JPH0441467A - Production of norephedrine derivative and optically active secondary alcohol - Google Patents

Abstract

NEW MATERIAL:A compound expressed by the formula (R<1> is linear or branched 2-8C alkyl; R<0> is styrene residue; n is 2-8). USE:Useful as a catalyst in producing optically active secondary alcohol by asymmetrically adding zinc dialkyl to aliphatic or aromatic aldehyde. Thereby, secondary alcohol is obtained in high optical purity and yield and used catalyst can be recovered and reused. PREPARATION:An N-alkyl norephedrine derivative is reacted with chloromethylstyrene resin in the presence of salt such as potassium carbonate to afford the compound expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel norephedrine derivative and a method for asymmetrically synthesizing an optically active secondary alcohol using the same as a catalyst.

Conventional Example Limbs In recent years, research on the asymmetric synthesis of optically active secondary alcohols through the addition reaction of dialkylzinc and aldehyde using chiral catalysts has attracted attention.

P., A., and Challoner et al. reported an example using N-alkylephedrine as a catalyst, but in alkylation of aliphatic aldehydes, the product is racemic (asymmetric yield 0%) (
P, A, Chaloner, S, A, R, Pere
ra.

Lett, 1987.3
013-3014). Noyori et al. used dimethylaminoisoborneol as a catalyst (J, Am, C
heIIp, Sec, 108 6071 (1986
) J, Organomet, Cheau, 38
2 19 (1990)), the asymmetric yield of alkylation is low for aliphatic aldehydes, and the asymmetric yield of heptanal ethylation is about 76%. In addition, leucinol (Tetra-hedron Lett, 25,
2823 (1984)), cinchona alkaloid (J,
Org, Chem, 52, 135 (198
7)), polymer-supported amino alcohol (dialkylaminoisoborneol or ephedrine) U, O
rg, Chew, .

52, 4140 (19B?)) discloses a reaction using an aromatic aldehyde, but does not disclose a method for synthesizing an optically active secondary alcohol using an aliphatic aldehyde. Not yet. In addition, as a method using an asymmetric source stoichiometrically rather than a catalytic reaction, Kaiyama et al. asymmetrically added butyllithium to isobutyraldehyde using an asymmetric diamino alcohol.
reported an example of synthesis with 80% e,e (J,
Am, Chem, Soc.

Dish 1455 (1979)). Optically active secondary alcohols are useful as raw materials for pharmaceuticals, fragrances, and asymmetric synthesis, and the present inventors have already attempted to improve the asymmetric yield by using aliphatic aldehydes in their production methods, as disclosed in Japanese Patent Application Laid-Open No. No. 133 discloses the use of a norephedrine derivative directly bonded to a polymer such as styrene resin.

Although a method has been developed to obtain a certain degree of asymmetric yield when producing secondary alcohols by catalytic reaction using monovalent aliphatic aldehydes, it is not sufficient to produce secondary alcohols from the reaction mixture of catalysts. The drawback is that it requires complicated operations for separation and recovery. Furthermore, methods that do not use a catalytic reaction require the use of a raw material such as an asymmetric diamino alcohol in a larger amount than the stoichiometric amount.

As a result of intensive research to solve the above problems, the inventor of the present invention has discovered that
We have developed a method in which an aliphatic or aromatic aldehyde is reacted with dialkylzinc in the presence of a catalytic amount of an asymmetric source to obtain a secondary alcohol with high reaction yield and good optical purity, and the asymmetric source can be recovered and reused. The present invention has been completed.

The present invention involves the asymmetric addition of dialkylzinc to an aliphatic or aromatic aldehyde using a polymeric norephedrine derivative such as a phenol resin or epoxy resin bonded to a styrene resin via a spacer having an appropriate chain length as a catalyst. The present invention relates to a method for producing an optically active secondary alcohol.

That is, the present invention has the following features: 1) The following - Shipbuilding (1) % formula % (wherein R' is a linear or branched carbon number 2 to 8
an alkyl group, Ro is a styrene residue, n is an integer of 2 to 8, or a norephedrine derivative represented by its enantiomer; and 2) a dialkyl zinc to an aliphatic or aromatic aldehyde;
- An optically active secondary compound characterized in that the asymmetric addition is carried out using a norephedrine derivative represented by the ship stock (1) (wherein Ro and R' have the above-mentioned meanings) or its enantiomer as a catalyst.
This is a method for producing alcohol.

The norephedrine derivative of the present invention (-Kanzo (1)) or its enantiomer can be prepared by the method described in the literature (K, 5oai et al.
at,, J, Chem, Soc, + Perki
It can be synthesized by reacting the N-alkylnorephedrine derivative synthesized by n Trans 1 + 1989109) with chloromethylstyrene resin in the presence of a base such as potassium carbonate. The reaction is carried out under reflux of an organic solvent. The organic solvents used include alcoholic solvents such as methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, diethyl ether,
Ether solvents such as tetrahydrofuran, toluene,
In addition to aromatic solvents such as benzene and xylene, hydrocarbon solvents such as hexane, heptane, and pentane, various solvents such as 2-pyrrolidone, acetonitrile, dimethylformamide, dioxane, dimethylsulfoxide, or acetone can be used.

Norephedrine, which is the raw material of the present invention, is commercially available alone or in the form of hydrochloride in both the (+) form and the (-) form.
By selectively using both, it is possible to synthesize a desired optically active secondary alcohol in the (+) or (-) form.

That is, according to the present invention, by using as a catalyst a norephedrine derivative supported on a polymer through a spacer represented by - Funazou (1) or its mirror image, an aldehyde compound (- Funazura (2) ) and dialkylzinc (−
An optically active secondary alcohol compound (-Funazo (4)) can be obtained with high optical purity and yield by an asymmetric addition reaction with Funazura (3)).

- In Funazura (2), R2 is an alkyl group having a straight chain, branched or cyclic structure having 1 to 20 carbon atoms, or an aryl group such as phenyl; - R3 in Funazura (3) is an alkyl group having a carbon number of 1 to 20 straight chain,
Each represents an alkyl group having a branched or cyclic structure.

Obtained optically active secondary alcohol compound (-Funakura (4)
) for (S) or (R) that displays the solid of (R)
, (S) Aldehyde compounds (-Funezo (
2)) Rz is a dialkyl zinc compound (-Funezo (3))
, and conversely, when R3 has priority over R2, the optically active secondary alcohol compound (-
(S) and (R), which display the three-dimensional objects in the ship's warehouse (4)), are exchanged.

The asymmetric addition reaction is carried out using an aliphatic or aromatic aldehyde and a catalyst in a solvent such as n-hexane, pentane, heptane, octane, cyclohexane, toluene, Hensen, xylene, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and mixtures thereof. This is done by dissolving or suspending in a solvent.

Next, a solution of dialkylzinc in toluene, benzene, tetrahydrofuran or n-hexane is added dropwise to this solution. It is preferable to carry out the reaction at a reaction temperature of -40'C to 80C for at least 3 hours or more.

The reaction is stopped by adding, for example, 1N hydrochloric acid, and after separating the catalyst, the reaction solution is extracted with ethylene chloride, etc. After drying the organic layer according to a conventional method, the solvent is distilled off, and if necessary, chromatography, Purify by distillation etc.

The amount of the asymmetric catalyst used is 0.001 to 0.5 in terms of the number of moles of nitrogen atoms derived from norephedrine contained in the catalyst per mole of aliphatic or aromatic aldehyde as a raw material.
A molar range is advantageous.

As explained above, the norephedrine derivative of the present invention has a spacer introduced between the polymer part and the amino alcohol part, which increases the degree of freedom of chiral amino alcohol. By using the derivative, a desired optically active secondary alcohol in the (+) or (−) form can be synthesized from an aliphatic or aromatic aldehyde and dialkylzinc with high optical purity and yield. On the other hand, since the derivative, which is a catalyst used for convenience, is a polymer, it can be recovered and reused, making it extremely useful industrially.

1 time■ Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 Synthesis of asymmetric catalyst An example of n=6, R=n-CJ* (la) is shown.

1.6-Hexanediol (38,3a + mol) was dissolved in DMF (20++/liter), and sodium hydride (13,0 mmol) was added under water cooling. Chloromethyl polystyrene (6,52 g) was added, and the mixture was heated at 60°C. The reaction was stopped by adding water under water cooling, and the treated resin was washed with water, benzene, and methanol, and then dried under reduced pressure (2smog) at 40°C for 4 hours to obtain 5 (6.71 g). Obtained.

5 (6.39 g) was refluxed in thionyl chloride for 48 hours, and thionyl chloride was distilled off under reduced pressure.

After washing the treated resin with water, THF, and methanol,
When dried under reduced pressure (2o+n+Hg) for 4 hours at 0°C, 6
(6.33g) was obtained.

Sodium iodide (18.9 mmol) was dissolved in acetone, 6 (5,81) was added, and the mixture was refluxed for 48 hours.

After washing the filtered resin with water, THF, and methanol,
When dried under reduced pressure (2 mmHg) at 0°C for 4 hours,
, 97g) was obtained.

The method of Zokuai et al. (J, CheIIl, Soc, Pe
(Is, 2R)-N-butylnorephedrine (2
, 14 mn+ol) was dissolved in toluene, and 7 (1,44 mn+ol) was dissolved in toluene.
g), potassium carbonate was added, and the mixture was refluxed for 100 hours. After washing the filtered resin with water, THF, and methanol, it was heated to 40°C.
When dried under reduced pressure (2suwHg) for 4 hours, 1 (1,28
g) was obtained. (From the results of elemental analysis (N) in 1), if the catalyst loading rate is calculated as 100%, the N content is 0.
．． It is 658 mmol/g. ) Synthesis was carried out by repeating the same reactions and operations as above, except that 1,4-butanediol and 1,12-dodecanediol were used as raw materials.

Example 2 Asymmetric addition of diethylzinc to various aldehydes in the presence of asymmetric catalyst (1a) Synthesis of (S)-1-phenylpropatol (R2=Ph) Catalyst 1a (298 mg) synthesized in Example 1 was heated under reduced pressure. After degassing, replace with argon, suspend in hexane (2 ml),
Benzaldehyde (0.98 mmol) was added dropwise under water cooling. After 15 minutes, 2.2*j2 of diethylzinc (1M hexane solution) was added dropwise. After 5 days, IM hydrochloric acid (reaction was stopped at 5 mJ, and the catalyst was filtered off by suction. The filtrate was extracted with dichloromethane and anhydrous sulfuric acid), dried with IM hydrochloric acid,
The solvent was removed under reduced pressure. The residue was subjected to TLC on silica gel (silica gel/ethyl acetate:hexane = 1:4 v/v
], (S)=1-phenylpropatol was obtained in a yield of 91%. Asymmetric yield 82% e, e, Optical rotation [α].

37.09” (C=5.12.CHCL)(S
) -3-Undec/-ol (R" = n-C, H, ,) Synthesis All the same operations as in Example 4 above were carried out except that n-nonylaldehyde was used instead of benzaldehyde (S)
-3-Undecanol was obtained with a yield of 75%. [α]. +
6,22° (C=6.15EtOH), asymmetric yield>9
9% e, e.

Catalyst Reuse Experimental Reactor Separately recovered catalyst was added with T) IF-3M hydrochloric acid (4:1).
was added and stirred for 4 hours, followed by filtration and washing (water-TI(P)
did. Next, THF-2M sodium hydroxide aqueous solution (
4:1) for 4 hours. It was filtered by suction, washed with water, THF, and methanol, dried under reduced pressure (2+amHg) at 40°C for 2 hours, and then reused.

As a result, (S)-3-undecanol was obtained with a yield of 80% according to the procedure amendment. [α]. +6.31° (C=5.24
゜EtOH) Chiral yield〉99% e, e.

Claims (1)

[Claims] 1) The following general formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R^1 is a linear or branched carbon number of 2 to 8
, R^0 is a styrene residue, n is an integer of 2 to 8, or a norephedrine derivative represented by its mirror image. 2) dialkylzinc to aliphatic or aromatic aldehyde,
General formula (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R^0 and R^1 have the meanings described above.)
1. A method for producing an optically active secondary alcohol, which comprises carrying out asymmetric addition of a norephedrine derivative represented by a norephedrine derivative or an enantiomer thereof as a catalyst.