CN110041346B - Low-cost preparation method of cefixime - Google Patents
Low-cost preparation method of cefixime Download PDFInfo
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- 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 45
- 229960002129 cefixime Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 39
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 39
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000002253 acid Substances 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 9
- 239000000543 intermediate Substances 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 46
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 37
- 238000001816 cooling Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- 239000012295 chemical reaction liquid Substances 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 2
- KFCMZNUGNLCSJQ-NFBKMPQASA-N (4-methoxyphenyl)methyl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1=C(CCl)CS[C@H]2N1C(=O)[C@H]2NC(=O)CC1=CC=CC=C1 KFCMZNUGNLCSJQ-NFBKMPQASA-N 0.000 abstract description 14
- 239000007858 starting material Substances 0.000 abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 238000010606 normalization Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 3
- BQIMPGFMMOZASS-CLZZGJSISA-N (6r,7r)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CO)=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 BQIMPGFMMOZASS-CLZZGJSISA-N 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 229940041006 first-generation cephalosporins Drugs 0.000 description 2
- 230000002140 halogenating effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- -1 phenylacetyl Chemical group 0.000 description 2
- 229940041008 second-generation cephalosporins Drugs 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a low-cost preparation method of cefixime, which comprises the following steps: reacting D-7-ACA and cefixime active ester to obtain a first intermediate; reacting the first intermediate with phosphorus pentachloride to obtain a reaction solution of a second intermediate; reacting the reaction solution of the second intermediate, sodium iodide, triphenylphosphine and formaldehyde to obtain a third intermediate; and hydrolyzing the third intermediate by using alkali liquor, adding acid to adjust the pH value after hydrolysis, and crystallizing to obtain cefixime. The preparation method of the cefixime with low cost adopts D-7-ACA as the starting material, the molecular weight of the D-7-ACA is about half of that of GCLE, so that the effective mole ratio of the D-7-ACA as the starting material is more than 2 times higher than that of GCLE, obviously, the cost is low, the quality is stable, and the process route is short.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a preparation method of cefixime with low cost.
Background
Cefixime (Cefixime) is a third-generation cephalosporin antibiotic developed by fuzier corporation for oral administration, and is suitable for treating respiratory, urinary and biliary tract infections caused by sensitive bacteria. Cefixime is highly stable against beta-lactamases produced by gram-negative bacilli, has a stronger antibacterial effect against gram-negative bacilli than first and second generation cephalosporins, and has a weaker antibacterial effect against gram-positive cocci than first and second generation cephalosporins.
China has already provided domestic cefixime bulk drugs in about 2000 years, and GCLE (7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester, molecular formula C is used as a common technology at that time24H23O5N2SCl) as raw material, through iodine substitution, wittig reaction to form carbon double bond, enzyme hydrolysis, 7-position side chain on active ester, then alkali hydrolysis to obtain the finished product cefixime. The process has the characteristics of large usage amount of GCLE raw material, low effective mole number, high cost, long line, and high cost although classical. There is also a second road reported by TenzeThe method comprises the steps of taking 7-ACA as a raw material, firstly grafting phenylacetyl at the 7-position, then grafting a benzhydryl protecting group of carboxyl at the 4-position, hydrolyzing an ester bond at the 3-position to obtain hydroxymethyl at the 3-position, then halogenating to obtain GCLE, namely preparing the GCLE by using the 7-ACA, and then preparing cefixime by the same route as preparing cefixime by the GCLE, wherein the route is long, the price of the 7-ACA is basically equivalent to that of the GCLE, so that the cost of the route is higher than that of the GCLE route, and the practical utilization value is not high.
Disclosure of Invention
The invention aims to provide a low-cost preparation method of cefixime, and solves the problem of high environmental protection pressure of the existing process.
The technical scheme adopted by the invention for solving the technical problem is as follows: a low-cost preparation method of cefixime comprises the following steps:
A. reacting D-7-ACA and cefixime active ester to obtain a first intermediate; wherein the structural formula of the first intermediate is as follows:
B. reacting the first intermediate with phosphorus pentachloride to obtain a reaction solution of a second intermediate; wherein the structural formula of the second intermediate is as follows:
C. reacting the reaction liquid of the second intermediate, sodium iodide, triphenylphosphine and formaldehyde to obtain a third intermediate; wherein the structural formula of the third intermediate is as follows:
D. hydrolyzing the third intermediate by using alkali liquor, adding acid to adjust the pH value after hydrolysis, and crystallizing to obtain cefixime
In the preparation method, in the step A, the mass ratio of the D-7-ACA to the cefixime active ester is 1: 1.7-3.5, preferably the mass ratio is 1: 1.8-2.5.
In the preparation method, in the reaction process of the step A, tetrahydrofuran and water are added into D-7-ACA and cefixime active ester, the temperature is controlled to be minus 10-30 ℃ under the stirring condition, tetrahydrofuran and triethylamine are slowly dropped, the reaction is maintained at minus 10-30 ℃, HPLC detection is carried out until the residue of the D-7-ACA on an HPLC map is lower than 0.5 percent (area normalization method), and the reaction liquid of a first intermediate is obtained.
In the preparation method, reaction liquid of a first intermediate obtained after reaction is extracted by an organic solvent, an extracted organic solvent phase is recovered, a water phase is adjusted to pH 2.5-4.5 by an acid solution, and the first intermediate is obtained by filtering and drying.
In the preparation method, in the step B, the mass ratio of the phosphorus pentachloride to the first intermediate is 0.42-0.85: 1, preferably in the range of 0.50-0.75: 1.
In the preparation method, in the reaction process of the step B, dichloromethane and dimethylacetamide are added into the first intermediate, the temperature is adjusted to-20 ℃ under stirring, phosphorus pentachloride is added in batches, the temperature is maintained at 0 ℃, the mixture is stirred for reaction, and HPLC detection is carried out until the residue of the first intermediate on HPLC is lower than 1.0% (area normalization method), so as to obtain the reaction liquid of the second intermediate.
In the preparation method, in the step C, the mass ratio of the sodium iodide to the first intermediate is 0.31-0.67: 1, preferably in the range of 0.33-0.48: 1; the mass ratio of triphenylphosphine to the first intermediate is 0.5-1.8: 1, preferably in the range of 0.6-1.2: 1; the mass ratio of the formaldehyde to the first intermediate is 0.05-3: 1, preferably in the range of 0.8-1.8: 1.
In the preparation method, in the reaction process of the step C, stirring the reaction liquid of the second intermediate obtained by the reaction in the step B at the temperature of 0-20 ℃, adding sodium iodide and water, heating to 25-65 ℃, adding triphenylphosphine, maintaining the temperature of 25-65 ℃, stirring for 1-6 hours, adding formaldehyde and acetone, cooling to-10-20 ℃, adding an alkali solution, maintaining the reaction temperature of-10-20 ℃, and reacting for 1-6 hours to obtain a suspension of a reacted third intermediate.
In the preparation method, acetone is added into suspension of a third intermediate obtained by reaction and dissolved, an acid solution is added for extraction, an organic phase is subjected to vacuum concentration until becoming turbid after layering, then methanol is added, the temperature is raised to 25-60 ℃, the mixture is slowly stirred for crystallization, then reduced pressure distillation is carried out until a large number of crystals are separated out, then water is added, the temperature is lowered to-10-20 ℃ after the addition, stirring and filtering are carried out, and the third intermediate is obtained after washing and drying.
In the preparation method of the present invention, step D specifically includes: adding water into the third intermediate, cooling to 0-20 ℃, dropwise adding an alkali solution for dissolving, cooling to 0-20 ℃ after complete dissolution, adding the alkali solution for hydrolysis, detecting by using HPLC until the residue of the third intermediate on HPLC is lower than 1.0% (area normalization method), adding an acid solution for neutralization until the pH is 5.0-8.0, then adding activated carbon, stirring for dehydration, filtering, adjusting the pH of the filtrate to 1.0-3.0 by using the acid solution, cooling after crystallization, filtering, and drying to obtain cefixime.
The low-cost preparation method of cefixime has the following beneficial effects: the preparation method of the cefixime with low cost adopts D-7-ACA as the starting material, the molecular weight of the D-7-ACA is about half of that of GCLE, so that the effective mole ratio of the D-7-ACA as the starting material is more than 2 times higher than that of GCLE, obviously, the cost is low, the quality is stable, and the process route is short.
Detailed Description
The preparation of low cost cefixime according to the invention is further illustrated by the following examples:
at present, with the gradual maturity of the D-7-ACA preparation process, the cost is continuously reduced, the quality is very stable, the effective mole number of the process is more than 2 times higher than that of GCLE, the GCLE molecular weight is 489.96, and the D-7-ACA molecular weight is 230.24, and the price difference between GCLE and D-7-ACA is not very large, so the advantage of preparing cefixime by using D-7-ACA as the starting material is more obvious. The process comprises the steps of taking D-7-ACA as an initial raw material, firstly reacting with cefixime side chain active methyl ester to obtain a first intermediate protected by 7-amino, then halogenating 3-hydroxy to obtain a second intermediate, iodinating, carrying out wittig reaction to obtain a third intermediate of a carbon double bond, and hydrolyzing a side chain protecting group to obtain the finished product of cefixime. The process route is short, the cost of raw materials is low, and the subsequent cost such as environmental protection is lower, so that the process route is a green process route with economic value.
The invention provides a low-cost preparation method of cefixime, which comprises the following steps:
s1, reacting D-7-ACA (hydroxymethyl-7-aminocephalosporanic acid, CAS number: 15690-38-7) and cefixime active ester (MICA active ester, CAS number: 246035-38-1) to obtain a first intermediate; specifically, the mass ratio of the D-7-ACA to the cefixime active ester is 1: 1.7-3.5, namely 1: 1.7 to 1: 3.5, adding tetrahydrofuran and water into the D-7-ACA and cefixime active ester in the mass ratio, slowly dropwise adding tetrahydrofuran and triethylamine under stirring at the temperature of-10-30 ℃, maintaining the temperature of-10-30 ℃ for reaction, detecting by using HPLC (high performance liquid chromatography) until the residue of the D-7-ACA on an HPLC (high performance liquid chromatography) spectrum is lower than 0.5% (area normalization method), obtaining a reaction liquid of a first intermediate, extracting the reaction liquid of the first intermediate by using an organic solvent, recovering an extracted organic solvent phase, adjusting the pH of an aqueous phase to 2.5-4.5 by using an acid solution, filtering and drying to obtain the first intermediate; wherein, the organic solvent for extraction includes but is not limited to esters, alcohols, and the like, such as ethyl acetate and the like; acid solutions include, but are not limited to, dilute hydrochloric acid, dilute sulfuric acid, and the like; see the first equation below:
s2, reacting the first intermediate with phosphorus pentachloride to obtain a reaction solution of a second intermediate; specifically, the mass ratio of the phosphorus pentachloride to the first intermediate is 0.42-0.85: 1, i.e., 0.42: 1 to 0.85: 1; adding dichloromethane and dimethylacetamide into the first intermediate, adjusting the temperature to-20 ℃ under stirring, adding phosphorus pentachloride in batches, maintaining the temperature at 0 ℃, stirring for reaction, and detecting by using HPLC (high performance liquid chromatography) until the residual quantity of the first intermediate is lower than 1.0% on HPLC (area normalization method), so as to obtain a reaction solution of a second intermediate; see the second equation below:
s3, reacting the reaction liquid of the second intermediate, sodium iodide, triphenylphosphine and formaldehyde to obtain a third intermediate; specifically, the mass ratio of the sodium iodide to the first intermediate is 0.31-0.67: 1; the mass ratio of triphenylphosphine to the first intermediate is 0.5-1.8: 1; the mass ratio of the formaldehyde to the first intermediate is 0.05-3: 1; stirring the reaction liquid of the second intermediate obtained by the reaction in the step B at 0-20 ℃, adding sodium iodide and water, heating to 25-65 ℃, adding triphenylphosphine, maintaining the temperature at 25-65 ℃ for stirring for 1-6 hours, adding formaldehyde and acetone, cooling to-10-20 ℃, adding an alkali solution such as a sodium hydroxide solution and the like, maintaining the reaction temperature at-10-20 ℃ for reaction for 1-6 hours to obtain a suspension of a reacted third intermediate, adding acetone for dissolution, adding an acid solution (such as dilute hydrochloric acid, dilute sulfuric acid and the like) for extraction, performing vacuum concentration on an extracted organic phase until the organic phase becomes turbid, adding methanol, heating to 20-60 ℃ for crystallization, slowly stirring for crystallization for 1-3 hours, starting reduced pressure distillation to precipitate a large amount of crystals, adding water, cooling to-10-20 ℃, preferably, the temperature is 0 ℃, and the third intermediate is obtained by stirring, filtering, washing and drying; see the third equation below:
s4, hydrolyzing the third intermediate by using alkali liquor, such as sodium hydroxide solution, and the like, adding acid (such as hydrochloric acid, sulfuric acid, and the like) to adjust the pH value after hydrolysis, and crystallizing to obtain cefixime; specifically, adding water into a third intermediate, cooling to 0-20 ℃, dropwise adding an alkali solution (such as a sodium hydroxide solution) for dissolving, cooling to 0-20 ℃ after complete dissolution, adding an alkali solution (such as a sodium hydroxide solution) for hydrolysis, detecting by using HPLC (high performance liquid chromatography) until the peak area residue of the third intermediate is lower than 1.0% (area normalization), adding an acid solution (such as a dilute hydrochloric acid solution, a dilute sulfuric acid solution and the like) for neutralization until the pH is 5.0-8.0, then adding activated carbon, stirring for dehydration, filtering, adjusting the pH of a filtrate to 1.0-3.0 by using an acid solution (such as a dilute hydrochloric acid solution, a dilute sulfuric acid solution and the like), cooling after crystallization, filtering, and drying to obtain cefixime, wherein the fourth reaction formula is as follows:
it should be noted that the concentration of the sodium hydroxide solution mentioned herein is usually 3% to 20%; the concentration of the dilute hydrochloric acid solution mentioned herein is generally 3% to 10%; the concentration of the dilute sulfuric acid solution mentioned herein is usually 3% to 10%.
The following is a detailed description of specific examples.
Example 1
Into a 1000ml reaction vessel, D-7-ACA40.0g, cefixime active ester 80g, THF (tetrahydrofuran) 280ml, and pure water 268ml were charged. Controlling the temperature to be 0-5 ℃ under stirring, slowly dropwise adding 40ml of THF (tetrahydrofuran) and 28ml of TEA (triethylamine), maintaining the temperature for about 1 hour, maintaining the temperature after the addition, reacting for 10 hours, and detecting that the D-7-ACA residue is less than 0.5% by HPLC to complete the reaction. The extraction was carried out twice with 400ml of ethyl acetate, the ethyl acetate phase was recovered after the extraction, and the aqueous phase was crystallized by adjusting the pH to 3.9-4.0 with 9% dilute hydrochloric acid, filtered and dried to obtain about 80.2g of the first intermediate.
Adding 60.0g of first intermediate into a dry and anhydrous reaction bottle, adding 250ml of dichloromethane, adding DMA20ml, cooling to 0-10 ℃ under stirring, adding 32g of phosphorus pentachloride in batches, stirring for 2 hours under the condition of maintaining the temperature, and detecting that the reaction of the first intermediate is less than 1% by HPLC (high performance liquid chromatography). After the reaction is finished, heating to 10-20 ℃, adding 19.5g of sodium iodide and 90ml of pure water under stirring, heating to 25-30 ℃, adding 35g of triphenylphosphine, and stirring for 2-3 hours under the condition of maintaining the temperature. Adding 74g of formaldehyde and 200ml of acetone, cooling to 20 ℃, dropwise adding 100ml of 5% sodium hydroxide, maintaining the reaction temperature at 15-20 ℃ for reacting for 2-3 hours, then adding 280ml of acetone for dissolving, and then adding 300ml of 0.1N hydrochloric acid for extracting. The organic phase was transferred to another reaction flask and distilled under vacuum to a volume of about 450 ml. And then adding 700ml of methanol, heating to 30-35 ℃ for crystallization, slowly stirring for crystallization for 1 hour, starting reduced pressure distillation, adding 180ml of water when the volume is about 600ml, completely adding, cooling to 0 ℃, stirring for 1 hour, filtering, washing and drying to obtain about 48.1g of a third intermediate.
40.0g of the third intermediate and 300ml of pure water are added into a 1000ml reaction bottle, and the temperature is reduced to below 5 ℃. Dropwise adding 6% sodium hydroxide for dissolving, cooling to nearly 0 ℃ after complete dissolution, hydrolyzing with 20% sodium hydroxide solution, monitoring by using HPLC, adding dilute hydrochloric acid solution for neutralizing to about pH7 when the residue of the third intermediate is less than 0.3%, then adding EDTA, sodium hydrosulfite and 5g of active carbon, stirring for dehydration for 20 minutes, filtering, and adjusting the pH of the filtrate to about 2.0-2.2 by using dilute hydrochloric acid solution for crystallization. And (3) cooling, filtering and drying to obtain about 38.6g of finished cefixime product.
Example 2
A1000 ml reaction vessel was charged with D-7-ACA40.0g, cefixime active substance 72g, THF (tetrahydrofuran) 280ml, and pure water 268 ml. And (3) controlling the temperature to be-10-5 ℃ under stirring, slowly dropwise adding 40ml of THF (tetrahydrofuran) and 28ml of TEA (triethylamine), maintaining the temperature for about 1 hour, maintaining the temperature after the addition, reacting for 12 hours, and detecting that the D-7-ACA residue is less than 0.5% by HPLC (high performance liquid chromatography), thus completing the reaction. Extracting with 400ml of ethyl acetate twice, recovering an ethyl acetate phase after extraction, adjusting the pH of a water phase to 3.3-3.5 by using 9% diluted hydrochloric acid, crystallizing, filtering, and drying to obtain about 79.3g of a first intermediate.
Adding 60.0g of first intermediate into a dry and anhydrous reaction bottle, adding 250ml of dichloromethane, adding DMA20ml, cooling to-10-0 ℃ under stirring, adding 30g of phosphorus pentachloride in batches, keeping the temperature and stirring for 2 hours, and detecting that the reaction of the first intermediate is less than 1% by HPLC (high performance liquid chromatography). After the reaction is finished, heating to 0-10 ℃, adding 28.8g of sodium iodide and 130ml of pure water under stirring, heating to 35-40 ℃, adding 36g of triphenylphosphine, and stirring for 1 hour under the condition of maintaining the temperature. Adding 108g of formaldehyde and 210ml of acetone, cooling to-10 ℃, dropwise adding 100ml of 5% sodium hydroxide, maintaining the reaction temperature at-10-5 ℃ for reacting for 1 hour, then adding 280ml of acetone for dissolving, and then adding 300ml of 0.1N hydrochloric acid for extracting. The organic phase was transferred to another reaction flask and distilled under vacuum to a volume of about 450 ml. And then adding 800ml of methanol, heating to 40-45 ℃ for crystallization, slowly stirring for crystallization for 1 hour, starting reduced pressure distillation, adding 200ml of water when the volume is about 600ml, cooling to 5 ℃, stirring for 2 hours, filtering, washing and drying to obtain about 46.9g of a third intermediate.
40g of the third intermediate is added into a 1000ml reaction bottle, 300ml of pure water is added, and the temperature is reduced to below 0-5 ℃. Dropwise adding 6% sodium hydroxide for dissolving, cooling to be close to 10 ℃ after complete dissolution, hydrolyzing with 20% sodium hydroxide solution, monitoring by using HPLC, adding dilute hydrochloric acid solution for neutralizing to about pH7 when the residue of the third intermediate is lower than 1.0%, then adding EDTA, sodium hydrosulfite and 5g of active carbon, stirring for dehydration for 20 minutes, filtering, and adjusting the pH of the filtrate to about 1.5-1.6 by using dilute hydrochloric acid solution for crystallization. And (3) cooling, filtering and drying to obtain about 38.1g of finished cefixime.
Example 3
A1000 ml reaction vessel was charged with D-7-ACA40.0g, cefixime active substance 100g, THF (tetrahydrofuran) 380ml, and pure water 355 ml. And (3) controlling the temperature to be 0-30 ℃ under stirring, slowly dropwise adding 60ml of THF (tetrahydrofuran) and 40ml of TEA (triethylamine), maintaining the temperature for about 2 hours, maintaining the temperature after the addition, reacting for 10 hours, and detecting that the D-7-ACA residue is less than 0.5% by HPLC (high performance liquid chromatography), thus completing the reaction. Extracting twice with 550ml ethyl acetate, recovering an ethyl acetate phase after extraction, adjusting the pH of a water phase to 3.6-3.7 by using 9% diluted hydrochloric acid for crystallization, filtering, and drying to obtain about 80.9g of a first intermediate.
Adding 60.0g of first intermediate into a dry and anhydrous reaction bottle, adding 250ml of dichloromethane, adding DMA20ml, cooling to 0 ℃ under stirring, adding 45g of phosphorus pentachloride in batches, keeping the temperature and stirring for 3 hours, and detecting that the reaction of the first intermediate is lower than 1% by HPLC to complete the reaction. After the reaction, the temperature is raised to 10-20 ℃, 19.8g of sodium iodide and 170ml of pure water are added under stirring, the temperature is raised to 45-50 ℃, 72g of triphenylphosphine is added, and the temperature is maintained and the stirring is carried out for 6 hours. Adding 48g of formaldehyde and 300ml of acetone, cooling to 20 ℃, dropwise adding 100ml of 5% sodium hydroxide, maintaining the reaction temperature at 5-20 ℃ for reacting for 6 hours, then adding 280ml of acetone for dissolving, and then adding 300ml of 0.1N hydrochloric acid for extracting. The organic phase was transferred to another reaction flask and distilled under vacuum to a volume of about 480 ml. And then adding 750ml of methanol, heating to 25-35 ℃ for crystallization, slowly stirring for crystallization for 1 hour, starting reduced pressure distillation, adding 210ml of water when the volume is about 600ml, completely adding, cooling to-10-0 ℃, stirring for 1 hour, filtering, washing and drying to obtain about 47.5g of a third intermediate.
And (3) adding 40g of the third intermediate into a 1000ml reaction bottle, adding 300ml of pure water, and cooling to below 10-20 ℃. And (3) dropwise adding 6% sodium hydroxide for dissolving, cooling to a temperature close to 10-20 ℃ after complete dissolution, hydrolyzing with 20% sodium hydroxide solution, monitoring by using HPLC (high performance liquid chromatography), adding a dilute hydrochloric acid solution for neutralizing to about pH7 when the residue of the third intermediate is less than 1.0%, then adding EDTA (ethylene diamine tetraacetic acid), sodium hydrosulfite and 5g of activated carbon, stirring for dehydrating for 20 minutes, filtering, and adjusting the pH of the filtrate to about 2.0 by using the dilute hydrochloric acid solution for crystallization. And (3) cooling, filtering and drying to obtain about 37.9g of finished cefixime product.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings, and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (5)
1. A low-cost preparation method of cefixime is characterized by comprising the following steps:
A. reacting D-7-ACA and cefixime active ester to obtain a first intermediate; wherein the structural formula of the first intermediate is as follows:
in the reaction process of the step A, adding tetrahydrofuran and water into D-7-ACA and cefixime active ester, slowly dropwise adding tetrahydrofuran and triethylamine at the temperature of-10-30 ℃ under the stirring condition, maintaining the temperature of-10-30 ℃ for reaction, and detecting by using HPLC until the residue of the D-7-ACA on an HPLC (high performance liquid chromatography) spectrum is lower than 0.5% to obtain a reaction liquid of a first intermediate;
extracting a reaction liquid of a first intermediate obtained after the reaction with an organic solvent, recovering an extracted organic solvent phase, adjusting the pH of a water phase to 2.5-4.5 with an acid solution, filtering and drying to obtain a first intermediate;
B. reacting the first intermediate with phosphorus pentachloride to obtain a reaction solution of a second intermediate; wherein the structural formula of the second intermediate is as follows:
in the reaction process of the step B, adding dichloromethane and dimethylacetamide into the first intermediate, adjusting the temperature to-20 ℃ under stirring, adding phosphorus pentachloride in batches, maintaining the temperature at 0 ℃, stirring for reaction, and detecting by using HPLC (high performance liquid chromatography) until the residual quantity of the first intermediate is lower than 1.0% on HPLC to obtain a reaction liquid of a second intermediate;
C. reacting the reaction liquid of the second intermediate, sodium iodide, triphenylphosphine and formaldehyde to obtain a third intermediate; wherein the structural formula of the third intermediate is as follows:
in the reaction process of the step C, stirring the reaction liquid of the second intermediate obtained by the reaction in the step B at the temperature of 0-20 ℃, adding sodium iodide and water, heating to 25-65 ℃, adding triphenylphosphine, maintaining the temperature of 25-65 ℃, stirring for 1-6 hours, adding formaldehyde and acetone, cooling to-10-20 ℃, adding an alkali solution, maintaining the reaction temperature of-10-20 ℃, and reacting for 1-6 hours to obtain a suspension of a reacted third intermediate;
adding acetone into a suspension of a third intermediate obtained by reaction, dissolving, adding an acid solution for extraction, carrying out vacuum concentration on an organic phase after layering until the organic phase becomes turbid, then adding methanol, heating to 25-60 ℃, slowly stirring for crystallization, then carrying out reduced pressure distillation until a large number of crystals are separated out, then adding water, cooling to-10-20 ℃ after adding, stirring for filtration, washing and drying to obtain a third intermediate;
D. hydrolyzing the third intermediate by using alkali liquor, adding acid to adjust the pH value after hydrolysis, and crystallizing to obtain cefixime
2. The process according to claim 1, wherein in step a, the mass ratio of D-7-ACA to cefixime active ester is 1: 1.7 to 3.5.
3. The preparation method of claim 1, wherein in the step B, the mass ratio of phosphorus pentachloride to the first intermediate is 0.42-0.85: 1.
4. the method according to claim 1, wherein in the step C, the mass ratio of the sodium iodide to the first intermediate is 0.31 to 0.67: 1; the mass ratio of triphenylphosphine to the first intermediate is 0.5-1.8: 1; the mass ratio of the formaldehyde to the first intermediate is 0.05-3: 1.
5. the method according to claim 1, wherein step D specifically comprises: adding water into the third intermediate, cooling to 0-20 ℃, dropwise adding an alkali solution for dissolving, cooling to 0-20 ℃ after complete dissolution, adding the alkali solution for hydrolysis, detecting by using HPLC (high performance liquid chromatography) until the peak area residue of the third intermediate is lower than 1.0%, adding an acid solution for neutralization until the pH value is 5.0-8.0, adding activated carbon, stirring for dehydration, filtering, adjusting the pH value of the filtrate to 1.0-3.0 by using the acid solution, cooling after crystallization, filtering, and drying to obtain cefixime.
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