WO1999052913A1

WO1999052913A1 - Process for producing cephem compounds

Info

Publication number: WO1999052913A1
Application number: PCT/JP1999/001942
Authority: WO
Inventors: Yutaka Kameyama
Original assignee: Otsuka Kagaku Kabushiki Kaisha
Priority date: 1998-04-14
Filing date: 1999-04-13
Publication date: 1999-10-21
Also published as: AU3443299A

Abstract

A process for producing cephem compounds represented by general formula (2) characterized by reacting a cephem compound represented by general formula (1) with a phenol optionally together with a protonic acid and thus deblocking the amino-protective group R1 and/or the carboxylate-protective groups R?2 and R3¿ at once to give the aimed cephem compound wherein R1 represents hydrogen, etc.; R2 represents tert-butyl, etc.; and R3 represents naphthylmethyl, etc.

Description

Description Manufacturing method of cef compound Technical field

The present invention relates to a cefmy conjugate represented by the general formula (2). This cefmyi conjugate (2) is a compound called cefixime, which is widely used as a cephalosporin-based oral agent, and has uses such as an antibacterial agent (the latest antibiotics handbook, 9th edition, ed. 8 7 pages 1 9 9 4 years).

In the production of the above compound (2), the amino group and the carboxinole group are protected by an appropriate protecting group.The cephalosporin antibiotics usually contain free amines, carboxylic acids or pharmaceutically acceptable salts thereof. Since they are used in a form, it is necessary to remove these protecting groups inexpensively and with high yield at the final step of the production without destroying other parts of molecule II. Background art

Conventionally, as a method for obtaining the above cefume compound (2), for example, a method comprising treating a cefume compound represented by the general formula (3) with a large excess of trifluoroacetic acid in the presence of anisol (Japanese Patent Publication No. 63-20443) No. 5) is known. CH ₂ (3)

(Wherein, Q ¹ represents an amino group or a protected amino group, Q ² represents a lower alkynole group substituted with a carboxy group or a protected carboxy group, and Q ³ represents a carboxy group or a protected carboxy group, respectively. In this method, the yield of the compound is low (35% in the example of the above-mentioned patent publication), and in addition, expensive trifluoroacetic acid (36 equivalents in the example of the above-mentioned patent publication) and anisol (the above-mentioned patent publication) are used. It is necessary to use a large amount of (6 equivalents in the examples in the gazette), and a large amount of loss must be expected when recovering and reusing trifluoroacetic acid after the deprotection reaction. Since a large amount of the strong acid trifluoroacetic acid is present during the reaction, the acid-labile β-lactam derivative is decomposed and the yield of the carboxylic acid compound produced is reduced.

As described above, the acid-labile method of deprotecting the amino or carboxylic acid protecting group of a 3-lactam derivative requires the use of a large amount of a strong acid such as trifluoroacetic acid. There are many problems in industrial production, such as low yield, high cost, and difficulty in recovering the used trifluoroacetic acid. At present, an industrial production method capable of producing the free cefem compound (2) in good yield by inexpensively and efficiently deprotecting the protecting group of 3) has not yet been established.

An object of the present invention is to eliminate two or more protecting groups of a cefm derivative (1) in which an amino group and a carboxyl group are protected at once without using expensive reagents and without using a large amount. Accordingly, the present invention provides a novel technology capable of efficiently producing the cefm derivative (2). Disclosure of the invention

The present invention relates to the use of the Cefmy conjugate represented by the general formula (1) with phenols alone or with protic acid and phenols to protect an amino group R ¹ and / or a carboxylic acid R ² , R ² . ^3. A process for producing a cefm compound, comprising deprotecting ³ at a stretch to produce a cefm compound represented by the general formula (2).

(In the formula, R ¹ represents a hydrogen atom, a formyl group, or a trityl group which may have an electron donating group on the phenyl ring. R ² represents a tert-butyl group, a naphthylmethyl group, an anthrinolemethinole group, a phenyl ring A benzyl group which may have an electron donor or a diphenylmethyl group which may have an electron donor on the phenyl ring R ³ represents a naphthylmethyl group, an anthrylmethyl group or an electron donating group on the phenyl ring; A benzyl group which may have a group or a diphenylmethyl group which may have an electron donating group on phenino.)

In the present invention, the stability of a β-lactam derivative which is unstable to a strong acid is ensured by using a relatively weak acid, an acid phenol alone or a phenol and a small amount of a protic acid, and the deprotection is performed in good yield. To produce the desired cefm compound Successful.

According to the present invention, acid-unstable] deprotection of the amino group ゃ carboxyl group of a 3-latatam derivative can be carried out at once and with high yield without using a large amount of a strong acid, and is industrially feasible. Can be provided. It is also superior in terms of waste because it mainly uses phenols that are relatively easy to recover.

Each group shown in this specification is specifically as follows.

Examples of the trityl group which may have an electron donating group on the phenyl ring represented by R ¹ include a tritinol group, a 4,4 ′, 4 ″ -trimethoxytrityl group, a 4,4 ′, 4 ′, 1′-trityl group. Examples include a tolylmethyl group.

Examples of the electron donating group which can be substituted on the phenyl ring of the benzyl group or diphenylmethyl group represented by R ² and R ³ include, for example, a lower alkyl group such as a hydroxy group, methyl, ethyl and tert-butyl, methoxy, ethoxy and the like. Lower alkoxy groups can be mentioned. The benzyl group and the diphenylmethyl group include those in which a substituted or unsubstituted phenyl group is bonded in the molecule via a methylene chain or a heteroatom.

Specific examples include a benzyl group, a 2,4,6-trimethylbenzyl group, a p-methoxybenzyl group, a 3,4,5-trimethoxybenzyl group, a 3,5-dimethoxy-4-hydroxybenzyl group, Ronyl, diphenylmethyl, ditolylmethyl and the like.

Examples of the phenols include substituted or unsubstituted phenols. Examples of the substituent on the phenol ring include a halogen atom such as a chlorine atom and a bromine atom, a lower alkyl group such as methyl and ethyl, and a lower alkoxy group such as methoxy and ethoxy. Examples of the substituted phenols include, for example, o-chlorophenol, m-chlorophenol, p-chlorophenol, o-clenephenol, m-cresophenol, p-cresol, m-methoxyphenol, and the like. . These phenols may be used alone or as a mixture of two or more. The amount used is 1 kg of compound (1). 0.5 to 20 Okg per unit, preferably about 1 to 5 Okg.

This reaction is usually carried out in a state in which phenols are in a molten state, and no solvent is required. It can also be used as a solvent. However, it is not preferable to use a large amount of these solvents since the above deprotection reaction is inhibited. The amount of water or organic solvent used is about the same as the phenols used. The reaction temperature of the above reaction is not lower than the temperature at which the reaction system does not solidify, for example, 115 ° C. to 110 ° C. C, preferably about 10 ° C to 70 ° C.

As the protonic acid, sulfonic acids such as benzene snolenic acid, p-toluenesulfonic acid, and methanesulfonic acid, mineral acids such as hydrochloric acid, sulfuric acid, perchloric acid, and phosphoric acid, formic acid, and acetic acid are preferable. In addition, carboxylic acids such as monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, monofluoroacetic acid, difluoroacetic acid, trifluoroacetic acid and the like are also strong acids which are too strong to be exemplified. However, the amount used is as small as 000 :! to 5 equivalents, preferably about 0.0 :! to 2 equivalents relative to compound (1), so that a strong acid can be used within that range.

The compound of the general formula (2) can be obtained as a substantially pure product by performing a usual extraction operation or crystallization operation, but can be purified by other methods. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to examples.

Example 1

Compound of general formula (1) (R ^{1 =} H, R ² = tert-Bu, R ³ = CH ₂ C ₆ H ₄ 〇CH ₃ — p, la) lg and p-toluenesulfonic acid monohydrate 360 mg Add 10 g of m-cresol and stir at room temperature for 3 hours. To the resulting solution was stirred with acetic acid E Ji Honoré 50 ml, 6% NaHC_〇 ₃ aqueous solution 20 ml, to a separatory funnel shifter And separate. The NaHC〇3 aqueous layer is further washed with 3 mL of ethyl acetate, and 0.5 g of activated carbon is added to remove the color. After cooling the obtained aqueous solution to 5 ° C and adjusting the pH to 2 using 4N hydrochloric acid, crystals precipitate. The precipitated crystals were filtered and dried under reduced pressure to obtain the target compound (2) trihydrate (2a, 80 Omg, 98.6%).

Ή NMR (D ₂₀ — NaHC〇 ₃ ) δ 3.48 (d, J = 18.0 Hz, 1 H), 3.60 (d, J = 18.OH z, 1H), 4.45 (s, 2H), 5.1 2 (d, J = 4.4Hz, 1H), 5.14 (d, J = 10.5Hz, 1H), 5.32 (d, J = l 6.5Hz, 1H), 5.68 (d , J = 4.4Hz, 1H), 6.63 (dd, J = 10.5, 16.5Hz, 1H), 6.92 (s, 1H).

Example 2

A similar experiment was conducted by changing 360 mg of p-toluenesulfonic acid monohydrate used in Example 1 to 1 ml of 6N-hydrochloric acid. As a result, the target compound (2) trihydrate (2a, 70 Omg, 90.1%). The NMR of the obtained compound 2a was completely consistent with that of Example 1.

Example 3

A similar experiment was conducted by changing 360 mg of p-toluenesulfonic acid monohydrate used in Example 1 to 1 ml of 50% sulfuric acid. As a result, the target compound (2) trihydrate (2a, 68 Omg , 84.3%). The 'Η NMR of the obtained compound 2a was completely consistent with that of Example 1.

Example 4

The same reaction as in Example 1 was carried out, and the post-treatment of the reaction solution was extracted. Instead of crystallization from water, direct crystallization with 200 ml of isopropyl ether was carried out. As a result, p-toluenesulfonic acid of compound (2) was obtained. The salt (2b, 971 mg 95.0%) was obtained. Ή NMR (DMSO-d ₆ ) δ 2.37 (s, 3H), 3.58 (d, J = 17.5 Hz, 1H), 3.82 (d, J = 17.5 Hz, 1 H), 4.65 (s, 2H), 5.21 (d, J = 4.8Hz, 1H), 5.30 (d, J = 11.0Hz, 1H), 5.59 (d, J = l 7. OHz, 1H), 5.79 (dd, J = 4.8, 7.8 Hz, 1 H), 6.91 (dd, J = 1 1.0, 1 7.0 Hz, 1 H), 6.96 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1 H), 9.71 (d, J = (7.8Hz, 1H).

Example 5

Instead of compound 1 a compound 1 b (R '= H, R 2 = tert -Bu, R 3 = CH P h 2) with, except that the 338mg amount of p- toluenesulfonic acid monohydrate As a result of performing the same reaction as in Example 1, compound (2) trihydrate (2a, 744 mg, 99.1%) was obtained. The 'ΗNMR of the obtained compound 2a was completely identical to that of Example 1.

Example 6

A similar experiment was conducted by replacing 338 mg of ρ-toluenesulfonic acid monohydrate used in Example 5 with lg of 6N-hydrochloric acid. As a result, the target compound (2) trihydrate (2a, 720 mg, 95.9%). The ¹ H NMR of the obtained compound 2a was completely consistent with that of Example 1.

Example 7

A similar experiment was conducted by changing 338 mg of p-toluenesulfonic acid monohydrate used in Example 5 to 1 ml of 5 °% sulfuric acid. As a result, the target compound (2) trihydrate (2a, 69 Omg, 9 1.8%). The ¹ H NMR of the obtained compound 2a was completely consistent with that of Example 1.

Example 8

Compound 1c instead of compound 1a

Using CH ₂ C ₆ H ₄ OCH ₃ -p) and performing the same reaction as in Example 1 except that the amount of p-toluenesulfonic acid was changed to 26 lmg, the compound (2) trihydrate (2 a, 504 mg, 86.8%). The ¹ H NMR of the obtained compound 2a was completely consistent with that of Example 1. Example 9

A similar experiment was conducted by changing 26 mg of p-toluenesulfonic acid monohydrate used in Example 8 to 0.73 g of 6N-hydrochloric acid. As a result, the target compound (2) trihydrate (2a , 48 Omg, 82.6%). The ¹ H NMR of the obtained compound 2a completely matched that of Example 1.

Example 10

A similar experiment was conducted by changing 261 mg of p-toluenesulfonic acid monohydrate used in Example 8 to 0.73 ml of 50% sulfuric acid. As a result, the target compound (2) trihydrate (2a, 466 mg, 80.2%). The ¹ H NMR of the obtained compound 2a completely matched that of Example 1.

Example 1 1

The same experiment as in Example 1 was conducted except that m-cresol used in Example 1 was changed to phenol and the reaction was carried out at 45 ° C. As a result, the target compound (2) trihydrate (2a , 59 Omg, 75.9%). The ¹ H NMR of the obtained compound 2a completely matched that of Example 1.

Example 12

Example 11 A similar experiment was performed by changing 36 pmg of p-toluenesulfonic acid monohydrate used in Example 1 to 6g of lg-hydrochloric acid. As a result, the target compound (2) trihydrate (2a, 583 mg , 75.0%). The 'Η NMR of the obtained compound 2a was completely consistent with that of Example 1.

Example 13

Example 11 A similar experiment was conducted by changing 360 mg of P-toluenesulfonic acid monohydrate used in 1 to 1 ml of 50% sulfuric acid. As a result, the target compound (2) trihydrate (2a, 562 mg, 72.3%). The ¹ H NMR of the obtained compound 2a was completely consistent with that of Example 1. Industrial applicability

According to the method of the present invention, the protecting group can be removed at a stretch by a simple operation from the Cefm derivative (1) having the amino group-carboxyl group protected. In the present invention, unlike the conventional method, a large amount of expensive reagents is not required, and a large amount of a strong acid is not required. Nature was assured. As a result,] -latatam derivative (2) can be industrially easily produced with high yield and high purity.

Claims

The scope of the claims

1. Using a phenol compound such as phenol or a phenol or phenol, the protecting group R ¹ and Z of the amino group or the protecting groups R ² and R ³ of the carboxylic acid can be formed at a stroke by using a phenol compound represented by the general formula (1). A method for producing a septum compound, comprising deprotecting to produce a septum compound represented by the general formula (2).

(In the formula, R ¹ represents a hydrogen atom, a forminole group, or a trityl group which may have an electron-donating group on the phenyl ring. R ² represents a tert-butynole group, a naphthinolemethyl group, an anthrylmethyl group, or a phenyl ring. Represents a benzyl group that may have an electron donating group, or a diphenylmethyl group that may have an electron donating † 4S on the phenyl ring, and R ³ represents an electron on the naphthylmethyl group, anthrylmethyl group, or the phenyl ring. A benzyl group which may have a donating group or a diphenylmethyl group which may have an electron donating group on phenino ^).

2. Benzyl group which may have an electron donating group on phenino ^ represented by R ² and R ³ is benzyl group, 2,4,6-trimethylbenzinole group, p-methoxybenzide 2. The process for producing a cephem compound according to claim 1, wherein the compound is a nore group, a 3,4,5-trimethoxybenzyl group, a 3,5-dimethoxy-14-hydroxybenzyl group or a pipanol group. .

3. The method for producing a septum compound according to claim 1, wherein the diphenylenomethyl group which may have an electron-donating group on phenino represented by R ² and R ³ is a diphenylmethyl group or a ditolylmethyl group.

4. The method for producing a septum compound according to claim 1, wherein the phenols are phenol, black phenol, cresol or methoxyphenol.

5. The process according to claim 1, wherein the phenols are used in an amount of about 0.5 to 20 Okg / kg of the compound (1).

6. The method for producing a cephem compound according to claim 1, wherein the protonic acid is a sulfonic acid, a mineral acid, or a carboxylic acid.

7. The method for producing a septum compound according to claim 1, wherein the amount of the protonic acid used is about 0.0001 to 5 equivalents to the compound (1).