KR101630204B1 - A process for producing a chiral beta hydroxycarbonyl compound and a process for producing the beta hydroxycarbonyl compound - Google Patents

Abstract

The present invention relates to a process for preparing a chiral beta hydroxycarbonyl compound and a chiral beta hydroxycarbonyl compound prepared thereby, and more particularly to a process for producing a chiral beta hydroxycarbonyl compound by using a catalyst composition comprising proline and an isothiouronium salt in an asymmetric aldol reaction To a chiral beta hydroxycarbonyl compound having improved stereoselectivity and a chiral beta hydroxycarbonyl compound thereby prepared.
The present invention shows an effect of improving the yield, mirror image selectivity and dihedral selectivity by using a catalyst composition comprising a proline derivative and an isothiouronium salt in an asymmetric aldol reaction.

Description

[0001] The present invention relates to a method for producing a chiral beta-hydroxy carbonyl compound and a beta-hydroxy carbonyl compound prepared by the same,

The present invention relates to a process for preparing a chiral beta hydroxycarbonyl compound and a chiral beta hydroxycarbonyl compound prepared thereby, and more particularly to a process for producing a chiral beta hydroxycarbonyl compound by using a catalyst composition comprising proline and an isothiouronium salt in an asymmetric aldol reaction To a chiral beta hydroxycarbonyl compound having improved stereoselectivity and a chiral beta hydroxycarbonyl compound prepared thereby.

Chirality means that the atoms bound to one carbon are arranged in different directions in the three-dimensional space, and chiral compounds, which are mirror images, are chemically identical but often have different biological activities. Thus, Research is actively underway.

The selective asymmetric synthesis of enantiomers can be divided into three main methods: the use of chiral auxiliaries, the use of chiral catalysts and Lewis acids, or the use of organic catalysts that do not contain metals as chiral catalysts. In particular, the organic catalyst has an advantage that it is easy to handle, is nontoxic to the human body, and is environmentally friendly.

Asymmetric aldol reaction is one of the common methods of forming carbon-carbon bonds. Beta hydroxycarbonyl compound, which is a compound produced by asymmetric aldol reaction, contains a compound useful as a functional group by containing a hydroxyl group and a carbonyl group, Is widely used in the synthesis of physiologically active substances including

J. Am. Chem. Soc. 2000, 122, 2395-2396. In which the proline is used as an organic catalyst, has been studied. However, due to the low solubility of proline in the organic solvent, the reactivity is limited and the presence of potential side reactions Aromatic aldehydes still exhibit low selectivity particularly in the case of aromatic aldehydes.

J. Am. Chem. Soc. 2000, 122, 2395-2396

The present invention provides a process for preparing a chiral beta hydroxycarbonyl compound and a chiral beta hydroxycarbonyl compound prepared thereby.

In order to solve the above-mentioned problems, the present invention provides a method for preparing a compound of formula (I)

[Chemical Formula 1]

Wherein R ₁ and R ₂ are each independently selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms, or a heteroaryl group,

R ₁ and R ₂ may be a cyclic compound having 5 to 10 carbon atoms bonded to each other)

(2)

(In Formula 2 R ₃ is hydrogen, C 1 -C 10 alkyl group, a cycloalkyl group having a carbon number of 5-10, hydrogen is _{-F, -Cl, -Br, -NO 2} , -CO (CH 2) nCH 3, - O (CH ₂₎ nCH _3, or is unsubstituted or substituted with -OH, carbon is N, O, or one selected from a substituted or unsubstituted allyl group having 4 to 10 carbon atoms ring with S, and

and n is an integer of 0 to 10)

Mixing the mixture with a compound represented by the following Chemical Formula 3 and Chemical Formula 4; And

(3)

(Wherein R ₄ is a hydrogen atom, a hydroxyl group, an ether group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an aryl group having 4 to 15 carbon atoms substituted or unsubstituted with N, O, or S, An alkoxy group having 1 to 10 carbon atoms, and an ester group having 1 to 10 carbon atoms,

* Stands for stereogenic center)

[Chemical Formula 4]

Wherein R ₅ is any one selected from the group consisting of hydrogen, an alkyl group having 1 to 10 carbon atoms, and an aryl group having 4 to 15 carbon atoms in which carbon is substituted or unsubstituted with N, O, or S,

R ₆ and R ₇ are each independently hydrogen, an alkyl group having 1 to 10 carbon atoms, and aryl having 4 to 15 carbon atoms in which hydrogen is substituted or unsubstituted with CF ₃ and carbon is substituted or unsubstituted with N, O, or S. Lt; RTI ID = 0.0 >

X ^- represents Cl ^- , Br ^- , I ^- , BPh ₄ ^- , BF ₄ ^- , PF ₆ ^- , CF ₃ CO ₂ ^- , R ₈ CO ₂ ^- , R ₈ SO ₃ ^- , and (R ₈ ) ₂ PO ₂ ^- < / RTI >

R ₈ is any one selected from the group consisting of hydrogen, an alkyl group having 1 to 10 carbon atoms, and an aryl group having 4 to 15 carbon atoms in which carbon is substituted or unsubstituted with N, O, or S;

Reacting a mixture of the compounds represented by Chemical Formulas 1 to 4 at 0 ° C to 5 ° C for 80 hours to 120 hours to prepare a chiral β-hydroxy carbonyl compound ≪ / RTI >

In the above process, the compounds represented by the general formulas (1) and (2) are used as reactants and the compounds represented by the general formulas (3) and (4) serve as catalysts. By the asymmetric aldol reaction as shown in the following reaction formula (1) Rocycarbonyl compound is prepared.

[Reaction Scheme 1]

The isothiouronium salt of the compound represented by the formula (4) has an increased acidity of N-H hydrogen as compared with thiourea, so that stronger hydrogen bond interactions can be obtained. In the above Scheme 1, the isothiourone salt of the present invention improves the electrophilicity of the carbonyl group through hydrogen bonding between the oxygen atom of the carbonyl group of the ketone compound and the NH of the isothiouronium salt to obtain a high yield of the beta hydroxy But also serves to increase the stereoselectivity due to steric hindrance through the hydrogen bonding action between the oxygen atom of the carboxyl group of proline and NH of the isothiouronium salt as shown in the mechanism below . Therefore, the larger the size of the alkyl group bonded to the sulfur atom of the isothiouronium salt is, the larger the size of the counter anion is, the more the degree of the steric hindrance increases and the stereoselectivity can be further increased.

In the process for preparing the chiral beta hydroxycarbonyl compound of the present invention, the compound represented by the above formula (1) is preferably selected from the group consisting of methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, diethyl ketone, ethyl propyl ketone, Ketone, propyl butyl ketone, dibutyl ketone, cyclopentanone, and cyclohexanone.

In the process for preparing the chiral beta hydroxycarbonyl compound of the present invention, the above-mentioned formula (2) is a compound represented by the following formula (5).

[Chemical Formula 5]

(Wherein R ₉ to R ₁₃ are each independently selected from H, F, Cl, Br, NO ₂ , CO (CH ₂ ) n CH ₃ , O (CH ₂ ) n CH ₃ ,

and n is an integer of 0 to 10)

In the process for preparing a chiral beta hydroxycarbonyl compound of the present invention, an organic solvent may be further added in the step of mixing the compound represented by the above formula (1) or (2), and the compound represented by the above formula And the reaction may proceed without an organic solvent.

In the process for producing the chiral beta hydroxycarbonyl compound of the present invention, the compound represented by the above-mentioned general formula (2) can be obtained by reacting the compound represented by the general formula (2) with benzaldehyde, 2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde, , 2-methoxybenzaldehyde, and 3-hydroxybenzaldehyde.

In the process for preparing the chiral beta hydroxycarbonyl compound of the present invention, the above-mentioned formula (3) is a compound represented by the following formula (6).

[Chemical Formula 6]

(Wherein R ₄ represents a hydrogen atom, a hydroxyl group, an ether group of 1 to 10 carbon atoms, an alkyl group of 1 to 10 carbon atoms, an aryl group of 4 to 15 carbon atoms in which the carbon atom is substituted or unsubstituted by N, O, or S, An alkoxy group having 1 to 10 carbon atoms, and an ester group having 1 to 10 carbon atoms)

In the production method of the chiral beta-hydroxy carbonyl compounds of the invention, the compound represented by the formula (3) L - characterized in that the proline (L -Proline).

In the process for preparing a chiral beta hydroxycarbonyl compound of the present invention, the compound represented by the formula (4) is any one selected from the following formulas (7) to (10).

(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

Wherein X ₁ ^- is any one selected from BF ₄ ^- , PF ₆ ^- , PhCO ₂ ^- , and CF ₃ CO ₂ ^-

X ₂ ^- represents Cl ^- , Br ^- , I ^- , and BPh ₄ ^- .

Y is any one selected from the group consisting of F, Cl, Br, and I)

In the method for producing a chiral beta hydroxycarbonyl compound of the present invention, 0.01 to 1 mol of the compound represented by the general formula (2) is added per 1 mol of the compound represented by the general formula (1).

In the process for preparing the chiral beta hydroxycarbonyl compound of the present invention, 0.01 to 1 mol of the compound represented by the general formula (4) is added per 1 mol of the compound represented by the general formula (3). Preferably, 0.2 to 1 mol, more preferably 0.3 to 0.7 mol, of the compound represented by the general formula (4) is added per 1 mol of the compound represented by the general formula (3).

In the process for preparing the chiral beta hydroxycarbonyl compound of the present invention, 0.01 to 0.5 mol of the compound represented by the general formula (3) is added per 1 mol of the compound represented by the general formula (2).

The present invention also provides a chiral beta hydroxycarbonyl compound represented by the following formula (11), which is produced by the production method of the present invention.

(11)

(Wherein R ₁ and R ₂ are each independently any one selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 5 to 10 carbon atoms, an aryl group having 5 to 10 carbon atoms, and a heteroaryl group,

R ₁ and R ₂ may be a cyclic compound having 5 to 10 carbon atoms bonded to each other,

R ₃ is a hydrogen, a cycloalkyl group, hydrogen of the alkyl group having 1 to 10 carbon atoms, having 5 to 10 -F, -Cl, -Br, -NO 2, -CO (CH 2) nCH 3, -O (CH 2) nCH ₃ , or an allyl group having 4 to 10 carbon atoms in which carbon is substituted or unsubstituted with N, O, or S, and n is an integer of 0 to 10)

In the chiral beta hydroxycarbonyl compound of the present invention, the chiral beta hydroxycarbonyl compound represented by the formula (11) is represented by the following chemical formulas (12) to (19).

[Chemical Formula 12]

[Chemical Formula 13]

(Wherein X in Formula 13 is any one selected from the group consisting of F, Cl, Br, and I)

[Chemical Formula 14]

(X in Formula 14 is any one selected from the group consisting of F, Cl, Br, and I)

[Chemical Formula 15]

(Wherein n is an integer of 0 to 10)

[Chemical Formula 16]

[Chemical Formula 17]

(In the above formula (17), n is an integer of 0 to 10)

[Chemical Formula 18]

[Chemical Formula 19]

The present invention shows an effect of improving the yield, mirror image selectivity and dihedral selectivity by using a catalyst composition comprising a proline derivative and an isothiouronium salt in an asymmetric aldol reaction.

Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention is not limited by the following examples.

< Example  1> Isothiouronium  Preparation of salt organic catalyst

< Example  1-1>

3,5-bis (trifluoromethyl) aniline (4 mL, 26 mmol, 1 eq) was added to 200 mL of dry tetrahydrofuran (THF) in a nitrogen atmosphere and triethylamine (4.2 mL, 30 mmol, 1.2 eq) was added slowly. Thiophosgene (0.78 mL, 10 mmol, 0.4 eq) was added to the solution over about 3 minutes, and the mixture was reacted at room temperature for 24 hours with stirring. After the reaction was completed, 200 mL of distilled water and diethyl ether (200 mL X 3) were added to extract the product, and then the solvent was removed. The extract was dissolved in dichloromethane and placed in a refrigerator (0 to 5 ° C) for one day to give a recrystallized white solid which was filtered and dissolved in THF, precipitated by precipitation with n-hexane and filtered to give a white solid 1,3-bis [3,5-bis (tri-fluoromethyl) phenyl] thiourea in a yield of 50% was obtained.

After dissolving 1,3-bis [3,5-bis (tri-fluoromethyl) phenyl] thiourea (Olg, 0.2 mmol, 1 eq) in methanol (8 ml), methyl iodine (0.25 ml, ) Was added, and the mixture was refluxed at 70 DEG C for 48 hours. After the reaction was completed, the isothiouronium salt was separated by precipitation using ethyl acetate, methanol, and hexane.

< Example  1-2 to 1-4>

Thiourea (1.0 eq) and alkyl halide (2.0 eq) were mixed in methanol and refluxed at 70-80 ° C for 24 hours. The product was precipitated by precipitation, 1-4 was synthesized.

< Example  2> Isothiouronium  Asymmetry using salt Aldol  reaction

< Example  2-1>

4-nitrobenzaldehyde (1 eq) and cyclohexanone (10 eq) were mixed at 0 ° C, and then L- propylene (0.15 eq) and the isothiouronium salt prepared in Example 1 (0.1 eq) Mixed, and reacted at 0 to 5 DEG C for 96 hours. The reaction was quenched by the addition of 20 ml of saturated NH ₄ Cl solution, the aqueous layer was separated and the product was extracted with CH ₂ Cl ₂ (20 ml X 3). The organic solution layer was dried using MgSO ₄ , and the solvent was removed using a rotary evaporator. The main product was purified by column chromatography using a hexane / ethyl acetate mixture (8: 2 by volume) and the results are shown in Table 2 below.

In the case of Entry 7, an isothiuronium salt substituted with an anion was used as a cocatalyst by further mixing L- propylene as a catalyst and isothiouronium salt prepared in Example 1 with NaBPh ₄ .

When the isothiouronium salt is used instead of thiourea in the cocatalyst, the yield and stereoselectivity of the isothiuronium salt are higher than that of thiourea. This shows that the acidity of NH 3 in the isothiouronium salt is higher than that of thiourea, This is due to the possibility of binding interaction.

< Example  2-2>

(2S) -2 - [(R) -hydroxy (4-nitrophenyl) -1H-pyrazolo [3,4-d] pyrimidine was obtained in the same manner as in Example 2-1 with the exception that the solvent used was changed to S-benzylisothiouronium iodide. ) Methyl] cyclohexanone was prepared and the results are shown in Table 3 below.

As shown in Table 3, it can be seen that the synthesis yield and stereoselectivity were higher when the aldol reaction proceeded in the absence of solvent than when using distilled water as a polar solvent or acetonitrile or hexane as a non-polar solvent.

In addition, when S-benzylisothiouronium iodide is used in an amount of 10 mol%, it can be confirmed that the effect is the highest.

< Example  2-3>

(2S) -2 - [(R) -hydroxy (4-nitrophenyl) methyl) methyl] thiophene was obtained in the same manner as in Example 2-1, except for using S-benzylisothiouronium iodide, ] Cyclohexanone was prepared and the results are shown in Table 4 below.

As shown in Table 4, it can be seen that the synthesis yield and stereoselectivity are higher as the reaction time is increased.

< Example  2-4>

(2S) -2 - [(R) -hydroxy (2-chlorophenyl) methyl] cyclohexanone was synthesized in the same manner as in Example 2-1, except that 2-chlorobenzaldehyde was used, Respectively.

< Example  2-5>

(2S) -2 - [(R) -hydroxy (2-chlorophenyl) methyl) thiophene was obtained in the same manner as in Example 2-4, except that S-benzylisothiouronium iodide was used, ] Cyclohexanone was prepared and the results are shown in Table 6 below.

As shown in Table 6, it can be seen that the synthesis yield and stereoselectivity are higher at a temperature lower than room temperature.

< Example  2-6>

Asymmetric aldol reaction was carried out in the same manner as in Example 2-1 using S-benzylisothiouronium iodide except that various aromatic aldehydes were used, and the results are shown in Table 7 below.

As shown in Table 7, it can be seen that the aromatic aldehyde having the methoxy group at the 2-position or the hydroxy group at the 3-position has a low yield. This is because the enamine intermediate has a negative influence on the nucleophilic addition reaction with the aromatic aldehyde, since the methoxy group and the hydroxy group act as an electron donating group (EDG).

< Example  3> Thiourea Bronsted acid Asymmetry using Aldol  reaction

< Example  3-1>

Asymmetric aldol reaction was carried out in the same manner as in Example 2-4 except that thiourea (0.10 eq) and bronsted acid (0.10 eq) were used as the catalyst composition, and the results are shown in Table 8 below.

< Example  3-2>

(2S) -2 - [(R) -hydroxy (4-nitrophenyl) methyl] cyclohexanone was prepared in the same manner as in Example 3-1, except that 4-nitrobenzaldehyde was used, Table 9 shows the results.

< Example  3-3>

Asymmetric aldol reaction was carried out in the same manner as in Example 3-1 using thiourea and Tetrafluoroboric acid except that various aromatic aldehydes were used, and the results are shown in Table 10 below.

Claims (12)

(A) mixing cyclohexanone and a compound represented by formula (2);
(2)

(In Formula 2 R ₃ is _{hydrogen, -Cl, -NO 2, -OCH 3} , -COCH 3, -OH, or Im)
The method comprising mixing any of the compounds selected from proline (L -Proline) and under formula 7 to 10 - (B) L to the mixture; And
(7)

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical formula 10]

Wherein X ₁ ^- is any one selected from BF ₄ ^- , PF ₆ ^- , PhCO ₂ -, and CF ₃ CO ₂ ^-
X ₂ ^- represents Cl ^- , Br ^- , I ^- , and BPh ₄ ^- .
Y is F)

(C) reacting the mixed mixture at 0 SIMILAR 5 DEG C for 80 SIMILAR 120 hours to form a chiral beta-hydroxy carbonyl compound selected from the following formulas (12) to (19) compound.
[Chemical Formula 12]

[Chemical Formula 13]

(Wherein X in Formula 13 is any one selected from the group consisting of F, Cl, Br, and I)
[Chemical Formula 14]

(X in Formula 14 is any one selected from the group consisting of F, Cl, Br, and I)
[Chemical Formula 15]

(Wherein n is an integer of 0 to 10)
[Chemical Formula 16]

[Chemical Formula 17]

(In the above formula (17), n is an integer of 0 to 10)
[Chemical Formula 18]

[Chemical Formula 19]

delete delete delete delete delete delete The method according to claim 1,
Wherein the compound represented by Formula 2 is added in an amount of 0.01 to 1 mole per 1 mole of the cyclohexanone.
The method according to claim 1,
Wherein the compound represented by any one of Chemical Formulas 7 to 10 is added in an amount of 0.01 to 1 mole per 1 mole of the L -proline.
The method according to claim 1,
Wherein the L -proline is added in an amount of 0.01 to 0.5 mol per 1 mol of the compound represented by the formula (2).
delete delete