JPH043400B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a method for producing cephalosporin derivatives. More specifically, the present invention relates to a method for producing compounds useful as intermediates for cephalosporin antibiotics. i.e. 3 of the cephalosporin compounds.
The present invention relates to a method for producing a 3-iodomethylcephalosporin compound useful as an intermediate for introducing various nucleophilic residues into the methyl group.

<Prior art and its problems> Conventionally, as a method for obtaining a 3-iodomethylcephalosporin compound from a 3-acyloxymethylcephalosporin compound, for example, JP-A-57-
As described in Japanese Patent No. 126492, a method using a strong acid such as sulfuric acid or sulfonic acid and a salt of hydroiodic acid such as NaI is known. However, in order to obtain the desired 3-iodomethyl compound in good yield, this method is not necessarily economical, as it is necessary to use expensive trichloromethanesulfonic acid in considerable excess, and furthermore, the starting material 3-iodomethyl compound must be used in considerable excess.
7 of Acyloxymethylcephalosporin Compounds
The amine must be substantially free, and there are restrictions on the raw material compounds to be used. On the other hand, Japanese Patent Publication No. 57-13553 describes a method for producing 3-halomethylcephalosporin compounds by reacting 3-acyloxymethylcephalosporin compounds with 3-halogenated boron. To obtain methylcephalosporin, 3
- It is necessary to prepare boron iodide [Ref. Augew. Chem., 69 , p. 478]
(1957)] cannot be called an industrially advantageous method.

<Object of the Invention> The present inventors have investigated various methods for producing 3-iodomethylcephalosporin compounds from 3-acyloxycephalosporin compounds in an industrially advantageous manner, and as a result, the inventors have developed 3-acyloxycephalosporin compounds. The present invention has been achieved by discovering that a 3-iodomethylcephalosporin compound can be industrially advantageously obtained by reacting the compound with hydroiodic acid or a salt thereof in the presence of 3-boron fluoride. It is.

<Disclosure of the invention> The present invention is based on the following formula [] [In the formula, R ₁ is an amino group, a protected amino group,
or represents an acylamino group, and R ₂ represents an acyloxy group. ] The following formula [], which is characterized by reacting a 3-acyloxymethylcephalosporin compound represented by the formula, a salt thereof, or an ester thereof with hydroiodic acid or a salt thereof in the presence of 3-boron fluoride. [In the formula, R ₁ is the same as the above definition. ] This is a method for producing a 3-iodomethylcephalosporin compound, a salt thereof, or an ester thereof.

R ₁ in the compound of formula [], which is the starting material of the present invention, represents an amino group, a protected amino group or an acylamino group, and is usually used as a free amino group, which is the simplest, for the reaction. However, the amino group may be protected with an appropriate protecting group or may be acylated with an acyl group. Examples of such protecting groups include those commonly used for amino groups in organic synthesis reactions. Specific examples include methyl carbamate, p-fluorenylmethyl carbamate, 2,2,2-trichloroethyl carbamate, t-butyl carbamate, phenyl carbamate, benzyl carbamate, various substituted benzyl carbamates, s-benzyl carbamate, etc. carbamate protecting groups; urea type protecting groups such as N'-piperidinylcarbonyl urea, N'-p-toluenesulfonylaminocarbonyl urea; formamide, acetamide, chloracetamide, trichloroacetamide, phenylacetamide, phenoxyacetamide, Substitution N
- Acylamide protecting groups such as propionylacetamide, benzamide, phthalimide; N-substituted alkyl protecting groups such as N-aryl, N-phenacil, N-benzyl, N-trityl, N-benzyloxymethyl; N-(N', N'-dimethylaminomethylene), N,N'-isopropylidenediamino, N
- Imino group protecting groups such as benzylidene; foreign atom protecting groups such as N-nitrone, N-oxide and diphenylphosphine; silyl protecting groups such as trimethylsilyl; salts with trifluoroacetic acid, formic acid, p-toluenesulfonic acid, etc. etc. In addition to the acyl group used as the above-mentioned protecting group, the acyl group of the acylamino group may be an acyl group used at the 7-position of cephalosporin for the original purpose of antibiotics, such as enhancing antibacterial activity. Such acyl groups may be selected from, for example, those used at the 6- and 7-positions of penicillins and cephalosporins, respectively, which are known so far. Examples of such acyl groups include the following.

(A) Formula [A] R ³ -CO- ...... [A] [In the formula, R ³ represents a hydrogen atom, alkyl, allyl or a heterocyclic group. ] A group represented by .

(B) Formula〔〕 [In the formula, R ⁴ represents a hydrogen atom, an amino acid residue, or a protecting group for an amino group. R ⁵ is alkyl,
Represents an allyl or heterocyclic group. ] Salt expressed as .

(C) Formula〔〕 [In the formula, R ⁶ is allyl or a heterocyclic group, n is 0
Represents an integer between ~2. R ⁵ is the same as defined above. ] A group represented by .

(D) Formula [D] [In the formula, R ⁷ represents an alkyl, allyl or heterocyclic group. R ⁸ represents a hydrogen atom or alkyl. ] A group represented by .

(E) Formula [E] [In the formula, R ⁷ is the same as the above definition. R ⁹ represents alkylene or alkenylene. R ¹⁰ represents allyl, a heterocyclic group, carboxyl or an ester thereof, or a mono- or dialkylamino group.

A group represented by

(F) Formula [F] [In the formula, R ¹¹ represents a hydrogen atom or a protecting group for a carboxyl group. R ⁷ is the same as the above definition. ] (G) Formula [G] [In the formula, R ⁷ is the same as the above definition. ] A group represented by .

(H) Formula [H] R ¹² -R ¹³ -CH ₂ -CO- ...... [H] [In the formula, R ¹² represents cyano, allyl, phenoxy, alkyl, acyloxy, alkenyl or a heterocyclic group. R ¹³ represents a simple bond or -S-. ] A group represented by .

The alkyl in R ₃ , R ⁵ , R ⁷ , R ⁸ , R ¹² in formulas [A] to [H] is preferably a straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl,
Ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-pentyl, n-hexyl,
Examples include isohexyl. Examples of alkenyl for R ¹² include vinyl, aryl, isopropenyl, and the like. R ³ , R ⁵ , R ⁶ , R ⁷ ,
As the heterocyclic group for ^R10 , a 5- to 8-membered ring containing one to several heteroatoms such as nitrogen, oxygen, and sulfur, or a condensed ring thereof having a bond on a carbon atom is used, such as a 2- or 3- frill, 2-
aminothiazole, 2-amino-3,5-thiazole, 2- or 3-thienyl, 2- or 3-
pyrrolidinyl, 2-, 3- or 4-pyridyl,
N-oxide-2-, 3- or 4-pyridyl,
2-, 3- or 4-piperidinyl, 2-, 3-
or 4-pyranyl, 2-, 3- or 4-thiopyranyl, pyrazinyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl,
3-,4- or 5-isothiazolyl, 3-,4
- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxide-3- or 4-pyridazinyl, 2-, 4-
or 5-pyrimidinyl, N-oxide-3-,
4- or 5-pyrimidinyl, piperazinyl, 4
- or 5-(1,2,3-thiadiazolyl),3
- or 5-(1,2,4-thiadiazolyl),
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 4- or 5-(1,2,3-oxadiazolyl), 3- or 5-(1,2,4-oxadiazolyl), 1,3, 4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3
- or 1,2,4-triazolyl, 1H or
2H-tetrazolyl, pyrido[2,3-d]pyrimidyl, benzopyranyl, 1,3-,1,5-,
Examples include 1,6-, 1,7-, 2,7- or 2,6-naphthyridyl, quinolyl, thieno(2,3-b]pyridyl and the like.

Examples of allyl of R ³ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ and R ¹² include phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl and the like.

Examples of alkylene for R ⁹ include methylene,
Examples include ethylene, trimethylene, and tetramethylene.

Examples of alkenylene for R ⁹ include vinylene,
Examples include isopropenylene.

These alkyls, alkenyls, allyls, heterocyclic groups, alkylenes, and alkenylenes may have one or more substituents of the same or different types, such as alkyls, alkoxys, alkenyls, etc. , allyl, aralkyl, mercapto, alkylthio, allylthio, aralkylthio, alkylsulfonyl, allylsulfonyl, hydroxy, oxo, thioxo,
Halogen, nitro, amino, monoalkylamino, dialkylamino, acylamino, cyano,
Carbamoyl, carbamoyloxy, carboxy, acyl, acyloxy, substituted alkyl, etc. are used.

Examples of the amino acid residue of ^R4 include glycine,
Examples include amino acid residues such as alanine and aspartic acid.

Examples of the protecting group for the amino group of R ⁴ include trichloroethoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, trityl, and formyl.

Examples of carboxyl esters of ^R10 include methoxycarbonyl, ethoxycarbonyl, n
-butoxycarbonyl and other esters.

Examples of the monoalkylamino group of ^R10 include methylamino, ethylamino, n-propylamino groups, etc., and examples of the dialkylamino group include dimethylamino, diethylamino, di-n-propylamino groups, etc. .

Examples of the protecting group for the carboxyl group of R ¹¹ include alkyl groups such as methyl, ethyl, and propyl.

Examples of the acyloxy group for R ¹² include acetyloxy, propionyloxy, butyryloxy, and valeryloxy groups.

R ₂ in the compound of formula [] is an acyloxy group, and the acetoxy group derived from cephalosporin C, which is the basic raw material for cephalosporin antibiotics, is most commonly used. Other acyloxy groups include, for example, trifluoroacetyloxy, trichloroacetyloxy, propionyloxy, 3-carboxypropionyloxy, 3-
Examples include ethoxycarbamoyloxy group.

4 of the compound of formula [] which is the starting material of the present invention
The carboxylic acid position is usually used in the reaction as a free carboxylic acid, but the carboxyl group may be salted or esterified. Examples of the salt include alkali metal salts such as sodium, potassium, and lithium; and organic amine salts such as ammonium trialkylammonium. As the ester, it is inert to the reaction and is commonly used as a protecting group for carboxyl groups in the field of organic chemistry. For example, methyl, ethyl, n-propyl, isopropyl, t
-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, 1-indanyl, phenancy, phenyl, p
-nitrophenyl, methoxymethyl, benzyloxymethyl, tetrahydropyranyl, diacylmethyl, 222-trichloroethyl, 2-trimethylsilylethyl, 2-methylthioethyl, 2-(p
-Ester residues such as -toluenesulfonyl)ethyl, trimethylsilyl, t-butyldimethylsilyl, s-t-butyl, s-phenyl, s-2-pyridyl; silyl groups such as trimethylsilyl, t-butyldimethylsilyl; thioester groups, etc. is used.

According to the present invention, the target compound of formula [] can be obtained by reacting the above-mentioned raw material [] with hydroiodic acid or a salt thereof in the presence of 3-boron fluoride. Examples of salts of hydroiodic acid include alkali metal salts such as lithium iodide, sodium iodide, and potassium iodide; organic ammonium salts such as tetramethylammonium iodide, tetraethylammonium iodide, and tetra-n-butylammonium iodide. It will be done. The amount of hydroiodic acid or its salt used is usually equimolar or slightly excessive based on the raw material ().

The other reaction reagent, 3-boron fluoride, can be used as an anhydrous free system or as an ether such as ethyl ether, an alcohol such as methanol or ethanol, an organic acid such as acetic acid, trifluoroacetic acid, or propionic acid, or a nitrile such as acetonitrile. It can also be used in the form of solvates such as amides. 3-
The amount used for boron fluoride raw material (1) is usually
It is used in an amount of 0.5 to 5 times the mole, preferably 1 to 4 times the mole.

The reaction is usually carried out in a solvent under heating or cooling. Examples of solvents used include acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, dioxane, sulfolane, sulfite anhydride, and nitrobenzene. The reaction temperature and time are appropriately selected depending on the solvent used and the form of the solvate of 3-boron fluoride used.

Usually, the reaction temperature is -10°C to 60°C, and the reaction time is several minutes to several hours.

Post-treatment after the reaction is carried out as follows. The reaction mixture is poured into a non-solvent with low solubility for the reaction mixture, such as ether, tetrahydrofuran, dioxane, etc., the resulting solid substance is separated, and then the solid substance is purified by ordinary purification methods such as recrystallization and chromatography. The desired 3-iodomethylcephalosporin compound can be isolated and purified.

This invention will be explained below with reference to Examples.

Example 1 2.72 g of 7-aminocephalosporanic acid
(10mmol), sodium iodide 1.5g (10mmol)
Add 5 ml (30 mmol) of a solution of 3-boron fluoride in acetonitrile to a mixture of 15 ml of acetonitrile under ice cooling, and stir at 30°C for 15 minutes. This solution was dispersed in 100 ml of ether, and the precipitate precipitated was dried under reduced pressure to obtain ocher-colored 7-amino-3-iodomethyl-cephem-4-carboxylic acid in a yield of 65%.

NMR (DCl) δ: 5.39 (d, 1H, J = 5Hz), 5.18 (d, 1H, J =
5Hz), 4.54 (s, 2H), 3.80 (brm, 2H) IR (Nudiyol): 1775cm ^-1 Example 2 7-Aminocephalosporanic acid 2.72g
(10mmol), sodium iodide 1.5g (10mmol)
To a mixture of 15 ml of acetonitrile was added 4.26 g (30 mmol) of 3-fluoroboron etherate under ice cooling, and the mixture was stirred at 40°C for 4 hours. This solution was treated in the same manner to give an ocher-colored 7-amino-3-iodomethyl-
Cefem-4-carboxylic acid was obtained with a yield of 32%.

Example 3 7-aminocephalosporanic acid 2.72g
(10 mmol) in a mixture of 15 ml of acetonitrile
-5 ml of boron fluoride acetonitrile solution
(30 mmol) was added under ice-cooling and stirred at 30°C for 15 minutes. This solution was treated in the same manner to obtain ocher-colored 7-amino-3-iodomethyl-cephem-4-carboxylic acid in a yield of 62%.

Example 4 5 ml (30 mmol) of an acetone solution of boron trifluoride is added to a mixture of 2.72 g of 7-aminocephalosporan, 1.5 g of sodium iodide and 15 ml of acetone under ice cooling, and the mixture is stirred at 30°C for 15 minutes. This solution was treated in the same manner to obtain ocher-colored 7-amino-3-iodomethyl-cephem-4-carboxylic acid in a yield of 53%.

Example 5 (6R,7R)-7-[(Z)-2-(2-bistrimethylsilylaminothiazol-4-yl)-2
-Methoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid 3.0 g,
A solution of boron trifluoride in acetonitrile in a mixture of 0.75 g of sodium iodide and 15 ml of acetonitrile
ml was added under ice-cooling, and the mixture was stirred at 40°C for 15 minutes. After the reaction, the same treatment as in Example 1 was carried out to obtain (6R,7R)-7.
-[(Z)-2-(2-bistrimethylsilylaminothiazol-4-yl)-2-methoxyiminoacetamide]-3-iodomethyl-3-cephem-4-carboxylate 1.40 g (yield 41%) was obtained. Ta.

Example 6 (6R,7R)-7-[(Z)-2-(2-bistritylaminothiazol-4-yl)-2-(2-methoxycarbonylpropyl-2-yloxyimino)acetamide]-3 -acetoxymethyl-3
To a mixture of 3.36 g of -cephem-4-carboxylic acid and 0.75 g of sodium iodide in 15 ml of acetonitrile, 5 ml of a solution of boron trifluoride in acetonitrile was added under ice cooling, and the mixture was stirred at 40°C for 15 minutes. Post-reaction Example 1
Perform the same process as (6R, 7R)-7-[(Z)-
2-(2-bistrimethylsilylaminothiazol-4-yl)-2-methoxycarbonylpropyl-2-yloxyimino)acetamide]-3
-iodomethyl-3-cephem-4-carboxylic acid
1.44 g (yield 38%) was obtained.

Reference Example 3.4 g of 7-amino-3-iodomethyl-cephem-4-carboxylic acid obtained in Example was suspended in 50 ml of acetonitrile, 7.5 g of bistrimethylsilylacetamide was added at room temperature, and after further stirring for 1 hour, -20 ℃, slowly added 1.0 g of 1-azabicyclo[3,3,0]octane and stirred at the same temperature for 1 hour to obtain 7-bistrimethylsilylamino-3-(1-azabicyclo[3,3,
0] An acetonitrile solution of trimethylsilyl ester of octane-1-io)methyl-3-cephem-4-carboxylic acid was prepared. Separately (Z)-2
4.2 g of -hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid was reacted with 2.1 g of PCl ₅ in 50 ml of dichloromethane at room temperature to give (Z)-2-hydroxyimino-2-(2 A solution of (tritylaminothiazol-4-yl) acetic acid chloride was prepared, and this solution was added to the above solution acid at room temperature to react. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure to obtain 13.5 g of foamy solid as a residue.

The foamy solid was dissolved in 200 ml of dimethyl sulfoxide, and a mixture of 2.0 ml of iodomethyl and 5.5 g of potassium carbonate was stirred at room temperature for 2 days. After reaction, water
The resulting precipitate was poured into 50 ml of trifluoroacetic acid containing 10% water and stirred vigorously for 3 hours at room temperature. 500ml of reaction solution
The resulting precipitate was collected by filtration, washed with acetone, and dried.

Extract the precipitate by thoroughly reslurrying the precipitate with 100 ml of water at 40°C and then filtering. Concentrate the extract and transfer to HP-
Purification was carried out in a 20 ion exchange resin column using a water-acetone mixed solvent while increasing the acetone ratio sequentially from 0 to 40%. 430 mg of solid material was obtained from the fraction mainly containing the title compound, and the estimated purity was 41% as confirmed by high performance liquid chromatography.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ₁ is an amino group, a protected amino group,
or represents an acylamino group, and R ₂ represents an acyloxy group. ] The following formula [], which is characterized by reacting a 3-acyloxymethylcephalosporin compound represented by the formula, a salt thereof, or an ester thereof with hydroiodic acid or a salt thereof in the presence of 3-boron fluoride. [In the formula, R ₁ is the same as the above definition. ] A method for producing a 3-iodomethylcephalosporin compound, a salt thereof, or an ester thereof.