WO1996023759A1 - Method of racemizing optically active carboxylic acids - Google Patents

Abstract

A method of racemizing optically active carboxylic acids at low temperature in a short time, which comprises adding 0.5-9.0 equivalents of water to one equivalent of a specified, optically active carboxylic acid in the presence of an inorganic base and heating the resulting mixture at 40-99 °C. This method is a practical and efficient racemization method applicable to industrial production processes, because it can dispense with severe reaction conditions and thus permits the use of general-purpose reactors.

Description

 Light damage Racemization method of optically active carboxylic acid

 The present invention relates to a method for racemizing an optically active carboxylic acid. More specifically, the present invention relates to a method for racemizing a carboxylic acid represented by the following formula (1), which reacts quickly at a low temperature.

Background art

[式中、 R,は、 以下の式（2)：

The following equation (1):

Wherein R, is the following equation (2):

(Wherein, R ₃ is water * atom, lower alkyl, phenyl or benzoyl, and R <is a hydrogen atom or a halogen atom)

Unsubstituted or substituted phenyl represented by the following, or the following formula (3):

 ^ <)

(Wherein, R ₅ is a hydrogen atom or lower alkoxy)

Unsubstituted naphthyl or substituted naphthyl represented by R ₂ is lower alkyl]

The compound represented by is used as a medicinal substance having an action such as anti-inflammatory and antipyretic or antipyretic or an intermediate thereof. For example, a compound of formula (1) in which is 3-benzoylphenyl and R ₂ is methyl, ie, 2- (3-benzoylphenyl) brobionic acid, is called ketobrofuune and is 41-isobutylfuel; The compound of formula (1) in which R ₂ is methyl, ie, 2- (4-isobutylphenyl) propionic acid, is called ibubrofin and is used as an anti-inflammatory and antipyretic agent.

 These compounds have an asymmetric sequence, and have (-)-integral and (+)-isomer. In many cases, only one of the optically active substances exhibits pharmacological activity. In this case, the other optically active substance having no or low pharmacological activity is converted into an optically active substance having high pharmacological activity. Will be needed. For this purpose, it is common to first racemize the former optically active substance, and then to separate the latter optically active substance having high pharmacological activity from this racemic substance.

 Conventionally, as a method of racemizing such a compound, a method of heating at a high S in a solvent in the presence of a base is generally used. For example, as a method of racemizing ketobloxin, a method of heating to 100 to 200 in a solvent, particularly water, in the presence of an organic amine or an inorganic basic compound is known. Flat, Japanese Patent Application Laid-Open No. 4-693566; Bertrand et al., Japanese Patent Application Laid-Open No. 6-5016863). For the racemization of ibuprofen, there are known methods such as heating at a flowing temperature in the presence of sodium hydroxide in 2-propanol and heating at a flowing temperature in the presence of triethylamine in octane. (Maninaran et al., US Patent No. 5,162,576).

However, the flat method requires more than 8 hours at 150 reaction temperatures to complete the reaction, and usually requires pressurization. Also, Bertrand et al. The method requires 12 hours at a reaction temperature of 100 ° C or higher. In addition, the method of Manimaran et al. Requires a reaction time of 15 hours at a high flow temperature. As described above, the known methods have disadvantages such as a high reaction temperature, a long reaction time, and a need for pressurization in some cases, and the material may be damaged in a general-purpose reactor. .

 The present inventors have proposed a method of converting an optically active form of the compound represented by the above formula (1) into a racemic form which does not have such a drawback, that is, a reaction temperature is low, a reaction time is short, and a severe reaction An attempt was made to develop a practical racemization method that does not require conditions and thus allows the use of a general purpose reactor, applicable to industrial manufacturing processes.

Disclosure of the invention

 As a result of various studies, the present inventors have found that the above-mentioned problem can be solved by the following method, and have completed the present invention.

That is, the present invention provides the following formula (1): CH (R ₂ ) —COOH (1)

[Wherein is the following equation (2):

(Wherein, R ₃ is a hydrogen atom, lower alkyl, phenyl or benzoyl, and R ₄ is a random atom or a halogen atom)

An unsubstituted or substituted funilil represented by the following, or the following formula (3):

(Wherein, R ₅ is a hydrogen atom or lower alkoxy)

Unsubstituted naphthyl or substituted naphthyl represented by

R ₂ is lower alkyl]

A racemization method for an optically active carboxylic acid represented by the formula: wherein the carboxylic acid is added with 0.5 to 9.0 equivalents of water with respect to the carboxylic acid in the presence of an inorganic base to form a 40 to 50 9 provides a method characterized by heating. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the method of the present invention will be described in detail.

 In the definition of the above formula (1), lower alkyl means a carbon or straight or branched alkyl having 1 to 6 atoms, for example, methyl, ethyl, n-propyl, isopropyl, butyl, etc. , Isobutyl, n-pentyl, neopentyl, n-hexyl and the like. Usually, the lower alkyl is often a direct- or branched-chain alkyl having 1 to 4 carbon atoms.

 Halogen atoms include fluorine, chlorine, bromine and iodine.

The lower alkyne refers to an alkoxy in which the alkyl moiety is a straight-chain or branched lower alkyl having 1 to 6 carbon atoms. Usually, the alkoxy is often an alkoxy moiety in which the alkyl moiety comprises a straight or branched chain alkyl having 1 to 4 carbon atoms. Such lower alkyls are as described above, and thus lower alkoxy includes methoxy, ethoxyquin, n-bromoxy, isopropoxy, n-butoxy, π-pentyloquin, n-hexyloxy, etc. It is. According to the method of the present invention, the optically active haponic acid represented by the above formula (1) can be efficiently racemized, but it is preferable to racemize a specific group of carboxylic acids. Specifically, it is preferred to racemize the carboxylic acid of formula (1) wherein R ₂ is methyl. Further, is a carboxylic acid of the formula (1) in which is 3-benzoylphenyl, 4-isobutylphenyl, 2-fluoro-4-biphenyl or 6-methoxy-12-naphthyl, and R ₂ is methyl. Racemization is preferred. It is also preferred to racemize the carboxylic acid of formula (1) wherein R ₂ is isopropyl.

 Specific examples of preferred carboxylic acids to be racemized according to the method of the present invention include the previously mentioned 2- (3-benzoylphenyl) propionic acid [ketobrophene] and 2- (4-isobutylphenyl) propionate. In addition to the acid [Ibubrophene], 2-phenylpropionic acid, 2- (4-benzoylphenyl) propionic acid, 2- (4-ethylfurunyl) propionic acid, 2- (3-isopropylphenyl) propionic acid, 2- ( 4- (n-butylphenyl) propionic acid, 2- (4-n-hexylphenyl) propionic acid, 2- (2-fluoro-4-biphenylinole) propionic acid [flurvibrophene], 2- (6-methoxy-2 —Naphthyl) propionic acid [nabroxen].

The optically active carboxylic acid used in the method of the present invention is usually one containing a large amount of the other optically active substance after one optically active substance is separated from (earth) rubonic acid. Therefore, the optical purity may be high or it may be relatively low. Carboxylic acids of any optical purity can be used in the present method. Further, an optically active carboxylic acid derived from another source may be used. The (earth) unit of the carboxylic acid represented by the above K formula (1) can be obtained from commercial products, or can be produced according to the method described in the literature. 3-1 2 8 3 7 French Patent No. 1.546.4878, Japanese Patent Publication No. 63-230652, U.S. Patent No. 3.904.682, U.S. Patent No. 4. No. 09/1977, U.S. Pat. No. 3.755.427, French patent M5 737, Masmoto et al. (Bioscience Biotechnology & Biochemistry, vol. 59, p. 720 ( 1 995)).

 The racemization reaction can be performed as follows. That is, a mixture of the optically active carboxylic acid, the inorganic group and water is heated and stirred. If desired, a suitable solvent may be added to the mixture to cause a reaction. After the reaction is completed, cool the reaction solution and acidify it to pH 1 or less with an appropriate acid (hydrochloric acid, sulfuric acid, etc.). Next, the mixture is extracted with an organic solvent immiscible with water (toluene, ethyl acetate, etc.), the organic layer is washed with water, dried, and the solvent is distilled off under reduced pressure to obtain a racemized carboxylic acid.

 The amount of water used in the present method is in the range of 0.5 to 9.0 equivalents, preferably 0.5 to 6.0 equivalents to the optically active carboxylic acid, according to the results of Examples described later. And more preferably 1.0 to 4.5 equivalents.

 As the inorganic base, for example, alkali metal or hydroxide of earth metal can be used. Preferred bases are sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, especially sodium hydroxide and potassium hydroxide.

The amount of the inorganic base to be used is 0.5 equivalent or more, preferably 1.0 to 2.0 equivalent, more preferably 1.5 to 2.0 equivalent based on the optically active carboxylic acid. If desired, a suitable solvent can be added to the reaction mixture. The addition of a solvent is preferable from the viewpoint of operability, for example, the fluidity of the entire reaction system is improved. The solvent to be added is not particularly limited as long as it is inert to the reaction mixture, and may be, for example, methyl alcohol, ethyl alcohol, or isopropyl alcohol. Alcohols such as alcohol, ethers such as methyl-t-butyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; aliphatic hydrocarbons such as hexane, heptane, and octane; aromatic hydrocarbons such as benzene, toluene, and xylene Hydrogens or a mixed solvent thereof 0

 Preferred solvents are non-polar solvents, selected from aliphatic hydrocarbons or aromatic hydrocarbons. Preferred aliphatic hydrocarbons are selected from the group consisting of hexane, heptane and octane, and preferred aromatic hydrocarbons are selected from the group consisting of benzene, toluene and xylene.

 It is also preferable to use a polar solvent such as a lower alcohol. Particularly preferred alcohol in the present invention is methyl alcohol.

 The reaction temperature may be between 40 and 99, at which temperature the reaction is usually completed within a few 10 minutes to 8 hours. Example

 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

 In these examples, wZw% represents wt% by weight, wZv% represents wt / vol%, and% e.e. Represents enantiomeric excess.

The optical purity of the optically active carboxylic acid was measured by a high-performance liquid chromatography method (hereinafter abbreviated as HPLC) under the following analytical conditions. Optical purity measurement of ketoprof L

 Column: CHRALCEL 0 J (manufactured by Daicel Chemical Industries) Mobile phase: hexane: isopropyl alcohol: trifluoroacetic acid

 (92: 8: 0.3)

 Flow speed: 1. Onil / min

 Detection: UV, 255nm

 Column temperature: normal temperature

Optical purity measurement of ibuprof X

 Column: CHRAL CEL 0 J (manufactured by Daicel Chemical Industries) Mobile phase: hexane: isopropyl alcohol: trifluoroacetic acid

 (100: 1: 0.1)

 Flow speed: 1. OBI / min

 Detection UV, 255ηη

 Power temperature: normal temperature

Optical purity measurement of nabroxene

 Column; Opti-pakTA [Waters] Mobile phase: hexane: isopropyl alcohol: trifluoroacetic acid

 (75: 25: 0.3)

 Flow speed: 0.8ml / min

 Detection: UV, 254nn

Column temperature; normal temperature Optical Purity Measurement of Fururubib Mouth Fuyun

 Column: CH I 1¾8 し 0? (Manufactured by Shinwa Kaye)

 Mobile phase; isopropyl alcohol: liquid (5:95)

 Buffer solution: 1 OmM NaPB (1ΟπΜ phosphate buffer + lmM

 (N, N-dimethyloctylamine, adjusted to pH 6.5 with NaOH)

 Flow speed: 0.9ml / min

 Detection: UV, 225ηπι

 Example 1 (1-1) Racemization of 2- (3-benzoylphenyl) propionic acid [ketobu-guchi-fuen]

 9 δ% e.e. (I) -1-2- (3-benzoylphenyl) propionic acid (hereinafter abbreviated as KET) (5.0 g, 19.7 mmol), sodium hydroxide (purity 96)

 64 g (39.4 mmol), water (1.25 g, 69.4 mmol, water ZKET = 25 wZw%, 3.52 mol / mol ratio), and toluene (4.3 ml) were placed in a SUS 304 reaction vessel, and heated at 95 for 30 minutes. . Then, ice water (4 Oal) was added to the reaction mixture, and the mixture was cooled to terminate the reaction. Next, the mixture was adjusted to pH 1 or less with 35 f / v) acid, and extracted with toluene (11.5 ml). The extract was washed with water and dried over anhydrous sodium sulfate, and then toluene was distilled off under reduced pressure to obtain white crystals (5. Og). The optical purity of the crystal was measured by HPLC to be 0% e.e. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

Table 1 below shows the results of experiments performed under the same reaction conditions as above S, but with the water equivalent to KET changed. table 1

 Water ZKET reaction time Optical purity after racemization

(Mol Z molar ratio) (w / w%) (min) (% e.e.)

 M C

 0 0 * ―

0.71 5 60 0

 1.41 10 40 0

 20 30 0

 4.23 30 30 0

 5.64 40 40 0

 ί. U 0 5 U 60 0

 8.47 60 90 0

 9.88 70 180 0

 11.3 80 360 0

 12.7 90 600 0

 14.1 丄 u u 600 4

 14.1 100 480 7

 28.2 200 480 26

 42.3 300 480 62

 70.δ 500 480 87

 141 1000 480 94

* Sodium hydroxide does not dissolve and the reaction is extremely slow. From this table, it is clear that when water is added in an amount of 0.5 to 9.0 equivalents, preferably 0.5 to 6.0 equivalents, and more preferably 1.0 to 4.5 equivalents, the reaction time can be extremely short and the reaction time can be extended. is there. Example 2 Racemization of (1-) 1-2- (4-isobutylphenyl) propionic acid [Ibubu Mouth Fen]

Use (95% ee) of (1-) 1-2- (4-isobutylfuunyl) propionic acid (hereinafter abbreviated as IBU) in place of (1-)-1- (3-benzoyl) phenylpropionic acid A racemization reaction was carried out in the same manner as in Example 1 except that the reaction was carried out. The results are shown in Table 2 below.

Table 2

 Water / I BU reaction time Optical purity after racemization

(Mol / mol ratio) (w / w%) (min) (% e.e.)

 0 0 * one

 0.57 5 45 0

 1.14 10 30 0

 1.72 15 30 0

 2.86 25 30 0

 4.01 35 30 0

 ΰ, 丄 u 30 0

 6.30 55 50 0

 7.44 65 100 0

 8.58 75 210 0

 9 73 85 380 0

 10.9 95 680 1

 22.9 200 480 20

 34.4 300 480 57

 57.2 500 480 86

 115 1000 480 94

* Sodium hydroxide does not dissolve and the reaction is extremely slow. From this table, it can be seen that when water is added in an amount of 0.5 to 9.0 equivalents, preferably 0.5 to 6.0 equivalents, more preferably 1.0 to 4.5 equivalents to IBU, the reaction time can be extremely short and the reaction time can be extended. it is obvious. Example 3 (I) Racemization of 2- (3-benzoylphenyl) propionic acid (KET)

 Using 7k (1.5 g, 83.3 mmol, water ZKET = 3 OwZw%, 4.23 mol Z mol ratio), racemization was performed in the same manner as in Example 1 except that heating was performed at a temperature of 80 for 60 minutes. Was. When the optical purity of the obtained white crystal (5. Og) was measured, it was 0% e.e. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

 Example 4 (I) Racemization of 1-2- (4-isobutylphenyl) propionic acid (IBU)

 Racemization was carried out in the same manner as in Example 2 except that 7XC 1.5 g. 83.3 mmol, water ZIBU-30w% (3.43 mol nomole ratio) was used and heating was performed at a temperature of 80 for 50 minutes. When the optical purity of the obtained white crystal (5. Og) was measured, it was 0% e. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

 Example 5 (I) Racemization of 2- (3-benzoylphenyl) propionic acid (CKET) (toluene-free system)

Under the same reaction conditions as in Example 1, water (1.5 g, 83.3π mol, water ΖΚΕΤ = 30 wZw%, 4.23 mol Z molar ratio) was used, and heated at a temperature of 80 ^e C for 50 minutes without using toluene. Racemization was performed. When the optical purity of the obtained white crystal (5. Og) was measured, it was 0% ee. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

 Example 6 (I) Racemization of (2-) (4-isobutylphenyl) propionic acid (IBU) (0.5-2.0 equivalents of NaOH)

Under the same reaction conditions as in Example 2, the equivalent of alkali to IBU was changed. And racemized. The results of this experiment are shown in Table 3 below.

実施例 7 (一）一 2—（4一イソブチルフエニル）プロピオン酸（ I BU) のラセミ化（MeOH/水の系）

Example 7 (I) Racemization of (2-) (4-isobutylphenyl) propionic acid (IBU) (MeOH / water system)

 95% ee of (1-)-1- (4-isobutylphenyl) propionic acid (5.0 g, 24.2 mmol), sodium hydroxide (purity 96%) (2.0 g, 48.4 mmol), water ( 1.5 g, 83.3 mmol, water ZKET = 30 * Zw%, 4.23 mol / molar ratio) and methyl alcohol (0.5 ml) were placed in a SUS 304 reaction vessel and heated at 95 ° C. for 9 hours. Then, ice water (4 Oml) was added to the reaction mixture, and the mixture was cooled to complete the reaction. Next, the mixture was adjusted to pH 1 or less with 35 (»/ v)% hydrochloric acid, and extracted with toluene (11.5 ml). The extract was washed with water and dried over anhydrous sodium sulfate, and then toluene was distilled off under reduced pressure to obtain white crystals (5. Og). When the optical purity of this zong crystal was measured by HPLC, it was 0% e.e. Also, NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

Example 8 (1) Racemization of 1-phenyl-2-methylbutanoic acid Instead of (1-) 1-2- (3-benzoylphenyl) propionic acid of Example 1, (1-) 1-2- (95% ee) 95% using phenyl-3-methylbutanoic acid The mixture was heated at ° C for 8 hours, and a racemization reaction was performed in the same manner. When the optical purity of the obtained white quartz (5. Og) was measured, it was 0% ee. NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

 Example 9 Racemization of 2- (6-methoxy-2-naphthyl) brobionic acid [nabroxen]

 95% 6.6. Of 2- (6-Methoxy-2-naphthyl) propionic acid (5.0 g, 21.7πmol), sodium hydroxide (purity 96%) (1.81 g 43.4 mmol), water (1.0 g, 55.5 mmol, water / nabroxen-20 wZw%, 4.2 3 mol / mol ratio) into a S US 304 reaction vessel, 95. Heated at C for 6 hours. Then, the reaction mixture was cooled by adding ice water (4 Onl) to terminate the reaction. Next, the mixture was adjusted to pH 1 or less with 35 (w / v)% hydrochloric acid, and extracted with toluene (11.5 ml). The extract was washed with water and dried over anhydrous sodium sulfate, and then toluene was distilled off under reduced pressure to obtain white crystals (5. Og). The optical purity of this crystal was measured by HPLC to be 0% e.e. Also, NMR and IR were consistent with the starting compound. That is, it was found that racemization was completely achieved with a recovery rate of 100%.

 Example 10 Racemization of 2- (2-fluoro-4-biphenylinole) propionic acid [furubibuchifuyun]

95% ee of 2- (2-fluoro-4-biphenylinole) propionic acid (0.4 g, 1.64 mmol), sodium hydroxide (96% purity) (0.135 g, 3.24 mmol), water (0.08 g, 4.44 mmol) , Water Z-flurbiprofen = 20 w / w%, 2.71 mol molar ratio) and toluene (1.7 ml) were placed in a SUS 304 reaction vessel, and heated at 95 for 5 hours. Then, ice water (40 ml) was added to the reaction mixture to cool it, and the reaction was terminated. Then _{35 (w / v)% P} H 1 or less with hydrochloric acid And extracted with toluene (11.5 ml). The extract was washed with water and dried over anhydrous sodium sulfate, and then toluene was distilled off under reduced pressure to obtain a white product (0.4 g). When the optical purity of the crystal was measured by HPLC, it was 0% ee. Also, NMR and IR were consistent with the starting compound. That is, it was found that complete racemization was achieved with a recovery of 100%.

Industrial applicability

 According to the method of the present invention, an optically active carboxylic acid can be racemized at a low temperature in a short time. That is, the present method is a practical and efficient racemization method applicable to industrial manufacturing processes, which does not require harsh reaction conditions and thus enables the use of a general-purpose reactor.

Claims

Scope of claim Equation (1) below R, -CH (R ₂ ) -COOH (1) [Where, is the following equation (2)

(Wherein R ₃ is a hydrogen atom, lower alkyl, phenyl or benzoyl, and R <is a hydrogen atom or a halogen atom) Unconverted or hidden unit represented by the following, or the following formula (3):

(Wherein, R ₅ is a hydrogen atom or lower alkoxy) Unsubstituted naphthyl or substituted naphthyl represented by R ₂ is low-alkyl A process for the racemization of an optically active carboxylic acid represented by the formula: wherein carboxylic acid is added with 0.5 to 9.0 equivalents of water to the carboxylic acid in the presence of an inorganic base, and heated at 40 to 99. A method that specializes in that. 2. The method of claim 1 wherein R ₂ racemizing optically active carboxylic acid of the formula (1) is methyl. 3. is 3-benzoylphenyl, 4-isobutylphenyl, 2-phenyl 2. The process according to claim 1, wherein the optically active haponic acid of formula (1), which is L-bilyl or 6-methoxy-2-naphthyl and is R 2 or methyl, is racemized. 4. The method according to claim 1, wherein the optically active carboxylic acid of the formula [1] in which R ₂ is isoprovir is racemized.  5. The method according to claim 1, wherein 0.5 to 6.0 equivalents of water are added to the carboxylic acid.  6. The method according to claim 1, wherein 1.0 to 4.5 equivalent of water is added to the carboxylic acid.  7. The method according to claim 1, wherein the inorganic base is sodium hydroxide and Z or potassium hydroxide.  8. The method according to claim 1, wherein 1.0 to 2.0 equivalents of an inorganic base are used relative to the carboxylic acid.  9. The method according to claim 1, wherein 1.5 to 2.0 equivalents of an inorganic base is used based on the carboxylic acid.  10. The method according to claim 1, wherein the reaction mixture is further reacted with a solvent. 1 1. The method according to claim 10, wherein the solvent is a non-polar solvent.  12. The method according to claim 11, wherein the non-polar solvent is an aliphatic hydrocarbon or an aromatic hydrocarbon.  1 3. The method according to claim 12, wherein the aliphatic hydrocarbon purple is selected from the group consisting of hexane, heptane and octane.  13. The method according to claim 12, wherein the aromatic hydrocarbon is selected from the group consisting of benzene, toluene, and quinylene.