JPH02300190A - Production of cephalosporin compound - Google Patents

Abstract

PURPOSE:To readily obtain the subject compound useful as an intermediate for synthesis of a cephalosporin-based antifiotic in high purity and high yield by reacting a cephalosporin compound with zinc in the presence of a cetic acid. CONSTITUTION:A compound expressed by formula II which is synthesized from a thiazolinoazethidinone derivative expressed by formula I [R<1> represents alkyl, alkenyl, (substituted) aryl, (substituted) arylmethyl or (substituted) phenoxymethyl; R<2> represents (protected) carboxyl] as a starting raw material is reacted with zinc in a molar amount of 3-10 times (based on the compound expressed by formula II) in an organic solvent (example; ethyl acetate or benzene) in the presence of acetic acid in a molar amount of 10-200 times (based on the compound expressed by formula II) (preferably used as a mixture with the organic solvent) at -30 to 50 deg.C for 0.2-3hr and purified by using column chromatography, etc., to afford the objective compound expressed by formula III.

Description

[Detailed description of the invention] The present invention relates to a method for producing cephalosporin compounds.

More specifically, the present invention relates to the general formula [wherein R1 represents an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylmethyl group, or a substituted or unsubstituted phenoxymethyl group, and R2 represents a carboxyl group or protected); represents a carboxyl group. ] It is related with the manufacturing method of the cephalosporin compound represented by these.

The cephalosporin compound represented by general formula (1) is
It is a useful compound as a synthetic intermediate that can be converted into cephalosporin antibiotics.

An object of the present invention is to provide a method for producing the cephalosporin compound of general formula (I) with simple operations and high purity and high yield.

In the above general formula (I), examples of the alkyl group represented by R1 include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and t-butyl; , butenyl, hexanyl, and other lower alkenyl groups having 2 to 6 carbon atoms. Examples of the aryl group include phenyl, naphthyl, etc., and examples of the substituted aryl group include phenyl groups having an aromatic ring containing a lower alkyl group, a halogen atom, a nitro group, a lower alkyloxy group, etc., such as tolyl, xylyl, etc. , p-chlorophenyl, p-nitrophenyl, p-methoxyphenyl and the like. Examples of the arylmethyl group include benzyl, naphthylmethyl, etc., and examples of the substituted arylmethyl group include phenylmethyl groups having a lower alkyl group, halogen atom, nitro group, lower alkyloxy group, etc. on the phenyl ring as a substituent, such as tolylmethyl. , p-chlorophenylmethyl, p-nitrophenylmethyl, p-methoxyphenylmethyl and the like. The substituted or unsubstituted phenoxymethyl group includes a phenoxymethyl group, a lower alkyl group as a substituent,
Examples include phenoxymethyl groups having a halogen atom, nitro group, lower alkyloxy group, etc. on the phenyl ring, such as tolyloxymethyl, p-chlorophenoxymethyl, p-nitrophenoxymethyl, and p-methoxyphenylmethyl.

Examples of the protected carboxyl group represented by R2 include esters represented by the general formula COOR' and acid amides represented by the general formula CONHR'. Examples of the above R' include common carboxylic acid protecting groups such as methyl, 2.2.2-)lichloroethyl, diphenylmethyl, benzyl, p-nitrobenzyl, isobutyl, and t-butyl.

According to the present invention, the cephalosporin compound of the above general formula (I) can be produced as follows.

That is, the general formula [wherein R1 represents an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylmethyl group, or a substituted or unsubstituted phenoxymethyl group, and R2 is a carboxyl group or a protected represents a carboxyl group. ] The above compound of general formula (I) can be obtained by reacting a cephalosporin compound represented by the following with zinc in the presence of acetic acid.

The compound of general formula (n) used as a starting material in the present invention is synthesized as follows.

[In the formula, R1 and R2 are the same as above. ] The thiazolinoazetidinone derivative represented by
Without changing the position of the double bond by reacting with an alkali metal nitrate, the group -0NO2 is introduced to form a thiazolinoazetidinone represented by the general formula [wherein R' and R2 are the same as above. After obtaining the derivative, the compound was mixed with the general formula 2% () in an aqueous solvent [where Z represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic residue, and X represents Represents a halogen atom.] By reacting with a sulfur-containing compound represented by the following formula, an azetidinoxy derivative represented by the general formula [wherein R1, R2 and Z are the same as above] is obtained.

Next, the compound of the general formula (n) can be obtained by reacting the compound of the general formula (Vl) with ammonia in an organic solvent.

Further, general formula (III) used as a starting material in the above method
For example, the compound has the general formula R' [wherein R1 and R2 are the same as above. ] From the known thiazolinoazetidinone derivatives represented by the following methods, for example, T etrahedron Letters, 22.
3193 (1981).

In the synthesis of the compound of the general formula (n) described above, the intermediate compound of the general formula (IV) is produced by the reaction of the starting material compound of the general formula (m) with a nucleophile (MNO3 (M is an alkali metal)). In this reaction, the chlorine atom at the allyl position of the compound of general formula (III) is substituted with a nucleophile without changing the position of the C═C double bond, resulting in the general formula (TV
) can be obtained.

Conventionally, the general formula (
IV) Compound (R1=methyl, t-butyl, R2=C
0OCH3, Y=OCCH3) has been reported [J, Am, Chem, Soc.

99.248 (1977)].

O (However, this method requires N-bromosuccinimide (N
It is necessary to use expensive reactants such as BS), requires several reaction steps due to the movement of double bonds, and has the disadvantages of low yield throughout the entire process, making it a practical method. I couldn't say it at all.

On the other hand, in the above-mentioned method, the compound of general formula (rV) can be obtained in high yield by a simple method and without movement of double bonds.

General formula (IV) from the compound of general formula (m) in the above method
The conversion to the compound can be carried out by the method shown in the reaction formula below.

Reaction Formula %Formula %() The method of the above reaction formula involves first reacting the raw material compound of general formula (III) with an alkali iodide, particularly preferably sodium iodide or potassium iodide, in an organic solvent.
Without changing the position of the double bond, the general formula [wherein R1 and R2 are the same as above]. ] is obtained. Then, the compound was dissolved in an organic solvent using the general formula % (1) [where M represents an alkali metal]. ] When reacted with an alkali metal nitrate represented by the following, a compound of the general formula (TV) can be obtained in high yield without changing the position of the double bond.

In the reaction between the raw material compound of general formula (m) and alkali iodide, a wide range of organic solvents can be used as long as they dissolve both, but aprotic polar solvents such as acetone, dimethyl Sulfoxide, dimethylformamide, etc. are preferably used. Among these, acetone is particularly preferred. The amount of these organic solvents used is usually about 5
~100 times the weight may be sufficient. The ratio of the raw material compound of general formula (III) and alkali iodide can be appropriately selected from a wide range, but in general, the latter should be used in an amount of about 1 to 10 times the former, preferably about 1 to 2 times the former. . The reaction is usually carried out at about 0 to 60°C, preferably 40 to 55°C.
It is generally completed in 0.5 to 4 hours.

In addition, in the reaction between the compound of general formula (■) and the salt of general formula (1), a wide range of organic solvents can be used as long as they dissolve both, but in particular, aprotic polar solvents, For example, acetone, dimethyl sulfoxide, dimethyl formamide, etc. are preferred, and dimethyl sulfoxide is particularly preferred. These organic solvents usually have the general formula (■
) is used in an amount of about 0.5 to 10 times the weight of the compound.

The ratio of the compound of general formula (■) and the salt of general formula (1) to be used can be appropriately selected within a wide range, but usually the latter is about 10 times the molar equivalent of the former, preferably about 5 times the molar equivalent of the latter. It is best to use about double the mole. The reaction is usually carried out at 0 to 100°C.
The temperature is preferably about 40 to 60°C. Further, in order to remove by-product alkali iodide from the reaction system, the reaction can be carried out in the presence of methyl methanesulfonate or thymel toluenesulfonate under reduced pressure of about 30 to 80 mmHg. The reaction is generally completed in about 0.5 to 6 hours, although it depends on the reaction conditions.

The compound of general formula (TV) obtained by the above method is:
Then, the general formula % formula % ( ) [wherein Z represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic residue, and X represents a halogen atom. By reacting with a sulfur-containing compound represented by the general formula (Vl
) is obtained.

Here, the substituted or unsubstituted aryl group represented by Z includes a phenyl group, a halogen atom as a substituent,
Examples include phenyl groups having a nitro group, such as p-nitrophenyl, pentachlorophenyl, trichlorophenyl, and the like. In addition, examples of the substituent or unsubstituted aromatic heterocyclic residue include 2-pyridyl, 2-benzothiazolyl, 1
,3.4-thiadiazol-2-yl,5-methyl-1
Examples include 3.4-thiadiazol-2-yl.

Examples of the halogen atom represented by X include chlorine, bromine, and iodine, with chlorine being particularly preferred.

The reaction between the compound of general formula (IV) and the sulfur-containing compound of bifurcated formula (V) is carried out in a water-containing organic solvent. As the organic solvent, dimethyl sulfoxide, dioxane, tetrahydrofuran, etc. can be used, and these are usually represented by the general formula (I
It is preferable to use about 5 to 50 times the weight of the compound V). The amount of water in the water-containing organic solvent can be appropriately selected from a wide range, but it is usually about 1 to 500 times, preferably about 10 to 100 times, the amount of water relative to the compound of formula (IV). Compounds of general formula (IV) and general formula (
The ratio of the compound V) to be used can be appropriately selected from a wide range, but the ratio of the latter to the former is usually about 1 to 10 times the molar equivalent of the former.
It is preferable to use about equimolar to 4 times the molar amount. The reaction is usually carried out at about -10 to 60°C, preferably around room temperature, and is generally completed in about 0.1 to 2 hours. still,
In this reaction, the yield may be improved by the presence of an inorganic or organic acid. Preferred inorganic acids include sulfuric acid and hydrochloric acid, and preferred organic acids include trifluoroacetic acid and p-toluenesulfonic acid.

The amount of these acids used is 1 for the bifurcated (TV) compound.
The amount may be about 10 moles.

The sulfur-containing compound of general formula (IV) above can be prepared by dissolving the corresponding disulfide or thiol in an inert solvent such as carbon tetrachloride, chloroform, methylene chloride, dioxane, tetrahydrofuran, etc. It can be produced by reacting a halogen. The compound of general formula (V) thus obtained may be isolated from the reaction mixture and subjected to the reaction, or the reaction mixture may be subjected to the reaction as it is.

The compound of general formula (Vl) obtained by the reaction of the above compound of general formula (IV) with the compound of general formula (V) is converted into the compound of general formula (II) by reacting with ammonia in an organic solvent. is converted into.

As the organic solvent, inert aprotic polar solvents such as dimethylformamide, dimethylacetamide, etc. are preferred, and dimethylformamide is particularly preferred. The ratio of the compound of general formula (VI) and ammonia to be used can be appropriately selected from a wide range, but usually the latter is about 10 times the molar equivalent of the former, preferably about 10 times the molar equivalent of the former.
It may be about 3 times the mole. The reaction is usually -78 to 20
The process is carried out at a temperature of about -40°C to about 5°C, and is generally completed in about 0.61 to 2 hours.

According to the above, the general formula [wherein RI and R2 are the same as above]. ] is obtained.

The compound of the above general formula (n) is prepared by reacting with zinc in the presence of acetic acid to form a compound of the general formula [wherein R1 and R2 are the same as above]. ] can be induced to a compound represented by

The Cephasporin compound represented by the general formula (I) is
It is an important synthetic intermediate that can be converted into cephalosporin antibiotics.

In the reaction to obtain compound (I) by reacting zinc in the presence of acetic acid with compound (II), the amount of acetic acid used is not particularly limited and can be appropriately selected from a wide range, but usually acetic acid is used as a reaction solvent, or Particularly preferably, it is used as a mixed solvent of another organic solvent and acetic acid. The organic solvent can be up to about 90% by volume in the mixed solvent, preferably about 20-70% by volume.
It is best to use it in moderation. The amount of acetic acid to be used may be about 10 to 200 times the molar amount of compound (II), regardless of whether it is used alone or mixed with other organic solvents. The ratio of compound (IF) and zinc to be used is not particularly limited and can be appropriately selected within a wide range.
It is preferable to use 3 to 10 times the mole, preferably 3 to 5 times the mole of II). The reaction temperature is usually -
It is carried out at a temperature of 30 to 50°C, preferably -10 to 30°C. As the other organic solvent used as the mixed solvent, a wide range of solvents that are inert to acetic acid and zinc under the reaction conditions can be used, such as esters such as ethyl acetate, methyl acetate, and methyl propionate, diethyl ether, tetrahydrofuran, and dioxane. Examples include ethers such as, halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform, and aromatic hydrocarbons such as benzene, toluene, and xylene. The reaction is usually completed in about 0.2 to 3 hours.

In addition, the general formulas (■) and (I
The compounds V) and (VI) may be isolated and subjected to the subsequent reaction, or may be used as a reaction mixture to the subsequent reaction. Further, the finally obtained compound of general formula (I) can be purified using conventional methods such as solvent extraction, column chromatography, and recrystallization.

Hereinafter, the manufacturing method of the present invention will be explained in more detail (Examples will be given). In addition, in the examples, ph represents a phenyl group.

Reference example 1 COOCH2P A 2-(3-benzyl-7-oxo-4-thia-2,6-
diazabicyclo[3,2,OFhept-2-ene-6-
benzyl)-3-chloromethyl-3-butenoate 94
．． Add 1.2 g of acetone to 6 mg to make a homogeneous solution. Add 64.3 mg of Nal to this and stir for 1.5 hours while heating to 55°C. Next, after cooling to room temperature, diluted with 5 yoke of ethyl acetate, washed with an aqueous Na2S203 solution, then washed with saturated brine, and diluted with Na2SO3.
4 and then concentrated to give 2-(3-benzyl-7-
Oxo-4-thia-2,6-diazabicyclo[3,2,
0]hept-2-en-6-yl)=benzyl 3-iodomethyl-3-butenoate is obtained as a colorless oil (1
13.0 mg, 99%).

NMR (δ, CDCf3) 3.63 (s, 2H), 3.83 (s, 2H),
4.95 (s, IH), 5.17 (s, 2H),
5.23 (s, 2H), 5.38 (s, IH),
5.87 (bs, 2H), 7.26 (s, 5H)
, 7.33 (s, 5H) Reference Example 2 0OCH3 COOCH.

2-(3-benzyl-7-oxo-4-thia-2,6-
Diazabicyclo[3,2,O]hept-2-ene-6-
Methyl)-3-chloromethyl-3-butenoate 376
Add 10 mg of acetone to make a homogeneous solution. N for this
Add 230 mg of aI and stir while heating to 55°C for 3 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed with an aqueous Na2S203 solution, then washed with saturated brine, dried over Na2SO4, and concentrated. The resulting pale yellow oily residue was chromatographed on a silica gel column using hexane-ethyl acetate (4:1) to obtain 2-(3-benzyl-7-oxo-4-thia-2,6-diazabicyclo). [3,2,O]
hept-2-en-6-yl)-3-iodomethyl-3
-Methyl butenoate is obtained (425 mg, 90%).

NMR (δ, CDCf3) 3.62 (bs, 2H), 3.74 (s, 3H)
, 3.87 (bs, 2H) , 5.04 (s, IH
), 5.21 (s, IH), 5.91 (bs, 2
H), 7.27 (s, 5H) Reference Example 3 COOCH2Ph 2-(3-phenoxymethyl-7-oxo-4-thia-
10 g of acetone was added to 374 mg of benzyl 2,6-diazabicyclo[3,2,0]hept-2-en-6-yl)-3-chloromethyl-3-butenoate to form a homogeneous solution. Add 1154 mg of Na to this and stir for 3 hours while heating to 55°C. Next, after cooling to room temperature, it is diluted with ethyl acetate, washed with an aqueous Na28203 solution, then washed with saturated brine, dried over Na2804, and concentrated. The resulting pale yellow oily residue was chromatographed on a silica gel column using benzene-ethyl acetate (30:1) to give 2-(3-phenoxymethyl-17-oxo-4-
Thia-2,6-diazabicyclo[3,2,01hept-
Benzyl 2-en-6-yl)-3-iodomethyl-3-butenoate is obtained (359 mg, 80%).

IR(neaO1796,1736cl'NMR(δ,
CDCf3) 3.73 (bs, 2H), 4.90 (s, 2
H), 5.00 (s, LH), 5.20
(s, 3H), 5.45 (s, IH), 5.85
and 6.01 (ABq, 2H, 4Hz), 6.7-7.4 (m, 5H), 7.34 (s, 5H) Reference example 4 COOCH2Ph ρk COOCH2Ph 2-(3-benzyl-7-oxo- 4-thia-2,6-
diazabicyclo[3,2,01hept-2-ene-6-
benzyl)-3-iodomethyl-3-butenoate 10
3.5 mg and 0.0 mg of dimethyl sulfoxide. Add 9TN2 to make a homogeneous solution. Add to this 380mg of N, aN O
Add and dissolve 40 mg of methyl methanesulfonate. The reaction system is heated to 48° C. and reacted for 4 hours while maintaining a reduced pressure of 45 to 50 mmHg using a water jet pump. After cooling to room temperature, an aqueous Na2S203 solution was added and vigorously stirred. This is extracted with ethyl acetate, and the organic layer is washed with saturated brine, dried over Na2804, and concentrated. The resulting yellow oily residue was chromatographed on a silica gel column using benzene-ethyl acetate (15:1) to obtain 2-(3-benzyl-
7-oxo-4-thia-2゜6-diazabicyclo[3,
Benzyl 2,01hept-2-en-6-yl)-3-nitroxymethyl-3-butenoate is obtained (68.5+n
g, 76%).

IR(neat) 1780.1740.1640.1
275c "1 NMR (, δ, cDC/!3) 3.85 (s, 2H), 4.74 (s, 2H),
5.01 (s, IH), 5.18 (s, 2H), 5
．． 22 (s, LH), 5.43 (s, IH), 5
．． 89 and 5.93 (ABq, 2H, 4Hz), 7.
28 (s, 5H), 7.34 (s, 5H) Non-reference 5 COOCH2Ph ε0OCH2Ph 2-(3-benzyl-7-oxo-4-thia-2,6-
diazabicyclo[3,2,0]hept-2-ene-6-
0.6 vol of dioxane is added to 29.7 ng of benzyl)-3-nitroxymethyl-3-butenoate to make a homogeneous solution, followed by adding 60 μl of 5% hydrochloric acid and reacting at room temperature for 15 minutes.

Apart from the above operation, 2-benzothiazolyl disulfide 3
Add dioxane 2W1 to 7.9+ag, heat in a hot water bath to make a homogeneous solution, and add 0.59M carbon tetrachloride solution of chlorine to this. 141ni) and react for 15 minutes. This is added to the above dioxane solution and reacted at room temperature for 5 minutes with stirring.

The reaction mixture is then passed through a short silica gel column using ethyl acetate and the eluate is concentrated under reduced pressure.

The obtained residue is dissolved in benzene, and benzene is distilled off again under reduced pressure. The residue of the mixture of colorless solid and colorless oil thus obtained was chromatographed on a silica gel column using benzene followed by benzene-ethyl acetate (4:1) to obtain 2-[3-phenylacetamide. Benzyl -4-(2-penzothiazolyldithio)-2-azetidinon-1-yl]-3-nitroxymethyl-3-butenoate is obtained (yield 70%).

I R(neat) 3280.1780.1740.
1670.1640.1270cm-NMR (δ, C
DCJ! 3) 3.66 (s, 2H), 5.10 (s, 2H),
5.14 (s, 2H), 5, 0-5. 3 (m, 2H), 5.40 (
s, IH), 5.51 (d, IH, 5Hz), 5, 56 (s, IH), 6.56 (
d, IH, 7,5Hz), 7, 1-7. 6
(m, 12H) 7.6-8. 0 (m, 2
H) Reference Example 6 COOCH2Ph COOCH2P h 2-[3-phenylacetamido-4-(2-benzothiazolyldithio)-2-azetidinon-1-yl]-3
-Benzyl ditroxymethyl-3-butenoate 35.7m
Add 0.7 hardness of dimethylformamide to g to make a homogeneous solution. This was cooled to -30 to 35°C, and a solution prepared by dissolving ammonia gas in dimethylfoamide (approximately 3.3 M
) Add 23 μl and react with stirring for 15 minutes. Excess ammonia is distilled off under reduced pressure using a vacuum pump while maintaining this at -30°C. Then, the solvent is distilled off while gradually returning the temperature to room temperature. The resulting pale yellow oily residue was chromatographed on a silica gel column using benzene and then benzene-ethyl acetate (4:1) to give 7-phenylacetamido-3-nitroxymethyl-3-cephem-4-. Benzyl carboxylate is obtained (yield 73%).

NMR (δ, CDC13) 3.36 and 3.48 (ABq, 2H, 18Hz
), 3, 60 (s, 2H), 4, 93
(d, 2H, 5Hz), 5.16 and 5.
58 (ABq, 2H, 12Hz), 5, 25
(s, 2H), 5.83 (dd, IH, 5Hz, 8Hz)
,6, 33 (d, IH, 8Hz) ,7,
28 (s, 5H)・, 7.34 (s,
5H), Additional Example 1 C00CH2PA COOCH2Pk 7-phenylacetamido-3-nitroxymethyl-3
Add 0.15 n of methylene chloride to 12.9 mg of benzyl -cephem-4-carboxylate to make a homogeneous solution. 5.2 mg of zinc powder is added to this and cooled to 0-5°C. Add 0.15 TN2 of acetic acid to this and react with stirring for 135 minutes. Then diluted by adding ethyl acetate 3me,
Washing with saturated NaHCO3 aqueous solution, followed by saturated brine, drying over Na2SO4, and concentration under reduced pressure yields benzyl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (10
．． 0 mg, 85%).

NMR (δ, CDCJ3) 2.60 (bs, IH), 3.52 (s, 2H)
, 3, 61 (s, 2H), 4.02 and 4.48 (ABq, 2H, 13,5Hz
), 4.90 (d, IH, 4Hz), 5.25 (s, 2H), 5.81 (dd, IH, 4Hz, 9Hz),
6, 51 (d, IH, 9Hz), 7.2
8 (s, 5H), 7.37 (s, 5H) (or more)

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is an alkyl group, an alkenyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylmethyl group, or a substituted or unsubstituted arylmethyl group. represents a phenoxymethyl group, and R^2 represents a carboxyl group or a protected carboxyl group. ] General formula ▲ Numerical formula, chemical formula, table, etc., characterized by reacting a cephalosporin compound represented by the following with zinc in the presence of acetic acid ▼ [In the formula, R^1 and R^2 are as defined above] same. ] A method for producing a cephalosporin compound represented by