CN104530082B - Cefathiamidine compound - Google Patents
Cefathiamidine compound Download PDFInfo
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- CN104530082B CN104530082B CN201410743249.1A CN201410743249A CN104530082B CN 104530082 B CN104530082 B CN 104530082B CN 201410743249 A CN201410743249 A CN 201410743249A CN 104530082 B CN104530082 B CN 104530082B
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- Prior art keywords
- cefathiamidine
- acetone
- reduced pressure
- under reduced
- triethanolamine
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- 229950005040 cefathiamidine Drugs 0.000 title claims abstract description 148
- -1 Cefathiamidine compound Chemical class 0.000 title claims abstract description 87
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 98
- JYXACOFERDBGGQ-RHSMWYFYSA-N cefathiamidine Chemical class S1CC(COC(C)=O)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CSC(NC(C)C)=NC(C)C)[C@H]21 JYXACOFERDBGGQ-RHSMWYFYSA-N 0.000 claims abstract description 73
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000003756 stirring Methods 0.000 claims abstract description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001914 filtration Methods 0.000 claims abstract description 25
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002425 crystallisation Methods 0.000 claims abstract description 20
- 230000008025 crystallization Effects 0.000 claims abstract description 20
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000005406 washing Methods 0.000 claims abstract description 14
- 239000008367 deionised water Substances 0.000 claims abstract description 13
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 13
- 239000000706 filtrate Substances 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012046 mixed solvent Substances 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 10
- 239000002244 precipitate Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004061 bleaching Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 150000002169 ethanolamines Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims 9
- 239000003610 charcoal Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 14
- 239000002253 acid Substances 0.000 abstract description 9
- 150000003839 salts Chemical class 0.000 abstract description 8
- 239000000243 solution Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 18
- 241000894006 Bacteria Species 0.000 description 12
- 230000000844 anti-bacterial effect Effects 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 208000015181 infectious disease Diseases 0.000 description 7
- 239000005864 Sulphur Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000004227 thermal cracking Methods 0.000 description 5
- 241000194033 Enterococcus Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000193996 Streptococcus pyogenes Species 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 201000005010 Streptococcus pneumonia Diseases 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- IKWLIQXIPRUIDU-UHFFFAOYSA-N 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCSC2CC(=O)N12 IKWLIQXIPRUIDU-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000009874 alkali refining Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000004500 asepsis Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940006460 bromide ion Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002845 discoloration 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
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 150000003952 β-lactams Chemical group 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
- C07D501/24—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
- C07D501/28—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by an aliphatic carboxylic acid, which is substituted by hetero atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of cefathiamidine compounds, prepare using the following method: step 1, by triethanolamine adding into acetone stirring and dissolving, it is subsequently added into deionized water, stirring and dissolving, then is gradually added cefathiamidine crude product, after stirring and dissolving, mixed liquor is dripped in acetone, white precipitate, filtering is precipitated, with acetone washing, filtering, is dried under reduced pressure, obtains cefathiamidine triethanolamine salt；Step 2, cefathiamidine triethanolamine salt is added to the in the mixed solvent of water and isopropanol, salt acid for adjusting pH is used under stiring, adds active carbon decoloring, is filtered, filtrate is added in isopropanol and is stirred ladder cooling crystallization, filtering, with acetone washing, is drained, it is dried under reduced pressure, obtains the cefathiamidine compound of high-purity.Cefathiamidine compound of the invention has many advantages, such as that purity is high, impurity is few, stability is high.
Description
Technical field
The present invention relates to a kind of cefathiamidine, especially a kind of cefathiamidine compound belongs to pharmaceutical technology field.
Background technique
Cefathiamidine, chemical name are as follows: (6R, 7R) -3 [(acetoxyl group) methyl] -7- [α-(N, N'- diisopropylamidinateand sulphur
Base)-acetylamino] 8- oxo -5- thia -1- azabicyclo [4,2,0] oct-2-ene -2- formic acid betaine.Molecular formula:
C19H28N4O6S2, molecular weight: 472.59.
Cefathiamidine is white or off-white color crystalline powder；It is almost odorless, have draw it is moist.
Cefathiamidine is first generation cephalosporin, is initiated for China for clinic.Antimicrobial spectrum is similar to cefoxitin, to gold
Portugal bacterium, Streptococcus viridans, the effect of pneumococcus are stronger, have unique antibacterial activity to enterococcus, be mainly used for S. aureus L-forms,
Respiratory tract infection caused by pneumococcus and streptococcus, infection of biliary tract, urinary tract infections, gynecological infection, septicemia, pneumonia, meningitis
Deng infection.
Since cefathiamidine has the unique molecular structure of amphoteric ion inner salt, heat meets light, meets moist lability, easily divides
Solution discoloration.Bromide ion is easily remained in the product if dealt with improperly using bromoacetyl bromide in cefathiamidine synthesis process.Furthermore
In the condensation reaction, solvent system selection is bad, is not easy to remove impurity, causes content in crude product low, influences clinical therapeutic effect.
At present there are mainly two types of the refining methds of cefathiamidine, one is by cefathiamidine crude product with solvent handle, through at
Core effect, the method for crystallising for controlling supersaturation concentration.Another kind is the method for using acid, alkali tune isoelectric point, easy with acid, alkali refining method
The beta-lactam structure for destroying cefathiamidine, if open loop gram causes product degradation, product content is reduced, is caused to product stability
It influences.
Summary of the invention
The purpose of the present invention is to provide a kind of cefathiamidine compounds, have cefathiamidine compound with high purity, miscellaneous
The advantages that matter is few, stability is high.
In order to solve the above technical problems, the chemical structural formula of cefathiamidine compound of the invention is
The cefathiamidine compound is prepared using the following method: step 1, triethanolamine adding into acetone stirring and dissolving connecing
Addition deionized water, stirring and dissolving, then be gradually added cefathiamidine crude product after stirring and dissolving, mixed liquor is dripped in acetone,
White precipitate is precipitated, filtering, with acetone washing, filtering is dried under reduced pressure, obtains cefathiamidine triethanolamine salt；
Step 2, cefathiamidine triethanolamine salt is added to the in the mixed solvent of water and isopropanol, uses hydrochloric acid under stiring
PH is adjusted, active carbon decoloring is added, is filtered, filtrate is added in isopropanol and is stirred ladder cooling crystallization, filtering is washed with acetone
It washs, drains, be dried under reduced pressure, obtain the cefathiamidine compound of high-purity.
Preferably, the molar ratio of triethanolamine and cefathiamidine is 1.1~2:1 in step 1, the third of triethanolamine is dissolved
The dosage of ketone is 1.2~2 times of triethanolamine, and the dosage of deionized water is the 10~15% of cefathiamidine, reaction temperature 25
~30 DEG C.
Preferably, the acetone dosage of crystallization is 12~16 times of cefathiamidine in step 1.
Preferably, the acetone dosage of washing is 2~2.5 times of cefathiamidine in step 1, wash 1~3 time, decompression
Drying temperature is 30~35 DEG C, and being dried under reduced pressure the time is 3~5 hours.
Preferably, the dosage of mixed solvent is 2.7~3.1 times of cefathiamidine triethanolamine salt in step 2, mix molten
Isopropanol dosage is 6.5~10 times of deionized water in agent.
Preferably, pH is 4.5~5.0 in step 2, concentration of hydrochloric acid is 3~8%.
Preferably, activated carbon dosage is the 5~10% of cefathiamidine triethanolamine salt, bleaching temperature 25 in step 2
~30 DEG C, bleaching time is 20~40 minutes.
Preferably, the isopropanol dosage of crystallization is 14~17 times of cefathiamidine triethanolamine salt in step 2.
Preferably, in step 2 stir ladder cool down Crystallization Process are as follows: by filtrate be added isopropanol after, with 0.5~2 DEG C/
Minute once cooled down, while being stirred with 30~50 revs/min of mixing speed, after being cooled to 2~5 DEG C, with 0.2~
0.5 DEG C/min is cooled down twice to -2~-5 DEG C, while being stirred with 60~80 revs/min of mixing speed, completes two
It is kept for temperature stirring and crystallizing 1~2 hour after secondary cooling.
Preferably, the acetone dosage of washing is 1.9~2.3 times of cefathiamidine triethanolamine salt in step 2, washing
1~3 time, being dried under reduced pressure temperature is 25~30 DEG C, and being dried under reduced pressure the time is 4~6 hours.
Using triethanolamine formed cefathiamidine triethanolamine salt, be since the toxicity of triethanolamine is low, it is highly-safe, it is more
Remaining triethanolamine dissolves in acetone removing, guarantees the quality of cefathiamidine.Deionized water, Ke Yizeng are added in acetone soln
Add the dissolubility of cefathiamidine, removes water-solubility impurity.Cefathiamidine is set to form cefathiamidine triethanolamine salt, it can be by cephalo
Sulphur amidine is separated from impurity, then is precipitated out cefathiamidine triethanolamine salt with acetone, makes impurity dissolution in acetone,
The cefathiamidine triethanolamine salt of high-purity can be made, gained amine salt purity is up to 98% or more.It is dried under reduced pressure cefathiamidine
Triethanolamine salt can sufficiently remove acetone, shorten drying time, prevent cefathiamidine triethanolamine salt oxygenolysis.By head
Spore sulphur amidine triethanolamine salt is added to the in the mixed solvent of water and isopropanol, is refined with salt acid for adjusting pH, can make cephalo
Sulphur amidine triethanolamine salt reacts completely, releases cefathiamidine, prevents cefathiamidine from decomposing.With active carbon decoloring, can remove
Impurity improves appearance color.Filtrate is added isopropanol and carries out crystallization, and impurity can be made to be dissolved in isopropanol and further removed
It goes, improves quality.It is stirred ladder cooling crystallization, cefathiamidine can be made adequately to be precipitated, and impurity is prevented to be precipitated.Decompression
Dry cefathiamidine, can sufficiently remove acetone, shorten drying time, prevent cefathiamidine oxygenolysis, and high-purity is made
Cefathiamidine compound, purity is up to 99.5% or more.Thermogravimetry table is carried out to cefathiamidine compound of the invention
Bright, thermal cracking temperature is 153.3 DEG C or more, cracking temperature of 133.8 DEG C much higher than commercially available cefathiamidine highly finished product, thermal cracking
Temperature is higher, and stability is better, and therefore, the stability of cefathiamidine compound of the invention is much higher than commercially available cefathiamidine
The stability of highly finished product.
The molar ratio of triethanolamine and cefathiamidine is 1.1~2:1, cefathiamidine can be made adequately to be recycled, and
The waste for preventing triethanolamine, reduces cost.The dosage for dissolving the acetone of triethanolamine is 1.2~2 times of triethanolamine, go from
The dosage of sub- water is the 10~15% of cefathiamidine, cefathiamidine can be made sufficiently to dissolve, and reaction temperature is 25~30 DEG C, can be with
Guarantee that cefathiamidine is complete, quickly generates cefathiamidine triethanolamine salt, prevents oxygenolysis.The acetone dosage of crystallization is
12~16 times of cefathiamidine, can be such that cefathiamidine triethanolamine salt is precipitated completely, and can reduce cost.Cefathiamidine three
It is 30~35 DEG C that ethanolamine salt, which is dried under reduced pressure temperature, and being dried under reduced pressure the time is 3~5 hours, can sufficiently remove acetone, is shortened dry
The dry time prevents cefathiamidine triethanolamine salt oxygenolysis.PH is 4.5~5.0, cefathiamidine can be made sufficiently to release, and is prevented
Only cefathiamidine decomposes, and concentration of hydrochloric acid is 3~8%, can preferably control the adjusting of pH.The isopropanol dosage of crystallization is head
14~17 times of spore sulphur amidine triethanolamine salt, it is ensured that crystallization effect prevents cefathiamidine from decomposing, and effectively removes impurity elimination
Matter reduces cost.After isopropanol is added in filtrate, once cooled down with 0.5~2 DEG C/min, while with 30~50 revs/min
The mixing speed of clock is stirred, and after being cooled to 2~5 DEG C, is cooled down twice with 0.2~0.5 DEG C/min to -2~-5 DEG C,
It is stirred simultaneously with 60~80 revs/min of mixing speed, is kept for temperature stirring and crystallizing 1~2 hour after completing reducing temperature twice,
The crystallization of available high-purity, and particle is uniform, can sufficiently recycle cefathiamidine, improves yield, and prevent water with ice
Form be precipitated, while other impurities being prevented to be precipitated.The temperature that is dried under reduced pressure of cefathiamidine is 25~30 DEG C, is dried under reduced pressure the time
It is 4~6 hours, can sufficiently removes acetone, shortens drying time, prevent cefathiamidine oxygenolysis.
The cefathiamidine compound obtained using the present invention is with high purity, impurity is few, stability is high, and purification of the invention
Method has many advantages, such as that easy to operate, few using quantity of solvent and cost is relatively low.
Specific embodiment
Embodiment of the present invention is described in detail combined with specific embodiments below.It should be appreciated that reality of the invention
It applies and is not limited by the following examples, the accommodation in any form and/or change made to the present invention fall within this hair
Bright protection scope.
Assay
Chromatographic condition and system suitability are filler with octadecylsilane chemically bonded silica；With phosphate buffer
(Anhydrous Disodium Phosphate 2.76g, citric acid 1.29g is taken to be dissolved in water and be diluted to 1000ml) acetonitrile (80:20) is flowing
Phase；Detection wavelength 254nm.It takes cefathiamidine reference substance appropriate, be dissolved in water and be quantitatively diluted in every 1ml containing cefathiamidine
The solution of 0.5mg heats 30 minutes in 90 DEG C of water-baths, and 10 μ l is taken to inject liquid chromatograph, records chromatogram, cefathiamidine peak
It should be greater than 2.0 with the separating degree at other impurities peak.
Measuring method takes this product appropriate, accurately weighed, and being dissolved in water and quantifying dilution is made in every 1ml containing about cefathiamidine
The solution of 0.1mg, precision measure 10 μ l and inject liquid chromatograph, record chromatogram；Separately take cefathiamidine reference substance appropriate, same to method
Measurement.By external standard method with calculated by peak area to get.
Related substance takes this product appropriate, adds flowing phased soln and dilutes the solution being made in every 1ml containing 0.5mg, as confession
Test sample solution；Precision measures the solution for quantitatively being diluted with mobile phase in right amount and being made and containing 5 μ g in every 1ml, as contrast solution.According to
Chromatographic condition under content determination item takes 10 μ l of contrast solution to inject liquid chromatograph, adjusts detection sensitivity, makes principal component color
The peak height of spectral peak is about the 20% of full scale, then accurate measurement test solution and each 10 μ l of contrast solution, is injected separately into liquid phase
Chromatograph, 4 times of record chromatogram to principal component peak retention time.It is single miscellaneous if any impurity peaks in test solution chromatogram
Mass peak area is not greater than 0.5 times (0.5%) of contrast solution main peak area, and it is molten that the sum of each impurity peak area is not greater than control
1.5 times (1.5%) of liquid main peak area, any peak for being less than 0.05 times of contrast solution main peak area in test solution chromatogram
It is negligible.
Embodiment 1
A kind of cefathiamidine compound, chemical structural formula are
The cefathiamidine compound is prepared using the following method:
It is added to stirring and dissolving in 98.5 grams of acetone by 82.1 grams of triethanolamine, is subsequently added into 24 grams of deionized water, stirring
Dissolution is kept for 25 DEG C of solution temperature, then is gradually added 236 grams of cefathiamidine crude product (purity 92.3%) and is reacted, and is stirred molten
Xie Hou continues stirring 15-25 minutes, mixed liquor is dripped in 2832 grams of acetone, and white precipitate, filtering, with 600ml acetone is precipitated
Three times, filtering is dried under reduced pressure for washing, and being dried under reduced pressure temperature is 30 DEG C, and being dried under reduced pressure the time is 5 hours, obtains cefathiamidine three
291 grams of ethanolamine salt, purity 98.2%.
By 291 grams of cefathiamidine triethanolamine salt, it is added to the in the mixed solvent of 105 grams of water and 681 grams of isopropanols, is being stirred
The lower salt acid for adjusting pH with concentration 3% is mixed to 4.5, adds 14.5 grams of active carbon to decolourize 40 minutes in 25 DEG C of temperature, filtering, by filtrate
It is added in 4074 grams of isopropanols and carries out crystallization, once cooled down with 0.5 DEG C/min, while with 30 revs/min of mixing speed
It is stirred.It after being cooled to 5 DEG C, is cooled down twice with 0.2 DEG C/min to -2 DEG C, while with 60 revs/min of mixing speed
It is stirred, is kept for temperature stirring and crystallizing 2 hours after completing reducing temperature twice, filter, twice with 700ml acetone washing, drain, subtract
Press dry it is dry, be dried under reduced pressure temperature be 25 DEG C, be dried under reduced pressure the time be 6 hours, obtain the cefathiamidine compound 192 of high-purity
Gram, purity 99.5%.
Embodiment 2
A kind of cefathiamidine compound, chemical structural formula are shown in embodiment 1, which makes using the following method
It is standby:
It is added to stirring and dissolving in 136 grams of acetone by 97.0 grams of triethanolamine, is subsequently added into 26 grams of deionized water, is stirred molten
Solution is kept for 26 DEG C of solution temperature, then is gradually added 236 grams of cefathiamidine crude product (purity 92.3%) and is reacted, stirring and dissolving
Afterwards, continue stirring 15-25 minutes, mixed liquor is dripped in 3068 grams of acetone, white precipitate is precipitated, filtering is washed with 660ml acetone
Wash it is secondary, filtering, be dried under reduced pressure, be dried under reduced pressure temperature be 32 DEG C, be dried under reduced pressure the time be 4 hours, obtain three second of cefathiamidine
291 grams of alcohol amine salt, purity 98.3%.
By 291 grams of cefathiamidine triethanolamine salt, it is added to the in the mixed solvent of 100 grams of water and 715 grams of isopropanols, is being stirred
The lower salt acid for adjusting pH with concentration 4% is mixed to 4.6, adds 17.5 grams of active carbon to decolourize 35 minutes in 26 DEG C of temperature, filtering, by filtrate
It is added in 4365 grams of isopropanols and carries out crystallization, once cooled down with 0.8 DEG C/min, while with 35 revs/min of mixing speed
It is stirred.It after being cooled to 4 DEG C, is cooled down twice with 0.3 DEG C/min to -3 DEG C, while with 65 revs/min of mixing speed
It is stirred, is kept for temperature stirring and crystallizing 1.5 hours after completing reducing temperature twice, filter, three times with 740ml acetone washing, drain,
It is dried under reduced pressure, being dried under reduced pressure temperature is 26 DEG C, and being dried under reduced pressure the time is 5 hours, obtains the cefathiamidine compound 192 of high-purity
Gram, purity 99.6%.
Embodiment 3
A kind of cefathiamidine compound, chemical structural formula are shown in embodiment 1, which makes using the following method
It is standby:
It is added to stirring and dissolving in 190 grams of acetone by 119 grams of triethanolamine, is subsequently added into 28 grams of deionized water, is stirred molten
Solution is kept for 27 DEG C of solution temperature, then is gradually added 236 grams of cefathiamidine crude product (purity 92.3%) and is reacted, stirring and dissolving
Afterwards, continue stirring 15-25 minutes, mixed liquor is dripped in 3304 grams of acetone, white precipitate is precipitated, filtering is washed with 690ml acetone
It washs three times, filtering is dried under reduced pressure, and being dried under reduced pressure temperature is 33 DEG C, and being dried under reduced pressure the time is 5 hours, obtains three second of cefathiamidine
291 grams of alcohol amine salt, purity 98.4%.
By 291 grams of cefathiamidine triethanolamine salt, it is added to the in the mixed solvent of 94 grams of water and 750 grams of isopropanols, is being stirred
The lower salt acid for adjusting pH with concentration 5% is mixed to 4.7, adds 20.4 grams of active carbon to decolourize 30 minutes in 27 DEG C of temperature, filtering, by filtrate
4510 grams of isopropanols are added and carry out crystallizations, are once cooled down with 1.0 DEG C/min, at the same with 40 revs/min of mixing speed into
Row stirring.After being cooled to 3 DEG C, be cooled down twice with 0.4 DEG C/min to -4 DEG C, at the same with 70 revs/min of mixing speed into
Row stirring, is kept for temperature stirring and crystallizing 1 hour after completing reducing temperature twice, is filtered, three times with 770ml acetone washing, is drained, and is depressurized
Dry, being dried under reduced pressure temperature is 27 DEG C, and being dried under reduced pressure the time is 5 hours, obtains 193 grams of cefathiamidine compound of high-purity,
Purity is 99.7%.
Embodiment 4
A kind of cefathiamidine compound, chemical structural formula are shown in embodiment 1, which makes using the following method
It is standby:
It is added to stirring and dissolving in 241 grams of acetone by 134 grams of triethanolamine, is subsequently added into 33 grams of deionized water, is stirred molten
Solution is kept for 28 DEG C of solution temperature, then is gradually added 236 grams of cefathiamidine crude product (purity 92.3%) and is reacted, stirring and dissolving
Afterwards, continue stirring 15-25 minutes, mixed liquor is dripped in 3540 grams of acetone, white precipitate is precipitated, filtering is washed with 720ml acetone
Wash it is secondary, filtering, be dried under reduced pressure, be dried under reduced pressure temperature be 34 DEG C, be dried under reduced pressure the time be 4 hours, obtain three second of cefathiamidine
291 grams of alcohol amine salt, purity 98.3%.
By 291 grams of cefathiamidine triethanolamine salt, it is added to the in the mixed solvent of 87 grams of water and 786 grams of isopropanols, is being stirred
The lower salt acid for adjusting pH with concentration 6% is mixed to 4.8, adds 23.3 grams of active carbon to decolourize 25 minutes in 28 DEG C of temperature, filtering, by filtrate
4656 grams of isopropanols are added and carry out crystallizations, are once cooled down with 1.5 DEG C/min, at the same with 45 revs/min of mixing speed into
Row stirring.After being cooled to 2 DEG C, be cooled down twice with 0.5 DEG C/min to -5 DEG C, at the same with 75 revs/min of mixing speed into
Row stirring, is kept for temperature stirring and crystallizing 2 hours after completing reducing temperature twice, is filtered, twice with 810ml acetone washing, is drained, and is depressurized
Dry, being dried under reduced pressure temperature is 28 DEG C, and being dried under reduced pressure the time is 4 hours, obtains 194 grams of cefathiamidine compound of high-purity,
Purity is 99.6%.
Embodiment 5
A kind of cefathiamidine compound, chemical structural formula are shown in embodiment 1, which makes using the following method
It is standby:
It is added to stirring and dissolving in 298 grams of acetone by 149 grams of triethanolamine, is subsequently added into 35 grams of deionized water, is stirred molten
Solution is kept for 30 DEG C of solution temperature, then is gradually added 236 grams of cefathiamidine crude product (purity 92.3%) and is reacted, stirring and dissolving
Afterwards, continue stirring 15-25 minutes, mixed liquor is dripped in 3776 grams of acetone, white precipitate is precipitated, filtering is washed with 750ml acetone
It washs once, filtering is dried under reduced pressure, and being dried under reduced pressure temperature is 35 DEG C, and being dried under reduced pressure the time is 3 hours, obtains three second of cefathiamidine
291 grams of alcohol amine salt, purity 98.2%.
By 291 grams of cefathiamidine triethanolamine salt, it is added to the in the mixed solvent of 82 grams of water and 820 grams of isopropanols, is being stirred
The lower salt acid for adjusting pH with concentration 8% is mixed to 5.0, adds 29.1 grams of active carbon to decolourize 20 minutes in 30 DEG C of temperature, filtering, by filtrate
4947 grams of isopropanols are added and carry out crystallizations, are once cooled down with 2.0 DEG C/min, at the same with 50 revs/min of mixing speed into
Row stirring.After being cooled to 2 DEG C, be cooled down twice with 0.2 DEG C/min to -5 DEG C, at the same with 80 revs/min of mixing speed into
Row stirring, is kept for temperature stirring and crystallizing 1 hour after completing reducing temperature twice, is filtered, primary with 850ml acetone washing, is drained, and is depressurized
Dry, being dried under reduced pressure temperature is 30 DEG C, and being dried under reduced pressure the time is 4 hours, obtains 194 grams of cefathiamidine compound of high-purity,
Purity is 99.6%.
Thermogravimetry (TGA)
The sample each 6 of the cefathiamidine compound of Example 1-5 and the commercially available cefathiamidine highly finished product of reference examples respectively
A progress TGA analysis, is warming up to 200 DEG C with the heating rate of 10 DEG C/min, the thermal cracking temperature of sample the results are shown in Table 1.
Table 1
The result shows that: the thermal cracking temperature of cefathiamidine compound of the invention is 153.3 DEG C or more, much higher than commercially available
The cracking temperature that 133.8 DEG C of cefathiamidine highly finished product, since thermal cracking temperature is higher, stability is better, therefore, head of the invention
The stability of spore sulphur amidine compound is much higher than the stability of commercially available cefathiamidine highly finished product.
Hot test
The sample each 1 of the cefathiamidine compound of Example 1-5 and the commercially available cefathiamidine highly finished product of reference examples respectively
Batch, sample opening is placed in clean container, is placed 10 days at a temperature of 60 DEG C, was sampled in the 0th day, the 5th day and the 10th day, by steady
Qualitative high spot reviews project is detected, and study on the stability the results are shown in Table 2.
Table 2
The result shows that: in hot test, cefathiamidine compound of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine highly finished product are obvious in the variations such as appearance character, related substance, content,
Therefore cefathiamidine compound of the invention is more stable, and stability is much higher than commercially available cefathiamidine highly finished product.YG
That is yellow green, yellow green, similarly hereinafter.
Accelerated test
The sample each 1 of the cefathiamidine compound of Example 1-5 and the commercially available cefathiamidine highly finished product of reference examples respectively
Batch, it is placed in 40 DEG C and 75% humidity light protected environment, the 1st after placement, the investigation of sampling in 2,3,6 months, with 0 month investigation number
According to being compared, test result is shown in Table 3.
Table 3
The result shows that: in accelerated test, cefathiamidine compound of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine highly finished product are obvious in the variations such as appearance character, related substance, content,
Therefore cefathiamidine compound of the invention is more stable, and stability is much higher than commercially available cefathiamidine highly finished product.
Long term test
The sample each 1 of the cefathiamidine compound of Example 1-5 and the commercially available cefathiamidine highly finished product of reference examples respectively
Batch, it is placed in 25 DEG C and 60% humidity light protected environment, the 3rd after placement, the investigation of sampling in 6,9,12 months, was investigated with 0 month
Data are compared, and test result is shown in Table 4.
Table 4
The result shows that: in long term test, cefathiamidine compound of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine highly finished product are obvious in the variations such as appearance character, related substance, content,
Therefore cefathiamidine compound of the invention is more stable, and stability is much higher than commercially available cefathiamidine highly finished product.
In vitro Bactericidal Experiments
Cefathiamidine compound prepared with embodiment 3 is adopted, carries out antibacterial examination using minimal inhibitory concentration (MIC) method
Test, use 0.1mol/L phosphate buffer (pH=6.0) as solvent, will test medicine dissolution, after two-fold dilution, medical fluid with
Muller-Hintin culture medium was mixed into a series of drug containing tablets that concentration is 512-0.015 μ g/ml in proportion, by 6-8 hours
Equal culture to be measured is diluted to the pipe of Maxwell 0.5 (10 with sterile saline8CFU/ml it) is diluted to 10 times (10 again7CFU/ml), will
The sample-adding that the bacterium solution for preparing is added after high pressure steam sterilization holds in plate, is seeded to respectively with MIC inoculation instrument dense containing difference
It spends on the culture medium of medical fluid, each vaccination 10 is measured in final inoculation4CFU.It sets 35 DEG C to cultivate 18 hours, sentence by NCCLS standard
Disconnected result.0.1ml solution is taken to be poured into not drug containing blood plate from naked eyes asepsis growth test tube again, 37 DEG C are cultivated 18 hours,
Clump count is recorded, the minimum liquor strength of clump count≤5 is minimum bactericidal concentration (MBC).Test result is shown in Table 5.
Table 5
Antibacterial activity in vitro experiments have shown that, cefathiamidine compound of the invention have preferable antibacterial, bactericidal effect, this
The cefathiamidine compound of invention to S. aureus L-forms, staphylococcus epidermis, streptococcus pneumonia, micrococcus scarlatinae, moraxelle catarrhalis,
Haemophilus influenzae etc. has significant antibiotic and sterilizing effect.
Internal antibacterial tests
NIH small white mouse 40 are selected, 18-22 grams of weight, half male and half female is divided into 4 groups, every group 10, tests preceding fasting
12 hours.Test the previous day, quantitative inoculated bacteria in 2ml nutrient broth, incubate 6 hours by 35 DEG C of temperature, and 0.1ml bacterium solution is then taken to turn
Kind is in 10ml nutrient broth, and 35 DEG C of temperature are incubated 18 hours, in 721 spectrophotometer 550 μm (S. aureus L-forms) and 680 μm (enterococcus)
Measure the light transmittance of every plant of bacterium solution under wavelength, the light transmittance of fixed every kind of bacterium solution of day-to-day test, for test original bacteria liquid, with 5%
Bacterial concentration needed for dry ferment liquid is diluted to infection animal.Respectively to four groups of mice by intraperitoneal injection S. aureus L-forms, pneumonia streptococcus
Bacterium, micrococcus scarlatinae, enterococcus, every mouse injection bacterium amount are 1MLD/0.5ml (MLD is minimum 100% lethal bacterium amount), mouse
6 hours secondary are subcutaneously injected give cefathiamidine compound prepared by embodiment 3 at once and after infection after infection, observe 7 days and move
Object existence number, calculates drug to the half protective number (ED of various bacterium infection mouse50), drug is to various bacterium infection mouse
Half protective number ED50, ED5095% fiducial limit (L95) is counted using Litchfield&Wilcoxon improvement Bliss program
It calculates, concrete outcome is shown in Table 6.
Table 6
Antibacterial activity in vivo experiments have shown that, cefathiamidine compound of the invention have preferable antibacterial, bactericidal effect, this
The cefathiamidine compound of invention there is significant antibacterial to kill S. aureus L-forms, streptococcus pneumonia, micrococcus scarlatinae, enterococcus etc.
Bacterium effect.
Claims (8)
1. a kind of preparation method of cefathiamidine compound, it is characterised in that: the preparation includes: step 1, by triethanolamine plus
Enter stirring and dissolving in acetone, be subsequently added into deionized water, stirring and dissolving, then is gradually added cefathiamidine crude product, after stirring and dissolving,
Mixed liquor is dripped in acetone, white precipitate is precipitated, filtering, with acetone washing, filtering is dried under reduced pressure, obtains cefathiamidine three
Ethanolamine salt；
Step 2, cefathiamidine triethanolamine salt is added to the in the mixed solvent of water and isopropanol, is adjusted under stiring with hydrochloric acid
PH adds active carbon decoloring, filtering, and filtrate is added in isopropanol and be stirred ladder cooling crystallization, filtering, with acetone washing,
It drains, is dried under reduced pressure, obtain cefathiamidine compound；
The molar ratio of triethanolamine and cefathiamidine is 1.1~2: 1 in the step 1, dissolves the dosage of the acetone of triethanolamine
It is 1.2~2 times of triethanolamine, the dosage of deionized water is the 10~15% of cefathiamidine, and reaction temperature is 25~30 DEG C；Institute
It states and stirs ladder cooling Crystallization Process in step 2 are as follows: after isopropanol is added in filtrate, once dropped with 0.5~2 DEG C/min
Temperature, while being stirred with 30~50 revs/min of mixing speed, after being cooled to 2~5 DEG C, carried out with 0.2~0.5 DEG C/min
Reducing temperature twice is stirred to -2~-5 DEG C with 60~80 revs/min of mixing speed, keeps temperature after completing reducing temperature twice
Degree stirring and crystallizing 1~2 hour.
2. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: crystallization in the step 1
Acetone dosage is 12~16 times of cefathiamidine.
3. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: washed in the step 1
Acetone dosage is 2~2.5 times of cefathiamidine, is washed 1~3 time, and being dried under reduced pressure temperature is 30~35 DEG C, when being dried under reduced pressure
Between be 3~5 hours.
4. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: mixed in the step 2
The dosage of solvent is 2.7~3.1 times of cefathiamidine triethanolamine salt, and in the mixed solvent isopropanol dosage is deionized water
6.5~10 times.
5. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: pH is in the step 2
4.5~5.0, concentration of hydrochloric acid is 3~8%.
6. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: active in the step 2
Charcoal dosage is the 5~10% of cefathiamidine triethanolamine salt, and bleaching temperature is 25~30 DEG C, and bleaching time is 20~40 minutes.
7. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: crystallization in the step 2
Isopropanol dosage is 14~17 times of cefathiamidine triethanolamine salt.
8. the preparation method of cefathiamidine compound according to claim 1, it is characterised in that: washed in the step 2
Acetone dosage is 1.9~2.3 times of cefathiamidine triethanolamine salt, is washed 1~3 time, and being dried under reduced pressure temperature is 25~30
DEG C, being dried under reduced pressure the time is 4~6 hours.
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| CN109734728A (en) * | 2019-01-30 | 2019-05-10 | 山东省分析测试中心 | A kind of cefathiamidine aqueous acetonitrile agent compound monocrystalline and preparation method thereof |
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| CN1141099C (en) * | 2000-12-06 | 2004-03-10 | 广州白云山制药股份有限公司 | Antibacterial cephalosporin composition |
| CN1603326A (en) * | 2004-07-30 | 2005-04-06 | 广州白云山制药股份有限公司 | Cefathiamidine mixed salt and process for preparing same |
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| CN1431211A (en) * | 2003-01-28 | 2003-07-23 | 广州白云山制药股份有限公司 | Amine salt of cefathiamiding, its preparing method and application |
| CN1603326A (en) * | 2004-07-30 | 2005-04-06 | 广州白云山制药股份有限公司 | Cefathiamidine mixed salt and process for preparing same |
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