases substantially in a commercially efficient way to overcome the difficult disadvantages to using l because of the polar organic solubility of the solvent is extremely low Chromatography conditions were completed.

Accordingly, an object of the present invention is to react hydroxyl derivatives to 3-methyl cyclopentadecan-1-one (II) to form dl -muscon ketal compound (III), and then hydrolyze them to form l -muscon (I). In the separation and purification method, dl -muscon ketal compound (III) is fractionated under normal phase chromatography conditions and then hydrolyzed to provide a method for stereoselectively separating l -muscon (I).

(Scheme 1)

In formula, R <_1> represents the functional group of the following structural formula.

On the other hand, the composition of the solvent as the mobile phase in the preparative chromatography method is tetrahydrofuran (THF): cyclohexane = (0-10%: 100-90%) or tetrahydrofuran (THF): normal hexane (n-Hexane ) Under (0-10%: 100-90%) pure phase column conditions.

Hereinafter, the present invention will be described in more detail.

In the conventional case, the carbon-substituted methyl group on the chemical properties of the compound is relatively insignificant with respect to the stereoselective functional group of the ketone introduced into the dl -muscon to enable optically active separation, so that the functional group to be introduced has a larger molecular size. It was necessary to select a compound and solve the problem of generating unwanted side reactions such as polymerization reaction when having other functional groups such as ester groups.

Therefore, it was confirmed that optically separated on a column or the like when D-thritol derivatives easily synthesized from L-Tartaric acid ester, which are easily obtained from natural products, were reacted with dl -muscon to form a ketal. Intensive study of the separation conditions, and secured the normal phase column conditions of the tetrahydrofuran (THF) / cyclohexane, tetrahydrofuran (THF) / normal hexane (n-Hexane) mobile phase, loading more than the reverse phase conditions Excellent results in terms of amount and economics were confirmed.

At this time, the column chromatography method is a net phase condition of the ratio of tetrahydrofuran (THF) / cyclohexane 0-10%, the ratio of tetrahydrofuran (THF) / normal hexane (n-Hexane) 0-10%. In reverse phase conditions, solvent re-extraction after separation, low loading due to low solubility, and long run time were not suitable for the process.

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

(Reagents and devices)

Among the reagents used in the experiment, cyclopentadecanone was used by Aldrich Sigma Co., Ltd. and other necessary reagents were purchased by using a special reagent, and other solvents were purified by a known method. The progress of all experiments was observed by TLC and the purity of the intermediates obtained was confirmed by HPLC. At this time, the column of HPLC used Silica SG80A, 4.6 X 250mm, 5μ, Shiseido Inc., and the specific rotation was measured using JASCO Polarimeter.

In particular, enantiomer access (ee%) of l-muscon was more accurately measured using HPLC. The column used was Chiralpak AS, Daicel. The HPLC instrument used is from Shiseido. During the synthesis, all compounds were identified by 1H-NMR and 13C-NMR. The model used at this time is a Varian, 200MHz NMR spectrometer. All compounds were dissolved in the same solvent of CDCl3, and chemical shifts were expressed as δ (ppm) from tetramethylsilane (TMS), an internal standard for the 1H spectrum, and CDCl3 as an internal standard for the 13C spectrum. (77.0) was used and expressed as δ (ppm). The mass selective detector (GC-MSD) used HP5970 MSD. The column used was SE-54, a carrier gas of helium, a flow rate of 1.0 mL / min, an inlet temperature of 280 ° C, and a detector of 300 ° C. UV / Vis spectrometer used JASCO.

Example 1 Synthesis and Separation of dl -Muscon Ketal (III)

3-methylcyclopentadecan-1-one (0.738 g), 1,4-di-O-benzyl-D-thritol (1.05 g) and p-toluene-sulfonic acid monohydrate (p-toluene-) in a round three-neck flask sulfonic acid monohydrate: 0.329g) is dissolved in benzene (25mL) solvent and reacted under reflux under nitrogen atmosphere. Fit a Dean-Stark trap to remove Azeotropically H ₂ O. TLC (hexane: ethyl acetate = 9: 1) analysis is used until the starting material is used up. The reaction solution is cooled to room temperature and then extracted with ether solvent. The organic layer was transferred to a separatory funnel and washed well with saturated NaHCO ₃ and brine, followed by removal of water with anhydrous MgSO ₄ , blowing solvent under reduced pressure to obtain a crude product, followed by silica gel column chromatography (hexane: ethyl acetate = 9: 1). 1.88 g (86%) of 3-methylcyclopentadecan-1-one-1,4-di-O-benzyl-D-thritol ketal (III) was obtained.

1H-NMR (CDCl3, δ) 0.95 (3, d, JHH = 6.2Hz, Doublet peak splitting results in peaks of isomers, respectively), 1.3-1.7 (27, m), 3.62 (4, d), 4.01 (2, t), 4.58 (4, s), 7.35 (10, 2 phenyl)

A preparative chromatography system was applied to separate the 3-methylcyclopentadecan-1-one-1,4-di-O-benzyl-D-thritol ketal isomeric compound obtained above. The column used SILICA AG80 S-20, 10mm X 250mm X 2, (Shiseido), the detection wavelength is 258nm, the composition of the solvent is 1.0% THF / normal hexane, the flow rate is 5mL / min at room temperature. The sample injected is 30 mg and the run time is 120 minutes. The preceding peak is (+)-3-methylcyclopentadecan-1-one-1,4-di-O-benzyl-D-thritol ketal, which is [α] d +5.99 (c = 1.0, CHCl 3). +)-3-Methylcyclopentadecan-1-one-1,4-Di-O-benzyl-D-threitol ketal) and the following peak is (-)-3 with [α] d -3.92 (c = 1.0, CHCl3) -Methylcyclopentadecan-1-one-1,4-di-O-benzyl-D-thritol ketal ((-)-3-Methylcyclopentadecan-1-one-1,4-Di-O-benzyl-D- threitol ketal).

In addition, increasing the length of the column (250 mm × 3) by 1.5 times doubled the loading in 1.2% tetrahydrofuran (THF) / normal hexane to 60 mg and the run time was 180 minutes. Therefore, the loading amount according to the column size is shown in Table 1 below.

Table 1

Column size 100 mm 200 mm 300 mm 400 mm Loading amount 6 g 24 g 54 g 96g

The composition of the solvent was found to be more adverse in terms of retention time than in the case of tetrahydrofuran (THF) / cyclohexane, ethyl acetate / normal hexane and ethyl acetate / cyclohexane than 1.2% THF / normal hexane.

Comparative Example 1 Separation of dl -muscon ketal (III) under reversed phase chromatography conditions

The 3-methylcyclopentadecan-1-one-1,4-di-O-benzyl-D-thritol ketal obtained in Example 1 is a preparative reverse phase chromatography system (C18, ODS) 10 mm X 250 mm X2 C18UG80 ( S-20) Shiseido, detection wavelength 258nm, flow rate 5mL / min, separation at room temperature. To see some separation effect, 90% acetonitrile in mobile phase and run time is 240 minutes. At this time, the loading amount is 4mg. Therefore, even if the column size increases to 100 mm, the loading amount is 0.4 g. Under these conditions, in order to obtain the separated mousse ketal, not only the re-extraction with an organic solvent, but also the low solubility of l -muscon ketal (III) is difficult to use commercially because the loading amount is too small.

From the above results, it was found that high purity muscon isomers are separable. However, since the solubility in polar organic solvents is extremely low, the purification in the reversed phase mode cannot be regarded as efficient in view of the fact that the sample load is small and the purification time is long. Further, when a preparative column having an inner diameter of 100 mm and a length of 500 mm is used, the single sample load is 0.38 g, and even if each isomer is recovered 100%, it is calculated to be 0.2 g or less. Moreover, one purification time is more than four hours.

Therefore, it is wise to choose another preparative method. As an alternative, preparative phase in the normal phase mode may be considered. As a result, the same experimental results as in Example were obtained.

The effect of the present invention is that dl -muscon racemate and threitol which are already commercially available in an industrially economical way to develop l -muscon synthesis process having useful optical activity that can be industrially produced commercially. By reacting the derivatives, it was possible to selectively separate the l- type optically active substance from the dl -muscon ketal racemate, thereby providing a mass production method.

Claims (2)

In a method of separating and purifying l -muscon (I) by reacting 3-methylcyclopentadecan-1-one (II) with pentol derivatives to form dl -muscon ketal compound (III) and then hydrolyzing them , And separating dl -muscon ketal compound (III) under normal phase chromatography conditions and then hydrolyzing it to stereoselectively separate l -muscon (I). (Scheme 1) In formula, R <_1> represents the functional group of the following structural formula. The method of claim 1, wherein the composition of the solvent as the mobile phase in the preparative chromatography method is tetrahydrofuran (THF): cyclohexane = (0 to 10%: 100 to 90%) or tetrahydrofuran (THF): normal hexane (n-Hexane) = (0 to 10%: 100 to 90%) A method for separating and purifying l -muscon (I) by stereoselective, characterized in that the separation under the normal column conditions.