JPH0588239B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial applications The present invention is based on the following formula (1)

The present invention relates to a novel 7-amino-3-pyridinium methyl-cephem derivative useful as an intermediate for cephalosporin antibiotics, represented by the formula: (wherein m represents a number of 1 or 2). Prior art Conventionally, (6R,7R)-7-amino-3-(1-pyridinium)methyl-3-cephem-4-carboxylate (hereinafter referred to as APC) was prepared by chemically converting the protecting group of the amino group at the 7-position. Alternatively, they have been produced by removing them using biological methods, but with conventional methods it has been difficult to isolate high-purity compounds with good yields that are more stable than the reaction solution with a relatively low content. . Therefore, the present inventor completed the present invention as a result of intensive studies to find a high-yield method for isolating a highly stable and highly pure salt of the present compound. Purpose of the invention The present invention is a highly stable crystalline APC.
It provides hydrobromide hydrate. According to the present invention, a hardly soluble, highly pure crystalline salt can be easily isolated without the need for special operations such as inoculation. Means for Solving the Problems The APC/hydrobromide/hydrate of the present invention can be produced by any of the following methods. (A) Add hydrobromic acid to a neutral solution containing APC, then add a water-miscible organic solvent such as isopropyl alcohol. (B) Hydrobromic acid is added to an aqueous solution containing APC and hydrohalic acid, and then isopropyl alcohol is added. Method (A) will be explained in more detail. The hydrobromic acid used is not particularly limited, and commercially available products can be used as they are, or may be used after being diluted with water. Hydrobromic acid, for APC,
If 2 to 5 times the mole is used, monohydrobromide/monohydrate will be produced, and if 10 times the mole or more is used, dihydrobromide/monohydrate will be produced.
Each dihydrate is selectively produced. The organic solvent to be used may be any organic solvent that is miscible with water, such as alcohols such as isopropyl alcohol and n-propyl alcohol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, and ketones such as acetone. It is isopropyl alcohol. Next, method (B) will be explained in more detail. Monohydrobromide obtained by method (A) or
A solution of APC hydrochloride dissolved in water, or
Adding 2 to 20 times the mole of hydrobromic acid, preferably 5 to 15 times the mole, to the above-mentioned hydrohalic acid and acidic solution of APC, and then adding isopropyl alcohol.
APC/dihydrobromide/dihydrate precipitates.
Similar to method (A), the hydrobromic acid used here is a commercially available product and can be used as it is or diluted with water. The amount of the organic solvent used in methods (A) and (B), such as isopropyl alcohol, is not particularly limited, and is generally preferably 10 to 20 times the amount of the aqueous solution used. In addition, the concentration of the APC aqueous solution used in methods (A) and (B) is not particularly limited, but is generally 3.
% to 30% is suitable. In these methods, crystallization occurs immediately upon adding hydrobromic acid or by adding an organic solvent. The operations of methods (A) and (B) may be carried out at room temperature, but may also be cooled to around 5°C. All of the compounds obtained in the present invention are characterized by low solubility in water. for example
Adding 10 times the mole of hydrobromic acid to a 15% aqueous solution of APC hydrochloride produces a sparingly soluble dihydrobromide.
Dihydrate precipitates out. When isopropyl alcohol is added to this, dihydrobromide dihydrate can be obtained in even higher yield (over 90%), so APC can be isolated more easily than in a dilute aqueous solution.
Therefore, the present invention is also useful in that it can be used, for example, to collect and purify dilute aqueous solutions such as fermentation liquids. The compounds obtained in the present invention are stable compounds, and hardly decompose even if left in a sealed tube at 60°C for one week. The compounds obtained according to the present invention are useful as intermediates for the production of cephalosporin antibiotics.

[Formula] (wherein R ¹ and R ² are the same or different and represent a hydrogen atom or a protecting group, and R ³ represents a hydrogen atom or an alkali metal) or an acylating agent equivalent thereto. The desired compound is then prepared by removing the protecting group if necessary. The present invention will be explained below with reference to Examples and Reference Examples. Example 1 (6R,7R)-7-Amino-3-(1-pyridinium)methyl-3-cephem-4-carboxylate (APC) 47.5 to 200 ml of an aqueous solution containing 18.7 mmol
Add 8.6 ml of % hydrobromic acid followed by 2.0 ml of isopropyl alcohol. After stirring for 30 minutes at room temperature, the precipitated crystals are collected by filtration and washed with 100 ml of isopropyl alcohol. Dry the crystals, APC・
6.79 g (93%) of monohydrobromide monohydrate was obtained. ¹ H-NMR (in D ₂ O) δ: (PPM) 3.54 (2H, ABq, J = 18.0Hz, CH ₂ at the 2nd position of the Cephem ring) 5.24 (1H, d, J = 5.0Hz, the 6th position of the Cephem ring H) 5.36 (1H, d, J = 5.0Hz, H at the 7th position of the Cefem ring) 5.53 (2H, ABq, J = 15.0Hz, CH ₂ at the 3rd position of the Cefem ring) 8.16 (2H, t, J = 7.0Hz, Pyridine H at positions 3 and 5) 8.65 (1H, t, J = 7.0Hz, H at 4th position of pyridine) 9.01 (2H, d, J = 7.0Hz, H at positions 2 and 6 of pyridine) IR (KBr) νcm ^{- 1} : 3400, 1795, 1610, 1480,
1395, 1335, 1150, 1050 Elemental analysis value C ₁₃ H ₁₆ N ₃ O ₄ SBr Actual measurement value C40.05, H4.13, N10.78,
Br20.63 Calculated value C40.01, H4.13, N10.77,
Br20.48 Melting point 160-170℃ (color decomposition) According to differential thermal analysis, this product shows an endothermic peak at 150-165℃ and an exothermic peak at 170-175℃. λ = 1.542 using this product's nickel filter
Powder X-ray diffraction using copper X-rays of Å shows the properties shown in Table 1 below. (However, in Table 1, S is strong, M is moderate,
W means weak, V means very much, and D means diffused.)

【table】

[Table] Example 2 Add water to 0.977g of APC/hydrobromide/monohydrate
Add 5 ml and 5 ml of 47.5% hydrobromic acid followed by 100 ml of isopropyl alcohol. After cooling on ice for 1 hour, the precipitated crystals were collected by filtration and diluted with isopropyl alcohol.
Wash with 30ml. After drying the crystals under reduced pressure, they were left in a desiccator with saturated saline for 4 hours.
APC/dihydrobromide/dihydrate 0.963g (79%)
I got it. ¹ H-NMR (in D ₂ O) δ: (PPM) 3.61 (2H, ABq, J = 18.0Hz, CH ₂ at the 2nd position of the Cephem ring) 5.29 (1H, d, J = 5.0Hz, the 6th position of the Cephem ring H) 5.43 (1H, d, J = 5.0Hz, H at the 7th position of the Cefem ring) 5.65 (2H, ABq, J = 15.0Hz, CH ₂ at the 3rd position of the Cefem ring) 8.18 (2H, t, J = 7.0Hz, Pyridine H at positions 3 and 5) 8.68 (1H, t, J = 7.0Hz, H at position 4 of pyridine) 9.04 (2H, d, J = 7.0Hz, H at positions 2 and 6 of pyridine) IR (KBr) νcm ^{- 1} : 3425, 2950, 1790, 1700,
1625, 1495, 1475 Elemental analysis value C ₁₃ H ₁₉ N ₃ O ₅ SBr ₂ Actual value C32.43, H3.80, N8.73, Br32.73 Measured value C31.92, H3.91, N8.59, Br32 .67 Melting point: 150-170°C (decomposition) According to differential thermal analysis, this product has a melting point of 50-90°C and 130°C.
Shows two endothermic peaks at ~150℃, 160-165℃
shows an exothermic peak. λ = 1.542 using this product's nickel filter
Powder X-ray diffraction using Å copper X-rays shows the properties shown in Table 2 below. (S, M, W, V, and D in the table each have the same meaning as in Table 1)

【table】

[Table] Example 3 Dissolve 3.56g of APC dihydrochloride in 9ml of water, 47.5%
Add 11.4 ml of hydrobromic acid. Add another 200 ml of isopropyl alcohol to the area where crystals have precipitated, and stir for 1 hour under ice cooling. The precipitated crystals were dried under reduced pressure, left in a desiccator with saturated saline, and APC・
4.29 g (90%) of dihydrobromide dihydrate was obtained. This product was consistent with the compound obtained in Example 2. Example 4 The same operation as in Example 1 was carried out using acetone instead of isopropyl alcohol to obtain APC monohydrobromide monohydrate.

Claims (1)

[Claims] 1. A 7-amino-3-pyridinium methyl-cephem derivative represented by the formula: (wherein m represents a number of 1 or 2).