CN111689988A - Cefixime impurity and synthesis method thereof - Google Patents
Cefixime impurity and synthesis method thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 73
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 title claims abstract description 70
- 229960002129 cefixime Drugs 0.000 title claims abstract description 70
- 238000001308 synthesis method Methods 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 10
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 claims abstract description 10
- 229960003719 cefdinir Drugs 0.000 claims abstract description 10
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 150000003952 β-lactams Chemical class 0.000 claims abstract description 3
- -1 (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido Chemical group 0.000 claims description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 238000003786 synthesis reaction Methods 0.000 claims description 21
- 230000002194 synthesizing effect Effects 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 20
- 238000011160 research Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 5
- 238000003908 quality control method Methods 0.000 abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 63
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 238000000967 suction filtration Methods 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000001291 vacuum drying Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002953 preparative HPLC Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 108700020474 Penicillin-Binding Proteins Proteins 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a cefixime impurity and a synthesis method thereof, wherein the method comprises the following steps: a. hydrolyzing beta-lactam of cefdinir with alkali to obtain an intermediate 1; b. reacting the intermediate 1 with acid to obtain an intermediate 2; c. protecting the amino group of the intermediate 2 with Boc anhydride to obtain an intermediate 3; d. reacting the intermediate 3 with methyl bromoacetate to obtain an intermediate 4; e. and (4) deprotecting the intermediate 4 with trifluoroacetic acid to obtain the target impurity. The invention has the advantages of easily obtained synthetic reaction materials, low cost, simple reaction operation, low requirement on reaction equipment, mild reaction conditions and high content of synthetic target products, provides a relatively convenient and reliable acquisition channel for researching cefixime impurities under the condition that the cefixime impurities are high in market price and cannot be bought at present, greatly reduces the cost, and has great promotion effect on further and extensive research on safety, reliability and stability of cefixime related medicaments and quality control in the production process.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to cefixime impurity and a synthesis method thereof.
Background
Cefixime is a third-generation oral cephalosporin with broad spectrum, high efficiency and enzyme resistance developed by fujize pharmaceutical co. Since its introduction in japan and the united states, respectively, in 1987 and 1989, it has been widely used clinically in over 80 countries by 1999. Cefixime inhibits the cell wall synthesis of bacterial dividing cells by combining with Penicillin Binding Proteins (PBPs), thereby causing the cell contents to overgrow and swell to be broken, leading the cell contents to leak out and killing the cells. Cefixime has the characteristics of wide antibacterial spectrum, strong bactericidal power, acid resistance and high stability to beta-lactamase. The traditional Chinese medicine composition is mainly used for treating respiratory tract infection, urinary system infection, biliary tract infection and the like in clinic.
The quality of the medicine is an important standard for measuring the quality of the medicine, and the quality of the medicine is determined by the curative effect and the toxic and side effect of the medicine, namely the effectiveness and the safety of the medicine. It is therefore desirable that the drug be within the therapeutic range without producing severe toxic effects and with little or no side effects. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause non-therapeutic toxic and side effects and must be controlled.
Through research, a specific impurity (Z) -7- (2-aminothiazole-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxo-6, 9-diazadec-6-en-11-acetic acid is generated in the cefixime production process, the impurity has no CAS number temporarily, the structural formula is shown below, and no synthetic method is reported so far.
In order to control the quality of the medicine, clear requirements are made on the cefixime impurity in the registration and declaration process of the medicine, however, the current international method is to carry out research, analysis and verification on the impurity reference substance of the medicine, and the evaluation of the consistency of the national imitation pharmacy requires that the content of the specific impurity is not higher than that of the original medicine. Meanwhile, in order to ensure the safety of the medicine, toxicological studies on the cefixime impurity are also needed, and particularly, the toxicity and the possible side effects of the cefixime impurity are researched and evaluated. However, since the cefixime impurity is a specific impurity and is rarely sold in the market, the cefixime impurity has important value for quality control and safety evaluation of cefixime medicaments based on the specific impurity, and therefore, the research on synthesis of the cefixime impurity has very important practical significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides cefixime impurities and a synthesis method thereof, the synthesis reaction materials are easy to obtain, the cost is low, the reaction operation is simple, the requirement on reaction equipment is not high, the reaction condition is mild, the content of the synthesized target product is high, under the condition that the cefixime impurities are high in market price and cannot be bought at present, a relatively convenient and reliable acquisition channel is provided for the research of the cefixime impurities, the cost is greatly reduced, and the invention has great promotion effect on the deeper and wider research of the safety, reliability and stability of related cefixime medicaments and the quality control in the production process.
The above object of the present invention is achieved by the following means.
In a first aspect, a process for preparing cefixime impurity comprises the following steps:
a. hydrolysis of the beta-lactam of cefdinir with base gives intermediate 1: (2R) -2- ((((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) (carboxy) methyl) -5-vinyl-3, 6-dihydro-2H-1, 3-thiazine-4-carboxylic acid;
b. reacting intermediate 1 with an acid to give intermediate 2: 2- ((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
c. protecting the amino group of intermediate 2 with Boc anhydride to give intermediate 3: 2- ((Z) -2- (2- ((tert-butoxycarbonyl) amino) thiazol-4-yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
d. reacting the intermediate 3 with methyl bromoacetate to obtain an intermediate 4: (Z) -7- (2- ((tert-butoxycarbonyl) amino) thiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxa-6, 9-diazaden-6-en-11-acetic acid;
e. deprotection of intermediate 4 with trifluoroacetic acid gave the desired impurity: (Z) -7- (2-aminothiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxo-6, 9-diazepan-6-en-11-acetic acid.
The synthetic route of the synthetic method is expressed by a structural formula as follows:
as an embodiment of the method for synthesizing cefixime impurity provided by the present invention, the alkali used in step a is one or two of sodium hydroxide, lithium hydroxide and potassium carbonate.
In one embodiment of the method for synthesizing cefixime impurity provided by the present invention, in the step a, the molar ratio of the base to cefdinir is (2-2.1): 1.
As an embodiment of the method for synthesizing cefixime impurity provided by the present invention, the acid used in step b is one or two of formic acid, trifluoroacetic acid, hydrochloric acid and sulfuric acid.
As an embodiment of the method for synthesizing cefixime impurities, the molar ratio of acid to the intermediate 1 in the step b reaction is (2-3): 1.
In the step c, the mole ratio of the Boc anhydride to the intermediate 2 is (1.05-1.1): 1.
In one embodiment of the method for synthesizing cefixime impurity provided by the present invention, in the step d, the molar ratio of methyl bromoacetate to the intermediate 3 is (1.05-1.1): 1.
In one embodiment of the method for synthesizing cefixime impurity provided by the invention, in the step e, the molar ratio of trifluoroacetic acid to the intermediate 4 is (10-15): 1.
As an embodiment of the method for synthesizing cefixime impurity provided by the present invention, the step a is a reaction at-20 ℃ to 10 ℃; the step b is to carry out reaction at the temperature of 10-20 ℃; the step c is to carry out reaction at 0-5 ℃; the step d is to carry out reaction at a temperature of-5 to 5 ℃; and the step e is carried out at 15-25 ℃.
As an embodiment of the method for synthesizing cefixime impurities, the reaction time in the step a is 1-1.5 hours; the reaction time of the step b is 2-3 hours; the reaction time of the step c is 3-4 hours; the reaction time of the step d is 4-5 hours; and e, the reaction time of the step e is 7-10 hours.
In a second aspect, cefixime impurity is synthesized by the above-mentioned synthesis method of cefixime impurity.
Compared with the prior art, the invention has the beneficial effects that:
the synthesis reaction material is easy to obtain, the cost is low, the reaction operation is simple, the requirement on reaction equipment is not high, the reaction condition is mild, the content of the synthesized target product is high, a relatively convenient and reliable acquisition channel is provided for the research of cefixime impurities under the condition that the cefixime impurities are high in market price and cannot be bought at present, the cost is greatly reduced, and the method has a great promotion effect on the deep and extensive research of the safety, reliability and stability of cefixime related medicaments and the quality control in the production process.
Step a, hydrolyzing lactam ring of cefdinir with alkali at ultralow temperature, and crystallizing by adjusting pH to obtain an intermediate 1 with gram-grade purity of more than 95%, so as to facilitate subsequent step research; step b, using a lower solvent material volume ratio, having high substrate concentration, and using mild acidic reaction conditions to obtain a high-purity intermediate 2; in the cde step, amino is protected firstly, and then a bromization reagent reacts with hydroxyl, so that side reaction is avoided, and target impurities with the purity of 95% can be obtained by performing crystallization, washing and drying after deprotection, so that a reliable method is provided for obtaining high-purity cefixime impurities.
Drawings
Fig. 1 is a carbon nuclear magnetic spectrum of cefixime impurity synthesized in example 1 of the present invention;
FIG. 2 is a hydrogen nuclear magnetic spectrum of cefixime impurity synthesized in example 1 of the present invention;
fig. 3 is an HPLC chromatogram of cefixime impurity synthesized in example 1 of the present invention;
fig. 4 is a mass spectrum of cefixime impurity synthesized in example 1 of the present invention.
Detailed Description
In order to overcome the technical problems described in the background art, the invention provides cefixime impurity and a synthesis method thereof. Specifically, the cefixime impurity is specifically (Z) -7- (2-aminothiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxo-6, 9-diazepam-6-en-11-acetic acid, and the synthesis method comprises the following steps:
step a: mixing alkali with cefdinir in a molar ratio of (2-2.1): 1 at-20 to-10 ℃, and reacting for 1-1.5 h to obtain an intermediate 1: (2R) -2- ((((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) (carboxy) methyl) -5-vinyl-3, 6-dihydro-2H-1, 3-thiazine-4-carboxylic acid;
step b: mixing and reacting acid with the intermediate 1 at a molar ratio of (2-3): 1 at 10-20 ℃ for 2-3 hours to obtain an intermediate 2: 2- ((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
step c: mixing Boc anhydride and the intermediate 2 at a molar ratio of (1.05-1.10): 1 at 0-5 ℃ for reaction for 3-4 hours to obtain an intermediate 3: 2- ((Z) -2- (2- ((tert-butoxycarbonyl) amino) thiazole-4-
Yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
step d: mixing methyl bromoacetate and the intermediate 3 in a molar ratio (1.05-1.1): 1 at-5 ℃ for reacting for 4-5 hours to obtain an intermediate 4: (Z) -7- (2- ((tert-butoxycarbonyl) amino) thiazole-4-
-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxa-6, 9-diazepan-6-en-11-acetic acid;
step e: at 15-25 ℃, mixing trifluoroacetic acid with a molar ratio of (10-15): 1 with the intermediate 4, and reacting for 7-10 hours to obtain cefixime impurities: (Z) -7- (2-aminothiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxo-6, 9-diazepan-6-en-11-acetic acid.
Wherein, the solvent used in the step c is one or two of tetrahydrofuran, acetonitrile and DMF; the acid-binding agent used in the step d is one of lithium hydroxide, potassium carbonate, triethylamine and DIPEA; and the ratio of the volume of the solvent to the trifluoroacetic acid in step e is 2: 1.
Specifically, the synthesis process of the cefixime impurity is expressed by the structural formula as follows:
the invention is described in further detail below with reference to the drawings and specific examples, but the examples are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. The materials, reagents and the like used in the examples of the present invention are commercially available.
Example 1
The embodiment provides a method for synthesizing cefixime impurities, which comprises the following steps:
a1 Synthesis of intermediate 1
The method comprises the following specific steps: adding 20g of cefdinir, 80mL of purified water and 30mL of methanol into a 250mL single-neck flask, stirring for 10 minutes at the temperature of-15 ℃, adding 2.4g of lithium hydroxide, stirring for 1.5 hours at the temperature of-15 ℃, adjusting the pH value to a turbid point by using 4M hydrochloric acid under the stirring at the temperature of-15 ℃, stirring for 20 minutes, then continuously adjusting the pH value to 3 +/-0.5 by using 4M hydrochloric acid, slowly stirring for 30 minutes at the temperature of-15 ℃, performing suction filtration, respectively washing a filter cake for 2 times by using 10mL of 50% acetonitrile aqueous solution, and performing vacuum drying for 3 hours at 30 ℃ to obtain 17.6g of light yellow powder with the HPLC purity of 97.56%.
b1 Synthesis of intermediate 2
The method comprises the following specific steps: adding 16.6g of intermediate 1 and 100mL of methanol into a 250mL single-neck flask, controlling the temperature to be 15 ℃, stirring for 5 minutes, adding 4.6g of formic acid, controlling the temperature to be 20 ℃, stirring for 3 hours, controlling the temperature to be 15 ℃, rotary-steaming reaction liquid to remove the solvent and the formic acid, adding 40mL of tetrahydrofuran, stirring until the solution is clear, slowly dropwise adding 60mL of methyl tert-butyl ether under the stirring of an ice bath, stirring for 30 minutes in the ice bath after dropwise adding, performing suction filtration, respectively washing a filter cake for 2 times by 10mL of the methyl tert-butyl ether, and performing vacuum drying for 2 hours at 30 ℃ to obtain 13.8g of light yellow powder with the HPLC purity of 96..
c1, synthesis of intermediate 3:
the method comprises the following specific steps: adding 12.4g of the intermediate 2 and 60mL of tetrahydrofuran into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at the temperature of 0-5 ℃ for 5 minutes, adding 6.9g of Boc anhydride and 3.4g of triethylamine, stirring at the temperature of 0-5 ℃ for 3.5 hours, slowly dropwise adding the reaction solution into another single-neck flask filled with 80mL of methyl tert-butyl ether under stirring, stirring at the temperature of 0-5 ℃ for 30 minutes after the dropwise adding is finished, performing suction filtration, washing a filter cake for 2 times by using 10mL of methyl tert-butyl ether respectively, performing suction filtration, and performing vacuum drying on the filter cake at the temperature of 30 ℃ for 2 hours to obtain 10.6g of light yellow powder with the HPLC purity of 93.27.
d1, synthesis of intermediate 4:
the method comprises the following specific steps: adding 5.13g of the intermediate 3 and 30mL of tetrahydrofuran into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at the temperature of-5 ℃ for 5 minutes, adding 1.1g of triethylamine and 1.6g of methyl bromoacetate, stirring at the temperature of-5 ℃ for 5 hours, removing the solvent by rotary evaporation at the temperature of 20 ℃ to obtain a yellow foamy solid, recrystallizing with methyl tert-butyl ether, performing suction filtration, and drying a filter cake at the temperature of 30 ℃ for 2 hours in vacuum to obtain 4.14g of light yellow powder with the HPLC purity of 95.03%.
e1, synthesis of cefixime impurity:
the method comprises the following specific steps: adding 2.93g of intermediate 4 and 15mL of dichloromethane into a 50mL single-neck flask, stirring for 5 minutes in an ice bath, adding 8g of trifluoroacetic acid, stirring for 8 hours at a temperature of 20 ℃, stirring for 5 minutes at a temperature of-5 ℃, adding 20mL of water, slowly adjusting the pH to 7-8 by using a sodium hydroxide solution, standing for layering, collecting an aqueous phase, extracting an organic phase by using 10mL of water, combining the aqueous phases, loading the sample to a preparative HPLC (high performance liquid chromatography) for purification, and freeze-drying to obtain 675mg of white-like powder with the HPLC purity of 95.78%.
Example 2
The embodiment provides a method for synthesizing cefixime impurities, which comprises the following steps:
a2 Synthesis of intermediate 1
The method comprises the following specific steps: adding 20g of cefdinir, 80mL of purified water and 40mL of acetonitrile into a 250mL single-neck flask, stirring for 10 minutes at the temperature of-15 ℃, adding 4.2g of sodium hydroxide, stirring for 1 hour at the temperature of-10 ℃, adjusting the pH value to a turbid point by using 4M hydrochloric acid under stirring at the temperature of-10 ℃, stirring for 20 minutes, then continuously adjusting the pH value to 3 +/-0.5 by using 4M hydrochloric acid, slowly stirring for 30 minutes at the temperature of-15 ℃, performing suction filtration, respectively washing a filter cake for 2 times by using 10mL of 50% acetonitrile aqueous solution, and performing vacuum drying for 3 hours at 30 ℃ to obtain 17.9g of light yellow powder with the HPLC purity of 96.87%.
b2 Synthesis of intermediate 2
The method comprises the following specific steps: adding 16.6g of intermediate 1 and 100mL of acetonitrile into a 250mL single-neck flask, controlling the temperature to be 15 ℃, stirring for 5 minutes, adding 11.4g of trifluoroacetic acid, controlling the temperature to be 25 ℃, stirring for 2.5 hours, controlling the temperature to be 20 ℃, carrying out rotary evaporation on reaction liquid to remove solvent and trifluoroacetic acid, adding 40mL of tetrahydrofuran, stirring until the solution is clear, slowly dropwise adding 60mL of methyl tert-butyl ether under the stirring of an ice bath, stirring for 30 minutes of the ice bath, carrying out suction filtration, washing a filter cake for 2 times by using 10mL of methyl tert-butyl ether respectively, and carrying out vacuum drying for 2 hours at 30 ℃ to obtain 13.54g of light yellow powder with the HPLC purity of 97.12%.
c2, synthesis of intermediate 3:
the method comprises the following specific steps: adding 12.4g of the intermediate 2 and 60mL of acetonitrile into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at the temperature of 0-5 ℃ for 5 minutes, adding 7.2g of Boc anhydride and 3.6g of triethylamine, stirring at the temperature of 0-5 ℃ for 3 hours, slowly dropwise adding the reaction solution into another single-neck flask filled with 80mL of methyl tert-butyl ether under stirring, stirring at the temperature of 0-5 ℃ for 30 minutes after dropwise adding, performing suction filtration, washing a filter cake for 2 times by using 10mL of methyl tert-butyl ether respectively, performing suction filtration, and performing vacuum drying on the filter cake at the temperature of 30 ℃ for 2 hours to obtain 11.1g of light yellow powder with the HPLC purity of 93.49%.
d2, synthesis of intermediate 4:
the method comprises the following specific steps: adding 5.13g of the intermediate 3 and 30mL of acetonitrile into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at 0 ℃ for 5 minutes, adding 1.15g of triethylamine and 1.65g of methyl bromoacetate, stirring at 0 ℃ for 4 hours, removing the solvent by rotary evaporation at 20 ℃ to obtain a yellow foamy solid, recrystallizing with methyl tert-butyl ether, performing suction filtration, and performing vacuum drying on a filter cake at 30 ℃ for 2 hours to obtain 4.73g of light yellow powder with the HPLC purity of 95.42%.
e2, synthesis of cefixime impurity:
the method comprises the following specific steps: adding 2.93g of intermediate 4 and 15mL of dichloromethane into a 50mL single-neck flask, stirring for 5 minutes in an ice bath, adding 8.55g of trifluoroacetic acid, stirring for 7 hours at a temperature controlled by 25 ℃, stirring for 5 minutes at a temperature controlled by-5 ℃, adding 20mL of water, slowly adjusting the pH to 7-8 by using a sodium hydroxide solution, standing for layering, collecting an aqueous phase, extracting an organic phase by using 10mL of water, combining the aqueous phases, loading the sample to a preparative HPLC (high performance liquid chromatography) for purification, and freeze-drying to obtain 621mg of white-like powder with the HPLC purity of 95.94%.
Example 3
The embodiment provides a method for synthesizing cefixime impurities, which comprises the following steps:
a3 Synthesis of intermediate 1
The method comprises the following specific steps: adding 20g of cefdinir, 80mL of purified water and 30mL of methanol into a 250mL single-neck flask, stirring for 10 minutes at the temperature of-15 ℃, adding 7.25g of potassium carbonate, stirring for 1.5 hours at the temperature of-10 ℃, adjusting the pH value to a turbid point by using 4M hydrochloric acid under stirring at the temperature of-10 ℃, stirring for 20 minutes, then continuously adjusting the pH value to 3 +/-0.5 by using 4M hydrochloric acid, slowly stirring for 30 minutes at the temperature of-15 ℃, performing suction filtration, respectively washing a filter cake for 2 times by using 10mL of 50% acetonitrile aqueous solution, and performing vacuum drying for 3 hours at 30 ℃ to obtain 16.91g of light yellow powder with the HPLC purity of 97.84%.
b3 Synthesis of intermediate 2
The method comprises the following specific steps: adding 16.6g of intermediate 1 and 90mL of methanol into a 250mL single-neck flask, controlling the temperature to be 15 ℃, stirring for 5 minutes, adding 14mL of concentrated hydrochloric acid, controlling the temperature to be 10 ℃, stirring for 3.5 hours, controlling the temperature to be 15 ℃, carrying out rotary evaporation on reaction liquid to remove solvent and formic acid, adding 40mL of tetrahydrofuran, stirring until the solution is clear, slowly dropwise adding 60mL of methyl tert-butyl ether under the stirring of an ice bath, stirring for 30 minutes in the ice bath, carrying out suction filtration, respectively washing a filter cake for 2 times by 10mL of methyl tert-butyl ether, and carrying out vacuum drying for 2 hours at 30 ℃ to obtain 14.1g of light yellow powder with the HPLC purity of 97.43%.
c3, synthesis of intermediate 3:
the method comprises the following specific steps: adding 12.4g of the intermediate 2 and 50mL of acetonitrile into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at the temperature of 0-5 ℃ for 5 minutes, adding 7g of Boc anhydride and 3.4g of triethylamine, stirring at the temperature of 0-5 ℃ for 3 hours, slowly dropwise adding the reaction solution into another single-neck flask filled with 80mL of methyl tert-butyl ether under stirring, stirring at the temperature of 0-5 ℃ for 30 minutes after dropwise adding, performing suction filtration, washing a filter cake for 2 times by using 10mL of methyl tert-butyl ether respectively, performing suction filtration, and performing vacuum drying on the filter cake at the temperature of 30 ℃ for 2 hours to obtain 10.19g of light yellow powder with the HPLC purity of 94.39%.
d3, synthesis of intermediate 4:
the method comprises the following specific steps: adding 5.13g of the intermediate 3 and 30mL of acetonitrile into a 100mL single-neck flask, stirring at room temperature until the mixture is clear, stirring at the temperature of-5 ℃ for 5 minutes, adding 1.18g of triethylamine and 1.7g of methyl bromoacetate, stirring at the temperature of-2.5 ℃ for 4 hours, removing the solvent by rotary evaporation at the temperature of 20 ℃ to obtain a yellow foamy solid, recrystallizing with methyl tert-butyl ether, performing suction filtration, and drying a filter cake at the temperature of 30 ℃ for 2 hours in vacuum to obtain 4.67g of light yellow powder with the HPLC purity of 95.47%.
e3, synthesis of cefixime impurity:
the method comprises the following specific steps: adding 2.93g of intermediate 4 and 20mL of dichloromethane into a 50mL single-neck flask, stirring for 5 minutes in an ice bath, adding 6.3g of trifluoroacetic acid, stirring for 7 hours at the temperature of 25 ℃, stirring for 5 minutes at the temperature of-5 ℃, adding 20mL of water, slowly adjusting the pH to 7-8 by using a sodium hydroxide solution, standing for layering, collecting an aqueous phase, extracting an organic phase by using 10mL of water, combining the aqueous phases, loading the sample to a preparative HPLC (high performance liquid chromatography) for purification, and freeze-drying to obtain 617mg of white-like powder with the HPLC purity of 96.01%.
Referring to fig. 1, the cefixime impurity is analyzed by carbon spectrum analysis, and the structural formula of the cefixime impurity has the following carbon atom number:
and (3) carbon spectrum analysis result of cefixime impurity:
referring to fig. 2, the cefixime impurity is analyzed by hydrogen spectrum, and the structural formula of the cefixime impurity is numbered as hydrogen atom:
and (3) analyzing the hydrogen spectrum of the cefixime impurity:
| h number | H type | Number of H | Chemical shift |
| 1 | - |
3 | 1.34～1.36 |
| 2 | - |
1 | 4.79 |
| 3 | -CH2- | 2 | 3.49～3.58 |
| 4 | - |
1 | 4.43～4.47 |
| 5 | - |
1 | 5.02～5.10 |
| 6 | - |
1 | 5.88～6.14 |
| 7 | - |
1 | Active hydrogen is not knocked out |
| 8 | - |
1 | 8.38～8.60 |
| 9 | -CH2- | 2 | 4.66 |
| 10 | - |
3 | 3.62～3.67 |
| 11 | - |
1 | 7.02～7.11 |
| 12 | - |
2 | 7.24 |
The carbon nuclear magnetic spectrum of the cefixime impurity synthesized in example 1 is shown in fig. 1, and the hydrogen nuclear magnetic spectrum, the HPLC spectrum and the mass spectrum are respectively shown in fig. 2, fig. 3 (the cefixime impurity itself is racemic, so the chromatographic peak is bimodal) and fig. 4. The cefixime impurity synthesized in the example is confirmed to have the chemical formula C17H19N5O8S2The structure is as follows:
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of cefixime impurity is characterized by comprising the following steps:
a. hydrolysis of the beta-lactam of cefdinir with base gives intermediate 1: (2R) -2- ((((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) (carboxy) methyl) -5-vinyl-3, 6-dihydro-2H-1, 3-thiazine-4-carboxylic acid;
b. reacting intermediate 1 with an acid to give intermediate 2: 2- ((Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
c. protecting the amino group of intermediate 2 with Boc anhydride to give intermediate 3: 2- ((Z) -2- (2- ((tert-butoxycarbonyl) amino) thiazol-4-yl) -2- (hydroxyimino) acetamido) -2- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) acetic acid;
d. reacting the intermediate 3 with methyl bromoacetate to obtain an intermediate 4: (Z) -7- (2- ((tert-butoxycarbonyl) amino) thiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxa-6, 9-diazaden-6-en-11-acetic acid;
e. deprotection of intermediate 4 with trifluoroacetic acid gave the desired impurity: (Z) -7- (2-aminothiazol-4-yl) -10- ((2R) -5-methyl-7-oxo-2, 4,5, 7-tetrahydro-1H-furan [3,4-d ] [1,3] thiazin-2-yl) -3, 8-dioxo-2, 5-dioxo-6, 9-diazepan-6-en-11-acetic acid.
2. The method for synthesizing cefixime impurity according to claim 1, wherein the alkali used in step a is one or two of sodium hydroxide, lithium hydroxide and potassium carbonate.
3. The method for synthesizing cefixime impurity according to claim 1, wherein in the step a, the molar ratio of the alkali to cefdinir is (2-2.1): 1.
4. The method for synthesizing cefixime impurity according to claim 1, wherein the acid used in step b is one or two of formic acid, trifluoroacetic acid, hydrochloric acid and sulfuric acid.
5. The method for synthesizing cefixime impurity according to claim 1, wherein the molar ratio of acid to intermediate 1 in the reaction of step b is (2-3): 1.
6. The method for synthesizing cefixime impurity according to claim 1, wherein the mole ratio of Boc anhydride to intermediate 2 in step c is (1.05-1.1): 1.
7. The method for synthesizing cefixime impurity according to claim 1, wherein in the step d, the molar ratio of methyl bromoacetate to intermediate 3 is (1.05-1.1): 1.
8. The method for synthesizing cefixime impurity according to claim 1, wherein in the step e, the molar ratio of trifluoroacetic acid to intermediate 4 is (10-15): 1.
9. The method for synthesizing cefixime impurity according to claim 1, wherein the step a is carried out at-20 ℃ to 10 ℃ for 1-1.5 hours; the step b is to carry out reaction for 2 to 3 hours at the temperature of 10 to 20 ℃; the step c is to carry out reaction for 3 to 4 hours at the temperature of 0 to 5 ℃; the step d is to carry out reaction for 4 to 5 hours at the temperature of minus 5 to 5 ℃; the step e is to carry out the reaction for 7 to 10 hours at a temperature of between 15 and 25 ℃.
10. A cefixime impurity synthesised by a synthesis process according to any one of claims 1 to 9.
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| CN103467495A (en) * | 2013-09-29 | 2013-12-25 | 天津理工大学 | Method for preparing cefixime compound |
| CN104193765A (en) * | 2014-08-12 | 2014-12-10 | 浙江普洛得邦制药有限公司 | Method for synthesizing cefixime |
| CN104447799A (en) * | 2014-12-25 | 2015-03-25 | 广州白云山天心制药股份有限公司 | Method of preparing cefmenoxime E isomers |
| CN110759933A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefdinir impurity G |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103467495A (en) * | 2013-09-29 | 2013-12-25 | 天津理工大学 | Method for preparing cefixime compound |
| CN104193765A (en) * | 2014-08-12 | 2014-12-10 | 浙江普洛得邦制药有限公司 | Method for synthesizing cefixime |
| CN104447799A (en) * | 2014-12-25 | 2015-03-25 | 广州白云山天心制药股份有限公司 | Method of preparing cefmenoxime E isomers |
| CN110759933A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefdinir impurity G |
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| CN113135939A (en) * | 2021-04-22 | 2021-07-20 | 梯尔希（南京）药物研发有限公司 | Cefixime impurity and preparation method thereof |
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