JPS6127399B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 2-azido-2-cephem compound, more specifically, a compound having the formula (In the formula, R ₁ represents an acylamino group, R ₂ represents an alkyl group or a substituted alkyl group, and R ₃ represents a hydrogen atom or acetoxy.) The compound represented by the formula is treated with a base to perform a dehydrogenation reaction. formula consisting of
(In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in the formula.)

Many of the cephalosporin antibiotics are effective against Gram-positive and Gram-negative bacteria, and have the advantage that they are stable against acids and penicillinase, and can be administered to patients who are hypersensitive to penicillin. It has attracted attention from all over the world, and several excellent antibiotics have been developed to date. However, since the emergence of resistant bacteria with these antibiotics is inevitable, there is a need for the development of newer antibiotics in these areas. On the other hand, most of the many cephalosporin antibiotics that have been developed so far are ranked 7th.
Or, various substituents have been introduced into the 3-position,
There are almost no known compounds with a substituent introduced at the 2-position.

The present inventors previously invented a method for introducing an azide group into the 2-position of a 2-cephem compound, and a halogen atom or an azide group into the 3-position. The present invention was completed based on the new finding that when a 2,3-diazide-cephalic compound is treated with a base, a dehydrogenation reaction occurs and a novel 2-azido-2-cephalic compound is obtained.

According to the invention, 2-azido-
2-Cefem compound is represented by the formula 2.3
It is synthesized by treating a -diazide-cephame compound with a base in the presence or absence of an inert solvent to perform a dehydrogenation reaction.

In the present invention, various 2,3-diazide-cephaem compounds are used as raw materials.
It is related to the dehydrogenation reaction between the azide group at position and the hydrogen atom at position 2, and the 3
The side chain groups bonded to the 4-, 7-, and 7-positions do not directly participate in the reaction of the present invention. Therefore, in general, these 2,3-diazide-cephame compounds can be used under the reaction conditions of the present invention, that is, in the dehydrogenation reaction with a base, as long as they do not cause substantially undesirable side reactions. It is possible to use. Preferred examples of such 2,3-diazide-cephem compounds include compounds represented by the formula. Specific examples of the group represented by the formula _R1 include, for example, phenylacetamide, α-amino-α- with a protected amino group,
Phenylacetamide, α-carboxy-α-phenylacetamide with protected carboxy group,
Phenoxyacetamide, phenylthioacetamide, α-amino-α-arylalkyl acetamide with amino group protected, α-amino-α-alkylacetamide with amino group protected, α
-Phenyl-α-acyloxyacetamide, sulfo-protected α-sulfo-α-phenylacetamide, α-alkyloxy-α-phenylacetamide, sulfo-protected α-sulfo-
Acylamino group-based ones such as α-alkylacetamide can be mentioned, and specific examples of the group represented by _R2 include methyl, ethyl, t-butyl,
2,2,2-trichloroethyl, benzyl, p-
Alkyl groups or substituted alkyl groups such as methoxybenzyl, p-nitrobenzyl, benzhydryl, trityl, ethoxymethyl, phenacyl and pivaloylmethyl may be mentioned, and specific examples of the group represented by _R3 include a hydrogen atom or acetoxy. be able to.

The 2,3-diazide-cephame compound represented by the formula used as a raw material in the present invention is represented by the formula (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in the formula.)
It is produced by reacting in an inert solvent such as carbon tetrachloride under conditions that generate a halogenated azide (using 2 or more moles of NaN ₃ per 1 mole of ICl).

The base used for carrying out the dehydrogenation reaction is 1,4-diazabicyclo[2,2,
2] Tertiary amines such as octane, trimethylamine, triethylamine, tripropylamine and tributylamine; secondary amines such as dimethylamine, diethylamine, dipropylamine and dibutylamine; and the like. Among these bases, 1,4-diazabicyclo[2.
2.2] Octane.

The amount of base used varies depending on the reaction conditions, such as the type of 2,3-diazide-cefam compound represented by the formula as a raw material, the type of base, and the type of inert solvent or its presence or absence. It is used in an amount of 1 mole to an excess mole per mole of the 2,3-diazide-cepham compound represented by the formula.

Examples of inert solvents include alcohols such as methanol, ethanol, propanol, and butanol, acetone and methyl ethyl ketones, esters such as methyl acetate, ethyl acetate, and methyl propionate, ether, tetrahydrofuran, and 1.
Ethers such as 4-dioxane, aromatic hydrocarbons such as benzene and toluene, dichloromethane,
Chlorine-containing compounds such as chloroform and carbon tetrachloride, nitriles such as acetonitrile, nitro group-containing compounds such as nitromethane and nitroethane, amides such as N/N-dimethylformamide, N/N-dimethylacetamide, and hexamethylphosphoramide. , sulfolane, dimethyl sulfoxide and carbon disulfide. These inert solvents are used to facilitate the dehydrogenation reaction with a base, but may not be present depending on the type of the base and the raw material 2,3-diazide-cephame compound.

The reaction time and reaction temperature are 2.
Although it is not constant because it is greatly affected by the type of 3-diazide-cephaam compound, the type and amount of the base, the type of inert solvent and its presence or absence, etc., in most cases the temperature is 30 minutes to 3 at 60 to -30°C. It is held for days.

After completion of the reaction, it is not necessary to use any special method to separate and purify the 2-azido-2-cephem compound of the formula from the reaction mixture, and any well-known means commonly used for such purpose, such as solvent extraction, etc.
The objective can be easily achieved by washing, solvent distillation, crystallization, recrystallization, column chromatography, etc. in some cases.

The compound of formula obtained by the method of the invention is 3-
By deriving a cefem compound or changing the azide group at the 2-position, it is possible to synthesize a new type of cephalosporin antibiotic. Extremely useful as a synthetic intermediate.

The present invention will be explained in more detail and concretely by referring to Reference Examples and Examples of the present invention, but these are not intended to limit the scope of the present invention.

Reference Example 1 p-Methoxybenzyl-7-phenylacetamide-2,3-diazide-3-methyl-cepham-4-carboxylate 2.60 g of NaN ₃ was suspended in dry nitromethane -5
A solution of 2.98 g of ICl dissolved in dry nitromethane was added dropwise over 10 minutes while stirring while maintaining the temperature at -10°C.
After stirring for a while, it was cooled to -30°C, and p-methoxybenzyl-7-phenylacetamido-3-methyl-2
- Add 1.81 g of cephaam-4-carboxylate in small portions. After keeping at -30°C for 10 minutes, the mixture was gradually returned to room temperature and stirring was continued for 2 hours and 10 minutes. After the reaction was completed, the reaction solution was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and washed with diluted sodium thiosulfate solution.
After washing with water and drying, the solvent was distilled off under reduced pressure to obtain 2.117 g (98.5%) of p-methoxybenzyl-7-phenylacetamido-3-methyl-2,3-diazide-cepham-4-carboxylate.

IRν ^KBr _nax cm ^-1 : 3280 (NH), 2110 (N ₃ ) 1775 (
β
-lactam), 1740 (CO ₂ R) 1660 (CONH) Reference example 2 p-methoxybenzyl-7-(α-t-butoxycarbonylamino-α-phenylacetamide)-3-methyl-2,3-diazide- Cepham-4-carboxylate NaN ₃ 497 mg was suspended in dry nitromethane, -5
A solution of 561 mg of ICl dissolved in dry nitromethane is added dropwise over 10 minutes while stirring while maintaining the temperature between ℃ and -10℃.
After stirring for a while, it was cooled to -40°C and p-methoxybenzyl-7-(α-t-butoxycarbonylamino-α
350 mg of -phenylacetamide)-3-methyl-2-cephem-4-carboxylate are added in small portions. After keeping at -35°C to -30°C for 30 minutes, stirring was continued for 2 hours while gradually returning the temperature to room temperature. After the reaction was completed, the reaction solution was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and washed with diluted sodium thiosulfate solution.
After washing with water and drying, the solvent was distilled off under reduced pressure. yield of 397 mg (98.8%). This is almost pure, but it becomes pure when column chromatography is performed using a silica gel column and a mixture of benzene and ethyl acetate (volume ratio 4:1) as the eluent.

IRν ^KBr _nax cm ^-1 : 3320 (NH), 2120 (N ₃ ) 1780 (
β
-lactam), 1740 (CO ₂ R) 1685 (OCONH) Example 1 p-methoxybenzyl-7-phenylacetamido-2-azido-3-methyl-2-cephem-4-carboxylate p-methoxybenzyl-7 -Phenylacetamide-2,3-diazide-3-methyl-cepham-4-carboxylate (2.04 g) was dissolved in dichloromethane, and while ice-cooled and stirred, 1,4-diazabicyclo[2.2.2]octane (658 mg) was dissolved in dichloromethane. Add the solution dropwise and leave it in an ice room overnight. After the reaction is completed, the reaction solution is washed with water, washed with dilute hydrochloric acid, washed with water, dried, and the solvent is distilled off, p-methoxybenzyl-
7-phenylacetamido-2-azido-3-methyl-2-cephem-4-carboxylate
Obtained in yield of 1.84g (98.0%). When this is purified using methanol, the melting point is 124°C to 127°C (decomposition).
becomes a crystal.

Elemental analysis C ₂₄ H ₂₃ N ₅ O ₅ S ₁ C H N Calculated value 58.41 4.70 14.19 Actual value 58.06 4.64 13.93 IRν ^KBr _nax cm ^-1 : 3270 (NH), 2110 (N ₃ ) 1785 (
β
-lactam), 1730 (CO ₂ R) 1650 (CONH) NMR τ (CDCl ₃ , 60MHz) 8.30 (3H, s), 6.43 (2H, s) 6.24 (3H, s), 5.26 (1H, s) 4.93 ( 2H, s), 4.65 (1H, d) 4.45 (1H, q), 2.97 (4H, q) 2.75 (5H, s) Example 2 p-methoxybenzyl-7-(α-t-butoxycarbonylamino-α p-methoxybenzyl-7-(α-t-butoxycarbonylamino-α-phenylacetamide)-2,3-diazide 187.9 mg of -3-methyl-cepham-4-carboxylate was dissolved in dichloromethane, and a solution of 51.6 mg of 1,4-diazabicyclo[2.2.2]octane dissolved in dichloromethane was added dropwise under ice-cooling and stirring, and the mixture was kept in an ice room overnight. put. After completion of the reaction, the reaction solution was washed with water, washed with dilute hydrochloric acid, washed with water and dried, and the solvent was distilled off to give p-methoxybenzyl-7-(α-t-butoxycarbonylamino-α
-phenylacetamido)-2-azido-3-methyl-2-cephem-4-carboxylate
Obtained in a yield of 165 mg (94.2%).

IRν ^KBr _nax cm ^-1 : 2110 (NN ₃ ) 1785 (β-lactam
) NMR τ (CDCl ₃ , 60MHz) 8.59 (9H, s), 8.28 (3H, s) 6.21 (3H, s), 5.23 (1H, s) 4.93 (2H, s), 4.79 (1H, d) 4.66 ( 1H, d), 4.37 (1H, q) 2.96 (4H, q), 2.67 (5H, s)

Claims (1)

[Claims] 1 formula (In the formula, R ₁ represents an acylamino group, R ₂ represents an alkyl group or a substituted alkyl group, and R ₃ represents a hydrogen atom or acetoxy.) The compound represented by the formula is treated with a base to perform a dehydrogenation reaction. An expression characterized by (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as in the formula.) A method for producing a 2-azido-2-cephem compound represented by the formula.