JPH047349B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pyrrolitidines. More specifically, the present invention provides a method for producing pyrrolitidines by reacting an olefin compound having a suitable leaving group in the molecule with atiridine, and then reacting the obtained pyrrolidine compound in the presence of a base. related to. A pyrrolitidine compound is a compound having the following basic structure. It is well known that many alkaloids exist in nature as compounds having such a pyrrolitidine skeleton. These compounds have various physiological and pharmacological effects, and there are many reports regarding their physiological and pharmacological effects. For example, there are reports such as: 1) Antitumor effect “Journal of Pharmaceutical Sciences (J.Pharm.Sci.)” 1968, 57 ,
1112 “Journal of Pharmaceutical Sciences (J.Pharm.Sci.)” 1967, 56 ,
541 "Journal of Natural Products (J.Nat.Prod.)" 1979, 42 , 603 2) Anti-inflammatory effect "Brit.J.Pharm." 1974,
51, 503 3) Hypoemic effect “Indian Journal of Pharmaceutics (Indian J.Pharm.)” 1974,
36, 90 “Indian Journal of Pharmaceutical Sciences (Indian J.
Pharm.Sci.)'' 1979, 4 , 131 4) Antileukemic effect ``Cancer and Chemotherapy'' 1978, 5 , 1081 5) Antispasmodic effect ``Farmakol. Toksikol. (Moscow)'' 1979,
42,509 6) Anti-miosis effect “Indian Journal of Experimental Biology (Indian J.Exp.
Biol) 1977, 15 , 397 These actions are just a few examples, and they provide a wide variety of physiological activities. Therefore, many methods for synthesizing compounds having a pyrrolitidine skeleton have also been reported. For example: 1) “J.Org.Chem.” 1974, 731 2) “Chem.Pharm.Bull.” 1982,
3167 3) “J.Am.Chem.Soc.” 1980,
7994 4) “Journal of Organic Chemistry” 1969, 1066 5) "Tetrahedron Lett." 1980, 3841 These synthesis examples are part of methods for synthesizing pyrrolitidine compounds, and there are many other reports. Synthesis Example 1) using the above-mentioned conventional method involves a small number of steps, but it is difficult to introduce a functional group, and in Example 2), special reagents must be used. In addition, Synthesis Example 3) of a compound having a functional group at the 7-position of pyrrolitidine not only requires a large number of steps, but also has disadvantages in terms of economy of raw materials, reagents, etc. Similar shortcomings have also been pointed out in other reports. The inventors conducted research aimed at solving the drawbacks of conventional methods and developing a synthetic method that can be widely applied to the synthesis of various pyrrolitidine derivatives, and have completed the present invention. The purpose of the invention is to provide the general formula [wherein R ¹ and R ² are hydrogen or hydroxy groups (optionally protected), or
R ¹ and R ² may together represent =O or a carbonyl protecting group; R ³ and R ⁴ represent -CO ₂ R, -COSR, -CN, -SO ₂ R, -S(O )
an electron-withdrawing functional group selected from R, -SR, -SeR, -Se(O)R, _-NO2 (where R is an alkyl or aryl group) or hydrogen, with the proviso that ^R3 and R In the method for producing a pyrrolitidine compound represented by the formula (except when both ⁴ are hydrogen), the general formula () (In the formula, ^X is a halogen atom or a leaving group selected from p-toluenesulfonyloxy group, ^{methanesulfonyloxy} group ^,
R ⁴ has the same meaning as above)), an olefin compound represented by the structural formula () The general formula () obtained by reacting with atiridine having Provided is a method for producing a pyrrolitidine compound, which comprises treating a pyrrolidine compound represented by the formula (wherein X, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above) in the presence of a base. It's about doing. The reaction formula for synthesizing pyrrolitidines by the method of the present invention is as follows. According to the method of the present invention, it is easy to introduce a functional group into the 7-position, and the desired pyrrolitidine compound can be synthesized in a short process without requiring special reagents or reaction conditions. As the pyrrolitidine compound obtained by the method of the present invention, in the general formula, R ¹ and R ² are:
is hydrogen or a hydroxy group or hydroxy protecting group (e.g. -OMe, -OAc, -OTHP (THP=tetrahydropyranyl), etc.), or R ¹
and R ² together may represent =O or a carbonyl protecting group (e.g. [Formula] [Formula], etc.), and R ³ and R ⁴ may represent an electron-withdrawing functional group (e.g. -CO ₂ R, -
COSR, −CN, −SO ₂ R, −S(O)R, −SR, −
Compounds such as SeR, -Se(O)R, _-NO2 (R = alkyl group or aryl group) or hydrogen (except when ^R3 and ^R4 are both hydrogen)
Examples thereof include ethylpyrrolitidine-1-exocarboxylate and ethyl-1-phenylselenopyrrolitidine-1-carboxylate. The starting compound (1) in the above reaction formula can be easily prepared according to a conventionally known general method for synthesizing olefins. X in general () is
These are halogen atoms such as Cl, Br, and I, or commonly used leaving groups such as p-toluenesulfonyloxy and methanesulfonyloxy groups. Atiridine (2) is an inexpensive compound with high reactivity, and when reacted with olefin compound (1), it gives pyrrolidine compound (3) at once. Then, by treating the obtained pyrrolidine compound (3) in the presence of a base, the desired pyrrolitidine compound (4) is obtained. Bases that can be used in this case include lithium diisopropylamide (LDA), t-BuOK, NaOMe, and NaH. If necessary, φSeCl,
Various functional groups can be introduced into the 1-position by reacting φSe・Seφ, φSCl, halogen, alkyl halide, etc. Furthermore, an olefin compound that is a raw material of the present invention
By selecting various types of (1), it is easy to synthesize not only the previously known pyrrolitidine compounds but also new pyrrolitidine compounds in a short process and economically. Furthermore, the compounds obtained by the method of the present invention can be used as important intermediates for conversion into various natural pyrrolitidine alkaloid compounds or for synthesizing other pyrrolitidine derivatives having useful physiological activities. The present invention will be explained in detail below using an example which is a preferred specific example of the manufacturing method of the present invention, but the present invention is not limited thereto. Example 1 (i) Ethyl-6-chloro-2-hexenoate (in the general formula, X=Cl, R ¹ , R ² , R ⁴
=H, R ³ =CO ₂ Et) Synthesis First, as the raw material olefin compound (1), ethyl-6-chloro-2-hexenoate was prepared as follows. 2 g of sodium hydride (60% oil) was suspended in anhydrous benzene (30 ml), 11.25 g of ethyl diethylphosphonoacetate was added with stirring, and 1
After stirring for an hour, 5.32 g of 4-chlorobutanal
Add anhydrous benzene solution (10 ml) of
Stir for hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. When the obtained oil was subjected to vacuum distillation (bp91-92℃, 3mmHg), 7.9g of olefin compound (1) (yield
89.6%) was obtained. The results of various analyzes on the product are as follows. IRν ^film _nax (cm ^-1 ): 1715 (-COO-) NMR (CDCl ₃ ) δ (ppm): 1.29 (3H, t, J=
7.1Hz, OCH ₂ CH ₃ ), 1.97 (2H, m, −CH ₂
−), 2.38 (2H, m, −CH ₂ −), 3.55 (2H,
t, J = 6.3Hz, CH ₂ Cl), 4.18 (2H, q, J
= 7.1Hz, −OCH ₂ −CH ₃ ), 5.86 (1H, dt, J
= 1.5 and 15.8Hz, olefinic proton), 6.91
(1H, dt, J = 6.8 and 15.8Hz, olefinic
proton) MS (m/z): 176 (M ⁺ ) HighMS: Calcd for C ₈ H ₁₃ O ₂ Cl; 176.0603 (M ⁺ ) Found; 176.0575 (M ⁺ ) (ii) Ethyl-N-(β-chloroethyl) -Synthesis of 2-pyrrolidine acetate (in the above general formula (), X = Cl, R ¹ , R ² , R ⁴ = H, R ³ = CO ₂ Et) A mixture of 5 g of the above compound (1) and 20 ml of atiridine (2) Stir at 0°C for 3.5 hours and add benzene.
After adding 50 ml, excess atiridine and solvent were distilled off at 10°C. When the obtained oil was subjected to vacuum distillation (bp 113-115°C, 3 mmHg), 4.51 g (yield 72.5%) of ethyl-H-(β-chloroethyl)-2-pyrrolidine acetate (3) was obtained as a colorless oil. obtained as. The results of various analyzes of the obtained product are as follows. IRν ^film _nax (cm ^-1 ): 1740 NMR (CDCl ₃ ) δ (ppm): 1.26 (3H, t, J=
7.1Hz, -CH ₃ ) 1.46-3.24 (11H, m, 5×
CH ₂ and CH), 3.54 (2H, t, J = 6.7Hz,
CH ₂ Cl), 4.31 (2H, q, J = 7.1Hz, −
OCH ₂ ) MS (m/z): 219 (M ⁺ ) (iii) Ethyl-pyrrolitidine-1-exo-carboxylate (R ¹ ,
Synthesis of R ² , R ⁴ = H, R ³ = CO ₂ Et) Diisopropylamine 0.77 ml, 15% n-butyllithium-hexane solution 3.5 ml and anhydrous
To a mixed solution of 15 ml of THF was added 15 ml of a THF solution containing 1 g of the compound (3) obtained above at -78°C. After stirring at -78°C for 3 hours, the mixture was further stirred at room temperature for 12 hours, 20 ml of water was added, and the mixture was extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. Further, when subjected to vacuum distillation (bp80-82℃, 3mmHg), 0.715g of ethyl-pyrrolitidine-1-exo-carboxylate (4) (yield 85.8%)
was obtained as a colorless oil. The results of various analyzes on the product are as follows. IRν ^film _nax (cm ^-1 ): 1735 NMR (CDCl ₃ ) δ (ppm): 1.26 (3H, t, J=
7.1Hz, CH ₃ ) 1.50−2.22 (6H, m, 3×
CH ₂ ), 2.40−3.31 (5H, m, 2×CH ₂ and
CH), 3.60 (1H, dt, J = 4.9 and 7.3Hz,
N-CH), 4.15 (2H, q, J = 7.1Hz,
OCH ₂ ) MS (m/z): 183 (M ⁺ ) Picrate: mp149-150℃ [Literature value 149-151℃,
"Journal of Organic Chemistry (JOC)" 1977, 1225] Example 2 Ethyl-1-phenylselenopyrrolitidine-1
-carboxylate (in general formula ())
R ¹ , R ² = H, R ³ = COOEt, R ⁴ = −Seφ (compound 4a) and R ¹ , R ² = H, R ³ = Seφ, R ⁴ =
Synthesis of COOEt (compound 4b) To a mixture of 3.1 ml of diisopropylamine, 14 ml of 15% n-butyllithium-hexane solution and 30 ml of THF, add 30 ml of a THF solution containing 2 g of compound (3) obtained as in Example 1 above. The mixture was added at -78°C, stirred at this temperature for 1 hour, then gradually raised to -40°C, and then cooled again to -78°C. Then, phenylselenenyl chloride (φ-
After adding 2.1 g of THF solution (SeCl) and stirring for 4 hours, 5 ml of water was added and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and 0.6 g of compound (4a) or (4b) (yield 19.5%) was obtained from the eluate of methylene chloride-methanol-ammonium hydroxide (90:9:1 v/v). ) was obtained as a pale yellow oil. Further elution yielded 0.5 g (yield 16.2%) of compound (4b) or (4a) as an oil. The results of various analyzes of the obtained product are as follows. 4a or 4b IRν ^film _nax (cm ^-1 ): 1725, 1580 NMR (CDCl ₃ ) δ (ppm): 1.22 (3H, t, J = 7.1
Hz, _CH3 ) 1.60-2.80 (8H, m), 3.08-3.70
(3H, m)4.13 (2H, q, J=7.1Hz−OCH ₂ )
7.23−7.65 (5H, m, 5×ArH) MS (m/z): 337 (M ⁺ ) Picrate: mp159−162℃ 4b or 4a IRν ^film _nax (cm ^-1 ): 1720, 1580 NMR (CDCl ₃ ) δ (ppm): 1.64 (3H, t, J = 7.1
Hz, _CH3 ) 1.85-3.27 (11H, m), 4.05 (2H,
q, J = 7.1Hz, OCH ₂ ), 7.21−7.61 (5H, m,
5×ArH) MS (m/z): 337 (M ⁺ ) Picrate: mp132-136°C [Table] The present invention has been described in detail with respect to specific examples thereof,
It will be appreciated that the invention is not limited to this particular embodiment and that many changes and modifications may be made without departing from the spirit of the invention.

Claims (1)

[Claims] 1 General formula () [wherein R ¹ and R ² are hydrogen or hydroxy groups (optionally protected), or
R ¹ and R ² may together represent =O or a carbonyl protecting group; R ³ and R ⁴ represent -CO ₂ R, -COSR, -CN, -SO ₂ R, -S(O )
an electron-withdrawing functional group selected from R, -SR, -SeR, -Se(O)R, _-NO2 (where R is an alkyl or aryl group) or hydrogen, with the proviso that ^R3 and R In the method for producing a pyrrolitidine compound represented by the formula (except when both ⁴ are hydrogen), the general formula () (wherein, X is a halogen atom or a leaving group selected from p-toluenesulfonyloxy group, methanesulfonyloxy group; R ¹ , R ² , R ³ and
R ⁴ has the same meaning as above)), an olefin compound represented by the structural formula () The general formula () obtained by reacting with atiridine having A method for producing a pyrrolitidine compound, which comprises treating a pyrrolidine compound represented by the formula (wherein X, R ¹ , R ² , R ³ and R ⁴ have the same meanings as above) in the presence of a base.