JPH08311069A - Production of exomethylenecepham - Google Patents

Abstract

PURPOSE: To industrially and readily produce an exomethylenecepham which is an important key intermediate for a new cephalosporin derivative from a cephemcarboxylic acid. CONSTITUTION: (A) A 3-cephemcarboxylic acid of formula I (R is H or an amino-protecting group) is converted into (B) an acid chloride of formula II according to a well-known method and the resultant acid chloride is then reacted with 1-5mol base (especially preferably N-methylpiperidine) and 1-10mol ester- forming alcohol (e.g. methyl alcohol, ethyl alcohol, allyl alcohol or benzyl alcohol) to afford (C) an exomethylenecephamcarboxylic acid ester of formula III (R' is an ester-forming alcohol residue). For example, benzyl 7- phenylacetamido-3-exomethylenecephamcarboxylate is cited as the compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for converting a 3-cephemcarboxylic acid represented by the general formula (II) into an exomethylenecepham carboxylic acid ester represented by the general formula (I).

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[0002]

2. Description of the Related Art The 3-cephemcarboxylic acid represented by the above general formula (II) is converted into the acid chloride represented by the general formula (III), and 1 to 5 mol of a tertiary amine base or solid base is used. And 1
It is known to form a cephemcarboxylic acid ester by reacting ˜10 mol of an ester-forming alcohol, and J. Org. Chem., 35 , 2429 (1970) and Japanese Patent Laid-Open No.
As reported in -13276, the general formula (IV)

Embedded image (In the formula, R is hydrogen or an amino protecting group, and R ′ represents a residue of an ester-forming alcohol.), 2-cephemcarboxylic acid ester is obtained.

[0003]

It is generally known that the antibacterial activity of cephalosporin derivatives is enhanced by chemical modification at the 3'position, and many derivatives have been studied.

[Chemical 4] As shown in Reaction Scheme 1, in the synthesis of the cephalosporin derivative, activation of the 3 ′ position is important for the derivative synthesis,
The compound in which the 3'position is activated is described in J. Am. Chem. Soc., 9
9, 2822 can be derived from exomethylenecepham skeleton represented by (1977) and US4042585 and as reported in DE2324272 easily general formula (I). Where X is C
and halogen atoms such as Br and Br. Further, this compound can be converted into a cephalosporin derivative by reacting with a nucleophile by a known method. Examples of the nucleophile are shown below.

Embedded image In addition, the nor-type cephalosporin derivative found in the oral cephalosporin derivative has a general formula as shown in reaction formula 2.
It can be easily synthesized by ozone oxidation of the exomethylenecepham skeleton represented by (I).

[Chemical 6] Thus, exomethylenecepham represented by the general formula (I) is an important key intermediate for a novel cephalosporin derivative. The present inventors paid attention to the above points and studied a novel method for producing an exomethylene skeleton which is easy to carry out industrially and is low in cost.

[0004]

[Means for Solving the Problems] J.Org.Chem., 35 , 2429 (19
70) and Japanese Patent Application Laid-Open No. 50-13276, 3-cephemcarboxylic acid represented by the general formula (II) is converted to an acid chloride represented by the general formula (III) to give 1 to 5 The 2-cephem carboxylic acid ester represented by the general formula (IV) is obtained by reacting mol of a tertiary amine base or solid base with 1 to 10 mol of an ester-forming alcohol.
This series of reactions is shown in Reaction Formula 3.

[Chemical 7] (In the formula, R is hydrogen or an amino-protecting group, and R'represents a residue of an ester-forming alcohol.) Here, R is an amino-protecting group well known in the art of penicillin and cephalosporin. The amino protecting group of the method includes, for example, benzoyl group, P-chlorobenzoyl group, p-nitrobenzoyl group, p-hydroxybenzoyl group, p-methoxybenzoyl group, phenylacetyl group, phenylglycyl group, and amino group protecting group. Phenylglycyl group, α-sulfophenylacetyl group, α-hydroxyphenylacetyl group, α-carbamoylphenylacetyl group, p-chlorophenylacetyl group, p-chlorophenoxyacetyl group, p-bromophenoxyacetyl group, p
-Methoxyphenoxyacetyl group, tetrazolylacetyl group, mercapto-substituted phenylacetyl group, 2-aminothiazolylacetyl group, furylacetyl group, thienylacetyl group, triphenylmethyl group, benzyloxycarbonyl group, t-butoxycarbonyl group , Trichloroethoxycarbonyl group and the like.

This reaction is considered to proceed through a ketene intermediate, but it is described by J. Org. Chem., 35 , 2429 (1970) and the general formula (Japanese Patent Application Laid-Open No. 50-13276). The ketene intermediate in the case where the 2-cephemcarboxylic acid ester represented by IV) is obtained is the ketene intermediate (1) shown in Reaction Scheme 3. However, when the present inventors convert 3-cephemcarboxylic acid represented by the general formula (II) into an acid chloride represented by the general formula (III) and react with a tertiary amine base, the It is believed that the ketene intermediate (2) is produced and reacts with the ester-forming alcohol to obtain the exomethylenecepham carboxylic acid ester represented by the general formula (I). They have found that they can be solved and completed the present invention. That is, the present invention is a process for producing an exomethylenecepham carboxylic acid ester (I), which comprises the following two steps. a) a step of converting 3-cephemcarboxylic acid represented by the general formula (II) into an acid chloride represented by the general formula (III) b) 1 to 5 mol of the acid chloride represented by the general formula (III) To the exomethylenecepham carboxylic acid ester represented by the general formula (I) by reacting 1 to 10 mol of an ester-forming alcohol with a base of

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As the first step, 3- represented by the general formula (II)
The cephemcarboxylic acid is converted to the acid chloride represented by the general formula (III). Conversion of acid chloride of carboxylic acid is a well-known method, and reagents used include phosgene, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, and Vilsmeier reagent represented by the formula (V). Further, these reactions are known to proceed smoothly if an anhydrous neutral solvent is used.

[Chemical 9]

In the second step, the chloride represented by the general formula (III) is treated with a base and an ester-forming alcohol as the reaction solution. Examples of bases used are tertiary amines or solid bases. Specific examples of the tertiary amine include N-methylpiperidine, N-ethylpiperidine, trimethylamine, triethylamine, diisopropylethylamine, pyridine, N, N'-dimethylaminopyridine, diazabicyclononane, diazabicycloundecene, triethylenediamine. , Tetramethylethylenediamine, etc. are considered, but N-methylpiperidine is most preferable. Examples of the solid base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide, solid bases thereof and alumina carrier, or solid bases and molecular sieves carrier. With triethylamine J.Org.Che
m., 35 , 2429 (1970) and Japanese Patent Application Laid-Open No. 50-13276, 2-cephemcarboxylic acid ester represented by the general formula (IV) is the main product. The alcohol used as the ester-forming alcohol means an alcohol having a hydroxyl group bonded to an aliphatic hydrocarbon or silicon, and this definition is an alcohol containing an aromatic ring as long as the hydroxyl group is bonded to an aliphatic carbon atom or silicon. Is also included. Examples of these alcohols include methyl alcohol, ethyl alcohol, t-butyl alcohol, allyl alcohol,
Examples thereof include 3-methyl-1-buten-3-ol, benzyl alcohol, p-methoxybenzyl alcohol, benzhydrol, t-butyldimethylsilanol and the like.
The alcohol used in the present invention is not limited to the above, but it is desirable that it can be easily converted from an ester to a corresponding acid. In addition, there is a difference in the reactivity of the primary, secondary and tertiary alcohols, the optimum is 2-3 equivalents for the primary and secondary alcohols, and 5-10 equivalents are required for the tertiary alcohols. The base used is 2
3 equivalents are desirable, and if less than this amount, the reaction is incomplete. The temperature used in this reaction varies depending on the type of alcohol, but is preferably -80 to 0 ° C. At temperatures above this, 3
-Isomerization to cephem ester occurs and yield decreases. Also, it is desirable to carry out this reaction in an anhydrous solvent,
Methylene chloride, chloroform, tetrahydrofuran, dimethoxyethane, ethyl acetate, acetonitrile and the like are used. At this time, the yield is improved by adding a small amount of hexamethylphosphoric triamide, dimethyl sulfoxide, dimethylformamide or the like.

[0008]

INDUSTRIAL APPLICABILITY According to the present invention, when the 3-cephemcarboxylic acid is introduced into an acid chloride and esterification is performed, the base used is exomethylenecepham carboxylic, which is an important key intermediate of a novel cephalosporin derivative. The acid ester can be selectively industrially applied and can be obtained at low cost.

[0009]

EXAMPLES Next, typical examples of the present invention will be given.
It goes without saying that the present invention is not limited to these.

Example 1 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid benzyl ester 1.26 g of phosphorus pentachloride in 30 ml of methylene chloride at 35 ° C.
Was dissolved and cooled to −40 ° C., and then 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid.2.
00 g is added, and the mixture is stirred at -40 ° C for 1.5 hours. The reaction solution was cooled to −60 ° C. and 1.32 ml of benzyl alcohol.
Is added dropwise, and then 2.32 ml of N-methylpiperidine is added dropwise in about 30 minutes. After stirring at -60 ° C for 1.5 hours, 5.0 ml of acetic acid was added, the temperature was raised to 0 ° C, and 0.25N was added.
Wash with hydrochloric acid, water, 2% sodium hydrogen carbonate solution, water. After drying over magnesium sulfate and drying to dryness, 3.20 g of a foamy solid was obtained. This was purified by silica gel chromatography and ODS chromatography, 1.31 g
Was obtained as a white solid. NMR was consistent with the indicated structure of the title compound.

NMR (CDCl ₃ ) δ 3.15 (1H, d),
3.60 (1H, d), 3.64 (1H, d), 5.10 (1H, s), 5.14 (1H,
d), 5.20 (1H, s), 5.22 (1H, S), 5.35 (1H, d), 5.65 (1
H, q), 6.15 (1H, bd), 7.20 ~ 7.40 (10H, m)

Example 2 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid benzyl ester Vilsmeier reagent ((V)) in 30 ml of methylene chloride
After adding 1.10 g and cooling to -15 ° C, 2.12 g of 7-phenylacetamido-3-methyl-3-cephem-4-carboxylic acid is added, and the mixture is stirred at -15 ° C for 1 hour. -6
After cooling to 0 ° C., 1.42 ml of benzyl alcohol was added dropwise, and then 2.31 g of N-methylpiperidine was added dropwise in about 30 minutes. After stirring at -60 ° C for 1 hour, the mixture was purified in the same manner as in Example 1 to obtain 1.34 g of a white solid. NMR was consistent with Example 1.

Example 3 7-Phenylacetamide-3-exomethylene sepha
Mumo-4-carboxylic acid benzyl ester 7-phenylacetamide-3 in 20 ml of benzene
-Methyl-3-cephem-4-carboxylic acid (1.50 g) is suspended, dimethylformamide (40 µl) and oxalyl chloride (0.78 ml) are added, and the mixture is stirred at 10 ° C for 2 hours.
The red reaction solution is dried to dryness, dissolved in 20 ml of methylene chloride and cooled to -60 ° C. Benzyl alcohol (0.99 ml) is added dropwise at the same temperature, and then N-methylpiperidine (1.61 ml) is added dropwise in about 30 minutes. 1.5 at -60 ° C
After stirring for hours, purification was carried out in the same manner as in Example 1 to obtain 0.80 g of white solid. NMR was consistent with Example 1.

Example 4 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid p-methoxybenzyl ester In the same manner as in Example 2 except that 1.58 ml of p-methoxybenzyl alcohol was used instead of benzyl alcohol, 1.59 g of a white solid was obtained. NMR was consistent with the indicated structure of the title compound.

NMR (CDCl ₃ ) δ 3.15 (1H, d), 3.
60 (1H, d), 3.63 (1H, d), 3.66 (1H, d), 5.10 (1H, s),
5.13 (1H, d), 5.16 (1H, d), 5.20 (1H, s), 5.22 (1H,
s), 5.35 (1H, d), 5.65 (1H, q), 6.10 (1H, d), 7.20 ~
7.40 (9H, m)

Example 5 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid p-methoxybenzyl ester It was treated in the same manner as in Example 4 except that tetrahydrofuran was used as the solvent instead of methylene chloride to obtain 1.58 g of a white solid. NMR was consistent with Example 4.

Example 6 7-Phenylacetamide-3-exomethylene sepha
After preparing m-4-carboxylic acid p-methoxybenzyl ester acid chloride, the same treatment as in Example 4 was carried out except that 3.3 ml of hexamethylenephosphoric triamide was added to the reaction solution, to obtain 1.92 g of white. A solid was obtained. NMR
Was in agreement with Example 4.

Example 7 7-Phenylacetamide-3-Exomethylene Sepha
Mu-4-carboxylic acid benzhydryl ester An acid chloride was prepared in the same manner as in Example 2, cooled to -60 ° C, added with 0.77 ml of N-methylpiperidine, and immediately heated to -45 ° C. A solution of 1.12 ml of N-methylpiperidine and 5.83 g of benzhydrol in methylene chloride was added dropwise at -45 ° C in about 30 minutes. At this time, the temperature in the system rose to -25 ° C. 5 minutes later, 5.0 ml acetic acid
Is added, the temperature is raised to 0 ° C., and the mixture is washed with 0.25N hydrochloric acid, water, 2% sodium hydrogen carbonate and water. Dry over magnesium sulfate and dry to dryness, silica gel chromatography, ODS
Purification by chromatography gave 1.53 g of white solid.

NMR (CDCl ₃ ) δ 3.10 1H (d), 3.50
1H (d), 3.64 1H (d), 3.67 1H (d), 5.15 1H (s), 5.25 1H
(s), 5.30 1H (s), 5.35 1H (d), 5.70 1H (q), 6.15 1H (d),
6.85 1H (s), 7.20 ~ 7.45 15H (m)

Example 8 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid methyl ester Instead of benzyl alcohol, 0.52 ml of methanol
Was treated in the same manner as in Example 2 except that a mixed solution of methanol and N-methylpiperidine was added dropwise.
Was obtained as a white solid. NMR was consistent with the indicated structure of the title compound.

NMR (CDCl ₃ ) δ 3.15 (1H, d), 3.
67 (1H, d), 3.63 (1H, d), 3.66 (1H, d), 3.75 (3H, s),
5.07 (1H, s), 5.19 (1H, s), 5.21 (1H, s), 5.40 (1H,
d), 5.70 (1H, q), 6.10 (1H, d), 7.20 ~ 7.40 (5H, m)

Example 9 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboxylic acid allyl ester Allyl alcohol 0.8 instead of benzyl alcohol
Using 6 ml, the same procedure as in Example 2 was carried out except that a mixed solution of allyl alcohol and N-methylpiperidine was added dropwise to obtain 1.72 g of a white solid. NMR was consistent with the indicated structure of the title compound.

NMR (CDCl ₃ ) δ 3.15 (1H, d),
3.66 (1H, d), 3.64 (1H, d), 3.68 (1H, d), 4.62 (1H,
d), 5.07 (1H, s), 5.21 (1H, s), 5.23 (1H, s), 5.28 (1
H, d), 5.31 (1H, d), 5.39 (1H, d), 5.69 (1H, q), 5.89
(1H, m), 6.10 (1H, d), 7.20 ~ 7.40 (5H, m),

Example 10 7-Phenylacetamide-3-exomethylene sepha
Mu-4-carboic acid t-butyl ester An acid chloride was prepared in the same manner as in Example 2, cooled to -60 ° C, added with 0.76 ml of N-methylpiperidine, and immediately heated to -40 ° C. A solution of 1.15 ml of N-methylpiperidine and 6.03 ml of t-butanol in methylene chloride was added dropwise at -40 ° C in about 30 minutes. At this time, the temperature in the system rose to -25 ° C. 5 minutes later acetic acid 5.0 ml
Was added and the temperature was raised to 0 ° C., 0.25N hydrochloric acid, water, 2%
Wash with sodium hydrogen carbonate solution, water. After drying with magnesium sulfate, the mixture was dried and purified by silica gel chromatography to obtain two types of white solids having different Rf values. The solid with the higher Rf value was repurified by ODS chromatography to obtain 1.03 g of a white solid. N
MR was consistent with the indicated structure of the title compound.

NMR (CDCl ₃ ) δ 1.45 (9H, s), 3.
15 (1H, d), 3.65 (1H, d), 3.60 (1H, d), 3.65 (1H, d),
4.92 (1H, s), 5.20 (2H, s), 5.40 (1H, d), 5.70 (1H,
q), 6.12 (1H, d), 7.20-7.40 (5H, m) NMR of 0.44 g of a white solid with a low Rf value showed the indicated structure of the 4-position epimer of exomethylenecepham.

NMR (CDCl ₃ ) δ 1.42 (9H, s), 3.
30 (1H, d), 3.65 (1H, d), 3.66 (1H, d), 3.67 (1H, d),
4.57 (1H, s), 4.95 (1H, d), 5.32 (1H, s), 5.34 (1H,
s), 5.45 (1H, q), 6.30 (1H, d), 7.20 ~ 7.40 (5H, m)

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yasushi Murai 788 Meiji Confectionery Co., Ltd., Kajiyama, Odawara, Kanagawa Prefecture (72) Inventor Katsuharu Iinuma 788 Meiji Confectionary Co., Ltd., Meiji Confectionery Co., Ltd.

Claims (1)

[Claims] 1. A method for producing an exomethylenecepham carboxylic acid ester represented by the general formula (I), comprising: a) converting the 3-cephem carboxylic acid represented by the general formula (II) into the general formula (III); B) conversion to the acid chloride represented by the general formula (III) by reacting the acid chloride represented by the general formula (III) with 1 to 5 mol of a base and 1 to 10 mol of an ester-forming alcohol. The production method characterized by the step of converting into an exo-methylene cepham carboxylic acid ester shown in. Embedded image (In the formula, R represents hydrogen or an amino protecting group, and R ′ represents a residue of an ester-forming alcohol.)