JP2691574B2 - Optically active pyrazolidinone derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to the following general formula (I) useful as a synthetic intermediate for thienamycin. [Wherein R ¹ represents a protective group for a carboxyl group, R ² represents a hydrogen atom, an optionally substituted alkyl, phenyl or aralkyl group], and an optically active pyrazolidinone derivative and a process for producing the same. It is a thing.

[Conventional technology and its problems]

Thienamycin is represented by the following formula (IV) It is an antibiotic represented by, and the conventional method for producing it is to use acetone dicarboxylic acid as a starting material (DG
Melillo, I.Shinkai, T.Liu.Ryan, M.Sletzinger, Tetrahed
ron Lett., 21,2783 (1980) and DG Melillo, T.Liu, KR
yan., M.Sletzinger, Tetrahedron Lett., 22,913 (198
1)) is known.

However, according to this method, in order to obtain an optically active substance, a stoichiometric amount of optically active phenethylamine is required, and the stereo structure of amino alcohol derived by this method does not match the final target compound. The inversion reaction is required, and the reagents used therefor are disadvantageous in that they are expensive, and it has been desired to develop a more economical method.

[Means for solving the problem]

The present inventor has conducted intensive studies in view of the above circumstances, and as a result, found that the above problems can be solved by using an optically active pyrazolidinone derivative represented by the general formula (I) as an intermediate, and completed the present invention. .

That is, the present invention provides an optically active pyrazolidinone derivative represented by the general formula (I) and a method for producing the same.

According to the method of the present invention, a pyrazolidinone derivative (I)
Is, for example, [Wherein, R ¹ represents a protective group for a carboxyl group] is added to the compound (II) represented by the following general formula (III) [In the formula, R ² represents a hydrogen atom, an optionally substituted alkyl, phenyl or aralkyl group], or a hydrazine or hydrazine derivative (III)
It is manufactured by reacting.

In the method of the present invention, compound (II) is dissolved in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran or dimethylformamide, and hydrazine or hydrazine derivative (III) is reacted at a reaction temperature of -45 to + 50 ° C. It is carried out by. This reaction is preferably carried out under an atmosphere of nitrogen or argon.

Examples of the compound (III) include hydrazine, methylhydrazine, ethylhydrazine, phenylhydrazine,
p-methoxyphenylhydrazine, 2,4-dimethoxyphenylhydrazine, p-chlorophenylhydrazine, p
-Tolylhydrazine, benzylhydrazine, p-methoxybenzylhydrazine, diphenylmethylhydrazine,
Examples include 2,4-dimethoxybenzylhydrazine and hydrazine acetate.

After completion of the reaction, the solvent is distilled off under reduced pressure and the compound (I) of the present invention is broken out when left in a cool place.

A typical example of the compound (I) of the present invention obtained as described above is (1'S, 2'R) -5- (2'-hydroxy-1'-methoxycarbonyl) propyl-pyrazolidine-3. -One, (1'S, 2'R) -1-methyl-5-
(2'-Hydroxy-1'-methoxycarbonyl) propylpyrazolidin-3-one, (1'S, 2'R) -1-
Ethyl-5- (2'-hydroxy-1'-methoxycarbonyl) propylpyrazolidin-3-one, (1'S,
2'R) -1-phenyl-5- (2'-hydroxy-
1'-methoxycarbonyl) propyl-pyrazolidine-
3-one, (1'S, 2'R) -1-p-methoxyphenyl-5- (2'-hydroxy-1'-butoxycarbonyl) propylpyrazolidin-3-one, (1'S, 2 ′
R) -1-2 ", 4" -dimethoxybenzyl-5- (2 '
-Hydroxy-1'-ethoxycarbonyl) propyl-
Pyrazolidin-3-one, (1'S, 2'R) -1-p-
Tolyl-5- (2'-hydroxy-1'-ethoxycarbonyl) propylpyrazolidin-3-one, (1'S,
2'R) -1-benzyl-5- (2'-hydroxy-
1'-methoxycarbonyl) propylpyrazolidine-3
-One, (1'S, 2'R) -1-p-methoxybenzyl-5- (2'-hydroxy-1'-methoxycarbonyl) propylpyrazolidin-3-one, (1'S, 2 '
R) -1-Diphenylmethyl-5- (2'-hydroxy-1'-methoxycarbonyl) propylpyrazolidine-
3-one, (1'S, 2'R) -1-2 ", 4" -dimethoxybenzyl-5- (2'-hydroxy-1'-methoxycarbonyl) propylpyrazolidin-3-one, (1 ′
S, 2′R) -1-Carbohydroxymethyl-5- (2 ′
-Hydroxy-1'-methoxycarbonyl) propylpyrazolidin-3-one and the like, but not limited thereto.

The above compound (I) of the present invention is further hydrogenated to give the compound of the following general formula (V) [Wherein R ¹ and R ² are the same as defined above], and the compound (V) can be obtained.

Specifically, for example, when R ² is a benzyl group, the compound (I) of the present invention is dissolved in a solvent such as dimethoxyethane,
Hydrogenation is carried out using palladium-carbon as a catalyst in the coexistence of -20% hydrochloric acid water, hydrogenolysis and hydrolysis are allowed to proceed, and after the catalyst is separated, the liquid is concentrated to dryness to give 4 (R) -5.
(S) -6 (R) -Amino-5-carbohydroxy-6
-Methyl-δ-lactone (compound (V), R ¹ and R ² are hydrogen atoms) is obtained. The compound (V) thus obtained is obtained from the above-mentioned literature (DG Melillo, I. Shinkai, T. et al.
Liu.Ryan, M.Sletzinger, Tetrahedrron Lett., 21,2783
(1980)) and is an important compound as an intermediate in the production of thienamycin.

〔The invention's effect〕

INDUSTRIAL APPLICABILITY The compound of the present invention is useful as a synthetic intermediate for thienamycin, and when it is used, thienamycin can be produced industrially advantageously.

〔Example〕

 Next, an example will be described.

Example 1 6 (R) -5-methoxycarbonyl-6-methyl-3,
2.0 g (11.8 mM) of 6-dihydropyran-2-one (compound (II), R ¹ is a methyl group) was dissolved by adding 20 ml of ethyl acetate (dry) under a stream of argon gas, heating to 40 ° C., and heating with benzyl. Hydrazine 1.44g (11.8mM) ethyl acetate (dry) 1
A 0 ml solution was added dropwise. Then, stir at 45 ℃ for 4 hours,
Then, the solvent was distilled off, 5 ml of ether (dry) and 1 ml of ethyl acetate (dry) were added, and the mixture was allowed to crystallize at 5 ° C. By passing this over, 2.24 g (yield 65%) of (1'S, 2 ′
R) -1-benzyl-5- (2'-hydroxy-1'-
Methoxycarbonylpropyl) pyrazolidin-3-one (compound (I), R ¹ is methyl group, R ² is benzyl group) was obtained. All the operations up to the above were performed under an argon stream. ¹ H NMR (400 MHz) δppm pyridine-d ₅ : 1.30 (3H, d, J = 6.22), 2.89 (1H, dd, J = 2.56,7.30),
2.94 (1H, dd, J = 2.56,7.36), 3.0 (1H, dd, J = 6.74,7.3
0), 3.72 (3H, -OCH 3), 3.84 (1H, dq, J = 2.56,6.22),
4.23 (2H, -N-C H 2 -ph), 4.25 (1H, m), 7.2~7.7 (5
H, aromatic) Example 2 6 (R) -5-methoxycarbonyl-6-methyl-3,
1.23 g (6.95 mM) of 6-dihydropyran-2-one (compound (II), R ¹ is a methyl group) was dissolved by adding 10 ml of dimethylformamide (dry) under an argon gas stream, and hydrazine acetate 0.63 g (6.95 mM) ) Was added as a solid and stirred overnight at room temperature. Then, dimethylformamide was distilled off under reduced pressure at 40 ° C. and purified by silica gel column chromatography (eluted with methylene chloride-methanol (95: 5)) to give 690 mg (yield 38%) of (1 ′S, 2 'R) -1-carbohydroxymethyl-5- (2'-hydroxy-1'-
Methoxycarbonylpropyl) pyrazolidin-3-one (compound (I), R ¹ is a methyl group, and R ² is a carbohydroxymethyl group) was obtained. All the operations up to the above were performed under an argon stream. ¹ H NMR (400 MHz) δ ppm pyridine-d ₅ : 1.38 (3H, d, J = 7.0), 2.90 (1H, dd, J = 3.15,17.98),
2.98 (1H, dd, J = 8.02,9.62), 3.13 (1H, dd, J = 5.38,17.
98), 3.30 (1H, m ), 3.74 (4H, -OC H 3, CH 3 C H OH -), 4.6
0 (1H, m) Example 3 6 (R) -5-methoxycarbonyl-6-methyl-3,
2.0 g (11.8 mM) of 6-dihydropyran-2-one (compound (II), R ¹ is a methyl group) was dissolved by adding 20 ml of methanol (dry) under a stream of argon gas, cooled with water to 0 ° C., and anhydrous hydrazine. 0.43 g (13.4 mM) was added dropwise. Then, the mixture was reacted at 0 ° C for 10 hours, then methanol was distilled off, and the residue was purified by silica gel column chromatography (eluted with methylene chloride-methanol (95: 5)) to give 760 mg (yield 32
%) Of (1'S, 2'R) -5- (2'-hydroxy-
1'-methoxycarbonylpropyl) pyrazolidine-3
-One (compound (I), R ¹ is a methyl group, R ² is a hydrogen atom)
I got ¹ H NMR (400 MHz) δ ppm methanol-d ₄ : 1.17 (3H, d, J = 6.22), 2.28 (1H, J = 4.57,6.67), 2.6
7 (1H, m), 2.70 (2H, m), 3.70 (3H), 4.02 (1H, m), 4.6
7 (1H, m) Example 4 6 (R) -5-methoxycarbonyl-6-methyl-3,
1.0 g (5.9 mM) of 6-dihydropyran-2-one (compound (II), R ¹ is a methyl group) was dissolved by adding 10 ml of ethyl acetate (dry) under an argon gas stream, and methyl hydrazine 27
A solution of 0 mg (5.9 mM) in 5 ml of ethyl acetate (dry) was added dropwise at room temperature. Then, the mixture was reacted at room temperature for 10 hours, then ethyl acetate was distilled off and purified by silica gel column chromatography (eluted with methylene chloride-methanol (98: 2)) to give 670 mg (yield 53%) (1 'S, 2'R) -5
There was obtained-(2'-hydroxy-1'-methoxycarbonylpropyl) -1-methylpyrazolidin-3-one (compound (I), R ¹ and R ² are hydrogen atoms). ¹ H NMR (400 MHz) δ ppm pyridine-d ₅ : 1.28 (3H, d = 6.28), 2.77 (1H, dd, J = 9.21,7.35), 2.
90 (1H, dd, J = 2.85,7.38), 2.92 (1H, dd, J = 7.35,9.0
5), 3.80 (3H), 3.85 (H, dq, J = 2.85, 6.28), 4.20 (1H,
m) Example 5 6 (R) -5-methoxycarbonyl-6-methyl-3,
1.0 g (5.9 mM) of 6-dihydropyran-2-one (compound (II), R ¹ is a methyl group) was dissolved by adding 10 ml of dimethylformamide (dry) under a stream of argon gas, and cooled to -10 ° C. A solution of 640 mg (5.9 mM) of phenylhydrazine in 5 ml of dimethylformamide (dry) was added dropwise. Then 0
The reaction was carried out at ℃ for 24 hours, then the solvent was distilled off, 5 ml of ether (dry) was added, and crystallization was carried out at 5 ℃, by passing this over 350 mg (yield 28%) of (1'S, 2 ′
R) -5- (2'-hydroxy-1'-methoxycarbonylpropyl) -1-phenylpyrazolidin-3-one (compound (I), R ¹ is a methyl group, R ² is a phenyl group) It was All the operations up to the above were performed under an argon stream. ¹ H NMR (400 MHz) δ ppm pyridine-d ₅ : 1.32 (3H, d, J = 6.40), 2.80 (1H, dd, J = 8.95,7.20),
2.92 (1H, dd, J = 2.12,7.41), 2.95 (1H, dd, J = 6.80,7.2
0), 3.70 (3H, s), 3.85 (H, dq, J = 2.56,6.40), 4.28 (1
H, m), 7.2 ~ 8.0 (5H, aromatic) Reference Example 1 10% Pd-C in a glass autoclave under argon gas.
(1'S, 2'R) -1-benzyl-5- (2 ') obtained in Example 1 dissolved in 500 mg, 20 ml dimethoxyethane.
1-g (3.4 mM) of -hydroxy-1'-methoxycarbonylpropyl) pyrazolidin-3-one and 20 ml of 1N-hydrochloric acid are mixed, and hydrogenolysis is carried out for 17 hours at a hydrogen pressure of 3 kg / cm ² and a temperature of 25 ° C. The resulting reaction solution was filtered and the solution was concentrated under reduced pressure and dried, 12N-hydrochloric acid (10 ml) was added thereto, and the mixture was refluxed for 4 hours and concentrated and dried to give 620 mg (yield 86.4%) (4R, 4S, 5R). -4-Amino-5-carbohydroxy-6-methyltetrahydro-pyran-2-one hydrochloride was obtained.

The obtained compound can be used as it is as a starting material for the synthesis of thienamycin, but can be further purified. Use Toyopearl TSK-HW40S for purification 2
Gelation is performed using distilled water as an eluent while measuring the absorbance at 10 nm, and the purified product is stirred for 24 hours in distilled water and then concentrated and dried under reduced pressure.

 The data of the obtained purified product are as follows.

▲ [a] ^{25 ℃} _D ▼ +4.09 (c = 1.05, H ₂ O) 61% ¹ H NMR (400MHz) δppm pyridine-d ₅ : 1.87 (3H, d, J = 6.40), 3.55 (1H, t , J = 9.0), 3.57 (1
H, dd, J = 4.8,17.1), 3.88 (1H, dd, J = 9.0,17.1), 4.96
(1H, dq, J = 9.0,6.4), 5.07 (1H, dt, J = 4.8,9.0)

 ─────────────────────────────────────────────────── --- Continuation of the front page (72) Inventor Toshiyuki Takezawa 3-19-8-203 Tani, Urawa City, Saitama Prefecture (72) Hidenori Unbayashi 1-4-9 Nakakaigan, Chigasaki City, Kanagawa Prefecture

Claims (2)

(57) [Claims] 1. The following general formula (I) [Wherein, R ¹ represents a protective group for a carboxyl group, and R ² represents a hydrogen atom, an optionally substituted alkyl, phenyl or aralkyl group]. 2. The following general formula (II) [Wherein, R ¹ represents a protective group for a carboxyl group] is added to the compound (II) represented by the following general formula (III) [In the formula, R ² represents a hydrogen atom, an optionally substituted alkyl, phenyl or aralkyl group], or a hydrazine or hydrazine derivative (III)
The following general formula (I) is characterized in that [Wherein R ¹ and R ² have the same meanings as described above], and a method for producing the optically active pyrazolidinone derivative.