JP2009040698A - Optically active proline ester derivative and method for producing n-formyl optically active proline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method by which a specific ligand compound used as a catalyst for activating trichlorosilane can be produced only by chemical reactions without a complicated treatment such as optical resolution. <P>SOLUTION: This method for producing an N-formyl optically active proline derivative represented by formula (III) (wherein, R<SP>1</SP>is a 6-12C aryl group) such as cis-N-formyl-α'-(2,4,6-triethylphenyl)-L-proline comprises hydrogen-reducing an N-aralkyloxycarbonyl optically active proline ester derivative, formylating the obtained optically active proline ester derivative with a formylation agent, and then hydrolyzing the resultant product. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  In the production of an N-formyl optically active proline derivative represented by the above formula (III), which is useful as an activator when trichlorosilane is used as a reducing agent, the present invention provides a novel optically active proline derivative. It is related with the method characterized by doing.

  Trichlorosilane, an extremely important compound as an industrial raw material for high-purity polycrystalline silicon, is not only reducible but also economically inexpensive, and withstand pressure used when hydrogen gas is used as the reducing agent. Since the reduction reaction can be carried out using a normal reaction vessel without using a vessel, application to organic chemistry has been increasingly performed in recent years.

For example, as a reduction reaction of a ketone compound to a secondary alcohol compound using trichlorosilane, a method of reducing in the presence of dimethylformamide (see Non-Patent Document 1) or N-formyl of a secondary amine having 3 or more carbon atoms In the presence of “a ligand compound that gives a signal at −15 to −120 ppm in a ²⁹ Si-NMR measurement at 74.9 MHz when mixed with trichlorosilane” (hereinafter also referred to as a specific ligand compound). There is known a method of reducing to (see Patent Document 1).

  However, in the former method (method of reducing in the presence of dimethylformamide), dimethylformamide does not have an asymmetric source, so that even if the asymmetric ketone compound is reduced, the generated alcohol compound exhibits asymmetry. There is no. On the other hand, in the latter method, an optically active compound having an optical purity of 44% ee is obtained by using an optically pure isomer of a compound derived from prolinol, proline amide or proline ester as the specific ligand compound. Although a secondary alcohol compound was successfully synthesized, it is not sufficient from the viewpoint of optical purity.

  Therefore, the present inventors have studied derivatives of pyrrolidine for the purpose of solving such problems. As a result, the optical purity of 50 was obtained by reducing an asymmetric ketone compound using trichlorosilane in the presence of an optically active N-piconoylpyrrolidine derivative. It has been found that an optically active secondary alcohol compound of ˜70% ee can be obtained (see Patent Document 2), and further the following formula (III) as a specific ligand compound

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms.)
And an optical purity of 80% ee or higher was achieved in the reduction reaction of the asymmetric ketone compound (see Patent Document 3).

Chemistry Letters, 1996, p. 407-408 Special Table 2000-053551 JP 2005-29503 A JP 2006-151856 A

  However, the following formula (III) found in the latter invention (the invention described in Patent Document 3)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms.)
N-formyl optically active proline derivative represented by the following formula (V)

(However, R ² represents an alkyl group having 1 to 6 carbon atoms.)
The N-formyl-methoxyproline derivative represented by the formula (VI) is reacted with a benzene derivative in the presence of a Lewis acid, and the following formula (VI)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, and R ² represents an alkyl group having 1 to 6 carbon atoms.)
The N-formyl-arylproline derivative represented by the above formula is optically resolved by a resolution means such as silica gel column chromatography and then hydrolyzed, and an unnecessary compound is produced in substantially the same amount as the target product. It was possible to synthesize only by the method.

  Therefore, an object of the present invention is to provide a method for obtaining a desired formyl optically active proline derivative only by chemical reaction without using optical resolution.

  In view of such a situation, the present inventors conducted further intensive studies, and as a result, the following formula (I)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
A novel N-aralkyloxycarbonyl optically active proline ester derivative represented by formula (II):

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, and R ² represents an alkyl group having 1 to 6 carbon atoms.)
Through the novel optically active proline ester derivative represented by the above, a method for synthesizing a desired N-formyl optically active proline derivative without optical resolution has been found, and the present invention has been completed.

  That is, the first aspect of the present invention is the following formula (I)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula:

  The second aspect of the present invention provides the following formula (II):

(Wherein, R ¹ is an aryl group having 6 to 12 carbon atoms, R ² represents an alkyl group having 1 to 6 carbon atoms.)
Is an optically active proline ester derivative.

  Further, the third invention is the following formula (IV)

(However, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
A methoxyproline ester derivative represented by the following formula (I) is reacted with a benzene derivative in the presence of a Lewis acid.

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
A step of synthesizing an N-aralkyloxycarbonyl optically active proline ester derivative represented by:
The N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) is reduced with hydrogen to give the following formula (II)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, and R ² represents an alkyl group having 1 to 6 carbon atoms.)
A step of synthesizing an optically active proline ester derivative represented by:
The optically active proline derivative represented by the formula (II) is formylated using a formylating agent and then hydrolyzed, and the following formula (III)

(Wherein, R ¹ is an aryl group having 6 to 12 carbon atoms.)
Is a method for producing an N-formyl optically active proline derivative represented by the formula:

  According to the present invention, since the target N-formyl optically active proline derivative can be synthesized without performing the optical resolution operation, it can be said that it is extremely important industrially.

  The N-aralkyloxycarbonyl optically active proline ester derivative of the first present invention is represented by the following formula (I).

Here, the formula R ¹ means an aryl group having 6 to 12 carbon atoms. Specific examples of the aryl group having 6 to 12 carbon atoms include phenyl group, 4-methylphenyl group, 2,4,6-trimethylphenyl group, 4-ethylphenyl group, 2,4,6-triethylphenyl group, A naphthyl group etc. can be mentioned. R ² in the above formula means an alkyl group having 1 to 6 carbon atoms. Specific examples of suitable alkyl groups having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, An isopropyl group, n-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like can be mentioned. Furthermore, R ³ in the above formula means an aralkyl group having 7 to 10 carbon atoms. Specific examples of suitable aralkyl groups having 7 to 8 carbon atoms include benzyl group, 4-methylbenzyl group, 4-methoxy group. Examples include benzyl group, 4-nitrobenzyl group, 4-chlorobenzyl group, 2,4-dichlorobenzyl group, 4-bromobenzyl group and the like.

  Specific examples of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I) include cis-N-benzyloxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline. Methyl ester, cis-N-benzyloxycarbonyl-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester, cis-N-benzyloxycarbonyl-α'-(4-methylphenyl) -L -Proline methyl ester, cis-N-benzyloxycarbonyl-α '-(4-ethylphenyl) -L-proline methyl ester, cis-N-benzyloxycarbonyl-α'-(4-isopropylphenyl) -L-proline Methyl ester, cis-N-benzyloxycarbonyl-α '-(4-ter -Butylphenyl) -L-proline ethyl ester, cis-N-benzyloxycarbonyl-α '-(2,4,6-trimethylphenyl) -L-proline ethyl ester, cis-N-benzyloxycarbonyl-α'- (4-Methylphenyl) -L-proline ethyl ester, cis-N-benzyloxycarbonyl-α '-(4-ethylphenyl) -L-proline ethyl ester, cis-N-benzyloxycarbonyl-α'-(4 -Isopropylphenyl) -L-proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-N- (4 -Nitrobenzyl) oxycarbonyl-α '-(2,4,6-trimethylphenyl) -L Proline methyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α '-(4-methylphenyl) -L-proline methyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α'-( 4-ethylphenyl) -L-proline methyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α '-(4-isopropylphenyl) -L-proline methyl ester, cis-N- (4-nitrobenzyl) ) Oxycarbonyl-α '-(4-tert-butylphenyl) -L-proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α'-(2,4,6-trimethylphenyl) -L -Proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α '-(4-methyl Ruphenyl) -L-proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α '-(4-ethylphenyl) -L-proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl -Α '-(4-isopropylphenyl) -L-proline ethyl ester, cis-N- (4-nitrobenzyl) oxycarbonyl-α'-(4-tert-butylphenyl) -L-proline ethyl ester, cis- N- (4-methoxybenzyl) oxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α'-(2, 4,6-trimethylphenyl) -L-proline methyl ester, cis-N- (4-methoxybenzyl) ) Oxycarbonyl-α '-(4-methylphenyl) -L-proline methyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α'-(4-ethylphenyl) -L-proline methyl ester, cis -N- (4-methoxybenzyl) oxycarbonyl-α '-(4-isopropylphenyl) -L-proline methyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α'-(4-tert-butyl Phenyl) -L-proline ethyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α '-(2,4,6-trimethylphenyl) -L-proline ethyl ester, cis-N- (4-methoxy Benzyl) oxycarbonyl-α '-(4-methylphenyl) -L-proline ethyl ester, ci -N- (4-methoxybenzyl) oxycarbonyl-α '-(4-ethylphenyl) -L-proline ethyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α'-(4-isopropylphenyl) -L-proline ethyl ester, cis-N- (4-methoxybenzyl) oxycarbonyl-α '-(4-tert-butylphenyl) -L-proline ethyl ester and the like can be mentioned.

  Among these, in particular, the N-formyl optically active proline derivative represented by the above formula (III), which is the final product, can be synthesized in high yield, and the asymmetric ketone compound is reduced with trichlorosilane to form an optically active secondary alcohol compound. Cis-N-benzyloxy-α '-(2,4,6-triethylphenyl) -L-proline methyl from the viewpoint that a high optical yield can be expected when used as an activator in the production of Ester, cis-N-benzyloxy-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester, cis-N-benzyloxy-α'-(2,4,6-triethylphenyl)- L-proline ethyl ester, cis-N-benzyloxy-α '-(2,4,6-trimethylphenyl) -L-proline ethyl ester, etc. It is preferable to use.

  The structure of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I) can be confirmed by any two or more of the following methods (i) to (iv).

(I) by measuring the ¹ H- nuclear magnetic resonance spectrum, it is possible to know the binding mode of the hydrogen atoms present in the compound. For example, the hydrogen spectrum of the benzene ring is shown around 7.0 ppm.

(Ii) By measuring the infrared absorption spectrum, characteristic absorption derived from the functional group of the compound can be observed. For example, an absorption spectrum of C═O is shown near 1750 cm ⁻¹ .

  (Iii) Elemental analysis is measured, and the component ratio of carbon, hydrogen, nitrogen and oxygen of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I) is measured. Thus, the molecular formula can be determined.

  (Iv) The MS spectrum can be measured to determine the molecular weight of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I).

  The optically active proline ester derivative represented by the formula (II) according to the second aspect of the present invention reductively desorbs the aralkyloxycarbonyl group of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I). Can be synthesized. Therefore, if the structure of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I) is defined, the structure of the optically active proline ester derivative represented by the formula (II) is uniquely determined.

  Specific examples of the optically active proline ester derivative represented by the formula (II) include cis-α ′-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-α ′-(2, 4,6-trimethylphenyl) -L-proline methyl ester, cis-α ′-(4-methylphenyl) -L-proline methyl ester, cis-α ′-(4-ethylphenyl) -L-proline methyl ester, cis-α '-(4-Isopropylphenyl) -L-proline methyl ester, cis-α'-(4-tert-butylphenyl) -L-proline ethyl ester, cis-α '-(2,4,6- Trimethylphenyl) -L-proline ethyl ester, cis-α '-(4-methylphenyl) -L-proline ethyl ester, cis-α'-( -Ethylphenyl) -L-proline ethyl ester, cis-α '-(4-isopropylphenyl) -L-proline ethyl ester, cis-α'-(2,4,6-triethylphenyl) -L-proline methyl ester Cis-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester, cis-α'-(4-methylphenyl) -L-proline methyl ester, cis-α '-(4-ethyl Phenyl) -L-proline methyl ester, cis-α '-(4-isopropylphenyl) -L-proline methyl ester, cis-α'-(4-tert-butylphenyl) -L-proline ethyl ester, cis-α '-(2,4,6-trimethylphenyl) -L-proline ethyl ester, cis-α'-(4-methylphenyl) L-proline ethyl ester, cis-α '-(4-ethylphenyl) -L-proline ethyl ester, cis-α'-(4-isopropylphenyl) -L-proline ethyl ester, cis-α '-(4- tert-butylphenyl) -L-proline ethyl ester, cis-α '-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-α'-(2,4,6-trimethylphenyl)- L-proline methyl ester, cis-α ′-(4-methylphenyl) -L-proline methyl ester, cis-α ′-(4-ethylphenyl) -L-proline methyl ester, cis-α ′-(4- Isopropylphenyl) -L-proline methyl ester, cis-α ′-(4-tert-butylphenyl) -L-proline ethyl ester Ter, cis-α '-(2,4,6-trimethylphenyl) -L-proline ethyl ester, cis-α'-(4-methylphenyl) -L-proline ethyl ester, cis-α '-(4- Ethylphenyl) -L-proline ethyl ester, cis-α '-(4-isopropylphenyl) -L-proline ethyl ester, cis-N-α'-(4-tert-butylphenyl) -L-proline ethyl ester, etc. Can be mentioned.

  Among these, the final product formyl optically active proline derivative represented by the above formula (III) can be synthesized in high yield, and an asymmetric ketone compound is reduced with trichlorosilane to produce an optically active secondary alcohol compound. From the viewpoint that a high optical yield can be expected when used as an activator, cis-α '-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-α'- (2,4,6-trimethylphenyl) -L-proline methyl ester, cis-α '-(2,4,6-triethylphenyl) -L-proline ethyl ester, cis-α'-(2,4,6 It is preferred to use -trimethylphenyl) -L-proline ethyl ester or the like.

The structure of the optically active proline ester derivative represented by the formula (II), as well as the N- aralkyloxycarbonyl optically active proline ester derivative represented by the formula (I), ¹ H- nuclear magnetic resonance spectra, infrared It can be confirmed by measuring any two or more of absorption spectrum, elemental analysis, and MS spectrum.

  An N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) and an N-formyl optically active proline represented by the above formula (III) via an optically active proline ester derivative represented by the above formula (II) It is the third present invention to synthesize the derivative.

  The N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) is synthesized from the methoxyproline ester derivative represented by the above formula (IV), but this compound is easily available as a reagent or an industrial raw material. L-proline as a starting material is reacted with an alcohol compound having 1 to 6 carbon atoms in the presence of hydrogen chloride to synthesize L-proline alkyl ester hydrochloride, and then reacted with aralkyloxycarbonyl chloride in the presence of a base. Which can be synthesized by the following formula (VII)

(However, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
The N-aralkyloxycarbonyl-L-proline ester derivative represented by the formula can be synthesized as a starting material.

  Any method may be used for the conversion reaction from the N-aralkyloxycarbonyl-L-proline ester derivative represented by the above formula (VII) to the methoxyproline ester derivative represented by the above formula (IV). It is preferable to produce it by electrolytic oxidation in the presence of a supporting electrolyte in a mixed solvent containing (this reaction is hereinafter referred to as “reaction A”).

  The supporting electrolyte used in the reaction A can be used without any limitation as long as it is a salt that dissolves in methanol or a mixed solvent containing methanol, but in general, a quaternary ammonium salt is preferably used. Specific examples thereof include tetramethylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetrabutylammonium tetrafluoroborate, tetramethylammonium toluenesulfonate, tetraethylammonium toluenesulfonate, tetrabutylammonium toluenesulfonate, and the like. .

The amount of the supporting electrolyte used in the reaction A is not particularly limited. However, if the amount is too small, the voltage becomes high, and if the amount is too large, a large amount of organic solvent for dissolving the supporting electrolyte is required. It is preferable to select from the range of 0.01 to 3 mol, more preferably 0.1 to 2.5 mol, with respect to the N-aralkyloxycarbonyl-L-proline ester derivative represented by the formula (VII). As the electrolysis method, a constant potential method and a constant current method are used, but the constant current method is preferable because the reaction time can be shortened. As the current density of the reaction A, since it has a specific value depending on the type of the N-aralkyloxycarbonyl-L-proline ester derivative represented by the above formula (VII), it cannot be generally described. 300 mA / cm ^2, still more are suitably chosen from the range of 2~200mA / cm ^2. The energization amount is 2 F / mol with respect to the N-aralkyloxycarbonyl-L-proline ester derivative represented by the above formula (VII), but usually from the range of 2 to 10 F / mol. It is selected while measuring the production amount of the target product.

  As the organic solvent used in the reaction A, methanol or a mixed solvent containing methanol is generally used. The mixed solvent containing methanol is a mixed solvent with a solvent compatible with methanol, and is generally preferably selected from water, acetonitrile, propionitrile, and a mixed solvent of ethanol and methanol. The amount of the solvent used in the reaction A is not particularly limited. However, if the amount is too large, it is not economical, and if the amount is too small, the supporting electrolyte is not completely dissolved. Therefore, it is usually represented by the above formula (VII). The initial concentration of the N-aralkyloxycarbonyl-L-proline ester derivative is preferably selected from a range of 1 to 60% by weight, more preferably 2 to 50% by weight.

  This reaction A does not require a special electrolytic cell, and is preferably carried out in a non-diaphragm electrolytic cell. As the anode, all anode materials that are stable under electrolytic conditions can be used, but platinum, gold, and graphite electrodes are preferably used. As the cathode material, any cathode material that is stable under electrolytic conditions can be used, but a copper, nickel, platinum, gold, or graphite electrode is preferably used.

  The electrolysis temperature is not particularly limited, but is usually carried out at a temperature below the boiling point of methanol because methanol is used as the solvent.

  When electrolytic oxidation of the N-aralkyloxycarbonyl-L-proline ester derivative represented by the above formula (VII) is performed under the above electrolysis conditions, a methoxyproline ester derivative represented by the above formula (IV) is produced. The method for isolating the compound is not particularly limited, and a known method can be adopted. For example, after completion of the reaction, the reaction solution is distilled off under reduced pressure, and an aqueous sodium hydrogen carbonate solution is added to the reaction residue. Thereafter, the organic solvent-soluble component can be extracted from the aqueous solution using ethyl acetate, and the ethyl acetate solution can be isolated by drying and distilling off.

  The methoxyproline ester derivative represented by the above formula (IV) thus isolated is purified by silica gel column chromatography, and then the N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I). It is used for the conversion reaction.

  Any method may be used for the conversion reaction from the methoxyproline ester derivative represented by the above formula (IV) to the N-aralkyloxycarbonyl optically active proline derivative represented by the above formula (I). It is preferable to produce by reacting a benzene derivative in the presence of an acid (hereinafter, this reaction is referred to as “reaction B”).

  As the Lewis acid used in the reaction B, commercially available reagents can be used without any limitation. Specific examples thereof include tin tetrachloride, titanium tetrachloride, aluminum trichloride, iron trichloride, boron trifluoride diethyl ether complex and the like. Among these, titanium tetrachloride, tin tetrachloride, boron trifluoride diethyl ether complex, and the like that can be expected to have a particularly high yield can be preferably used. The amount of the Lewis acid to be used is not particularly limited. However, if the amount is too small, the reaction rate becomes slow, and if the amount is too large, the post-treatment step of the Lewis acid becomes complicated. It is preferable to select from a range of 0.01 to 5 mol, and further 0.1 to 2 mol, with respect to 1 mol of the methoxyproline ester derivative shown.

  As the benzene derivative used in Reaction B, commercially available reagents can be used without any limitation. Specific examples thereof include benzene, toluene, ethylbenzene, 1,3,5-trimethylbenzene, 1,3,5-triethylbenzene and the like. Among these, 1,3,5-trimethylbenzene, 1,3,5-triethylbenzene, and the like, which can be expected to have high optical purity by a reduction reaction, can be preferably used. As the amount of the benzene derivative to be used, since it is a stoichiometric reaction and can also serve as a solvent, it is usually used in an amount of 1 mol or more per 1 mol of the methoxyproline ester derivative represented by the formula (IV). Although there is no restriction | limiting in particular, When using another organic solvent, it is good to select from the range of 1-10 mol, Preferably it is 1-5 mol.

  In the reaction B, when a benzene derivative is not used as a solvent, the reaction is generally performed in an organic solvent. As a kind of solvent to be used, a solvent that does not react with Lewis acid is used without any limitation. Specific examples thereof include methylene chloride, chloroform, carbon tetrachloride, nitrobenzene and the like. Among these solvents, methylene chloride, which has high solubility of the reaction substrate and can be expected to have a high yield, is preferably used. The amount of the solvent used in this reaction B is not particularly limited. However, if the amount is too large, it is not economical, and if the amount is too small, the supporting electrolyte is not completely dissolved. The initial concentration of the methoxyproline ester derivative is preferably 1 to 60% by weight, more preferably 2 to 50% by weight.

  Although there is no restriction | limiting in particular about the temperature of reaction B, since reaction does not advance when temperature is too low, since side reaction is promoted when too high, it is the range of -78-30 degreeC normally, Preferably it is -78-10 degreeC. It is preferable to select from.

  The reaction time for reaction B varies greatly depending on the reaction temperature and the amount of the catalyst, so it cannot be generally stated, but usually 1 to 30 hours are sufficient.

  The method for isolating the N-aroxycarbonyl optically active proline ester derivative represented by the above formula (I) obtained as described above is not particularly limited, and a known method can be adopted. For example, after completion of the reaction, an aqueous solution of sodium bicarbonate is added to the reaction solution, the organic solvent soluble component is extracted with methylene chloride, and the methylene chloride solution is dried and distilled off to be isolated. Can do.

  The N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) thus isolated is a cis isomer single compound. The N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) thus isolated is purified by silica gel column chromatography, and then the optically active proline ester represented by the above formula (II). It is subjected to a conversion reaction to a derivative.

  Any method may be used for the conversion reaction from the N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) to the optically active proline derivative represented by the above formula (II). It is preferable to convert by hydrogen reduction under a metal catalyst (hereinafter, this reaction is referred to as “reaction C”).

  As the metal catalyst used in the reaction C, a metal catalyst usually used for hydrogen reduction can be used without any limitation. Specific examples thereof include Raney nickel, Raney cobalt, palladium activated carbon, platinum activated carbon, platinum oxide and the like. Among these, palladium activated carbon and platinum activated carbon which can be expected to have a particularly high reduction yield can be preferably used. The amount of the metal catalyst to be used is not particularly limited. However, if the amount is too small, the reaction does not proceed. If the amount is too large, side reactions are promoted. Therefore, N-aralkyl represented by the above general formula (I) is used. It is preferable to select from the range of 0.0001 to 0.1 parts by weight, and further 0.001 to 0.01 parts by weight with respect to 100 parts by weight of the oxycarbonyl optically active proline ester derivative.

  As the organic solvent used in the reaction C, an organic solvent which does not react with hydrogen and in which the metal catalyst can be easily dispersed can be used without any limitation. Specific examples thereof include alcohols such as methanol, ethanol, n-propanol, isopropanol, and tert-butyl alcohol, ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane, benzene, toluene, xylene, and the like. And aromatic hydrocarbons such as hexane and heptane. Among these solvents, alcohols such as methanol, ethanol, n-propanol, isopropanol, and tert-butyl alcohol can be preferably used from the viewpoint that the reaction proceeds mildly.

  The amount of the organic solvent used in the reaction C is not particularly limited. However, if the amount is too large, it is not economical. If the amount is too small, the N-aralkyloxycarbonyl optically active proline represented by the above formula (I) is used. Since the ester derivative is not dissolved, the initial concentration of the N-aralkyloxycarbonyl optically active proline ester derivative represented by the above formula (I) is usually 0.1 to 60% by weight, more preferably 1 to 30% by weight. It is preferable to select from.

  The hydrogen pressure of reaction C is not particularly limited, but if the pressure is too low, the reaction does not proceed. If the pressure is too high, a special reaction vessel is required, so usually 0.1 to 10 atmospheres, preferably 0 It is preferable to select from the range of 5 to 5 atmospheres.

  Reaction C usually proceeds easily under the above reaction conditions, but an organic base may coexist for the purpose of increasing the reaction yield. As the organic base used in the reaction C, commercially available reagents can be used without any limitation. Specific examples thereof include aliphatic amines such as triethylamine, tripropylamine, tributylamine, dimethylisopropylamine, N, N-dimethylaniline, N, N-diethylaniline, N, N-dimethylbenzylamine, N , N-diethylbenzylamine, 4-N, N-dimethylpyridine, 4-piperidinopyridine and other aromatic amines. Among these, triethylamine, tripropylamine, tributylamine and the like that can be expected to have a particularly high yield can be preferably used. The amount of the base to be used is not particularly limited. However, if the amount is too small, the reaction does not proceed. If the amount is too large, the post-treatment operation becomes complicated. Therefore, N— represented by the above formula (I) is used. It is preferable to select from the range of 1 to 10 moles, and more preferably 1 to 5 moles per mole of the aralkyloxycarbonyl optically active proline ester derivative.

  Although there is no restriction | limiting in particular about the temperature of reaction C, since reaction does not advance when temperature is too low, since side reaction is promoted when it is too high, Usually, it is the range of -20-60 degreeC, Preferably it is 0-40 degreeC. It is preferable to select from.

  The reaction time for reaction C varies greatly depending on the reaction temperature and the type and amount of the catalyst, so it cannot be generally stated, but usually 1 to 30 hours is sufficient.

  The method for isolating the optically active proline ester derivative represented by the above formula (II) obtained as described above is not particularly limited, and a known method can be adopted. For example, after completion of the reaction, the optically active proline ester derivative represented by the above formula (II) can be isolated by filtering the metal catalyst by Celite filtration and then removing the organic solvent by distillation under reduced pressure. it can. The obtained optically active proline ester derivative represented by the above formula (II) can be purified using silica gel column chromatography, but can also be used for the formylation reaction using the following formylating agent as it is. It is possible (hereinafter, this reaction is referred to as “Reaction D”).

  As the formylating agent used in Reaction D, a normal formylating agent can be used without any limitation. Specific examples thereof include formic acid / acetic anhydride, methyl formate, ethyl formate, propyl formate, and phenyl formate. Among these, formic acid / acetic anhydride, methyl formate, ethyl formate, and the like can be suitably used from the viewpoint that the reaction easily proceeds. As the amount of the formylating agent to be used, since it is a stoichiometric reaction and can also serve as a solvent, it is usually 1 mol or more with respect to 1 mol of the optically active proline ester derivative represented by the above formula (II). If it uses, there will be no restriction | limiting in particular, However, When using another organic solvent, it is preferable to select from the range of 1-30 mol, Preferably it is 1-10 mol.

  In the reaction D, when a formylating agent is not used as a solvent, the reaction is generally performed in an organic solvent. As a kind of the solvent to be used, a solvent that does not react with the formylating agent or the optically active proline ester derivative represented by the above formula (II) can be used without any limitation. Specific examples thereof include aliphatic halides such as methylene chloride, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, diethyl ether, Mention may be made of ethers such as tetrahydrofuran and 1,4-dioxane. Among these, methylene chloride and tetrahydrofuran, which have high solubility of the reaction substrate and can be expected to have a high yield, are preferably used. The amount of the solvent used in this reaction D is not particularly limited. However, if the amount is too large, it is not economical, and if the amount is too small, the optically active proline ester derivative represented by the above formula (II) cannot be completely dissolved. Therefore, it is usually preferable to select from the range in which the initial concentration of the optically active proline ester derivative represented by the above formula (II) is 1 to 60% by weight, further 2 to 50% by weight.

  Although there is no restriction | limiting in particular about the temperature of reaction D, since reaction does not advance when temperature is too low, since side reaction is promoted when too high, it is -20-60 degreeC normally, Preferably it is the range of -10-40 degreeC. It is preferable to select from.

  The reaction time for reaction D varies greatly depending on the reaction temperature and the amount of the catalyst, so it cannot be generally stated, but usually 1 to 30 hours are sufficient.

  The method for isolating the product obtained as described above is not particularly limited, and a known method can be employed. For example, after completion of the reaction, an aqueous solution of sodium bicarbonate is added to the reaction solution, the organic solvent soluble component is extracted with methylene chloride, and the methylene chloride solution is dried and distilled off to be isolated. Can do.

  The method for purifying the product thus isolated is not particularly limited, but in general, the compound can be dissolved in a mixed solvent of hexane / ethyl acetate and purified by silica gel column chromatography. .

  Next, for the hydrolysis of the compound, for example, the compound may be dissolved in methanol and then an alkaline aqueous solution such as an aqueous sodium hydroxide solution may be added and reacted at room temperature for about 2 hours. After completion of the reaction, ethyl acetate is added to the aqueous solution to remove organic solvent-soluble components, and the aqueous solution is neutralized with an aqueous sodium sulfite solution. After neutralization, methylene chloride is added to extract the reaction product, and the extract is dried and evaporated to obtain the N-formyl optically active proline derivative represented by the above formula (III).

The structure of the N-formyl optically active proline derivative represented by the above formula (III) is, as described in Patent Document 3, ¹ H-nuclear magnetic resonance spectrum, infrared absorption spectrum, elemental analysis, and MS spectrum. This can be confirmed by measuring the above.

  The N-formyl optically active proline derivative of the present invention produced in this manner is useful as an activator when trichlorosilane is used as a reducing agent. For example, when an optically active secondary alcohol compound is produced from an asymmetric ketone compound using trichlorosilane as a reducing agent, an optically active proline derivative obtained by the method of the present invention can be used as an activator, which is as high as 80% or more. An optically pure secondary alcohol compound can be produced.

  EXAMPLES Hereinafter, although an Example is hung up and this invention is demonstrated concretely, this invention is not restrict | limited at all by these.

Production Example 1
A thermometer and two graphite electrodes (2 cm long × 5 cm wide) were attached in a beaker type diaphragm electrolysis cell having a capacity of 100 ml, one serving as a cathode and one serving as an anode. In this electrolytic cell, N-benzyloxycarbonyl-L-proline methyl ester 2.633 g (10 mmol), tetraethylammonium p-toluenesulfonate (Wako Pure Chemical Reagent special grade) 0.301 g (10 mmol), methanol (Wako Pure Chemical Reagent special grade) ) 50 ml was added. While stirring the reaction solution with a magnetic stirrer, an electric charge of 9.5 F / mol was applied at 0 ° C. under a constant current (300 mA, about 16 V) condition. After completion of the reaction, the reaction solvent was distilled off, 80 ml of saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with 10 ml of ethyl acetate. The obtained ethyl acetate solution was dried over magnesium sulfate and filtered, and then ethyl acetate was distilled off. The obtained residue was subjected to silica gel column chromatography (developing solution: ethyl acetate: n-hexane = 1: 3). As a result, 1.925 g (yield 66) of N-benzyloxycarbonyl-α'-methoxy-L-proline methyl ester was obtained. %) Acquired.

Example 1
(1) Synthesis of the compound represented by the above formula (I) In a 50 ml cocoon flask, 0.283 ml (1.5 mmol) of 1,3,5-triethylbenzene in dichloromethane (0. 75 ml) solution was added and 0.059 mL (0.5 mmol) of tin tetrachloride was added dropwise. Thereto was slowly added dropwise a solution of 0.146 g (0.5 mmol) of N-benzyloxycarbonyl-α′-methoxy-L-proline methyl ester in dichloromethane (0.75 ml). After stirring at -78 ° C for 1 hour, the temperature was slowly raised and the mixture was stirred at 0 ° C for 11 hours. The reaction solution was poured into ice water (20 g), and the organic matter was extracted with chloroform (20 ml × 3). After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 10: 1 and 6: 1) to obtain 0.077 g of a colorless oil.

As a result of measuring the infrared absorption spectrum of the obtained oily substance, based on the carboxyl groups in 1755 cm ^-1, to obtain an absorbent based on amide group 1705 cm ^-1. Further, the results of measuring the nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane standard: deuterated chloroform solvent) are as follows.

  A multiplet peak corresponding to 7 hydrogen atoms was observed at 6.50-7.40 ppm, corresponding to the benzene ring protons of (b) and (c). A multiplet peak corresponding to 3 hydrogen atoms was observed at 4.80-5.20 ppm, which corresponded to protons of (a) methylene group and (e) methine group. A multiplet peak corresponding to one hydrogen atom was observed at 4.50 to 4.60 ppm, which corresponded to the peak of the methine group in (d). A broad singlet peak corresponding to three hydrogen atoms was observed at 3.77 ppm, which corresponded to the methyl group peak in (f). A multiplet peak corresponding to 10 hydrogen atoms was observed at 1.95-3.10 ppm, which corresponded to the methylene group peaks of (g), (h) and (i). A multiplet peak corresponding to 9 hydrogen atoms was observed at 0.86-1.32 ppm, which corresponded to the methyl group peak in (j).

Moreover, when the mass spectrum was measured, it became a measured value 423.2394 with respect to the calculated value 423.2410 corresponding to the estimated molecular formula C ₂₆ H ₃₃ NO ₄ , confirming the validity of the molecular formula.

From the above results, it was revealed that the colorless oil was cis-N-benzyloxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline methyl ester. The isolation yield was 36%. Further, the optical rotation at 27.5 ° C. of this compound was [α] _D ^27.5 = −42.3 (C = 1.0, chloroform).

(2) Synthesis of the compound represented by the formula (II) The cis-N-benzyloxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline methyl obtained by the above method in an insulator flask To a solution of 0.847 g (2 mmol) of ester and 0.279 ml (2 mmol) of triethylamine in methanol (5 ml) was added 5% palladium activated carbon (0.030 mg), and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere of 1 atm. After completion of the reaction, the reaction solution was filtered through Celite, and the solvent was concentrated under reduced pressure to obtain a colorless oil.

As a result of measuring the infrared absorption spectrum of the obtained colorless oil, give absorption based the amino group in 3350 cm ^-1, to obtain a absorption based on carboxyl group 1735 cm ^-1. Further, the results of measuring the nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane standard: deuterated chloroform solvent) are as follows.

  A singlet peak corresponding to two hydrogen atoms was observed at 6.89 ppm, which corresponds to the proton of the benzene ring in (b). A triplet peak corresponding to one hydrogen atom was observed at 4.57 ppm and corresponded to the proton of the methine group in (d). A triplet peak corresponding to one hydrogen atom was observed at 3.87 ppm, corresponding to the peak of the methine group in (c). A singlet peak corresponding to 3 hydrogen atoms was observed at 3.76 ppm, which corresponds to the peak of the methyl group in (e). A multiplet peak corresponding to 6 hydrogen atoms was observed at 2.50-2.90 ppm, which corresponded to the methylene group peak in (h). A multiplet peak corresponding to 4 hydrogen atoms was observed at 2.00-2.35 ppm, which corresponded to the methylene group peaks in (f) and (g). A singlet peak corresponding to 9 hydrogen atoms was observed at 1.23 ppm, which corresponded to the methyl group peak in (i). The amino group proton of (a) was a broad peak and could not be assigned.

Further, when the mass spectrum was measured, the measured value 289.2037 was obtained with respect to the calculated value 289.2042 corresponding to the estimated molecular formula C ₁₈ H ₂₇ NO ₂ , confirming the validity of the molecular formula.

  The above results revealed that the colorless oil was cis-α '-(2,4,6-triethylphenyl) -L-proline methyl ester.

(3) Synthesis of the compound represented by the above formula (III) To the cis-α '-(2,4,6-triethylphenyl) -L-proline methyl ester in the insulator flask obtained by the above method, formic acid ( 6 ml) and acetic anhydride (2 ml) were added, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (10 ml) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent n-hexane: ethyl acetate = 3: 1) to find cis-N-formyl-α '-(2,4,6-triethylphenyl) -L-proline methyl ester. (0.372 g, yield 58%) was obtained as a colorless oil. To an insulator flask containing this compound, 8 ml of water, 0.048 g (0.6 mmol) of sodium hydroxide (special grade of Wako Reagent) and 2 ml of methanol were added and reacted at room temperature for 2 hours.

  After completion of the reaction, 20 ml of ethyl acetate was added to separate the aqueous phase, and the aqueous phase was acidified with sodium hydrogen sulfate and extracted three times with 20 ml of methylene chloride. The obtained methylene chloride solution was dried over magnesium sulfate, and methylene chloride was distilled off to give cis-N-formyl-α '-(2,4,6-triethylphenyl) -L-proline as white crystals. 354 g (yield 100%) was obtained.

Example 2
(1) Synthesis of compound represented by formula (I) The same operation as in Example 1 was performed except that trimethylbenzene was used instead of triethylbenzene. As a result, 1.435 g of colorless oil was obtained.

As a result of measuring an infrared absorption spectrum of the obtained oily substance, absorption based on a carbonyl group was obtained at 1753 cm ⁻¹ . Further, the results of measuring the nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane standard: deuterated chloroform solvent) are as follows.

A broad singlet peak corresponding to 5 hydrogen atoms was observed at 7.10-7.35 ppm, corresponding to the proton of the benzene ring in (b). A singlet peak corresponding to two hydrogen atoms was observed at 6.79 ppm, corresponding to the proton of the benzene ring in (c). A multiplet peak corresponding to 3 hydrogen atoms was observed at 4.90-5.15 ppm, corresponding to the protons of the methylene group and (e) methine group of (a). A multiplet peak corresponding to one hydrogen atom was observed at 4.55-4.63 ppm, corresponding to the peak of the methine group in (d). A broad singlet peak corresponding to three hydrogen atoms was observed at 3.74 ppm, which corresponded to the methyl group peak in (f). A multiplet peak corresponding to 13 hydrogen atoms was observed at 2.02-2.45 ppm, which corresponded to the methylene group peak in (g) and (h) and the methyl group peak in (i). The measured mass spectrum, relative to the calculated value 381.1940 corresponding to the estimated molecular formula _C 23 _H 27 NO _4, confirming next measured value 381.1938, the validity of the molecular formula.

From the above results, it was revealed that the colorless oil was cis-N-benzyloxycarbonyl-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester. The isolation yield was 51%. Further, the optical rotation of this compound at 26.7 ° C. was [α] _D ^26.7 = −49.6 (C = 1.0, chloroform).
(2) Synthesis of the compound represented by the above formula (II) cis-N-benzyl instead of cis-N-benzyloxycarbonyl-α '-(2,4,6-triethylphenyl) -L-proline methyl ester The same operation as in Example 1 was performed except that oxycarbonyl-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester was used. As a result, a colorless oil was obtained.

As a result of measuring the infrared absorption spectrum of the obtained colorless oil, give absorption based the amino group in 3350 cm ^-1, to obtain a absorption based on carboxyl group 1740 cm ^-1. Further, the results of measuring the nuclear magnetic resonance spectrum (σ: ppm: tetramethylsilane standard: deuterated chloroform solvent) are as follows.

  A singlet peak corresponding to two hydrogen atoms was observed at 6.82 ppm, which corresponds to the proton of the benzene ring in (b). A triplet peak corresponding to one hydrogen atom was observed at 4.59 ppm, corresponding to the proton of the methine group in (d). A triplet peak corresponding to one hydrogen atom was observed at 3.85 ppm, which corresponds to the peak of the methine group in (c). A singlet peak corresponding to 3 hydrogen atoms was observed at 3.75 ppm, which corresponded to the peak of the methyl group in (e). A multiplet peak corresponding to 6 hydrogen atoms was observed at 2.43 ppm, corresponding to the methyl group peak in (h). A multiplet peak corresponding to 3 hydrogen atoms was observed at 2.24 ppm, which corresponded to the methyl group peak in (i). A multiplet peak corresponding to 4 hydrogen atoms was observed at 1.95-2.35 ppm, corresponding to the methylene group peaks in (g) and (h). The amino group proton of (a) was a broad peak and could not be assigned.

The measured mass spectrum, relative to the calculated value 247.1572 corresponding to the estimated molecular formula _C 15 _H 21 NO _2, confirming next measured value 247.1581, the validity of the molecular formula.

  The above results revealed that the colorless oil was cis-α '-(2,4,6-trimethylphenyl) -L-proline methyl ester.

(3) Synthesis of the compound represented by the above formula (III) In place of cis-α '-(2,4,6-triethylphenyl) -L-proline methyl ester, cis-α'-(2,4,6- The same operation as in Example 1 was performed except that trimethylphenyl) -L-proline methyl ester was used.

  As a result, 0.512 g (yield 98%) of cis-N-formyl-α '-(2,4,6-trimethylphenyl) -L-proline was obtained as a colorless oil.

Example 3 (Example of secondary alcohol synthesis)
Under a nitrogen atmosphere, 0.036 g (0.3 mmol) of acetophenone (special grade of Wako Pure Chemicals), cis-N-formyl-α '-(2,4,6-triethyl) phenyl-L-proline was added to a 10 ml cocoon flask. Add 0.009 g (0.03 mmol) and 1.5 ml of methylene chloride and stir under ice cooling. To this solution, 0.5 ml of methylene chloride solution in which 0.09 ml (0.9 mmol) of trichlorosilane (manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved was added and reacted at 0 ° C. for 30 minutes and at room temperature for 24 hours.

  After completion of the reaction, 10 ml of saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to decompose excess trichlorosilane, and extraction was performed with 10 ml × 3 of methylene chloride. After the obtained methylene chloride solution was dried, methylene chloride was distilled off, and the residue was isolated and purified by silica gel chromatography (developing solution, ethyl acetate: hexane = 1: 5). As a result, (R) -1-phenyl-1 -0.027 g (74% yield) of ethanol was obtained. Moreover, it was 95% ee when the optical purity of this compound was measured by the high performance liquid chromatography.

Example 4
The same operation as in Example 3 was performed, except that the optically active proline derivative was replaced with cis-N-formyl-α '-(2,4,6-trimethyl) phenyl-L-proline. As a result, 0.026 g (yield 73%) of (R) -1-phenyl-1-ethanol was obtained. Moreover, it was 89% ee when the optical purity of this compound was measured by the high performance liquid chromatography.

Claims (3)

Formula (I)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
An N-aralkyloxycarbonyl optically active proline ester derivative represented by the formula: The following formula (II)

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms, and R ² represents an alkyl group having 1 to 6 carbon atoms.)
An optically active proline ester derivative represented by: Formula (III) below

(However, R ¹ represents an aryl group having 6 to 12 carbon atoms.)
A method for producing an N-formyl optically active proline derivative represented by formula (1), comprising the following steps (1) to (3):
(1) The following formula (IV)

(However, R ² represents an alkyl group having 1 to 6 carbon atoms, and R ³ represents an aralkyl group having 7 to 10 carbon atoms.)
A step of reacting the methoxyproline ester derivative represented by the formula (1) with a benzene derivative in the presence of a Lewis acid to synthesize the N-aralkyloxycarbonyl optically active proline ester derivative according to claim 1,
(2) The step of synthesizing the optically active proline ester derivative of claim 2 by hydrogen reduction of the N-aralkyloxycarbonyl optically active proline ester derivative of claim 1;
(3) A step of synthesizing the N-formyl optically active proline derivative represented by the above formula (III) by subjecting the optically active proline derivative according to claim 2 to formylation using a formylation agent, followed by hydrolysis.