WO2013115595A1

WO2013115595A1 - Method for preparing compound by novel michael addition reaction using water or various acids as additive

Info

Publication number: WO2013115595A1
Application number: PCT/KR2013/000829
Authority: WO
Inventors: 박애리; 김봉찬; 안지은; 이희봉
Original assignee: 주식회사 엘지생명과학
Priority date: 2012-02-03
Filing date: 2013-02-01
Publication date: 2013-08-08
Also published as: TN2014000329A1; MA35906B1; PE20142331A1; BR112014018985B1; AU2013215796B2; SG11201404396TA; CO7030967A2; EA201491463A1; KR20130090360A; AU2013215796A1; MY168411A; ZA201405598B; CN104159884A; MX2014009309A; PH12014501704A1; CL2014002029A1; MX355336B; BR112014018985A2; KR101539761B1; CN104159884B

Abstract

The present invention relates to a novel method for preparing a compound represented by chemical formula 1 using water or various acids as an additive in a Michael addition reaction of a Michael receptor represented by chemical formula 2 and a compound represented by chemical formula 3.

Description

Process for preparing compounds through new Michael-addition reaction using water or various acids as additives

The present invention relates to a method for preparing a compound of Formula 1, which can be used as an intermediate such as pharmaceuticals, pesticides, electronic materials or liquid crystals, through a new Michael-addition reaction using water or various acids as an additive. will be.

Compounds of the general formula (1) have various skeletons and have biological activities, and thus are widely used as intermediates for synthesizing pharmaceuticals, pesticides, electronic materials or liquid crystal materials.

[Formula 1]

In Chemical Formula 1,

A is R ₁ -C (═O) —, nitrile, substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl, or substituted or unsubstituted C ₆ -C ₁₀ arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C ₁ -C ₁₀ alkyl; Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; Substituted or unsubstituted C ₆ -C ₁₀ aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C ₁ -C ₅ alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo (═O) group. Or unsaturated C ₆ -C ₁₀ cycloalkyl,

R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C ₁ -C ₁₀ alkyl; Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; Substituted or unsubstituted C ₆ -C ₁₀ aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C ₁ -C ₅ alkoxy; Nitrile; And substituted or unsubstituted C ₁ -C ₁₀ alkyl sulfonyl,

R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C ₁ -C ₄ alkyl,

P ₁ is selected from the group consisting of benzyl, methyl, ethyl, i-propyl and t-butyl groups.

Formula 1 has an advantage of being useful in the synthesis of various organic compounds because it has an ester skeleton that can be easily substituted with other substrates. Therefore, the research on the manufacturing method of the formula (1) is extensive, various synthesis methods have been developed by organic synthetic chemists and reported in many documents.

Compounds having organofluorine derivatives in the compound of Formula 1 have been actively studied, especially in the Itsumaro Kumadaki group (Setsunan University, Japan). However, there are many limitations in synthesizing compounds with these organofluorine derivatives through the Michael-addition reaction. Such limitations include firstly the use of excess copper powder (more than 6 equivalents), secondly, a relatively long reaction time (1-7 hours) and finally a relatively low yield (20-70%). This can be a problem in terms of cost and time when synthesizing in large quantities using existing reactions [ Chem. Pharm. Bull . 1999 , 47 , 1023; Chem. Pharm. Bull . 2000 , 48 , 1023; J. Fluorine Chem . 2003 , 121 , 105; J. Fluorine Chem . 2004 , 125 , 509].

As an example of a method known to be capable of synthesizing the compound of Formula 1, there is a method of Michael-adding a compound of Formula 2 and a compound of Formula 3 using copper powder.

[Formula 2]

[Formula 3]

In the above, A, R2 to R6 and P ₁ are the same as defined in Formula 1, and X is halogen (ie F, Cl, Br, or I).

However, the conventional Michael-addition reaction using only copper powder has a problem of requiring a relatively long reaction time, and has a disadvantage in that it is difficult to obtain the compound of Formula 1 in high yield due to the generation of impurities.

It is an object of the present invention to provide a novel process for producing a compound of formula 1 in high yield.

Thus, the present invention provides a new preparation of the compound of formula (I). According to the present invention, in the preparation of the following Chemical Formula 1 compound by the Michael-addition reaction of the following Chemical Formula 2 and the Chemical Formula 3 in the presence of a copper powder, reacting water or an acid or a mixture thereof There is provided a process for the preparation of the compound of formula 1, which is added to the mixture:

[Formula 1]

[Formula 2]

[Formula 3]

In the above,

P ₁ is selected from the group consisting of benzyl group, methyl group, ethyl group, i-propyl group and t-butyl group,

X is halogen (ie, F, Cl, Br, or I).

In the present invention, 'alkyl' refers to a straight or branched carbon chain having 1 to 10 (or 1 to 4) carbon atoms. Specifically, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl and the like can be included.

In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated mono- or poly-carbocyclic ring having 3 to 10 ring carbon atoms. Specifically, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like can be included.

"Aryl" in the present invention refers to an aromatic mono- or poly-carbocyclic ring having 6 to 10 ring carbon atoms. Specifically, phenyl, naphthalenyl, or the like may be included.

In the present invention, "heteroaryl" refers to an aromatic ring composed of 5 to 10 ring constituent atoms including 1 to 2 oxygen, nitrogen or sulfur as a hetero atom. Specifically, furan, pyran, isobenzofuran, chroman, and the like may be included.

In the present invention, 'alkoxy' refers to a group in which linear or branched carbon chain terminal oxygen of 1 to 5 carbon atoms is bonded. Specifically, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, t-butoxy, pentoxy, neo-pentoxy and the like are included. Can be.

In the present invention, when A, and R1 to R6 are substituted groups, it is chloro, iodo, bromo, methyl, ethyl, n-propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, And one or more substituents selected from acetyl.

According to an embodiment of the present invention, independently in the formula 1 and 2,

A is R ₁ -C (═O) —, nitrile, substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl, or substituted or unsubstituted C ₆ -C ₁₀ arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C ₁ -C ₅ alkyl; Substituted or unsubstituted C ₃ -C ₆ cycloalkyl; Substituted or unsubstituted C ₆ -C ₈ aryl; Substituted or unsubstituted 5-membered to 8-membered heteroaryl; And substituted or unsubstituted C ₁ -C ₅ alkoxy, or, when A is bonded to R 3, A, R 3 and the carbons to which they are bonded together, together with an oxo (═O) group Forms a substituted saturated or unsaturated C ₆ -C ₁₀ cycloalkyl,

R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C ₁ -C ₅ alkyl; Substituted or unsubstituted C ₃ -C ₆ cycloalkyl; Substituted or unsubstituted C ₆ -C ₈ aryl; Substituted or unsubstituted 5- to 8-membered heteroaryl; Substituted or unsubstituted C ₁ -C ₅ alkoxy; Nitrile; And substituted or unsubstituted C ₁ -C ₁₀ alkyl sulfonyl.

The method for preparing the compound of Formula 1 according to the present invention is characterized by using water or various acids as an additive in Michael-addition reaction of the compound of Formula 2 and compound of Formula 3 in the presence of copper powder. According to one embodiment of the present invention, the compound of formula 1 may be prepared, for example, via Scheme 1 below.

Scheme 1

In Scheme 1,

a is copper powder, additives (water or various acids), amine compounds and solvents,

A, R2, R3, R4, R5, R6, P ₁ and X are as defined above.

In the method for preparing the compound of formula 1 of the present invention, the amount of copper powder is not particularly limited, but in consideration of various conditions, it is preferable to use 1.0 to 6.0 equivalents with respect to 1 mole of the compound of formula 2, and 2.0. It is more preferable to use it in the range equivalent or more.

In the method for preparing the compound of formula 1 of the present invention, water or various acids or mixtures thereof are used as specific additives of the reaction. Acids usable in the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Or organic acids such as formic acid, acetic acid, tartaric acid, or the like, may be used alone or in combination of two or more thereof. In particular, in consideration of stability and convenience of the reaction, it is preferable to use water or acetic acid as the additive. In the present invention, the amount of water or acid used as the additive is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents, based on 1 mol of the compound of Formula 2.

Formula 1 compound preparation method of the present invention can be carried out in the presence of an amine compound. In this case, N, N, N ', N'- tetramethylethylenediamine (TMEDA; N, N, N ', N '-Tetramethylethylenediamine), N, N, N', N'- tetramethyl-1,3- Propanediamine (TMPDA; N, N, N ', N' -tetramethyl-1,3-propanediamine), N, N, N', N ', N'- pentamethyldiethylenetriamine (PMDTA; N, N, N ', N', N'- Pentamethyldiethylenetriamine), 2- (dimethylamino) ethyl ether, N, N -dimethyl-2- (4-methyl - 1-1 - piperazylyl An amine compound such as ethanamine ( N, N- dimethyl-2- (4-methyl-1-1-piperazylyl) ethanamine) may be used, but is not limited thereto. The amount of the amine compound used is preferably in the range of 0.1 to 6 equivalents, and more preferably in the range of 0.1 to 1 equivalents based on 1 mole of the compound of Formula 2 above. In one embodiment of the present invention, TMEDA is typically used.

The solvent used in the method for preparing the compound of formula 1 of the present invention is a conventional organic solvent, acetonitrile, aliphatic nitriles, halogenated aliphatic hydrocarbons (eg dichloromethane, dichloroethane, etc.) or cyclized ethers (eg tetrahydrofuran) , 1,4-dioxane, etc.), but is not limited thereto. In one embodiment of the present invention, tetrahydrofuran is typically used.

Michael-addition reaction of the compound of Formula 2 and Formula 3 may be carried out at any temperature in the range from 15 ℃ to reflux temperature.

The reaction time of the present invention may vary depending on the conditions of the reactants, the type of solvent, the amount of the solvent, and the like, but the reaction time can be significantly reduced as compared to the conventional method under the same conditions. TLC, ¹ H NMR, HPLC, GC, etc. After confirming that the starting compound of the general formula (2) is all consumed, the reaction is terminated. After the reaction is completed, the solvent is distilled off under reduced pressure, and then the compound of Formula 1 may be separated and purified through a conventional method such as column chromatography.

According to the present invention, the compound of formula 1 may be prepared using water or various acids or mixtures thereof, which have not been tried so far, as an additive, and the reaction time may be significantly shortened and the synthesis yield may be increased as compared with the prior art. . Therefore, by using the manufacturing method of the present invention it is possible to commercially mass-produce the compound of formula (1) useful as intermediates such as pharmaceuticals, pesticides, electronic materials or liquid crystal materials.

The present invention as described above will be described in more detail with reference to the following examples, the following examples are provided to help the understanding of the present invention is not limited to the scope of the present invention.

Example 1 Synthesis of Diethyl 2,2-difluoropentanedioate

Copper powder (700 mg) and tetrahydrofuran (5.8 mL) were placed in a reaction vessel and stirred at 50 ° C, to which ethyl acrylate (0.50 g) and ethyl bromodifluoroacetate (2.53 g) were added, TMEDA (0.29 g) and acetic acid (0.27 g) were added dropwise, followed by reaction for 0.5 hours, and then the reaction was terminated. 10% ammonium chloride aqueous solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to diethyl 2,2-difluoropentane. Dioate (1.09 g, yield: 97.4%) was obtained.

In the same manner as above, but diethyl 2.2-difluoropentanedioate (1.08 g, yield: 96.4%) was obtained using water (0.10 g) instead of acetic acid.

Example 2: Synthesis of ethyl 2,2-difluoro-2- (3-oxocyclohexyl) acetate (Ethyl 2,2-difluoro-2- (3-oxocyclohexyl) acetate)

Copper powder (1.65 g) and tetrahydrofuran (7.60 mL) were placed in a reaction vessel and stirred under reflux conditions, followed by 2-cyclohexen-1-one (0.50 g) and ethyl bromodifluoroacetate (2.64 g). ) Was added dropwise, TMEDA (0.30 g) and acetic acid (0.28 g) were added dropwise, followed by reaction for 4 hours and then terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-2. -(3-oxocyclohexyl) acetate (1.12 g, yield: 97.8%) was obtained.

Example 3: Synthesis of Ethyl 2,2-difluoro-3-methyl-5-oxoheptanoate

Copper powder (1.94 g) and tetrahydrofuran (7.4 mL) were placed in a reaction vessel and stirred under reflux, followed by 4-hexen-3-one (0.50 g) and ethyl bromodifluoroacetate (2.59 g). Was added, TMEDA (0.30 g) and acetic acid (0.28 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-3. -Methyl-5-oxoheptanoate (1.04 g, yield: 91.9%) was obtained.

Example 4 Synthesis of Ethyl-2,2-difluoro-5-oxohexanoate

Copper powder (0.48 g) and tetrahydrofuran (5.21 mL) were placed in a reaction vessel and stirred at room temperature, to which methyl vinyl ketone (0.25 g) and ethyl bromodifluoroacetate (1.14 mL) were added, and TMEDA (0.21 g) and acetic acid (0.19 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-2,2-difluoro-. 5-oxohexanoate (0.63 g, yield: 91.0%) was obtained.

Example 5: Synthesis of ethyl-4-cyano-2,2-difluorobutanoate

Copper powder (1.26 g) and tetrahydrofuran (13.8 mL) were placed in a reaction vessel and stirred at room temperature, to which acrylonitrile (0.50 g) and ethyl bromodifluoroacetate (4.78 g) were added dropwise, and TMEDA (0.55 g) and acetic acid (0.51 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-4-cyano-2,2. -Difluorobutanoate (1.52 g, yield: 91.1%) was obtained.

In addition, ethyl-4-cyano-2,2-difluorobutanoate (1.48 g, yield: 88.7%) was obtained in the same manner as the above method, but using water (0.17 g) instead of acetic acid.

Example 6 Synthesis of Ethyl 2,2-difluoro-3-methyl-5-oxopentanoate

Copper powder (1.81 g) and tetrahydrofuran (10.40 mL) were added to the reaction vessel, and the mixture was stirred under reflux conditions. To this was added dropwise crotoaldehyde (0.50 g) and ethyl bromodifluoroacetate (3.62 g). TMEDA (0.41 g) and acetic acid (0.39 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residues, followed by extraction with methyl t-butylether and ethyl-4-cyano-2,2. -Difluorobutanoate (0.79 g, yield: 57.0%) was obtained.

In this embodiment, the yield (23%) and the improvement of the yield of 34% compared to the reaction time (3 hours) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) and the reaction time of 2 hours can be achieved.

Example 7: Synthesis of Ethyl 2,2-difluoro-5-exo-3-phenylhexanoate

Copper powder (0.32 g) and tetrahydrofuran (10.4 mL) were added to the reaction vessel and stirred under reflux conditions, followed by dropwise addition of chalcone (0.50 g) and ethyl bromodifluoroacetate (1.22 g). , TMEDA (0.14 g) and acetic acid (0.13 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether and ethyl 2,2-difluoro-5. -Exo-3-phenylhexanoate (833 mg, yield: 34.8%) was obtained.

In this embodiment, the yield improvement of 11.8% compared to the yield (23%) of the prior art ( J. Fluorine Chem . 2003 , 121 , 105) could be achieved. In addition, while the reaction time (1 hour) itself was the same as in the prior art, while in the prior art, TMEDA is added after stirring for 1 hour after adding other reactants, while in the present invention, the total time required is substantially longer because this process is not necessary. Could be shortened.

Example 8: Synthesis of ethyl 2,2-difluoro-4- (phenylsulfonyl) butanoate (Ethyl 2,2-difluoro-4- (phenylsulfonyl) butanoate)

Copper powder (0.40 g) and tetrahydrofuran (4.40 mL) were added to the reaction vessel and stirred at 50 ° C, to which phenyl vinylsulfone (0.50 g) and ethyl bromodifluoroacetate (1.51 g) were added dropwise, TMEDA (0.17 g) and acetic acid (0.16 g) were added sequentially, followed by reaction for 1 hour, and then the reaction was terminated. 10% aqueous ammonium chloride solution was added to the resultant mixture, and the resultant mixture was filtered through a pad of celite to remove copper residue, followed by extraction with methyl t-butylether to give ethyl 2,2-difluoro-4. -(Phenylsulfonyl) butanoate (0.74 g, yield: 85.2%) was synthesized.

Claims

In preparing the compound of Formula 1 through Michael-addition reaction of the compound of Formula 2 and the compound of Formula 3 in the presence of copper powder, adding water or an acid or a mixture thereof to the reaction mixture Method for preparing compound of formula 1 characterized in that:

[Formula 1]

[Formula 2]

[Formula 3]

In the above,

A is R 1 -C (═O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5-membered to 10-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo (═O) group. Or unsaturated C 6 -C 10 cycloalkyl,

R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 10 alkyl; Substituted or unsubstituted C 3 -C 10 cycloalkyl; Substituted or unsubstituted C 6 -C 10 aryl; Substituted or unsubstituted 5- to 10-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl,

R5 and R6 are each independently hydrogen; Halogen (ie, F, Cl, Br, or I); And substituted or unsubstituted C 1 -C 4 alkyl,

P 1 is selected from the group consisting of benzyl group, methyl group, ethyl group, i-propyl group and t-butyl group,

X is halogen.
The method of claim 1,

A is R 1 -C (═O) —, nitrile, substituted or unsubstituted C 1 -C 10 alkylsulfonyl, or substituted or unsubstituted C 6 -C 10 arylsulfonyl, wherein R 1 is hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5-membered to 8-membered heteroaryl; And substituted or unsubstituted C 1 -C 5 alkoxy, or when A is bonded to R 3, A, R 3 and the carbons to which they are each bonded together are saturated with an oxo (═O) group. Or unsaturated C 6 -C 10 cycloalkyl,

R2, R3 and R4 are each independently hydrogen; Substituted or unsubstituted C 1 -C 5 alkyl; Substituted or unsubstituted C 3 -C 6 cycloalkyl; Substituted or unsubstituted C 6 -C 8 aryl; Substituted or unsubstituted 5- to 8-membered heteroaryl; Substituted or unsubstituted C 1 -C 5 alkoxy; Nitrile; And substituted or unsubstituted C 1 -C 10 alkyl sulfonyl.
The method of claim 1, wherein the copper powder is used in an amount of 1.0 to 6.0 equivalents based on 1 mole of the compound of Formula 2.
The method of claim 1, wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Organic acids selected from formic acid, acetic acid and tartaric acid; Or a mixture thereof.
The method of claim 1, wherein the amount of water or acid is in the range of 0.1 to 6 equivalents based on 1 mole of the compound of Formula 2.
6. The process according to claim 1, further comprising adding an amine compound to the reaction mixture upon reaction of the compound of formula 2 with the compound of formula 3. 7.
The method of claim 6, wherein tetramethylethylenediamine is used in an amount of 0.1 to 6 equivalents based on 1 mole of the compound of Formula 2.