JPS6411009B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel reducing agent that can be used to reduce an organic compound having a carbonyl group (ketone group or aldehyde group) in its structural formula to the corresponding alcohol. This invention relates to a novel lithium aluminum hydride-based reducing agent partially decomposed with a substituted ephedrin/equivalent ratio and a N-substituted aniline 2-equivalent ratio. More specifically, the present invention relates to the general formula () [In the formula, R ₁ represents a lower alkyl group or a benzyl group, and Ph represents a phenyl group. ] N-substituted ephedrin/equivalent ratio and general formula () [In the formula, R ₂ represents a lower alkyl group or a phenyl group, and Ph represents a phenyl group. ] It is a novel modified lithium aluminum hydride-based reducing agent obtained by reacting the N-substituted aniline 2 equivalent ratio represented by the following with the lithium aluminum hydride/equivalent ratio. Here, the N-substituted ephedrin represented by the general formula () includes (-)-isomer, (+)-isomer and racemate. The lower alkyl group for R ₁ in the general formula () includes methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, iso-butyl,
Examples include straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms, such as sec-butyl, and preferably a methyl group. In addition, in the general formula ()
The lower alkyl group for _R2 is methyl, ethyl,
Examples include straight chain alkyl groups having 1 to 4 carbon atoms such as propyl and butyl groups, with methyl and ethyl groups being preferred, and ethyl groups being more preferred. Conventionally, many reagents are known that reduce the carbonyl group of an organic compound having a ketone structure (ie, C=0) or an aldehyde structure (ie, ^HC =0) to a hydroxyl group. For example, sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium aluminum hydride,
Examples include lithium tri-tert-butoxyaluminum hydride, lithium tri-methoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, sodium aluminum hydride, etc., and these reagents can be used to carry out the reduction reaction. When this process is carried out, the carbon atom bonded to the resulting hydroxyl group often becomes an asymmetric carbon atom, and in this case, the product has two types: one in which the asymmetric carbon is in the R-coordination, and one in which the asymmetric carbon is in the S-coordination.
- It will be obtained as a mixture of equal amounts with the one in the -coordination, i.e. as a racemate. However, in the case of physiologically active substances such as pharmaceuticals, it is common for only one symmetrical substance to exhibit excellent physiological activity, and therefore the other symmetrical substance is usually not required. For these reasons, the development of asymmetric reducing reagents for selectively obtaining only one of the symmetry bodies is being actively conducted. Among them, many attempts have been made regarding modified lithium aluminum hydride, which is obtained by partially decomposing lithium aluminum hydride with an optically active substance, and asymmetric ring element reagents with good selectivity have been discovered, but all of them are as follows. It has its drawbacks. For example, a modified lithium aluminum hydride partially decomposed using N-methylefedrine and 3,5-dimethylphenol was prepared by Vigneron et al.
and JPVigneron, Tetrahedron Letters,
1974, 2065; JPVigneron and I. Jacquet,
Tetrahedron, 32 , 939 (1976); JPVigneron
and V. Bloy, Tetrahedron Letters, 1979 ,
2683; Idem, Ibid 19780 , 1735), but in this method, the 3,5-dimethylphenol used as an additive mixes with the alcohol, which is a reduced product, and is difficult to separate. It has a disadvantage that it has a weak chemical yield and a poor chemical yield when reducing α, β-unsaturated ketones, aldehydes, etc. In addition, modified lithium aluminum hydride partially decomposed with a proline derivative was produced by Mukaiyama et al. (T.
Mukaiyama, M. Asami, J. Hanna and S.
Kobayashi, Chemistry Letters, 1979 , 783;
M.Asami, H.Ohono, S.Kobayashi and T.
Mukaiyama, Bull.Chem.Soc.Japan, 51 , 1869
(1978); M. Asami and T. Mukaiyama,
Heterocycles, 12 , 499 (1979)), but this method has the disadvantage that proline used as an asymmetric source is expensive and its synthesis requires several steps. In addition, in recent years, modified lithium aluminum hydride partially decomposed with binaphthyl alcohol derivatives and alcohol has been developed by R. Noyori, I. Tomino and
Y.Tanimoto, J.Am Chem.Soc. 101 , 3129
(1979); R. Noyori, I. Tomino and M.
Nishizawa, Ibid., 101 , 5843 (1979)), but this method had drawbacks such as the need to synthesize and resolve the chiral source, and difficulties in separating the alcohol form as the reduction product. It has disadvantages such as low chemical yield and low chemical yield. The inventors of the present invention have conducted extensive studies in order to overcome the above drawbacks and develop an excellent modified lithium aluminum hydride reducing agent that meets all of the following three requirements. 1. Reduction reaction proceeds with high chemical yield and asymmetric yield. 2 Chiral source used by the generated alcohol
Easier to separate than additives etc. 3 The asymmetric source used is one that can be obtained in large quantities at low cost, and can be easily obtained after the completion of the reaction.
Optical pure can be recovered with high yield and reused. As a result, the present inventors have discovered an excellent modified lithium aluminum hydride reducing agent that overcomes the drawbacks of conventional modified lithium aluminum hydride reducing agents, satisfies all the three requirements above, and is industrially practicable. The present invention was completed. According to the present invention, the reducing agent of the present invention comprises an N-substituted ephedrin/equivalent ratio represented by the general formula (), a lithium aluminum hydride/equivalent ratio, and a 2-equivalent ratio of N-substituted aniline represented by the above general formula (). It is obtained by reacting with. The reaction is carried out under anhydrous conditions under an inert gas atmosphere such as nitrogen or argon. The reaction solvent is not particularly limited as long as it does not participate in the reaction, but dimethyl ether, diethyl ether, tetrahydrofuran, diglyme, methylal, toluene, etc. are used, and diethyl ether is preferably used. A reaction temperature of 0 to 100°C is sufficient, but it is preferably carried out at room temperature to 40°C. Further, the reaction time is not particularly limited, but 1 to 3 hours is sufficient. N-methylephedrin represented by the general formula () in which R ₁ represents a methyl group is obtained by reductive methylation (K.
Nakajima, Nippon Kagaku Zasshi, 81 , 1476 (1960)) can be easily synthesized in one step. Furthermore, although the lithium aluminum hydride used is normally used in the form of a solution in the production of such modified lithium aluminum hydride reducing agents, according to the present invention, the lithium aluminum hydride may not necessarily be used as a solution. It is sufficient to use it by suspending it in a reaction solvent, and it can be said to be suitable for industrial production. The modified lithium aluminum hydride reducing agent of the present invention obtained in this way has the following general formula () [In the formula, R ₁ , R ₂ and Ph are as described above. ] It is estimated to have the structural formula shown below. The reducing agent of the present invention thus obtained is usually used in the next reduction reaction without being isolated from the reaction solution. The reducing agent of the present invention can be used as a reducing agent for converting a carbonyl group of an organic compound having a ketone structure or an aldehyde structure into a hydroxyl group. Even if the organic compound to be reduced has a functional group such as an ester, carboxylic acid, amide, or olefin in its structural formula, no side reactions will occur, and only the carbonyl group will react, so it will not have a ketone or aldehyde structure. Any organic compound may be used as long as it has the following properties. Preferred organic compounds are compounds having a ketone structure that produces an asymmetric center as a result of reduction. Reduction with the reducing agent of the present invention is carried out under an inert gas atmosphere such as nitrogen or argon under anhydrous conditions using the reducing agent of the present invention and an organic compound having a ketone or aldehyde structure. The amount used in the reaction of the reducing agent of the present invention is the organic compound/
Any ratio may be used as long as it is equal to or higher than /equivalent to the equivalent, but a ratio of 1 to 5 equivalents is preferable. The reaction solvent is not particularly limited as long as it does not participate in the reaction, but dimethyl ether, diethyl ether, tetrahydrofuran, diglyme, methylal, toluene, etc. are used.
More preferably diethyl ether is used. The reaction temperature is -100 to 100°C. When carrying out the asymmetric reduction reaction, it is preferable to carry out the reaction at -78 to -100°C. Although the reaction time is not particularly limited, 1 to
6 hours is sufficient. After carrying out the reduction reaction under these conditions, an aqueous solution of mineral acids such as hydrochloric acid and sulfuric acid is added to the reaction solution, and the organic solvent layer is separated, dried, and the organic solvent is distilled off to easily obtain the desired product. It is possible to obtain only the alcohol form with high yield. N-substituted ephedrin () and N
-Substituted aniline () can be prepared by adding an alkali aqueous solution such as a caustic soda aqueous solution or a caustic potassium aqueous solution to the aqueous layer, and then using an organic solvent that dissolves N-substituted ephedrin () and N-substituted aniline (), e.g. A mixture of the two can be recovered in an almost quantitative yield by a simple operation of extracting with ethyl acetate, drying, and distilling off the organic solvent. Moreover, these can also be recovered separately by distillation under reduced pressure. The N-substituted ephedrin () thus recovered can be recovered as optical pure without any racemization, and can be reused as is. Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Reference example Synthesis of (-)-N-methylephedrin Ephedrin hydrochloride (30.3 g, 0.15 mol) was dissolved in warm water (60 ml), and dissolved in a 40% caustic soda aqueous solution (15 mol).
ml, 0.15 mol) and 85%-formic acid (21.7 g,
After heating to reflux, a 35% formalin solution (15 g, 0.18 mol) was added dropwise over 20 minutes. After the dropwise addition, heating and refluxing was continued for 3 hours, and then the reaction solution was concentrated to 1/2 volume, and a 40% caustic soda aqueous solution was added to adjust the pH to 11. Take the crystals precipitated at
It was recrystallized from methanol. Yield 23g (Yield 84
%) mp86.5 ~ 87.5℃, [α] ²⁰ _D = -29.5゜ (C =
4.54, MeOH) Example 1 Preparation of modified lithium aluminum hydride reducing agent Dry ether (10
ml) was added, the mixture was heated to reflux, a solution of (-)-N-methylefedrin (1 g, 5.56 mmol) in dry ether (10 ml) was added, and the reaction was stirred at the same temperature for 1 hour. Next, N-ethylaniline (1.35g, 11.12m
mol) in dry ether (10 ml) and reacted with stirring at the same temperature for 1 hour, a total of 363 ml of hydrogen gas was generated, and an ether solution of a modified lithium aluminum hydride reducing agent with the following physical properties was obtained. Ta. Infrared absorption spectrum (neat): ν; 3420, 2960,
1780, 1600, 1500, 1450, 1380 cm ^-1 Reference example 1 Reduction of acetophenone The reaction solution of Example 1 was cooled to -78°C, and acetophenone (360 mg, 3 mmol) was dissolved in dry ether (10
ml) solution was added, and the mixture was stirred and reacted at the same temperature for 3 hours. After the reaction was completed, 1N hydrochloric acid (24ml) was added to separate the ether layer, and the ether layer was diluted with 10% hydrochloric acid (20ml),
The mixture was washed with saturated brine (20 ml x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain (S)(-)-1-phenylethanol. Yield 330 mg (yield 90%) [α] ²⁰ _D = -36.4° (C =
7.45, cyclopentane) Optical purity 84% Aqueous layer and 10% - combined hydrochloric acid washing solution, 10% -
Add caustic soda aqueous solution (30 ml) to adjust the pH to 11, then extract with ethyl acetate (50 ml x 3), wash the extract with saturated saline (50 ml x 3), dry, and distill off the ethyl acetate. A mixture of N-methylefedrin and N-ethylaniline was obtained. amount of profit
2.4g (yield 100%) The mixture can then be separately recovered by distilling the mixture under reduced pressure. N-methylephedrin; bp120℃/0.01mmHg
Yield 850mg [α] ²⁰ _D = -29.0゜ (C = 6.50, MeOH) N-ethylaniline; bp87-90℃/15mmHg
Amount obtained: 1.3 g Reference Example 2 Table 1 shows the results of reducing various ketone bodies in the same manner as in Reference Example 1. [Table] [Table] Example 2 Reduction of benzylideneacetone Dry ether (10
ml) was added thereto, heated to reflux, and a solution of (-)-N-methylefedrin (1.83 g, 10.2 mmol) in dry ether (20 ml) was added, followed by reaction with stirring at the same temperature for 1 hour.
Then N-ethylaniline (2.47g, 20.4mmol)
Add a solution of dry ether (10 ml) of
The reaction was stirred for hours. The reaction solution was then cooled to -78°C, a solution of benzylidene acetone (439 mg, 3 mmol) in dry ether (5 ml) was added, and the reaction was stirred at the same temperature for 3 hours. After the reaction is complete, add 1N hydrochloric acid (42ml) to separate the ether layer, and add 1% hydrochloric acid (20ml) to the ether layer.
(x2), washed with saturated brine (20mlx3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain (S)(-)-benzylideneethanol. Yield: 435 mg (yield 98%) [α] ²⁰ _D = 24.2° (C =
5.16, CHCl ₃ ) Optical purity 98% Reference Example 3 Table 2 shows the results of reducing various ketone bodies in the same manner as in Example 2. [Table] [Table] Example 3 Under a stream of argon, lithium aluminum hydride (1.44 g, 38 mmole) was suspended in ether (70 ml), and (-)-1(R), 2(S)-N-methyl ether was suspended in ether (70 ml). Dorin (K, Nakajima, Japanese Science Magazine,
81, 1476 (1960). ) (mp86.5−87.5℃, [α] ²⁰ _D−
29.5゜, (C=4.54, methanol)) (6.81g, 38m
A solution of N-ethylaniline (9.21 g, 76 mmole) in ether (60 ml) was added thereto, and an ether solution (100 ml) of N-ethylaniline (9.21 g, 76 mmole) was added thereto. was prepared. The ether solution of the reducing reagent was heated to −78°C.
Cool to 2-acetyl-5,8-dimethoxy-
3.4-dihydronaphthalene (2.20g, 9.47mmole)
An ether solution (200 ml) of was gradually added, and the reaction was stirred at the same temperature for 3 hours. After the reaction was completed, 1N-hydrochloric acid (152 ml, 152 mmole) was added, and ethyl acetate (150 mmole) was added.
ml×2). The extracts were combined into 1% aqueous hydrochloric acid (150ml x 2), 5% aqueous sodium bicarbonate solution (150ml), water (150ml x 3), and saturated saline (150ml).
and dried over anhydrous magnesium sulfate. Filter and distill to obtain crude (-)-2-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4
- Dihydronaphthalene as pale yellow crystals (2.43g, 94
% yield), [α] ²⁰ _D −18.9° (C = 1.83, ethanol)
obtained as. [α] ²⁰ _D −20.5° (C=1.07, ethanol) obtained from this sample by the procedure described below (−)-2-(1′(S)-hydroxy)ethyl-5,8-dimethoxy If the optical purity of -3,4-dihydronaphthalene is 100%, this sample has an optical purity of 92%. The obtained crystals were recrystallized from hexane (130ml) to achieve optical purity of 100%.
pure (-)-2-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene as colorless needle crystals (1.8 g, 81%), mp88-89
C, [α] ²⁰ _D −20.5° (C=1.07, ethanol). IRν ^CHCl3 _nax cm ^-1 : 3600, 1260, 1100 (alcohol)
.
NMR (in CDCl ₃ ): 1.32 (3H, d, J = 6Hz, CH
(OH)CH 3 ), 2.00−2.36 (2H, m, CH 2 _{C =} ),
2.12 (1H, s, OH ), 2.64-2.88 (2H, m, CH
₂ CH ₂ C=), 3.74 (6H, s, two OC H ₃ ), 4.40
(1H, q, J=6Hz, C H (OH), 6.60 (2H,
s, aromatic protons), 6.72 (1H, brs, =C
H), Anal. Calcd for C ₁₄ H ₁₈ O ₃ :C, 71.77,;
H, 7.74. Found: C, 71.57; H, 7.76. On the other hand, the remaining 1N hydrochloric acid layer extracted with ethyl acetate was made alkaline (PH > 12) with a 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (150 ml x 2). The ethyl acetate extracts were combined, washed with saturated brine (150 ml), and dried over anhydrous potassium carbonate.
When filtered and distilled, (-)-1(R), 2(S)-N-
1 of methylefedrin and N-ethylaniline:
Two mixtures were obtained as a pale yellow oil (16.3 g, quantitative recovery). Example 4 A reducing agent was prepared in the same manner as in Example 3 using the chiral source shown in Table 3 instead of N-methylephedrine in Example 3, and 2-acetyl-5,8-dimethoxy- 3,4-dihydronaphthalene was reduced. The results are shown in Table 3. [Table] Example 5 Table 4 was used instead of N-ethylaniline in Example 3.
Using the Additive shown in Example 3, a reducing agent was prepared in the same manner as in Example 3, and 2-acetyl-5,8-
Dimethoxy-3,4-dihydronaphthalene was reduced. The results are shown in Table 4. 【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a lower alkyl group or a benzyl group, and Ph represents a phenyl group. ] N-substituted ephedrin/equivalent ratio and general formula [In the formula, R ₂ represents a lower alkyl group or a phenyl group, and Ph represents a phenyl group. ] A novel modified lithium aluminum hydride-based reducing agent obtained by reacting a 2-equivalent ratio of N-substituted aniline represented by the following with a lithium aluminum hydride/equivalent ratio. 2. The reducing agent according to claim 1, wherein R ₁ is a lower alkyl group. 3. The reducing agent according to claim 1, wherein R ₂ is a lower alkyl group. 4. The reducing agent according to claim 1, wherein R ₁ and R ₂ are lower alkyl groups. 5. The reducing agent according to claim ₁ , wherein R 1 is a methyl group and R ₂ is an ethyl group.