JPS61178961A - Production of azetidinone derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for synthesizing cephalosporin based antibiotics directly in high yield, by reacting a penicillin sulfoxide derivative with ammonium sulfinate and/or alpha-disulfone. CONSTITUTION:A compound expressed by formula I [R<1> is H, halogen or alkoxy; R<2> is R<1>, (substituted) alkyl or (substituted) amino; R<1> and R<2> together form carbonyl; R<3> is H or protecting group of the carboxyl] or a compound expressed by formula III or both are reacted in the presence of 1-10mol%, based on the compound expressed by formula I, acid catalyst and an inorganic salt in a molar amount of 0.5-3 times based on the compound expressed by formula I at 70-120 deg.C, preferably 90-110 deg.C to give the aimed compound expressed by formula IV, e.g. p-methoxybenzyl-2-(3-phenylacetamido-4- benzenesulfonylthio-2-azet idinon-1-yl)-3-methyl-3-butenoate.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing azetidinone derivatives, and more specifically to a method for producing azetidinone derivatives, more specifically, a compound of the general formula [wherein R1 is a hydrogen atom, a halogen atom, or a lower alkyl atom]
R2 represents a hydrogen atom, an AO atom, a lower alkyl group, a substituted or unsubstituted lower alkyl group, or a substituted or unsubstituted a3) group, or R1 and R2 represent a Both indicate carbonyl groups. R3 represents a hydrogen atom or a carbonyl group protecting group. R' represents a substituted or unsubstituted phenyl group. This invention relates to a method for producing an azetidinone derivative represented by the following.

The atidinone derivative represented by the above general formula (W) is
It is an important compound as an intermediate for the synthesis of cephalosporin antibiotics.

As a conventionally known method for producing the technical compound (W), there is, for example, the method described in JP-A-50-129590. This method can be expressed as a reaction formula as follows.

[In the formula, R'', R2, R3, and R4 are the same as above.] Although the above publication does not describe the yield of compound (P/) obtained by such a method, the present inventor When they tried the above method again, they found that compound (IV) could only be obtained in a low yield, and it was found to be extremely disadvantageous from an industrial perspective (see Comparative Example below).

Also J, C, S, Perkin /, 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 (
W) is not obtained, and only compound (V') in which the double bond of compound (IV) is isomerized is obtained. Moreover, the compound (7) obtained by this method is a compound that cannot be used as a synthetic intermediate for the tfaOsporin antibiotic, which is the final object of the present invention.

At present, no method has yet been established that uses compound (1) as a starting material and can produce the desired compound (■) in a high yield.

In view of the current situation, the present inventors conducted intensive research to develop a method for producing compound (W) that does not have the above-mentioned drawbacks, and as a result, completed the present invention.

That is, the present invention relates to the general formula [where BL, B2 and R3 are the same as above]. ] and the general formula R”SO
NH [In the formula, Ba is the same as above. ] An ammonium sulfic acid salt and/or a general formula % formula % [wherein R4 is the same as above. ] by reacting with α-disulfone represented by the general formula [where BL, R2, R3 and R4 are the same as above. ]
The present invention relates to a method for producing an azethylnon derivative, which is characterized in that the azethylnon derivative is obtained by a.

Specific examples of the halogen atom shown as Ri in this specification include F, C4, Br, I, and the like. Further, specific examples of the lower alkoxy group represented by R1 include, for example, metgyushi, etoshishi, pubogyushi, i-zuobogyshi, zutogyushi, l-
Examples include butoshi group.

Specific examples of the halogen atom shown as R2 in this specification include F, C4, Br, 1, and the like. Specific examples of the lower alkoxy group represented by R2 include, for example,
Examples include ci, puO$ushi, i-propoxy, butoxy, I-butoxy, and the like. Specific examples of the substituted or unsubstituted lower alkyl group represented by R2 include methyl, ethyl, propyl, i-propyl, butyl, I-butyl, 2-methoxydiethyl, and 2-methoxymethyl. Diethyl 12-benzylobovine diethyl, 1-dihydrobeef diethyl, ■-methobeef diethyl, 2-benzilobeef diethyl, 2-(r-dutyldimethylsilylo+cy)ethyl,
1-(r-butyldimethylsilyl-dimethyl) ethyl dimethyl, benzyl-dimethyl) -butyldimethylsilyl-dimethyl, ri00 methyl, pOv: methyl, fluoromethyl, dimethyl Trifluoromethyl and the like can be mentioned. Further, specific examples of the substituted amino group represented by R2 include benzamide, p-riOObenzamide, l-nitrobenzamide, to-human-0-bovine dibenzanide, to-meth-bovine dibenzanido, phenylacedo Amide, phenyldilysylamide and phenyldilysylamide with protected amino group, phenyltalicylamide and phenyldilysylamide with protected amino group, α-sulfonylphenylamide, α-Cydro+cyphenylamidoamide, α-Calocylphenylamidoamide,
Diphenylacetamide in door-met, door-ri Oo phenyl t door-tritodo 1 no human O + siphenylat t door-trido α-naphthylaceto-dore 1β-naphthylacet t door-trido phenocya t door amide, door-cutetralylylaceto Examples include trido, thiophenylacedoanide, 2-aminothiarylylacetoamide, 2-aminothiarylylacetoamide with an amino group protected, furylacedoamide group, etc., or a protected amino group. can be mentioned. As the protecting group used for the protected amino group, “Pro
tectingGroslrx in 0ryttni
The protecting groups described in Chapter 7 can be used.Specific examples of protected amino groups include 0-dimethylcarbamate group, 1-dimethyl-2-cyanoethylcarbamate group, I-butylcarbamate group, l- atamantyl carbamate group, benzyl carbamate group, t-ditho
Benzyl carbamate group, diphenylmethyl carbamate group, phthalimide group, 2,3-diphenylmaleimide group, N-phenacylamino group, N-methoxyphthylatrino group, N-2-riOOeth+dimethylamino group, N- Penzyl dimethylamino group, N-dimethylamino group, N-benzyl dimethylamino group, N-e-dimethylamino group
Benzylamino group, N-di(methoxydiphenyl)methylamino group, N-triphenylmethylaeno group, N-
(diphenyl-lysylmethyl)amino group, N-trimethylsilyla trino group, N-t-butyldimethylsilyla trino group, 1 benzenesulfenamide group, 1 door-meth+sibenzenesulfonamide group, 1 Examples include phenacylsulfonamide groups.

As the protecting group for the carboxylic group shown as R3 herein, Tktodσra jP', Gree
Protective Gram by n
A wide range of protecting groups can be used as described in Chapter 5, ``S0rytxnie 5ynthesis'', and specifically, methyl, ethyl, benzyl, to-methoxydibenzyl, trimethoxydibenzyl, trimethoxydibenzyl, diphenyl, diphenyl. Methyl, his(diphenyl)methyl, ditolylmethyl, phenyl-t-meth+diphenylmethyl 1α-diphenyl ethyl, α-diphenyl
Metobeef diphenyl-β-tric00 ethyl, triku00
Ethyl, florenil! -butyl, trityl, α-diphenylethyl, cumyl, benzyl, -m:
Trobenzyl, p, p-dinito O-pecidyl 1 phenacyl, to-prodephenacyl, I-methoxycarbonyl 2
Examples include -ogyu sopu 0jiru, metgyu shed beef dimethyl, metgyu dimethyl, Beni Jjiro beef dimethyl, i-propo beef dimethyl, and the like.

Specific examples of substituted phenyl groups shown as R4 herein include, for example, tolyl, 4-riOO phenyl, 2,4-zig00 phenyl, 2,4,6-tric00 phenyl, DOO-p0V : phenyl, 2,4-dibu〇7phenyl, 4-methobef diphenyl, 2,4-dimethobef diphenyl, 3.4.5-) remethobef diphenyl,
imaichi nido 0 phenyl, 2I imaichi dinido 0 phenyl, 2-
Nido phenyl group and the like can be mentioned.

The penicillin sulfocyto derivative (1) used as a starting material in the present invention can be easily synthesized by a known method (Chemistry asd Bialley
afβ-Lactam Antibiotics,
! 7o1. lEdited by R.

BlMarin and M, Gtprman) Os JL/Finic acid ayenium salt (1) can be prepared by known methods such as W, E, Truerand 7tM, Mmr.
pky, Cktm, RItp, , now 8,6
9 (1951), and cyanmonia by a known method. Further, α-disulfo:/@ can be expressed by a known method, for example, G, C1Dty*szr, Jr.

J, Ory, Cktm, 31.3418 (1966)
It can be synthesized by the method described in .

To carry out the present invention, the penicillin sulfonate derivative (1) is reacted with the sulfinic acid ammonium salt (1) and/or the α-disulfone salt. The amount of ammonium sulfinate salt (1) and/or α-disulfone (alpha-disulfone) used varies depending on the type of raw material used, but it is usually used per equivalent of penicillin sulfonate derivative (1). 1 to 5 equivalents are used, preferably 1 to 3 equivalents.

The organic solvent used in the present invention is preferably a single solvent or a mixture of two or more solvents having a boiling point of 70° C. or higher, and aprotic organic solvents are particularly preferred. Specific examples of organic solvents include ethers such as isopropylene ether, butyl ether, and dioxane; ketones such as methyl ethyl ketone and diethyl ketone;
Mumethane, zuOv: Form, halogenated hydrocarbons such as trichlorethylene, toluene, bovine silane/benzene,
ri0rubent! Aromatic hydrocarbons such as silica, butyl acetate,
Esters such as ethyl diionate and ethyl butanoate,
Examples of the solvent include one type or a mixed solvent of two or more types selected from nitriles such as acetonitrile and dionitrile. The amount of organic solvent to be used depends on the type of raw material used, but it cannot be stated unconditionally, but it is usually 5 to 5 +
00 times, preferably in the range of 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 desired azetidinone derivative (conversion) is further improved compared to when no acid catalyst is present. Specific examples of the acid catalyst used in the present invention include Lewis acids such as iron chloride, zinc chloride, aluminum chloride hydrate, and organic acids such as acetic acid, oxalic acid, and square acid. The amount of acid catalyst used is usually 0.5 to 207%, preferably 1 to 107%, based on the penicillin sulfocyto derivative (1).

When the reaction of the present invention is carried out in the presence of an inorganic salt, the yield of the desired azetidinone derivative (I) 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 CaSO4, CaCl2, Ca(
NO3)2, My(42, MgSO3, My(NO3)
2, Na25oa, Ha2So3SKH5O,,KF
etc. and hydrates thereof. The amount of inorganic salt used is usually 0.5 to 1 Ovl, JL, preferably 0.5 to 3 per 17 g of penicillin sulfocytoderivative (I).
v: nt is used.

The reaction temperature of the present invention varies depending on the type of raw material a and the type of solvent used, but it is usually carried out in the range of 70 to 120°C, preferably 90 to 110''C.

Although the reaction time varies depending on the type of raw materials used and the reaction temperature, the reaction is usually completed in 2 to 5 hours. After the reaction is completed, the desired azetidinoshi derivative (conversion) can be obtained as a substantially pure product by performing a usual post-treatment. If further purification is necessary, conventional purification methods 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 (derived material) can be obtained directly from the penicillin sulfonyl derivative (1).
can be manufactured. Further, according to the method of the present invention, the desired azetidinone derivative (conversion) can be produced with a simple operation and a high yield of 85% or more. Ammonium sulfinate salt (1) and α-disulfone (capital) used in the present invention
Since it is relatively stable in organic solvents and has good reactivity, it is sufficient to use it in an equivalent amount or a small excess amount relative to penicillin sulfonate (1), and it is also economical. .

Example 1 In a reactor equipped with a cooling tube, 6-phenylacedoamide penicillin-1-oxycyto-3-carboxylic acid-methoxybenzyl ester 100-benzene sulfinate was added. 70η, anhydrous calcium chloride 70■
Weigh out 2.4q of squaric acid. 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.

The obtained crude product was purified using a silica gel column with a yield of 92%.
! (xsulfonylthio-2-azededinon-l-yl)-
3-Methyl-3-butenoate was obtained. Product N
The MR spectra are shown in Table 6.

Comparative Example l (CV) of Example 1 of JP-A-50-129590
6-phenolamidepenicillanic acid-l-dibenzyl ester-1β-saikoside)
using 6-phenylacedotridobenicilasiic acid-normetox dibenzyl ester-1β-saikoside, /'-)
When benzenesulfinic acid was used instead of luenesulfonic acid and the other reaction treatments were carried out in the same manner as (Cv) in Example 1 of JP-A-50-129590, l-methoxybenzyl-2-(3- Phenylacedeamide-4-
Benzedisulfonylthio-2-azetitanocy-1-yl)-3-methyl-3-dthenoate was obtained in a yield of 17%.

Comparative Example 2 (CVl
), 6-phenylacedoamide benicilanic acid-to-meth+
Dibenzyl ester! β-Ogyuside was used, benzenesulfonyl cyanide was used in place of toluenesulfonyl cyanide, and other reaction treatments were conducted in JP-A-50-1.
When treated in the same manner as Example +o (Cvx) of Publication No. 29590, p-methoxaldibenzyl-2-(3-phenylacetamido-4-benzenesulfonylthio-2-azededinon-1-yl)-3- Methyl-3-pudenoate was obtained with a yield of 36%.

Examples 2 to 8 The same procedure as in Example I was carried out except that the compounds shown in Table 1 were used as the inorganic salts added. The NMR spectrum of the product completely matched the compound obtained in Example 1.

1g1 Table Examples 9 to I3 The same procedure as in Example 1 was carried out except that the compound shown in Table 2 was used as the acid catalyst to be added. The NMR spectrum of the product completely matched the compound obtained in Example 1.

Table 2 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. The NMR spectrum of the product completely matched the compound obtained in Example 1.

Table 3 Examples 25 to 47 The same procedure as in Example 1 was carried out except that the raw material (1) was changed to the compound shown in Table 4. NMR of the obtained product (II)
are shown in Table 6.

(1) (Transfer) Example
To 48: Jt! Example 1 except that 7211 g of diphenyl disulfone was used instead of 70 μm of ammonium sulfinate.
When treated in the same manner as above, the desired product was obtained with a yield of 95%. The NMR spectrum of the product completely matched the compound obtained in Example 1.

Example 49 When treated in the same manner as in Example 1 using 30 μm of a:/Y:nium benzenesulfinate and 40 μm of diphenyldisulfone instead of 70 μm of ammonium benzenesulfinate, the desired product was obtained with a yield of 91%. obtained at a rate. Product N
The MR spectrum completely matched that of the compound obtained in Example 1.

Example 50 The same process as in Example 1 except that anhydrous calcium chloride and squaric acid were not used yielded 85% of the desired product.
was obtained in a yield of . The NMR spectrum of the product completely matched the compound obtained in Example 1.

Example 51 6-phenylacedotridopenicillin-l-oxydodo-3-carboxylic acid methyl ester 80 1. / -fi-) 88 da of dildisulfone, 40 g of anhydrous calcium chloride and IMg of squaric acid are weighed out. Next, add 5 ml of ethyl butanoate and stir to form a suspension. The reactor was maintained at 100°C, immersed in an oil bath, and stirred for 4 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 is purified using silica talc 0 madotarahi, the yield is 8.
Methyl-2-(3-phenylacedoide trido-now-) at 9%
Toichi methylbenzenesulfonylthio-2-azededinon-1-yl)-3-methyl-3-dthenoate was obtained. The NMR spectrum of the product completely matched the compound obtained in Example 28.

Examples 52 to 54 The same procedure as in Example 51 was carried out except that the reagents shown in Table 5 were used instead of di-tolyl disulfone. Product N
The MR spectra are shown in Table 6.

Table 5

Claims (5)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) [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, or a lower alkoxy group. , represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted amino group, or R^
Both 1 and R^2 represent a carbonyl group. R^3 represents a hydrogen atom or a protecting group for a carboxyl group. A penicillin sulfoxide derivative represented by the general formula R^4SO_2NH_4 (II) [wherein R^4 represents a substituted or unsubstituted phenyl group. ]
Ammonium sulfinate salt represented by and/or general formula R^4SO_2SO_2R^4 (III) [wherein R^4 is the same as above. [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, in which the reaction is carried out in the presence of an inorganic salt. (4) Claim 1 in which the reaction is carried out in the presence of an acid catalyst
The method according to any one of Items 3 to 3. (5) The method according to any one of claims 1 to 4, wherein the reaction is carried out at 70 to 120°C.