JP2018138519A - Method for producing 2-hydroxyester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method that can produce 2-hydroxyester at low cost, with efficiency, and on an industrial scale, in the reaction of a glycidic ester and a Grignard reagent used for the production of the 2-hydroxyester.SOLUTION: The present invention provides a method for producing 2-hydroxyester represented by formula (3) with improved yield based on a Grignard reagent, the method including mixing and reacting the Grignard reagent with a mixture of a glycidic ester represented by formula (1) and a copper salt, at a temperature higher than or equal to -20°C.SELECTED DRAWING: None

Description

  The present invention relates to an industrially suitable production method of 2-hydroxyester.

  2-Hydroxyesters are important compounds as pharmaceuticals, cosmetics, agricultural chemicals, and intermediates thereof. For example, 2-hydroxy-9- (Z) -octadecenoic acid that is easily derived from 2-hydroxyesters has been subjected to clinical trials as an anticancer agent. Further, 2-hydroxy fatty acids having 10 or more carbon atoms derived from 2-hydroxyester are used as a cosmetic raw material as a constituent of ceramide.

  Examples of the method for producing 2-hydroxyester include a method for producing cyanohydrin from aldehyde and hydrocyanic acid to convert a cyano group to an ester, a method for reducing 2-ketoester, and a method for converting an α-position of an ester to a hydroxyl group after halogenation. Methods are known. Among them, a method of reacting a cuprate prepared from a Grignard reagent and a copper salt with a glycidic acid ester is also one of effective production methods.

  As a specific example of this method, in Patent Document 1, CuI (3 mmol) and methylmagnesium bromide (60 mmol) are mixed at 15 ° C., the mixed solution is cooled to −78 ° C., and then (S) -n-butyl glycidate ( 21 mmol) is added to obtain n-butyl (S) -2-hydroxybutanoate (21 mmol) as a product.

In Patent Document 2, Li ₂ CuCl ₄ (25 mmol) and cyclopentylmagnesium bromide (270 mmol) are mixed at 50 ° C., and after the mixed solution is cooled to −78 ° C., methyl (R) -glycidate (245 mmol) is added. Gave n-butyl (159-172 mmol) (R) -2-hydroxy-3-cyclopentylpropionate as the product.

In Patent Document 3, CuBr ₂ · SMe ₂ complex (51 mmol) and n-butylmagnesium chloride (97 mmol) are mixed at −78 ° C., and (R) -benzyl glycidate (47 mmol) is added, thereby (R) — Benzyl hydroxyheptanoate (47 mmol) is obtained as product.

  The prior arts for reacting cuprates prepared from the above Grignard reagents and copper salts with glycidic acid esters use excess amounts of Grignard reagents relative to the glycidic acid esters, and the yield based on the glycidic acid ester is Although it is high, the yield based on the Grignard reagent is 35% in Patent Document 1, 59 to 64% in Patent Document 2, 48% in Patent Document 3, and 64% at maximum (Patent Document 2). . In general, since Grignard reagents are expensive, it is difficult to say that any prior art has achieved a sufficient yield in terms of yield based on Grignard reagents. In addition, any of the prior arts requires an extremely low temperature condition such as −78 ° C., and an ultra-low temperature facility is required, which is not suitable for implementation on an industrial scale.

US Patent Application Publication No. 2010/0063063 International Publication No. 2007/013555 International Publication No. 2013/187480

  The problem to be solved by the present inventors with respect to the above prior art is to avoid low-temperature conditions that hinder the implementation of the industrial scale in the reaction of glycidic acid ester and Grignard reagent used in the production of 2-hydroxyester. There is. Another object is to improve the yield based on the Grignard reagent in the reaction between the glycidic acid ester and the Grignard reagent.

As a result of intensive studies on the reaction between the glycidic acid ester and the Grignard reagent, the present inventors have improved the yield based on the Grignard reagent by adopting a reagent addition order different from that of the prior art. At the same time, reaction control in the temperature range, which is easy to implement on an industrial scale, was achieved. Thereby, it came to establish the manufacturing method of efficient 2-hydroxyester.
That is, the present invention provides the following formula (1):

(In the formula, R ^1, an optionally substituted alkyl group having 1 to 15 carbon atoms, which may have a substituent alkenyl group having 2 to 15 carbon atoms, which may have a substituent An aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 15 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 15 carbon atoms which may have a substituent. The mixture of glycidic acid ester and copper salt is subjected to the following formula (2) at a temperature of −20 ° C. or higher;

(Wherein, R ² is an optionally substituted alkyl group having 1 to 30 carbon atoms, which may have a substituent alkenyl group having 2 to 30 carbon atoms, which may have a substituent An alkynyl group having 2 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms which may have a substituent, a heteroaryl group having 6 to 30 carbon atoms which may have a substituent, and a substituent; Represents an aralkyl group having 7 to 30 carbon atoms, or a cycloalkyl group having 3 to 30 carbon atoms which may have a substituent, and X represents a chlorine atom, a bromine atom, or an iodine atom. The following formula (3), characterized by mixing a Grignard reagent:

(Wherein R ¹ and R ² are the same as above).

  According to the present invention, the reaction can be controlled within a temperature range which can be easily carried out on an industrial scale, and the yield based on the Grignard reagent can be improved to 64% or more.

The present invention is described in detail below.
In the present invention, the following formula (1);

In a mixture composed of a glycidic acid ester and a copper salt represented by the formula (2):

By mixing a Grignard reagent represented by the following formula (3):

The 2-hydroxyester represented by these is manufactured.

In the compound (1) and the compound (3), R ¹ is an alkyl group having 1 to 15 carbon atoms which may have a substituent and an alkenyl having 2 to 15 carbon atoms which may have a substituent. Group, an aryl group having 6 to 15 carbon atoms which may have a substituent, an aralkyl group having 7 to 15 carbon atoms which may have a substituent, or 3 to 15 carbon atoms which may have a substituent Represents a cycloalkyl group. Specifically, for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl Group, n-decyl group, n-dodecyl group, vinyl group, allyl group, benzyl group, 1-phenethyl group, phenyl group, 1-naphthyl group, 2-naphthyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, or A cyclohexyl group and the like. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; hydroxyl group; alkoxy group such as methoxy group and ethoxy group; methylthio group; trifluoromethyl group; acetyl group; A nitro group; a carboxyl group; an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group; The number of substituents is not particularly limited. R ¹ is preferably a methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl. Group, n-decyl group and n-dodecyl group, more preferably methyl group, ethyl group, n-butyl group, n-hexyl group or n-dodecyl group.

In the compound (2) and the compound (3), R ² is an optionally substituted alkyl group having 1 to 30 carbon atoms and an optionally substituted alkenyl group having 2 to 30 carbon atoms. Group, an alkynyl group having 2 to 30 carbon atoms which may have a substituent, an aryl group having 6 to 30 carbon atoms which may have a substituent, and 6 to 30 carbon atoms which may have a substituent It represents a heteroaryl group, an aralkyl group having 7 to 30 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 30 carbon atoms which may have a substituent. Specifically, for example, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl Group, n-octyl group, n-decyl group, n-dodecyl group, n-octadecyl group, n-icosyl group, vinyl group, allyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group, 6- Heptenyl group, 7-octenyl group, ethynyl group, 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, 6-heptynyl group, 7-octynyl group, benzyl group, 1-phenethyl group, phenyl Group, 1-naphthyl group, 2-naphthyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-thiophenyl group, 2-furyl group, cyclopropyl group, cyclobutyl group Group, a cyclopentyl group, or a cyclohexyl group. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; alkoxy group such as methoxy group and ethoxy group; methylthio group; trifluoromethyl group; acetyl group; benzoyl group; Nitro group; carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group. The number of substituents is not particularly limited. R ² is preferably methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl. Group, n-octyl group, n-decyl group, n-dodecyl group, n-octadecyl group, n-icosyl group, vinyl group, allyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group, 6- Heptenyl group, 7-octenyl group, ethynyl group, 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, 6-heptynyl group, 7-octynyl group, benzyl group, 1-phenethyl group, phenyl Group, 1-naphthyl group, 2-naphthyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-thiophenyl group, 2-furyl group, cyclopropyl group, cyclyl A butyl group, a cyclopentyl group, or a cyclohexyl group, more preferably an n-butyl group, an n-pentyl group, an n-hexyl group, an allyl group, or a 3-butenyl group.

  In the compound (2), X represents a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom or a bromine atom.

  Here, the glycidic acid ester represented by the formula (1) may be a racemate or an optically active substance. In the case of a racemate, Heterocycles, 2014, 89 (2), 487-493. According to the method described in (Ochiai et al.), It can be easily produced. Specifically, a sodium hypochlorite aqueous solution may be allowed to act on an easily available acrylic ester in the presence of an ammonium salt catalyst.

  Next, the reaction conditions of the present invention will be described. This reaction is characterized in that a Grignard reagent represented by the formula (3) is mixed with a solution obtained by previously mixing the glycidic acid ester represented by the formula (1) and a copper salt. There is no restriction | limiting in particular in the mixing method of the said compound (1) and copper salt. About the mixing method of the said compound (2), the said compound (2) may be added with respect to the mixed solution of the said compound (1) and copper salt, and the said compound (1) and the said compound (2) may be added. A mixed solution of copper salts may be added. Preferably, the compound (2) may be added to the mixed solution of the compound (1) and copper salt. The addition time of the compound (2) is preferably 0.1 minutes or longer, more preferably 5 minutes or longer, particularly preferably 30 minutes or longer.

  The use amount of the glycidic acid ester represented by the formula (1) in this reaction is not preferable in terms of cost and post-treatment if it is too much, so the upper limit is preferably 20 equivalents to the compound (2), More preferably, it is 10 equivalents, and particularly preferably 3 equivalents. The lower limit is preferably 0.7 equivalents, more preferably 0.8 equivalents, and particularly preferably 0.9 equivalents relative to the compound (2).

There is no restriction | limiting in particular as said copper salt, Either monovalent copper to accept | permit and acceptable bivalent copper may be sufficient. Specifically, for _{example, CuF, CuCl, CuBr, CuI} , CuF 2, CuCl 2, CuBr 2, CuI 2, Cu (OAc), Cu (OCOCF3), Cu (OAc) 2, Cu (OCOCF 3) 2, Cu _{(acac) 2, CuCN, Cu} (CN) 2, CuCO 3, CuOMe, Cu (OMe) 2, CuClO 4, Cu (ClO 4) 2, CuSCF3, Cu 2 O, CuO, Cu 2 S, CuS, Cu 2 _{SO 4, CuSO 4, CuNO 3} , Cu (NO 3) 2, Cu (BF 4) 2, CuOTf, such as Cu _{(OTf) 2} and the like. _{Preferably, CuCl, CuBr, CuI, CuCl} 2, CuBr 2, Cu (OAc), Cu (OAc) 2, CuCN, Cu 2 O, is CuO, or CuSO _4, more preferably CuCl, CuBr, CuI, CuCl ₂ or CuBr ₂ , particularly preferably CuCl, CuBr, or CuI. Moreover, these copper salts may form a complex with lithium chloride, dimethyl sulfide, pyridine and the like for stabilization.

  If the amount of the copper salt used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 50 equivalents, more preferably 10 equivalents, particularly preferably 3 equivalents to the compound (2). Is equivalent. The lower limit is preferably 0.01 equivalents relative to the compound (2), more preferably 0.1 equivalents, and particularly preferably 0.5 equivalents.

  The reaction solvent for this reaction is not particularly limited as long as it does not affect the reaction. Specific examples thereof include tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether and the like. Ether solvents such as acetonitrile, nitrile solvents such as acetonitrile and propionitrile; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, xylene, ethylbenzene and mesitylene Halogenated solvents such as methylene chloride and 1,2-dichloroethane; N, N-dimethylformamide, N, N-dimethylacetamide, N, N-diethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2- Piro It can be used phosphonic acid triamide solvents such as hexamethylphosphoric acid triamide; Dong, N- methyl -ε- caprolactam, hexamethylphosphoramide system such as an amide solvent; urea solvents such as dimethyl propylene urea. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited. Preferred are ether solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, and more preferred are tetrahydrofuran, diethyl ether, or methyltetrahydrofuran.

  If the amount of the reaction solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore the upper limit is preferably 100 times the weight of the compound (2), and more preferably 50 times the weight. Particularly preferred is 20 times the weight. The lower limit is preferably 0.1 times the weight of the compound (2), more preferably 0.5 times the weight, and particularly preferably 1 times the weight.

  The reaction temperature in this reaction is preferably −20 ° C., more preferably −10 ° C. as the lower limit from the viewpoint of not requiring special cooling equipment and lowering the energy consumption when carried out on an industrial scale. Yes, particularly preferably 0 ° C. Moreover, in order to shorten reaction time and to reduce the production | generation of a by-product, as an upper limit, Preferably it is 120 degreeC, More preferably, it is 80 degreeC, Especially preferably, it is 50 degreeC.

  The reaction time in this reaction is not particularly limited and may be appropriately set. The upper limit is preferably 100 hours, more preferably 50 hours, and particularly preferably 25 hours. The lower limit is preferably 0.1 hour, more preferably 1 hour, and particularly preferably 3 hours.

  As a method for obtaining the product from the reaction solution after the reaction, a general process for obtaining the product from the reaction solution may be performed. For example, water or an aqueous ammonium chloride solution is added to the reaction solution after completion of the reaction, and an extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like. When the reaction solvent and the extraction solvent are distilled off from the obtained extract by operations such as heating under reduced pressure, the desired product is obtained. The target product obtained in this way has sufficient purity that can be used in subsequent steps, but in order to further increase the purity, general purification techniques such as crystallization, fractional distillation, column chromatography, etc. The purity may be further increased.

  Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention in any way.

Reference Example 1 Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol), and the temperature was set to −5 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes. After stirring at −5 ° C. for 1 hour, n-butyl glycidate (141 mg, 1 mmol) was added and stirred at −5 ° C. for 23 hours (yield based on Grignard reagent: 1%).

Reference Example 2 Preparation of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol), and the temperature was set to 40 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes. After stirring at 40 ° C. for 1 hour, n-butyl glycidate (141 mg, 1 mmol) was added and stirred at 40 ° C. for 23 hours (Yield based on Grignard reagent: 0%).

Reference Example 3 Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to −5 ° C. Subsequently, 1M tetrahydrofuran solution (1.5 mL, 1.5 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, followed by stirring at −5 ° C. for 21 hours (yield based on Grignard reagent: 53%).

Reference Example 4 Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to −5 ° C. Subsequently, 1M tetrahydrofuran solution (2 mL, 2 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, followed by stirring at −5 ° C. for 1 hour (yield based on Grignard reagent: 45%).

(Example 1) Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to -5 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, followed by stirring at −5 ° C. for 23 hours (Yield based on Grignard reagent: 72%).

(Example 2) Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to 40 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, and the mixture was stirred at 40 ° C. for 17 hours (yield based on Grignard reagent: 78%).

Example 3 Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuI (19 mg, 0.1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to -5 ° C. did. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 10 minutes, and the mixture was stirred at −5 ° C. for 2 hours (Yield based on Grignard reagent: 55%).

(Example 4) Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuBr (143 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to -5 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, and the mixture was stirred at −5 ° C. for 23 hours (yield based on Grignard reagent: 68%).

(Example 5) Production of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuCl (99 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to -5 ° C. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, followed by stirring at −5 ° C. for 23 hours (yield based on Grignard reagent: 52%).

Example 6 Preparation of n-butyl 2-hydroxynonanoate Tetrahydrofuran (5 mL) was added to CuBr ₂ (223 mg, 1.0 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to 20 ° C. did. Subsequently, 1M tetrahydrofuran solution (1 mL, 1 mmol) of n-hexylmagnesium bromide was added dropwise over 5 minutes, and the mixture was stirred at 20 ° C. for 7 hours (yield based on Grignard reagent: 50%).

Example 7 Preparation of n-butyl 2-hydroxyheptanoate THF (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to 20 ° C. Subsequently, a 2M tetrahydrofuran solution (0.5 mL, 1 mmol) of n-butylmagnesium chloride was added dropwise over 5 minutes, followed by stirring at 20 ° C. for 19 hours (yield based on Grignard reagent: 74%).

Example 8 Production of n-butyl 2-hydroxy-5-hexenoate Tetrahydrofuran (5 mL) was added to CuI (190 mg, 1 mmol) and n-butyl glycidate (141 mg, 1 mmol), and the temperature was set to 20 ° C. did. Subsequently, a 0.7M diethyl ether solution (1.4 mL, 1 mmol) of allylmagnesium bromide was added dropwise over 5 minutes, followed by stirring at 20 ° C. for 17 hours (yield based on Grignard reagent: 60%).

Claims (6)

Following formula (1);

(In the formula, R ^1, an optionally substituted alkyl group having 1 to 15 carbon atoms, which may have a substituent alkenyl group having 2 to 15 carbon atoms, which may have a substituent An aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 15 carbon atoms which may have a substituent, or a cycloalkyl group having 3 to 15 carbon atoms which may have a substituent. The mixture of glycidic acid ester and copper salt is subjected to the following formula (2) at a temperature of −20 ° C. or higher;

(Wherein, R ² is an optionally substituted alkyl group having 1 to 30 carbon atoms, which may have a substituent alkenyl group having 2 to 30 carbon atoms, which may have a substituent An alkynyl group having 2 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms which may have a substituent, a heteroaryl group having 6 to 30 carbon atoms which may have a substituent, and a substituent; Represents an aralkyl group having 7 to 30 carbon atoms, or a cycloalkyl group having 3 to 30 carbon atoms which may have a substituent, and X represents a chlorine atom, a bromine atom, or an iodine atom. The following formula (3), characterized by mixing a Grignard reagent:

(In formula, R < ¹ >, R < ² > is the same as the above.) The manufacturing method of 2-hydroxyester represented. The manufacturing method according to claim 1, wherein the copper salt is CuCl, CuBr, or CuI. The manufacturing method according to claim 1, wherein the copper salt is used in an amount of 0.1 equivalent or more with respect to the compound (2). The said compound (1) is used 0.7 equivalent or more with respect to the said compound (2), The manufacturing method in any one of Claims 1-3 characterized by the above-mentioned. Wherein ^{R 1} is a methyl group, an ethyl group, n- butyl group, a n- hexyl group, or n- dodecyl group, The process according to any one of claims 1 to 4. The R ² is an n-butyl group, an n-pentyl group, an n-hexyl group, an allyl group, or a 3-butenyl group, and the X is a chlorine atom or a bromine atom. The production method described in 1.