CN102260280A - Preparation method of latamoxef disodium - Google Patents

Abstract

The invention relates to a production method of latamoxef sodium which can be used as an antibacterial drug. The preparation method of latamoxef sodium of the present invention comprises removing the protective group from the SI compound in an organic solvent under the action of trifluoroacetic acid and carbocation absorbent; then adding R ₄ CO ₂ to the alcohol, ketone or ester Na solution, filtering and washing the solid to obtain the crude product of latamoxef sodium; finally dissolving the crude product of latamoxef sodium in water and extracting it with an organic solvent, decolorizing with activated carbon, and freeze-drying in the aqueous phase to obtain latamoxef sodium. The invention provides a brand-new method for synthesizing Latamoxef Sodium from a single-configuration intermediate, directly reacting with sodium carboxylate to obtain the crude Latamoxef Sodium, and the final obtained refined product meets the standards of the Chinese Pharmacopoeia without the need for purification. Adsorption resin purification reduces the amount of purified water, improves production efficiency, reduces energy consumption, reduces equipment investment, and is suitable for industrial production.

Description

The preparation method of latamoxef sodium

technical field

The invention relates to a production method of latamoxef sodium which can be used as an antibacterial drug.

Background technique

Latamoxycephalic acid and Latamoxycephalic acid sodium are oxycephem antibiotics developed by Shionogi Pharmaceutical Co., Ltd. in Japan. In 1981, they were first listed in Germany under the trade name "Festmoxin". After 1982, they were mainly sold in Japan and South Korea for Clinically, the trade name is "shiomarin". At present, Hainan Hailing Chemical Pharmaceutical Co., Ltd. mainly imports raw materials from Japan and then repacks the preparations in China. At present, there is no production of its products in China. Latamoxef has a broad antibacterial spectrum, and its antibacterial activity is similar to that of the third-generation cephalosporins. Its effect on Gram-negative bacilli is 4 to 16 times stronger than that of general cephalosporins, and its effect on anaerobic bacteria, especially Bacteroides fragilis, is obviously superior. It is suitable for the first, second and third generation cephalosporins; it is highly stable to β-lactamase and has a strong antibacterial effect on enzyme-producing drug-resistant negative bacilli and Staphylococcus aureus; the T1/2 is long, and the blood concentration is maintained for a long time. High content in cerebrospinal fluid.

Latamoxef sodium chemical name: (6R,7R)-7-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7-methoxy-3-[(1-methyl-1H -tetrazol-5-yl)thiomethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt

Because the 7-position amino side chain of Latamoxef sodium has chirality,

Therefore, it is stipulated in the Chinese Pharmacopoeia that the ratio of the peak area of the Latamoxef R isomer to the Latamoxef S isomer peak area should be 0.8 to 1.4.

Currently, J.Med.Chem., 1982, 463-482, US4138486, US4180571, US4323567 reported the synthesis of Latamoxef sodium.

The preparation methods of latamoxefalic acid all use the compound of general formula I as raw material to obtain it by removing the protecting group, and undergo a sodium-hydrogen exchange reaction with sodium carboxylate to obtain latamoxef sodium. Among them, the compound with general formula I whose 7-position amino side chain is a mixture of R/S configuration, hereinafter referred to as R, S-I, if the 7-position amino side chain is a compound of S configuration, hereinafter referred to as S-I

Compound (R, S-I) was added dropwise a nitromethane solution of aluminum trichloride in dichloromethane at 0°C. After the reaction was complete, it was purified with HP-20 adsorption resin, and eluted with water and methanol in sequence to obtain refined Laoxine Cephalic acid. (J.Med.Chem., 1982,463-482, US4138486, US4180571, US4323567) Latamoxefur acid reacts with sodium carboxylate to obtain the crude product of Latamoxef sodium (J.Med.Chem., 1982,463-482) , in order to reach the standard for clinical use, the crude product of latamoxef sodium was made into 0.11%～0.19% dilute solution overadsorbed resin (XAD-2000, SP-207), eluted and purified with methanol/water or acetone/water mixture, and reduced The eluate was concentrated under pressure, neutralized with sodium hydroxide and then freeze-dried to obtain the refined latamoxef sodium (GB2153823).

There is following shortcoming in the method for preparing latamoxef sodium at present:

1), when preparing compound (R, S)-I, since it is an amorphous powder, silica gel column chromatography purification is required, which not only increases post-processing steps, affects production efficiency, but also increases equipment investment;

2), in order to obtain the high-purity latamoxycetidine, need to carry out adsorption resin desalination purification treatment, in order to remove elution solvent methanol (or acetone) and water, not only need low-temperature decompression distillation to reclaim methyl alcohol (or acetone), and in order to reduce The destruction of Latamoxefac requires membrane concentration to remove water, which not only increases the processing steps, but also increases the equipment investment;

3), when latamoxef acid is neutralized with sodium hydroxide in the aqueous phase, latamoxef sodium is obtained, and the alkali will damage latamoxef and reduce the purity of latamoxef sodium.

EP0051457 and EP0098545 disclose the method for preparing the S-I compound of single configuration,

Compared with R, S-I compounds, S-I compounds with a single configuration have the following advantages:

1. The single-configuration S-I compound is a crystal, which can be easily refined by crystallization and purification during the preparation and synthesis, which is conducive to the expansion of production capacity; while the compound of R, S-I mixed rotation is amorphous, which requires silica gel column chromatography to purify and prepare, which restricts production capacity. the bottleneck.

2. Since the single-configuration S-I compound is a crystal, the purity is higher, and fewer impurities are brought into the next step, resulting in a higher purity of the final product.

We found that although the S-I compound of a single configuration has the above advantages, there is no report on how to synthesize Latamoxef sodium by the S-I compound of a single configuration so far.

Contents of the invention

The object of the present invention is to provide a method for preparing latamoxef sodium from the S-I compound of a single configuration, which is suitable for industrial production.

The technical scheme that the present invention takes is as follows:

The preparation method of latamoxef sodium, the steps are as follows:

(a), compound S-I in an organic solvent, under the action of trifluoroacetic acid and carbocation absorbent, removes the protecting group to obtain compound II

Wherein R ₁ represents hydrogen or a protecting group for hydroxyl, R ₂ and R ₃ represent carboxyl protecting groups;

(b), compound II is dissolved in alcohol, ketone or ester, R ₄ CO ₂ Na solution is added, the solid is filtered and washed to obtain the crude product of latamoxef sodium

Wherein R ₄ is an alkyl group;

(c), dissolving the crude product of latamoxef sodium in water, extracting it with an organic solvent, decolorizing it with activated carbon, and freeze-drying in the water phase to obtain latamoxef sodium.

For further understanding content of the present invention, each step is described as follows:

_R in the step (a) represents hydrogen or a protecting group for a hydroxyl group, if _R represents a protecting group for a hydroxyl group including well-known ones that can react with a hydroxyl group and can be removed under acidic conditions without causing other moieties in the molecule Any undesired change of hydroxyl protecting group, such as: p-methoxybenzyl, benzhydryl, trityl, tert-butyl, tetrahydropyranyl, tetrahydrofuranyl, etc.; R ₁ is preferably hydrogen or para Methoxybenzyl.

R in the step (a) represents a _carboxyl protecting group including well-known carboxyl protecting groups capable of reacting with carboxyl groups and capable of being removed under acidic conditions without causing any undesired changes in other parts of the molecule, such as: p-methoxybenzyl, trityl, tert-butyl, tetrahydropyranyl, tetrahydrofuranyl, etc.; p-methoxybenzyl or benzhydryl is preferred.

The carboxyl protecting group represented by _R3 in the step (a) includes the carboxyl protecting group well known in the cephalosporin industry that can react with or remove a carboxyl group without causing any undesired changes in other parts of the molecule. Typical examples include C1-C8 ester-forming alkyl groups (such as methyl, methoxymethyl, ethyl, ethoxyethyl, iodoethyl, propyl, isopropyl, butyl, isobutyl, tri Chloroethyl, tert-butyl, etc.), C3-C8 alkenyl (such as: propenyl, vinyl, isopropenyl, phenylpropenyl, hexenyl, C7-C19 aralkyl (benzyl, methyl benzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, benzhydryl, phenethyl, trityl, di-t-butylhydroxy Benzyl, phenacyl, etc.), C6~C12 aromatic groups (phenyl, tolyl, diisopropylphenyl, xylyl, trichlorophenyl, pentachlorophenyl, etc.), C1~C12 Amino groups (such as: acetone oxime, acetophenone oxime, etc.), C3~C12 alkylated methyl groups (such as: trimethylsilyl, dimethylmethoxysilyl, tert-butyldimethylsilane group, etc.), p-methoxybenzyl or benzhydryl is preferred.

The carbocation adsorbent described in step (a) includes C2～C15 sulfide (such as: ethyl sulfide, phenylmethyl sulfide, etc.), C7～C15 aromatic ether (such as: anisole, Phenethyl ether, etc.), C2～C15 mercapto-containing compounds (such as: thiophenol), preferably anisole, the amount (volume) of anisole and the amount (mass) ratio of compound I are 0.5～10:1 , preferably 1 to 5:1.

The organic solvent described in the step (a), can use various solvents, as long as they do not have harmful influence to this reaction, they can be selected as: the halogenated alkane of C1～C4 (such as: dichloromethane, chloroform, dichloromethane Ethane, etc.), C1~C4 nitriles (such as: acetonitrile, propionitrile, etc.), C1~C8 acetates (such as: ethyl acetate, methyl acetate, etc.), C1~C4 ethers (such as: ether, Tetrahydrofuran, etc.), C3-C4 amides (such as: dimethylformamide, dimethylacetamide, etc.), C6-C10 benzene-containing solvents (such as: toluene, xylene, chlorobenzene, etc.); preferably dichloromethane or chloroform.

The reaction temperature described in the step (a) is -70°C to 30°C, and the best is -30°C to 20°C.

The mass ratio of trifluoroacetic acid and compound I in step (a) is 0.5-10:1, preferably 1-5:1.

Step (a) After the reaction is completed, ether solvents are added to precipitate latamoxycephalic acid. The ether solvents include C1-C8 ethers, such as diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and the like. Preference is given to diethyl ether, isopropyl ether or methyl tert-butyl ether.

The alcohol described in step (b) is C1～C8 alcohol (such as methanol, ethanol, propanol, etc.), preferably methanol, ethanol or isopropanol; the described ketone is C1～C8 ketone (such as acetone, 2 -butanone, methyl tert-butyl ketone, etc.), preferably acetone or 2-butanone; the ester is C1～C8 ester (such as ethyl formate, ethyl acetate, isopropyl acetate, tert-butyl acetate , ethyl propionate, etc.), preferably ethyl acetate, isopropyl acetate or tert-butyl acetate.

R ₄ CO ₂ Na in the step (b) is C1-C10 organic sodium alkanoate (such as sodium acetate, sodium propionate, sodium butyrate or sodium isooctanoate, etc.), preferably sodium isooctanoate.

The R ₄ CO ₂ Na solution described in step (b) is a solution made of R ₄ CO ₂ Na and an organic solvent. The organic solvent has no special requirements, as long as it dissolves R ₄ CO ₂ Na, they can be selected Such as: C1~C4 halogenated alkanes (such as: dichloromethane, chloroform, dichloroethane, etc.), C1~C4 nitriles (such as: acetonitrile, propionitrile, etc.), C1~C8 acids (such as: ethyl formate , ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl propionate, etc.), C1-C4 ethers (such as diethyl ether or tetrahydrofuran, etc.), C3-C4 amides (such as: dimethylformamide, Dimethylacetamide, etc.), C6-C10 benzene-containing solvents (such as toluene, xylene, chlorobenzene, etc.), C1-C8 ketones (such as: acetone, 2-butanone, methyl tert-butyl ketone, etc. ); preferably ethyl acetate, isopropyl acetate, tert-butyl acetate, tetrahydrofuran, acetone or 2-butanone.

The molar amount of R ₄ CO ₂ Na in step (b) is 2.0-10 times that of compound I, preferably 2.2-3.5 times.

The reaction temperature of step (b) is -20°C to 50°C, the most optimal is -5°C to 10°C.

The amount of purified water used in step (c) is not particularly limited, as long as the latamoxef sodium is dissolved, preferably 0.5-50% of the weight of the latamoxef sodium.

The organic solvent described in step (c) is C1～C4 halogenated alkanes (such as: dichloromethane, chloroform, dichloroethane, etc.), C1～C8 acetate (such as: ethyl acetate, methyl acetate, Isopropyl acetate, etc.), C1-C4 ethers (such as: ether, tetrahydrofuran, etc.), C6-C10 benzene-containing solvents (such as: toluene, xylene, chlorobenzene, etc.), C1-C8 ketones (such as 2- butanone, etc.); preferably ethyl acetate, isopropyl acetate or 2-butanone.

Beneficial effects of the present invention:

1), the present invention provides a kind of brand-new method for synthesizing latamoxef sodium by the intermediate of single configuration. Compound S-I is obtained after deprotection and racemization of Latamoxefor, and the crude product of Latamoxef Sodium obtained after directly reacting with sodium carboxylate without purification is finally dissolved in water, extracted with an organic solvent, and freeze-dried in the aqueous phase The refined product of latamoxef sodium can be obtained, and the product meets the standards of the Chinese Pharmacopoeia;

2), the post-treatment of the present invention does not require column chromatography purification, adsorption resin purification, and low-temperature membrane concentration, which improves production efficiency, reduces energy consumption, reduces equipment investment, and is suitable for industrial production.

Detailed ways

Example 1

Compound (S)-I (R1=p-methoxybenzyl, R2=p-methoxybenzyl, R3=benzhydryl) (3.5Kg) was dissolved in dichloromethane (2L), cooled to 0°C , add anisole (15L), dropwise add trifluoroacetic acid (3.5Kg), keep warm at 0°C for 1.0h, add dropwise methyl tert-butyl ether (20L), stir, filter, and dissolve the solid with acetone (20L), Cool to 0°C, add sodium isooctanoate (1.9Kg)/acetone (30L) dropwise, after the addition is complete, react for 30min, filter, dissolve the solid in deionized water (8L), wash with isopropyl acetate (5L), and decolorized with activated carbon, filtered, and freeze-dried to obtain Latamoxef Sodium. Yield: 87.5%.

Example 2

Compound (S)-I (R1=H, R2=p-methoxybenzyl, R3=benzhydryl) (3Kg) was dissolved in dichloromethane (5L), cooled to -20°C, and anisole was added (8L), add trifluoroacetic acid (13Kg) dropwise, keep warm at -20°C to -15°C for 1.0h, heat up to 0°C to 15°C for 1.0h, recover dichloromethane and trifluoroacetic acid under reduced pressure, add diethyl ether ( 20L), stirred, filtered, dissolved the solid with methanol (6L), cooled to -5～10°C, added dropwise sodium isooctanoate (1.4Kg)/tetrahydrofuran (60L), after the dropwise addition was completed, reacted for 30min, filtered, and the solid was dissolved in In deionized water (10 L), washed with ethyl acetate (5 L), decolorized with activated carbon in the aqueous phase, filtered, and lyophilized to obtain Latamoxef sodium. Yield: 90%.

Example 3

Compound (S)-I (R1=H, R2=p-methoxybenzyl, R3=benzhydryl) (3Kg) was dissolved in dichloromethane (10L), cooled to -30°C, and anisole was added (3L), add trifluoroacetic acid (18Kg) dropwise, and slowly heat up to -10°C~0°C for 1.5h after dropping, add isopropyl ether (50L) dropwise, stir, filter, and dissolve the solid with ethyl acetate (25L) , cooled to 0 ~ 10 ° C, dropwise added sodium isooctanoate (1.4Kg) / ethyl acetate (20L), after the dropwise addition was completed, reacted for 30min, filtered, the solid was dissolved in deionized water (10L), butanone (5L) Wash, decolorize with activated carbon in the aqueous phase, filter, and freeze-dry to obtain Latamoxef Sodium. Yield: 92%.

Example 4

Compound (S)-I (R1=hydrogen, R2=p-methoxybenzyl, R3=p-methoxybenzyl) (2.8Kg) was dissolved in chloroform (10L), cooled to -30°C, added benzenesulfide Phenol (6Kg), add trifluoroacetic acid (8Kg) dropwise, slowly heat up to 0°C and react for 1.0h after dropping, add isopropyl ether (40L) dropwise, stir, filter, dissolve the solid with ethanol (20L), and cool to 0°C , add sodium isooctanoate (1.9Kg)/acetone (30L) dropwise, the dropwise addition is completed, react for 30min, filter, dissolve the solid in deionized water (8L), wash with 2-butanone (5L), decolorize the water phase activated carbon, Filter and freeze-dry Latamoxef Sodium. Yield: 89.5%.

Example 5

Compound (S)-I (R1=hydrogen, R2=benzhydryl, R3=benzhydryl) (3.7Kg) was dissolved in chloroform (10L), cooled to -10°C, added sulfide anisole (6L ), add trifluoroacetic acid (6Kg) dropwise, and slowly heat up to 0-10°C to react for 1.0h after dropping, add methyl tert-butyl ether (30L) dropwise, stir, filter, and dissolve the solid with isopropanol (20L), Cool to 0°C, add sodium isooctanoate (1.9Kg)/acetone (30L) dropwise, after the addition is complete, react for 30min, filter, dissolve the solid in deionized water (8L), wash with isopropyl acetate (5L), and Decolorized with activated carbon, filtered, and freeze-dried to obtain Latamoxef Sodium. Yield: 89.5%.

Example 6

Replace the methyl alcohol in embodiment 2 with ethanol, other constant, yield: 90.2%

Example 7

Replace the ethyl acetate in embodiment 1 with isopropyl acetate, other constant, yield: 92%

Example 8

Replace the acetone in embodiment 3 with 2-butanone, other unchanged, yield: 87%

Example 9

The trifluoroacetic acid charging amount in embodiment 1 is 10Kg, other is constant, yield: 86%

Example 10

Replace the dichloromethane in embodiment 3 with chloroform, other constant, yield: 90.5%

Example 11

The trifluoroacetic acid charging amount in embodiment 3 is 6Kg, other is constant, yield: 85%

Example 12

The trifluoroacetic acid charging amount in embodiment 4 is 4Kg, other is constant, yield: 83%

Example 13

Replace the Virahol in embodiment 5 with acetone, other unchanged, yield: 91.6%

Claims (13)

1. the preparation method of Latamoxef Sodium, step is as follows:

(a), compound S-I in organic solvent, under trifluoroacetic acid and the effect of carbonium ion absorption agent, remove protecting group and get formula II compound:

R wherein ₁Represent the protecting group of hydrogen or hydroxyl, R ₂, R ₃The representation carboxy protecting group;

(b), Compound I I is dissolved in alcohol, ketone or the ester adding R ₄CO ₂Na solution with solid filtering, washing, obtains the crude product of Latamoxef Sodium

R wherein ₄Be alkyl;

(c), organic solvent extraction is used in the dissolving crude product of Latamoxef Sodium back in water, after activated carbon decolorizing, water freeze-drying obtain Latamoxef Sodium.

2. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: R ₁For hydrogen or to methoxy-benzyl.

3. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: R ₂Representative is to methoxy-benzyl or diphenyl-methyl.

4. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: R ₃Representative is to methoxy-benzyl or diphenyl-methyl.

5. the preparation method of Latamoxef Sodium as claimed in claim 1, it is characterized in that: the carbonium ion sorbent material comprises methyl-phenoxide, thiophenol and thioanisole.

6. the preparation method of Latamoxef Sodium as claimed in claim 5, it is characterized in that: the volumetric usage of methyl-phenoxide is 0.5～10 times of Compound I weight.

7. the preparation method of Latamoxef Sodium as claimed in claim 1, it is characterized in that: the mass ratio of trifluoroacetic acid and Compound I is 0.5～10: 1.

8. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: step (a) reaction finishes the back and adds ether solvent and separate out latamoxef acid, and said ether solvent is the ether of C1～C8.

9. the preparation method of Latamoxef Sodium as claimed in claim 8, it is characterized in that: the ether of said C1～C8 is ether, isopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF).

10. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: said R in the step (b) ₄CO ₂Na is organic alkanoic acid sodium of C1～C10.

11. the preparation method of Latamoxef Sodium as claimed in claim 10 is characterized in that: R ₄CO ₂Na is meant Sodium isooctanoate.

12. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: R in the step (b) ₄CO ₂The consumption of Na is 2.2～3.5 of a Compound I molar weight.

13. the preparation method of Latamoxef Sodium as claimed in claim 1 is characterized in that: the organic solvent described in the step (c) is ethyl acetate, isopropyl acetate or 2-butanone.