CN115232151A - New synthesis method of ceftriaxone sodium - Google Patents
New synthesis method of ceftriaxone sodium Download PDFInfo
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- CN115232151A CN115232151A CN202210932611.4A CN202210932611A CN115232151A CN 115232151 A CN115232151 A CN 115232151A CN 202210932611 A CN202210932611 A CN 202210932611A CN 115232151 A CN115232151 A CN 115232151A
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- 229960000479 ceftriaxone sodium Drugs 0.000 title claims abstract description 39
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 title claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000002148 esters Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 12
- 229960004755 ceftriaxone Drugs 0.000 claims abstract description 11
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims abstract description 11
- 239000003223 protective agent Substances 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- 238000002444 silanisation Methods 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000005265 energy consumption Methods 0.000 abstract description 4
- 239000000047 product Substances 0.000 description 17
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- 239000012535 impurity Substances 0.000 description 12
- 229940124350 antibacterial drug Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
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- 235000017281 sodium acetate Nutrition 0.000 description 7
- -1 1, 2,5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl Chemical group 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
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- 239000013078 crystal Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010018612 Gonorrhoea Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 208000012839 conversion disease Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000001786 gonorrhea Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010056519 Abdominal infection Diseases 0.000 description 1
- 206010060968 Arthritis infective Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 206010051548 Burn infection Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- BYHXLDZDSZVDJH-UHFFFAOYSA-N acetic acid;1,3-thiazole Chemical compound CC(O)=O.C1=CSC=N1 BYHXLDZDSZVDJH-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 238000009835 boiling Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
-
- 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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a preparation method of ceftriaxone sodium, which is characterized by comprising the following steps: protecting amino and carboxyl of 7-ACT with a protective agent, directly condensing with AE-active ester to obtain ceftriaxone acid, and directly salinizing to obtain a target product. The method simplifies process, reduces process energy consumption, and improves product conversion rate.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a novel synthesis method of an antibacterial drug ceftriaxone sodium.
Background
Ceftriaxone sodium is chemically known as sodium (6R, 7R) -3- [ [ (1, 2,5, 6-tetrahydro-2-methyl-5, 6-dioxo-1, 2, 4-triazin-3-yl) thio ] methyl ] -7- [ [ (2-amino-4-thiazolyl) methoxyiminoacetyl ] amino ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate and has the following structural formula:
ceftriaxone sodium is a long-acting antibiotic drug in the third-generation cephalosporins, has bactericidal effects on a plurality of gram-positive bacteria, gram-negative bacteria and anaerobic bacteria, and is highly stable to most of beta-lactamase produced by the bacteria, so that the antibacterial effect is enhanced. The cephalosporin antibiotics are widely applied to respiratory tract infection and urinary system infection which are sensitive to the cephalosporin antibiotics clinically, including pyelonephritis and gonorrhea, meningitis, burn infection, postoperative infection, bone joint, soft tissue, skin and wound infection, abdominal infection and the like, and the prophylaxis of infection in an operative period, are used as first-line medicaments for treating gonorrhea at present, and are also one of 22 clinically-applied cephalosporin antibiotics preparation varieties approved by the state at present.
At present, the technology of the variety is mainly that 7-aminocephalosporanic acid (7-ACA) and triazine acid (TTZ) are subjected to three-position condensation under the action of acetonitrile and boron trifluoride complex thereof to generate (6R, 7R) -7-amino-3- [ [ 6-carboxyl-2-methyl-5-oxo-2, 5-dihydro-1, 2, 4-triazine-3-yl sulfur ] methyl ] -3-cephem-4-carboxylic acid (7-ACT), then the product is subjected to catalytic condensation with 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid benzothiazole ester in solvents such as dichloromethane or tetrahydrofuran/water and the like to synthesize the ceftriaxone acid by organic base, then sodium acetate solution is added to form salt, solvent crystals such as acetone and the like are added dropwise to crystallize, and the ceftriaxone sodium solid after complete drying is obtained by centrifugal separation.
In the above process, since the 7-ACT parent nucleus has amino and carboxyl groups with relatively strong activity, if the parent nucleus is not protected, the reaction selectivity of the condensation reaction with 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid phenylthiazole ester (AE-active ester) is poor, and the reaction conversion rate is not high. The method is easy to generate new unknown impurities or polymers, not only brings certain hidden danger to the quality safety of the medicine, but also is not beneficial to the control of the medicine cost, so that a new synthesis technology is needed to improve the medicine quality, reduce the cost and lighten the medication burden of common people.
Disclosure of Invention
The invention aims to overcome the defects in the technology, the 7-ACT and the silanization reagent are adopted to simultaneously protect the amino and the carboxyl of the 7-ACT in an anhydrous environment, then the 7-ACT and the 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thioacetic acid phenylthiazole ester are directly condensed into the ceftriaxone acid, finally, the sodium acetate aqueous solution is directly used for extraction and salt formation, and the solvent is used for crystallization to obtain the ceftriaxone sodium.
Thus, the problems that amino and carboxyl with stronger activity on the 7-ACT parent nucleus have poor reaction selectivity and low reaction conversion rate with 2-methoxyimino-2- (2-amino-4-thiazolyl) - (z) -thiacetophenone thiazole acetate condensation (AE-active ester) and are easy to generate new unknown impurities or polymers are solved. Meanwhile, the process of acidification and crystallization of ceftriaxone acid is omitted, and a high-quality ceftriaxone sodium product is obtained by directly carrying out deprotection and salt formation solvent crystallization by using a sodium acetate aqueous solution, so that the process is simplified, the process energy consumption is reduced, and the product conversion rate is improved.
In order to achieve the purpose, the invention provides a preparation method of ceftriaxone sodium, which is characterized by comprising the following steps: protecting amino and carboxyl of 7-ACT with a protective agent, directly condensing with AE-active ester to obtain ceftriaxone acid, and directly salinizing to obtain a target product.
Further, the invention provides a method for synthesizing the antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the protective agent is a reagent capable of simultaneously protecting an amino group and a carboxyl group.
Further, the invention provides a method for synthesizing an antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the protective agent is a silanization reagent.
Preferably: silylation agents such as hexamethyldisilazane, hexamethyldisilazane and BSA.
Further, the synthesis method of the antibacterial drug ceftriaxone sodium provided by the invention is also characterized in that the specific preparation process is as follows:
s1, adding 7-ACT and a protective agent into a reaction solvent under an anhydrous condition, and performing reflux reaction for 4-12 hours to obtain a 7-ACT protective group solution;
the reaction solvent herein is preferably a low-boiling solvent such as: alkyl halides, esters, ethers, ketones, preferably such as: one or more of dichloromethane, trichloromethane, dimethyl carbonate, carbon tetrachloride, tetrahydrofuran, acetone, trichloromethane, dimethyl carbonate, etc. are mixed as the reaction solvent, and the reaction temperature is preferably controlled in 30-50 deg.c, most preferably 38-42 deg.c.
S2, cooling the 7-ACT protecting group solution prepared in the S1 to below 10 ℃, adding AE-active ester, reacting for 2-20 hours, and sequentially performing extraction, elution, protection, salt formation and solvent crystallization by using a pH adjusting reagent to obtain a target product.
The 7-ACT and AE-active ester are condensed without additional catalytic reaction of organic base and the like, the reaction condition is milder and more controllable, the generation of other impurities is not facilitated, and the product conversion rate is improved. The byproducts such as urea or M generated by the reaction can be recovered by plate-and-frame filtration, so that the process recovery cost is reduced.
After the 7-ACT and the AE-active ester react, ethanol/water or other solvents are not needed to be added for acidification and crystallization, and after the ceftriaxone acid is obtained by separation, the ceftriaxone acid is synthesized with sodium salt reagents such as sodium acetate and the like to obtain the ceftriaxone sodium. But directly adding sodium acetate aqueous solution for salt formation and purification, simplifying the process, shortening the process period and reducing the process energy consumption.
Further, the invention provides a method for synthesizing an antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the molar ratio of the protective agent to 7-ACT is 0.5-2: 1. the mass ratio is 0.4-1:1.
further, the invention provides a method for synthesizing an antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the weight ratio of the reaction solvent to the 7-ACT is 5-100: 1.
further, the invention provides a method for synthesizing the antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the molar ratio of the 7-ACT to the AE-active ester is 1.75-1.45. Preferably 1.95 to 1.2. The mass percentage concentration of the reaction is 8-30%.
Further, the invention provides a method for synthesizing the antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: the addition amount of the pH adjusting agent is set at the end point of the addition when the pH value of the reaction system is within the range of 6.8-7.8.
Further, the invention provides a method for synthesizing an antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: in step S1, after the reaction is finished, a protective gas is used for protection. Preventing oxygen and moisture from causing decomposition of the product.
Further, the invention provides a method for synthesizing an antibacterial drug ceftriaxone sodium, which is characterized by comprising the following steps: in S2, the processing procedure after the reaction is finished is as follows:
s2-1, adding pure water to quench the reaction after the reaction is finished; the consumption of the pure water is 4-5 times of the feeding amount of 7-ACT.
S2-2, controlling the pH of the solution to be 6.8-7.8 by using a pH adjusting reagent to fully form salt;
and S2-3, crystallizing by adopting a solvent, centrifuging and drying to obtain a ceftriaxone sodium solid.
The crystallization solvent after salt formation can be one or more selected from ketone solvent (such as acetone), alcohol solvent (such as methanol, ethanol, propanol, butanol, etc.), and ether solvent (such as diethyl ether, tetrahydrofuran, dioxane, etc.).
The pH adjusting agent is generally one or more of sodium acetate, sodium bicarbonate, sodium carbonate, disodium hydrogen phosphate, glacial acetic acid, etc.
Active carbon can be added after S2-1 for decolorization for 5-30min.
The invention has the following functions and effects:
the ceftriaxone sodium produced by the method has high purity, good color grade and high product conversion rate. The maximum impurity of the synthesized ceftriaxone sodium can be controlled below 0.07 percent.
In the method, the amino and carboxyl with stronger activity of 7-ACT are protected firstly and then synthesized with AE-active ester to obtain a target product, and the target product is directly deprotected and salified with a sodium salt reagent aqueous solution to obtain ceftriaxone sodium without acidification and separation processes, so that the process is simplified, the energy consumption is saved, the product conversion rate is improved, the impurities are reduced, and the product purity is improved.
Drawings
FIG. 1 is a standard magenta outer image;
FIG. 2 is a magenta exogram produced in example 1;
FIG. 3 is an extramagenta image produced in example 2;
FIG. 4 is a magenta exogram produced in example 3;
FIG. 5 is an analysis spectrum of impurities corresponding to the product of example 1;
FIG. 6 is an analysis spectrum of impurities corresponding to the product of example 2;
FIG. 7 is an analytical spectrum of impurities corresponding to the product of example 3.
Detailed Description
Examples 1,
200ml of dimethyl carbonate, 7-ACT 20g and HMDS 8g were added at room temperature. Controlling temperature at 38-42 deg.C, timing, reflux reacting for 12hr, cooling to below 10 deg.C under nitrogen protection, adding AE-active ester 22g, reacting at the temperature for 8hr
Then adding 100ml of purified water and 13-17g of sodium acetate, and stirring for 30-60min. Adjusting pH to 6.8-7.8, adding 2g active carbon, decolorizing for 20min, and filtering. The temperature of the filtrate is controlled to be 15-25 ℃, 700ml of acetone is dripped, and crystals are separated out. Filtering, washing a filter cake with acetone, draining, washing with acetone, and drying in vacuum to obtain 34.1g of ceftriaxone sodium.
The purity of the high-pressure liquid phase is 99.7 percent, the conversion rate is 95.7 percent, and the maximum single impurity content is 0.04 percent.
Examples 2,
100ml of methylene chloride, 100ml of chloroform, 7-ACT 20g and BSU 20g were added at room temperature. Controlling temperature at 38-42 deg.C, timing, reflux reacting for 4hr, cooling to below 10 deg.C under nitrogen protection, adding 21.5g AE-active ester, reacting at the temperature for 20hr
Then adding 80ml of purified water and 10-12g of sodium bicarbonate, and stirring for 30-60min. Adjusting pH to 6.8-7.8, adding 2g active carbon, decolorizing for 20min, and filtering. Controlling the temperature of the filtrate at 15-25 ℃, and dripping 600ml of butanone to separate out crystals. Filtering, washing a filter cake with butanone, and drying in vacuum to obtain 34g of ceftriaxone sodium.
The purity of the high-pressure liquid phase is 99.79 percent, the conversion rate is 95.5 percent, and the maximum single impurity content is 0.05 percent.
Examples 3,
100ml of carbon tetrachloride, 100ml of chloroform, 7-ACT 20g and BSA 12g were added at room temperature. Controlling temperature at 38-42 deg.C, timing, reflux reacting for 8hr, cooling to below 10 deg.C under nitrogen protection, adding AE-active ester 22.5g, reacting at the temperature for 10hr
Then adding 90ml of purified water and 11-15g of sodium carbonate, and stirring for 30-60min. Adjusting pH to 6.8-7.8, adding 2g active carbon, decolorizing for 20min, and filtering. The temperature of the filtrate is controlled at 15-25 ℃, 900ml of ethanol is dripped, and crystals are separated out. Filtering, washing the filter cake with ethanol, draining, washing with ethanol, and vacuum drying to obtain 33.9g ceftriaxone sodium.
The purity of the high-pressure liquid phase is 99.79 percent, the conversion rate is 95.2 percent, and the maximum single impurity content is 0.05 percent.
Comparative example (c),
150ml of methylene chloride, 20g of 7-ACT, 22g of AE-active ester, 2.6ml of purified water and 80ml of ethanol are added at room temperature, 16ml of triethylamine is dropwise added at 0-5 ℃, and the reaction is carried out at the temperature for 4-6 hours.
After the reaction, 30ml of purified water is added, and the mixture is stirred for 30-60min. Adding 35ml of ethanol, adjusting the pH value to 2.0-3.0 by using dilute hydrochloric acid, crystallizing and filtering. And pumping the filter cake to obtain a wet ceftriaxone acid product.
Adding the obtained wet product of ceftriaxone acid into 100ml of pure water, adjusting pH to 6.8-7.8 with sodium bicarbonate to dissolve the ceftriaxone acid in a salified manner, adding 2g of active carbon, stirring and decoloring for 20min, filtering, and dropwise adding 700ml of acetone into the filtrate to precipitate crystals. Filtering, washing a filter cake with acetone, and drying in vacuum to obtain 30g of ceftriaxone sodium.
The purity of the high-pressure liquid phase is 98.97%, the conversion rate is 84.3%, and the maximum single impurity content is 0.35%.
Claims (10)
1. A synthetic method of ceftriaxone sodium is characterized in that:
protecting amino and carboxyl of 7-ACT with a protective agent, directly condensing with AE-active ester to obtain ceftriaxone acid, and directly salinizing to obtain a target product.
2. The method for synthesizing ceftriaxone sodium as claimed in claim 1, wherein:
the protective agent is a reagent capable of simultaneously protecting amino and carboxyl.
3. The method for synthesizing ceftriaxone sodium according to claim 1, wherein the method comprises the following steps:
the protective agent is a silanization reagent.
4. The method for synthesizing ceftriaxone sodium according to claim 1, wherein the specific preparation process is as follows:
s1, adding 7-ACT and a protective agent into a reaction solvent under an anhydrous condition, and performing reflux reaction for 4-12 hours to prepare a 7-ACT protective group solution;
s2, cooling the 7-ACT protective group solution prepared in the S1 to below 10 ℃, adding AE-active ester, reacting for 2-20 hours, and sequentially carrying out extraction, elution, preservation, salt formation and solvent crystallization by using a pH adjusting reagent to obtain a target product.
5. The method for synthesizing ceftriaxone sodium as claimed in claim 4, wherein:
the molar ratio of the protective agent to 7-ACT is 0.5-2: 1.
6. the method for synthesizing ceftriaxone sodium as claimed in claim 4, wherein:
the weight ratio of the reaction solvent to the 7-ACT is 5-100: 1.
7. the method for synthesizing ceftriaxone sodium as claimed in claim 4, wherein:
the molar ratio of 7-ACT to AE-active ester is 1.75-1.45.
8. The method for synthesizing ceftriaxone sodium according to claim 4, wherein the method comprises the following steps:
the adding amount of the pH adjusting reagent takes the pH value of the reaction system within the range of 6.8-7.8 as the adding end point.
9. The method for synthesizing ceftriaxone sodium according to claim 4, wherein the method comprises the following steps:
in step S1, after the reaction is finished, a protective gas is used for protection.
10. The method for synthesizing ceftriaxone sodium as claimed in claim 4, wherein:
in S2, the processing procedure after the reaction is finished is as follows:
s2-1, adding pure water to quench the reaction after the reaction is finished;
s2-2, controlling the pH of the solution to be 6.8-7.8 by using a pH adjusting reagent to fully form salt;
s2-3, crystallizing by adopting a solvent, centrifuging and drying to obtain a ceftriaxone sodium solid.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19990011517A (en) * | 1997-07-24 | 1999-02-18 | 최기연 | Method for preparing Ceftriaxone Sodium |
| CN109575048A (en) * | 2018-12-26 | 2019-04-05 | 辽宁美亚制药有限公司 | A kind of preparation method of Cefotaxime Sodium |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19990011517A (en) * | 1997-07-24 | 1999-02-18 | 최기연 | Method for preparing Ceftriaxone Sodium |
| CN109575048A (en) * | 2018-12-26 | 2019-04-05 | 辽宁美亚制药有限公司 | A kind of preparation method of Cefotaxime Sodium |
| CN111440197A (en) * | 2020-04-09 | 2020-07-24 | 辽宁美亚制药有限公司 | Preparation method of ceftriaxone sodium |
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