JP3771128B2 - Novel synthesis method of febrifugine and febrifugine compounds - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The invention of this application relates to a novel method for synthesizing febrifudine and its derivatives. More specifically, in the invention of this application, after reacting a ketone with tin (II) triflate, it reacts with 2,3-disubstituted-N-benzyloxycarbonylpiperidine in the presence of Lewis acid to stereoselect febrifugine and its derivatives. The present invention relates to a method of synthesizing easily and easily.
[0002]
[Prior art and its problems]
There are many nitrogen-containing cyclic compounds in biologically important natural substances and pharmaceuticals. Febrifugine (1) and isofebrifudine (1 ') are alkaloids extracted from Chinese plants, Dichroa febrifuga and Hydrangea, and are known to have potent antimalarial activity (Koepfli, JB; Mead Brockman, JA, Jr. J. Am. Chem. Soc. 1947, 69, 1837; ibid 1949, 71, 1048; Ablondi, F .; Gordon, S .; Morton, J., II; Williams, JHJOrg Chem. 1952, 17, 14 and others). Halofuginone (2) is used as an antiparasitic feed additive for preventing coccidiosis in poultry production. Recently, it has been reported that halofuginone (2) inhibits collagen production, has attracted attention as a therapeutic agent for scleroderma, and is undergoing clinical trials.
[0003]
[Chemical 3]
[0004]
The inventors of this application have previously elucidated and reported a method for synthesizing febrifugine and isofebrifugine by asymmetric synthesis using a catalyst (Kobayashi, S .; Ueno, M .; Suzuki, R .; Ishitani, H .; Kim, H.-S .; Wataya, YJOrg.Chem. 1999, 64, 6833; Kobayashi, S .; Ueno, M .; Suzuki, R .; Ishitani, H. Tetrahedron Lett. 1999, 40, 2175). In order for these febrifugine compounds to exhibit antimalarial activity, it is considered essential that an OH group is present at the 3-position of the piperidine ring in the six-membered ring system.
[0005]
Moreover, in order to realize an increase in the antimalarial activity and a reduction in toxicity of the febrifugine compound, synthesis of various febrifudine derivatives is desired. As such a method, for example, a coupling reaction between an acyliminium cation and an enolate is considered.
[0006]
Recently, the biological properties of saccharides have attracted attention in the fields of chemistry and biology, and various stereoselective glycosylation methods utilizing anomeric and adjacent group effects have been studied. Therefore, it is expected that the same technique can be applied to the imino rearrangement of the C-glycosylation reaction as described above.
[0007]
To date, various Lewis acids (eg, BF ₃ .Et ₂ O, TiCl ₄ , SnCl ₄ , etc.) activate piperidine and pyrrolidine derivatives and react with nucleophiles at the 2-position. Has been reported to give. However, although the alkylation reaction of 2-substituted piperidine and pyrrolidine using such a method has been reported, there are few reports on 2,3-diastereoselectivity in piperidine systems (Yang, C. et al. -F .; Xu, Y.-M .; Liao, L.-X .; Zhou, W.-S. Tetrahedron Lett. 1998, 39, 9227; David, M .; Dhimane, H .; Vanucci-Bacque, C .; Lhommet, G. Synlett 1998, 206, etc.), and there are limited examples of synthesizing 2- and 3-positions with high diastereoselectivity (Plehiers, M .; Hootele, C. Can 1996, 74, 2444; Sugisaki, CH; Carroll, PJ; Correia, CRD; Tetrahedron Lett. 1998, 39, 3413; Batey, RA; MacKay, B .; Santhakumar, VJAm.Chem.Soc. 1999 , 121, 5075; Adelbrecht, J.-C .; Craig, D .; Dymock, BW; Thorimbert, S. Synlett 2000, 467). In addition, what has been reported is in most cases the classical method requiring a stoichiometric amount of Lewis acid.
[0008]
Therefore, the invention of this application has been made in view of the circumstances as described above, solves the problems of the prior art, synthesizes 2,3-disubstituted piperidines with high stereoselectivity, febrifugine and its It is an object to provide a simple method for synthesizing a derivative.
[0009]
[Means for Solving the Problems]
The inventors have so far conducted research to develop new synthesis methods and catalyst systems. In that process, metal triflates such as Sc (OTf) ₃ , Yb (OTf) ₃ , Hf (OTf) ₄ , etc. are various functionalities such as aldehydes, imines, acylhydrazones, acetals, and aminals in catalytic amounts. It has been found and reported to effectively activate the group and cause a new carbon-carbon bond reaction.
[0010]
Based on such knowledge, the inventors have conducted extensive research, and as a result, have found a method for stereoselectively synthesizing 2,3-disubstituted piperidines, and have led to the invention of this application. .
[0011]
That is, the invention of this application is to solve the above problems. First, the following chemical formula (I)
[0012]
[Formula 4]
[0013]
Is reacted with tin (II) triflate and diisopropylethylamine, and then the following chemical formula (II)
[0014]
[Chemical formula 5]
[0015]
(Wherein R ¹ and R ² each represent a hydrocarbon group which may have the same or different substituent, and Cbz represents a benzyloxycarbonyl group) Provided is a method for synthesizing febrifugine and its derivatives, in which substituted -N-benzyloxycarbonylpiperidine is reacted in the presence of a Lewis acid and treated with a strong acid.
[0016]
Second, the invention of this application provides a method for synthesizing the aforementioned febrifugine and derivatives thereof, wherein the Lewis acid is Sc (OTf) ₃ .
[0019]
DETAILED DESCRIPTION OF THE INVENTION
The method for synthesizing febrifudine and its derivatives of the invention of this application has the following chemical formula (I)
[0020]
[Chemical 6]
[0021]
Is reacted with tin (II) triflate and diisopropylethylamine, and then the following chemical formula (II)
[0022]
[Chemical 7]
[0023]
(Wherein R ¹ and R ² each represent a hydrocarbon group which may have the same or different substituent, and Cbz represents a benzyloxycarbonyl group) A substituted -N-benzyloxycarbonylpiperidine is reacted in the presence of a Lewis acid and treated with a strong acid.
[0024]
At this time, the ketone represented by the chemical formula (I) is quinazolone, but it may be obtained by any method. For example, it can be synthesized by the method described in Burgess, LE; Gross, EK; Jurka, J. Tetrahedron Lett. 1996, 37, 3255. Such a ketone is represented by the following chemical formula (III)
[0025]
[Chemical 8]
[0026]
Tin (II) enolate is obtained by reacting with tin (II) triflate represented by the formula: Such a tin (II) enolate has the following chemical formula (IV)
[0027]
[Chemical 9]
[0028]
It may be isolated and may be isolated, but when synthesized and used in situ, 2,3-disubstituted-N-benzyloxycarbonyl is obtained with high stereoselectivity and yield. Preferred is the product obtained by coupling with piperidine. In addition, tin (II) enolate represented by the chemical formula (IV) is more reactive than other enolates such as silyl enol ether. At this time, in order to increase the yield, it is preferable that the amount of ketone used is about 1.0 to 5.0 equivalents and the amount of tin (II) triflate is twice that amount. Further, diisopropylethylamine is preferably added in an amount equivalent to or slightly more than tin (II) triflate.
[0029]
By coupling 2,3-disubstituted-N-benzyloxycarbonylpiperidine as represented by chemical formula (II) in the presence of a catalytic amount of Lewis acid to tin (II) enolate obtained in situ, febrifugine A derivative is obtained. Such a derivative has the following structure.
[0030]
[Chemical Formula 10]
[0031]
In the 2,3-disubstituted-N-benzyloxycarbonylpiperidine of the chemical formula (II), R ¹ and R ² are the same or different hydrocarbon groups which may have a substituent as described above. And preferably an alkyl group such as methyl, ethyl or isopropyl, a benzyl group, or an acetyl group. That is, as —OR ¹ and —OR ² , a methoxy group, an ethoxy group, an acetoxy group, a benzyloxy group, and the like are considered. Particularly preferably, R ¹ is an acetoxy group or benzyloxy group, and R ² is an acetoxy group.
[0032]
The Lewis acid used in the method for producing febrifudine and the febrifudine derivative of the invention of this application is a coupling reaction of tin (II) enolate and 2,3-disubstituted-N-benzyloxycarbonylpiperidine as described above in a catalytic amount. Any metal triflates such as Sc (OTf) ₃ , Yb (OTf) ₃ , Hf (OTf) ₄ may be used as long as they can proceed with high yield. Among these, Sc (OTf) ₃ is particularly preferable because it can realize high stereoselectivity and yield. Further, the addition amount of Lewis acid is not particularly limited, but it works sufficiently with a catalyst amount of about 0.05 to 1 equivalent with respect to the ketone. More preferably, it is 0.1 to 0.5 equivalent.
[0033]
The 2,3-disubstituted-N-benzyloxycarbonylpiperidine used in the method for synthesizing febrifudine and its derivatives of the invention of this application may be obtained by any method. For example, J.Org.Chem. 1999, 64, 6833 and Tetrahedron Lett. 1999 40, 2175 but it may also be synthesized by the method described in.
[0034]
Then, following the coupling reaction in the presence of a Lewis acid, the target febrifugine or a derivative thereof can be obtained by treatment with a strong acid such as HBr or HCl. Of course, the strong acid may be other than these, and may be a mixed acid such as HBr / AcOH.
[0035]
In the method for synthesizing febrifudine and its derivatives as described above, conditions such as reaction solvent, reaction temperature, reaction time and the like are not particularly limited. The solvent is preferably an organic solvent capable of dissolving starting materials and reactants, and examples thereof include dichloromethane and chloroform. The reaction temperature is not particularly limited, but the synthesis method of the invention of this application can provide a sufficiently high yield and stereoselectivity even at a relatively low temperature of about −10 to 80 ° C. Furthermore, reaction time can be changed according to the Lewis acid used, reaction temperature, etc., and is not specifically limited.
[0036]
Hereinafter, embodiments will be described with reference to the accompanying drawings, and embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects are possible in detail.
[0037]
【Example】
<Example 1>
Febrifugin was synthesized according to the following reaction formula [X].
[0038]
Embedded image
[0039]
(1) Synthesis of (S) -2-benzyloxy-5-hydroxy-N-methoxy-N-methylpentanamide (B) N 2 O-dimethylhydroxyamine hydrogen chloride (0.42 mmol) in CH ₂ Cl ₂ ( 1.5 ml) solution was added trimethylaluminum in n-hexane (0.98 M, 0.42 ml) at −15 ° C. The reaction mixture was heated to room temperature, stirred for 1 hour, and then cooled to -15 ° C. Compound A (0.Og. Chem. 1999, 64, 6833, Tetrahedron Lett. 1999, 40, 2175, Snlett 1993, 911, Chem. Lett. 1994, 217 etc. was synthesized in the reaction mixture. 14 mmol) in CH ₂ Cl ₂ (1.5 ml) was added at −15 ° C., heated to room temperature, and stirred for 24 hours. A 15% potassium sodium tartrate aqueous solution was added to the obtained mixed solution, and the mixture was stirred for 1 hour and then filtered through a celite pad. The filtrate was extracted twice with CH ₂ Cl ₂ and the entire organic layer was dried over Na ₂ SO ₄ , filtered and dried in vacuo.
[0040]
The residue was dissolved in a 1N aqueous solution of hydrogen chloride and THF (1/5, 3 ml) and stirred at room temperature for 5 hours. After neutralization, the mixture was extracted twice with CH ₂ Cl ₂ and the organic layer was washed with brine and dried over Na ₂ SO ₄ . After filtration, the residue obtained by vacuum drying was purified by silica gel chromatography to obtain Compound B as a colorless oil in a yield of 65%.
[0041]
Table 1 shows the identification results of Compound B.
[0042]
[Table 1]
[0043]
(2) Synthesis method A of compound C: Compound B (0.117 mmol), triphenylphosphine (0.467 mmol) and diphenylphosphoryl azide (0.233 mmol) were added to dry THF (0.8 ml), and DEAD (0 .467 mmol) in dry THF (0.3 ml) was added at 0 ° C.
[0044]
The reaction solution was heated to room temperature and stirred for 1 hour, after which the solvent was removed in vacuo and the residue was purified by silica gel chromatography to give the corresponding azide. This azide was dissolved in EtOH (5 ml) and treated with a few drops of 1N aqueous HCl to effect catalytic hydrolysis for 3 hours (10% Pd—C, 10 atm).
[0045]
The catalyst was filtered off and the solvent was removed under vacuum. The obtained residue was dissolved in a THF-water (2 / 1d, 15 ml) mixed solvent, and NaHCO ₃ (0.584 mmol) and benzyloxycarbonyl chloride (0.467 mmol) were added. The mixed solution was stirred at 0 ° C. for 1 hour and extracted three times with CH ₂ Cl ₂ .
[0046]
The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and dried in vacuo. The residue was purified by silica gel chromatography to give Compound C as a colorless oil in 42% yield (2 steps).
[0047]
Method B: Compound C ′ (0.78 mmol) synthesized by the method described in J. Med. Chem. 1988, 31, 204, N, O-dimethylhydroxyamine hydrogen chloride (0.83 mmol), and triethylamine (0. 82 mmol) in CH ₂ Cl ₂ (2 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrogen chloride (0.94 mmol) at room temperature. After the mixture solution was stirred at room temperature for 3 hours, the reaction was quenched with water and the mixture was extracted 3 times with CH ₂ Cl ₂ .
[0048]
The organic layer was washed with 1N aqueous HCl, water and brine, dried over Na ₂ SO ₄ , filtered and dried in vacuo. The residue was purified by silica gel chromatography to obtain Compound C as a colorless oil in 89% yield.
[0049]
Table 2 shows the identification results.
[0050]
[Table 2]
[0051]
(3) Synthesis of (3S) -N-benzyloxycarbonyl-2,3-dihydroxypiperidine ((3S) -D) In a solution of compound C (0.493 mmol) in dry ether (2 ml), LiAlH ₄ (1.77 mmol) was added. ) Was added at 0 ° C. and stirred for 1.5 hours. After the reaction was quenched with water, the mixture was filtered through a celite pad and the filtrate was extracted twice with ethyl acetate.
[0052]
The organic layer was washed with water and brine, dried over Na ₂ SO ₄ , filtered and vacuum dried. The residue was purified by silica gel chromatography to obtain (3S) -D as a colorless oil in a yield of 91% (diastereomer mixture).
[0053]
When the diastereomeric ratio was determined by ¹ H NMR, it was found that the mixing ratio varied depending on the treatment method. In the above method, the cis / trans ratio was 56/44, and in the system that was quenched with a potassium sodium tartrate solution, the cis / trans ratio was 34/66. (3S) -D (cis / trans = 56/44) was obtained as a colorless oil.
[0054]
The identification results are shown in Table 3.
[0055]
[Table 3]
[0056]
(4) Synthesis of 2,3-diacetoxy-N-benzyloxycarbonylpiperidine ((3S) -E) Compound D (cis / trans = 100/0, 1.75 mmol) and 4-N, N-dimethylaminopyridine ( Acetic anhydride (10.6 mmol) was added to a solution of 0.18 mmol) in triethylamine (1.5 ml) at room temperature. After stirring the reaction solution for 3 hours, the reaction was quenched with a saturated aqueous NaHCO ₃ solution at 0 ° C.
[0057]
The reaction solution was extracted twice with ethyl acetate, and the organic layer was washed with water (5 times), saturated aqueous NaHCO ₃ solution, and brine. Dry over Na ₂ SO ₄ , filter and vacuum dry.
[0058]
The obtained crude product was purified by silica gel chromatography to obtain Compound E as a colorless oil (cis / trans = 95/5). The diastereomeric ratio was determined by ¹ H NMR.
[0059]
Similarly, (3S) -E (cis / trans = 57/43) was obtained using (3S) -D (cis / trans = 56/44) obtained in (3) above.
[0060]
The identification results are shown in Table 4.
[0061]
[Table 4]
[0062]
(5) Synthesis of (3S) -trans-O-acetyl-N-benzyloxycarbonylfebrifudine ((3S) -trans-F) Tin (II) triflate (0.367 mmol) and chemical formula (I)
[0063]
Embedded image
[0064]
A solution of diisopropylethylamine (0.377 mmol) in CH ₂ Cl ₂ (0.5 ml) was added at 0 ° C. to a CH ₂ Cl ₂ (0.5 ml) dispersion of a ketone (0.184 mmol). The reaction mixture was heated to room temperature, stirred for 1 hour and then heated to reflux. Sc (OTf) ₃ (0.018 mmol) was added to the reflux solution, and the chemical formula (VI)
[0065]
Embedded image
[0066]
2,3-diacetoxy-N-benzyloxycarbonylpiperidine (0.092 mmol) in CH ₂ Cl ₂ (0.3 ml) was added. The mixed solution was heated under reflux for 30 minutes and then cooled to room temperature. The reaction was quenched with saturated aqueous NaHCO ₃ and the mixture was extracted twice with CH ₂ Cl ₂ . The organic layer was washed with water and brine, dried over Na ₂ SO ₄ and then filtered to remove the solvent under vacuum.
[0067]
The residue was purified by silica gel chromatography to give trans-F (high polarity) and cis-F (low polarity) in 55% and 14% yields, respectively.
[0068]
The identification results of trans-F (colorless powder) and cis-F (colorless oil) are shown in Table 1.
[0069]
[Table 5]
[0070]
Further, (3S) -trans-F was synthesized in the same manner.
[0071]
[Α] _D ²⁵ m-51.3 (c = 0.80, CHCl ₃ ).
(6) Synthesis of febrifugine (1) (3S) -trans-F (0.052 mmol) was dissolved in 25% HBr / AcOH (3 ml) at 0 ° C., and this mixed solution was stirred for 30 minutes. Piperidine (2 ml) was added and the resulting mixture was made basic by adding saturated aqueous NaHCO ₃ solution. The mixture was extracted 3 times with CH ₂ Cl ₂ and the organic layer was washed with brine, then dried over Na ₂ SO ₄ , filtered and dried in vacuo.
[0072]
The residue was dissolved in MeOH (5 ml), NaOMe (0.065 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between water and CH ₂ Cl ₂ and the aqueous layer was extracted with CH ₂ Cl ₂ .
[0073]
The organic layer was washed with brine, then dried over Na ₂ SO ₄ , filtered and dried in vacuo. Purification by silica gel chromatography gave 1 in 25% yield (2 steps). This substance was previously identified by the inventors as a standard sample (J. Org. Chem. 1999, 64, 6833; Tetrahedron Lett 1999, 40, 2175).
[0074]
【The invention's effect】
As described in detail above, the present invention provides a method for synthesizing febrifudine and its derivatives with high stereoselectivity and yield. According to the synthesis method of the present invention, febrifudine and its derivatives can be synthesized easily at low temperature, so that it is expected to become a foothold for chemical synthesis of various natural substances.

Claims (2)

The following chemical formula (I)
Is reacted with tin (II) triflate and diisopropylethylamine, and then the following chemical formula (II)
(Wherein R ¹ and R ² each independently represent a hydrocarbon group which may have a substituent, and Cbz represents a benzyloxycarbonyl group) A method for synthesizing febrifugine and febrifugine derivatives, in which a substituted -N-benzyloxycarbonylpiperidine is reacted in the presence of a Lewis acid and treated with a strong acid. The method for synthesizing febrifugine and febrifugine derivatives according to claim 1, wherein the Lewis acid is Sc (OTf) ₃ .