JPH0597864A - Production of 2-exomethylenepenam derivative - Google Patents

Abstract

PURPOSE:To easily obtain in high yield the title compound in high purity by reaction of an allenyl beta-lactam compound with a metallic reducing agent. CONSTITUTION:The objective compound can be obtained by reaction at -20 to 100 deg.C of (A) a compound of the formula (R<1> is H, halogen, amino, etc.; R<2> is H, halogen, lower alkoxy, lower acyl, etc., or, R<1> and R<2> are combined into =O; R<3> is H or carboxylic acid-protecting group; X is SO2R<4> or SR<4>; R<4> is aryl or nitrogen-contg. aromatic heterocycle) with (B) a metallic reducing agent (e.g. metallic lead, metallic titanium) in a solvent (e.g. N,N-dimethylformamide). It is preferable that a metal larger in ionization tendency than the metallic reducing agent be made to coexist in the reaction system (e.g. a combination: Pb/Al or Ti/Zn). The amount of the metallic reducing agent to be used is 1-10 molar times that of the compound of the formula.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a 2-exomethylene penum derivative.

[0002]

2. Description of the Related Art Conventionally, as a 2-exomethylene penam derivative represented by the general formula [Chemical Formula 2], only a compound in which R ¹ is an amino group or a protected amino group and R ² is a hydrogen atom is known. However, as a synthetic method thereof, J. Chem.
Soc., Chem. Only the method described in Commun., 81 (1987) is known. However, this method has a low yield and requires complicated reaction operations and separation operations everywhere in the reaction process, and is not a satisfactory practical method at all.

[0003]

[Chemical 2]

(In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group, or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group,
A lower alkyl group, a hydroxyl group, or a hydroxyl group having a protected hydroxyl group as a substituent, a hydroxyl group, or a protected hydroxyl group is shown. Further, R ¹ and R ² indicate = 0. R ³ represents a hydrogen atom or a carboxylic acid protecting group. )

[0005]

SUMMARY OF THE INVENTION The object of the present invention is to avoid the above-mentioned problems of the conventional method, to perform a safe and simple operation, and to be an industrially advantageous method with high yield and high purity. −
It is an object of the present invention to provide a method capable of producing an exomethylene penum derivative.

[0006]

According to the present invention, an allenyl β-lactam compound represented by the general formula [Chemical formula 1] is reacted with a metal reducing agent to give a 2-exo represented by the general formula [Chemical formula 2]. The present invention relates to a method for producing a 2-exomethylene penum derivative, which is characterized in that a methylene penam derivative is obtained.

[0007]

[Chemical 1]

(In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group, or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group,
A lower alkyl group, a hydroxyl group, or a hydroxyl group having a protected hydroxyl group as a substituent, a hydroxyl group, or a protected hydroxyl group is shown. Further, R ¹ and R ² indicate = 0. R ³ represents a hydrogen atom or a carboxylic acid protecting group. X is a group —SO ₂
Shows a R ⁴ or a group -SR ^4. R ⁴ represents an aryl group which may have a substituent or a nitrogen-containing aromatic heterocyclic group which may have a substituent. )

In the present invention, the allenyl β-lactam compound represented by the above-mentioned general formula [Chemical formula 1] used as a starting material is a novel compound which has not been published in the literature, and is represented by, for example, the general formula [Chemical formula 3]. It can be produced by reacting the azetidinone derivative with a base.

[0010]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ and X are the same as above.
R ⁵ represents a lower alkyl group which may have a substituent or an aryl group which may have a substituent. )

Each group shown in the present specification is specifically as follows. In the following description, unless otherwise specified, the halogen atom means, for example, fluorine, chlorine, bromine, iodine or the like. What is a lower alkyl group?
For example, it means a linear or branched C ₁ -C ₄ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. The aryl group means, for example, phenyl, naphthyl and the like.

Examples of the protected amino group represented by R ¹ include phenoxyacetamide, p-methylphenoxyacetamide, p-methoxyphenoxyacetamide, p-chlorophenoxyacetamide, p-bromophenoxyacetamide. , Phenylacetamide, p-methylphenylacetamide, p-methoxyphenylacetamide, p
-Chlorophenylacetamide, p-bromophenylacetamide, phenylmonochloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, phenylacetoxyacetamide, α-oxophenylacetamide, thienylacetamide, benzamide, p-methylbenzamide, p -T-butylbenzamide, p-methoxybenzamide, p-chlorobenzamide, p-bromobenzamide, or Theodora W. Gr
eene's "Protective Groupsin Organic Synthesi"
Chapter 7 of s "(hereinafter simply referred to as" references ") (p218-287)
Or a phenylglycylamide and a protected phenylglycylamide of an amino group, p-
Examples thereof include hydroxyphenylglycylamide and p-hydroxyphenylglycylamide in which an amino group, a hydroxyl group, or both are protected. Examples of the protecting group for the amino group of phenylglycylamide and p-hydroxyphenylglycylamide include the groups described in Chapter 7 (p218 to 287) of the above literature. Further, as the protective group for the hydroxyl group of p-hydroxyphenylglycylamide, the second group of the above-mentioned document is used.
The groups described in Chapter (p10 to 72) can be exemplified.

The lower alkoxy group represented by R ² includes, for example, straight chain or branched chain such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy. C _{1 to} C ₄
An alkoxy group can be exemplified.

The lower acyl group represented by R ² includes, for example, formyl, acetyl, propionyl, butyryl,
Examples thereof include linear or branched C _{1 to} C ₄ acyl groups such as isobutyryl.

As the protected hydroxyl group of a lower alkyl group having a hydroxyl group represented by R ² or a protected hydroxyl group as a substituent and the protected group of a protected hydroxyl group represented by R ² , see Chapter 2 of the above-mentioned document. Various groups described in (p10 to 72) can be exemplified. The substituted lower alkyl group represented by R ² is a substituent of the same or different type selected from a hydroxyl group or a protected hydroxyl group represented by the above, and one or more may be substituted on the same or different carbon. Good.

Examples of the carboxylic acid protecting group represented by R ³ include benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, diphenylmethyl group, trichloroethyl group and tert.
Examples thereof include a -butyl group and groups described in Chapter 5 (p152 to 192) of the above literature.

Examples of the nitrogen-containing aromatic heterocyclic group represented by R ⁴ which may have a substituent include, for example, thiazol-2-yl and thiadiazole-
Examples thereof include 2-yl, benzothiazol-2-yl, oxazol-2-yl, benzoxazol-2-yl, imidazol-2-yl, benzimidazol-2-yl, pyramidinyl and pyridyl groups.

The type of the substituent which may be substituted on the aryl group or the nitrogen-containing aromatic heterocyclic group represented by R ⁴ is 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, an alkylthio group or an arylthio group represented by the group R ⁶ S- (R ⁶ is a lower alkyl group or an aryl group), a formyloxy group, a group R An acyloxy group represented by ⁶ COO- (R ⁶ is the same as above), a formyl group, an acyl group represented by a group R ⁶ CO- (R ⁶ is the same as the above), and a group R ⁶ O- (R ⁶ is alkoxy group or an aryloxy group represented by the same) to the carboxyl group, alkoxycarbonyl group or represented by group R ⁶ OCO- (R ⁶ have the same meanings as defined above) is an aryloxy group It can be exemplified. The aryl group or nitrogen-containing aromatic heterocyclic group for R ⁴ is selected from the above substituents 1
It may be substituted with one or more substituents of the same or different type.

[0020] Examples of the lower alkyl group, or a substituted may have substituent aryl group represented by R ^5, the same substituents as those described in the substituents in R ⁴ can be exemplified. R
^One or more lower alkyl groups or aryl groups in ⁵ may be substituted on the same or different carbon with the same or different kinds of substituents selected from the above-mentioned substituents.

In the present invention, when the allenyl β-lactam compound represented by the general formula [Chemical formula 1] used as a starting material is produced, the azetidinone derivative represented by the general formula [Chemical formula 3] is used. React with base in a suitable solvent. The base used is preferably an aliphatic or aromatic amine. Specific examples thereof include triethylamine,
Diisopropylamine, ethyldiisopropylamine,
Tributylamine, DBN (1,5-diazabicyclo [4.3.
0] nonene-5), DBU (1,8-diazabicyclo [5.4.
0] undecene-7), DABCO (1,4-diazabicyclo [2.2.2] octane), piperidine, N-methylpiperidine, 2,2,6,6-tetramethylpiperidine, morpholine,
N-methylmorpholine, N, N-dimethylaniline, N,
N-dimethylamino pyridine etc. can be illustrated.

The amount of these bases to be used is generally 1 to 12 times mol, preferably 1 mol, based on the compound of the general formula [Chemical Formula 3].
Use ~ 6 times the molar amount. The solvent can be widely used as long as it dissolves the compound of the general formula [Chemical Formula 3] and is inactive under the reaction conditions, for example, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, Lower alkyl esters of lower carboxylic acids such as propyl acetate, butyl acetate, methyl propionate and ethyl propionate, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve,
Ethers such as dimethoxyethane, cyclic ethers such as tetrahydrofuran and dioxane, acetonitrile,
Propionitrile, butyronitrile, isobutyronitrile, nitriles such as valeronitrile, benzene, toluene, xylene, chlorobenzene, substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane, trichloroethane, Halogenated hydrocarbons such as dibromethane, propylene dichloride, carbon tetrachloride and freons, hydrocarbons such as pentane, hexane, heptane and octane, cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane, dimethylformamide , Dimethylacetamide and other amides, dimethylsulfoxide and the like, and these may be used alone or in admixture of two or more. Further, these solvents may contain water as needed. The amount of such a solvent used is about 0.5 to 200 liters, preferably about 1 to 50 liters per 1 kg of the compound of the general formula [Chemical Formula 3]. The reaction is -70 ℃ ~ 100 ℃,
It is preferably carried out in the range of -50 ° C to 50 ° C.

In the present invention, the allenyl β-lactam compound represented by the general formula [Chemical Formula 1] synthesized from the compound of the general formula [Chemical Formula 3] by the above-mentioned method is isolated by a conventional isolation operation such as extraction. Then, the reaction is carried out as it is with a metal reducing agent without any special purification operation,
It can also be converted into a 2-exomethylene penum derivative represented by.

The above reaction is usually carried out in a solvent. As the solvent, any conventionally known solvent can be widely used as long as it dissolves the compound of the general formula [Chemical Formula 1] and is inactive under the conditions of the reaction, for example, methanol, ethanol, propanol, isopropanol, butanol, tert. -Alcohols such as butanol, methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, lower alkyl esters of lower carboxylic acids such as ethyl propionate, acetone , Methyl ethyl ketone, methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone,
Ketones such as diethyl ketone, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane and other ethers, tetrahydrofuran, dioxane and other cyclic ethers, acetonitrile, propio Nitriles such as nitrile, butyronitrile, isobutyronitrile, valeronitrile, benzene, toluene, xylene, chlorobenzene,
Substituted or unsubstituted aromatic hydrocarbons such as anisole, dichloromethane, chloroform, dichloroethane,
Halogenated hydrocarbons such as trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride and freons, hydrocarbons such as pentane, hexane, heptane and octane, cycloalkanes such as cyclopentane, cyclohexane, cycloheptane and cyclooctane Amides such as dimethylformamide and dimethylacetamide,
Examples thereof include dimethyl sulfoxide, and these may be used alone or in combination of two or more. Further, these solvents may contain water as needed. The amount of such a solvent used is 0.5 per 1 kg of the compound of the general formula [Chemical formula 1].
Approximately 200 liters, preferably approximately 1 to 50 liters.

Examples of the metal reducing agent used in the above reaction include metal lead, metal titanium, metal zirconium, metal gallium, metal bismuth, metal antimony and the like. The shape of the metal to be reacted is not particularly limited, and a wide range of forms such as powder, plate, lump or wire can be used, but powder metal is advantageous for completing the reaction at a lower temperature in a shorter time. Used for. When a powdered metal is used as the metal reducing agent, its particle size can be selected from a wide range, but a particle size of about 10 to 500 mesh is preferably used. The amount of these metal reducing agents used is about 1 to 10 times mol atom, preferably about 1 to 4 times mol atom with respect to the compound of the general formula [Chemical Formula 1].

In the present invention, the amount of the metal reducing agent used can be extremely reduced by coexisting a metal having a greater ionization tendency than the metal reducing agent in the reaction system.
Post-treatment after the reaction becomes easy and the reaction can be performed at a lower temperature and in a shorter time. Specific examples of the combination of the above metal reducing agent and a metal having a greater ionization tendency than that include Pb / Al, Bi / Al, Ti / Zn, Ga / Zn,
Zr / Zn, Sb / Zn, Te / Zn, Pb / Zn, Bi / Zn,
Examples include Bi / Mg, Bi / Sn, Sb / Sn and the like. These metals can be used alone or in combination of two or more.
There is no particular limitation on the shape of these metals to be used, and a wide variety of shapes such as powder, plate, foil, lump or wire are used, but powder metal is advantageous for promoting the reaction more smoothly. Used. The particle size of the powdery metal can be selected from a wide range, but a particle size of about 10 to 300 mesh is preferably used. The amount of these metals used is usually about 1 to 50 times mol atom, preferably about 1 to 10 times mol atom to the compound of the general formula [Chem. 1].

When a metal having a greater ionization tendency than the above-mentioned metal reducing agent is used in the present invention, it is more preferable to use a compound of the metal instead of the above-mentioned metal reducing agent.

Specific examples of the above metal compounds include lead halides such as lead fluoride, lead chloride, lead bromide and lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, and the like. Inorganic lead such as lead phosphate, lead acetate such as lead acetate, lead oxalate, lead stearate, etc., lead oxide, lead hydroxide, titanium fluoride, titanium chloride, titanium bromide, titanium iodide, etc. Inorganic titanium oxides such as titanium sulfate and titanium nitrate, gallium halides such as gallium fluoride, gallium chloride, gallium bromide and gallium iodide, gallium sulfate such as gallium sulfate, gallium nitrate and gallium perchlorate, and fluorides zirconium,
Zirconium chloride, zirconium bromide, zirconium iodide, etc., zirconium halide, zirconium sulfate, tellurium bromide, tellurium chloride, tellurium iodide, etc. tellurium halide, bismuth fluoride, bismuth chloride, bismuth bromide, bismuth iodide, etc. Bismuth halide, bismuth nitrate, bismuth sulfate, etc., inorganic bismuth oxide, bismuth oxide, antimony fluoride, antimony bromide, antimony bromide, antimony iodide, etc., antimony halides, antimony sulfate, antimony oxide, antimony oxide, etc. Can be illustrated. The amount of these metal compounds to be used may theoretically be such that one molecule is present in the reaction system, but it is usually about 0.0001 to 2.0 times the molar amount of the compound of the general formula [Chemical Formula 1]. ..

The reaction temperature of the above reaction varies depending on the starting materials, the solvent used, etc. and cannot be generally stated, but it is usually -20 to
The temperature is about 100 ° C, preferably 0 to 50 ° C. In this reaction, if the reaction is carried out under the irradiation of ultrasonic waves, the reaction may proceed more quickly.

After completion of the above reaction, the desired 2-exomethylene penam derivative of the general formula [Chemical Formula 2] can be isolated in a substantially pure form by, for example, performing a conventional extraction operation. If further purification is required, conventional purification means such as recrystallization or column chromatography may be adopted.

[0031]

EXAMPLES The present invention will be further clarified with reference to the following Reference Examples and Examples. Incidentally, Ph represents a phenyl group.

Reference Example 1 Compound of the general formula [Chemical formula 4] → Compound of the general formula [Chemical formula 5]

[0033]

[Chemical 4]

[0034]

[Chemical 5]

Compound of the general formula [Chemical Formula 4] [R ¹ = phenylacetamide, R ² = H, R ³ = diphenylmethyl, X =
1 g of phenylsulfonyl, R ⁵ = trifluoromethyl] is dissolved in 10 ml of N, N-dimethylformamide. After cooling this to -30 ° C, 0.43 ml of triethylamine
Is added and stirred at -30 ° C for 1 hour to react. The reaction mixture was extracted with ethyl acetate, the extract was washed with water and dried over anhydrous sodium sulfate. When the extract is concentrated under reduced pressure, the compound of the general formula [Chemical Formula 5] [R ¹ , R ² , R ³ and X are the same as above] is obtained with a yield of 99%. NMR (CDCl ₃ ); δppm 3.61 (s, 2H), 5.31 (dd, 1H, J = 5Hz and 7
Hz), 5.57 and 5.70 (ABq, 2H, J = 15Hz), 5.8
4 (d, 1H, J = 5Hz), 6.02 (d, 1H, J = 7H
z), 6.81 (s, 1H), 7.22 to 7.73 (m, 20H)

Reference Examples 2-8 Using the starting compounds shown in Table 1, the same reaction as in Example 1 was carried out to obtain the compounds shown below. Compound of General Formula [Chemical Formula 3] → Compound of General Formula [Chemical Formula 1]

[0037]

[Table 1]

The NMR data will be summarized below. NMR (CDCl ₃ ); δppm

Compound (1b): 3.58 (s, 2H), 3.80
(S, 3H), 5.10 (s, 2H), 5.32 (dd, 1H, J
= 5Hz and 8Hz), 5.60and 5.47 (ABq, 2H, J
= 15Hz), 5.87 (d, 1H, J = 5Hz), 6.08 (d, 1
H, J = 8Hz), 6.85 to 7.83 (m, 14H)

Compound (1c): 3.59 (s, 2H), 3.74
(S, 3H), 5.33 (dd, 1H, J = 5Hz and 8Hz),
5.54 and 5.64 (ABq, 2H, J = 15Hz), 5.88 (d,
1H, J = 5Hz), 6.02 (d, 1H, J = 8Hz), 7.2
0 ~ 7.90 (m, 10H)

Compound (1d): 3.67 (s, 2H), 5.25
(Dd, 1H, J = 5Hz and 8Hz), 5.69 (d, 1H,
J = 5Hz), 5.60 and 5.76 (ABq, 2H, J = 15H)
z), 6.71 (s, 1H), 7.00 to 7.34 (m, 20H)

Compound (1e): 3.02 (dd, 1H, J = 2.6
Hz and 15.7Hz), 3.58 (dd, 1H, J = 5.4Hz and 1
5.7Hz), 3.79 (s, 3H), 5.17 (s, 2H), 5.47a
nd5.60 (ABq, 2H, J = 15.2Hz), 5.62 (dd, 1
H, J = 2.6Hz and 5.4Hz), 6.87 to 7.89 (m, 9H)

Compound (1f): 2.99 (dd, 1H, J = 2.6
Hz and 15.7Hz), 3.53 (dd, 1H, J = 5.5Hz and 1
5.7Hz), 5.56 (dd, 1H, J = 2.6Hz and 5.5Hz) 5.
54 and 5.66 (ABq, 2H, J = 15.2Hz), 6.88 (s,
1H), 7.29 ~ 7.76 (m, 15H)

Reference Examples 9 to 11 The same reaction as in Example 1 was carried out except that the reaction solvent and the reaction temperature were changed, and the compound of the general formula [Chemical Formula 5] was obtained in the yields shown in Table 2.

[0045]

[Table 2]

Example 1 Compound of general formula [Chemical formula 6] → compound of general formula [Chemical formula 7]

[0047]

[Chemical 6]

[0048]

[Chemical 7]

Compound of the general formula [Chemical Formula 6] [R ¹ = phenylacetamide, R ² = H, R ³ = p-methoxybenzyl,
X = phenylsulfonyl] (100 mg) was dissolved in 1 ml of N, N-dimethylformamide. To this, 50 mg of zinc powder was added, then 50 mg of BiCl ₃ was added, and the mixture was reacted at room temperature for 30 minutes with stirring. 1 to the reaction solution thus obtained
N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography to obtain a compound of the general formula [Chemical formula 7] [R ¹ = phenylacetamide, R ² = H, R ³ = p-methoxybenzyl] in a yield of 92%. Obtained in. NMR (CDCl ₃ ); δppm 3.61 (ABq, 2H, J = 16Hz), 3.80 (s, 3H),
5.11 (s, 2H), 5.18 (t, 1H, J = 1Hz), 5.2
4 (t, 1H, J = 1Hz), 5.35 (t, 1H, J = 1H)
z), 5.57 (d, 1H, J = 4Hz), 5.75 (dd, 1H,
J = 4Hz and 9Hz), 6.07 (d, 1H, J = 9H
z), 6.85 to 7.40 (m, 9H)

Example 2 Compound of general formula [Chemical formula 8] → compound of general formula [Chemical formula 9]

[0051]

[Chemical 8]

[0052]

[Chemical 9]

Compound of the general formula [Chemical formula 8] [R ¹ = phenylacetamide, R ² = H, R ³ = diphenylmethyl, X =
[Phenylenylsulfonyl] 200 mg as a starting material, and the same reaction as in Example 1 is performed below to obtain a compound of the general formula [Chem. 9] [R ¹ = phenylacetamide, R ² = H, R ³ = diphenylmethyl] in a yield. It was obtained in 89%. NMR (CDCl ₃ ); δppm 3.62 (s, 2H), 5.26 to 5.28 (m, 2H), 5.37
(T, 1H, J = 2Hz), 5.61 (d, 1H, J = 4Hz),
5.76 (dd, 1H, J = 4Hz and 9Hz), 6.14 (d,
1H, J = 9Hz), 6.82 (s, 1H), 7.20 to 7.41
(M, 15H)

Example 3 Compound of general formula [Chemical Formula 10] → compound of general formula [Chemical Formula 11]

[0055]

[Chemical 10]

[0056]

[Chemical 11]

50 mg of the compound of the general formula [Chemical Formula 10] [R ¹ = phenylacetamide, R ² = H, R ³ = methyl, X = phenylsulfonyl] was added to 0.5 m of N, N-dimethylformamide.
dissolve in 1. 50mg zinc powder and 10μl TiCl ₄
Was added and reacted at room temperature for 25 minutes with stirring. The same post-treatment as in Example 1 was carried out to obtain a compound of the general formula [Formula 11] [R ¹ = phenylacetamide, R ² = H, R ³ = methyl] in a yield of 95%. NMR (CDCl ₃ ); δppm 3.62 (ABq, 2H, J = 16Hz), 3.78 (s, 3H),
5.19 (t, 1H, J = 2Hz), 5.28 (t, 1H, J = 2)
Hz), 5.40 (t, 1H, J = 2Hz), 5.60 (d, 1H,
J = 4Hz), 5.77 (dd, 1H, J = 4Hz and 9H
z), 6.20 (d, 1H, J = 9Hz), 7.27 to 7.39 (m, 5
H)

Example 4 Compound of general formula [Chemical Formula 12] → compound of general formula [Chemical Formula 13]

[0059]

[Chemical formula 12]

[0060]

[Chemical 13]

The compound of the general formula [Chem. 12] [R ¹ = R ² =
Using 189 mg of H, R ³ = p-methoxybenzyl, X = phenylsulfonyl] as a starting material, the following reaction was carried out in the same manner as in Example 1 to obtain a compound of the general formula [Chemical Formula 13] [R ¹ = R ² = H,
R ³ = p-methoxybenzyl] was obtained in 88% yield. NMR (CDCl ₃ ); δppm 3.16 (dd, 1H, J = 1.5Hz and 16Hz), 3.66 (dd,
1H, J = 4Hz and 16Hz), 3.82 (s, 3H), 5.13
(S, 2H), 5.24 (dd, 1H, J = 1.8Hz and 1.8H
z), 5.28 (dd, 1H, J = 1.8Hz and 1.8Hz), 5.32
(Dd, 1H, J = 1.8Hz and 1.8Hz), 5.38 (dd, 1
H, J = 1.5Hz and 4Hz), 6.87 to 7.30 (m, 4H)

Example 5 Compound of general formula [Chemical Formula 14] → compound of general formula [Chemical Formula 15]

[0063]

[Chemical 14]

[0064]

[Chemical 15]

A compound of the general formula [Chemical Formula 14] [R ¹ = R ² =
H, R ³ = diphenylmethyl, X = phenylsulfonyl] 720 mg was used as a starting material, and a reaction was carried out in the same manner as in Example 1 below to give a compound of the general formula [C 15] [R ¹ = R ² = H,
R ³ = diphenylmethyl] was obtained with a yield of 86%. NMR (CDCl ₃ ); δppm 3.12 (dd, 1H, J = 1.5Hz and 16.0Hz), 3.60 (d
d, 1H, J = 4.1Hz and 16.0Hz), 5.23 (dd, 1H,
J = 1.8Hz and 1.8Hz), 5.32 (dd, 1H, J = 1.8Hz
and 1.8Hz), 5.36 (dd, 1H, J = 1.5Hz and 4.1H
z), 5.37 (dd, 1H, J = 1.8Hz and 1.8Hz), 6.87
(S, 1H), 7.27 to 7.35 (m, 10H)

Examples 6 to 11 The same reaction as in Example 1 was carried out except that the metal and the metal salt were changed, and the compound of the general formula [Chemical Formula 7] [R ¹ = phenylacetamide, R ² = H, R ³ = P-methoxybenzyl] was obtained. The results are shown in Table 3.

[0067]

[Table 3]

[0068]

INDUSTRIAL APPLICABILITY In the present invention, the desired general formula [Chemical formula 2]
The 2-exomethylene penum derivative represented by is produced by a simple operation, an industrially advantageous method, and a high yield and a high purity.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI technical display location // A61K 31/43 ADZ 7252-4C (72) Inventor Mitsuo Sasaoka Kagasuno Kawauchi, Tokushima City, Tokushima Prefecture 463 Otsuka Chemical Co., Ltd.Tokushima Research Institute (72) Inventor Takashi Shiroi Kagasuno, Tokushima City, Tokushima Prefecture 463 Otsuka Chemical Co., Ltd. Tokushima Research Institute (72) Inventor, Kameyama Toyo Kameyama 463 Oka, Kawauchi Town, Tokushima Prefecture Kagaku Co., Ltd. Tokushima Research Center

Claims (1)

[Claims] 1. An allenyl β-represented by the general formula:
A method for producing a 2-exomethylenepenum derivative, which comprises reacting a lactam compound with a metal reducing agent to obtain a 2-exomethylenepenum derivative represented by the general formula [Chemical Formula 2]. [Chemical 1] (In the formula, R ¹ represents a hydrogen atom, a halogen atom, an amino group, or a protected amino group. R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a lower acyl group, a lower alkyl group, a hydroxyl group, or a protected amino group. Represents a lower alkyl group having a hydroxyl group as a substituent, a hydroxyl group, or a protected hydroxyl group, R ¹ and R ² represent ═O, R ³ represents a hydrogen atom or a carboxylic acid protecting group, and X represents Group -SO ₂ R ⁴ or group -S
R ⁴ is shown. R ⁴ represents an aryl group which may have a substituent or a nitrogen-containing aromatic heterocyclic group which may have a substituent. ) [Chemical 2] (In the formula, R ¹ , R ² and R ³ are the same as above.)