CN117304212A - Preparation method of cefcapene pivoxil impurity - Google Patents
Preparation method of cefcapene pivoxil impurity Download PDFInfo
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- CN117304212A CN117304212A CN202311248892.2A CN202311248892A CN117304212A CN 117304212 A CN117304212 A CN 117304212A CN 202311248892 A CN202311248892 A CN 202311248892A CN 117304212 A CN117304212 A CN 117304212A
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- compound
- organic solvent
- cefcapene pivoxil
- acid
- cefcapene
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- 239000012535 impurity Substances 0.000 title claims abstract description 37
- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 title claims abstract description 36
- 229950004627 cefcapene pivoxil Drugs 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 9
- XIXNSLABECPEMI-VURMDHGXSA-N (z)-2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]pent-2-enoic acid Chemical compound CC\C=C(/C(O)=O)C1=CSC(NC(=O)OC(C)(C)C)=N1 XIXNSLABECPEMI-VURMDHGXSA-N 0.000 claims abstract description 7
- 238000009833 condensation Methods 0.000 claims abstract description 3
- 230000005494 condensation Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 229940126062 Compound A Drugs 0.000 claims description 14
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 14
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 7
- HJJRIJDTIPFROI-NVKITGPLSA-N cefcapene Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 HJJRIJDTIPFROI-NVKITGPLSA-N 0.000 claims description 7
- 229960002966 cefcapene Drugs 0.000 claims description 7
- 239000002243 precursor Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 2
- BXVSAYBZSGIURM-UHFFFAOYSA-N 2-phenoxy-4h-1,3,2$l^{5}-benzodioxaphosphinine 2-oxide Chemical compound O1CC2=CC=CC=C2OP1(=O)OC1=CC=CC=C1 BXVSAYBZSGIURM-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000011160 research Methods 0.000 abstract description 7
- 238000000746 purification Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004458 analytical method Methods 0.000 abstract description 4
- 239000013558 reference substance Substances 0.000 abstract description 3
- 238000013461 design Methods 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000013074 reference sample Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract 2
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- -1 2-aminothiazol-4-yl Chemical group 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 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 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000005406 washing Methods 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
- C07D501/24—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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefcapene pivoxil impurities, which starts with 7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride and (Z) -2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid, and obtains the cefcapene pivoxil impurities through condensation, substitution, hydrolysis and substitution, and has the advantages of reasonable route design, easily obtained raw materials, strong operability and convenient purification. The purity of the prepared target product can reach more than 98.0%, a reference sample is provided for cefcapene pivoxil research, a reference substance is provided for clinical, pharmacological and pharmacokinetic analysis research of the cefcapene pivoxil, and the method has important research value.
Description
Technical Field
The invention belongs to a compound synthesis method, and particularly relates to a preparation method of cefcapene pivoxil impurities.
Background
Cefcapene pivoxil (cefapime), chemical name (6R, 7R) -7- ((Z) -2- (2-aminothiazol-4-yl) pent-2-enaminoxy) -3- ((carbamoyl) methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxic acid, was the third generation oral cephalosporin antibiotics developed by Japanese salt wild pharmaceutical Co, and was marketed in Japan for the first time in 1997, and is mainly used for treating respiratory tract, urinary tract, skin/soft tissue, eyes and otorhinolaryngological infections caused by sensitive bacteria.
Any drug may contain small amounts of impurities due to synthesis, storage, etc. The research of impurities is an important content of medicine development, and whether the impurities can be comprehensively and accurately controlled is directly related to the quality controllability and the safety of the medicine. Therefore, the purity of the medicine must be ensured in the aspects of medicine supply, production, research, clinical use and the like. The impurities are regularly researched and controlled within a safe and reasonable limit range, so that the effectiveness and safety of the medicine can be ensured. In the quality control process, high-purity impurities are needed to be used as reference substances or standard substances of related substances. The compound D shown in the structural formula is cefcapene pivoxil impurity in the nootropic herb net, and no synthesis method of the impurity compound is reported at present.
Disclosure of Invention
The invention aims to: the invention aims to provide a preparation method of cefcapene pivoxil impurities.
The technical scheme is as follows: the preparation method of the cefcapene pivoxil impurity comprises the following steps:
(1) Taking a compound I7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride and a compound II (Z) -2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid, adding into an organic solvent, adding a condensation reagent and alkali, and reacting to obtain a compound A:
(2) Adding the compound A into an organic solvent, adding the compound III cefcapene precursor acid and alkali, and reacting to obtain a compound B:
(3) Adding the compound B into an organic solvent, adding acid, and reacting to obtain a compound C:
(4) Adding the compound C into an organic solvent, adding alkali and a compound IV, wherein R is Cl or I, and reacting to obtain a cefcapene pivoxil impurity compound D, namely, a cefcapene pivoxil impurity:
preferably, the organic solvent in the step (1) is at least one of dichloromethane, acetonitrile, tetrahydrofuran and DMF, and the volume ratio of the compound I to the organic solvent is 1:2-1:20.
Preferably, the condensing agent in the step (1) is EDCI, DCC, HOAT, HOBT, POCl 3 At least one of the bases is TEA, DIPEA, DMA, DMAP, the molar ratio of the compound I to the condensing agent is 1:1-1:3, the molar ratio of the compound I to the base is 1:2-1:8, the reaction temperature is-30-40 ℃, and the stirring is carried out for 1-20 hours during the reaction.
Preferably, the organic solvent in the step (2) is at least one of tetrahydrofuran, 1, 4-dioxane, DMF and DMSO, and the volume ratio of the compound A to the organic solvent is 1:5-1:40.
Preferably, the base in the step (2) is triethylamine, DIPEA, K 2 CO 3 、Na 2 CO 3 、NaHCO 3 At least one of the compounds A and the alkali in a molar ratio of 1:1-1:5; compound A and chemical conversionThe mol ratio of the cefcapene precursor acid of the compound III is 1:1-1:3; the reaction temperature is 10-80 ℃ and the reaction time is 8-24 hours.
Preferably, the organic solvent in the step (3) is at least one of dichloromethane, tetrahydrofuran, acetonitrile and DMF, and the volume ratio of the compound B to the organic solvent is 1:5-1:30.
Preferably, the acid in the step (3) is HCl or H 2 SO 4 At least one of formic acid and trifluoroacetic acid, wherein the volume ratio of the compound B to the acid is 2:1-1:20; the reaction temperature is 0-60 ℃ and the reaction time is 2-8 hours.
Preferably, in the compound IV in the step (4), R is I.
Preferably, the organic solvent in the step (4) is at least one of acetonitrile, tetrahydrofuran, acetone, methanol and DMF, and the volume ratio of the compound C to the organic solvent is 1:5-1:30.
Preferably, the base in the step (4) is triethylamine, diisopropylethylamine, naHCO 3 、KHCO 3 、K 2 CO 3 At least one of (a) and (b); the molar ratio of the compound C to the alkali is 1:1-1:8; the reaction temperature is between 50 ℃ below zero and 40 ℃ and the reaction time is between 1 and 8 hours.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the invention provides a preparation method of cefcapene pivoxil impurity, which has the advantages of reasonable preparation route design, easily obtained raw materials, strong operability and convenient purification; the purity of the prepared target product can reach more than 98.0%, a reference sample is provided for cefcapene pivoxil research, and a reference substance is provided for clinical, pharmacological and pharmacokinetic analysis research of cefcapene pivoxil.
Drawings
FIG. 1 is a nuclear magnetic resonance chart of cefcapene pivoxil impurity, which is compound D provided in example 1 of the present invention;
fig. 2 is a liquid phase diagram of the cefcapene pivoxil impurity, which is compound D provided in example 1 of the present invention.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings.
Experiment consumable: 7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride (synthesized in one step by taking 7-phenylacetylamino-3-chloromethyl-4-cephalosporanic acid p-methoxybenzyl ester (GCLE) as a raw material); (Z) -2- (2-t-Butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid (CAS: 86978-24-7) was purchased from Hua Tide Ten technologies Co., ltd. (Lot: 200803); cefcapene precursor acid (CAS: 153012-37-4) was purchased from Zhejianghua pharmaceutical Co., ltd (Lot: 201202).
The preparation method of cefcapene pivoxil impurity has the following synthetic route:
example 1
(1) Preparation of Compound A: 15.00g of 7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride and 13.35g of (Z) -2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid are dissolved in 150mL of acetonitrile, 12.59g of DCC, 8.24g of HOBT, 15.4mL of TEA are added in an ice bath for reaction at 25 ℃ for 16 hours, TLC monitors the end of the reaction, the reaction solution is dried by spin-drying, and 18.90g of compound A is obtained as a white solid through silica gel column purification, and the yield is 78.7%;
(2) Preparation of compound B: 18.90g of Compound A and 19.06g of cefcapene precursor acid were taken and dissolved in 378mL of DMF and then 6.04 and g K were added 2 CO 3 After the reaction is carried out for 16 hours at 25 ℃, TLC monitors the end of the reaction, the reaction liquid is added into 1.5L of water, ethyl acetate is extracted for three times, the organic phase is combined and washed by saturated saline water, the organic phase is dried by anhydrous sodium sulfate and filtered, the filtrate is dried in a spinning way, the solid is pulped by isopropyl ether, 29.75g of compound B white solid is obtained by filtration, and the yield is 87.6%;
(3) Preparation of compound C: 20.00g of Compound B was dissolved in 200mL of tetrahydrofuran, 1N HCl 200mL was added under ice bath and reacted at 25℃for 3 hours, and TLC was monitored for the end of the reaction using NaHCO 3 Neutralization to ph=7, spiral removal of tetrahydrofuran, precipitation of a large amount of solids, filtration and drying gave 13.21g of compound C as a pale yellow solid in 91.1% yield;
(4) Compound DNamely, the preparation of cefcapene pivoxil impurity: 10g of Compound C are taken up in 100mL of DMF and 4.97g of NaHCO are added 3 3.6mL of iodomethyl pivalate is added dropwise at the temperature of minus 10 ℃, the reaction is kept for 7 hours, TLC monitors the end of the reaction, the reaction is added into 500mL of water, a large amount of solid is separated out, the solid is filtered, and the solid is dissolved in acetonitrile and water and filtered. Purification was performed using a hanbang UV3000/NP7000 high performance liquid chromatograph, wherein column DAC-50, packing C18 (ODS-RPS), 8um, wavelength 220nm, mobile phase a phase acetonitrile, mobile phase B phase water, gradient: 35-75%, purifying time is 35 min, flow speed is 40mL/min, 7.55g of cefcapene pivoxil impurity white solid is obtained by freeze-drying, and yield is 66.5%.
Analysis of results: as shown in figures 1 and 2, the cefcapene pivoxil impurity obtained is correct by detecting NMR, HPLC is 98.8312%, the yield of each step is more than 65%, the total yield of four steps is 41.8%, the raw materials are easy to obtain, the operability is strong, the purification is convenient, and the purity of the target product is high.
Example 2
(1) Preparation of Compound A: 10.00g of 7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride and 7.36g of (Z) -2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid were dissolved in 200mL of tetrahydrofuran, and 4.54g of POCl was added in an ice bath 3 15.8mL of TEA is reacted for 2 hours at the temperature of 5 ℃, TLC monitors the end of the reaction, 400mL of water is added for quenching the reaction, the reaction is extracted for 2 times by ethyl acetate, the organic phases are combined and washed for 2 times by water, anhydrous sodium sulfate is dried, filtration and spin drying are carried out, and 15.00g of compound A white solid is obtained, and the yield is 93.6%;
(2) Preparation of compound B: dissolving 15.00g of compound A and 15.13g of cefcapene precursor acid into 450mL of DMSO, then adding 4.8mL of TEA, reacting for 6 hours at 50 ℃, monitoring the end of the reaction by TLC, adding the reaction liquid into 1.5L of water, extracting by ethyl acetate three times, washing the organic phase by saturated saline, drying the organic phase by anhydrous sodium sulfate, filtering, spin-drying the filtrate, pulping the solid by isopropyl ether, filtering to obtain 20.69g of compound B as a light yellow solid, and obtaining 76.8% of yield;
(3) Preparation of compound C: 15.00g of compound B is dissolved in 150mL of dichloromethane, 150mL of TFA is added under ice bath, the reaction is carried out for 1 hour at 5 ℃, TLC monitors the end of the reaction, spin-drying and n-hexane beating are carried out to obtain 10.5g of compound C as yellow solid, and the yield is 96.5%;
(4) Preparation of compound D, cefcapene pivoxil impurity: 10g of compound C is dissolved in 200mL of acetonitrile, 9.9mL of TEA is added, 5.3mL of iodomethyl pivalate is dropwise added in an ice bath for reaction at room temperature for 4 hours, TLC monitors the end of the reaction, the reaction is filtered and dried, and the solid is purified by a silica gel column to obtain 6.20g of cefcapene pivoxil impurity white solid, and the yield is 54.6%.
Analysis of results: the total four-step yield of the cefcapene pivoxil impurity is 37.9%, the raw materials are easy to obtain, the operability is strong, and the pure product can be obtained after the final silica gel column.
Claims (10)
1. The preparation method of the cefcapene pivoxil impurity is characterized by comprising the following steps of:
(1) Taking a compound I7-amino-3-chloromethyl-3-cefazolin-4-carboxylic acid p-methoxybenzyl hydrochloride and a compound II (Z) -2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoic acid, adding the organic solvent, adding a condensation reagent and alkali, and reacting to obtain a compound A:
(2) Adding the compound A into an organic solvent, adding the compound III cefcapene precursor acid and alkali, and reacting to obtain a compound B:
(3) Adding the compound B into an organic solvent, adding acid, and reacting to obtain a compound C:
(4) Adding the compound C into an organic solvent, adding alkali and a compound IV, wherein R is Cl or I, and reacting to obtain a compound D, namely cefcapene pivoxil impurity:
2. the method for preparing cefcapene pivoxil impurity according to claim 1, wherein the organic solvent in the step (1) is at least one of dichloromethane, acetonitrile, tetrahydrofuran and DMF, and the volume ratio of the compound I to the organic solvent is 1:2-1:20.
3. The method for preparing cefcapene pivoxil impurity according to claim 1, wherein the condensing agent in the step (1) is EDCI, DCC, HOAT, HOBT, POCl 3 At least one of the bases is TEA, DIPEA, DMA, DMAP, the molar ratio of the compound I to the condensing agent is 1:1-1:3, the molar ratio of the compound I to the base is 1:2-1:8, the reaction temperature is-30-40 ℃, and the stirring is carried out for 1-20 hours during the reaction.
4. The method for preparing cefcapene pivoxil impurity according to claim 1, wherein the organic solvent in the step (2) is at least one of tetrahydrofuran, 1, 4-dioxane, DMF and DMSO, and the volume ratio of the compound A to the organic solvent is 1:5-1:40.
5. The process for preparing cefcapene pivoxil impurity according to claim 1, wherein the base in step (2) is triethylamine, DIPEA, K 2 CO 3 、Na 2 CO 3 、NaHCO 3 At least one of the compounds A and the alkali in a molar ratio of 1:1-1:5; the mol ratio of the compound A to the cefcapene precursor acid of the compound III is 1:1-1:3; the reaction temperature is 10-80 ℃ and the reaction time is 8-24 hours.
6. The method for preparing cefcapene pivoxil impurity according to claim 1, wherein the organic solvent in the step (3) is at least one of dichloromethane, tetrahydrofuran, acetonitrile and DMF, and the volume ratio of the compound B to the organic solvent is 1:5-1:30.
7. The method for preparing cefcapene pivoxil impurity according to claim 1, wherein the acid in the step (3) is HCl, H 2 SO 4 At least one of formic acid and trifluoroacetic acid, wherein the volume ratio of the compound B to the acid is 2:1-1:20; the reaction temperature is 0-60 ℃ and the reaction time is 2-8 hours.
8. The process for the preparation of cefcapene pivoxil impurity according to claim 1, wherein R in compound IV in step (4) is I.
9. The method for preparing cefcapene pivoxil impurity according to claim 1, wherein the organic solvent in the step (4) is at least one of acetonitrile, tetrahydrofuran, acetone, methanol and DMF, and the volume ratio of the compound C to the organic solvent is 1:5-1:30.
10. The process for preparing cefcapene pivoxil impurity according to claim 1, wherein the base in step (4) is triethylamine, diisopropylethylamine, naHCO 3 、KHCO 3 、K 2 CO 3 At least one of (a) and (b); the molar ratio of the compound C to the alkali is 1:1-1:8; the reaction temperature is between 50 ℃ below zero and 40 ℃ and the reaction time is between 1 and 8 hours.
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