KR19990011517A - Method for preparing Ceftriaxone Sodium - Google Patents

Abstract

The present invention relates to a method for preparing ceftriaxone sodium, and more particularly, to protect the cephalosporin derivative represented by the following formula (2) with a silyl group, which is 2-mercaptobenzothiazole-2- (2-aminothia After reacting with zol-4-yl) -2-cin-methoxyiminoacetate, a tertiary amine is added to the reaction solution along with water to adjust the pH to 8.0 to 8.5. The present invention relates to a novel manufacturing method having excellent economic efficiency for preparing sodium ceftriaxone represented by the formula (1) in a state in which a sodium-containing organic solution is added without sterilization.

Description

Method for preparing Ceftriaxone Sodium

The present invention relates to a method for preparing ceftriaxone sodium, and more particularly, to protect the cephalosporin derivative represented by the following formula (2) (hereinafter referred to as 7-ACT) with a silyl group, and 2-mercaptobenzothia After reacting with sol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate and adding tertamine with water to the reaction solution, adjust the pH to 8.0-8.5 The present invention relates to a novel economic method for producing ceftriaxone sodium represented by the general formula (1) in an unsterilized state by immediately adding a sodium-containing organic solution to the water layer without separating the axonic acid.

Formula 1

Formula 2

Ceftriaxone sodium represented by the formula (1) is a known compound, stable to beta lactamase, the longest half-life among existing cefem compounds, and widely used as an antibiotic for injection because it exhibits a wide range of antimicrobial activity against gram positive and gram negative bacteria. have.

British Patent No. 2,146,332A and US Patent No. 4,327,210 disclose a method for preparing ceftriaxone acid or its sodium salt using 7-ACT represented by Chemical Formula 2 as a starting material.

Schematic of the preparation of ceftriaxone acid from 7-ACT represented by the formula (2) disclosed in British Patent No. 2,146,332A is shown in Scheme 1 below.

According to Scheme 1, a compound represented by Formula 3 protected with a silyl group is prepared using N, O -bis (trimethylsilyl) acetamide as a silylating agent in 7-ACT represented by Formula 2. After reacting the compound represented by Formula 3 with 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate (hereinafter referred to as MAEM), , H ₂ O and KHCO ₃ were added to separate the aqueous layer, and a mixed solution of ethyl acetate and butanol (8/2) was added thereto, the pH was adjusted to 2, extracted with ethyl acetate and butanol as an organic solvent, and concentrated under reduced pressure. Then ether was added to obtain the desired ceftriaxone acid.

However, the manufacturing method takes a long time of more than 15 hours at 35 ~ 40 ℃, the manufacturing process is also very complicated, there is a problem of low economic efficiency.

In addition, US Pat. No. 4,327,210 discloses a method for preparing sodium ceftriaxone from 7-ACT represented by Chemical Formula 2, which is briefly shown in Scheme 2 below.

In the case of the compound represented by Chemical Formula 5, which is used in the above Reaction Scheme 2, a process of introducing chloroacetyl chloride as an amino protecting group, a process of preparing an acid chloride using PCl ₅ , and the like are prepared using a complicated preparation process and a difficult to handle reagent. In addition, there have been many problems in industrial production, such as a separate process for removing chloroacetyl chloride introduced into the protecting group.

In the present invention, an effort is made to prepare a sodium ceftriaxone represented by the formula (1) in a high yield by a relatively low-cost reagent and a simple manufacturing process, as a result of the formula 2 in British Patent No. 2,146,332A Instead of adjusting the pH to 2 using KHCO ₃ and water in the reaction solution in which the silyl group was introduced as a protecting group in the 7-ACT, and reacted with MAEM, alkaline conditions of pH 8.0 to 8.5 were used by using tertiary amine and water. After adjusting, the sodium compound was immediately added to the water layer to directly separate the ceftriaxone sodium represented by Chemical Formula 1, thereby completing the present invention.

Therefore, the present invention uses inexpensive reagents and directly prepares ceftriaxone sodium, which is useful as an injectable agent, without separation of ceftriaxone acid by simple pH manipulation of the reaction solution of 7-ACT and MAEM protected with silyl group. The purpose is to provide a way to.

In the present invention, a silylating agent is reacted with a cephalosporin derivative represented by the following Chemical Formula 2 to prepare a compound represented by the following Chemical Formula 3, and 2-mercaptobenzothiazole-2- (2- In the process for preparing ceftriaxone acid by reaction with aminothiazol-4-yl) -2-cin-methoxyiminoacetate, and then producing ceftriaxone sodium by a conventional method,

When the reaction of the compound represented by Formula 3 and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate represented by the following Formula 7 is completed After adding water and tertiary amine to the solution, adjusting the pH to 8.0 to 8.5, and then putting a sodium-containing organic solution into the water layer in which the ceftriaxone amine salt represented by the formula (8) is present, was prepared aseptically. A method for producing sodium ceftriaxone represented by the following Chemical Formula 1.

Formula 2

Formula 1

Referring to the present invention in more detail as follows.

The present invention provides a method for producing ceftriaxone sodium directly from a reaction solution by reacting 7-ACT protected with silyl group and MAEM, and then adding a sodium compound in an alkalinized state of the reaction solution without separating the ceftriaxone acid. The present invention is particularly useful for the industrial production of ceftriaxone sodium because it is possible to prepare sodium salts by a simple operation of adjusting the pH of the reaction solution without the process of separating the ceftriaxone acid. In particular, conventionally, ceftriaxone acid was prepared, and when prepared as an injection, ceftriaxone sodium was prepared by dissolving using a base in an organic solvent and then performing a sterile treatment. However, ceftriaxone sodium prepared aseptically in the present invention has better heat stability than ceftriaxone acid, and thus has long-term storage stability, and when used as an injection, water without using an organic solvent or a base is used. It is economical as it performs aseptic treatment process in the dissolved state.

The process for preparing ceftriaxone sodium according to the present invention is briefly shown in Scheme 3 below.

First, a compound protected by the silyl group represented by Chemical Formula 3 is prepared by reacting 7-ACT represented by Chemical Formula 2 with a silylating agent. The silylation reaction is carried out in a conventional organic solvent and depending on the silylating agent used, but the reaction is carried out in the range of -20 ~ 60 ℃, preferably 30 ~ 35 ℃. As the silylating agent, those commonly used are, for example, N, O -bis (trimethylsilyl) acetamide, hexamethyldisilane, hexamethyldisilazane, trimethylchlorosilane, 1.3-bis (trimethylsilyl) urea, dichloro Dimethylsilane and the like can be used. In particular, when 1,3-bis (trimethylsilyl) urea or dichlorodimethylsilane is used as the silylating agent, the reaction time with the following MAEM is significantly reduced to about 4 hours. The silylating agent is used in a molar ratio of 2.0 to 2.1 with respect to 1 mole of 7-ACT represented by the formula (2).

MAEM is reacted with a compound protected by the silyl group represented by Formula 3 prepared above. At this time, the reaction solvent is a conventional organic solvent, preferably methylene chloride. The reaction temperature is maintained at 0 to 50 ° C, preferably 30 to 35 ° C, and MAEM is used at a molar ratio of 1.2 to 1.22 per mole of the compound represented by Formula 3.

When the reaction is completed, water and tertiary amine are added to the reaction solution to alkalinize the pH of the solution to 8.0 to 8.5, thereby converting Ceftriaxone amine salt represented by Chemical Formula 8. At this time, the tertiary amine may be used as a tertiary alkylamine compound, for example trimethylamine and triethylamine. Therefore, the pH range of the solution is maintained at 8.0 to 8.5, so that the ceftriaxone amine salt represented by the formula (8) present in the aqueous layer is stable and can be extracted most efficiently, and the reaction with the following sodium compound can be optimized. . However, when the pH of the solution is less than 8.0, the ceftriaxone amine salt represented by the formula (8) is not easy to extract into the aqueous layer, there is a problem in that the process hassle and the yield is reduced to be repeatedly extracted several times. On the other hand, when the pH of the solution exceeds 8.5, the ceftriaxone amine salt represented by the formula (8) is decomposed to produce a side reaction product, which causes a problem in yield and purity deterioration.

A water layer is taken from the alkaline reaction solution, and a sodium compound is added thereto to prepare ceftriaxone sodium as an object of the present invention. In this case, sodium 2-ethyl hexanoate or sodium acetate is used as the sodium compound, which is used in a molar ratio of 2.0 to 2.1 with respect to 1 mole of the ceftriaxone amine salt represented by Chemical Formula 8. The sodium compound may be an organic solvent such as alcohols having 1 to 5 carbon atoms such as methanol, ethanol or propanol, ketones having 3 to 6 carbon atoms such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, or these It is preferable to dissolve in a mixed solvent of bar, because the reason is that the ceftriaxone sodium precipitates slowly and crystals grow large, so that the target product can be obtained in a crystal form rather than powder.

As described above, the preparation method of the present invention can prepare ceftriaxone sodium useful as an injection by pH manipulation of a reaction solution without crystallizing ceftriaxone acid, and also as 1,3-bis (trimethyl) as a silylating agent. In the case of selecting and using silyl) urea or dichlorodimethylsilane, the reaction time can be greatly reduced.

The present invention will be described in more detail with reference to Examples, but the present invention is not limited to Examples.

Example 1

The cephalosporin derivative (7-ACT; 135 g) represented by the formula (2) was suspended in methylene chloride (1620 mL), and then 1.3-bis (trimethylsilyl) urea (155.3 g) was added as a silylating agent at 30 to 35 ° C. The silylation reaction was performed for 1 hour 30 minutes to quantitatively obtain a compound protected by the silyl group represented by Chemical Formula 3. Compounds protected by the silyl group represented by the formula (3) include 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate using methylene chloride as a reaction solvent. (MAEM; 153 g) was added and the mixture was reacted at 30-35 ° C. for 4 hours and 30 minutes. When the reaction was completed, H ₂ O (540 ml) was added and triethylamine (47.3 ml) was added to adjust the pH of the reaction solution to 8.0-8.5. Adjusted to. After separating the aqueous layer, a mixture of sodium-2-ethyl hexanoate (122 g) and methanol (600 ml) was slowly added dropwise to the aqueous layer, and when the crystals were precipitated, the mixture was stirred for 1 hour, and then isopropanol (700 ml) was added thereto. Stirred for 1 hour more. The precipitated crystals were filtered off, washed with acetone (800 mL), and dried under vacuum to give aseptic untreated ceftriaxone sodium (197 g, 81.9% yield).

Melting Point: 155 ℃ (dec.)

Molecular Weight: 661.59

Empirical _{formula: C 18 H 16 N 8 O} 7 S 3 Na 2 · 3.5H 2 O

IR spectrum (KBr pellet): 1758 (β-lactamcarbonyl group) cm- ¹

¹ H-NMR (D ₂ O, ppm): δ 3.62 (s, 3H, NCH ₃ ), 3.98 (s, 3H, OCH ₃ ), 6.99 (s, 1H, 5-thiazolyl-H)

Example 2

Prepared in the same manner as in Example 1 except using ethanol (700 mL) instead of methanol (600 mL) to obtain sodium ceftriaxone (200 g, yield 83.1%).

Example 3

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (205 g, yield 85.2%) was obtained using a mixed solvent of methanol (500 mL) and ethanol (500 mL) instead of methanol (600 mL).

Example 4

Prepared in the same manner as in Example 1 except using ethyl acetate (700 mL) instead of methanol (600 mL) to obtain sodium ceftriaxone (202 g, yield 84%).

Example 5

Prepared in the same manner as in Example 1 except using cecetriaxone sodium (200 g, yield 83.1%) using acetone (700 mL) instead of methanol (600 mL).

Example 6

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (201 g, yield 83.6%) was obtained using a mixed solvent of methanol (500 mL) and acetone (500 mL) instead of methanol (600 mL).

Example 7

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (198 g, yield 82.3%) was obtained by using a mixed solvent of methanol (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL). .

Example 8

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (201 g, yield 83.6%) was obtained using a mixed solvent of ethanol (500 mL) and acetone (500 mL) instead of methanol (600 mL).

Example 9

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (199 g, yield 82.7%) was obtained using a mixed solvent of ethanol (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL). .

Example 10

Prepared in the same manner as in Example 1, except that ceftriaxone sodium (197 g, yield 81.9%) was obtained using a mixed solvent of acetone (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL). .

Example 11

Prepared in the same manner as in Example 1 except using dichlorodimethylsilane (94.5 g), MAEM (155 g), triethylamine (132.3 mL), and sodium-2-ethylhexanoate (125 g) as the silylating agent. Ceftriaxone sodium (200 g, yield 83.1%) was obtained.

Example 12

Prepared in the same manner as in Example 11 except using Cethanol (700 mL) instead of methanol (600 mL) to obtain sodium ceftriaxone (201 g, yield 83.6%).

Example 13

Prepared in the same manner as in Example 11, except that ceftriaxone sodium (203 g, yield 84.4%) was obtained using a mixed solvent of methanol (500 mL) and ethanol (500 mL) instead of methanol (600 mL).

Example 14

Prepared in the same manner as in Example 11 except using ethyl acetate (700 mL) instead of methanol (600 mL) to obtain sodium ceftriaxone (201 g, yield 83.6%).

Example 15

Prepared in the same manner as in Example 11 except using cecetriaxone sodium (199 g, yield 82.7%) using acetone (700 mL) instead of methanol (600 mL).

Example 16

Prepared in the same manner as in Example 11 except using methanol (500 mL) and acetone (500 mL) instead of methanol (600 mL) to obtain ceftriaxone sodium (200 g, yield 83.1%).

Example 17

Prepared in the same manner as in Example 11 except using methanol (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL) to obtain sodium ceftriaxone (199 g, yield 82.7%).

Example 18

Prepared in the same manner as in Example 11 except using ceftriaxone sodium (200 g, yield 83.1%) using ethanol (500 mL) and acetone (500 mL) instead of methanol (600 mL).

Example 19

Prepared in the same manner as in Example 11 except using ceftriaxone sodium (200 g, yield 83.1%) using ethanol (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL).

Example 20

Prepared in the same manner as in Example 11 except using cetoneriaxone sodium (198 g, yield 82.3%) using acetone (500 mL) and ethyl acetate (500 mL) instead of methanol (600 mL).

Example 21

Prepared in the same manner as in Example 1 except using sodium acetate (61 g) instead of sodium-2-ethyl-hexanoate (122 g) to obtain ceftriaxone sodium (198 g, yield 82.3%).

Example 22

Prepared in the same manner as in Example 11, except using sodium acetate (63 g) instead of sodium-2-ethyl-hexanoate (125 g) to obtain ceftriaxone sodium (200 g, yield 83.1%).

Example 23

Ceftriaxone sodium (100 g) obtained in Example 1 was dissolved in H ₂ O (30 mL), filtered aseptically by membrane filtration, and then sterile filtered methanol (50 mL) and ethanol (30 mL) were added thereto. After crystallization, sterile filtered isopropanol (70 ml) was added, stirred for 1 hour, filtered, washed with acetone (50 ml), and vacuum-dried to obtain sterilized ceftriaxone sodium (100 g, 100% yield). .

The present invention is prepared in a non-sterile state of ceftriaxone sodium which is useful as a direct injection by adjusting the reaction solution reacted with 7-ACT protected by silyl group and MAEM under alkaline conditions and then immediately adding sodium-containing organic solution to the water layer. Ceftriaxone Sodium is thermally stable compared to Ceftriaxone acid, so it has excellent long-term storage stability, and when prepared as an injection, it is dissolved in water without addition of organic solvents or bases, and is easily sterile filtered through the membrane. In addition, the use of relatively inexpensive 1,3-bis (trimethylsilyl) urea or dichlorodimethylsilane as a silylating agent for silylating 7-ACT can significantly reduce the silylation reaction and reaction time with MAEM. It has an effect to make.

Claims (5)

Next, a silylating agent is reacted with a cephalosporin derivative represented by Formula 2 to prepare a compound represented by Formula 3, and 2-mercaptobenzothiazole-2- (2-aminothiazole represented by Formula 7 below In the process for producing ceftriaxone acid by reacting with 4-yl) -2-cin-methoxyiminoacetate, and then producing ceftriaxone sodium by a conventional method, When the reaction of the compound represented by Formula 3 and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate represented by the following Formula 7 is completed After adding water and tertiary amine to the solution, adjusting the pH to 8.0 to 8.5, and then putting a sodium-containing organic solution into the water layer in which the ceftriaxone amine salt represented by the formula (8) is present, was prepared aseptically. A method for producing sodium ceftriaxone represented by the following Chemical Formula 1. Formula 2 Formula 3 Formula 7 Formula 8 Formula 1 The method of claim 1, wherein the sodium-containing organic solution is sodium 2-ethyl hexanoate or sodium acetate dissolved in an organic solvent. The method for preparing ceftriaxone sodium according to claim 2, wherein the organic solvent is an alcohol solvent having 1 to 5 carbon atoms, a ketone solvent having 3 to 6 carbon atoms, ethyl acetate, or a mixed solvent thereof. The method of claim 1, wherein the silylating agent is 1,3-bis (trimethylsilyl) urea or dichlorodimethylsilane. The method for producing ceftriaxone sodium according to claim 1, wherein triethylamine is used as the tertiary amine.