JPH06145175A - Production of 3-alkoxymethyl-cephalosporin derivative - Google Patents

Abstract

PURPOSE:To efficiently produce the subject derivative of high purity, useful, e.g. as a raw material of cephalosporin-based antibiotics in a high yield without environmental pollution by reacting aminoacetoxymethylcephemcarboxylic acid (salt) under a specified condition. CONSTITUTION:With 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (salt) of formula I, an alkoxylane of formula (R<3>)xSi(OR<2>)4-x (R<3> is R<1>; x is 0 to 3) or this alkoxylane and a lower alcohol of formula R<2>OH are reacted in the presence of an organic sulfonic acid of formula R<1>SO3H (R<1> is a lower alkyl or an aryl) or a lower alkoxysulfonic acid of formula R<2>OSO3H (R<2> is a lower alkyl). Thereby, the objective 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid (salt) of formula II is obtained.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid or a salt thereof. This compound is important as a raw material for cephalosporin antibiotics having excellent antibacterial activity.

[0002]

2. Description of the Related Art Conventionally, a method for producing 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid is 7
-Amino-3-acetoxymethyl-3-cephem-4-
A method of reacting a carboxylic acid (hereinafter referred to as 7-ACA) with a lower alcohol in the presence of (a) boron trifluoride or a boron trifluoride complex (JP-A-61-289093).
No.), (b) 7-ACA is reacted with a protonic acid, a Lewis acid or a complex compound thereof with boric acid esters, ortho organic acid esters or acetals (JP-A-2-
49790), (c) a lower alcohol solution containing 7-ACA and lower alkoxysulfonic acid, and a method of reacting in the presence of a tri-lower alkyl borate and / or methylals (EP485204).

[0003]

Among these methods,
In the method (a), a large amount of lactone is produced as a by-product, and the isolation process of the target compound is complicated. Further, in the method (b), it is not easy to remove the metal compound used as a catalyst after the reaction,
It cannot be said that the method is industrially preferable. Although the yield of the method (c) by the present applicants is good, the boron compound is contained in the waste water generated during the production, which is a problem in terms of environmental protection.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the above problems, 7-ACA or a salt thereof was treated with an alkoxy compound in the presence of an organic sulfonic acid or a lower alkoxysulfonic acid. By reacting silanes or the alkoxysilanes with a lower alcohol, the target compound can be obtained with high purity and high yield, and the waste water contains almost no silicon compound, which is beneficial for environmental protection.
The present invention has been completed by finding a method for producing amino-3-alkoxymethyl-3-cephem-4-carboxylic acid or a salt thereof. I.e.

[0005]

DETAILED DESCRIPTION OF THE INVENTION General Formula (1)

[0006]

[Chemical 3]

7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid or salt thereof represented by
General formula (2) R ¹ SO ₃ H (2) [wherein R ¹ is a lower alkyl group and aryl group] or an organic sulfonic acid represented by the general formula (3) R ² OSO ₃ H (3) [wherein R ² is a lower alkyl group] in the presence of a lower alkoxysulfonic acid represented by the general formula (4) (R ³ ) _x Si (OR ² ) _4-x (4) [wherein R ³ is a lower alkyl group and An aryl group, R ² is the above group, x is an integer of 0 to 3] or alkoxysilanes represented by the formula (5) R ² OH (5) [R ² is the above group] General formula (6) characterized by reacting with a lower alcohol shown

[0008]

[Chemical 4]

[In the formula, R ² is the above-mentioned group] 7-
A process for producing amino-3-alkoxymethyl-3-cephem-4-carboxylic acid or a salt thereof.

In the present invention, the salt of the compound represented by the general formula (1) or the general formula (6) means a salt in the carboxyl group or an acid addition salt in the amino group which is present in the free state thereof. Examples of the salt in the group include salts with alkali metals and alkaline earth metals, ammonium salts, salts with nitrogen-containing organic bases, and the like in the amino group, mineral acids such as hydrochloric acid and sulfuric acid. Acid addition salts with carboxylic acids such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid, etc., acid addition salts with sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, methoxysulfonic acid, etc. Etc.

[0011] R ¹ of the organic sulfonic acid represented by R ¹ SO ₃ H in the general formula for use in the present invention (2) is a lower alkyl group and aryl group, examples of the organic sulfonic acid, lower alkyl Mention may be made of sulphonic acid and arylsulphonic acid. Examples of R ¹ being a lower alkyl group include groups such as methyl, ethyl, propyl and butyl, and examples of the lower alkyl sulfonic acid include methane sulfonic acid, ethane sulfonic acid, propane sulfonic acid and Butane sulfonic acid etc. are mentioned. Examples of R ¹ being an aryl group include phenyl group and tolyl group, and examples of the aryl sulfonic acid thereof include benzene sulfonic acid and p-toluene sulfonic acid.

Examples in which R ^{2 of the} lower alkoxy sulfonic acid represented by R ² OSO ₃ H of the general formula (3) used in the present invention is a lower alkyl group include methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Examples of the lower alkoxy sulfonic acid include methoxy sulfonic acid, ethoxy sulfonic acid, propoxy sulfonic acid, isopropoxy sulfonic acid, butoxy sulfonic acid and isobutoxy sulfonic acid.

The method for producing the lower alkoxy sulfonic acid used in the present invention can be obtained by reacting chlorosulfonic acid or sulfuric anhydride with an equimolar amount or more of a lower alcohol. When chlorosulfonic acid is used, It is desirable to sufficiently discharge and remove hydrogen chloride from the system by using nitrogen gas or the like. In addition, when sulfuric acid anhydride is used, it can be produced by reacting at a lower temperature than when chlorosulfonic acid is used. In any case, if necessary, a solvent that does not adversely affect the reaction,
For example, an organic chlorine-based solvent such as dichloromethane and dichloroethane can be used.

In the present invention, when a lower alkoxy sulfonic acid is used, the lower alkoxy group is
Since the effect of replacing the acetoxyl group in the general formula (1), R ² a lower alkoxy sulfonic acid is the same as R ² in the general formula (6). In the present invention, an organic sulfonic acid and a lower alkoxy sulfonic acid may be mixed and used.

7-ACA of the organic sulfonic acid represented by R ¹ SO ₃ H of the general formula (2) or the lower alkoxy sulfonic acid represented by R ² OSO ₃ H of the general formula (3) used in the present invention. The amount used is not particularly limited, but is generally used in equimolar to 100-fold molar amounts,
It is preferable to use 3 to 50 times mol. When the amount of the acid used is less than this mole, the reaction rate becomes slow, and when it is more than 100 mole, the yield improvement as much as the addition is not observed.

Among the alkoxysilanes represented by (R ³ ) _x Si (OR ² ) _4-x of the general formula (4) used in the present invention, preferable examples include Si (OR ² ) ₄ or (R ³ ) Si (OR ² ) ₃ can be mentioned.

R ^{3 in the} general formula (4) is a lower alkyl group or an aryl group, and examples of the lower alkyl group include groups such as methyl, ethyl, propyl, isopropyl, butyl and isobutyl. Examples of the aryl group of R ³ and R ³ include a phenyl group and a tolyl group. R ² in the general formula (4) is a lower alkyl group and is the same group as R ^{2 in the} general formula (3).

Examples of the alkoxysilanes include Si
(OCH ₃ ) ₄ , Si (OC ₂ H ₅ ) ₄ , Si (OC ₃
H ₇ ) ₄ , Si (O-isoC ₃ H ₇ ) ₄ , Si (OC ₄ H
₉ ) ₄ , Si (O-isoC ₄ H ₉ ) ₄ CH ₃ Si (OCH
₃ ) ₃ , CH ₃ Si (OC ₂ H ₅ ) ₃ , CH ₃ Si (O
_{C 3 H 7) 3, CH} 3 Si (O-isoC 3 H 7) 3, CH
₃ Si (OC ₄ H ₉ ) ₃ , CH ₃ Si (O-isoC ₄ H
₉ ) ₃ , (CH ₃ ) ₂ Si (OCH ₃ ) ₂ , (CH ₃ )
₂ Si (OC ₄ H ₉ ) ₂ , (CH ₃ ) ₃ Si (OCH
_{3), (CH 3) 3} Si (OC 4 H 9), C 2 H 5 Si
(OCH ₃ ) ₃ , C ₂ H ₅ Si (OC ₂ H ₅ ) ₃ , (C
₂ H ₅ ) ₂ Si (OCH ₃ ) ₂ , (C ₂ H ₅ ) ₂ Si
(OC ₂ H ₅ ) ₂ , (C ₂ H ₅ ) ₃ Si (OC ₂ H
_{5), C 3 H 7 Si} (OCH 3) 3, iso-C 3 H 7 Si
(OCH ₃ ) ₃ , C ₄ H ₉ Si (OCH ₃ ) ₃ , iso-C
_{4 H 9 Si (OCH 3)} 3, C 6 H 5 Si (OCH 3)
₃ , C ₆ H ₅ Si (OC ₂ H ₅ ) ₃ , C ₆ H ₅ Si (O
_{C 3 H 7) 3, C} 6 H 5 Si (O-isoC 3 H 7) 3, C
₆ H ₅ Si (OC ₄ H ₉ ) ₃ , C ₆ H ₅ Si (O-isoC
₄ H _{9) 3,} and the like _{(C 6 H 5) 2 Si} (OCH 3) 2 and _{(C 6 H 5) 3 Si} (OCH 3).

In the present invention, the alkoxysilanes are
When the types of alkoxyl groups are the same, alkoxysilanes in which x is 0 to 3 can be mixed and used.

The amount of the alkoxysilanes used in the present invention is generally 0.25 with respect to 7-ACA.
Used in a molar amount of 20 to 20 times, and 0.5 to 10 times.
It is preferable to use a double molar amount.

[0021] R ² alkoxysilanes used in the present invention is the same as R ² in the general formula (6).

[0022] In the present invention, examples R ² is a lower alkyl group of lower alcohols R ² OH represented by the general formula (5) used in combination with alkoxysilanes, methyl, ethyl, propyl, isopropyl, butyl And isobutyl and the like, and examples of the lower alcohol include methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol and the like.

In the present invention, the total amount of lower alcohol used relative to 7-ACA is not particularly limited, but is generally 10 times or less the molar amount.

[0024] R ² lower alcohol used in the present invention is the same as R ² in the general formula (6).

The use of a lower alcohol in combination with the alkoxysilanes accelerates the reaction in the present invention.

In the present invention, a suitable organic solvent can be used, and examples thereof include nitriles such as acetonitrile and propionitrile, carboxylic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid, nitromethane, Nitroalkanes such as nitroethane and nitropropane, halogenated alkanes such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride, halogenated alkenes such as dichloroethylene and trichloroethylene, alkanes such as n-hexane and heptane, cyclohexane Alicyclic alkanes such as dimethyl sulfate, diethyl sulfate, and other sulfuric acid esters, dimethyl carbonate, diethyl carbonate, carbonic acid esters such as dipropyl carbonate and dibutyl carbonate, dioxane, tetrahydrofuran, diethyl ether, diisopro Ethers such as ether ether and ethylene glycol dimethyl ether, organic acid esters such as methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, dimethyl adipate and diethyl adipate, and sulfolane. If necessary, each organic solvent can be used together. Preferred organic solvents include carbonic acid esters, organic acid esters, sulfolane and the like, and most preferably sulfolane.

In carrying out the present invention, it is preferable that the raw materials used, the organic solvent and the water content in the reaction system are anhydrous or as close to anhydrous as possible.

The order of addition of the raw materials in the present invention is arbitrary, but usually 7-ACA or a salt thereof is mixed with an organic solvent, a lower alkyl sulfonic acid, an organic sulfonic acid and alkoxysilanes or a mixture of alkoxysilanes and an alcohol. Addition to a solution, or suspension or dissolution of 7-ACA or a salt thereof in an organic solvent is used as an organic sulfonic acid, a lower alkoxy sulfonic acid, and alkoxysilanes or a mixed solution of an alkoxysilane and an alcohol. There is a method of adding or vice versa.

The reaction temperature in the present invention is not particularly limited, but is usually -30 ° C to 80 ° C, preferably -10 ° C to 60 ° C.

The time required for the reaction of the present invention mainly depends on the kind and amount of raw materials used and the reaction temperature,
It is several minutes to several tens of hours.

In the present invention, as a method for removing the silicon compound, after the reaction is completed, the reaction mixture is added to water or ice, the pH of the reaction mixture is adjusted to around 8, and the precipitated silicon compound is filtered off. After the reaction, the reaction mixture is added to water or ice, and then the silicon compound is removed by extraction with halogenated alkanes such as dichloromethane, benzene, toluene and xylene, and aromatic alkenes. Yes, after removing the silicon compound, p in the filtrate or aqueous layer
The target compound can be obtained by adjusting H to 3 to 4, collecting the precipitated crystals by filtration, and drying under reduced pressure. If it is necessary to further purify it, dissolve it in aqueous ammonia, alkaline solution or hydrochloric acid or sulfuric acid, and then treat with an adsorbent (such as activated carbon and synthetic adsorbents such as styrene-based high-porous polymer) and treat it. This can be achieved by adjusting the pH of the liquid and collecting the precipitated crystals of the target compound by filtration and drying.

Further, when the target compound is collected in a free form, it can be converted into a salt form by a conventional method, if necessary. Further, when the target compound is collected in the form of a salt, it can be converted into a free form by a conventional method if necessary, and the obtained free form can be converted into another desired salt. it can. These conversions can also be carried out subsequently without isolation of the respective products.

The method for synthesizing the lower alkoxy sulfonic acid used in the present invention will be specifically described below with reference to examples.

Synthesis Example 1 349.5 g (3 mol) of chlorosulfonic acid was added to 96 g (3 mol) of methyl alcohol at 15 to 20 ° C.
The mixture was heated to 40 ° C. and nitrogen gas was passed through for 4 hours to remove hydrogen chloride produced, to obtain 336 g of methoxysulfonic acid.

Synthesis Example 2 Methyl alcohol 38.4 g (1.2 mol) 15-2
After adding 116.5 g (1 mol) of chlorosulfonic acid at 0 ° C., the mixture was heated to 40 ° C. and nitrogen gas was passed for 4 hours to remove hydrogen chloride produced, thereby obtaining 118 g of a methyl alcohol solution of methoxysulfonic acid. It was

Synthetic Example 3 80 g (1 mol) of anhydrous sulfuric acid was added to 32 g (1 mol) of methyl alcohol at -5 to 0 ° C. for reaction to obtain 112 g of methoxysulfonic acid.

[0037]

EXAMPLES The method of the present invention will now be specifically described with reference to examples, but the method of the present invention is not limited thereto.

7-amino-3-methoxymethyl-3-se
Preparation method of fem-4-carboxylic acid Example 1 To 50 ml of sulfolane, 25 g of methoxysulfonic acid obtained in Synthesis Example 1 and 6.8 g of tetramethoxysilane were added and cooled to 0 ° C., and then 2.74 g of 7-ACA was added. The mixture was stirred at 10 ° C for 3 hours and 20 minutes. HPLC of reaction progress
After completion of the reaction, the reaction mixture was poured into crushed ice,
Next, ammonia water is added to adjust the pH to 8, and the precipitated silicon compound is filtered and removed. Silicon in this filtrate is 30
It was ppm. Next, the pH of this filtrate was adjusted to 3.5, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.29 g of crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. . Add water to the crude crystals,
Then, the solution was adjusted to pH 8 with aqueous ammonia and dissolved. The solution was treated with activated carbon, filtered, washed with water, and hydrochloric acid was added to the filtered solution to adjust the pH to 3.5 to precipitate the target compound. The precipitated crystals were collected by filtration, washed with water and dried to obtain 1.95 g (yield 80%) of the highly pure target compound.

Example 2 Reaction was carried out in the same manner as in Example 1 to obtain crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid.
The crude crystals were dissolved in aqueous ammonia and then adjusted to pH 8, the solution was applied to an adsorption column (polystyrene high-porous polymer), and the eluate was adjusted to pH 3.5 with hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 1.83 g (yield 75%) of a highly pure target compound.

Example 3 25 g of sulfolane, 25 g of methoxysulfonic acid obtained in Synthesis Example 1 and trimethoxymethylsilane 6.1
After adding g and cooling to -5 ° C, 15 ml of sulfolane
And 7-ACA (2.74 g) were added, and the mixture was stirred at 10 ° C for 3 hours and 20 minutes. The progress of the reaction is followed by HPLC, and after the reaction is completed, the reaction mixture is put into crushed ice, dichloromethane is further added thereto, and the silicon compound is extracted into the dichloromethane layer, and liquid separation is removed. The silicon content in the water layer was 5 ppm. Next, add ammonia water to the aqueous layer to adjust the pH to 3.5.
Adjusted to. The precipitated crystals were collected by filtration, washed with water and dried to give crude 7-amino-3-methoxymethyl-3-cephem-4-
2.29 g of carboxylic acid was obtained. The crude crystals were treated in the same manner as in Example 1 to obtain 1.95 g of the highly pure target compound (yield 8
0%).

Example 4 To 50 ml of sulfolane, 21 g of methanesulfonic acid and 6.8 g of tetramethoxysilane were added, cooled to 10 ° C., 2.74 g of 7-ACA was added, and the mixture was stirred at 20 ° C. for 3 hours. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.78 g (yield 73%) of a highly pure target compound.

Example 5 To 50 ml of sulfolane, 21 g of methanesulfonic acid and 6.1 g of trimethoxymethylsilane were added, cooled to 10 ° C., 2.74 g of 7-ACA was added, and the mixture was stirred at 20 ° C. for 3 hours. Thereafter, the same treatment as in Example 3 was carried out to obtain 1.68 g (yield 69%) of a highly pure target compound.

Example 6 To 50 ml of sulfolane, 25 g of methoxysulfonic acid obtained in Synthesis Example 1, 6.8 g of tetramethoxysilane and 1.5 ml of methyl alcohol were added, cooled to 0 ° C., and then 2.74 g of 7-ACA was added. And stirred at 10 ° C. for 3 hours. The reaction mixture was then treated in the same manner as in Example 1 to obtain 1.95 g (yield 80%) of the highly pure target compound of high purity.

Example 7 25 g of methoxysulfonic acid obtained in Synthesis Example 1 and 6.1 g of trimethoxymethylsilane were added to 50 ml of sulfolane.
After adding 1.5 ml of methyl alcohol and cooling to 0 ° C., 2.74 g of 7-ACA was added and the mixture was stirred at 10 ° C. for 3 hours. Thereafter, the same treatment as in Example 3 was carried out to obtain 1.93 g (yield 79%) of a highly pure target compound.

Example 8 To 50 ml of sulfolane, 21 g of methanesulfonic acid, 6.8 g of tetramethoxysilane and 1.
After adding 5 ml and cooling to 10 ° C, 7-ACA2.7
4 g was added and the mixture was stirred at 20 ° C. for 2 hours and 20 minutes. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.71 g of the highly pure target compound.
(Yield 70%) was obtained.

Example 9 20 g of sulfolane was added with 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and 4.4 g of dimethoxydimethylsilane.
After adding and cooling to 20 degreeC, 7-ACA2.74g was added and it stirred at 30 degreeC for 1 hour and 15 minutes. Hereinafter, Example 3
The same treatment as in (1) gave 1.59 g (yield 65%) of the highly pure target compound.

Example 10 To 20 ml of sulfolane, 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and 7.6 g of methoxytrimethylsilane were obtained.
After adding and cooling to 20 degreeC, 7-ACA2.74g was added and it stirred at 30 degreeC for 1 hour and 15 minutes. Hereinafter, Example 3
The same treatment as in (1) was performed to obtain 1.27 g (yield: 52%) of a highly pure target compound.

Example 11 To 20 ml of sulfolane, 10 g of methoxysulfonic acid obtained in Synthesis Example 2 and 2.7 g of tetramethoxysilane were added and cooled to 0 ° C., and then 2.74 g of 7-ACA was added and the mixture was kept at 10 ° C. for 4 hours. Stir for 30 minutes. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.83 g of the highly pure target compound (yield: 75
%) Was obtained.

Example 12 To 20 ml of sulfolane, 10 g of methoxysulfonic acid obtained in Synthesis Example 3 and 2.7 g of tetramethoxysilane were added and cooled to 0 ° C., and then 2.74 g of 7-ACA was added and the mixture was kept at 10 ° C. for 6 hours. It was stirred. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.85 g (yield: 76%) of a highly pure target compound.

Example 13 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and 20 ml of trimethoxymethylsilane were added to 20 ml of dichloromethane.
After adding 5 g and cooling to 10 ° C, 7-ACA2.74
g was added and the mixture was stirred at 20 ° C. for 2 hours and 30 minutes. After completion of the reaction, the reaction mixture is put into crushed ice, the silicon compound is extracted into a dichloromethane layer, and liquid separation is removed. 4 in the water layer
It was ppm. Then add ammonia water to the aqueous layer to adjust the pH.
Was adjusted to 3.5. The precipitated crystals were collected by filtration, washed with water and dried to obtain 1.95 g of crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. This crude crystal was treated in the same manner as in Example 1 to give a highly pure target compound 1.63.
g (yield 67%) was obtained. Example 14 To 20 ml of dimethyl carbonate, 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and 2.7 g of tetramethoxysilane were added and cooled to 10 ° C., and then 2.74 g of 7-ACA was added and the mixture was heated at 20 ° C. for 2 hours and 30 minutes. It was stirred. Thereafter, the same treatment as in Example 1 was carried out to obtain 1.76 g of the highly pure target compound (yield 7
2%) was obtained.

Example 15 To 20 ml of dimethyl adipate, 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and 2.5 g of trimethoxymethylsilane were added and cooled to 10 ° C., and then 7-ACA.2.
74 g was added and the mixture was stirred at 20 ° C. for 3 hours and 30 minutes. After that,
Treated in the same manner as in Example 3, to give highly purified target compound 1.71.
g (yield 70%) was obtained.

Example 16 In 20 ml of sulfolane, 10 g of methoxysulfonic acid obtained in Synthesis Example 1 and trimethoxyphenylsilane 3.
After adding 6 g and cooling to 0 ° C, 7-ACA2.74 g
Was added and the mixture was stirred at 10 ° C. for 6 hours. Thereafter, the same treatment as in Example 3 was carried out to obtain 1.86 g of a highly pure target compound (yield: 76
%) Was obtained.

A comparative example will be shown below.

Comparative Example To 20 ml of sulfolane, 13.5 g of methoxysulfonic acid obtained in Synthesis Example 1 4.4 g of trimethyl borate and 2.4 ml of methanol were added and cooled to 10 ° C., and then 7-
2.74 g of ACA was added and the mixture was stirred at 20 ° C. for 1 hour and 30 minutes. The progress of the reaction was monitored by HPLC, and after the reaction was completed, the reaction mixture was put into crushed ice, and then aqueous ammonia was added to the reaction mixture to obtain p.
The mixture was adjusted to H3.5, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.24 g of crude 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The boron content in this filter wash liquid was 0.6%. Water was added to the crude crystals, which was then adjusted to pH 8 with aqueous ammonia and dissolved. The solution was treated with activated carbon, filtered, and hydrochloric acid was added to the filtrate to adjust the pH to 3.5. The precipitated crystals were collected by filtration, recrystallized, washed with water and dried to obtain 1.90 g (yield 78%) of a highly pure target compound.

[0055]

According to the present invention, 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid or a salt thereof can be obtained from 7-ACA or a salt thereof in high purity and high yield, A method that is beneficial for environmental conservation of wastewater is provided.

[Procedure amendment]

[Submission date] October 27, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

Examples of the alkoxysilanes include Si
(OCH ₃ ) ₄ , Si (OC ₂ H ₅ ) ₄ , Si (OC ₃
H ₇ ) ₄ , Si (O-isoC ₃ H ₇ ) ₄ , Si (OC ₄ H
₉ ) ₄ , Si (O-isoC ₄ H ₉ ) ₄ , CH ₃ Si (OC
_{H 3) 3, CH 3 Si} (OC 2 H 5) 3, CH 3 Si
(OC ₃ H ₇ ) ₃ , CH ₃ Si (O-isoC ₃ H ₇ ) ₃ ,
CH ₃ Si (OC ₄ H ₉ ) ₃ , CH ₃ Si (O-isoC ₄
H ₉ ) ₃ , (CH ₃ ) ₂ Si (OCH ₃ ) ₂ , (CH
₃ ) ₂ Si (OC ₄ H ₉ ) ₂ , (CH ₃ ) ₃ Si (OC
_{H 3), (CH 3)} 3 Si (OC 4 H 9), C 2 H 5 S
i (OCH ₃ ) ₃ , C ₂ H ₅ Si (OC ₂ H ₅ ) ₃ ,
(C ₂ H ₅ ) ₂ Si (OCH ₃ ) ₂ , (C ₂ H ₅ ) ₂ S
i (OC ₂ H ₅ ) ₂ , (C ₂ H ₅ ) ₃ Si (OC ₂ H
_{5), C 3 H 7 Si} (OCH 3) 3, iso-C 3 H 7 Si
(OCH ₃ ) ₃ , C ₄ H ₉ Si (OCH ₃ ) ₃ , iso-C
_{4 H 9 Si (OCH 3)} 3, C 6 H 5 Si (OCH 3)
₃ , C ₆ H ₅ Si (OC ₂ H ₅ ) ₃ , C ₆ H ₅ Si (O
_{C 3 H 7) 3, C} 6 H 5 Si (O-isoC 3 H 7) 3, C
₆ H ₅ Si (OC ₄ H ₉ ) ₃ , C ₆ H ₅ Si (O-isoC
₄ H _{9) 3,} and the like _{(C 6 H 5) 2 Si} (OCH 3) 2 and _{(C 6 H 5) 3 Si} (OCH 3).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0053

[Correction method] Change

[Correction content]

Example 17 The methoxyx obtained in Synthesis Example 1 was added to 20 ml of sulfolane.
Rufonic acid 10 g and trimethoxybutylsilane 3.2
After adding g and cooling to 0 ° C., 2.74 g of 7-ACA
In addition, the mixture was stirred at 10 ° C for 5 hours. After that, the same as in Example 3
To give 1.88 g of high-purity target compound (yield 77
%) Was obtained. A comparative example is shown below.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Setsuo Watanabe 788 Kuchi, Takatsu-ku, Kawasaki, Kanagawa Sankyo Organic Synthesis Co., Ltd. (72) Kiyomi Yamaguchi 788 Hisa, Takatsu-ku, Kawasaki, Kanagawa Sankyo Organic Synthesis Co., Ltd. (72) Inventor Shigeru Miyamoto Sankyo Organic Synthesis Co., Ltd. 788 Kuchi, Takatsu-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Keisuke Kato 788 Hisachi Takatsu-ku, Kawasaki, Kanagawa Sankyo Organic Synthesis Co., Ltd. (72) Inventor Tomio Sasao 173 Nakahara Uejuku, Hiratsuka-shi, Kanagawa Sankyo Stock Association In-house (72) Inventor Kiyofumi Iijima 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company

Claims (1)

[Claims] 1. A general formula: 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid or a salt thereof represented by the general formula R ¹ S
O ₃ H [wherein R ¹ is a lower alkyl group or an aryl group]
Or an organic sulfonic acid represented by the general formula R ² OSO ₃
H [wherein R ² is a lower alkyl group] in the presence of a lower alkoxy sulfonic acid represented by the general formula (R ³ ) _x Si
(OR ² ) _4-x [wherein R ² is the above-mentioned group, R ³ is a lower alkyl group and an aryl group, and x is an integer of 0 to 3] or the alkoxysilanes and the general formula R ² OH [R ² is the above group] is reacted with a lower alcohol represented by the general formula: 7-amino-3-indicated by [in the formula, R ² is the above group]
A process for producing an alkoxymethyl-3-cephem-4-carboxylic acid or a salt thereof.