JP3459134B2 - Method for producing exomethylene penum compound - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention
Compounds are used, for example, in the synthesis of β-lactamase inhibitors.
An important intermediate (Bawldwin, et al., J. Che.
m. Soc., Chem. Commun., 1987, 81; To
rii, et al., Antibit. Chem Lett., 1993,
3,2253). 2. Description of the Related Art Conventionally, the present invention is represented by the general formula (2).
The method for producing exomethylene penum compounds
Pena derived from penicillin as shown in (A)
Decarboxylation of 2-carboxylic acid by Poomerer type transfer reaction
A known synthesis method is known (Bawldwin, et al., JC
hem. Soc., Chem. Commun., 1987, 81)
In this method, the reaction process is as long as 8 steps and the overall yield is high.
6% or less, not a very practical method
No. [0003] Further, as shown in FIG.
Hydrolysis of allenyl β-lactam compound obtained from
A synthesis method by dissolution followed by intramolecular cyclization (S. Torii, et.
al., Tetrahedron Lett., 1991, 32, 74.
45) Reductive cyclization of allenyl β-lactam compounds
(S. Torii, et al., Synlett, 19)
92,878; Torii, et al., Chemistry Ex
press, 1992, 7, 885, J. Am. Chem. Soc., Ch
em. Commun., 1992, 1793) is known.
Is an unstable allene compound as an intermediate in each case
Reaction on an industrial scale,
There are various problems such as complicated work. [0005] SUMMARY OF THE INVENTION The object of the present invention is to
The halogenated β-lactam compound represented by the formula (1)
A new metal reduction system and a new electrolytic reduction system
Allenization, exomethylenepe
Simultaneously and efficiently perform the naming, and represented by the general formula (2)
Exomethylene penum compound by simple operation
To provide a method that can be produced with high yield and high purity
It is in. [0007] The present invention provides a compound represented by the general formula (1):
Standard oxidation-reduction of the represented halogenated β-lactam compound
At least one of the metals having a potential of -0.3 (V / SCE) or less
Has an equimolar amount and a higher standard redox potential than the metal
0.0001 to 10 times the molar amount of the metal compound
Or by using the electrolytic reduction method, the general formula
To obtain the exomethylene penum compound represented by (2).
A method for producing an exomethylene penum compound characterized by
Related. [0008] [Where R ¹ Is a hydrogen atom, amino group or protected amino
Represents a group. R ^Two Is hydrogen atom, halogen atom, lower alcohol
A xy group, a lower acyl group, or a hydroxyl group as a substituent
Represents a lower alkyl group having a protected hydroxyl group. R
^Three Represents a hydrogen atom or a carboxylic acid protecting group. R ^Four Is a substituent
Represents an aryl group which may have X is a halogen source
And Y represents a halogen atom or a leaving group. n is 0-2
Is shown. [0009] [Where R ¹ , R ^Two And R ^Three Is the same as above. Each group shown in the present specification is
Physically, each is as follows. R ¹ Protection indicated by
Protected group in
Organic Synthesis (Protrusive Groups in Or)
ganic Synthesis, Theodora W. By Greene, 198
One year, hereinafter simply referred to as “literature”, Chapter 7 (218-
287), phenoxy
Acetamide, p-methylphenoxyacetamide, p
-Methoxyphenoxyacetamide, p-chloropheno
Xyacetamide, p-bromophenoxyacetamide
Phenylacetamide, p-methylphenylacetamide
Amide, p-methoxyphenylacetamide, p-chloro
Rophenylacetamide, p-bromophenylacetoa
Mid, phenylmonochloroacetamide, phenyldic
Loroacetamide, phenylhydroxyacetamide,
Thienylacetamide, phenylacetoxyacetamide
, Α-oxophenylacetamide, benzamide,
p-methylbenzamide, p-methoxybenzamide,
p-chlorobenzamide, p-bromobenzamide,
Phenylglycylamide or amino-protected phenyl
Glycylamido, p-hydroxyphenylglycylamido
P or one or both of amino and hydroxyl groups are protected
Amides such as hydroxyphenylglycylamide;
Examples of imides such as talimide and nitrophthalimide
Wear. Phenylglycylamide and p-hydroxyphen
Examples of the amino-protecting group for nylglycylamido include
It is described in Chapter 7 of the literature (pp. 218-287)
Various groups can be exemplified. In addition, p-hydroxyphenylg
Examples of the protecting group for the hydroxyl group of lysylamide include those described in
Examples of various groups described in Chapter 2 (pages 10 to 72)
it can. R ^Two The halogen atom represented by, for example,
Atoms such as fluorine, chlorine, bromine and iodine
it can. R ^Two Examples of the lower alkoxy group represented by
For example, methoxy, ethoxy, n-propoxy, isopro
Poxy, n-butoxy, isobutoxy, sec-butoxy
Linear or branched C such as tert-butoxy ₁ ~ C _Four of
An alkoxy group can be exemplified. R ^Two Lower acyl represented by
Examples of the group include, for example, formyl, acetyl, propioni
Linear or branched C such as butyl, butyryl, isobutyryl, etc.
₁ ~ C _Four Can be exemplified. R ^Two A hydroxyl group or a protected hydroxyl represented by
Protected water of a lower alkyl group having a substituent as a substituent
An acid group, and R ^Two A protected hydroxyl-protecting group represented by
Are described in Chapter 2 (pages 10 to 72) of the above document.
Examples of the group include: R ^Two The substitution low indicated by
The lower alkyl group may be a hydroxyl group or a protected group shown above.
The same or different types of substituents selected from hydroxyl groups
Even if it is substituted one or more times on the same or different carbons
Good. As the lower alkyl group, for example, methyl, ethyl
, N-propyl, isopropyl, n-butyl, isobu
Straight chain such as chill, sec-butyl, tert-butyl, etc.
Or branched C ₁ ~ C _Four And the alkyl group of
You. R ^Three As a protecting group for the carboxylic acid represented by
Is shown in Chapter 5 of the above document (pp. 152-192).
Allyl groups, benzyl groups, p-methoxy,
Cibenzyl group, p-nitrobenzyl group, diphenylmethyl
, A trichloromethyl group, a tert-butyl group, etc.
Wear. R ^Four May have a substituent represented by
Aryl groups include phenyl, naphthyl, nitrogen-containing
Examples include a heterocyclic group. Types of nitrogen-containing heterocyclic groups and
Benzothiazole, triazole, thiazo
And a tetrazole group. These ants
Examples of the types of substituents that may be substituted with
Halogen atom (for example, fluorine, chlorine, bromine, iodine
Etc.), C ₁ ~ C _Four Linear or branched alkoxy group
(For example, methoxy group, ethoxy group, etc.), C ₁ ~ C _Four Straight chain
Alternatively, a branched alkylthio group (eg, methylthio
Group, ethylthio group, etc.), C ₁ ~ C _Four Straight or branched chain of
Alkylsulfonyloxy group (for example, methanesulfonyl
Ruoxy group, trifluoromethanesulfonyloxy group
Etc.), an aromatic sulfonyloxy group which may have a substituent
(For example, benzenesulfonyloxy group, toluenesulfo
Nyloxy group, etc.), C ₁ ~ C _Four Straight or branched chain
Alkyl group (for example, methyl group, ethyl group, etc.), amino group,
C as a substituent ₁ ~ C _Four Linear or branched alkyl of
An amino group having one or two groups (eg, methylamino
Group, dimethylamino group, ethylamino group, diethylamino
A hydroxyl group, R'COO- (R 'is a phenyl group,
Ryl group or C ₁ ~ C _Four Linear or branched alkyl of
Group) represented by an acyloxy group (for example, phenylcarbo)
Nyloxy group, acetyloxy group, etc.), R'CO- (R '
Is the same as above) (for example, phenyl
Carbonyl, acetyl, etc.), nitro, cyano,
And phenyl group. These substituents are represented by Ar.
When the aryl to be substituted is a phenyl group, 1 to 5, especially
1 to 3 aryl groups represented by Ar are naphthyl
In case 1-7, especially 1-3, same or different type
It may be substituted. The halogen atom represented by X and Y is
Examples include nitrogen, chlorine, bromine, and iodine. Indicated by Y
The leaving group may be a lower alkylsulfur which may have a substituent.
Honyloxy group (for example, methanesulfonyloxy group,
Trifluoromethanesulfonyloxy group, trichlorometa
Sulfonyloxy group), aromatic sulfonyloxy group
(For example, benzenesulfonyloxy group, toluenesulfo
Nyloxy group, etc.), halogenated sulfonyloxy group (eg,
For example, fluoromethanesulfonyloxy group), lower alkyl
Killphosphonyloxy group (for example, trimethyloxy group,
Triethyloxy group, tributylphosphonyloxy group
Etc.), aromatic phosphonyloxy group (for example, triphenyl
Phosphonyloxy group, tolylphosphonyloxy group
Etc.) can be exemplified. The starting material of the present application is represented by the general formula (1).
The halogenated β-lactam compound is, for example,
It can be manufactured by the following method. That is, the document is known
(S. Torii et. Al., Chemistry Lett., 199
0,1867), β-lacta represented by the general formula (3)
A compound having an optionally substituted sulfo group in an inert solvent.
With acid anhydride or sulfonic acid halide and organic base
To produce phosphorus halide compounds
By using the compound, the desired compound can be obtained. Embedded image [Where R ¹ , R ^Two , R ^Three , R ^Four And n are the same as above. Specifically, this reaction is carried out in a suitable solvent.
Be done. Examples of usable solvents include, for example, methyl formate.
, Ethyl formate, propyl formate, butyl formate, methyl acetate
, Ethyl acetate, propyl acetate, butyl acetate, propio
Of lower carboxylic acids such as methyl phosphate and ethyl propionate
Lower alkyl esters, acetone, methyl ethyl keto
, Methyl propyl ketone, methyl butyl ketone, methyl
Ketones such as isobutyl ketone and diethyl ketone;
Ethyl ether, ethyl propyl ether, ethyl butyl
Diether, dipropyl ether, diisopropyl ether
Ter, dibutyl ether, methyl cellosylbu, dimethy
Ethers such as cyetane, tetrahydrofuran, diox
Cyclic ethers such as sun and dioxolan, acetonitrile
, Propionitrile, butyronitrile, isobutyroni
Nitriles such as tolyl and valeronitrile, benzene,
Placement of ruene, xylene, chlorobenzene, anisole, etc.
Substituted or unsubstituted aromatic hydrocarbons, dichlorometa
, Chloroform, dichloroethane, trichloroethane
, Dibromoethane, propylene dichloride, tetrachloride
Carbon, halogenated hydrocarbons such as fluorocarbons, pentane,
Aliphatic hydrocarbons such as hexane, heptane, and octane;
Cyclopentane, cyclohexane, cycloheptane,
Cycloalkanes such as crooctane, dimethylforma
Amide, diethylformamide, dimethylacetamide, etc.
Amides and cyclic amides such as N-methylpyrrolidinone
And dimethyl sulfoxide. This
These are used alone or in combination of two or more. Ma
These organic solvents contain water as necessary.
May be. These solvents are compounds 1 of the general formula (3)
Usually about 10 to 200 liters per kg, preferably
It is preferable to use about 20 to 100 liters. Above
The reaction temperature is usually about -78 to 60 ° C, preferably
~ -40 to 30 ° C. As the type of base used
Means trimethylamine, dimethylethylamine,
N, N, such as tylamine and diisopropyloxyethylamine
N-tri-lower alkylamines, N-methylpiperidi
N-lower alkyl seals such as N-ethyl N-ethylpiperidine
Chloalkanes, N-methylmorpholine, N-ethylmo
N-lower alkyl azaoxy cycloalkals such as ruphorin
, N-benzyl-N, N-dimethylamine, N-benzyl
N-phenyl lower such as benzyl-N, N-diethylamine
Alkyl-N, N-di-lower alkylamines, N, N-di
N, N-dialkyl aromatic amines such as methylaniline
Or nitrogen-containing aromatic amines such as pyridine, diazabicyclo
Bicyclic amines such as undecene and diazabicyclononene and
And mixtures thereof. Base in the above reaction
Is usually used as β-la represented by the general formula (3).
1 to 10 equivalents to the octamate compound, but if necessary
For example, there is a β-lactam compound represented by the general formula (3).
It is advisable to add more bases until they are no longer needed. General formula obtained
The halogenated β-lactam compound represented by (1) is usually
Can be used for the next reaction.
Can also be. The thus obtained general formula (1)
Standard for halogen atom of halogenated β-lactam compound
Only a small amount of metals having an oxidation-reduction potential of -0.3 (V / SCE) or less
Standard redox at least equimolar and higher than the metal
0.0001 to 10-fold molar amount of metal compound having potential
And the electrolytic reduction method in an organic solvent
Exometyl represented by the general formula (2)
It can be converted to an impenam compound. In the above reaction of the present invention, as shown below,
An allene intermediate is formed as an intermediate, followed by
S-SOnR ^Four Of the general formula (2)
It is thought to be producing a methylenepenam derivative
You. Embedded image The standard oxidation-reduction potential is -0.3 (V / SC)
E) The following metals include, for example, magnesium, aluminum
Examples of these include nickel, zinc, iron, nickel, tin, and lead.
Uses magnesium, aluminum, zinc, tin
Preferably. There are no particular restrictions on the shape of these metals.
Suitable for a wide range of powder, plate, foil, lump, needle, etc.
It can be selected as desired, but more preferably powdered metal or foil gold
It is better to use a genus. Particle size of powdered metal is wide range
From about 100 to 300 mesh
It is desirable to use one. The amount of these metals used is
Usually about 1 to 50 times the molar amount of the compound of the general formula (1)
The amount is preferably about 1 to 10 times the molar amount. Has a higher standard oxidation-reduction potential than the above metals.
The metal compound to be used is a lead compound (eg, lead fluoride, salt, etc.).
Lead halides such as lead iodide, lead bromide and lead iodide, lead nitrate, sulfuric acid
Inorganic salts such as lead acid, lead perchlorate, lead borate, lead carbonate and lead phosphate
Fatty acids such as lead, lead acetate, lead oxalate, lead stearate
Lead, lead oxide, lead hydroxide, etc.), copper compounds (eg, copper fluoride,
Copper halides such as copper chloride, copper bromide, and copper iodide, copper nitrate,
Inorganic such as copper sulfate, copper perchlorate, copper borate, copper carbonate, copper phosphate
Salt copper, copper acetate, copper oxalate, etc.), titanium compound (for example,
Titanium fluoride, titanium chloride, titanium bromide, titanium iodide, etc.
Inorganic such as titanium halide, titanium nitrate and titanium sulfate
Titanium salt, bismuth compound (for example, bismuth fluoride, chloride
Halogen such as bismuth, bismuth bromide and bismuth iodide
Inorganic vinyl chloride such as bismuth chloride, bismuth nitrate and bismuth sulfate
Antimony compounds (e.g.,
Antimony fluoride, antimony chloride, antimony bromide, yo
Antimony halides such as antimony uride, antisulfate
Inorganic salts such as mon bismuth, bismuth oxide, etc.), nickel
Compounds (eg nickel fluoride, nickel chloride, nickel bromide)
Nickel, nickel halides such as nickel iodide,
Nickel, nickel sulfate, nickel perchlorate, nickel borate
, Nickel carbonate, inorganic phosphates such as nickel phosphate,
Nickel fatty acids such as nickel acetate, tetrachloronickel
Tetraethylammonium oleate (II)
Tetraethylammonium nickel (II) acid, hexaan
Min nickel (II), tris (ethylenediamine)
Kel (II) sulfate, ethylenediaminetetraaquaani
Kel (II) sulfate monohydrate, dinitrobis (ethylenedi
Amine) nickel (II), bis (N, O-dimethylethyl)
Nickel such as range amine) nickel (II) perchlorate
Inorganic complex, dichloro (bipyridyl) nickel (II),
Loro (n-cyclopentadienyl) (triphenylphos
Fin) nickel (II), dibromobis (triphenyl
Phosphine) nickel (II), dichlorobis {1,1′-
(Diphenylphosphino) ferrocene｝ nickel (II)
Nickel (II) organic complexes such as tetrakis (triphenyl)
Ruphosphine) nickel (0), tris (triphenyl
Phosphine) nickel (0), nickel (0) acetyl
Acetonato, nickel (0) hexafluoroacetyla
Nickel (0) organic complex such as setnat)
You. These metal compounds may be used alone or in combination of two or more.
May be used. These metal compounds have the general formula (1)
0.0001 to 30 times the molar amount of the compound
Preferably, it is used in a molar amount of 0.001 to 10 times.
Is good. The standard oxidation-reduction potential is -0.3 (V / SC)
E) The following metals and standard redox potentials higher than said metals:
Examples of combinations of metal compounds having
For example, Al / Pb compounds, Al / Bi compounds, Zn / Pb compounds
, Zn / Bi compound, Mg / Bi compound, Mg / Cu compound
, Sn / Ti compound, Sn / Bi compound, Sn / Sb compound
And more preferably an Al / Pb compound, Zn
/ Bi compounds. As the solvent used in this reaction, for example,
Methyl formate, ethyl formate, propyl formate, butyl formate,
Methyl acetate, ethyl acetate, propyl acetate, butyl acetate,
Lower alcohols such as methyl propionate and ethyl propionate
Lower alkyl esters of kill carboxylic acids, acetone,
Methyl ethyl ketone, methyl propyl ketone, methyl butyl
Tyl ketone, methyl isobutyl ketone, diethyl ketone
Ketones, diethyl ether, ethyl propyl ether
Ter, ethyl butyl ether, dipropyl ether, di
Isopropyl ether, dibutyl ether, methyl cello
Solvents, ethers such as dimethoxyethane, tetrahydride
Cyclic ethers such as lofuran, dioxane and dioxolane
, Acetonitrile, propionitrile, butyronitrile
, Isobutyronitrile, valeronitrile and other nitriles
Benzene, toluene, xylene, chlorobenzene,
Substituted or unsubstituted aromatic hydrocarbons such as anisole
, Dichloromethane, chloroform, dichloroethane,
Trichloroethane, dibromoethane, propylene dichloro
Ride, carbon tetrachloride, halogenated hydrocarbons such as fluorocarbons
, Pentane, hexane, heptane, octane and other fats
Aromatic hydrocarbons, cyclopentane, cyclohexane, cyclone
Cycloalkanes such as loheptane and cyclooctane;
Amides such as methylformamide and dimethylacetamide
, Cyclic amides such as N-methylpyrrolidinone, dimethyl
Rusulfoxide and the like can be mentioned. These alone
Or a mixture of two or more. Also these solvents
Can also be used as a water-containing solvent. These solvents
Is usually 10 to 20 per kg of the compound of the general formula (1).
About 0 liter, preferably about 20-100 liter
Good to be used. The reaction temperature of the above reaction is usually -10 to 80
C, preferably in the range of 0 to 50C. With room temperature
The reaction of the present invention proceeds well even at a near reaction temperature. Also
If necessary, in a sealed container, or an inert gas such as nitrogen gas.
You can also do it in the game. Table obtained by general formula (2) obtained
Exomethylene penum derivatives used in conventional purification operations
Can be more isolated. In the reaction of the present invention,
By electrolytically reducing the compound (1) in an organic solvent,
The desired exomethylene penam of the general formula (2)
Derivatives can be manufactured. Used in the electrolytic reduction reaction of the present invention
Organic solvents having a standard oxidation-reduction potential of -0.3.
(V / SCE) at least equimolar amounts of metals below
0.000 having a higher standard redox potential than the metal
For use in reactions that are reduced by 1 to 10 times the amount of metal compound
All the solvents used can be used. When performing the electrolytic reduction reaction of the present invention
For example, a supporting electrolyte is added to the reaction system. For example perchlorine
Lithium oxide, sodium perchlorate, magnesium perchlorate
Metal perchlorate, ammonium perchlorate, perchloric acid
Ammonium tetrachloride, tetrabutyl ammonium perchlorate
Ammonium perchlorate such as ammonium, ammonium chloride
, Ammonium bromide, ammonium iodide,
Traethylammonium, tetrabutylammonium bromide
Ammonium halides such as
Metal borofluoride such as sodium fluoride, tetraethyl borofluoride
Boron such as ammonium and tetrabutylammonium borofluoride
Ammonium fluoride salt, triethylamine, collidine, ru
Thidine, pyridine, piperidine, N-methylmorpholine
1,5-diazabicyclo [3,4,0] nonene-5
(DBN) 1,5-diazabicyclo [5,4,0] un
Amines such as decene-5 (DBU), acetic acid, monochlor
Examples include carboxylic acids such as acetic acid and trifluoroacetic acid.
You. These indicator electrolytes may be used alone or in combination of two or more.
It is used by mixing, preferably the above carboxylic acids
used. The amount of supporting electrolyte used is
Usually about 0.1 to 100% by weight, preferably 0.1 to 50% by weight
%. In the electrolytic reduction according to the method of the present invention,
Electrodes used for ordinary electrolytic reactions can be widely used. Ingredient
Physically, platinum, tin, aluminum
Metal, stainless steel, nickel, lead oxide, carbon, iron oxide, titanium
Etc. and cathode materials such as platinum, tin, aluminum
Can be used for nickel, stainless steel, zinc, lead, copper, carbon, etc.
However, preferably, as a cathode material, tin, zinc, lead, copper
It is better to use etc. When performing the electrolytic reduction of the present invention
Is the same as or equal to the oxidation-reduction potential of the cathode material used.
Metal halides and inorganic salts having the following oxidation-reduction potential
When adding salts with organic acids or salts or oxides with organic acids,
Efficiency may be improved. Examples of the above additives include
Metal halogens such as tin, zinc, lead, bismuth, and titanium
(Eg, fluoride, chloride, bromide, iodide, etc.),
Salts with inorganic salts (eg nitrates, sulfates, perchlorates, boron)
Acid salts, phosphates, carbonates, etc.), and salts with organic acids (eg,
Oxalate, stearate, acetate, etc.), oxides, etc.
it can. These additives may be used alone or in combination of two or more.
Can be used. Such an additive has the general formula (1)
It is preferable to use about 0.1 to 1 times mol. Use the above additives
If there is no need to use a supporting electrolyte,
There is a case. In the electrolytic reduction of the present invention, the anode and cathode are separated by a diaphragm
However, there is no need to separate them, and in a single tank
It is characterized by being able to do so. The reaction temperature is usually -10
C. to 50.degree. The electrolysis reaction is carried out by a constant current electrolysis method and a constant voltage electrolysis method.
Either solution can be used, but the equipment and operation
It is preferable to employ a constant current electrolysis method from the viewpoint of simplicity.
Electrolysis can be DC or AC electrolysis,
Switching can be performed every 1 to 30 seconds. Current density
The degree is usually 1 to 500 mA / cm ^Two , Preferably 1 to 50 m
A / cm ^Two Should be within the range. The amount of electricity is the electrolytic cell used
, The type of starting compound (1),
Although it depends on the type of the medium and cannot be said unconditionally, it is usually 2 to 1
0 F / mol, preferably 2-5 F / mol,
The reaction is completed when the above electricity is supplied. General obtained
The exomethylene penum derivative represented by the formula (2) is usually
Can be isolated by a purification operation. The present invention will be described in detail with reference to the following examples.
You. Ph is C ₆ H _Five -, Et is ethyl, Bu is spot
And bpy represent (bipyridyl). Example 1 Compound (1a) (R ¹ = PhCH _Two CONH, R ^Two = H, R
^Three = CH _Two C ₆ H _Four OCH _Three -P, R ^Four = Ph, X = Cl, Y =
Cl) 100 mg, lead bromide 100 mg and aluminum powder
100 mg is weighed into a 10 ml eggplant type flask, and N, N-
Add 2 ml of dimethylformamide and stir at room temperature for 1 hour
You. Pour the reaction solution into 1N hydrochloric acid and add ethyl acetate
Extraction was performed, washing twice with water and once with saturated saline.
Thereafter, drying was performed over anhydrous sodium sulfate. Got
After the solvent was distilled off under reduced pressure, the residue was
Purified and separated by column chromatography, Compound 2a (6
(7 mg, 99%). ¹ 1 H NMR (CDCl _Three ) Δ: 3.61 (s, 2H),
5.25 (m, 2H), 5.35 (m, 1H), 5.59
(D, J = 4.0 Hz, 1H), 5.75 (dd, J =
4.0, 8.9 Hz, 1H), 6.12 (d, J = 8.9H)
z, 1H), 6.84 (s, 1H), 7.22-7.40
(M, 15H) Example 2 The starting material was a compound (1b) (R ¹ = PhCH _Two CONH,
R ^Two = H, R ^Three = CHPh _Two , R ^Four = Ph, X = Cl, Y = C
Compound obtained by performing the same reaction as in Example 1 in place of l)
Compound 2b (68 mg, 97%) was obtained. ¹ 1 H NMR (CDCl _Three ) Δ: 3.61 (s, 2H),
3.80 (s, 3H), 5.11 (s, 2H), 5.18
(Dd, J = 1.5, 1.7 Hz, 1H), 5.24 (d
d, J = 1.5, 2.2 Hz, 1H), 5.35 (dd,
J = 1.7, 2.2 Hz, 1H), 5.57 (d, J = 4.
0Hz, 1H), 5.75 (dd, J = 4.0, 9.3H
z, 1H), 6.07 (d, J = 9.3 Hz, 1H),
6.85 to 7.40 (m, 9H) Example 3 The starting material was a compound (1c) (R ¹ = PhCH ^Two CONH,
R ^Two = H, R ^Three = CH _Three , R ^Four = Ph, X = Cl, Y = Cl)
Compound 2c was obtained by performing the same reaction as in Example 1 except that
(60 mg, 98%) was obtained. ¹ 1 H NMR (CDCl _Three ) Δ: 3.63 (ABq, J =
2.7Hz, 2H), 3.78 (s, 3H), 5.19
(Dd, J = 1.9, 1.9 Hz, 1H), 5.28 (d
d, J = 1.9, 1.9 Hz, 1H), 5.40 (dd,
J = 1.9, 1.9 Hz, 1H), 5.60 (d, J = 4.
0Hz, 1H), 5.77 (dd, J = 4.0, 8.8H
z, 1H), 6.20 (d, J = 8.8 Hz, 1H),
7.27 to 7.37 (m, 5H) Example 4 The starting material was a compound (1d) (R ¹ = H, R ^Two = H, R ^Three =
CH _Two C ₆ H _Four OCH _Three -P, R ^Four = Ph, X = Cl, Y = C
Compound obtained by performing the same reaction as in Example 1 in place of l)
Compound 2d (54 mg, 90%) was obtained. ¹ 1 H NMR (CDCl _Three ) Δ: 3.16 (dd, J = 1.
5, 16.0 Hz, 2H), 3.66 (dd, J = 4.
0, 16.0 Hz, 1H), 3.82 (s, 3H),
5.13 (s, 2H), 5.24 (dd, J = 1.8, 1.
8Hz, 1H), 5.28 (dd, J = 1.8, 1.8H
z, 1H), 5.32 (dd, J = 1.8, 1.8 Hz,
1H), 5.38 (dd, J = 1.5, 4.0 Hz, 1
H), 6.87-7.30 (m, 4H) Example 5 The starting material was a compound (1e) (R ¹ = H, R ^Two = H, R ^Three =
CHPh _Two , R ^Four = Ph, X = Cl, Y = Cl)
As a result of performing the same reaction as in Example 1, compound 2e (55 mg,
87%). ¹ 1 H NMR (CDCl _Three ) Δ: 3.12 (dd, J = 1.
5, 16.0 Hz, 2H), 3.60 (dd, J = 4.1,
16.0 Hz, 1H), 5.23 (dd, J = 1.8,
1.8 Hz, 1 H), 5.32 (dd, J = 1.8, 1.8
Hz, 1H), 5.36 (dd, J = 1.5, 4.1 Hz,
1H), 5.37 (dd, J = 1.8, 1.8 Hz, 1
H), 6.87 (s, 1H), 7.27-7.35 (m,
10H). Example 6 The starting material was a compound (1f) (R ¹ = PhCH _Two CONH,
R ^Two = H, R ^Three = CH _Two C ₆ H _Four OCH _Three −p, R ^Four = Ph, X
= Cl, Y = OSO _Two CF _Three ) In the same manner as in Example 1.
As a result of the reaction, compound 2a (49 mg, 86%) was obtained.
Was done. The obtained spectrum data of 2a was obtained in Example 1.
Perfectly matched it. Example 7 The starting material was a compound (1 g) (R ¹ = PhCH _Two CONH,
R ^Two = H, R ^Three = CHPh _Two , R ^Four = Ph, X = Cl, Y = O
SO _Two CF _Three ) And the same reaction as in Example 1 was performed.
Result Compound 2b (51 mg, 85%) was obtained. Obtained
2a is completely identical to that of Example 1.
I did. Example 8 The starting material was a compound (1h) (R ¹ = PhCH _Two CONH,
R ^Two = H, R ^Three = CH _Two C ₆ H _Four OCH _Three -P, R ^Four = Ph, X
= Cl, Y = OSO _Two C ₆ H _Four CH _Three Example instead of -p)
Compound 2a (50 mg, 7
6%). The spectrum data of 2a obtained is
It was completely identical to that of Example 1. Example 9 The starting material was a compound (1i) (R ¹ = PhCH ^Two CONH,
R ^Two = H, R ^Three = CHPh _Two , R ^Four = Ph, X = Cl, Y = O
SO _Two C ₆ H _Four CH _Three The same reaction as in Example 1 except for -p)
As a result, compound 2b (52 mg, 72%) was obtained.
Was. The obtained spectrum data of 2a is that of Example 1.
Exactly matched. Examples 10 to 18 The same procedures as in Example 1 were carried out except that the reducing agent was changed as follows. Example Metal Compound Amount Used Metal Yield (%) 10 PbBr _Two 0.1 eq. Al 92 11 PbBr _Two 1 eq. Zn 75 12 PbCl _Two 1 eq. Al 80 13 Pb (OAc) _Two 1 eq. Al 70 14 BiCl _Three 1 eq. Al 72 15 BiCl _Three 1 eq. Zn 83 16 BiCl _Three 1 eq. Sn 72 17 AlCl _Three 1 eq. Zn 85 18 AlCl _Three 1 eq. Mg 71 Examples 19 to 24 The same procedures as in Example 1 were carried out except that the solvent was changed as follows. Example Solvent Yield (%) 19 NMP 98 20 DMA 93 21 HMPA 82 22 DMF / CH _Two Cl _Two 79 23 DMF / CF _Three COOH 98 24 NMP / CF _Three Example 25 Compound (1a) (R ¹ = PhCH _Two CONH, R ^Two = H, R
^Three = CH _Two C ₆ H _Four OCH _Three −p, R ^Four = Ph, X = Cl, Y =
Cl) 100 mg, lead bromide 11 mg and tetraethylammonium
Weigh 50mg of tosylate into a 20ml test tube with branches.
And add 10 ml of N, N-dimethylformamide and stir
Understand. This is equipped with an aluminum anode and a platinum cathode.
And 7.5 mA (5 mA / cm ^Two ) Under the current of 5F / mol
Energize the volume. The reaction solution was poured into 1N hydrochloric acid, and acetic acid was added.
Extract with ethyl, wash twice with water, wash with saturated saline 1
After drying, dry over anhydrous sodium sulfate.
Was. The solvent was distilled off under reduced pressure from the obtained extract,
Can be purified and separated by silica gel column chromatography.
Compound 2a (54 mg, 80%) was obtained. Examples 26 to 36 The following were conducted by changing the electrodes while keeping the other conditions as they were.
An example is shown. Example Anode Cathode Yield (%) 26 Al C 70 27 Al Al 75 28 Al Pb 72 29 Al Zn 78 30 Al Sn 76 31 Sn Pt 69 32 Sn Pb 74 33 Sn Sn 72 34 Zn Pb 75 n Pb Pb 76 Examples 37-44 The following conditions were used while the other conditions were not changed and the supporting electrolyte was changed.
Examples are shown below. Example Electrolyte Yield (%) 37 Et _Four NBr 65 38 Et _Four NClO _Four 73 39 Bu _Four NBr 62 40 LiClO _Four 68 41 H _Two SO _Four 70 42 CH _Three COOH 73 43 CH _Three COOH 70 44 Bu _Four NBF ₆ Examples 45 to 51 The following conditions were used while keeping the other conditions unchanged and changing the additives.
An example will be described. Example Additive Yield (%) 45 PbCl _Two 78 46 PbI _Two 75 47 BiCl _Three 72 48 TiCl _Four 74 49 SbCl _Three 68 50 NiCl _Two (Bpy) 71 51 ZrCl _Four Examples 52 to 57 The following examples were carried out by changing the solvent while keeping the other conditions as they were.
An example is shown. Example Solvent Yield (%) 52 NMP 95 53 DMA 90 54 HMPA 78 55 DMF / CH _Three COOH 96 56 DMF / CF _Three COOH 98 57 NMP / CF _Three COOH 98 Application Example 1 For example, exomethylene penum (2e) obtained by the present invention
Starting material, and having a β-lactamase inhibitory activity.
The method of synthesizing nem compounds is described in Bioorganic and Medicina.
l Chemistry Letters, 3, 2253 (1993)
Has been described. The outline of this synthesis method is as follows.
Ozone-decomposition of methylene penum compound (A) to form ketone
(B). Trifluoromethanesulfonic anhydride and
The reaction is carried out in the presence of a base, and
After reaction with various thiols (RSH), penem
This leads to compound (D). Deprotection and purification of this product
Compound (E) having β-lactamase inhibitory activity was obtained
It is. Embedded image The halogenated β- of the general formula (1) of the present invention
Starting from lactam compounds, new metal reduction systems and new
By constructing and developing a standard electrolytic reduction system,
Efficient exomethylene penum conversion at the same time
An exomethylene penum derivative of the formula (2) is safe and convenient
Manufactured by operation and with high yield and high purity.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C25B 3/04 (72) Inventor Yutaka Kameyama 463 Kagasuno, Kawauchi-cho, Tokushima City, Tokushima Prefecture Otsuka Chemical Co., Ltd. Tokushima Research Laboratory (56) References JP-A-4-283584 (JP, A) JP-A-5-97864 (JP, A) Tetrahedron Let t. , Vol. 32, No. 50, p. 7445-7448 (1991) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 499/00-499/897 REGISTRY (STN) CA (STN)

Claims (1)

(57) [Claims 1] The halogenated β- represented by the general formula (1)
The lactam compound is prepared by standard oxidation-reduction potential of -0.3 (V / S
CE) 0.0001 to 10 having at least equimolar amounts of the following metals and a higher standard redox potential than said metals:
A method for producing an exomethylene penum compound, characterized in that an exomethylene penum compound represented by the general formula (2) is obtained by reducing with a double molar amount of a metal compound or using an electrolytic reduction method. Embedded image [In the formula, R ¹ represents a hydrogen 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, or a hydroxyl group or a lower alkyl group having a protected hydroxyl group as a substituent. R
³ represents a hydrogen atom or a carboxylic acid protecting group. R ⁴ represents an aryl group which may have a substituent. X represents a halogen atom, Y represents a halogen atom or a leaving group. n is 0-2
Is shown. [Chemical formula 2] Wherein R ¹ , R ² and R ³ are as defined above. ]