JPH0546334B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to a method for producing azetidinone derivatives, more specifically, the general formula [In the formula, R ¹ represents a hydrogen atom, a halogen atom, or a lower alkoxy group, and R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted amino group. , or R ¹ and R ² both represent carbonyl groups. R ³ represents a hydrogen atom or a carboxyl group protecting group. R ⁴ represents a substituted or unsubstituted phenyl group. ] The present invention relates to a method for producing an azetidinone derivative represented by the following. The azetidinone derivative represented by the above general formula () is an important compound as an intermediate for synthesizing cephalosporin antibiotics. Conventional technology Conventionally known manufacturing methods for compound () include, for example, JP-A-50-129590 and JP-A-Sho 51-
There is a method described in Publication No. 110593. This method can be expressed as a reaction formula as follows. [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. ] Although the above publication does not mention the yield of compound () obtained by such a method, when the present inventors tried the above method again, they found that compound () could be obtained with a low yield. However, it turned out to be very disadvantageous industrially (see Comparative Example 1 and Comparative Example 2 below). Furthermore, JCSPerkin I, 1456 (1974) describes a method in which the reaction described in the above publication is carried out in the presence of N,N-diethylaniline. However, if this method is followed, the target compound () is not obtained, but only a compound () in which the double bond of the compound () is isomerized is obtained. Moreover, the compound () obtained by this method cannot be a synthetic intermediate for the cephalosporin antibiotic, which is the final object of the present invention. At present, no method has yet been established that uses compound () as a starting material and can produce the desired compound () all at once with good yield. Means for Solving the Problems In view of the current situation, the present inventors conducted intensive research to develop a method for producing the compound () that does not have the above-mentioned drawbacks, and as a result, they were able to complete the present invention. Ivy. That is, the present invention is based on the general formula [In the formula, R ¹ , R ² and R ³ are the same as above. ] and the penicillin sulfoxide derivative represented by the general formula R ⁴ SO ₂ NH ₄ [wherein R ⁴ is the same as above. ] and/or a sulfinic acid ammonium salt represented by the general formula R ⁴ SO ₂ SO ₂ R ⁴ ( ) [wherein R ⁴ is the same as above. ] by reacting with α-disulfone represented by the general formula [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. The present invention relates to a method for producing an azetidinone derivative, which is characterized by obtaining an azetidinone derivative represented by the following. Specific examples of the halogen atom shown as R ¹ in this specification include F, Cl, Br, I
etc. can be mentioned. Specific examples of the lower alkoxy group represented by R ¹ include methoxy, ethoxy, propoxy, i-propoxy, butoxy, and t-butoxy groups. Specific examples of the halogen atom shown as R ² in this specification include F, Cl, Br, I
etc. can be mentioned. Specific examples of the lower alkoxy group represented by ^R2 include methoxy, ethoxy, propoxy, i-propoxy, butoxy, and t-butoxy groups. Specific examples of the substituted or unsubstituted lower alkyl group represented by R ² include methyl,
Ethyl, propyl, i-propyl, butyl, t-
Butyl, 2-hydroxyethyl, 2-methoxyethyl, 2-benzyloxyethyl, 1-hydroxyethyl, 1-methoxyethyl, 2-benzyloxyethyl, 2-(t-butyldimethylsilyloxy)ethyl, 1-(t -butyldimethylsilyloxy)ethyl, hydroxymethyl, benzyloxymethyl, t-butyldimethylsilyloxymethyl, chloromethyl, bromomethyl, fluoromethyl, dichloromethyl, trifluoromethyl, and the like. Specific examples of the substituted amino group represented by ^R2 include benzamide, p-chlorobenzamide, p-nitrobenzamide, p-hydroxybenzamide, p-
-Methoxybenzamide, phenylacetamide, phenylglycylamide and phenylglycylamide with amino group protected, p-hydroxyphenylglycylamide and phenylglycylamide with amino group protected, α-sulfonyl Phenylacetamide, α-hydroxyphenylacetamide, α-carbamoylphenylacetamide, p-methoxyphenylacetamide, p-chlorophenylacetamide, p-hydroxyphenylacetamide, α-naphthylacetamide,
β-naphthylacetamide, phenoxyacetamide, p-chlorophenoxyacetamide, p-
Bromophenoxyacetamide, p-methoxyphenoxyacetamide, tetrazolylacetamide, thiophenylacetamide, 2-aminothiazolyl acetamide and amino group protected 2
Examples include -aminothiazolyl acetamide, furylacetamide groups, and protected amino groups. Protecting groups for protected amino groups include Theodora W.Green
“Protective Groups in Organic” by “Protective Groups in Organic
The protecting groups described in Chapter 7 of ``Synthesis'' can be used.
Specific examples of the protected amino group include methyl carbamate group, 9-florenylmethyl carbamate group, 2,2,2-trichloroethyl carbamate group, 2-trimethylsilyl carbamate group, 1,1-dimethylpropyl carbamate group,
1,1-dimethyl-2-cyanoethyl carbamate group, t-butyl carbamate group, 1-adamantyl carbamate group, benzyl carbamate group,
p-nitrobenzyl carbamate group, diphenylmethyl carbamate group, phthalimide group, 2,3
-diphenylmaleimide group, N-phenacylamino group, N-methoxymethylamino group, N-2-chloroethoxymethylamino group, N-benzyloxymethylamino group, N-pivaloyloxydimethylamino group, N-benzylamino group group, N-o-nitrobenzylamino group, N-di(p-methoxyphenyl)methylamino group, N-triphenylmethylamino group, N-(diphenyl-4-pyridylmethyl)amino group, N-trimethylsilylamino group group, Nt-butyldimethylsilylamino group, benzenesulfenamide group, p-methoxybenzenesulfonamide group, phenacylsulfonamide group, and the like. As the protecting group for the carboxyl group shown as R ³ in this specification, “Protective Groups in Organic
A wide range of protecting groups can be used, including methyl, ethyl, benzyl, p
-methoxybenzyl, trimethoxybenzyl, trimethoxydichlorobenzyl, piperonyl, diphenylmethyl, bis(p-methoxyphenyl)methyl, ditolylmethyl, phenyl-p-methoxyphenylmethyl, α-p-methoxyphenylethyl, α-p -methoxyphenyl-β-trichloroethyl, trichloroethyl, florenil, t-
Butyl, trityl, α-diphenylethyl, cumyl, p-nitrobenzyl, o-nitrobenzyl,
o,p-dinitrobenzyl, phenacyl, p-bromophenacyl, 1-methoxycarbonyl-2-
Examples include oxopropyl, methoxyethoxymethyl, methoxymethyl, benzyloxymethyl, and i-propoxymethyl groups. Specific examples of the substituted phenyl group shown as R ⁴ herein include, for example, tolyl,
4-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 4-bromophenyl, 2,4-dibromophenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl,
Examples include 3,4,5-trimethoxyphenyl, 4-nitrophenyl, 2,4-dinitrophenyl, and 2-nitrophenyl groups. Penicillin sulfoxide derivatives () used as starting materials in the present invention can be easily synthesized by known methods (Chemistry and Biology of
β−Lactam Antibiotics, vol.1Edited by RB
Morin and M.Gorman). Ammonium sulfinate salt () can be prepared by known methods such as WE
Truce and AMMurphy, Chem.Rev., 48 , 69
(1951) by reacting sulfinic acid with ammonia using a known method. Also α-disulfone ()
using known methods, such as GCDenxer, Jr., J.
It can be synthesized by the method described in Org.Chem., 31 , 3418 (1966). To carry out the present invention, a penicillin sulfoxide derivative () is reacted with an ammonium sulfinate salt () and/or an α-disulfone (). The amount of ammonium sulfinate salt () and/or α-disulfone () to be used varies depending on the type of raw material used, but cannot be generalized.
It is usually used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, per 1 equivalent of penicillin sulfoxide derivative (). The organic solvent used in the present invention has a boiling point of 70
A single solvent or a mixture of two or more solvents having a temperature of 0.degree. C. or higher is preferred, and aprotic organic solvents are particularly preferred. Specific examples of organic solvents include ethers such as isopropyl ether, butyl ether, and dioxane, ketones such as methyl ethyl ketone and diethyl ketone, halogenated hydrocarbons such as trichloroethane, dibromomethane, bromoform, and trichloroethylene, toluene, xylene, One type or a mixture of two or more types selected from aromatic hydrocarbons such as benzene and chlorobenzene, esters such as butyl acetate, ethyl propionate, and ethyl butanoate, and nitriles such as acetonitrile and probionitrile. Examples include solvents. The amount of organic solvent to be used varies depending on the type of raw material used, but cannot be generalized, but it is usually 5 to 5% by weight relative to the penicillin sulfoxide derivative ().
It is used in a range of 100 times, preferably 10 to 50 times. When the reaction of the present invention is carried out in the presence of an acid catalyst, the yield of the target azetidinone derivative () is further improved compared to the case where no acid catalyst is present. Specific examples of acid catalysts used in the present invention include Lewis acids such as iron chloride, zinc chloride, aluminum chloride hexahydrate, acetic acid,
Examples include organic acids such as oxalic acid and squaric acid. The amount of acid catalyst used is usually 0.5 to 20 mol% based on the penicillin sulfoxide derivative ().
Preferably it is used in an amount of 1 to 10 mol%. When the reaction of the present invention is carried out in the presence of an inorganic salt, the yield of the target azetidinone derivative () is further improved compared to the case where the inorganic salt is not present. As the inorganic salt used in the present invention, alkali metal salts and alkaline earth metal salts are used. Specific examples include CaSO ₄ , CaCl ₂ , Ca(NO ₃ ) ₂ , MgCl ₂ ,
_MgSO4 , Mg _{( NO3} ) ₂ , _Na2SO4 , _{Na2SO3 ,}
Examples include KHSO ₄ , KF, etc., and hydrates thereof.
The amount of the inorganic salt used is usually 0.5 to 10 mol, preferably 0.5 to 3 mol, per 1 mol of penicillin sulfoxide derivative (). The reaction temperature of the present invention varies depending on the type of raw materials and the type of solvent used and is not constant, but is usually 70 to 120℃.
The temperature is preferably 90 to 110°C. Although the reaction time varies depending on the type of raw materials used and the reaction temperature and is not constant, the reaction is usually completed in 2 to 5 hours. After the reaction is completed, the desired azetidinone derivative () can be obtained as a substantially pure product by performing a usual post-treatment. If further purification is necessary, conventional purification means such as recrystallization and column chromatography may be used. Effects of the Invention According to the method of the present invention, the target azetidinone derivative () can be directly produced from the penicillin sulfoxide derivative (). Further, according to the method of the present invention, the desired azetidinone derivative () can be produced with a simple operation and a high yield of 85% or more. Ammonium sulfinate salt () and α-disulfone () used in the present invention are relatively stable in organic solvents and have good reactivity, so they are used in an equivalent amount or in a small excess amount relative to penicillin sulfoxide (). It is sufficient to use
It is also excellent economically. Example 1 6-phenylacetamidopenicillin-1-oxide-3 was added to a reactor equipped with a Dimroth condenser.
-Carboxylic acid p-methoxybenzyl ester 100
mg, ammonium benzenesulfonate 70 mg, anhydrous calcium chloride 70 mg and squaric acid 2.4 mg
Weigh out. Next, add 5 ml of toluene and stir to form a suspension. The reactor was immersed in an oil bath maintained at 105°C and stirred for 3 hours. After the reaction is completed, the mixture is allowed to cool to room temperature and extracted with ethyl acetate-saturated brine. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure to yield a colorless oil. When the obtained crude product was purified using silica gel column chromatography, p-methoxybenzyl-2-(3-phenylacetamide-4-
Benzenesulfonylthio-2-azetidinone-1
-yl)-3-methyl-3-butenoate was obtained. The NMR spectrum of the product is shown in Table 6. Comparative example 1 (C) of Example 1 of JP-A-50-129590
6-phenylacetamidopenicillanic acid p-methoxybenzyl ester-1β-oxide was used in place of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester-1β-oxide, and p-toluenesulfonic acid Benzene sulfuric acid was used instead of , and the other reaction treatments were as described in (C) of Example 1 of JP-A-50-129590.
When treated in the same manner, p-methoxybenzyl-2
-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-
3-Methyl-3-butenoate was obtained with a yield of 17%. Comparative example 2 (C) of Example 1 of JP-A-50-129590
, 6-phenylacetamidopenicillanic acid-p-methoxybenzyl ester-1β-oxide was used instead of 6-phenoxyacetamidopenicillanic acid-p-nitrobenzyl ester-1β-oxide, and p-toluenesulfonylcyana When benzenesulfonyl cyanide is used in place of the compound and the other reaction treatments are carried out in the same manner as in Example 1 (C) of JP-A-50-129590, p
-Methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate was obtained in a yield of 36%. Comparative Example 3 p-methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-
Azetidinon-1-yl)-3-methyl-3-butenoate was obtained. Yield 21% Comparative Example 4 p-Methoxybenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2 −
Azetidinon-1-yl)-3-methyl-3-butenoate was obtained. Yield 23% Examples 2 to 8 The same procedure as in Example 1 was carried out except that the compounds shown in Table 1 were used as the inorganic salts added. of the product
The NMR spectrum completely matched that of the compound obtained in Example 1.

[Table] Examples 9 to 13 The same procedure as in Example 1 was carried out except that the compounds shown in Table 2 were used as the acid catalysts added. of the product
The NMR spectrum completely matched that of the compound obtained in Example 1.

[Table] Examples 14 to 24 The same procedure as in Example 1 was carried out except that the organic solvent used was the compound shown in Table 3. of the product
The NMR spectrum completely matched that of the compound obtained in Example 1.

[Table] Examples 25 to 47 The same procedure as in Example 1 was carried out except that the raw materials () were changed to the compounds shown in Table 4. NMR of the obtained product () is shown in Table 6.

【table】

【table】

[Table] Example 48 Example 1 except that 72 mg of diphenyldisulfone was used instead of 70 mg of ammonium benzenesulfinate.
When treated in the same manner as above, the desired product was obtained in 95% yield. The NMR spectrum of the product is shown in Example 1.
It was completely consistent with the compound obtained in . Example 49 The same procedure as in Example 1 was carried out using 30 mg of ammonium benzenesulfinate and 40 mg of diphenyldisulfone instead of 70 mg of ammonium benzenesulfinate, and the desired product was obtained in a yield of 91%. The NMR spectrum of the product completely matched the compound obtained in Example 1. Example 50 The same procedure as in Example 1 was carried out except that anhydrous calcium chloride and squaric acid were not used, and the desired product was obtained with a yield of 85%. NMR of product
The spectrum completely matched that of the compound obtained in Example 1. Example 51 6-phenylacetamidopenicillin-1-oxide-3 was added to a reactor equipped with a Dimroth condenser.
- Weigh out 80 mg of carboxylic acid methyl ester, 88 mg of di-p-tolyl disulfone, 40 mg of anhydrous calcium chloride, and 1 mg of squaric acid. Next, add 5 ml of ethyl butanoate and stir to form a suspension. The reactor was immersed in an oil bath maintained at 100°C and stirred for 4 hours. After the reaction was completed, it was allowed to cool to room temperature, and ethyl acetate was added.
Extract with saturated saline. The organic layer is dried over anhydrous sodium sulfate and then concentrated under reduced pressure to yield a colorless oil. When the obtained crude product was purified using silica gel chromatography, the yield was 89.
% of methyl-2-(3-phenylacetamide-
4-p-Methylbenzenesulfonylthio-2-azetidinon-1-yl)-3-methyl-3-butenoate was obtained. The NMR spectrum of the product completely matched the compound obtained in Example 28. Examples 52-54 The same procedure as in Example 51 was repeated, except that the reagents listed in Table 5 were used instead of di-p-tolyldisulfone. The NMR spectrum of the product is shown in Table 6.

【table】

【table】

【table】

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydrogen atom, a halogen atom, or a lower alkoxy group, and R ² represents a hydrogen atom, a halogen atom, a lower alkoxy group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted amino group. , or R ¹ and R ² both represent carbonyl groups. R ³ represents a hydrogen atom or a carboxyl group protecting group. A penicillin sulfoxide derivative represented by the general formula R ⁴ SO ₂ NH ₄ () [wherein R ⁴ represents a substituted or unsubstituted phenyl group]. ] and/or a sulfinic acid ammonium salt represented by the general formula R ⁴ SO ₂ SO ₂ R ⁴ ( ) [wherein R ⁴ is the same as above. ] by reacting with α-disulfone represented by the general formula [In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above. ] A method for producing an azetidinone derivative, the method comprising obtaining an azetidinone derivative represented by the following. 2. The method according to claim 1, wherein the reaction is carried out in an organic solvent. 3. The method according to claim 1 or 2, wherein the reaction is carried out in the presence of an inorganic salt. 4. The method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of an acid catalyst. 5. The method according to any one of claims 1 to 4, wherein the reaction is carried out at 70 to 120°C.