KR100229174B1 - Process for preparation of sodium ceftriaxone - Google Patents

Abstract

The present invention relates to a method for preparing ceftriaxone sodium, more specifically, a cephalosporin derivative represented by the following Chemical Formula 2 and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) After reacting -2-cin-methoxyiminoacetate under a specific reaction solvent and basic conditions, a sodium-containing organic solution is immediately added to the water layer without the separation process of ceftriaxone acid and is represented by the following formula (1). The present invention relates to a novel production method having excellent economic efficiency of directly preparing ceftriaxone sodium.

Description

Method for preparing Ceftriaxone Sodium

The present invention relates to a method for preparing ceftriaxone sodium, more specifically, a cephalosporin derivative represented by the following Chemical Formula 2 and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) After reacting -2-cin-methoxyiminoacetate under a specific reaction solvent and basic conditions, a sodium-containing organic solution is immediately added to the water layer without the separation process of ceftriaxone acid and is represented by the following formula (1). The present invention relates to a novel production method having excellent economic efficiency of directly preparing ceftriaxone sodium.

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 the preparation of ceftriaxone acid or its sodium salt using the cephalosporin derivative represented by Chemical Formula 2 (hereinafter referred to as "7-ACT") as a starting material. A method is disclosed.

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 the formula (3) protected by a silyl group is prepared using N, O-bis (trimethylsilyl) acetamide as a silylating agent in 7-ACT represented by the formula (2). Then, the compound represented by the formula (3) and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate (hereinafter referred to as "MAEM") are reacted. After addition, 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, followed by extraction with organic solvent ethyl acetate and butanol and reduced pressure. After concentration, 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 addition, the present applicant introduced a silyl group to 7-ACT represented by the formula (2) as a protecting group, and after adjusting the alkali solution of pH 8.0-8.5 using tertiary amine and water in the reaction solution reacted with MAEM, sodium in the water layer immediately A patent application has been invented for inventing a method for directly separating a ceftriaxone sodium represented by Chemical Formula 1 by adding a compound (Korean Patent Application No. 97-34647). This method uses inexpensive reagents and directly prepares ceftriaxone sodium, which is useful as an injection, without the separation of ceftriaxone acid by simple pH manipulation of the reaction solution of 7-ACT and MAEM protected by silyl groups. There is an effect of shortening the manufacturing process. In particular, in the general method, ceftriaxone acid is synthesized and stored, and when prepared as an injection, ceftriaxone sodium is prepared using an organic solvent and a base in a sterile system. The non-sterilized ceftriaxone sodium is prepared with better heat stability than acid and long-term storage stability, and in the case of injection, it is easily dissolved in water without using organic solvent or base. Economic performance is also excellent because it is performed.

In the present invention, in order to further improve the manufacturing method of the Republic of Korea Patent Application No. 97-34647, the introduction of the silyl protecting group to 7-ACT represented by the formula ( ₂ ), omitting the alcohol or a mixture of alcohol and water in dichloromethane (CH ₂ Cl ₂ ) In the one-pot reaction in which the mixed solution is mixed as a reaction solvent and directly reacts the 7-ACT represented by the formula (2) and MAEM in the presence of a tertiary amine base and immediately adds a sodium compound to the water layer. The present invention was completed by preparing Ceftriaxone Sodium represented by the formula (1).

Therefore, the present invention omits the introduction of the silyl protecting group in Korean Patent Application No. 97-34647 and directly reacts the reaction solution of 7-ACT and MAEM under specific reaction conditions, and is also useful as an injection without separating the reaction intermediate. It is an object of the present invention to provide an improved manufacturing method for synthesizing triaxone sodium by one-group reaction.

The present invention introduces a silyl protecting group to the cephalosporin derivative represented by the following formula (2), and then reacts with the MAEM represented by the following formula (7) to produce a ceftriaxone acid, and then the ceftriaxone sodium by a conventional method In the manufacturing method,

In the presence of a mixed solvent of dichloromethane (CH ₂ Cl ₂ ) / alcohol or dichloromethane (CH ₂ Cl ₂ ) / alcohol / water and tertiary amine base without introducing a silyl protecting group to the cephalosporin derivative represented by the formula ( ₂ ) Next, the cephalosporin derivative represented by the following formula (2) and the MAEM represented by the following formula (7) are directly reacted, and then the sodium-containing organic solution is added to the water layer containing the ceftriaxone amine salt represented by the following formula (8) and aseptically treated. It is characterized by a method for producing sodium ceftriaxone represented by the following formula (1) in a state that is not.

Formula 2

Formula 1

Referring to the present invention in more detail as follows.

The preparation method according to the present invention can omit the process of introducing a protecting group to 7-ACT by using a specific reaction solvent and tertiary amine base, and also without separating the ceftriaxone acid or its amine salt produced as a reaction intermediate. The one-pot reaction, which enables the production of sodium salts directly from the reaction solution, is useful for the industrial production of ceftriaxone sodium.

Particularly, in the present invention, when a mixed solvent of dichloromethane / alcohol or dichloromethane / alcohol / water is used as the reaction solvent, when a single non-polar organic solvent such as dichloromethane is used, the reaction does not proceed properly due to a decrease in the solubility of the reactants. In addition, when a single polar solvent such as alcohol or water is used, the solubility of not only the reactants but also impurities may be high, thereby decreasing the purity of the target product. In addition, when water is used together as the reaction solvent, if the amount of water is too high, it is not economically preferable because an excess of an organic solvent should be used to improve the purity of the target.

However, in the present invention, by using dichloromethane as a non-polar organic solvent and an appropriate amount of alcohol or a mixture of alcohol and water as a polar solvent together, the production process time is shortened, solubility of the reactants is increased, and impurities are easily extracted by using an organic solvent. Can be removed to increase the purity of the object.

In the mixing ratio of such a mixed solvent, a polar solvent (alcohol or a mixture of alcohol and water) is used at 100: 8-12 (v / v) with respect to dichloromethane. There is a problem that takes a long time off the reaction, and when used in excess, there is a problem that the purity and yield of the target product is lowered due to side reactions. In addition, in the mixing ratio of alcohol and water, it is preferable to use water less than 100: 70 (v / v) with respect to alcohol. If the amount of water to alcohol is used in excess, the solubility of the reactants may increase, but side reactions may occur. .

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

First, 7-ACT represented by Formula 2 and MAEM represented by Formula 7 are reacted, and MAEM is used in a molar ratio of 1.0 to 1.5 with respect to 1 mole of 7-ACT represented by Formula 2.

The reaction solvent at this time is a dichloromethane / alcohol or a mixed solvent of dichloromethane / alcohol / water as described above. As the alcohol, alcohols having 1 to 5 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, butanol, pentanol, and the like are used. Reaction temperature is -50-100 degreeC, Preferably it is -10-10 degreeC.

In addition, the reaction is carried out in the presence of a tertiary amine base, the tertiary amine may be used as a tertiary alkylamine compound, for example trimethylamine, triethylamine. The tertiary amine base is added so that 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 water layer as a reaction product is stable and can be extracted most efficiently. The reaction with the following sodium compounds 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.

When the reaction of 7-ACT represented by Chemical Formula 2 and MAEM represented by Chemical Formula 7 is completed, the aqueous layer is taken and sodium compound is added thereto to prepare sodium ceftriaxone. In this case, sodium 2-ethyl hexanoate or sodium acetate is used as the sodium compound, which is used at 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. Reaction temperature is -50-100 degreeC, Preferably it is 10-25 degreeC.

As described above, the preparation method of the present invention can omit the introduction of the protecting group to 7-ACT represented by the formula (2), which is used as a reactant due to the setting of specific reaction conditions, and a high production yield within a short reaction time. To Ceftriaxone Sodium represented by the formula (1) can be prepared.

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

Example 1

Cephalosporin derivative (7-ACT; 135 g) and 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) -2-cin-methoxyiminoacetate (MAEM; 182.3 g) was suspended in dichloromethane (1750 mL). To this was added H ₂ O (135 mL) and methanol (205 mL), cooled to 0 ° C. and triethylamine (155.3 mL) was slowly added dropwise. After reacting at 10 ° C. for 4 hours, when the reaction is completed, H ₂ O (400 ml) is added, the aqueous layer is separated, and a mixture of sodium-2-ethyl hexanoate (125 g) and methanol (400 ml) is added to the aqueous layer. After the dropwise addition, crystals precipitated and stirred for 1 hour, then isopropanol (650 ml) was added, followed by further stirring for 30 minutes. The precipitated crystals were filtered, washed with acetone (750 mL), and vacuum-dried at 40 ° C. for 6 hours to give aseptic untreated ceftriaxone sodium (193 g, yield 80.2%).

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

[α] _D ²⁵ = -165 ° (c = 1, H ₂ O)

IR spectrum (KBr): 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 for using ethanol (205 mL) instead of methanol (205 mL) in the reaction of 7-ACT and MAEM aseptically treated sodium ceftriaxone (194.4 g, yield 80.8%) )

Example 3

Prepared in the same manner as in Example 1, except in the reaction of 7-ACT and MAEM isopropanol (205 mL) instead of methanol (205 mL) was not sterilized Ceftriaxone sodium (199.7g, yield 83.0% )

Example 4

Prepared in the same manner as in Example 1, except for the use of n-propanol (205 mL) instead of methanol (205 mL) in the reaction of 7-ACT and MAEM aseptic treatment of sodium ceftriaxone (197.2 g, yield 82.0%).

Example 5

Manufactured in the same manner as in Example 1, except that sodium-2-ethyl hexanoate (125 g) was added to the aqueous layer, instead of methanol (400 mL), a mixed solvent of ethanol (500 mL) and acetone (500 mL). It was dissolved in and added, resulting in unsterilized ceftriaxone sodium (202.1 g, yield 84.0%).

Example 6

Prepared in the same manner as in Example 1 except that sodium-2-ethyl hexanoate (125 g) was added to the aqueous layer, instead of methanol (400 mL), ethanol (500 mL) and ethyl acetate (500 mL) were mixed. It was dissolved in the solvent and added, and as a result, sodium steftriaxone (204 g, yield 84.8%) was obtained.

Example 7

Prepared in the same manner as in Example 1 except that sodium-2-ethyl hexanoate (125 g) was added to the aqueous layer, instead of methanol (400 mL), mixed with ethyl acetate (500 mL) and acetone (500 mL). It was dissolved in the solvent and added, and as a result, sodium steftriaxone (202.5 g, yield 84.2%) was obtained.

Example 8

Prepared in the same manner as in Example 2 except that sodium-2-ethyl hexanoate (125 g) was mixed with ethyl acetate (500 mL) and acetone (500 mL) instead of methanol (400 mL) when added to the aqueous layer. It was dissolved in the solvent and added, and as a result, sodium steftriaxone (201.6 g, yield 83.8%) was obtained.

Example 9

Prepared in the same manner as in Example 3, except that ethyl acetate (500 mL) and acetone (500 mL) were added instead of methanol (400 mL) when sodium-2-ethyl hexanoate (125 g) was added to the aqueous layer. It was dissolved in the solvent and added, and as a result, sodium steftriaxone (204.9 g, yield 85.2%) was obtained.

Example 10

Prepared in the same manner as in Example 4 except mixing sodium-2-ethyl hexanoate (125 g) to the aqueous layer, instead of methanol (400 mL), mixing ethyl acetate (500 mL) and acetone (500 mL) It was dissolved in a solvent and added, and as a result, sodium steftriaxone (203.3 g, yield 84.5%) was obtained.

Example 11

Prepared in the same manner as in Example 1 except using only methanol (205 mL) in the reaction of 7-ACT and MAEM to obtain unsterilized ceftriaxone sodium (195 g, yield 81.1%). .

Example 12

Prepared in the same manner as in Example 1 except using ethanol (205 mL) without water in the reaction of 7-ACT and MAEM to obtain aseptic untreated ceftriaxone sodium (196g, yield 81.5%). .

Example 13

Prepared in the same manner as in Example 1, except in the reaction of 7-ACT and MAEM using only isopropanol (205 mL) without water to sterilized ceftriaxone sodium (204.5g, yield 85.0%) Got it.

Example 14

Prepared in the same manner as in Example 1, except in the reaction of 7-ACT and MAEM using only n-propanol (205 mL) without water aseptically treated sodium ceftriaxone (198 g, yield 82.3%) Got.

Example 15

Prepared in the same manner as in Example 1, except that sodium acetate (63 g) was used instead of sodium-2-ethyl hexanoate (125 g). As a result, unsterilized ceftriaxone sodium (193.6 g, yield 80.5) %) Was obtained.

Example 16

Prepared in the same manner as in Example 11, except that sodium acetate (63 g) was used instead of sodium-2-ethyl hexanoate (125 g), and as a result, unsterilized sodium ceftriaxone (195.3 g, yield 81.2). %) Was obtained.

In the present invention, 7-ACT and MAEM are reacted directly in the presence of a specific solvent and a tertiary amine base, and then a sodium-containing organic solution is directly added to the water layer to prepare Ceftriaxone Sodium, which is useful as an injection, in an aseptic state. The sodium ceftriaxone sodium is stable to heat compared to the ceftriaxone acid and has long-term storage stability, and when prepared as an injection, it is dissolved in water without addition of an organic solvent or base and aseptically filtered through a membrane. In addition, the introduction of the protecting group into 7-ACT is omitted by setting specific reaction conditions, and the production yield is high and the reaction time is short.

Claims (4)

Next, after introducing a silyl protecting group to the cephalosporin derivative (7-ACT) represented by the following Chemical Formula 2, 2-mercaptobenzothiazol-2- (2-aminothiazol-4-yl) represented by the following Chemical Formula 7 In the process for producing ceftriaxone acid by reacting with 2-cin-methoxyiminoacetate (MAEM), and then producing ceftriaxone sodium by a conventional method, A mixed solvent of dichloromethane (CH ₂ Cl ₂ ) / alcohol or dichloromethane (CH ₂ Cl ₂ ) / alcohol / water without introducing a silyl protecting group into the cephalosporin derivative represented by Chemical Formula 2 (7-ACT) and 3 In the presence of a secondary amine group, a 7-ACT represented by the following Chemical Formula 2 and a MAEM represented by the following Chemical Formula 7 are directly reacted, and a sodium-containing organic solution is added to the water layer in which the ceftriaxone amine salt represented by the following Chemical Formula 8 is present. Method for producing sodium ceftriaxone represented by the following formula (1), characterized in that the preparation is prepared in a non-sterile treatment state. Formula 2

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 of claim 2, wherein the organic solvent is an alcohol having 1 to 5 carbon atoms, a ketone solvent having 3 to 6 carbon atoms, ethyl acetate, or a mixed solvent thereof. The method for producing ceftriaxone sodium according to claim 1, wherein triethylamine is used as the tertiary amine base.