CN108017658B - Synthesis method of cefprozil - Google Patents
Synthesis method of cefprozil Download PDFInfo
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- CN108017658B CN108017658B CN201711429626.4A CN201711429626A CN108017658B CN 108017658 B CN108017658 B CN 108017658B CN 201711429626 A CN201711429626 A CN 201711429626A CN 108017658 B CN108017658 B CN 108017658B
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- 229960002580 cefprozil Drugs 0.000 title claims abstract description 37
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 title claims abstract description 36
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 19
- 229940125782 compound 2 Drugs 0.000 claims abstract description 18
- 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 claims abstract description 13
- SZBDOFWNZVHVGR-QMMMGPOBSA-N methyl (2s)-2-amino-2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)[C@@H](N)C1=CC=C(O)C=C1 SZBDOFWNZVHVGR-QMMMGPOBSA-N 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 22
- 239000012043 crude product Substances 0.000 claims description 22
- 238000001914 filtration Methods 0.000 claims description 19
- 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 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- 229940126214 compound 3 Drugs 0.000 claims description 16
- 239000002608 ionic liquid Substances 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 claims description 10
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 7
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 230000000171 quenching effect Effects 0.000 claims description 6
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 4
- 229910021135 KPF6 Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 10
- 238000007239 Wittig reaction Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 230000026045 iodination Effects 0.000 abstract description 2
- 238000006192 iodination reaction Methods 0.000 abstract description 2
- 238000002444 silanisation Methods 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 abstract 1
- 238000001035 drying Methods 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- WVEBQVBMPNXJCK-UHFFFAOYSA-N hexane;trimethylalumane Chemical compound C[Al](C)C.CCCCCC WVEBQVBMPNXJCK-UHFFFAOYSA-N 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 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 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012263 liquid product Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- ZYLDQHILNOZKIF-OXLALJFOSA-N (6r,7r)-7-azaniumyl-8-oxo-3-[(z)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(\C=C/C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 ZYLDQHILNOZKIF-OXLALJFOSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- -1 cefprozil compound Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- BCMPVBNNIHFSLU-UFHPHHKVSA-N benzhydryl (6r,7r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)CCl)C(=O)OC(C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)CC1=CC=CC=C1 BCMPVBNNIHFSLU-UFHPHHKVSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 239000002699 waste material Substances 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
- C07D501/14—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
-
- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a synthesis method of cefprozilThe synthesis method comprises the following steps: taking 7-ACA as a starting material, carrying out iodination and Wittig reaction after silanization protection to generate a compound 2; the compound 2 is in AlMe3And catalyzing the reaction product and the L-p-hydroxyphenylglycine methyl ester to generate a compound 1, namely the target product cefprozil. The invention has high conversion rate, simple process and high cis-isomer content, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a synthesis method of cefprozil.
Background
Cefprozil (Cefprozil), chemical name: the (6R, 7R) -7- [ (2R) -amino (4-hydroxyphenyl) acetamido ] -8-oxo-3- (1-propenyl) -5-thio-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is a second-generation cephalosporin antibiotic, is a cephalosporin spectrum antibacterial drug developed by American Behcet Gem company, has strong antibacterial activity on G +, G-bacteria and anaerobic bacteria, has particularly outstanding activity on G + bacteria, and is clinically used for light and medium infections caused by sensitive bacteria, including upper and lower respiratory tract infections, and skin soft tissue infections. The structural formula is shown as the following formula I:
because the C3-position of cefprozil is connected with an allyl group, the compound has two geometrical isomers, one is cis-cefprozil, the other is trans-cefprozil, and a mixture is clinically used, the cis-trans isomer is reported in literature to be the same in chemical stability and activity against gram-positive streptococcus and staphylococcus, but the cis-antibacterial activity is 6-8 times of that against gram-negative Escherichia coli, Klebsiella pneumoniae and the like. Several preparation methods have been reported for the synthesis of cefprozil, as follows:
route 1: U.S. patents US4694079, US2004132992, chinese patent publication No. CN1694888, etc. all use GCLE as raw material to synthesize 7-APCA. The synthetic route is as follows:
the 7-APCA is synthesized by using GCLE as a raw material, the synthesis yield is low, the molar yield is about 60 percent, and the defects of shortage of GCLE domestic goods sources, higher raw material price, long synthesis step, complex operation, more three-waste discharge and the like exist.
Route 2: patent CN 101798312B discloses a method for preparing cefprozil compound, which adopts 7-phenylacetamide-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE) as raw material, and prepares cefprozil through multi-step reaction and purification. In the route, because the side chain at the 3-position is not selective, more E-type isomer byproducts are mixed in the Z-type product, and because the structure and the property are similar, the E-type isomer byproducts are difficult to separate and even can be remained in the final cefprozil, so that the drug effect of the drug is influenced; phenol, trifluoroacetic acid, phosphorus pentachloride and the like which have great harm to the environment are needed, the corrosivity is strong, the reaction condition is harsh, and the yield is low. The synthetic route is as follows:
route 3: CN101225088B discloses a cefprozil preparation method, which comprises the steps of taking 3-acetoxymethyl-5-sulfur-7-amino-8-oxygen-1-azabicyclooctan-2-alkene-2 carboxylic acid (7-ACA) as a starting material, combining with acetaldehyde through wittig reaction, reacting with D-p-hydroxyphenylglycine dane potassium salt, and hydrolyzing to obtain cefprozil. Although the method is simple in reaction and simple and convenient in operation, the Wittig reaction yield is not high, the reaction is slow and the selectivity is poor, and a Z-type product is mixed with more E-type isomer byproducts which are difficult to separate due to similar structures and properties and even can be remained in the final cefprozil, so that the drug effect and the safety of the drug are influenced. The synthetic route is as follows:
route 4: patent CN101058584B reports a method for synthesizing cefprozil key intermediate 7-amino-3-propenyl cefproic acid by 7-ACA, the process replaces GCLE with low-cost and easily available 7-ACA, and the process has the advantages of low raw material cost, simple and easy process route and the like, but the yield is low, and the weight yield (calculated by 7-ACA) of 7-amino-3-propenyl cefproic acid is only 0.38-0.4. Meanwhile, the Wittig reaction yield is low, the reaction is slow, the selectivity is poor, more E-type isomer byproducts are mixed in the Z-type product, and the content of trans-isomer is too high, so that the drug effect and the safety of the drug are influenced. The specific synthetic route is as follows:
in summary, currently, the reported methods for synthesizing cefprozil mainly adopt two routes: 1) 7-ACA is used as an initial raw material, propenyl is introduced at the 3-position, a side chain is introduced after 7-position deprotection, and cefprozil is prepared by hydrolysis. 2) GCLE or GCLH is used as starting material, such as US4694079, CN101024649, etc. The common disadvantages are too complicated reaction steps, low conversion rate, low purity of the obtained product and too high content of trans-isomer. Therefore, a synthesis technology which has simple process, high conversion rate and high cis-isomer content and is suitable for large-scale industrial production needs to be researched and developed.
Disclosure of Invention
The invention aims to provide a novel synthesis process which is simple in process, high in conversion rate and high in cis-isomer content, is suitable for large-scale industrial production and is applied to synthesis of cefprozil or other compounds, aiming at overcoming the defects in the prior art. The technical scheme of the invention is as follows:
the synthesis method of cefprozil is characterized by comprising the following steps:
1) under the protection of nitrogen, 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooctan-2-ene-2 carboxylic acid (7-ACA) and N, O-bis (trimethylsilyl) acetamide (BSA) are dissolved in acetonitrile, stirred and reacted for 4 hours at room temperature, N-diethylaniline and trimethylsilyl iodide (TMSI) are dropwise added, the reaction is carried out for 1 hour at the temperature of 10-15 ℃, and triphenylphosphine (PPh) is added3) The reaction was continued for 1h, and sodium hexamethyldisilazide (NaN (SiMe) was added3)2) Stirring at room temperature for 45min, and performing post-treatment to obtain a compound 3;
2) dissolving Compound 3 in [ C ]4MIm]PF6Adding acetaldehyde and DBU (1, 8-diazabicyclo [5.4.0 ]) into the ionic liquid under stirring]Undec-7-ene) at room temperature for 1.5 h. The mixture is extracted by ethyl ether, and then,and (5) carrying out reduced pressure evaporation to obtain a crude product. Adding the crude product into a mixed solvent of methanol and water, stirring l h, filtering, washing, and vacuum drying to obtain a compound 2;
3) slowly dissolving the compound 2 in dichloromethane, fully stirring, and gradually adding a catalyst of trimethylaluminum (AlMe)3) Adding levo-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2 hours, cooling to room temperature, adding water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30 minutes, decoloring and filtering, adding a dilute hydrochloric acid aqueous solution into the filtrate, adjusting the pH to about 5.0, separating out solids, stirring, performing suction filtration, washing a filter cake with acetone, draining, and performing vacuum drying to obtain a cefprozil crude product;
in the step 1), the mass ratio of the 7-ACA, the BSA, the TMSI, the triphenyl phosphorus and the hexamethyl disilazane sodium is 1: 1.0-1.3: 1-1.2: 1-1.1: 1. Preferably, the mass ratio of 7-ACA, BSA, TMSI, triphenylphosphine, and sodium hexamethyldisilazide is 1:1.15:1.1:1.05: 1.
In the step 2), the mass ratio of the compound 3, acetaldehyde and DBU is 1: 1.2-1.6: 0.4-0.7; KPF6In [ C ]4MIm]PF6The mole fraction of (1) is 0.60; the volume ratio of methanol to water in the mixed solvent is 1:1. Preferably, the mass ratio of the compound 3, acetaldehyde and DBU is 1:1.4: 0.55.
In the step 3), the mass ratio of the compound 2, trimethylaluminum and L-p-hydroxyphenylglycine methyl ester is 1.0-1.2: 1.0-1.5: 1.0; the mass fraction of the solute of the dilute hydrochloric acid aqueous solution is 6 percent. Preferably, the mass ratio of the compound 2, the trimethylaluminum and the methyl levo-p-hydroxyphenylglycine is 1.1:1.25: 1.0.
Compared with the prior art, the synthesis method of cefprozil has the characteristics of mild reaction conditions, high product purity, high cis-isomer content, stable process, easy amplification, suitability for industrial production and the like, and has the core advantages that 7-ACA is used as an initial raw material, iodination and Wittig reactions occur after silanization protection, and ionic liquid is used as a catalyst, so that excessive cefprozil E isomer is prevented from being generated, and the drug effect of the drug is prevented from being influenced; meanwhile, trimethyl aluminum is used as a catalyst in ester amine condensation, so that the reaction activity is improved. The preparation method is suitable for industrial amplification requirements, and provides another important and practical novel compound for synthesis of cefprozil or other compounds.
Abbreviations used in the specification and claims have the following meanings:
Detailed Description
The technical solution of the present invention is further described in the following non-limiting examples.
Example 1
Step 1) under the protection of nitrogen, placing 10.89g (40mmol) of 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooctan-2-ene-2 carboxylic acid, 100mL of acetonitrile and 46mmol of N, O-bis (trimethylsilyl) acetamide (BSA) in a reaction bottle, stirring at room temperature for reaction for 4h, dropwise adding 4-6 mL of N, N-diethylaniline and 44mmol of iodotrimethylsilane (TMSI), reacting at 10-15 ℃ for 1h, adding 11.02g (42mmol) of triphenylphosphine, continuing to react for 1h, adding 7.34g (40mmol) of sodium hexamethyldisilazide, stirring at room temperature for 45min, separating an organic layer, washing with water, washing with 20% w/w NaCl aqueous solution, anhydrous MgSO (MgSO)4Drying to obtain 22.16g of compound 3 with 89.6% yield.
Step 2)
[C4MIm]PF6Preparation of ionic liquid: 6.896g KPF will be dissolved in the solution650mL of the acetone solution was placed in a 250mL three-necked flask, and then 10mL of a solution containing 5.47g of [ C ] was added dropwise4MIm]White precipitate appears immediately in acetone solution of Br, after stirring for 2h at room temperature, solid KBr separated out is removed by suction filtration, acetone is removed by rotary evaporation, and the temperature is reduced to room temperature to obtain a yellow liquid crude product. Using 30mL CH2Cl2Treating for 3-5 times until removing KBr solid, drying the dichloromethane solution of the ionic liquid with anhydrous magnesium sulfate overnight, filtering, and removing dichloromethane by rotary evaporation to obtain pale yellow viscous liquid product [ C4MIm]PF6。
18.55g (30mmol) of Compound 3 was dissolved in 50mL of [ C ]4MIm]PF6While stirring, acetaldehyde (1.85 g, 42mmol) and DBU (1, 8-diazabicyclo [5.4.0 ] were added]Undec-7-ene) 2.51g, and reacted at room temperature for 1.5 h. Extract with ether (3X 40mL), combine the ether layers, and evaporate the ether under reduced pressure to obtain the crude product. The residue after extraction with diethyl ether was extracted with toluene (3X 40mL) and the remaining POPh was added3And extraction is convenient for the repeated use of the ionic liquid. Adding the crude product into a mixed solvent of 30mL of methanol and 30mL of water, stirring l h after the addition is finished, filtering, washing a filter cake by 50mL of methanol, and drying in vacuum to obtain a yellow product, namely 6.95g of the compound 2, with the yield of 96.34%, the purity of 99.82% and the cis-trans ratio of 98.1: 1.9.
Step 3) preparing a trimethylaluminum hexane solution with the concentration of 2M at the temperature of 5 ℃ for later use; slowly dissolving 5.28g (22mmol) of compound 2 in 50mL of dichloromethane, fully stirring, gradually adding 12.5mL (25mmol) of 2M trimethylaluminum hexane solution, stirring at room temperature for 2h, adding 3.62g (20mmol) of L-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2h, monitoring the completion of the reaction by TLC, cooling to room temperature, adding 50mL of water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30min, decoloring and filtering, adding 6% dilute hydrochloric acid into the filtrate, adjusting the pH to about 5.0 to separate out a solid, stirring, performing suction filtration, washing a filter cake with acetone, performing suction drying, and performing vacuum drying to obtain 7.56g of a cefprozil crude product, wherein the yield is 96.83%, and the purity is 99.63%.
Example 2
Step 1) under the protection of nitrogen, placing 10.89g (40mmol) of 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooctan-2-ene-2 carboxylic acid, 100mL of acetonitrile and 40mmol of N, O-bis (trimethylsilyl) acetamide (BSA) in a reaction bottle, stirring at room temperature for reaction for 4h, dropwise adding 4-6 mL of N, N-diethylaniline and 40mmol of iodotrimethylsilane (TMSI), reacting at 10-15 ℃ for 1h, adding 10.49g (40mmol) of triphenylphosphine, continuing to react for 1h, adding7.34g (40mmol) of sodium hexamethyldisilazide was added, stirred at room temperature for 45min, and the organic layer was separated and washed with water, followed by 20% w/w aqueous NaCl solution, anhydrous MgSO4Drying gave 20.11g of Compound 3 in 81.3% yield.
Step 2)
[C4MIm]PF6Preparation of ionic liquid: 6.896g KPF will be dissolved in the solution650mL of the acetone solution was placed in a 250mL three-necked flask, and then 10mL of a solution containing 5.47g of [ C ] was added dropwise4MIm]And (3) immediately generating a white precipitate in the acetone solution of Br, stirring at room temperature for 2 hours, filtering to remove the separated solid KBr, removing the acetone by rotary evaporation, and cooling to room temperature to obtain a yellow liquid crude product. With 30mLCH2Cl2Treating for 3-5 times until removing KBr solid, drying the dichloromethane solution of the ionic liquid with anhydrous magnesium sulfate overnight, filtering, and removing dichloromethane by rotary evaporation to obtain pale yellow viscous liquid product [ C4MIm]PF6。
18.55g (30.0mmol) of Compound 3 was dissolved in 50mL of [ C ]4MIm]PF6While stirring, 1.59g (36.0mmol) of acetaldehyde and DBU (1, 8-diazabicyclo [5.4.0 ] were added]Undec-7-ene) 1.83g, and reacted at room temperature for 1.5 h. Extract with ether (3X 40mL), combine the ether layers, and evaporate the ether under reduced pressure to obtain the crude product. The residue after extraction with diethyl ether was extracted with toluene (3X 40mL) and the remaining POPh was added3And extraction is convenient for the repeated use of the ionic liquid. Adding the crude product into a mixed solvent of 30mL of methanol and 30mL of water, stirring l h after the addition is finished, filtering, washing a filter cake by 50mL of methanol, and drying in vacuum to obtain a yellow product, namely 6.62g of the compound 2, with the yield of 90.82%, the purity of 98.85% and the cis-trans ratio of 92.2: 7.8.
Step 3) preparing a trimethylaluminum hexane solution with the concentration of 2M at the temperature of 5 ℃ for later use; slowly dissolving 4.80g (20mmol) of compound 2 in 50mL of dichloromethane, fully stirring, gradually adding 10mL (20mmol) of 2M trimethylaluminum hexane solution, stirring at room temperature for 2h, then adding 3.62g (20mmol) of L-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2h, monitoring the completion of the reaction by TLC, cooling to room temperature, adding 50mL of water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30min, decoloring and filtering, adding 6% dilute hydrochloric acid into the filtrate, adjusting the pH to about 5.0 to precipitate a solid, stirring, performing suction filtration, washing a filter cake with acetone, pumping, and performing vacuum drying to obtain 6.92g of a cefprozil crude product, wherein the yield is 87.27%, and the purity is 98.21%.
Example 3
Step 1) under the protection of nitrogen, placing 10.89g (40mmol) of 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooctan-2-ene-2 carboxylic acid, 100mL of acetonitrile and 52mmol of N, O-bis (trimethylsilyl) acetamide (BSA) in a reaction bottle, stirring at room temperature for reaction for 4h, dropwise adding 4-6 mL of N, N-diethylaniline and 40mmol of iodotrimethylsilane (TMSI), reacting at 10-15 ℃ for 1h, adding 11.54g (44mmol) of triphenylphosphine, continuing to react for 1h, adding 7.34g (40mmol) of sodium hexamethyldisilazide, stirring at room temperature for 45min, separating an organic layer, washing with water, washing with 20% w/w NaCl aqueous solution, anhydrous MgSO (MgSO)4Drying gave 21.05g of Compound 3 in 85.1% yield.
Step 2)
[C4MIm]PF6Preparation of ionic liquid: 6.896g KPF will be dissolved in the solution650mL of the acetone solution was placed in a 250mL three-necked flask, and then 10mL of a solution containing 5.47g of [ C ] was added dropwise4MIm]And (3) immediately generating a white precipitate in the acetone solution of Br, stirring at room temperature for 2 hours, filtering to remove the separated solid KBr, removing the acetone by rotary evaporation, and cooling to room temperature to obtain a yellow liquid crude product. With 30mLCH2Cl2Treating for 3-5 times until removing KBr solid, drying the dichloromethane solution of the ionic liquid with anhydrous magnesium sulfate overnight, filtering, and removing dichloromethane by rotary evaporation to obtain pale yellow viscous liquid product [ C4MIm]PF6。
18.55g (30mmol) of Compound 3 was dissolved in 50mL of [ C ]4MIm]PF6While stirring, acetaldehyde (1.98 g, 45mmol) and DBU (1, 8-diazabicyclo [5.4.0 ] were added]Undec-7-ene) 2.74g, and reacted at room temperature for 1.5 h. Extract with ether (3X 40mL), combine the ether layers, and evaporate the ether under reduced pressure to obtain the crude product. The residue after extraction with diethyl ether was extracted with toluene (3X 40mL) and the remaining POPh was added3And extraction is convenient for the repeated use of the ionic liquid. Adding the crude product into a mixed solvent of 30mL of methanol and 30mL of water, stirring l h after the addition is finished, filtering, washing a filter cake by 50mL of methanol, and drying in vacuumA yellow product, i.e. 6.75g of compound 2, was obtained in 93.21% yield, 99.36% purity, with a cis-trans ratio of 96.4: 3.6.
Step 3) preparing a trimethylaluminum hexane solution with the concentration of 2M at the temperature of 5 ℃ for later use; slowly dissolving 5.28g (22mmol) of compound 2 in 50mL of dichloromethane, fully stirring, gradually adding 15mL (30mmol) of 2M trimethylaluminum hexane solution, stirring at room temperature for 2h, then adding 3.62g (20mmol) of L-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2h, monitoring the completion of the reaction by TLC, cooling to room temperature, adding 50mL of water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30min, decoloring and filtering, adding 6% dilute hydrochloric acid into the filtrate, adjusting the pH to about 5.0 to precipitate a solid, stirring, performing suction filtration, washing a filter cake with acetone, performing suction drying, and performing vacuum drying to obtain 7.17g of a cefprozil crude product, wherein the yield is 91.28%, and the purity is 99.03%.
Example 4
Step 1) under the protection of nitrogen, placing 10.89g (40mmol) of 3-acetoxymethyl-5-sulfur-7-amino-8-oxo-1-azabicyclooctan-2-ene-2 carboxylic acid, 100mL of acetonitrile and 52mmol of N, O-bis (trimethylsilyl) acetamide (BSA) in a reaction bottle, stirring at room temperature for reaction for 4h, dropwise adding 4-6 mL of N, N-diethylaniline and 48mmol of iodotrimethylsilane (TMSI), reacting at 10-15 ℃ for 1h, adding 11.54g (44mmol) of triphenylphosphine, continuing to react for 1h, adding 7.34g (40mmol) of sodium hexamethyldisilazide, stirring at room temperature for 45min, separating an organic layer, washing with water, washing with 20% w/w NaCl aqueous solution, anhydrous MgSO (MgSO)4Drying gave 21.64g of Compound 3, yield 87.5%.
Step 2)
[C4MIm]PF6Preparation of ionic liquid: 6.896g KPF will be dissolved in the solution650mL of the acetone solution was placed in a 250mL three-necked flask, and then 10mL of a solution containing 5.47g of [ C ] was added dropwise4MIm]And (3) immediately generating a white precipitate in the acetone solution of Br, stirring at room temperature for 2 hours, filtering to remove the separated solid KBr, removing the acetone by rotary evaporation, and cooling to room temperature to obtain a yellow liquid crude product. With 30mLCH2Cl2Treating for 3-5 times until removing KBr solid, drying the dichloromethane solution of the ionic liquid with anhydrous magnesium sulfate overnight, filtering, and removing dichloromethane by rotary evaporation to obtainTo pale yellow viscous liquid product [ C4MIm]PF6。
18.55g (30mmol) of Compound 3 was dissolved in 50mL of [ C ]4MIm]PF6While stirring, 2.11g (48mmol) of acetaldehyde and DBU (1, 8-diazabicyclo [5.4.0 ] were added]Undec-7-ene) 3.19g, and reacted at room temperature for 1.5 h. Extract with ether (3X 40mL), combine the ether layers, and evaporate the ether under reduced pressure to obtain the crude product. The residue after extraction with diethyl ether was extracted with toluene (3X 40mL) and the remaining POPh was added3And extraction is convenient for the repeated use of the ionic liquid. Adding the crude product into a mixed solvent of 30mL of methanol and 30mL of water, stirring l h after the addition is finished, filtering, washing a filter cake by 50mL of methanol, and drying in vacuum to obtain a yellow product, namely 6.67g of the compound 2, with the yield of 91.71%, the purity of 99.07% and the cis-trans ratio of 94.2: 5.8.
Step 3) preparing a trimethylaluminum hexane solution with the concentration of 2M at the temperature of 5 ℃ for later use; slowly dissolving 5.76g (24mmol) of compound 2 in 50mL of dichloromethane, fully stirring, gradually adding 15mL (30mmol) of 2M trimethylaluminum hexane solution, stirring at room temperature for 2h, then adding 3.62g (20mmol) of L-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2h, monitoring the completion of the reaction by TLC, cooling to room temperature, adding 50mL of water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30min, decoloring and filtering, adding 6% dilute hydrochloric acid into the filtrate, adjusting the pH to about 5.0 to precipitate a solid, stirring, performing suction filtration, washing a filter cake with acetone, pumping, and performing vacuum drying to obtain 7.34g of a cefprozil crude product, wherein the yield is 93.59%, and the purity is 99.27%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (8)
1. The synthesis method of cefprozil is characterized by comprising the following operation steps:
1) under the protection of nitrogen, 3-acetoxymethyl-5-sulfur-7-amino-8Dissolving-oxy-1-azabicyclooctan-2-ene-2 carboxylic acid (7-ACA) and N, O-bis (trimethylsilyl) acetamide (BSA) in acetonitrile, stirring at room temperature for reaction for 4h, dropwise adding N, N-diethylaniline and trimethylsilyl iodide (TMSI), reacting at 10-15 ℃ for 1h, and adding triphenylphosphine (PPh)3) The reaction was continued for 1h, and sodium hexamethyldisilazide (NaN (SiMe) was added3)2) Stirring for 45min at room temperature, and performing post-treatment to obtain a compound 3, wherein the mass ratio of the 7-ACA, BSA, TMSI, triphenylphosphine and sodium hexamethyldisilazide is 1: 1.0-1.3: 1-1.2: 1-1.1: 1;
2) dissolving Compound 3 in [ C ]4MIm]PF6Adding acetaldehyde and DBU (1, 8-diazabicyclo [5.4.0 ]) into the ionic liquid under stirring]Undecyl-7-ene), reacting at room temperature for 1.5h, extracting with diethyl ether, distilling under reduced pressure to obtain a crude product, adding the crude product into a mixed solvent of methanol and water, stirring for lh, filtering, washing, and vacuum drying to obtain a compound 2;
3) slowly dissolving the compound 2 in dichloromethane, fully stirring, and gradually adding a catalyst of trimethylaluminum (AlMe)3) Adding levo-p-hydroxyphenylglycine methyl ester in batches, controlling the temperature to 35 ℃ for reaction for 2 hours, cooling to room temperature, adding water for quenching reaction, standing for layering, collecting a water phase, adding activated carbon, stirring for 30 minutes, decoloring and filtering, adding a dilute hydrochloric acid aqueous solution into the filtrate, adjusting the pH to about 5.0, separating out solids, stirring, performing suction filtration, washing a filter cake with acetone, draining, and performing vacuum drying to obtain a cefprozil crude product;
2. the method for synthesizing cefprozil according to claim 1, wherein in step 2), the mass ratio of the compound 3, acetaldehyde and DBU is 1: 1.2-1.6: 0.4-0.7; KPF6In [ C ]4MIm]PF6The molar fraction in (b) is 0.60.
3. The method for synthesizing cefprozil according to claim 1, wherein in step 2), the volume ratio of methanol to water in the mixed solvent is 1:1.
4. The method for synthesizing cefprozil according to claim 1, wherein in step 3), the mass ratio of the compound 2, trimethylaluminum and L-p-hydroxyphenylglycine methyl ester is 1.0-1.2: 1.0-1.5: 1.0.
5. The method for synthesizing cefprozil according to claim 1, wherein in step 3), the solute of the dilute aqueous hydrochloric acid solution has a mass fraction of 6%.
6. The method for synthesizing cefprozil according to claim 1, wherein in step 1), the mass ratio of the 7-ACA, BSA, TMSI, triphenylphosphine and sodium hexamethyldisilazide is 1:1.15:1.1:1.05: 1.
7. The method for synthesizing cefprozil according to claim 2, wherein in step 2), the ratio of the amounts of the compound 3, acetaldehyde and DBU is 1:1.4: 0.55.
8. The method for synthesizing cefprozil according to claim 4, wherein in step 3), the mass ratio of the compound 2, trimethylaluminum and methyl levo-p-hydroxyphenylglycinate is 1.1:1.25: 1.0.
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| CN86105568A (en) * | 1985-07-29 | 1987-04-01 | 布里斯托尔-米尔斯公司 | 3-propenyl cynnematin solvate |
| CN101058584A (en) * | 2007-05-23 | 2007-10-24 | 上海骏捷生化科技有限公司 | Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid |
| CN101225088A (en) * | 2008-01-17 | 2008-07-23 | 南通康鑫药业有限公司 | Method for preparing cephalosporin propylene |
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| CN86105568A (en) * | 1985-07-29 | 1987-04-01 | 布里斯托尔-米尔斯公司 | 3-propenyl cynnematin solvate |
| CN101058584A (en) * | 2007-05-23 | 2007-10-24 | 上海骏捷生化科技有限公司 | Method of preparing cefprozil parent nucleus 7-amino-3-propenylcephalosporanic acid |
| CN101225088A (en) * | 2008-01-17 | 2008-07-23 | 南通康鑫药业有限公司 | Method for preparing cephalosporin propylene |
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