JP3010382B2 - Method for producing (R) -2-propoxybenzene derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing an optically active compound (R) -2-substituted propoxybenzene derivative useful as an intermediate for producing an antibacterial compound.

[0002]

2. Description of the Related Art Ofloxacin has a strong antibacterial activity and a broad antibacterial spectrum and is widely used as a synthetic antibacterial agent.
On the other hand, the pyridobenzoxazine derivative described in JP-A-62-252790 is an optically resolved form of ofloxacin, has an absolute configuration of (S), and exhibits higher antibacterial activity than a racemic form. It has been known. To synthesize this optically active pyridobenzoxazine derivative, (R) -2,3-dihalogeno-6-nitro-[(2-
Hydroxypropyl) oxy] benzene derivative (1b)
A method using the following reaction formula is proposed as a production method in Japanese Patent Application Laid-Open No. 2-732.

Embedded image [Wherein, R ′ represents a hydroxyl-protecting group]

However, this method uses an optically active (R) -1,2-propanediol derivative (2b) as a raw material.
Which has the following problems. (1) It is difficult to procure high-purity non-natural D-lactic acid, which is an asymmetric source, stably and inexpensively. (2) The optical purity is reduced in a multi-step synthesis step from the unnatural D-lactic acid to the compound (2b). (3) The above process was not an industrial method such as using a lithium aluminum hydride-ether solution.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide (R) -1,2-propanediol derivative (2
(R) -2,3-Dihalogeno-6-nitro-[(2-hydroxypropyl) oxy] without b)
It is to provide a method for producing a benzene derivative (1b).

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on a method for producing a (R) -2-hydroxypropoxybenzene derivative (1b) having a high optical purity, and as a result, have found that asymmetric acylation using an esterase is effective. (R) -2,3-dihalogeno-6-nitro-[(2-hydroxypropyl) having high optical purity at normal temperature and normal pressure by hydrolysis
The present inventors have found that an [oxy] benzene derivative (1b) can be produced in high yield, and have completed the present invention.

The reaction of the present invention is represented by the following reaction formula.

Embedded image Wherein X ¹ and X ² are the same or different and represent a halogen atom, and the group —OC (O) R ¹ represents a fatty acid residue.
The present invention is characterized in that a fatty acid is reacted with the (±) -2-hydroxypropoxybenzene derivative (1a) in the presence of lipase or pancreatin (R) -2.
Method for producing acyloxypropoxybenzene derivative (3b) [referred to as method (a)]; (±) -2-acyloxypropoxybenzene derivative (3a) or (R) -2
A method for producing (R) -2-hydroxypropoxybenzene derivative (1b), which comprises hydrolyzing acyloxypropoxybenzene derivative (3b) in the presence of lipase or pancreatin (referred to as method (b));
And (±) -2-hydroxypropoxybenzene derivative (1a) in the presence of lipase or pancreatin,
(R) -2-hydroxypropoxybenzene derivative characterized by reacting fatty acids and then hydrolyzing the obtained (R) -2-acyloxypropoxybenzene derivative (3b) in the presence of lipase or pancreatin. It is intended to provide the production method (referred to as method (c)) of (1b).

The compound (1a) used as a starting material in the present invention is, for example, 3- (2,3-dihalogeno-6-
It can be easily produced by a method of reducing (nitrophenyl) oxy-2-propanone, a method described in JP-A-1-250369, and the like. Hereinafter, each method will be described.

[0008] Method (a): This method is preferably carried out under conditions where a large amount of water does not exist, or while removing water outside the system, and particularly preferably in an organic solvent.
Examples of the organic solvent used include lower ketones, ethers, halogenated hydrocarbons, lower hydrocarbons, alicyclic hydrocarbons, and aromatic hydrocarbons. Specifically, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, dimethyl ether, diisopropyl ether, chloroform, hexane, cyclohexane, benzene, toluene, xylene or a mixed solvent obtained by mixing these solvents as necessary can be used. . In order to obtain the desired product in high yield, it is particularly preferable to use an ether solvent. The amount of the solvent is the same as that of the compound (1
It is preferable that the weight is 0 to 500 times, especially 1 to 100 times the weight based on a).

As fatty acids used as acylating agents, fatty acid ester compounds, fatty acid anhydrides and fatty acid amides are used. More specifically, mention may be made of methyl acetate, ethyl acetate, vinyl acetate, methyl hexanoate, propyl hexanoate, acetic anhydride, propionic anhydride, acetate amide and the like.

[0010] Esterase in the present invention means lipase or pancreatin. These esterases are not particularly limited, and include esterases produced by microorganisms and esterases derived from animals and plants. Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following. Lipase of Pseudomonas sp. [Lipase P (manufactured by Amano Pharmaceutical)], Lipase of Aspergillus sp. [Lipase MY (Meito Sangyo)], Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter lipase [ Lipase Joint BSL (Joint Sake Purification)], Lipase of Chromobacterium sp. ], Other lipases (manufactured by Nagase Sangyo), lipase L (manufactured by Amano Pharmaceutical), lipase CE5
(Amano Pharmaceutical), Pancreatin F (Amano Pharmaceutical). Further, the use form of the esterase in the present invention includes:
Purified enzymes, crude enzymes, enzyme-containing substances, microbial cultures, cultures, microbial cells, culture filtrates and those obtained by treating them may be used as they are, ion exchange resins such as Dowex, Amberlite, etc., Eupergit. Immobilized on a suitable immobilization carrier such as bromocyan-activated Sephadex or Celite.

Further, regarding the molar ratio of the compound (1a), the fatty acids and the esterase, the fatty acids are
a) 0.5-1000 molar equivalents, more preferably 10
３００300 molar equivalents may be used, and the esterase depends on the specific activity of the esterase.
a) 0.001 to 100 times, more preferably 0.01 to 1 times on the basis
What is necessary is just to add so that it may become 0 times weight. The reaction temperature is preferably -20C to 100C, particularly preferably 20C to 50C.

The absolute configuration of the obtained compound (3b) depends on the origin of the esterase used, but when lipase P is used, it is only the R-isomer. On the other hand, S-form compounds that have not undergone acylation are also present in the reaction system, but the target compound and unreacted compounds are easily separated and purified by ordinary methods such as column chromatography and distillation. be able to. The obtained R-isomer can be chemically deacylated by a conventional method to lead to the compound (1b).

Method (b): This method uses the compound (3)
In this method, a compound (1b) having high optical purity is synthesized by using the compound (3b) obtained by the methods (a) and (a) or the compound (3b) prepared by another method as a raw material. The origin of the compound (3b) is not particularly limited, but the optical purity is such that it can be actually called an optically active substance, that is, 5
What is necessary is just 0% ee or more. However, this does not limit the application of the present method to the compound (3b) having an optical purity of 50% ee or less. The use of the compound (3b) in which R ¹ is a propyl group or a butyl group as a raw material is particularly preferable because the optical purity of the compound (1b) is increased.

The solvent used in this method includes water and a buffer generally used in biochemistry, such as a phosphate buffer, a citrate buffer, a succinate buffer, a glycine buffer, and a buffer known as a so-called Good buffer. The buffer may have an ionic strength concentration of 0 to 500 mM, more preferably 50 to 200 mM,
The pH may be in the range of 3 to 11, more preferably 5 to 9. The solvent is 1 to 1000 with respect to the substrate weight.
It may be used so that the weight is doubled, more preferably 10 to 100 times. At this time, when a lower alcohol such as methanol and ethanol, an organic solvent miscible with water such as acetone and acetonitrile, and an aprotic polar solvent such as DMF, DMSO and DMI are added up to about 1/20 volume of the solvent, the reaction proceeds. May be effective in increasing speed.

The esterase is the same as that used in the above acylation reaction (a). Furthermore, the molar ratio of the compound (3b) to the esterase depends on the specific activity of the esterase.
What is necessary is just to add so that it may become the weight of 100 times, more preferably 0.01 to 10 times. The reaction temperature is -20 ° C to 10 ° C.
0 ° C, especially 20 ° C to 50 ° C, is preferred.

The absolute configuration of the obtained compound (1b) depends on the origin of the esterase used, but when lipase P is used, only the R-isomer is obtained. On the other hand, although the S-form compound that has not been hydrolyzed is also present in the reaction system, the target compound and the unreacted S-form compound are separated by a usual method such as column chromatography or distillation. It can be separated and purified.

Method (c): Compound (1a) is acylated in the presence of esterase according to method (a) to obtain compound (3b) having high optical purity, and compound (3b) is further converted to compound (b). Hydrolysis with an esterase according to the method yields the compound (1b) with extremely high optical purity. When lipase P is used as the esterase, the absolute configuration of the obtained product is the R configuration. Further, compound (3b) can be easily obtained by acylating compound (1b) thus obtained by a conventional method.

[0018]

The present invention relates to (R) -2,3-dihalogeno-6-nitro-[(2-hydroxypropyl) oxy].
In the step of producing the benzene derivative (1b) or (R) -2,3-dihalogeno-6-nitro-[(2-acyloxypropyl) oxy] benzene derivative (3b),
It is characterized by using asymmetric acylation by esterase or hydrolysis reaction to obtain high-purity optically active target product under mild conditions of normal temperature and normal pressure without using optically active raw materials. It is possible to avoid problems such as a decrease in optical purity that occurs when an expensive optically active material is used to lead to a target product through a multi-step process under drastic conditions, as in the chemical synthesis method described above.

[0019]

The present invention will be specifically described below with reference to examples and reference examples. 1) Measurement of optical purity (HPLC total area method) Column used: Ciralcel OD (manufactured by Daicel Chemical Industries) Elution condition: Ethanol 100% 1.0 ml / min Detection condition: UV 254 nm In addition, in the optical purity measurement, all compounds were dried tetrahydrofuran. / Pretreatment with 3,5-dinitrobenzoyl chloride in pyridine at 60 ° C. for 1 hour and analysis as a 3,5-dinitrobenzoyl derivative. Also, (3b)
Prior to this pretreatment, the mixture was treated at 70 ° C. for 3 hours in a mixed solution of methanol and 1N hydrochloric acid for 3 hours, and the optical purity of the chemically deacetylated product was measured.

Reference Example 1 (±) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(±) -1a:
X ¹ = X ² = F] 4.62 g (20 mmol) of 3- (2,3-difluoro-6-nitrophenyl) oxy-2-propanone was added to methanol 5
It was dissolved in 0 ml, and 10 ml of water was added thereto. After adding 10 ml of 1N hydrochloric acid with stirring under ice cooling, a solution of 200 mg (5.29 mmol) of sodium borohydride dissolved in 2 ml of water was added dropwise. This operation of adding hydrochloric acid and sodium borohydride solution was repeated 5 times over 2 hours. After the reaction, the mixture was extracted with chloroform, and the chloroform layer was washed with water.
It was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was subjected to column chromatography to give (±) -2,3.
4.53 g (97% yield) of -difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene was obtained. This product was converted into a p-toluenesulfonic acid ester derivative by a conventional method.
This was consistent with the literature value described in JP-A-69.

Example 1 (±) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(±) -1a:
X ¹ = X ² = F] to (R) -2,3-difluoro-6
- nitro - [(2-acetoxy-propyl) oxy] benzene ^{[(R) -3b: X 1 =} X 2 = F, R 1 = CH 3 ]
Conversion to (±) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene 400 mg (1.72 mm
ol) was dissolved in 2 ml of a liquid mixture of isopropyl ether and vinyl acetate monomer at a volume ratio of 1: 1. Then, 200 mg of lipase P was added in powder form, and the mixture was stirred at room temperature for 4 hours. During this time, the lipase was not dissolved but was in a suspended state.
After the completion of the reaction, the lipase was removed by filtration with a 0.45 micron membrane filter, and the obtained filtrate was concentrated. An operation of adding 10 ml of isopropyl ether to the obtained oily material and concentrating the mixture was performed three times, and an operation of adding 10 ml of ethyl acetate and concentrating was performed once. The oil obtained here was subjected to column chromatography to give (R) -2,3-difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene 1
90 mg (80% yield vs. theory) were obtained. Optical purity is 9
4.0% ee. After deacetylation of this product by the method described in the section on optical purity measurement, the melting point of the product obtained as a p-toluenesulfonic acid ester derivative coincided with that in the literature.

Reference Example 2 (±) -2,3-difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene [(±) -3a:
X ¹ = X ² = F, R ¹ = CH ₃ ] (±) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene 500 g (2.15 mm
ol) was dissolved in 1.5 ml of pyridine, and 1.5 ml of acetic anhydride was added dropwise with stirring under ice cooling. Then at room temperature overnight
Stirring was continued. The reaction solution was poured into ice water and extracted with chloroform. The chloroform layer was washed sequentially with 1N hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off and (±) -2,3-difluoro-6-nitro-
[(2-acetoxypropyl) oxy] benzene 400
mg (68%).

Example 2 (±) -2,3-difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene [(±) -3a:
X ¹ = X ² = F, R ¹ = CH ₃ ] from (R) -2,3-
Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b: X ¹ = X ² =
F] Conversion to 400 mg (1.451 mmol) of (±) -2,3-difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene obtained in Reference Example 2, 100 mM monopotassium phosphate / phosphorus 2 ml of disodium acid buffer pH 7.0, lipase P
100 mg was added, and the mixture was stirred at room temperature for 5 hours. Chloroform was added to the reaction solution, followed by extraction. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated, and the residue obtained was purified by silica gel chromatography, and purified by (R) -2,3-difluoro-6-nitro. -[(2-hydroxypropyl)
130 mg of [oxy] benzene (76% yield versus theory)
Obtained. The optical purity was 93.2% ee. The p-toluenesulfonic acid ester derivative was made into a p-toluenesulfonic acid ester derivative by a conventional method, and the melting point was in agreement with that in the literature.

Example 3 (R) -2,3-Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b:
X ¹ = X ² = F] In the same manner as in Example 1, 4.53 g of (±) −2,
3-Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene is asymmetrically acylated to give (R)-
2,3-Difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene was obtained in 2.46 g, 96.6% ee. According to the method of Example 2, 100 mM
In a reaction solvent obtained by adding 20 ml of acetone to 150 ml of a monopotassium phosphate / disodium phosphate buffer pH 7.0, the mixture was treated with 2.5 g of lipase P at room temperature for 6 hours to obtain (R) -2,
1.49 g of 3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene (yield versus theory 66
%). The optical purity was 99.6% ee. As described above, the method from (1a) to (1b) via (3b) is obtained at an astonishingly high optical purity of 99.6% ee as described above.

Example 4 (R) -2,3-Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b:
X ¹ = X ² = F] Synthesis of (±) -2,3-difluoro-6-nitro-[(2-acetoxypropyl) oxy] benzene 1 g of a 100 mM citrate buffer containing 10% methanol, pH 7, 100
3 ml with 10 g of pancreatin F (Amano Pharmaceutical)
Treated at 0 ° C. for 13 hours. When the reaction solution was analyzed by high performance liquid chromatography, the reaction rate was 98% (vs. theory) and the optical purity was 99.8% ee. By purifying the reaction-terminated liquid in the same manner as in Example 2,
387 mg of (R) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene (yield)
92%). The optical purity was 99.8% ee.

Example 5 (R) -2,3-Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b:
Synthesis of X ¹ = X ² = F] 1 g of (±) -2,3-difluoro-6-nitro-[(2-butyryloxypropyl) oxy] benzene 10%
100 ml of 100 mM citrate buffer containing methanol
Plus 30 g of 1 g of Lipase M-AP (Amano Pharmaceutical)
It processed at 13 degreeC and 13 hours. When the reaction solution was analyzed by high performance liquid chromatography, the reaction rate was 99% (vs. theory) and the optical purity was 99.8% ee. By purifying the reaction-terminated liquid in the same manner as in Example 2,
360 mg of (R) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene (yield
94%). The optical purity was 99.8% ee.

Example 6 (R) -2,3-Difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b:
X ¹ = X ² = F] Synthesis of (±) -2,3-difluoro-6-nitro-
[±] -2,3-Difluoro-6-nitro-[(2
The reaction was carried out in the same manner as in Example 4 using -valeryloxypropyl) oxy] benzene, and the reaction was analyzed by high performance liquid chromatography. The conversion was 99% (vs. theory) and the optical purity was 99.8% ee. there were. By purifying the reaction-terminated liquid in the same manner as in Example 2,
340 mg of (R) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene (yield
93% of theory). The optical purity was 99.8% ee.

Example 7 (R) -2,3-difluoro-6-nitro-[(2-hydroxypropyl) oxy] benzene [(R) -1b:
X ¹ = X ² = F] The reaction was carried out in the same manner as in Example 5 except that the enzymes shown in Table 1 were used instead of the lipase M-AP of Example 5. The (R) -2,3-difluoro-6-nitro-[(2-
Hydroxypropyl) oxy] benzene was analyzed by high performance liquid chromatography to obtain the results shown in Table 1.

[0029]

[Table 1]

──────────────────────────────────────────────────の Continuing from the front page (72) Inventor Hideki Arifusa 2256 Nakanosato, Fujikawa-cho, Anbara-gun, Shizuoka Prefecture Inside Ihara Chemical Industry Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) C12P 41/00 BIOSIS (DIALOG)

Claims (3)

(57) [Claims] 1. The following general formula: Wherein X ¹ and X ² are the same or different and represent a halogen atom, and a fatty acid is reacted with the (±) -2-hydroxypropoxybenzene derivative (1a) in the presence of lipase or pancreatin. Characterized by
The following general formula: [In the formula, the group —C (O) R ¹ represents a fatty acid residue, and X ¹ and X ²
Has the same meaning as described above.] A method for producing (R) -2-acyloxypropoxybenzene derivative (3b) 2. The following general formula: Wherein X ¹ and X ² are the same or different and represent a halogen atom, and the group —C (O) R ¹ represents a fatty acid residue.
-2-acyloxypropoxybenzene derivative (3a)
Or hydrolyzing the (R) -2-acyloxypropoxybenzene derivative (3b) in the presence of lipase or pancreatin, characterized by the following general formula: [Wherein X ¹ and X ² are as defined above], wherein the (R) -2-hydroxypropoxybenzene derivative (1
The manufacturing method of b). 3. The following general formula: Wherein X ¹ and X ² are the same or different and represent a halogen atom, and a fatty acid is reacted with the (±) -2-hydroxypropoxybenzene derivative (1a) in the presence of lipase or pancreatin. And then obtained the following general formula: [In the formula, the group —C (O) R ¹ represents a fatty acid residue, and X ¹ and X ²
Is hydrolyzed in the presence of lipase or pancreatin, wherein the (R) -2-acyloxypropoxybenzene derivative (3b) is hydrolyzed in the presence of lipase or pancreatin. [Wherein X ¹ and X ² are as defined above], wherein the (R) -2-hydroxypropoxybenzene derivative (1
The manufacturing method of b).