JP3518627B2 - Method for producing optically active 5-hydroxymethyloxazolidinone derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The optically active 5-hydroxymethyloxazolidinone derivative in the present invention is a pharmaceutical intermediate,
For example, it is used as a useful raw material intermediate such as an HIV protease inhibitor.

[0002]

2. Description of the Related Art As a method for producing an optically active 5-hydroxymethyloxazolidinone derivative, an optically active 3-amino-1,2-diol derivative is treated with diphosgene at -20 ° C. in a mixed solvent of methylene chloride and triethylamine 1: 1. Method of reacting (Bull. Soc. Chim. Fr.,
129,585 (1992)) is known.

[0003]

However, it is said that the above-mentioned method is industrially advantageous because it uses a large amount of base, needs to be reacted at a low temperature, and uses highly toxic diphosgene. It is difficult and the yield is not sufficient, about 70%.

In general, when a 5-hydroxymethyloxazolidinone derivative is obtained by cyclizing a 3-amino-1,2-diol derivative, it is a 6-membered ring compound.
It is expected that the hydroxyoxazinone derivative will be produced as a by-product. In particular, when the aminodiol is an erythro form, it is expected that the 6-membered ring compound is likely to be by-produced due to the steric hindrance because the substituent at the 4,5-position of oxazolidinone has a cis configuration.

[0005]

[Means for Solving the Problems] The inventors of the present invention have keenly sought an industrially advantageous production method which is capable of selectively obtaining an optically active 5-hydroxymethyloxazolidinone derivative in a high yield and is safe and easy to operate. As a result of examination, the present invention has been achieved.
That is, the present invention relates to the following (1) to ( 6 ). (1) Formula (1)

[0006]

[Chemical 3]

(In the formula, R is a hydrocarbon residue having 1 to 10 carbon atoms, and the steric configurations of * 2 and * 3 are the S configuration or the R configuration.) Optically active 3-amino-1, Formula (2), characterized in that the 2-diol derivative is cyclized in the presence of a base in a solvent.

[0008]

[Chemical 4]

(In the formula, the steric configurations of * 4 and * 5 represent the S configuration or the R configuration.) The present invention relates to a process for producing an optically active 5-hydroxymethyloxazolidinone derivative.

(2) The method of (1) using isopropanol as the solvent. (3) The method of (1) using an alkali metal hydroxide or an alkali metal alcoholate as the base. (4) The method of (1) using isopropanol as a solvent and an alkali metal alcoholate as a base.

(5) In the compound represented by the formula (2), the stereo configurations * 4 and * 5 are both S (4S,
The method of (1) of 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one. (6) In the compound represented by the formula (2), * 4 and *
The stereo configurations of 5 are both S configurations (4S, 5S) -4-
Benzyl-5-hydroxymethyloxazolidine-2-
On (4) method.

The hydrocarbon residue having 1 to 10 carbon atoms represented by R in the formula (1) in the present invention may be saturated, unsaturated, linear, cyclic or a combination thereof, and specifically, Examples thereof include an alkyl group, an aralkyl group and an aryl group. These may have a substituent that does not participate in the reaction. Examples of the alkyl group include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, cyclopentyl and cyclohexyl. Examples of the aralkyl group include benzyl, p-methoxybenzyl,
Examples include p-nitrobenzyl and the like. Further, examples of the aryl group include groups such as substituted or unsubstituted phenyl, for example, phenyl, p-tolyl, p-chlorophenyl and the like.

The cyclization of the compound of formula (1) is carried out by dissolving the compound of formula (1) in a solvent and reacting it in the presence of a base at 0 ° C. to a solvent reflux temperature, preferably 20 ° C. to 60 ° C. Is done by doing. The reaction is usually completed in several hours, but may be stirred overnight.

Examples of the solvent for dissolving the compound of the formula (1) used in the reaction of the present invention include alcohols such as methanol, ethanol, propanol and isopropanol, water-soluble solvents such as tetrahydrofuran and N, N-dimethylformamide. Or a mixed solvent thereof can be used, but when the compound of formula (1) is an erythro body, it has a solubility such that an alkali metal salt of the compound of formula (2), which is the object of the present invention, precipitates. It is not particularly limited as long as it is one, but isopropanol is particularly preferable.

Preferred examples of the base used in the reaction include (1) alkali metal hydroxides such as sodium hydroxide and potassium hydroxide (2) sodium methylate, sodium ethylate, sodium isopropylate, potassium Examples thereof include alkali metal alcoholates such as tert-butyrate. These bases may be used as solids or in the form of solutions. For example, (1) the alkali metal hydroxide may be added to the reaction solution as a solid, preferably methanol, ethanol,
It may be added as a lower alcohol solution such as propanol or an aqueous solution. Further, (2) the alkali metal alcoholate may be used as a powder or in a corresponding alcohol solution,
Further, when the reaction solvent is alcohol, an alkali metal may be added to the reaction solution to form an alcoholate in the system.
In the case of an aqueous solution of an alkali metal hydroxide or a lower alcohol solution, it is preferable to use one having a concentration of 15% (V / V) to a saturated concentration. In the case of an alcohol solution of an alkali metal alcoholate, the concentration is usually 10 to 35% (V / V), and a commercially available product may be used. The amount of the base used is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to the compound of formula (1), and the reaction is carried out. As one of the preferred embodiments for synthesizing the erythro derivative, when isopropanol is used as a solvent for dissolving the compound of formula (1) and a solvent such as water, methanol, or ethanol is used as a solvent for dissolving a base, the reaction system as a whole is It is in the form of a mixed solvent. And in that case, the proportion of isopropanol is preferably 80% (V / V) or more,
More preferably, it is 90% (V / V) or more, and the proportion of the other solvent such as methanol, ethanol or water is 20 % (V / V).
/ V) or less, preferably 10% (V / V) or less.

After completion of the reaction, the reaction solution is acidified by adding diluted mineral acid water such as dilute sulfuric acid or dilute hydrochloric acid, and then water is further added and cooled, and the precipitated crystals are collected by filtration or ethyl acetate or the like. The target compound of formula (2) can be obtained in a high yield by extracting with the organic solvent of and then distilling off the solvent.

Examples of the compound of the formula (1) in the present invention include the following. (1) (2S, 3S) -3-Methoxycarbonylamino-4-phenyl-1,2-butanediol (2) (2S, 3S) -3-Ethoxycarbonylamino-4-phenyl-1,2-butanediol (3) (2S, 3S) -3-Isobutyloxycarbonylamino-4-phenyl-1,2-butanediol (4) (2S, 3S) -3-Benzyloxycarbonylamino-4-phenyl-1,2- Butanediol (5) (2R, 3R) -3-Ethoxycarbonylamino-4-phenyl-1,2-butanediol (6) (2R, 3S) -3-Ethoxycarbonylamino-4-phenyl-1,2- Butanediol

These compounds of formula (1) are disclosed in JP-A-6-
279372, or in accordance with it, (2
S or 2R, 3S or 3R) -alkoxycarbonylamino-2-hydroxy-4-phenylbutyric acid ester is reduced to the corresponding aminodiol form, or (2S or 2R, 3S or 3R) -3-amino-4
-Phenyl-1,2-butanediol can be obtained by a conventional method, for example, by carbamation with a carbamate-forming agent such as chlorocarbonic acid esters.

[0019]

EXAMPLES The present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one 9.04 g of a 50% aqueous potassium hydroxide solution was added to 140 m.
17.73 g of (2S, 3 in 1 of isopropanol
S) -3-Ethoxycarbonylamino-4-phenyl-
Added to 1,2-butanediol. 30-40 reaction mixture
After stirring at C for about 4 hours, the desired potassium salt was precipitated. Thereafter, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 1 to 3, the reaction solution was concentrated to about half the volume, 40 ml of water was added, and the mixture was crystallized at -10 to 0 ° C for about 1 hour, filtered, and cooled with cold water. Washed with water, dried, and (4S, 5S) -4-benzyl-5.
-Hydroxymethyloxazolidin-2-one 13.5
8 g (yield 93.6%) was obtained as white crystals. The HPLC area ratio of this crystal was 99.5%.

[0021]   Analysis confirmation     HPLC column: Inertsil (trade name) ODS-2                           250 x 4.6 mm ID                   Eluate; 0.02M NH4H2PO4 (pH 2.5)                           CH3CN = 7: 3 (V / V)                 Dissolution rate: 1 ml / min                     Detection; UV254nm   Retention time Target compound 4.78 min                                           6-membered ring isomer 4.33 min             HPLC area ratio at the end of reaction Target compound 92.0%                                           6-membered ring isomer 1.3%

¹ H-NMR (DMSO-d ₆ ) δ (ppm) 2.69, 2.94 (2dd, 2H) 3.64 (t, 2H, J = 5.4 Hz, CH 2 OH) 4.14 (dt , 1H) 4.53 (dt, 1H) 5.04 (t, 1H, J = 5.4 Hz, OH) 7.20 to 7.35 (m, 5H) 7.53 (s, 1H) Melting point 171 to 173 ° C. Specific rotation [α] _D ²⁰ = −72 ° (c = 1.16, methanol)

Reference Example 1 (4S, 5S) -4-Benzyl-5-hydroxymethyloxazolidin-2-one 0.65 g of 50% aqueous potassium hydroxide solution was added to 1.27 g of methanol in 10 ml of methanol.
(2S, 3S) -3-Ethoxycarbonylamino-4
-Phenyl-1,2-butanediol. The reaction solution was stirred at 40 ° C. for about 5 hours, concentrated hydrochloric acid was added to the reaction solution to neutralize it, and the reaction solution was concentrated to almost half the volume, and 5 ml of water was added.
Was added, and the mixture was crystallized at -10 to 0 ° C for about 1 hour, filtered,
It was washed with cold water and dried to obtain 0.44 g (yield 44.4%) of (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one as pale yellow crystals. The HPLC area ratio of this crystal was 88.7%.

[0024]   Analysis confirmation     HPLC Same conditions as in Example 1             HPLC area ratio at the end of reaction Target compound 64.5%                                           6-membered ring isomer 20.9%

Example 3 (4S, 5S) -4-Benzyl-5-hydroxymethyloxazolidin-2-one 6.95 g of a 28% sodium methylate solution in methanol was added to 7.60 g of (2S) in 60 ml of isopropanol. , 3S) -3-Ethoxycarbonylamino-4-
Added to phenyl-1,2-butanediol. When the reaction solution was stirred at 30 to 40 ° C. for about 4 hours, the target sodium salt was precipitated. Then, add concentrated hydrochloric acid to the reaction solution to neutralize it, then concentrate the reaction solution to almost half the volume and add 25 ml of water.
Was added, and the mixture was crystallized at -10 to 0 ° C for about 1 hour, filtered,
The extract was washed with cold water and dried to give (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one (5.89 g, yield 94.7%) as white crystals.

Example 4 (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one 1.35 g of 25% potassium hydroxide in methanol was added to
1.27 g (2S, in 10 ml isopropanol)
3S) -3-Ethoxycarbonylamino-4-phenyl-1,2-butanediol. The reaction solution is 30 to 5
After stirring at 0 ° C. for about 3 hours, the target potassium salt was precipitated. Then, add concentrated hydrochloric acid to the reaction solution to adjust the pH to 1 to 3,
The reaction solution was concentrated to about half the volume, 5 ml of water was added, and the mixture was crystallized at -10 to 0 ° C for about 1 hour, filtered, washed with cold water, and dried (4S, 5S)- 4-benzyl-5
-Hydroxymethyloxazolidin-2-one 0.91
g (yield 87.8%) was obtained as white crystals.

Example 5 (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one 1.27 g of (2S, 3S) -3-ethoxycarbonylamino-4-phenyl-1,2-butane The diol was dissolved in 138 mg of sodium metal dissolved in 15 ml of isopropanol and added to a prepared sodium isopropylate solution. When the reaction solution is stirred at 40 to 50 ° C. for about 2 hours,
The desired sodium salt was precipitated. After that, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 1 to 3, the reaction solution was concentrated to almost half the volume, 5 ml of water was added, and the mixture was crystallized at -10 to 0 ° C for about 2 hours, filtered, and cooled with cold water. Wash with, dry (4S,
5S) -4-Benzyl-5-hydroxymethyloxazolidin-2-one (0.91 g, yield 87.8%) was obtained as white crystals.

[0028]

[0029]   Analysis confirmation     HPLC Same conditions as in Example 1   Retention time Target compound 5.04 min                                           6-membered ring isomer 4.54 min             HPLC area ratio at the end of reaction Target compound 98.2%                                           6-membered ring isomer 0.3%

¹ H-NMR (DMSO-d ₆ ) δ (ppm) 2.69 to 2.90 (m, 2H) 3.12 to 3.27 (m, 1H) 3.29 to 3.46 (m , 1H) 3.76 to 3.86 (m, 1H) 4.12 to 4.20 (m, 1H) 5.04 (t, 1H, J = 5.7 Hz, OH) 7.19 to 7.27. (M, 5H) 7.73 (s, 1H) Melting point 112-114 ° C Specific optical rotation [α] _D ²⁰ = -52 ° (c = 1.12, methanol)

[0031]

According to the present invention, optically active 3-amino-
Using a 1,2-diol derivative as a raw material, an optically active 5-hydroxymethyloxazolidinone derivative can be selectively obtained in a high yield under safe conditions with good operability and mild conditions.

Claims (3)

(57) [Claims] 1. A formula (1) (In the formula, R is a hydrocarbon residue having 1 to 10 carbon atoms, and the steric configurations of * 2 and * 3 are both S configuration or both R configuration.) Optically active 3-amino-1, 2-diol derivative,
Formula (2) characterized by cyclization in the presence of a base in isopropanol alone or a mixed solvent containing 80% or more of isopropanol (In the formula, the configurations of * 4 and * 5 are both S configuration or R configuration.
The arrangement is shown. The manufacturing method of the optically active 5-hydroxymethyl oxazolidinone derivative represented by these. 2. The method according to claim 1, wherein an alkali metal hydroxide or an alkali metal alcoholate is used as the base. 3. In the compound represented by the formula (2), * 4 and
* 3: Both configurations are S configuration (4S, 5S) -4-
Benzyl-5-hydroxymethyloxazolidine-2-
The method of claim 1, which is on.