JP3219833B2 - Method for producing 4-substituted propylazetidin-2-one derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 4-substituted propylazetidin-2-one derivative.

[0002]

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In the formula, R ¹ represents a protecting group for a hydroxyl group;
² represents a hydrogen atom or an amino-protecting group, a compound represented by the following formula: methyl chlorocarbonate, ethyl chlorocarbonate, chlorocarbonate
Isobutyl carbonate, diphenylphosphoryl chloride, methyl chloride
Rusulfonyl, thionyl chloride, trifluoroacetic anhydride and
And dicyclohexylcarbodiimide
Reacting any one of the selected carboxylic acid activators, base and imidazole, and then reacting with the following formula

[0004]

Embedded image Mg (O ₂ CCH ₂ CO ₂ R ³ ) ₂ (II) wherein R ³ represents a carboxy-protecting group, and a magnesium malonate compound represented by the following formula (I): )

[0005]

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Wherein R ¹ , R ² and R ³ are as defined above, 4-substituted propylazetidine-2
The present invention relates to a method for producing an -one derivative.

[0007]

2. Description of the Related Art (3)
S, 4R) -3-[(1R) -1-substituted oxyethyl]
The 4-[(1R) -1-methyl-3-substituted oxycarbonyl-2-oxo] propylazetidin-2-one derivative can be an important synthetic intermediate of 1β-methylcarbapenem compound having antibacterial activity. Is known (for example, JP-A-63-170377).

The compound of the formula (I) is prepared by a method (3S, 4R) -3- represented by the formula (III).
[(1R) -1-substituted oxyethyl] -4-[(1R)
It has been reported that -1-carboxyethyl] azetidin-2-one derivative can be synthesized as a raw material (Heterocycles, vol. 21, p29 (1984)). In this method, a compound of the formula (I) is obtained by reacting a compound of the formula (III) with a carboxylic acid activator, carbonyldiimidazole and a magnesium malonate compound.

[0009] However, if the method described in the above-mentioned literature is to be carried out on an industrial scale, carbonyldiimidazole used as a reagent is expensive and unstable at ordinary temperature, so that the production cost increases and the raw materials are stored for a long time. Problems such as difficulty in performing Such a problem is a serious drawback of the above-mentioned method when attempting to produce the compound of the formula (I) in large quantities, but until now no attempt has been made to overcome this drawback. It is the current situation.

[0010]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above circumstances, and provides a method for producing a large amount of a compound of the formula (I) at a low cost using a compound of the formula (III) as a raw material. To provide.

Hereinafter, the present invention will be described in detail. In order to facilitate understanding, the manufacturing method of the present invention will be described by dividing it into three steps shown in the following schematic diagrams.

[0012]

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In the formula, R ¹ , R ² and R ³ are as defined above.

As used herein, the term "lower" refers to a group or compound to which this term is attached having 1 to 7 carbon atoms.
, Preferably 1 to 4. The “lower alkyl group” may be linear or branched, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl
tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups and the like.

Further, as the "protecting group for hydroxyl group", for example, silyl groups such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenyl-tert-butylsilyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-nitrobenzyloxy It includes a substituted or unsubstituted benzyloxycarbonyl group such as carbonyl, and other commonly used hydroxyl-protecting groups.

Further, the "amino protecting group" can be any protecting group known per se as a protecting group for an amino group in the field of peptide chemistry, for example, an aromatic acyl group: for example, phthaloyl; benzoyl, or Benzoyl substituted by halogen, nitro or lower alkyl such as chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, toluoyl; naphthoyl; phenylacetyl; phenoxyacetyl; benzenesulfonyl, p-tert-butylbenzenesulfonyl, toluene Aliphatic or halogenated aliphatic carboxylic acid acyl groups such as lower alkyl-substituted benzenesulfonyl such as sulfonyl: for example, camphorsulfonyl, methanesulfonyl, formyl, acetyl, valeryl, caprylyl, n-decanoyl, Liloyl, pivaloyl, halogenoacetyl (eg, monochloroacetyl, monobromoacetyl, dichloroacetyl, trichloroacetyl), etc.
Esterified carboxy group: for example, carbamoyl or ethoxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc. Thiocarbamoyl group: For example, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and the like or a thiocarbamoyl group corresponding thereto and the like.

Examples of the "carboxy-protecting group" include, for example, ester residues, such as methyl, ethyl, n-propyl, isopropyl, and the like.
lower alkyl ester residues such as n-, iso-, sec-, tert-butyl and n-hexyl ester; aralkyl ester residues such as benzyl, p-nitrobenzyl, o-nitrobenzyl and p-methoxybenzyl; acetoxymethyl , Propionyloxymethyl, n-, iso
And lower aliphatic acyloxymethyl residues such as-, butyryloxymethyl and pivaloyloxymethyl.

Hereinafter, the present invention will be described in accordance with each step of the schematic diagram.

(A) This step is a step of reacting the compound of the formula (III) with a base and a carboxylic acid activator (excluding carbonyldiimidazole) in an inert organic solvent.

Examples of the inert organic solvent used in this step include ether solvents such as ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as toluene, xylene and cyclohexane; halogenated hydrocarbon solvents such as dichloromethane and chloroform. Ethyl acetate; acetonitrile, etc., and acetonitrile is particularly preferably used.

As the base, for example, trimethylamine,
Tri (lower) alkylamines such as triethylamine and N, N-diisopropyl-N-ethylamine; for example, N, N-di (lower) alkylaminopyridines such as pyridine, picoline, lutidine, N, N-dimethylaminopyridine Pyridine compounds; quinolines; N- (lower) alkyl morpholines such as N-methylmorpholine; N, N-di (lower) alkylbenzylamines such as N, N-dimethylbenzylamine; Can be triethylamine, N, N-dimethylaminopyridine or the like. The amount of the base used varies depending on the type of the carboxylic acid activator used, but is usually about 0.03 per mole of the compound of the formula (III).
Suitably, it is used in a proportion of 5 to about 3 mol, preferably 0.08 to 2.2 mol.

As the carboxylic acid activator, those which are inexpensive as compared with carbonyldiimidazole and which can withstand long-term storage at room temperature are preferable. For example, chlorocarbonates such as methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate are preferable. An alkyl compound; diphenylphosphoryl chloride; methylsulfonyl chloride; thionyl chloride; trifluoroacetic anhydride; dicyclohexylcarbodiimide is used, and ethyl chlorocarbonate and isobutyl chlorocarbonate are particularly preferred. The amount of these carboxylic acid activators to be used is not critical and can be changed as appropriate, but is usually about 0.5 to about 3 mol, preferably 0.7 mol, per mol of the compound of the formula (III).
Suitably, it is used in a proportion of .about.1.5 mol.

The reaction is carried out by any of the following methods: (1) In an inert organic solvent, a base is added to the compound of the formula (III) and stirred, and then a carboxylic acid activator is added and further stirred. (2) A method of adding a base to a carboxylic acid activator in an inert organic solvent and stirring the mixture, then adding a compound of the formula (III) and further stirring the mixture; (3) In an inert organic solvent Adding a base to the compound of the formula (III) and stirring, adding the obtained reaction solution to a solution obtained by previously dissolving a carboxylic acid activator in an inert organic solvent, and further stirring. It can be done by performing.

The temperature at the time of addition and stirring varies depending on the type of the carboxylic acid activator to be used. However, when any of the above methods is used, it is generally a relatively low temperature of -78 ° C. to room temperature. Is preferred.

The reaction time varies depending on which of the above methods is used, but can usually be in the range of about 5 minutes to 4 hours.

Although not essential, the solvent used in this step is preferably anhydrous, and the stirring is desirably performed under an inert atmosphere, for example, a nitrogen gas or argon atmosphere.

(B) This step is a step of adding imidazole to the reaction solution obtained in the above step (a) and stirring the mixture.

The amount of imidazole added is not particularly limited and is generally used in a proportion of about 0.5 to about 3 mol, preferably 0.7 to 2.5 mol, per mol of the compound of the formula (III). Is appropriate.

The temperature at the time of addition and stirring varies depending on the type of the carboxylic acid activator, but it is usually preferable that the temperature is relatively low at about -78 ° C. to room temperature.

Under these conditions, stirring is generally from 5 minutes to
Can be performed for 2 hours.

This step is not essential, but is preferably performed in an inert atmosphere, for example, a nitrogen gas or argon gas atmosphere.

(C) This step is a step in which a magnesium malonate compound of the formula (II) is added to the reaction solution obtained in the above step (b) and reacted to obtain a compound of the formula (I).

The amount of magnesium malonate compound added is not critical and can be varied as appropriate, but is usually from about 0.5 to about 3 moles, preferably from 0.7 to 3 moles, per mole of compound of formula (III). Suitably a proportion of 2.5 moles.

The reaction temperature is not strictly limited, but is generally from about room temperature to about 100 ° C., preferably about 40 ° C.
C. to about 80C.

Under such conditions, the reaction is generally completed in about 30 minutes to 36 hours.

The magnesium malonate compound used in this reaction is represented by the following formula:

[0037]

HOCOCH ₂ COOR ³ wherein R ³ is as defined above, and is reacted with anhydrous magnesium chloride in the presence of a base in the above inert organic solvent. It can also be carried out by deriving the above-mentioned magnesium malonate compound, adding it to the reaction solution obtained in the step (b) without isolation, and reacting it under the same conditions as described above. In this case, the amount of the malonic acid half ester used is usually preferably about 2 molar equivalents of magnesium chloride, and the base used is preferably triethylamine.

The above reactions in this step are not essential,
It is desirable to carry out the reaction under an anhydrous condition in an inert atmosphere, for example, a nitrogen gas or argon gas atmosphere.

After completion of the reaction, the desired compound of formula (I) can be isolated by subjecting it to a treatment or purification procedure usually performed.

If the present invention is carried out according to the above steps,
The compound of the formula (I) can be produced easily and in good yield from the compound of the formula (III), and it is not necessary to use particularly expensive reagents such as carbonyldiimidazole. In this regard, the present invention relates to the above-described conventional production method (Heterocycles, vol. 21, p29 (198)
It can be said that the method is more suitable for industrial production than 4)).

Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited by these descriptions.

In the following description, the following abbreviations will be used.

PNB; p-nitrobenzyl

[0044]

【Example】

Example 1 Ethyl chlorocarbonate (1)

[0045]

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Compound (1) 1 g of anhydrous acetonitrile 1
0 ml solution in a nitrogen stream, triethylamine 0.46
Add ml and stir at room temperature for 5 minutes. To this solution, 360 mg of ethyl chlorocarbonate was added under ice-cooling, and the mixture was stirred for 10 minutes. Then, 271 mg of imidazole was added.
Stir for 0 minutes. On the other hand, 1.345 g of malonic acid mono-p-nitrobenzyl ester and anhydrous magnesium chloride 26
To a solution of 8 mg of anhydrous acetonitrile in 5 ml of anhydrous acetonitrile was added 0.78 ml of triethylamine in a stream of nitrogen under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. After adding this solution to the reaction solution obtained above, the mixture is stirred at 65 ° C. for 2 hours in a nitrogen stream. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 6.3 ml of ethyl acetate.
And then washed successively with a 20% aqueous sodium hydrogen carbonate solution and saturated saline. After the obtained solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 1.344 g of the target compound (2) as white crystals (yield 84. 8%).

¹ H-NMR (CDCl ₃ ) δ: 1.25
(3H, d), 1.30 (3H, d), 2.90 (2H,
m), 3.65 (2H, s), 3.83 (1H, m),
4.15 (1H, m), 5.27 (2H, s), 6.03
(1H, bs), 7.55, 8.27 (4H, aromatic ring proton) Example 2 Ethyl chlorocarbonate (2) Compound (1) 120.6 g of anhydrous acetonitrile 1.2 l
42.5 g of triethylamine is added to the solution in a nitrogen stream, and the mixture is stirred at room temperature for 10 minutes. To this solution was added 45.57 g of ethyl chlorocarbonate under ice-cooling, and the mixture was stirred for 10 minutes. Then, 32.68 g of imidazole was added, and the mixture was cooled to room temperature.
Stir for 0 minutes. On the other hand, malonic acid mono p-nitrobenzyl ester 162.7 g and anhydrous magnesium chloride 32.
A solution of 68.82 g of triethylamine in 61 ml of anhydrous acetonitrile was added to 38 g of anhydrous acetonitrile 609 ml of the solution in a nitrogen stream under ice cooling, and the mixture was returned to room temperature and stirred for 30 minutes. After adding this solution to the reaction solution obtained above, the mixture is stirred at 65 ° C. for 4 hours in a nitrogen stream. The obtained reaction solution was treated according to the method described in Example 1 to obtain 116.9 of the target compound (2) as white crystals.
8 g (61.2% yield) were obtained.

The NMR spectrum of this product was completely consistent with that obtained in Example 1.

Example 3 Ethyl chlorocarbonate (3) 26.04 g of ethyl chlorocarbonate anhydrous acetonitrile 4
The 57 ml solution was cooled to about -5 DEG C. and 26.31 g of triethylamine in 152 ml of anhydrous acetonitrile were added.
The solution is added dropwise over 52 minutes, and the mixture is further stirred at the same temperature for 30 minutes. 60.3 g of compound (1) is added to the obtained reaction solution at the same temperature in a stream of nitrogen, and the mixture is stirred for 30 minutes. Then, 19.07 g of imidazole is added, and the mixture is returned to room temperature and stirred for 30 minutes. On the other hand, 81.33 g of malonic acid mono-p-nitrobenzyl ester and anhydrous magnesium chloride 1
A solution of 34.41 g of triethylamine in 30.5 ml of anhydrous acetonitrile is added to a solution of 6.18 g of anhydrous acetonitrile in 457 ml of nitrogen under ice-cooling in a nitrogen stream, and the mixture is returned to room temperature and stirred for 30 minutes. After adding this solution to the reaction solution obtained above, the mixture is stirred at 65 ° C. for 3 hours in a nitrogen stream.
The resulting reaction solution was treated according to the method described in Example 1 to obtain the target compound (2) as white crystals.
3.08 g (86.8% yield) was obtained.

The NMR spectrum of this product completely coincided with that obtained in Example 1.

Example 4 Ethyl chlorocarbonate (4) Compound (1) 180.9 g of anhydrous acetonitrile 457
ml of triethylamine in a nitrogen stream at room temperature.
Add 8.94 g and stir for 20 minutes. The resulting reaction solution was cooled to −19 ° C. and ethyl chlorocarbonate was 78.12.
g in 1370 ml of anhydrous acetonitrile was added dropwise over 45 minutes and stirred at the same temperature for 30 minutes. 57.19 g of imidazole is added to the obtained reaction solution under ice cooling, and the mixture is stirred for 30 minutes while returning to room temperature. On the other hand, 244 g of malonic acid mono p-nitrobenzyl ester and 48.6 g of anhydrous magnesium chloride were added to 1370 m of anhydrous acetonitrile.
1 solution of triethylamine 10 under ice cooling in a nitrogen stream.
A solution of 3.2 g of 91 ml of anhydrous acetonitrile is added, and the mixture is returned to room temperature and stirred for 30 minutes. After adding this solution to the reaction solution obtained above, the mixture is stirred at 65 ° C. for 3 hours in a nitrogen stream. The resulting reaction solution was treated according to the method described in Example 1 to obtain 258.2 g (yield: 89.9%) of the target compound (2) as white crystals.

The NMR spectrum of the product completely matched the one obtained in Example 1.

Example 5 Ethyl chlorocarbonate (5) Compound (1) 361.8 g of anhydrous acetonitrile 915
ml of triethylamine in a nitrogen stream at room temperature.
Add 7.9 g and stir at room temperature for 20 minutes. The resulting reaction solution was cooled to −25 ° C. with ethyl chlorocarbonate 15
62 g of a solution of 6.2 g of anhydrous acetonitrile in 2740 ml
And the mixture is stirred at the same temperature for 35 minutes. At the same temperature, 114.4 g of imidazole is added to the resulting reaction solution, and the mixture is stirred for 30 minutes while returning to room temperature. On the other hand, 488 g of malonic acid mono-p-nitrobenzyl ester and 97 g of anhydrous magnesium chloride in anhydrous acetonitrile 274
To a 1 ml solution, triethylamine 2
A solution of 06.4 g of 183 ml of anhydrous acetonitrile was added, and the mixture was returned to room temperature and stirred for 1 hour. After adding this solution to the reaction solution obtained above, the mixture is stirred at 65 ° C. for 2.5 hours in a nitrogen stream. The target compound (2) was obtained by treating the obtained reaction solution according to the method described in Example 1.
Was obtained as white crystals (501.9 g, yield 87.4%).

The NMR spectrum of this product completely coincided with that obtained in Example 1.

Example 6 To a solution of 1 g of isobutyl chlorocarbonate compound (1) in 10 ml of anhydrous acetonitrile was added 0.46 ml of triethylamine in a nitrogen stream, and the mixture was stirred at room temperature for 5 minutes. After the solution was cooled to -30 ° C, 0.50 ml of isobutyl chlorocarbonate was added, and the mixture was stirred for 4 minutes under the same conditions. Then, imidazole 27
After adding 1 mg and stirring at −30 ° to −15 ° C. for 15 minutes, the mixture is returned to room temperature and further stirred for 15 minutes. On the other hand, a solution of 1.345 g of malonic acid mono-p-nitrobenzyl ester and 268 mg of anhydrous magnesium chloride in 5 ml of anhydrous acetonitrile was added with 0.1 ml of triethylamine in a stream of nitrogen under ice cooling.
After adding 78 ml, the mixture is returned to room temperature and stirred for 1 hour.
After adding this solution to the reaction solution obtained above, it is stirred at 65 ° C. for 2.5 hours in a nitrogen stream. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was 6.3 ml of ethyl acetate.
And washed successively with a 1N aqueous hydrochloric acid solution, a 5% aqueous sodium hydrogen carbonate solution and a saturated saline solution. After the obtained solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 1.379 g of the desired compound (2) as white crystals.
(86.9% yield).

The NMR spectrum of this product completely coincided with that obtained in Example 1.

Example 7 Dicyclohexylcarbodiimide compound (1) 500 mg and dimethylaminopyridine 2
After adding 376 mg of dicyclohexylcarbodiimide to a 5 mg solution of acetonitrile in a nitrogen stream under ice-cooling, the mixture is returned to room temperature and stirred for 15 minutes. 124 mg of imidazole is added to this solution and stirred for another hour.
On the other hand, malonic acid mono p-nitrobenzyl ester 674
To a solution of mg and 134 mg of anhydrous magnesium chloride in 2.5 ml of anhydrous acetonitrile was added 0.39 ml of triethylamine under ice-cooling in a nitrogen stream, and the mixture was returned to room temperature and stirred for 1 hour. After this solution is added to the reaction solution obtained above, the mixture is stirred at 60 ° C. for 2 hours in a nitrogen stream. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue obtained was dissolved in 3.2 ml of ethyl acetate, and the solution obtained by filtering off the insoluble matter was filtered to give a 1N aqueous solution of hydrochloric acid, a 5% aqueous solution of sodium hydrogen carbonate and Wash sequentially with saturated saline. After the obtained solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 573 mg of the target compound (2) as white crystals (yield: 72.2).
4%).

The NMR spectrum of this product was determined according to Example 1 above.
Completely matched with those obtained in. Example 8 A solution of 500 mg of the thionyl chloride compound (1) in 5 ml of anhydrous acetonitrile was cooled to -30 ° C, and 0.23 m of triethylamine was cooled.
and 0.17 ml of thionyl chloride are added, and the mixture is stirred at the same temperature for 20 minutes in a nitrogen stream. Then, 113 mg of imidazole and 0.23 ml of triethylamine are added, and the mixture is further stirred for 24 hours. On the other hand, 0.39 ml of triethylamine was added to a solution of 674 mg of malonic acid mono-p-nitrobenzyl ester and 134 mg of anhydrous magnesium chloride in 2.5 ml of anhydrous acetonitrile under ice-cooling in a nitrogen stream, and the mixture was returned to room temperature and stirred for 1 hour. After adding this solution to the reaction solution obtained above, the mixture is stirred at 60 ° C. for 2.5 hours in a nitrogen stream. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue obtained was dissolved in 3.2 ml of ethyl acetate, and washed successively with a 1N aqueous hydrochloric acid solution, a 5% aqueous sodium hydrogen carbonate solution and a saturated saline solution. After the obtained solution was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography to give 496 mg of the target compound (2) as white crystals (62.6% yield). )
Obtained.

The NMR spectrum of this product completely coincided with that obtained in Example 1.

Example 9 Methylsulfonyl chloride, diphenylphosphoryl chloride,
Aqueous trifluoroacetic acid The reaction was carried out using methylsulfonyl chloride, diphenylphosphoryl chloride and trifluoroacetic anhydride according to the method described in Example 4 above.
The target compound (2) was obtained at a yield of 1.3% and 38.0%.

Claims (2)

(57) [Claims] [Claim 1] The following formula: In the formula, R ¹ represents a protecting group for a hydroxyl group, the R ² represents a hydrogen atom or an amino protecting group, in the compounds represented, methyl chlorocarbonate, chlorocarbonate et
Chill, isobutyl chlorocarbonate, diphenyl phosphoryl chloride
, Methylsulfonyl chloride, thionyl chloride, anhydrous trif
From fluoroacetic acid and dicyclohexylcarbodiimide
Any one of the carboxylic acid activating agent selected from the group consisting, of a base and imidazole are reacted, then the following formula: 2] ^{_{Mg (O 2 CCH 2 CO 2}} R 3) in 2 (II) formula, ^{R 3} Represents a carboxy-protecting group, and is reacted with a magnesium malonate compound represented by the following formula (I): In the formula, R ¹ , R ² and R ³ are as defined above, A method for producing a 4-substituted propylazetidin-2-one derivative represented by: 2. The carboxylic acid activator is one of methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, diphenylphosphoryl chloride, methylsulfonyl chloride, thionyl chloride, trifluoroacetic anhydride, and dicyclohexylcarbodiimide. 2. The production method according to 1.