JPH06116250A - Production of n-@(3754/24)2-alkenoyl)-2-oxazolidinone derivative - Google Patents

Abstract

PURPOSE:To obtain the compound useful as an intermediate for synthesizing an antiviral agent safely, inexpensively and in high yield by reacting an N- silyl-2-oxazolidinone derivative with a 2-alkenoyl halide derivative. CONSTITUTION:A compound of formula I (R<1> to R<4> are H or lower alkyl; R<5> to R<7> are lower alkyl or phenyl) is reacted with a compound of formula II (R<8> to R<10> are H, lower alkyl, lower alkoxycarbonyl or halogenocarbonyl; X is halogen) in the absence of a solvent or in an aprotic solvent (e.g. methylene chloride) at 0-100 deg.C to give a compound of formula III. N-(3- Methoxycarbonylpropenoyl)-2-oxazolidinone may be cited as the compound of formula III and is a synthetic intermediate for a new cyclobutane-based antiviral agent. The objective compound can be produced under a neutral and mild reaction condition without using an expensive metal reagent and low-temperature facilities.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The object of the present invention is to provide an optically active cyclobutane derivative (Y.
yashi and K. Narasaka, Chem. Lett., (1989), 793, Y.
Ichikawa, A. Narita, A. Shiozawa, Y. Hayashi, and K. Na
rasaka, J. Chem. Soc., Chem. Commun., (1989), 1919, JP-A-3-95165), which is an important intermediate in the synthesis.
The present invention relates to an industrial production method of a-(2-alkenoyl) -2-oxazolidinone derivative.

[0002]

The preparation of N- (2-alkenoyl) -2-oxazolidinone derivatives is obtained, for example, by reacting 2-oxazolidinone with an organic metal such as n-butyllithium or a metal hydride such as sodium hydride. 2
-Synthesis by reaction of a metal salt of oxazolidinone with a 2-alkenoyl halide derivative is known (K. Na-r
asaka, N-Iwasawa, M. Inoue, T. Yamada, M. Nakashima,
and J. Sugimori, J. Am, Chem. Soc. 111, 5340 (198
9), DAEvans, KTChapman, and J. Bisaha, J. Am. Che
m. Soc., 110, 1238 (1988).

[0003]

However, in the above reaction, side reactions are likely to occur due to the influence of the metal salt of 2-oxysazolidinone, the metal reagent, or the reaction temperature, resulting in a decrease in yield and quality. In addition, the reaction conditions require low-temperature equipment, and the metal reagent used is expensive and unstable, which poses a handling problem such as danger. Therefore, it is difficult to carry out the synthesis method industrially. Therefore, it has been desired to develop an industrial production method of an N- (2-alkenoyl) -2-oxazolidinone derivative which is industrially advantageous and safe by using mild reaction conditions.

[0004]

[Means for Solving the Problems] In order to solve the above-mentioned problems, as a result of intensive studies, by using an N-silyl-2-oxazolidinone derivative as a reaction product, the target N-
The inventors have found that a (2-alkenoyl) -2-oxazolidinone derivative can be mass-produced safely, inexpensively and in high yield, and completed the present invention.

That is, the present invention provides (1) the general formula (1)

[Chemical 4] (In the formula, R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, or a substituted or unsubstituted lower alkyl group,
R ⁵ , R ⁶ and R ⁷ each independently represent a lower alkyl group or a phenyl group) N-silyl-2-
Oxazolidinone derivative and general formula (II)

[0006]

[Chemical 5] (In the formula, R ⁸ , R ⁹ and R ¹⁰ each independently represent hydrogen, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, or a halogenocarbonyl group, and X represents chlorine, bromine, iodine or the like. Indicates a halogen atom)
And reacting with a 2-alkenoyl halide derivative represented by the general formula (III)

[0007]

[Chemical 6] (In the formula, R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, or a substituted or unsubstituted lower alkyl group,
R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group,
Or represents a halogenocarbonyl group) N-
The present invention relates to a method for producing a (2-alkenoyl) -2-oxazolidinone derivative.

Next, the present invention will be described in detail. The substituted or unsubstituted lower alkyl group for R ¹ , R ² , R ³ and R ⁴ in the present invention means C which may have a substituent.
_{1 to} C _{5 represents} an optionally branched alkyl group. C ₁ ~ C
Examples of the optionally branched alkyl group of ₅ include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl groups. Examples of the substituent include phenyl, halogenophenyl substituted with Cl and F, and methoxyphenyl.

The lower alkyl group for R ⁵ , R ⁶ and R ⁷ is a C ₁ -C ₅ alkyl group which may be branched, and examples thereof include methyl, ethyl, propyl, isopropyl and n-butyl. , T-butyl and isobutyl groups. The phenyl group may have a substituent.

Further, the substituted or unsubstituted lower alkyl group for R ₈ , R ₉ and R ₁₀ is the above-mentioned R ₁ , R ₂ , R
It has the same definition as in ₃ and R ₄ . The lower alkoxycarbonyl group is C ₁ -C ₈ lower alkoxycarbonyl which may be branched, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, pentoxy. Indicates carbonyl and the like.

The present invention will be described in more detail. A compound represented by the general formula (I) is reacted with a compound represented by the general formula (II) in a solvent-free or aprotic solvent. The compound represented by the general formula (III) can be obtained in high yield.

In the present production method, the molar ratio of the compound represented by the general formula (I) to the compound represented by the general formula (II) may be such that one of the compounds is used in an equimolar amount or more. , And preferably in the range of equimolar to 1.5 times.

The reaction solvent may be used if necessary.
Usually, it is desirable to use a solvent in order to carry out the reaction smoothly. Specific examples of the solvent include ethers such as ethyl ether, isopropyl ether, tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and trichloroethylene, Alternatively, an aprotic solvent that does not adversely affect the reaction of benzene, toluene, aromatic hydrocarbons such as xylene, etc. is preferable.

The reaction temperature can be used in the range of -40 ° C to the boiling point of the solvent, but is preferably in the range of 0 ° C to 100 ° C.

The compound represented by the general formula (III) is isolated from the reaction solution by extracting with water and a solvent such as ethyl acetate or methylene chloride, and then the layer containing the target compound is concentrated. The compound of the general formula (III) can be obtained in a high yield by isolating the obtained concentrated residue directly or after purification by silica gel column chromatography using a crystallization method with a solvent.

In order to produce the compound represented by the general formula (I) used as a raw material in the present invention, the method described in the literature (Japanese Patent Publication No. 55-4757, HRKricheldorf, Justus) is used.
LiebigsA nn.Chem., (1973), 772). That is, a 2-oxazolidinone derivative and a silylating agent such as trimethylsilyl chloride, hexamethyldisilazane, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, and an aprotic non-proton such as methylene chloride, tetrahydrofuran, acetonitrile, and benzene are used. Triethylamine, pyridine, in an active solvent
1,8-diazabicyclo (5,4,0) undecene-7
By reacting in the presence of a base such as (DBU), the compound represented by the general formula (I) can be obtained.

The compound represented by the general formula (I) may be used in the next step after it is in an unisolated state or after isolation and purification. It is preferable to use it in the next reaction in an industrially advantageous unisolated state. From the economical point of view, the silylating agent is preferably trimethylsilyl chloride or hexamethyldisilazane. As the base, triethylamine and the like, which are easy to concentrate and remove, are preferable.

Effect Example of effect Reaction temperature Reaction conversion rate Isolation yield Example 3 Room temperature or higher 89.8% 77.0% Comparative example 3 0 ° C. 35.5% Comparative example 1-20 ° C. 49.9% 41.2 % Comparative Example 2 −70 ° C. 59.8%

[0019]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Reference Example 1 Preparation of N-trimethylsilyl-2-oxazolidinone 2-oxazolidinone (8.708 g, 0.100 mo)
l), tetrahydrofuran (150 ml) and trimethylsilyl chloride (11.556 g, 0.106 m)
ol) in a mixed solution at room temperature.
4.5 ml, 0.104 mol) is added dropwise. After dropping
The reaction is terminated by stirring under reflux for 0.5 hour.

After cooling the reaction solution, under an argon gas atmosphere,
The precipitated triethylamine hydrochloride is filtered off. After the filtrate was concentrated under reduced pressure, vacuum distillation (boiling point 107-110 ° C / 4-5
mmHg) to obtain the target product N-trimethylsilyl-2-oxazolidinone (12.192 g, 7
6.55 mmol, yield 76.6%) is obtained.

NMR (60 MHz, CDCl3, trimethylsilyl group (9H)) δ: 3.1-3.5 (m, 2
H), 3.8-4.3 (m, 2H).

Example 1 Production of N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone N-trimethylsilyl-2-oxazolidinone (1.60 g, 10.0 mmol) obtained in Reference Example 1 was converted to fumaric acid chloride. Add monomethyl ester (1.49 g, 80% purity, 8.0 mmol). Crystals start to precipitate, but the reaction is terminated by stirring overnight at room temperature.

The reaction mixture is concentrated under reduced pressure, ethyl acetate is added to the concentrated residue, and the mixture is washed with 5% aqueous sodium hydrogen carbonate solution and then with saturated brine. The ethyl acetate layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue (1.63 g).

Silica gel chromatography of the residue
N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone (1.594 g, HP) which is the target product by purification with (3.5 g / developing solvent methylene chloride)
LC purity 92%, 7.36 mmol, yield 92.0%)
To get

HPLC purity measuring method Column: ODS (6.0 mmID × 200 mm), Eluent: 1% phosphoric acid / acetonitrile = 80/20, Flow rate: 1.0 ml / min, Detection: UV wavelength 254 nm, Column temperature: 35 C, internal standard substance: p-hydroxybenzoic acid.

Example 2 Production of N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone N-trimethylsilyl-2-oxazolidinone (1.17 g, 7.34 mmol) obtained in Reference Example 1 in methylene chloride (5 ml) ) To the solution was added the monomethyl ester of fumaric acid chloride (1.60 g, purity 75%, 8.08 mmo
A solution of l) in methylene chloride (5 ml) is added. The reaction is completed by stirring under reflux for 6 hours.

The reaction mixture was treated in the same manner as in Example 1 to obtain the desired product N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone (1.18 g, HPL).
C purity 97%, 5.75 mmol, yield 78.3%) is obtained.

Example 3 Preparation of N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone 2-oxazolidinone (34.832 g, 0.400 m)
ol), tetrahydrofuran (400 ml) and trimethylsilyl chloride (47.96 g, 0.44 mo)
l) to the mixed solution at room temperature, triethylamine (60 m
1, 0.429 mol) is added dropwise. After the dropping, under reflux,
The silylation reaction is completed by stirring for 0.5 hour.

The reaction solution is concentrated under reduced pressure to remove excess trimethylsilyl chloride and triethylamine together with tetrahydrofuran. Methylene chloride (40
0 ml) and the monomethyl ester of fumaric acid chloride (54.6 g, purity 69%, 0.2536 mol). The reaction is terminated by stirring at room temperature for 9 hours and then at reflux for 3.5 hours. After concentrating the reaction solution under reduced pressure,
Ethyl acetate is added to the concentrated residue, and the mixture is washed with 5% aqueous sodium hydrogen carbonate solution and then saturated brine. The ethyl acetate layer is separated and treated with activated carbon, and then the reaction conversion rate is measured by the HPLC method. Reaction conversion rate 89.8% (45.35 g, 0.
2277 mol) is obtained.

The ethyl acetate solution was concentrated under reduced pressure and then crystallized using ethyl acetate and a hexane solvent to obtain N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone (38.9 g, HPLC purity) as a target. 99%, 0.1953 mol, yield 77.0%) is obtained.

NMR (200 MHz, CDCl3) δ:
3.82 (s, 3H), 4.11, 4.50 (m, m,
2H, 2H), 6.95 (d, 1H, J = 16Hz),
8.15 (d, 1H, J = 16Hz) FAB MASS C8H9NO5 Calcd. 199 Found 199

Example 4 Production of N- (3-chlorocarbonylpropenoyl) -2-oxazolidinone N-trimethylsilyl-2-oxazolidinone (1.409 g, 8.847 mmol) obtained in Reference Example 1
Fumaric acid dichloride at 23 ° C. (4.245 g, 27.
75 mmol) in methylene chloride (18 ml). 1 hour at -23 ° C, 1 hour at 0 ° C, then 1 hour at room temperature
By stirring for a time, a solution of N- (3-chlorocarbonylpropenoyl) -2-oxazolidinone in methylene chloride is obtained. After cooling the above reaction solution to -23 ° C, methanol
(10 ml) was added, and the mixture was stirred at that temperature for 1 hour and then at room temperature for 0.5 hour.
As a result of HPLC analysis as -methoxycarbonylpropenoyl) -2-oxazolidinone, the reaction conversion rate was 92.
%Met.

Comparative Example Preparation of N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone (Preparation of sodium salt of 2-oxazolidinone) 2-oxazolidinone (1.74 g, 20.0 mmol), tetrahydrofuran (10 ml) and hexa A solution of methylphosphoric triamide (2 ml) is added dropwise to a suspension of 60% sodium hydride (0.839 g, 21.0 mmol) in tetrahydrofuran (10 ml). Then, after stirring under reflux for 0.5 hour, tetrahydrofuran (15 ml) was further added, and the mixture was stirred at room temperature for 1 hour to obtain a suspension of sodium salt of 2-oxazolidinone.

Comparative Example 1 After the suspension of the sodium salt of 2-oxazolidinone obtained above was cooled to -20 ° C, the monomethyl ester of fumaric acid chloride (3.265 g, purity 80%, 17.6 m) was used.
A solution of (mol) in tetrahydrofuran (6 ml) was added dropwise over 0.5 hour while maintaining the same temperature, and further 1
The reaction is terminated by stirring for 1 hour at room temperature.

The reaction solution was poured into a mixed solution of ethyl acetate and saturated aqueous ammonium chloride solution and extracted. The ethyl acetate layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated saline solution and dried over anhydrous sodium sulfate. Is measured by the HPLC method. Reaction conversion 49.9% (1.749 g, 8.78)
mmol). The ethyl acetate solution was concentrated under reduced pressure, and the residue was treated by silica gel chromatography in the same manner as in Example 1 to give N- (3-methoxycarbonylpropenoyl) -2-oxazolidinone (1.
623 g, HPLC purity 89%, 7.25 mmol, yield 41.2%).

Comparative Example 2 A sodium oxazolidinone sodium salt suspension was treated in the same manner as in Comparative Example 1 except that the reaction temperature of −20 ° C. in Comparative Example 1 was changed to −70 ° C., and then the reaction conversion rate was measured by the HPLC method. taking measurement. Reaction conversion rate 59.8% (2.093 g, 10.5
1 mmol) is obtained.

Comparative Example 3 A sodium oxazolidinone sodium salt suspension was treated in the same manner as in Comparative Example 1 except that the reaction temperature of -20 ° C. in Comparative Example 1 was changed to 0 ° C., and then the reaction conversion rate was measured by the HPLC method. To do. Reaction conversion rate 35.5% (1.245 g, 6.25 m)
mol) is obtained.

[0039]

EFFECTS OF THE INVENTION By using the production method of the present invention, neutral and mild reaction conditions and a simple isolation and purification method can be realized, which is an important intermediate necessary for the development of novel cyclobutane antiviral agents. N- (2 represented by the formula (III)
Industrial production of the -alkenoyl) -2-oxazolidinone derivative can be carried out safely, at low cost and in high yield.

Claims (1)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, or a substituted or unsubstituted lower alkyl group,
R ⁵ , R ⁶ and R 7 each independently represent a lower alkyl group or a phenyl group) N-silyl-2-
Oxazolidinone derivatives and general formula (II) (In the formula, R ⁸ , R ⁹ and R ¹⁰ each independently represent hydrogen, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group, or a halogenocarbonyl group, and X represents chlorine, bromine, iodine or the like. Indicates a halogen atom)
A 2-alkenoyl halide derivative represented by the general formula (III): (In the formula, R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, or a substituted or unsubstituted lower alkyl group,
R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, a substituted or unsubstituted lower alkyl group, a lower alkoxycarbonyl group,
Or a halogenocarbonyl group)
Process for producing-(2-alkenoyl) -2-oxazolidinone derivative