JP3240422B2 - Method for producing β-lactam compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel process for producing a .beta.-lactam compound which is a raw material for .beta.-lactam antibiotics and .beta.-amino acids.

[0002]

2. Description of the Related Art Heretofore, many methods for synthesizing a β-lactam ring have been known, but no examples of synthesis by the method of the present invention are known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel technique capable of easily producing a β-lactam compound from an inexpensive allyl alcohol derivative in one step. The β-lactam compound produced by the method of the present invention is a useful intermediate which can open not only β-lactam antibiotics but also various β-amino acids by opening the lactam ring by hydrolysis. It is.

[0004]

According to the present invention, there is provided a compound represented by the general formula (1):

[0005]

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[Wherein R ¹ represents a lower alkyl group or an aryl group. R ² and R ³ represent a hydrogen atom or a lower alkyl group. R ⁴ represents a hydrogen atom, a lower alkyl group or a protected hydroxyl group. An allyl alcohol derivative represented by the general formula (2) in the presence of carbon monoxide gas and a palladium catalyst:

[0007]

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[Wherein R ⁵ is a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An aryl group which may be substituted, an aromatic heterocyclic group which may have a substituent, a benzoyl group which may have a substituent or a lower alkyloxycarbonyl group which may have a substituent. Show. R ⁶ represents a lower alkyl group which may have a substituent or an aryl group which may have a substituent. With an imine compound represented by the general formula (3)

[0009]

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Wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above. And a method for producing a β-lactam compound.

Each group shown in the present specification is specifically as follows. In the description of the present specification, unless otherwise specified, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like. A lower alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.
- means a straight or branched C ₁ -C ₄ alkyl group such as butyl group. Further, the aryl group is, for example, phenyl,
It means a naphthyl group or the like.

Examples of the protected hydroxyl group represented by R ⁴ include “Protective Group” by Theodora W. Greene.
s in Organic Synthesis ", Chapter 2 (p10-72).

[0013] lower alkyl group represented by R ^5, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, substituted lower alkyl groups and aryl groups represented by benzoyl group and a lower alkyloxycarbonyl group and R ⁶ Examples of the substituents which may be included include a halogen atom, a hydroxyl group, a nitro group, a cyano group, an aryl group, a lower alkyl group, an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a mercapto group, and a group R ⁷ An alkylthio group to an arylthio group represented by S- (R ⁷ is a lower alkyl group or an aryl group), a formyloxy group, a group R ⁷ CO
An acyloxy group represented by O- (R ⁷ is the same as described above), a formyl group, an acyl group represented by a group R ⁷ CO- (R ⁷ is the same as described above), a group R ⁷ O- (R ⁷ is the same )
In represented by an alkoxy group or an aryloxy group, a carboxyl group, an alkoxycarbonyl group or the group R ⁷ OCO- (R ⁷ is as defined above) represented by the exemplified such an aryloxycarbonyl group. In R ⁵ and R ^6, the lower alkyl group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, benzoyl group and lower alkyloxycarbonyl group are one or more of the same or different types selected from the above substituents. It may be substituted with a substituent.

In the present invention, the allyl alcohol derivative represented by the general formula (1) used as a starting material is, for example, a compound represented by the general formula (4)

[0015]

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Wherein R ² , R ³ and R ⁴ are as defined above. And a dialkyl chlorophosphate or a diaryl chlorophosphate in the presence of a base according to a conventional method.

The imine compound represented by the general formula (2) is, for example, an aldehyde represented by the general formula R ⁵ CHO (R ⁵ is the same as described above) and an aldehyde represented by the general formula R ⁶ NH ₂ (R
⁶ is the same as above. Can be easily synthesized by a dehydration reaction with the amine compound represented by the general formula (1).

In the present invention, the allyl alcohol derivative represented by the general formula (1) produced above is reacted with an imine compound represented by the general formula (2) in the presence of carbon monoxide gas, a palladium catalyst and a base. By doing so, a β-lactam compound represented by the general formula (3) is produced.

The palladium catalyst used in this reaction is not particularly limited, and may be divalent or zero-valent, and may be used alone or in the form of a complex. These palladium catalysts may be used in the form of a salt or in combination with a suitable ligand. Examples of the salt include a chlorinated product, a brominated product, an iodide product, a complex salt, a sulfate, a perchlorate, an acetylacetone salt or a phosphine complex, an acetonitrile complex, a benzonitrile complex, and a phenylacetonitrile complex thereof. Examples of the zero-valent complex include tetrakis (triphenylphosphine) palladium, tetrakis (tri-2-furylphosphine) palladium,
Tetrakis (tri-2-thienylphosphine) palladium, tris (dibenzylideneacetonyl) bispalladium, tris (dibenzylideneacetone) dipalladium,
Tris (dibenzylideneacetone) dipalladium chloroform, bis (dibenzylideneacetone) palladium,
Examples thereof include bis (dibenzylideneacetone) palladium chloroform, tris (tribenzylideneacetylacetone) dipalladium, and tris (tribenzylideneacetylacetone) dipalladium chloroform. The amount of the palladium catalyst used is not particularly limited, but is usually 0.1 to 0.1 with respect to the compound of the general formula (1).
It is good to use 001 to 1 times mole, preferably 0.01 to 0.5 times mole. Examples of the ligand used together with the divalent complex and the zero-valent complex include ordinary trimethylphosphine, triethylphosphine, tri-n-propylphosphine,
Tri-iso-propylphosphine, tri-n-butylphosphine, dimethylphenylphosphine, diethylphenylphosphine, di-n-propylphenylphosphine, di-iso-propylphenylphosphine, di-n
-Butylphenylphosphine, triphenylphosphine, tri (ortho-tolyl) phosphine, tri (para-
Tolyl) phosphine, tri (para-methoxyphenyl)
Phosphine, tricyclopentylphosphine, tricyclohexylphosphine, tri-2-furylphosphine,
Monodentate ligands such as tri-2-thienylphosphine, 1,2
-Bis-diphenylphosphinoethane, 1,3-bis-
Phosphines such as bidentate ligands such as diphenylhephosphinopropane, 1,4-bis-diphenylphosphinobutan, and diphenylphosphinoferrocene; trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, triphenyl phosphite And the like. These ligands may be used in amounts that stabilize the catalyst, and are usually used in an amount of 1 to 10 equivalents to the catalyst. The catalyst may be supported, and 5% -palladium / carbon, 10% -palladium / carbon, etc., which are well known as hydrogenation catalysts, may be used.

Examples of the base used in this reaction include an inorganic base, an aliphatic amine, an aromatic amine and the like. Specific examples of the inorganic base include potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate and the like. Specific examples of the aliphatic amine and the aromatic amine include triethylamine, diisopropylamine, ethyldiisopropylamine, tributylamine, dicyclohexylmethylamine, 1,5-diazabicyclo [4.
3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU), 1,4-
Diazabicyclo [2.2.2] octane (Dabco), piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, 2,4,6-collidine, morpholine, N-methylmorpholine, N, N -Dimethylaniline, pyridine, N, N-dimethylaminopyridine and the like. The amount of these bases used is represented by the general formula (2)
Usually 1 to 10 equivalents to the imine compound represented by
Preferably, 1 to 5 equivalents are used.

As the organic solvent used in the present reaction, a conventional solvent can be used as long as it dissolves the allyl alcohol derivative represented by the general formula (1) and the imine compound represented by the general formula (2) and is inert to the reaction. Known ones can be widely used, for example, methyl formate, ethyl formate, propyl formate,
Butyl formate, methyl acetate, ethyl acetate, propyl acetate,
Lower alkyl esters of lower carboxylic acids such as butyl acetate, methyl propionate and ethyl propionate, and ethers such as diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve and dimethoxyethane , Tetrahydrofuran, cyclic ethers such as dioxane, etc., nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and substituted or unsubstituted aromatic carbons such as benzene, toluene, xylene, chlorobenzene, and anisole Hydrogens, dichloromethane, chloroform, dichloroethane, propylene dichloride, halogenated hydrocarbons such as carbon tetrachloride, pentane, hexane,
Hydrocarbons such as heptane and octane, cyclopentane,
Cycloalkanes such as cyclohexane, cycloheptane and cycloocta; amides such as dimethylformamide and dimethylacetamide; and dimethylsulfoxide. These solvents are used alone or in combination of two or more. The amount of the solvent to be used is about 0.5 to 200 liters, preferably about 1 to 50 liters per 1 kg of the compound of the general formula (1).

The reaction of the present invention can be carried out under cooling, at room temperature or under heating.
Preferably, it is performed in the range of 0 to 100 ° C.

This reaction is carried out in the presence of carbon monoxide gas, and is usually 1 to 200 kg / cm ² , preferably 1 to 200 kg / cm ² .
The reaction is preferably carried out under a pressure of about 70 kg / cm ² .

The thus-prepared compound of the general formula (3) can be obtained as a substantially pure product by carrying out a usual extraction operation or crystallization operation after completion of the reaction, but of course, it can be purified by other methods. be able to.

[0025]

According to the present invention, a β-lactam compound can be easily produced in one step from an inexpensive allyl alcohol derivative.

[0026]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the invention.

Reference Example 1 Allyl alcohol (0.68 ml) and pyridine (0.
81 ml) of a methylene chloride solution (5 ml) was cooled to 0 ° C., and diethyl chlorophosphate (1.45 m) was added thereto.
Add l). The reaction is carried out by stirring the reaction mixture at room temperature for 15 hours. After completion of the reaction, the reaction mixture is transferred to water and extracted three times with ethyl acetate. After the extract is washed with saturated saline, the solvent is distilled off under reduced pressure. When the obtained concentrated residue is purified by column chromatography, 1.0 g (yield 52%) of allyl diethyl phosphate is obtained.

Reference Example 2 p-Anisidine (1.23 g) and phenylglyoxal monohydrate (1.52 g) were added to methylene chloride (15 m
1) and added to molecular sieve 4A (567)
mg) and p-toluenesulfonic acid (3 mg). The mixture is stirred at room temperature for 15 hours to carry out the reaction. After completion of the reaction, the molecular sieve 4A is filtered off through a celite layer. The filtrate is poured into a saturated aqueous solution of sodium bicarbonate and extracted three times with ethyl acetate. The extracts are combined, washed with a saturated saline solution, dried over sodium sulfate, and then concentrated to obtain the desired imine compound almost quantitatively.

Example 1 Tetrahydrofuran (5 ml), allyl diethyl phosphate (86.1 mg) and the imine synthesized in Reference Example 2 (71.7 mg) were added to an autoclave and dissolved. To this, add dicyclohexylmethylamine (0.127m
l), tris (dibenzylideneacetone) dipalladium chloroform (9.2 mg) and triphenylphosphine (9.5 mg) were added, and the tube was sealed.
Pressurize to a pressure of 0 kg / cm ² . The reaction is performed at room temperature for 5 hours under the pressurized condition of carbon monoxide gas. After completion of the reaction, the reaction mixture is transferred into water and extracted three times with ethyl acetate. After the extract is washed with a saturated saline solution, the solvent is distilled off under reduced pressure to obtain a crude product. The resulting crude product is
After purification by column chromatography, (3,
4-cis) -1-p-methoxyphenyl-3-vinyl-
4-benzoyl-2-azetidinone (hereinafter referred to as “compound (3
a) ") in an amount of 53.8 mg (58% yield).

IR (neat): 1688 (C = C), 1
748,1770 (β-lactam CO) cm ^-1 Example 2 Dicyclohexylmethylamine of Example 1 was replaced with diisopropylethylamine, and carbon monoxide gas was 10 kg / cm ^2.
Example 1 was conducted except that the reaction was carried out at room temperature under pressure for 5 hours.
When the reaction is carried out under the same conditions as described above, compound (3a) is obtained in a yield of 54%.

Example 3 When the reaction is carried out under the same conditions as in Example 1 except that the solvent is changed from tetrahydrofuran to benzene, compound (3a) is obtained in a yield of 38%.

Example 4 The reaction was conducted in the same manner as in Example 1 except that the ligand was changed from triphenylphosphine to tri (ortho-tolyl) phosphine.
Is obtained in a yield of 31%.

Example 5 When the reaction was carried out under the same conditions as in Example 1 except that the ligand was changed from triphenylphosphine to tri (para-methoxyphenyl) phosphine, compound (3a) was obtained. Obtained at a rate of 36%.

Example 6 The reaction was carried out under the same conditions as in Example 1 except that the ligand was changed from triphenylphosphine to 1,2-bis-diphenylphosphinoethane, whereby the compound (3a) was obtained. Is obtained in a yield of 20%.

Example 7 The reaction was carried out under the same conditions as in Example 1 except that the palladium catalyst was changed from tris (dibenzylideneacetone) dipalladium chloroform to palladium acetate. Obtained at 49%.

Example 8 The reaction was carried out under the same conditions as in Example 1 except that the base was changed from dicyclohexylmethylamine to 2,4,6-collidine, whereby the compound (3a) was obtained in a yield of 2
Obtained at 9%.

Example 9 Example 1 was repeated except that the base was changed from dicyclohexylmethylamine to tri-n-butylamine.
When the reaction is carried out under the same conditions as described above, compound (3a) is obtained in a yield of 29%.

Example 10 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-trans) -1-n-propyl-3-vinyl-4-
Phenyl-2-azetinone (hereinafter, referred to as “compound (3b)”) is obtained with a yield of 72%.

IR (neat): 1638 (C = C), 1
756 (β-lactam CO) cm ^-1 Example 11 A reaction was carried out under the same conditions as in Example 10 except that the allyl alcohol derivative was changed from allyl diethyl phosphate to triallyl phosphate.
Compound (3b) is obtained in a yield of 33%.

Example 12 The reaction was carried out under the same conditions as in Example 10 except that the allyl alcohol derivative was changed from allyl diethyl phosphate to allyl diphenyl phosphate. The compound (3b) was obtained in a yield of 48%. Can be

Example 13 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-Trans) -1-benzyl-3-vinyl-4-phenyl-2-azetidinone is obtained with a yield of 73%.

IR (neat): 1638 (C = C), 1
748 (β-lactam CO) cm ⁻¹ Example 14 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-Trans) -1-benzyl-3-vinyl-4-furfuryl-2-azetidinone is obtained in a yield of 86%.

IR (neat): 1640 (C = C), 1
744 (β-lactam CO) cm ^-1 Example 15 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-Trans) -1-benzyloxycarbonylmethyl-3-vinyl-4-furfuryl-2-azetidinone is obtained in a yield of 47%.

IR (neat): 1640 (C = C), 1
744,1770 (β-lactam CO) cm ⁻¹ Example 16 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-trans) -1-benzyl-3-vinyl-4-α-
Methylstyryl-2-azetidinone is obtained in a yield of 47%.

IR (neat): 1638 (C = C), 1
744 (β-lactam CO) cm ⁻¹ Example 17 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-Trans) -1-benzyloxycarbonylmethyl-3-vinyl-4-α-methylstyryl-2-azetidinone is obtained in a yield of 61%.

IR (neat): 1640 (C = C), 1
746, 1760 (β-lactam CO) cm ⁻¹ Example 18 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-cis) -1-p-anisyl-3-vinyl-4-methoxycarbonyl-2-azetidinone is obtained in a yield of 11%.

IR (neat): 1640 (C = C), 1
725, 1752 (β-lactam CO) cm ⁻¹ Example 19 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-cis) -1-n-propyl-3-vinyl-4-benzoyl-2-azetidinone is obtained in a yield of 50%.

IR (neat): 1690 (C = C), 1
748,1760 (β-lactam CO) cm ^-1 Example 20 (3,4-cis) -1-
(Β, β-Dimethoxyethyl) -3-vinyl-4-benzoyl-2-azetidinone is obtained with a yield of 63%.

IR (neat): 1690 (C = C), 1
748,1765 (β-lactam CO) cm ^-1 Example 21 (3,4-cis) -1-p-
Methoxyphenyl-3-α-methylvinyl-4-benzoyl-2-azetidinone is obtained in a yield of 38%.

IR (neat): 1688 (C = C), 1
740,1760 (β-lactam CO) cm ⁻¹ Example 22 The reaction was carried out under the same conditions as in Example 1 except that the reaction temperature was changed from room temperature to 70 ° C.
4-Trans) -1-benzyl-3-α-methylvinyl-4-furfuryl-2-azetidinone is obtained in 98% yield.

IR (neat): 1649 (C = C), 1
744 (β-lactam CO) cm ⁻¹

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Michio Sasaoka 463 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture Inside the Tokushima Research Laboratory, Otsuka Chemical Co., Ltd. Inside Tokushima Research Laboratories Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 205/08 C07D 405/06 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula (1) [In the formula, R ¹ represents a lower alkyl group or an aryl group. R
² and R ³ represent a hydrogen atom or a lower alkyl group. R ⁴
Represents a hydrogen atom, a lower alkyl group or a protected hydroxyl group. An allyl alcohol derivative represented by the general formula (2) in the presence of carbon monoxide gas and a palladium catalyst: Wherein R ⁵ is a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An aryl group which may be substituted, an aromatic heterocyclic group which may have a substituent, a benzoyl group which may have a substituent, and a lower alkyloxycarbonyl group which may have a substituent. R ⁶ represents a lower alkyl group which may have a substituent or an aryl group which may have a substituent. ]
By reacting with an imine compound represented by the general formula (3): Wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above. ] A method for producing a β-lactam compound, characterized by obtaining a β-lactam compound represented by the formula: 2. The process for producing a β-lactam compound according to claim 1, wherein the reaction is carried out in the presence of a base.