CN103467496A - Preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose - Google Patents
Preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 239000012043 crude product Substances 0.000 claims abstract description 20
- 239000000047 product Substances 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 64
- 238000006243 chemical reaction Methods 0.000 claims description 48
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 31
- 238000005406 washing Methods 0.000 claims description 27
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 21
- 150000007970 thio esters Chemical class 0.000 claims description 21
- 235000019270 ammonium chloride Nutrition 0.000 claims description 18
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000004090 dissolution Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 159000000000 sodium salts Chemical class 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- 150000003863 ammonium salts Chemical class 0.000 claims description 5
- -1 filters Substances 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
- 239000001103 potassium chloride Substances 0.000 claims description 4
- 235000011164 potassium chloride Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical class CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 230000008030 elimination Effects 0.000 claims description 2
- 238000003379 elimination reaction Methods 0.000 claims description 2
- NVIAYEIXYQCDAN-MHTLYPKNSA-N (6r,7s)-7-azaniumyl-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C)=C(C([O-])=O)N2C(=O)[C@H]([NH3+])[C@@H]12 NVIAYEIXYQCDAN-MHTLYPKNSA-N 0.000 claims 6
- 239000003814 drug Substances 0.000 abstract description 6
- 108090000204 Dipeptidase 1 Proteins 0.000 abstract description 5
- 102000006635 beta-lactamase Human genes 0.000 abstract description 5
- 229930186147 Cephalosporin Natural products 0.000 abstract description 4
- 230000000845 anti-microbial effect Effects 0.000 abstract description 4
- 229940124587 cephalosporin Drugs 0.000 abstract description 4
- 150000001780 cephalosporins Chemical class 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 96
- 238000003756 stirring Methods 0.000 description 77
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000003610 charcoal Substances 0.000 description 31
- 239000003643 water by type Substances 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000010410 layer Substances 0.000 description 25
- 238000002425 crystallisation Methods 0.000 description 22
- 230000008025 crystallization Effects 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000007788 liquid Substances 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 238000001291 vacuum drying Methods 0.000 description 17
- 239000002585 base Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 235000015320 potassium carbonate Nutrition 0.000 description 12
- 238000007670 refining Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- 230000002087 whitening effect Effects 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229940127249 oral antibiotic Drugs 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960002588 cefradine Drugs 0.000 description 2
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 2
- SWXVUIWOUIDPGS-UHFFFAOYSA-N diacetone alcohol Natural products CC(=O)CC(C)(C)O SWXVUIWOUIDPGS-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- KIYRSYYOVDHSPG-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetamide Chemical compound NC(=O)[C@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-SSDOTTSWSA-N 0.000 description 1
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 description 1
- 229960004041 cefetamet Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229940047526 cephalexin monohydrate Drugs 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- YGZIWEZFFBPCLN-UHFFFAOYSA-N n,3-bis(2-chloroethyl)-4-hydroperoxy-2-oxo-1,3,2$l^{5}-oxazaphosphinan-2-amine Chemical compound OOC1CCOP(=O)(NCCCl)N1CCCl YGZIWEZFFBPCLN-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- COFDRZLHVALCDU-LICLKQGHSA-N s-(1,3-benzothiazol-2-yl) (2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoethanethioate Chemical compound N=1C2=CC=CC=C2SC=1SC(=O)/C(=N/OC)C1=CSC(N)=N1 COFDRZLHVALCDU-LICLKQGHSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000011091 sodium acetates Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a preparing method of 7-((thiazolyl hydroxyl imino group) acetamido)-3-methyl cephalosporanic acid and another purpose. The preparing method and another purpose are suitable for cephalosporin chemical medicine production enterprises. The preparing method is suitable for crude products and refined products of compound (II) and suitable for preparing compound (III) through the compound (II). The preparing method can test the antimicrobial activity of the compound (II) and the compound (III). The beta-lactamase hydrolysis tolerance of the compound (II) and the compound (III) and the beta-lactamase stability are structurally analyzed. The compound (II) and the compound (III) have antimicrobial activity.
Description
Technical field
The present invention relates to the synthetic field of chemical pharmacy, be particularly suitable for cephalosporin chemicals manufacturing enterprise.
Background technology
7-aminodesacetoxycephalosporanic acid, be called for short 7-ADCA, is one of semisynthetic important intermediate of cynnematin, by penicillin ring enlargement, formed.Structural formula is:
The C of 7-ADCA
7the amino group of position can react the various cephalosporin medicament of generation from various different side chains, and these medicines are all large usage quantity on market, more ripe microbiotic.
general structure is:
（Ⅰ）
As:
7-ADCA reacts the Cefetamet acid generated, R=(2-amino-4-thiazolyl herein with 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester)-the 2-(methoxyimino)-kharophen.C
2be oral antibiotic after the carboxyl resterification of position.
7-ADCA reacts the Cephradine generated, R=2-amino-2-(1.4-cyclohexenyl herein with methyl dihydrogen benzene glycinate) kharophen.For oral and injection microbiotic.
7-ADCA reacts the Cephalexin Monohydrate Micro/Compacted generated, R=2-amino-2-phenylacetylamino herein with the D-phenylglycinamide.For oral antibiotic.
7-ADCA reacts the S 578 generated, R=2-amino-2-(4-hydroxy phenyl herein with the glycin mixed anhydride) kharophen.For oral antibiotic.
These are all cynnematin medicines commonly used in current medical market.C by 7-ADCA
7the bit amino group can react and generate various cephalosporin medicament from various different side chains, and this advanced research is also constantly carrying out.
Summary of the invention
Purpose of the present invention provides 7-[(thiazolyl oxyimino) kharophen]-preparation method and another purposes of 3-methyl Cephalosporanic acid.
Technical solution of the present invention is:
One, the preparation of compound (II):
The chemistry of compound (II) is by name: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(acetyl methoxyimino) kharophen]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.Referred to as 7-[(thiazolyl oxyimino) kharophen]-3-methyl Cephalosporanic acid.
The structural formula of compound (II):
1, reacting of 7-ADCA and side chain thioesters, the chemistry of side chain thioesters is by name: (Z)-2-(2-aminothiazole-4-yl)-2-acetyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters.
1), the preparation of compound (II) crude product
Under the existence of solvent and alkali; 7-ADCA and side chain thioesters carry out condensation reaction at a certain temperature; react complete; carry out extracting and demixing impurity elimination, activated carbon decolorizing; generate intermediate: (6R; 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(acetyl methoxyimino) kharophen]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; then use the basic hydrolysis Deprotection; activated carbon decolorizing, re-use the acid out crystalline substance and obtain compound (II) crude product.Filtration, washing, drying.
In preparation method provided by the invention, in described reactions steps, described reaction solvent, extraction solvent and refining in solvent be selected from tetrahydrofuran (THF), DMF (N, dinethylformamide), any or multiple in DMA (N,N-dimethylacetamide), acetone, methylene dichloride, trichloromethane, water, benzene, toluene, ethanol, methyl alcohol, ethyl acetate, acetonitrile.
In the preferred embodiment of the invention: the mixing solutions of the preferred tetrahydrofuran (THF) of solvent for use and DMF, consumption is that to make the weight ratio of 7-ADCA and mixing solutions be 1:6～1:20, preferably 1:10.Weight ratio between tetrahydrofuran (THF) and DMF is preferably 6.1:1.
In the preferred embodiment of the invention, the preferred methylene dichloride of extraction solvent used.
Described alkali is organic bases, is sodium-acetate, triethylamine, tripropyl amine, Tributylamine or Sodium isooctanoate, and preferred triethylamine.The weight ratio of 7-ADCA and alkali is 1:0.47～1:0.7.
Weight ratio between described 7-ADCA and active side chain thioesters is 1:1.77～1:4; Temperature of reaction is controlled at 10～37 ℃, preferably 20 ℃.
In described hydrolysis reaction step, agents useful for same is ammonium chloride and salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, triethylamine, and preferably ammonium chloride and salt of wormwood.The weight ratio of 7-ADCA and ammonium chloride is 1:0.5～1:3.Add alkali number and be as the criterion with PH, control PH=7.5～9.5.Hydrolysis temperature is controlled at-10～20 ℃, preferably 5～15 ℃.
Described recrystallization temperature is controlled at 0～37 ℃, preferably 18 ℃
2), compound (II) is refining
Process for purification (1)
Crude product, under the existence of solvent, is used alkali to make at a certain temperature its dissolving, after adding remove impurity with active carbon, decolouring, uses the acid out crystalline substance to obtain compound (II) finished product, filters washing, drying.
In the present invention preferably in refining embodiment: the mixing solutions of solvent for use preferably water, acetone and methyl alcohol, consumption is that to make the weight ratio of crude product and mixing solutions be 1:12～1:110, is preferably 1:41.Weight ratio between water, acetone and methyl alcohol is preferably 35:5:1.
Process for purification (2)
Crude product is under solvent and sour existence, and reaction at a certain temperature generates mixture, filters, and solid, with after alkali dissolution, obtains compound (II) finished product with the acid out crystalline substance, filters, and washs drying.
In process for purification provided by the invention, preferably use acetonitrile, consumption is that to make the weight ratio of crude product and solvent be 1:5～1:40, preferred weight ratio is 1:8.
The acid of using in the reaction of described generation mixture is phosphoric acid, the vitriol oil, preferably 85% phosphoric acid.Crude product and sour weight ratio are 1:0.9～1:9, preferably 1:3.4.
Temperature of reaction is controlled at 15～45 ℃, preferably 20 ℃.Reaction times is controlled at 0.5～6 hour, preferably 3 hours.
Two, the preparation of compound (III):
Described compound (III), chemistry (6R by name, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(oxyimino) kharophen]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate salt, this carboxylate salt can be sodium salt, sylvite and ammonium salt.
Be about to compound (II) and be dissolved in the mixed solution of solvent and alkali, after adding the charcoal filtration, filtrate is added dropwise in acetone to crystallization, filtration, washing, drying under 20～35 ℃.
Described solvent is one or more of water, methyl alcohol, ethanol, ethyl acetate.
Described alkali is sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, salt of wormwood, sodium acetate, potassium acetate, bicarbonate of ammonia.
Antibiotic drug sensitive experiment (agar diffusion method):
From antibiotic susceptibility lab diagram, learn: though anti-microbial activity, not as the Cefdinir of the wide spectrum of the third generation, is better than or equals the Cephradine of the first-generation.
Advantage of the present invention is:
From structure, analyze, compound (II) and compound (III), the structure due to the methoxy subunit (oxime type) that cis-configuration is arranged on 7-β position, can hinder the β-lactamase molecule to approach beta-lactam nucleus, thereby can tolerate the β-lactamase hydrolysis.Add on side chain and there is the cefotaxime base, can be stable to β-lactamase.Under the overall situation that resistance is day by day serious now, develop some new compounds with anti-microbial activity has its necessity more.
The accompanying drawing explanation
Fig. 1: the proton nmr spectra of the compounds of this invention (II);
Fig. 2: the mass spectrum of the compounds of this invention (II);
Fig. 3: the infrared spectra of the compounds of this invention (II).
Specific embodiment
One, prepare compound (II)
1, the preparation of compound (II) crude product
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 8.5～8.9, react and become clear to solution in 1 hour, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 83%, purity 91%.
Embodiment 2
Add 20 gram 7-ADCA, 35 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 110 milliliters of tetrahydrofuran (THF)s, 18 milliliters of DMF, under 0～5 ℃, add the triethylamine of 13 milliliters in 30 minutes, add, approximately within 6 hours, to 7-ADCA is residual, be less than 0.5% 37 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 10 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 8.5～8.9, react and become clear to solution in 1 hour, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 70%, purity 85%.
Embodiment 3
Add 20 gram 7-ADCA in reaction flask, 80 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters, 342 milliliters of tetrahydrofuran (THF)s, 56 milliliters of DMF, under 0～5 ℃, add the triethylamine of 19 milliliters in 30 minutes, add, approximately within 15 hours, to 7-ADCA is residual, be less than 0.5% 10 ℃ of reactions, add 600 milliliters of 300 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 100 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 60 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 8.5～8.9, react and become clear to solution in 1 hour, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 87%, purity 88%.
Embodiment 4
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 230 milliliters of acetone and 70 ml methanol, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 12 hours, to 7-ADCA is residual, be less than 0.5% 17 ℃ of reactions, add 200 milliliters, water and 450 milliliters of ethyl acetate, stir 30 minutes, pour the separating funnel layering into, with 50 milliliters of ethyl acetate washing water layers, remove organic phase after layering.Add gac 5 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 8.5～8.9, react and become clear to solution in 1 hour, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 85%, purity 90%.
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 8.0～8.0, react and become clear to solution in 4 hours, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 70%, purity 87%.
Embodiment 6
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 5% salt of wormwood control PH between 9.0～9.5, react and become clear to solution in 0.5 hour, add gac 5 grams, stir 50 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 75%, purity 85%.
Embodiment 7
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 5% sodium carbonate control PH between 8.5～8.9, react and become clear to solution in 1 hour, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain micro-yellow solid.Yield is 83%, purity 90%.
Embodiment 8
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 10% sodium bicarbonate control PH between 8.5～8.9, react and become clear to solution in 3 hours, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain micro-yellow solid.Yield is 80%, purity 89%.
Embodiment 9
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 20% saleratus control PH between 8.5～8.9, react and become clear to solution in 2.5 hours, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain micro-yellow solid.Yield is 81%, purity 88%.
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 5～15 ℃, use 1% sodium hydroxide control PH between 8.5～8.9, react and become clear to solution in 50 minutes, add gac 5 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain pale yellow solid.Yield is 80%, purity 89%.
Embodiment 11
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 30 milliliters of ethyl acetate in filtrate, add 22 gram ammonium chlorides, at 5～15 ℃, use triethylamine control PH between 8.5～8.9, react and become clear to solution in 2 hours, add gac 5 grams, stir 30 minutes, the filter charcoal after, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ stirrings 2 hours, filter, washing, vacuum-drying, obtain pale yellow solid.Yield is 80%, purity 87%.
Embodiment 12
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at 20 ℃, use 5% salt of wormwood control PH between 7.5～8.0, react and become clear to solution in 45 minutes, add gac 4 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 80%, purity 87%.
Embodiment 13
Add 20 gram 7-ADCA, 40 grams (Z)-2-(thiazolamine-4 base)-2 acetyl methoxyimino thioacetic acids-2-[4-morpholinodithio thioesters in reaction flask, 190 milliliters of tetrahydrofuran (THF)s, 30 milliliters of DMF, under 0～5 ℃, add the triethylamine of 15 milliliters in 30 minutes, add, approximately within 10 hours, to 7-ADCA is residual, be less than 0.5% 20 ℃ of reactions, add 400 milliliters of 150 milliliters, water and methylene dichloride, stir 30 minutes, pour the separating funnel layering into, 80 milliliters of organic layer waters are washed, combining water layer, with 50 milliliters of washed with dichloromethane water layers, remove organic phase after layering.Add gac 4 gram decolourings in water, after the filter charcoal, add 22 gram ammonium chlorides, at-10 ℃, use 5% salt of wormwood control PH between 9.0～9.5, react and become clear to solution in 3.5 hours, add gac 5 grams, stir 30 minutes, after the filter charcoal, in room temperature with 4% hydrochloric acid crystallization to PH=3.0, be cooled to 5 ℃ and stir 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 70%, purity 86%.
2, compound (II) is refining
Get 10 gram crude products, add 350 ml waters, 50 milliliters of acetone, 10 ml methanol, 5 ℃, control PH<7.5, by dissolution of solid, add gac 2 grams with ammoniacal liquor, stir 30 minutes, the filter charcoal, use 2N hydrochloric acid crystallization to PH=3.0 in room temperature, is cooled to 5 ℃ and stirs 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 80～85%, purity 96～97%.
Refining embodiment 2
Get 10 gram crude products, add 105 ml waters, 19 milliliters of acetone, 4 ml methanol, 5 ℃, control PH<7.5, by dissolution of solid, add gac 2 grams with ammoniacal liquor, stir 30 minutes, the filter charcoal, use 2N hydrochloric acid crystallization to PH=3.0 in room temperature, is cooled to 5 ℃ and stirs 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 90%, purity 93%.
Refining embodiment 3
Get 10 gram crude products, add 880 ml waters, 156 milliliters of acetone, 32 ml methanol, 5 ℃, control PH<7.5, by dissolution of solid, add gac 2 grams with ammoniacal liquor, stir 30 minutes, the filter charcoal, use 2N hydrochloric acid crystallization to PH=3.0 in room temperature, is cooled to 5 ℃ and stirs 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 75%, purity 97%.
Refining embodiment 4
Get 10 gram crude products, add water 400 ml waters, 60 milliliters of ethyl acetate, 10 ml methanol, 5 ℃, control PH<7.5, by dissolution of solid, add gac 2 grams with ammoniacal liquor, stir 30 minutes, the filter charcoal, use 2N hydrochloric acid crystallization to PH=3.0 in room temperature, is cooled to 5 ℃ and stirs 2 hours, filter, washing, vacuum-drying, obtain white solid.Yield is 80～85%, purity 96～97%.
Get 10 gram crude products, add 100 milliliters of acetonitriles, 20 milliliters of vitriol oils, 20 ℃ of reactions 3 hours, filter, and drains.Solid is joined, and in 400 ml waters, under 5 ℃, control PH<7.5, by after dissolution of solid, add carbon decoloring with ammoniacal liquor, to PH=3.0, filters washing, drying with 2N hydrochloric acid crystallization.Yield is 60～70%, purity 98～99%.
Refining embodiment 6
Get 10 gram crude products, add 100 milliliters of acetonitriles, 20 milliliter of 85% phosphoric acid, filter 20 ℃ of reactions in 1 hour, drains.Solid is joined in 300 ml waters, and under 5 ℃, control PH<7.5, by after dissolution of solid, add carbon decoloring with ammoniacal liquor, to PH=3.0, filters washing, drying with 2N hydrochloric acid crystallization.Yield is 60～70%, purity 98～99%.
Refining embodiment 7
Get 10 gram crude products, add 60 milliliters of acetonitriles, 5 milliliter of 85% phosphoric acid, filter 45 ℃ of reactions in 0.5 hour, drains.Solid is joined in 300 ml waters, and under 5 ℃, control PH<7.5, by after dissolution of solid, add carbon decoloring with ammoniacal liquor, to PH=3.0, filters washing, drying with 2N hydrochloric acid crystallization.Yield is 65%, purity 92%.
Refining embodiment 8
Get 10 gram crude products, add 500 milliliters of acetonitriles, 50 milliliter of 85% phosphoric acid, filter 15 ℃ of reactions in 6 hours, drains.Solid is joined in 300 ml waters, and under 5 ℃, control PH<7.5, by after dissolution of solid, add carbon decoloring with ammoniacal liquor, to PH=3.0, filters washing, drying with 2N hydrochloric acid crystallization.Yield is 58%, purity 99.6%.
Fusing point: 184～188 ℃ (decomposition)
Proton nmr spectra:
1h NMR (400MHz, DMSO) δ 9.31 (s, 1H), 7.11 (s, 2H), 6.65 (s, 1H), 5.58 (d, J=4.5Hz, 1H), 4.96 (d, J=4.6Hz, 1H), 3.40 (d, J=18.1Hz, 1H), 3.11 (t, J=13.4Hz, 1H), 1.90 (s, 3H) .(is referring to Fig. 1).
Mass spectrum: molecular formula: C
13h
13n
5o
5s
2.C,40.72；H,3.42；N,18.27；
O, 20.87; S, 16.73(is referring to Fig. 2).
Infrared: IR cm
-1:3265,3172,3062,2955,2851,2763,1763,1648,1534～1513,1398,1285(is referring to Fig. 3).
Two, the preparation of compound (III) salt:
1.7 gram sodium carbonate are dissolved in 350 ml waters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 4.5 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sodium salt.Yield is 86%, and purity is 99.4%.Fusing point: 191～195 ℃ (decomposition).
Embodiment 2
1.7 gram sodium carbonate are dissolved in 300 ml waters and 50 ml methanol, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 4 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sodium salt.Yield is 87%, and purity is 99.4%.
Embodiment 3
1.3 gram dissolution of sodium hydroxide, in 300 ml waters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 4 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sodium salt.Yield is 87%, and purity is 99.3%.
Embodiment 4
2.9 gram sodium bicarbonates are dissolved in 370 ml waters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 5 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sodium salt.Yield is 85%, and purity is 99.2%.
2.9 gram sodium acetates are dissolved in 500 ml waters and 200 milliliter of 95% ethanol, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 7 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sodium salt.Yield is 70%, and purity is 99.0%.
Embodiment 6
2.2 gram salt of wormwood are dissolved in 560 ml waters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 7 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sylvite.Yield is 83%, and purity is 99.5%.Fusing point: 187～190 ℃ (decomposition).
Embodiment 7
3.4 gram potassium acetates are dissolved in 550 ml waters, 230 milliliter of 95% ethanol, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 7 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) sylvite.Yield is 72%, and purity is 99.1%.Embodiment 8
2.7 gram bicarbonate of ammonia are dissolved in 590 ml waters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, to digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 8 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) ammonium salt.Yield is 80%, and purity is 99.6%.Fusing point is 180～183 ℃ (decomposition)
Embodiment 9
2.7 gram bicarbonate of ammonia are dissolved in the methyl alcohol of 490 ml waters and 100 milliliters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 7 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) ammonium salt.Yield is 83%, and purity is 99.6%.
2.7 gram bicarbonate of ammonia are dissolved in the ethyl acetate of 500 ml waters and 30 milliliters, are chilled to 5 ℃, stir and approximately in 30 minutes, by 10, digest compound (II) finished product and slowly add down, until all molten clear after, add gac 2 grams under equality of temperature, stir 30 minutes, filter, standby.In another reaction flask, add 7 liters of acetone, under 20～35 ℃, aforesaid liquid is slowly splashed in acetone, just there is crystal to separate out, growing the grain is 30 minutes, approximately remaining liquid is all being splashed in acetone in 2 hours.Drip off, be cooled to 0～5 ℃, stir 2 hours, filter, use acetone rinsing, drying.Obtain whitening compound (III) ammonium salt.Yield is 84%, and purity is 99.5%.
Claims (5)
1.7-[(the thiazolyl oxyimino) kharophen]-preparation method of 3-methyl Cephalosporanic acid, it is characterized in that: under solvent and alkali existence, 7-ADCA and active side chain thioesters (Z)-2-(thiazolamine-4-yl)-2-acetyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters carries out condensation reaction at 0 ℃～5 ℃, described 7-ADCA and mixing solutions weight ratio are 1:6～1:20, weight ratio between described 7-ADCA and active side chain thioesters is 1:1.77～1:4, the weight ratio of described 7-ADCA and alkali is 1:0.47～1:0.7, temperature of reaction is controlled at 10～37 ℃, weight ratio between tetrahydrofuran (THF) and DMF is 6.1:1, react complete, carry out the extracting and demixing impurity elimination, activated carbon decolorizing, generate intermediate: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(acetyl methoxyimino) kharophen]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, then add alkali and ammonium chloride hydrolysis Deprotection, the weight ratio of 7-ADCA and ammonium chloride is 1:0.5～1:3, control PH=7.5～9.5, hydrolysis temperature is controlled at-10～20 ℃.After activated carbon decolorizing, room temperature is used the acid out crystalline substance to obtain compound (II) crude product, filtration, washing, drying, then by making with extra care to obtain compound (II) finished product.
2. 7-[(thiazolyl oxyimino according to claim 1) kharophen]-preparation method of 3-methyl Cephalosporanic acid, the weight that it is characterized in that 7-ADCA and mixing solutions is 1:10.
3. 7-[(thiazolyl oxyimino according to claim 1) kharophen]-preparation method of 3-methyl Cephalosporanic acid, it is characterized in that temperature of reaction is controlled at 20 ℃, hydrolysis temperature is controlled at 5～15 ℃.Hydrolyzed PH value is controlled at 8.5～8.9.
4. 7-[(thiazolyl oxyimino according to claim 1) kharophen]-preparation method of 3-methyl Cephalosporanic acid, it is characterized in that process for purification is as follows:
1. process for purification (1)
Crude product, under the existence of solvent, is used alkali to make at a certain temperature its dissolving, after adding remove impurity with active carbon, decolouring, uses the acid out crystalline substance to obtain compound (II) finished product, filters washing, drying;
2. or process for purification (2)
Crude product is under solvent and sour existence, and reaction at a certain temperature generates mixture, filters, and solid, with after alkali dissolution, obtains compound (II) finished product with the acid out crystalline substance, filters, and washs drying.
5.7-[(the thiazolyl oxyimino) kharophen]-another purposes of 3-methyl Cephalosporanic acid, another purposes that it is characterized in that compound (II) is compound (III), compound (III) chemistry (6R by name, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(oxyimino) kharophen]-8-oxo-3-methyl-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate salt, this carboxylate salt can be sodium salt, sylvite and ammonium salt.
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| CN103980293A (en) * | 2014-05-21 | 2014-08-13 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Method for preparing 3-ethenyl-7-(thiazolemethoxyimino)cephalosporanic acid |
| CN105753885A (en) * | 2016-03-22 | 2016-07-13 | 江西富祥药业股份有限公司 | Aspoxicillin synthesis process |
| CN110343120A (en) * | 2019-08-15 | 2019-10-18 | 浙江普洛得邦制药有限公司 | A kind of preparation method of 3- methyl Cefdinir |
| CN110372726A (en) * | 2019-06-14 | 2019-10-25 | 广州艾奇西医药科技有限公司 | The preparation method of cephalo hydroxyl oxime sodium crystal |
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| CN103833772A (en) * | 2014-02-28 | 2014-06-04 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Method for synthesizing cephalosporin |
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| CN105753885A (en) * | 2016-03-22 | 2016-07-13 | 江西富祥药业股份有限公司 | Aspoxicillin synthesis process |
| CN110372726A (en) * | 2019-06-14 | 2019-10-25 | 广州艾奇西医药科技有限公司 | The preparation method of cephalo hydroxyl oxime sodium crystal |
| CN110343120A (en) * | 2019-08-15 | 2019-10-18 | 浙江普洛得邦制药有限公司 | A kind of preparation method of 3- methyl Cefdinir |
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