JP2955886B2 - Pyrrolidine derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate of a penem compound and a carbapenem compound having antibacterial activity and a method for producing the same. More specifically, JP-A-60-19787
JP, JP-A-60-58987 and JP-A-60-104088
General formula (1), which is an important intermediate when constructing the side chain portion of the 2-position of penem compounds and carbapenem compounds known to have excellent antibacterial activity in the publication

Embedded image Wherein Ph represents a phenyl group, R represents an amino-protecting group, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group or a substituted lower alkyl group, and R ₂ represents a lower alkyl group. Or a lower alkenyl group, an aralkyl group or a substituted lower alkyl group, or R ₁ and R ₂ are bonded to each other to form an alkylene chain, or an alkylene chain via an oxygen atom, a sulfur atom, or a nitrogen atom substituted with a lower alkyl group. The chain represents a 4- to 7-membered cyclic amino group together with an adjacent nitrogen atom. ]
And a method for producing the same.

[0002]

2. Description of the Related Art As an intermediate for producing a penem compound and a carbapenem compound described in the above publication, a compound represented by the general formula (3):

Embedded image Wherein R, R ₁ and R ₂ have the same meaning as described above. ] Are known.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have found that the compound of the present invention represented by the general formula (1) is more excellent in crystallinity than the compound represented by the general formula (3). The present invention has been found to be a very useful intermediate for mass production of compounds and carbapenem compounds, and has completed the present invention.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention and a method for producing the same will be described in detail below. In the compound of the present invention represented by the general formula (1), examples of the protecting group for the amino group represented by R include a lower alkoxycarbonyl group such as tert-butyloxycarbonyl, for example, 2-ethyliodoxycarbonyl, Halogeno lower alkoxycarbonyl groups such as 2,2,2-trichloroethyloxycarbonyl, for example, allyloxycarbonyl, 2-
Lower alkenyloxycarbonyl groups optionally substituted by halogen atoms such as chloroallyloxycarbonyl, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl An aralkyloxycarbonyl group can be mentioned.

The lower alkyl groups represented by R ₁ and R ₂ include, for example, alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples thereof include alkenyl groups having 2 to 4 carbon atoms such as propenyl and butenyl. Examples of the aralkyl group include phenyl groups such as benzyl, substituted benzyl and phenethyl or carbon atoms substituted with a substituted phenyl group. Examples of the substituted lower alkyl group include a hydroxyl group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a carbamoyl group, a carboxyl group, a lower alkoxycarbonyl group, and an aralkyloxy group. To mention an alkyl group having 1 to 4 carbon atoms substituted by a carbonyl group or the like. it can.

R ₁ and R ₂ represent an alkylene chain bonded and bonded together or an alkylene chain via an oxygen atom, a sulfur atom or a lower alkyl-substituted nitrogen atom, and formed together with an adjacent nitrogen atom.
Examples of the 7-membered cyclic amino group include an azetidino group,
Examples thereof include a piperidino group, a pyrrolidino group, a morpholino group, a thiomorpholino group, and an N-methylmorpholino group.

The compound of the present invention represented by the general formula (1) has stereoisomers based on the asymmetric carbon at the 2-position and 4-position, and these isomers are all represented by a single formula for convenience. Of course, the present invention includes all these isomers. However, suitable intermediates for penem compounds and carbapenem compounds include [2S,
4S] and [2R, 4R] coordination compounds.

General formula (1)

Embedded image [Wherein, Ph, R, R ₁ and R ₂ have the same meaning as described above. The compound of the present invention represented by the general formula (2)

Embedded image [Wherein, X represents an active ester group of a hydroxyl group, and R and R ₁
And R ₂ have the same meaning as described above. Can be obtained by subjecting an alkali metal thiobenzoate to heat treatment in an inert solvent.

Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, aromatic halogenated hydrocarbons such as chlorobenzene and o-dichlorobenzene, and non-solvents such as acetonitrile, dimethylformamide, dimethylacetamide and sulfolane. Protic polar solvents and mixed solvents of these organic solvents can be mentioned, and preferred are toluene and dimethylformamide or a mixed solvent of chlorobenzene and dimethylformamide.

The alkali metal salt used as the alkali metal salt of thiobenzoic acid includes lithium, sodium and potassium, and preferably potassium.

The reaction temperature can be in the range of 50 ° C. to 150 ° C.
It is preferable to carry out in the range of 0 ° C. After completion of the reaction, the product can be obtained by a usual organic chemical technique. However, the present production method is characterized in that the product can be obtained by crystallization purification after distilling off the solvent.

The compound of the present invention represented by the general formula (1) obtained by the above method is converted into a mercaptan derivative by a hydrolysis reaction or a solvolysis reaction using an alkali metal base as shown in the following reaction formula. It is then converted into penem compounds and carbapenem compounds having excellent antibacterial activity by known methods.

Embedded image [Wherein, Ph, R, R ₁ and R ₂ have the same meaning as described above. ]

The starting compound represented by the general formula (2) used in the method of the present invention is obtained from 4-hydroxyproline in the Journal of Antibiotics 43 (5), 5
19 to 532 (1990).

[0014]

EXAMPLES Next, the present invention will be described more specifically with reference to examples and reference examples, but the present invention is of course not limited thereto. The meanings of the abbreviations used in the following Examples and Reference Examples are as follows.

Ms: methanesulfonyl group, Me: methyl group, Ph: phenyl group.

Embodiment 1- (1)

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(2S, 4R) -N, N-dimethyl-1-
To an oily residue (30 g) containing allyloxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinecarboxamide (25.3 g) was added toluene (145 ml), dimethylformamide (145 ml), and potassium thiobenzoate (14.2 g). And stirred at 70 ° C. for 4.5 hours. The reaction solution was cooled to 30 ° C. or lower, and toluene (700 ml), 1
A 0% saline solution (700 ml) was added for extraction and separation. After separation, the aqueous layer was re-extracted with toluene (200 ml), and the toluene layer was combined with the previous organic layer and washed five times with 10% saline (350 ml). did. After drying over magnesium sulfate, the solvent was distilled off. N-Hexane (51 ml) and ethyl acetate (8.5 ml) were poured into the obtained oily residue, heated to 60 ° C, and stirred for 30 minutes. After cooling to 30 ° C., 5 g of seed crystal was added, and the mixture was stirred for 1 hour.
Stirred for hours. The precipitated crystals were collected, washed with a mixed solvent of n-hexane and ethyl acetate (70:30) and dried under reduced pressure to give (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-. Benzoylthio-2-pyrrolidinecarboxamide (13.6 g) was obtained.

Melting point (mp): 99.5-101.5 ° C .; IR (Nujol): 1690, 1665, 1650 cm ⁻¹ .

In the above method, potassium thioacetate is used instead of potassium thiobenzoate (2S,
The melting point (mp) of 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-acetylthio-2-pyrrolidinecarboxamide was 75 to 76 ° C.

Example 1- (2) Toluene was added to an oily residue containing (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinecarboxamide (4.14 g). (30 ml), dimethylformamide (8 ml) and potassium thiobenzoate (2.8 g) were added, and the mixture was stirred at 70 ° C. for 5 hours. After water (20 ml) was added to the reaction solution and the layers were separated, the aqueous layer was re-extracted with toluene (30 ml), and the toluene layer was combined with the previous organic layer and washed twice with water (20 ml).
After drying over magnesium sulfate, the solvent was distilled off, and the obtained oily residue was crystallized from a mixed solvent of n-hexane and ethyl acetate to give (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4 -Benzoylthio-2-pyrrolidinecarboxamide (2.19 g) was obtained.

Example 1- (3) Toluene was added to an oily residue containing (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinecarboxamide (4.09 g). (40 ml) and potassium thiobenzoate (2.45)
g) was added and the mixture was stirred under reflux for 3 hours. Toluene (40 ml) was added to the reaction solution, and the mixture was washed three times with 10% saline (30 ml). After drying over magnesium sulfate, the solvent was distilled off, and the obtained oily residue was crystallized from a mixed solvent of n-hexane and ethyl acetate to give (2S, 4S) -N, N-dimethyl-1.
-Allyloxycarbonyl-4-benzoylthio-2-
Pyrrolidine carboxamide (1.77 g) was obtained.

Reference Example 1

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Thiobenzoic acid (30.4 g) was added to methanol (1
6 ml) and add potassium hydroxide (11.2
g) in methanol (40 ml) was added dropwise.
After stirring for about 30 hours, about 40 ml of methanol was distilled off under reduced pressure. The concentrated residue was dissolved in ethyl acetate (300 ml), cooled with ice, n-hexane (120 ml) was added dropwise, and the mixture was stirred for 30 minutes. The precipitated crystals were collected, washed with a mixed solvent of n-hexane and ethyl acetate, and dried under reduced pressure to obtain potassium thiobenzoate (23.5 g).

Reference Example 2

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Trans-4-hydroxy-L-proline (35.9 g) and sodium hydroxide (23.9 g) were added to water (330
ml), and a solution of allyl chlorocarbonate (36.3 g) in methylene chloride (250 ml) was added dropwise under ice-cooling, followed by stirring for 2 hours. The aqueous layer was separated from the reaction solution, washed twice with methylene chloride (100 ml), and made acidic by dropwise addition of concentrated sulfuric acid (25 g) at 30 ° C. or lower. Next, sodium chloride (120 g) was added, and the mixture was extracted twice with ethyl acetate (220 ml). After drying the ethyl acetate extract with magnesium sulfate,
The solvent was distilled off and trans-1-allyloxycarbonyl-
Crude crystals of 4-hydroxy-L-proline (62 g) were obtained. The crude crystals were repulped and refined with toluene to give a melting point (m
p) Trans-1-allyloxycarbonyl-4-hydroxy-L-proline (56.1 g) at 93-94 ° C. was obtained.

IR (Nujol): 3300, 1740, 1675, 1645 cm ⁻¹ .

Reference Example 3

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Trans-1-allyloxycarbonyl-
Crude crystals (31 g) containing 4-hydroxy-L-proline (28.6 g) were dissolved in methylene chloride (465 ml), triethylamine (6.6 g) was added thereto, and methylene chloride (95 ml) was added under reflux. An azeotropic dehydration was performed by distilling the same amount. After performing azeotropic dehydration three more times by the same operation, the mixture was cooled to -10 ° C, and methanesulfonyl chloride (37.4 g) was injected. Next, triethylamine (2
5 g) was added dropwise at −5 ° C. or lower, and the mixture was stirred for 1 hour. Then, dimethylamine hydrochloride (21.3 g) was added, and triethylamine (40 g) was added dropwise at −5 ° C. or lower, and the mixture was stirred for 1 hour. A 10% saline solution (125 m
l) was added and the mixture was separated. The methylene chloride layer was separated with 1N aqueous hydrochloric acid (250 ml) and 1N aqueous sodium hydroxide (125 ml).
ml), sequentially washed with 10% saline (125 ml × 2 times),
After drying over magnesium sulfate, the solvent was distilled off, and (2S, 4
42.5 g of an oily residue containing (R) -N, N-dimethyl-1-allyloxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinecarboxamide (36 g) was obtained.
The residue was crystallized with a mixed solvent of n-hexane and ethyl acetate to obtain crystals having a melting point (mp) of 64 to 66 ° C.

IR (Nujol): 1685, 1645 cm ^-1 .

Reference Example 4

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(2S, 4S) -N, N-dimethyl-1-
Allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide (3.62 g) was added to methanol (5.
2 ml), and a 28% sodium methoxide-methanol solution (2.025 g) was added dropwise under ice-cooling, followed by stirring for 30 minutes. Methylene chloride (20 ml) and water (20 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was separated with methylene chloride (20 ml).
Then, 2,6-di-t-butyl-4-methylphenol (BHT) (22 mg) was added, and 2N aqueous hydrochloric acid (5.5 ml) was added dropwise under ice-cooling to acidify the solution. The mixture was extracted twice with methylene (20 ml) and then with methylene chloride (10 ml), and the solvent was distilled off under reduced pressure to give an oily (2S, 4S)
N, N-dimethyl-1-allyloxycarbonyl-4-
Mercapto-2-pyrrolidinecarboxamide (2.45
g) was obtained.

IR (neat): 1700, 1650 cm ^-1 ; NMR (CDCl ₃ ) δ: 1.85 (1H, m), 1.88 (1H, d, J =
8.9Hz), 2.65 (1H, m), 2.92 (1 / 3x3H, S), 2.94 (2 / 3x3H, S), 3.00 (1
/3x3H,S),3.05(2/3x3H,S), 3.20 (1H, m), 3.36 (1H, t, J = 1
0.0Hz), 4.02 (1H, m), 4.51 to 4.67 (3H, m), 5.14 to 5.29 (2
H, m), 5.84 (1H, m).

Continuation of the front page (56) References JP-A-60-10088 (JP, A) JP-A-60-19787 (JP, A) JP-A-3-275685 (JP, A) JP-A-5-230061 (JP) , A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 207/00-207/50 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) Wherein Ph represents a phenyl group, R represents an amino-protecting group, R ₁ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aralkyl group or a substituted lower alkyl group, and R ₂ represents a lower alkyl group. Or a lower alkenyl group, an aralkyl group or a substituted lower alkyl group, or R ₁ and R ₂ are bonded to each other to form an alkylene chain, or an alkylene chain via an oxygen atom, a sulfur atom, or a nitrogen atom substituted with a lower alkyl group. The chain represents a 4- to 7-membered cyclic amino group together with an adjacent nitrogen atom. ]
A pyrrolidine derivative represented by the formula: 2. General formula (2) derived from 4-hydroxyproline [Wherein, X represents an active ester group of a hydroxyl group, R represents an amino-protecting group, R ₁ represents a hydrogen atom, a lower alkyl group, lower alkenyl group, an aralkyl group or a substituted lower alkyl group, R ₂ Represents a lower alkyl group, a lower alkenyl group, an aralkyl group or a substituted lower alkyl group, or R ₁ and R ₂ are bonded to each other to form an alkylene chain, or an oxygen atom, a sulfur atom or a nitrogen atom substituted with a lower alkyl group. Represents a 4- to 7-membered cyclic amino group together with an adjacent nitrogen atom, which represents an alkylene chain via Wherein the intermediate represented by the general formula (1) is heat-treated with an alkali metal salt of thiobenzoic acid. [In the formula, Ph represents a phenyl group, and R, R ₁ and R ₂
Has the same meaning as described above. ] A method for producing a pyrrolidine derivative represented by the formula: