CN112661723A - Method for producing cefdinir active ester - Google Patents
Method for producing cefdinir active ester Download PDFInfo
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- CN112661723A CN112661723A CN202011577666.5A CN202011577666A CN112661723A CN 112661723 A CN112661723 A CN 112661723A CN 202011577666 A CN202011577666 A CN 202011577666A CN 112661723 A CN112661723 A CN 112661723A
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- active ester
- cefdinir active
- ethyl
- phosphite
- cefdinir
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- 150000002148 esters Chemical class 0.000 title claims abstract description 51
- 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 title claims abstract description 49
- 229960003719 cefdinir Drugs 0.000 title claims abstract description 49
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000001816 cooling Methods 0.000 claims abstract description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 22
- 150000001412 amines Chemical class 0.000 claims abstract description 17
- 239000012043 crude product Substances 0.000 claims abstract description 13
- 239000012442 inert solvent Substances 0.000 claims abstract description 12
- 150000008301 phosphite esters Chemical class 0.000 claims abstract description 12
- 150000007530 organic bases Chemical class 0.000 claims abstract description 11
- 239000012266 salt solution Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- -1 alkali metal salt Chemical class 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 8
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical group CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 4
- JUXXCHAGQCBNTI-UHFFFAOYSA-N 1-n,1-n,2-n,2-n-tetramethylpropane-1,2-diamine Chemical compound CN(C)C(C)CN(C)C JUXXCHAGQCBNTI-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 238000005886 esterification reaction Methods 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 8
- 230000032050 esterification Effects 0.000 abstract description 7
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000002351 wastewater Substances 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000008346 aqueous phase Substances 0.000 abstract description 3
- 239000013078 crystal Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000010828 elution Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 6
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GQLGFBRMCCVQLU-SVGQVSJJSA-N (6r,7r)-7-azaniumyl-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C=C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@H]21 GQLGFBRMCCVQLU-SVGQVSJJSA-N 0.000 description 1
- BPINJMQATUWTID-UHFFFAOYSA-N 3,3-dimethylpentane-2,2-diamine Chemical compound CCC(C)(C)C(C)(N)N BPINJMQATUWTID-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
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- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a method for producing cefdinir active ester, belonging to the technical field of medicine synthesis. The method comprises the steps of taking ethyl demethylaminothiazolime as a raw material, dissolving ethyl demethylaminothiazolime by using organic base and inert solvent, reacting, cooling, adding acetic anhydride, and continuing to react to obtain an acetylated organic amine salt solution of the ethyl demethylaminothiazolime; then, phosphite ester is added dropwise, and DM is added by controlling the charging time to obtain a crude product; and dissolving the crude product, and crystallizing to obtain the cefdinir active ester. The invention avoids the processes of forming acid in aqueous phase and removing crystal water in the traditional process, and does not produce waste salt and waste water; the organic alkali is used as a hydrolytic agent and an esterification catalyst, so that the dosage of the ester catalyst is reduced, and the cefdinir active ester with the purity of more than 99.40 percent can be obtained by a DMF/R-OH elution method.
Description
Technical Field
The invention relates to a method for producing cefdinir active ester, belonging to the technical field of medicine synthesis.
Background
Cefdinir active ester, the chemical name is: s-2-benzothiazolyl- (Z) -2- (2-aminothiazole-4-yl) -2-acetoxyiminothioacetate, CAEM for short, and its molecular formula14H10O3N4S3The molecular weight is 378, the CAS is 104797-47-9, and the molecular structure is as follows:
cefdinir is one of important third-generation semisynthetic cephalosporin antibiotics, has the characteristics of strong bactericidal power, wide antibacterial spectrum and difficult generation of drug resistance, is widely applied clinically, and is one of the latest oral cephalosporin medicaments in the market at present. At present, 7-AVCA is generally synthesized by an active ester method, and the active ester is mostly prepared by using a cephalosporin side chain modified by mercaptobenzothiazole.
Chinese patent CN105130925A discloses a method for preparing cefdinir active ester, which uses ethyl desmethylaminothiazolate as raw material, and comprises hydrolysis treatment with inorganic alkali solution, acylation with acetic anhydride, acetone reflux dehydration, and condensation reaction with dibenzothiazyl disulfide to obtain cefdinir active ester, wherein the HPLC content is higher than 98.5%, but the yield is lower, the hydrolysis and acylation steps all need water as solvent, which can result in more residues of hydrolysis and acylation products in solvent water, and affect the final yield, the wastewater amount is large, and dehydration also needs a large amount of acetone for high-temperature reflux dehydration, which is not favorable for environmental protection and continuous production, and is not favorable for subsequent esterification reaction when the dehydration effect is not good.
Patent US4888429 discloses a method for preparing cefdinir active ester, which comprises using ethyl noraminothiazolime as raw material, forming salt of ethyl methotrexate in toluene solvent under the protection of triphenylchloromethane, acylating in tetrahydrofuran, and reacting with DM in acetonitrile solvent under the action of triethyl phosphite to obtain cefdinir active ester.
At present, the most common method for mass production of cefdinir active ester is aqueous phase solvent, and the cefdinir active ester is prepared by hydrolysis, acylation, acid regulation, dehydration and condensation processes, and has the defects of difficult control of pH value, difficult removal of crystal water, unstable product quality, low purity, large amount of waste water generation, environmental protection and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a method for producing cefdinir active ester, which uses organic alkali as a hydrolytic agent and an esterification catalyst simultaneously, avoids the conditions of low purity and unqualified quality in the traditional process, has high product purity and less waste water and salt, can recycle reaction solvent, and is green and environment-friendly.
The method for producing cefdinir active ester comprises the following steps:
(1) dissolving ethyl demethylaminothiazolime acid serving as a raw material by using a mixed solvent consisting of organic base and an inert solvent, reacting, cooling, adding acetic anhydride, and continuing to react to obtain an acetylated organic amine salt solution of the demethylthiazolime acid;
(2) dripping phosphite ester, controlling the charging time, adding DM, cooling, and performing suction filtration to obtain a cefdinir active ester crude product;
(3) and dissolving the crude cefdinir active ester product by using DMF, dropwise adding R-OH for crystallization, performing suction filtration, and drying to obtain the cefdinir active ester.
Wherein:
the organic base is a mixed solution of organic amine and alkali metal salt.
The organic amine is trimethylamine, triethylamine, tetramethylethylenediamine, tetramethylpropylenediamine, tetrabutylammonium chloride, propylamine or tripropylamine.
The alkali metal salt is sodium methoxide, potassium ethoxide, sodium ethoxide or potassium tert-butoxide.
The molar ratio of the organic amine to the alkali metal salt is 1-1.5: 1.
The inert solvent is one or more of dichloromethane, acetonitrile, benzene or carbon tetrachloride; the mass ratio of the inert solvent to the organic base is 5-20: 1.
The molar ratio of acetic anhydride to ethyl noraminothiazolime is 1.5-1.8: 1; the molar ratio of the alkali metal salt to the ethyl noraminothiazolime carboxylate is 1-1.2: 1.
The phosphite ester is triethyl phosphite, trimethyl phosphite, tributyl phosphite or triphenyl phosphite.
The molar ratio of the phosphite ester to dibenzothiazyl Disulfide (DM) is 0.9-1.1: 1; the molar ratio of DM to ethyl noraminothiazolime is 1-1.3: 1. The molar ratio of the phosphite ester to the DM is generally 1.25-1.3: 1, and the organic alkali can be used as a hydrolyzing agent and an esterification catalyst at the same time, so that the use amount of the phosphite ester in the esterification catalyst is reduced more compared with the prior art.
The inert solvent R-OH is methanol, ethanol, isopropanol or tert-butanol; the volume ratio of R-OH to DMF is 1.5-2.0: 1.
The method for producing cefdinir active ester provided by the invention more specifically comprises the following steps:
(1) dissolving ethyl noraminothiazolime as a raw material by using a mixed solvent consisting of organic base and an inert solvent, reacting for 1-4 h, cooling to 0-25 ℃, adding acetic anhydride, controlling the pH value of the system to be 5-10, controlling the temperature to be 38-42 ℃, and reacting for 1-3 h to obtain an acetylated organic amine salt solution of the noraminothiazolime;
(2) cooling to 5-15 ℃, dropwise adding phosphite ester, adding DM within 0.5-2 h, preserving heat, cooling, and performing suction filtration to obtain a cefdinir active ester crude product;
(3) and dissolving the crude cefdinir active ester product by using DMF, dropwise adding R-OH for crystallization, performing suction filtration, and drying to obtain the cefdinir active ester.
The method comprises the steps of taking ethyl demethylaminothiazolime as a raw material, dissolving ethyl demethylaminothiazolime by using organic base and inert solvent, reacting, cooling, adding acetic anhydride, and continuing to react to obtain an acetylated organic amine salt solution of the ethyl demethylaminothiazolime; then, phosphite ester is added dropwise, and DM is added by controlling the charging time to obtain a crude product; and dissolving the crude product, and crystallizing to obtain the cefdinir active ester.
Compared with the prior art, the invention has the advantages that:
(1) the invention avoids the conditions of low purity and unqualified quality caused by abnormal esterification reaction in the traditional process;
(2) the invention avoids the processes of forming acid in aqueous phase and removing crystal water in the traditional process, and does not produce waste salt and waste water;
(3) the used organic alkali can be simultaneously used as a hydrolytic agent and an esterification catalyst, so that the use of inorganic alkali is avoided, and waste salt and wastewater is not generated; the organic base is used as a hydrolytic agent and an esterification catalyst, so that the consumption of the esterification catalyst is reduced;
(4) the method has the advantages of few process steps, high product purity, recyclable reaction solvent, environmental protection;
(5) the cefdinir active ester with the purity of more than 99.40 percent can be obtained by adopting a DMF/R-OH elution method.
Drawings
FIG. 1 is a chromatogram of the product of example 1.
FIG. 2 is a chromatogram of the product of example 2.
FIG. 3 is a chromatogram of the product of example 3.
FIG. 4 is a chromatogram of the product of example 4.
FIG. 5 is a chromatogram of the product of example 5.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
At normal temperature, adding 20.16g of potassium tert-butoxide, 12.6g of tetramethylpropanediamine and 400ml of acetonitrile into a three-neck flask, stirring for 30min, adding 50g of ethyl noraminothiazolime, stirring for 4h, cooling to 25 ℃, dropwise adding 29.4g of acetic anhydride, adjusting the pH value to about 6.1, and reacting at 40 ℃ for 1h to obtain an acetylated organic amine salt solution of the noraminothiazolime;
cooling to 15 ℃, dropwise adding 23.0g of triethyl phosphite, adding 56.5g of DM within 30min, keeping the temperature for 1h, cooling to below 0 ℃, and performing suction filtration to obtain a crude product of cefdinir active ester;
dissolving the filter cake with 200ml DMF, dripping 360ml methanol for 1h, filtering, and vacuum drying at 40 ℃ for 4h to obtain 65.5g of cefdinir active ester, wherein the molar yield is 74.02%, and the purity is 99.45%. The HPLC data are shown in Table 1, and the spectra are shown in FIG. 1.
Table 1 table of HPLC data for example 1
Example 2
Adding 24.80g of potassium tert-butoxide, 18g of triethylamine and 400ml of acetonitrile into a three-neck flask at normal temperature, stirring for 30min, adding 50g of ethyl noraminothiazolximate, stirring for 4h, cooling to 25 ℃, dropwise adding 29.8g of acetic anhydride, adjusting the pH value to be about 8.4, and reacting at 40 ℃ for 1h to obtain an acetylated organic amine salt solution of the noraminothiazolximate;
cooling to 15 ℃, dropwise adding 28.2g of triethyl phosphite, adding 56.8g of DM within 60min, keeping the temperature for 1h, cooling to below 0 ℃, and performing suction filtration to obtain a crude product of cefdinir active ester;
and dissolving the filter cake with 300ml of DMF, dropwise adding 500ml of methanol for 1h, carrying out suction filtration, and drying for 4h in vacuum at 40 ℃ to obtain 60.1g of cefdinir active ester, wherein the molar yield is 68.33%, and the purity is 99.58%. The HPLC data are shown in Table 2, and the spectra are shown in FIG. 2.
Table 2 example 2HPLC data table
| Peak # | Retention time | Area of | Area% | Degree of separation | Tailing |
| 1 | 0.949 | 5250 | 0.049 | 0.000 | 0.000 |
| 2 | 1.264 | 3642 | 0.034 | 0.000 | 0.000 |
| 3 | 1.374 | 1898 | 0.016 | 0.000 | 0.000 |
| 4 | 1.499 | 7236 | 0.061 | 0.406 | 0.000 |
| 5 | 1.674 | 2579 | 0.037 | 0.076 | 0.000 |
| 6 | 1.905 | 4389 | 0.050 | 0.389 | 0.000 |
| 7 | 2.120 | 10667456 | 99.580 | 1.267 | 1.021 |
| 9 | 2.857 | 1928 | 0.018 | 3.898 | 1.013 |
| 10 | 3.266 | 964 | 0.009 | 2.124 | 1.579 |
| 11 | 4.168 | 3857 | 0.036 | 2.991 | 0.000 |
| 12 | 5.155 | 1821 | 0.015 | 2.510 | 0.025 |
| 13 | 6.047 | 10800 | 0.089 | 2.887 | 1.094 |
| 14 | 17.990 | 1821 | 0.015 | 29.662 | 1.067 |
Example 3
Adding 13.9g of sodium methoxide, 16g of propylamine and 400ml of acetonitrile into a three-neck flask at normal temperature, stirring for 30min, adding 50g of ethyl demethylaminothiazolime, stirring for 4h, cooling to 25 ℃, dropwise adding 30g of acetic anhydride, enabling the pH value to be about 5.2, and reacting for 1h at 40 ℃ to obtain an acetylated organic amine salt solution of demethylaminothiazolime;
cooling to 15 ℃, dropwise adding 26.8g of triethyl phosphite, adding 56.5g of DM within 90min, keeping the temperature for 1h, cooling to below 0 ℃, and performing suction filtration to obtain a crude product of cefdinir active ester;
dissolving the filter cake with 400ml DMF, dripping 600ml methanol for 1h, filtering, and vacuum drying at 40 ℃ for 4h to obtain 57.5g of cefdinir active ester, wherein the molar yield is 65.48%, and the purity is 99.59%. The HPLC data are shown in Table 3, and the spectra are shown in FIG. 3.
Table 3 example 3HPLC data table
| Peak # | Retention time | Area of | Area% | Degree of | Tailing factor | |
| 1 | 0.947 | 4453 | 0.054 | 0.000 | 0.000 | |
| 2 | 1.225 | 2062 | 0.025 | 0.000 | 0.000 | |
| 3 | 1.282 | 1319 | 0.016 | 0.000 | 0.000 | |
| 4 | 1.383 | 5244 | 0.061 | 0.474 | 0.000 | |
| 5 | 1.676 | 2627 | 0.031 | 0.983 | 0.000 | |
| 6 | 1.918 | 8821 | 0.104 | 0.921 | 0.000 | |
| 7 | 2.137 | 8061656 | 99.590 | 1.282 | 1.093 | |
| 8 | 2.691 | 971 | 0.012 | 3.549 | 1.169 | |
| 9 | 2.882 | 1456 | 0.018 | 1.216 | 1.085 | |
| 10 | 3.079 | 729 | 0.009 | 1.175 | 1.189 | |
| 11 | 3.299 | 2912 | 0.036 | 1.313 | 1.740 | |
| 12 | 4.218 | 1308 | 0.015 | 3.885 | 0.000 | |
| 13 | 6.118 | 1941 | 0.024 | 7.153 | 1.008 | |
| 14 | 18.297 | 436 | 0.005 | 31.106 | 0.978 |
Example 4
Adding 24.80g of potassium tert-butoxide, 18g of triethylamine and 400ml of acetonitrile into a three-neck flask at normal temperature, stirring for 30min, adding 50g of ethyl noraminothiazolximate, stirring for 4h, cooling to 25 ℃, dropwise adding 29.8g of acetic anhydride, adjusting the pH value to be about 8.4, and reacting at 40 ℃ for 1h to obtain an acetylated organic amine salt solution of the noraminothiazolximate;
cooling to 15 ℃, dropwise adding 25.7g of triethyl phosphite, adding 56.8g of DM within 120min, keeping the temperature for 1h, cooling to below 0 ℃, and performing suction filtration to obtain a crude product of cefdinir active ester;
and dissolving the filter cake with 300ml of DMF, dropwise adding 500ml of tert-butyl alcohol for 1h, carrying out suction filtration, and drying in vacuum at 40 ℃ for 4h to obtain 57.1g of cefdinir active ester, wherein the molar yield is 64.91% and the purity is 99.48%. The HPLC data are shown in Table 4, and the spectra are shown in FIG. 4.
Table 4 example 4HPLC data table
Example 5
Adding 13.9g of sodium methoxide, 16g of propylamine and 400ml of acetonitrile into a three-neck flask at normal temperature, stirring for 30min, adding 50g of ethyl demethylaminothiazolime, stirring for 4h, cooling to 25 ℃, dropwise adding 30g of acetic anhydride, enabling the pH value to be about 5.2, and reacting for 1h at 40 ℃ to obtain an acetylated organic amine salt solution of demethylaminothiazolime;
cooling to 15 ℃, dropwise adding 24.3g of triethyl phosphite, adding 56.5g of DM within 60min, keeping the temperature for 1h, cooling to below 0 ℃, and performing suction filtration to obtain a crude product of cefdinir active ester;
dissolving the filter cake with 400ml DMF, dripping 600ml tert-butyl alcohol for 1h, filtering, and vacuum drying at 40 ℃ for 4h to obtain 55.5g of cefdinir active ester, wherein the molar yield is 63.20% and the purity is 99.55%. The HPLC data are shown in Table 5, and the spectra are shown in FIG. 5.
Table 5 example 5HPLC data table
| Peak # | Retention time | Area of | Area% | Degree of | Tailing factor | |
| 1 | 0.941 | 4609 | 0.053 | 0.000 | 0.000 | |
| 2 | 1.27 | 2435 | 0.028 | 1.322 | 0.000 | |
| 3 | 1.374 | 1217 | 0.014 | 0.419 | 0.000 | |
| 4 | 1.503 | 3911 | 0.045 | 0.575 | 0.000 | |
| 5 | 1.67 | 2521 | 0.029 | 0.449 | 0.000 | |
| 6 | 1.909 | 5998 | 0.069 | 0.769 | 0.000 | |
| 7 | 2.128 | 8657990 | 99.550 | 1.128 | 1.084 | |
| 8 | 2.684 | 1303 | 0.015 | 3.127 | 1.133 | |
| 9 | 2.875 | 956 | 0.011 | 1.191 | 1.025 | |
| 10 | 3.070 | 1478 | 0.017 | 2.066 | 1.697 | |
| 11 | 3.289 | 2521 | 0.029 | 0.794 | 0.000 | |
| 12 | 3.978 | 5737 | 0.066 | 6.792 | 1.983 | |
| 13 | 6.104 | 6171 | 0.071 | 6.903 | 1.115 | |
| 14 | 18.299 | 261 | 0.003 | 20.754 | 0.985 |
Claims (10)
1. A method for producing cefdinir active ester, which comprises the following steps:
(1) dissolving ethyl demethylaminothiazolime acid serving as a raw material by using a mixed solvent consisting of organic base and an inert solvent, reacting, cooling, adding acetic anhydride, and continuing to react to obtain an acetylated organic amine salt solution of the demethylthiazolime acid;
(2) dripping phosphite ester, controlling the charging time, adding DM, cooling, and performing suction filtration to obtain a cefdinir active ester crude product;
(3) and dissolving the crude cefdinir active ester product by using DMF, dropwise adding R-OH for crystallization, performing suction filtration, and drying to obtain the cefdinir active ester.
2. The method for producing cefdinir active ester according to claim 1, wherein the organic base is a mixture of organic amine and alkali metal salt.
3. The method of claim 2, wherein the organic amine is trimethylamine, triethylamine, tetramethylethylenediamine, tetramethylpropylenediamine, tetrabutylammonium chloride, propylamine or tripropylamine, and the alkali metal salt is sodium methoxide, potassium ethoxide, sodium ethoxide or potassium tert-butoxide.
4. The method for producing cefdinir active ester according to claim 2, wherein the molar ratio of the organic amine to the alkali metal salt is 1-1.5: 1.
5. The process for producing cefdinir active ester according to claim 1, wherein the inert solvent is one or more of dichloromethane, acetonitrile, benzene or carbon tetrachloride; the mass ratio of the inert solvent to the organic base is 5-20: 1.
6. The method for producing cefdinir active ester according to claim 1, wherein the molar ratio of acetic anhydride to ethyl noraminothiazolime is 1.5-1.8: 1; the molar ratio of the alkali metal salt to the ethyl noraminothiazolime carboxylate is 1-1.2: 1.
7. The method of claim 1, wherein the phosphite ester is triethyl phosphite, trimethyl phosphite, tributyl phosphite, or triphenyl phosphite.
8. The method for producing cefdinir active ester according to claim 1, wherein the molar ratio of phosphite ester to DM is 0.9-1.1: 1; the molar ratio of DM to ethyl noraminothiazolime is 1-1.3: 1.
9. The process for producing cefdinir active ester according to claim 1, wherein the inert solvent R-OH is methanol, ethanol, isopropanol or tert-butanol; the volume ratio of R-OH to DMF is 1.5-2.0: 1.
10. The process for producing cefdinir active ester according to any one of claims 1 to 9, comprising the steps of:
(1) dissolving ethyl noraminothiazolime as a raw material by using a mixed solvent consisting of organic base and an inert solvent, reacting for 1-4 h, cooling to 0-25 ℃, adding acetic anhydride, controlling the pH value of the system to be 5-10, controlling the temperature to be 38-42 ℃, and reacting for 1-3 h to obtain an acetylated organic amine salt solution of the noraminothiazolime;
(2) cooling to 5-15 ℃, dropwise adding phosphite ester, adding DM within 0.5-2 h, preserving heat, cooling, and performing suction filtration to obtain a cefdinir active ester crude product;
(3) and dissolving the crude cefdinir active ester product by using DMF, dropwise adding R-OH for crystallization, performing suction filtration, and drying to obtain the cefdinir active ester.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113214186A (en) * | 2021-05-18 | 2021-08-06 | 山东昌邑四方医药化工有限公司 | Refining method of cefdinir active ester |
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| CN105503853A (en) * | 2015-12-29 | 2016-04-20 | 山东金城柯瑞化学有限公司 | Synthetic method of cefdinir activated thioester |
| CN106432134A (en) * | 2016-09-13 | 2017-02-22 | 山东金城柯瑞化学有限公司 | Purifying method for cefacetrile side chain active ester |
| CN107892676A (en) * | 2017-12-21 | 2018-04-10 | 山东金城柯瑞化学有限公司 | The preparation method of Cefdinir active thioester |
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| CN105503853A (en) * | 2015-12-29 | 2016-04-20 | 山东金城柯瑞化学有限公司 | Synthetic method of cefdinir activated thioester |
| CN106432134A (en) * | 2016-09-13 | 2017-02-22 | 山东金城柯瑞化学有限公司 | Purifying method for cefacetrile side chain active ester |
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| CN113214186A (en) * | 2021-05-18 | 2021-08-06 | 山东昌邑四方医药化工有限公司 | Refining method of cefdinir active ester |
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