CN106008555A - Cefdinir synthesizing technology - Google Patents
Cefdinir synthesizing technology Download PDFInfo
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- CN106008555A CN106008555A CN201610548324.8A CN201610548324A CN106008555A CN 106008555 A CN106008555 A CN 106008555A CN 201610548324 A CN201610548324 A CN 201610548324A CN 106008555 A CN106008555 A CN 106008555A
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- Prior art keywords
- cefdinir
- acid
- synthesis technique
- stirring
- retort
- Prior art date
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- 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 64
- 229960003719 cefdinir Drugs 0.000 title claims abstract description 58
- 238000005516 engineering process Methods 0.000 title abstract description 12
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000009833 condensation Methods 0.000 claims abstract description 22
- 230000005494 condensation Effects 0.000 claims abstract description 22
- 150000002148 esters Chemical class 0.000 claims abstract description 17
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 55
- 238000003756 stirring Methods 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 239000010410 layer Substances 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 27
- 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 claims description 22
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000012065 filter cake Substances 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000007670 refining Methods 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 230000003301 hydrolyzing effect Effects 0.000 claims description 12
- 238000001514 detection method Methods 0.000 claims description 10
- 235000011056 potassium acetate Nutrition 0.000 claims description 9
- 238000005070 sampling Methods 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000003610 charcoal Substances 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000005259 measurement Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000001117 sulphuric acid Substances 0.000 claims description 7
- 235000011149 sulphuric acid Nutrition 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- -1 oxyimino group Chemical group 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- GQLGFBRMCCVQLU-UHFFFAOYSA-N 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(N)C21 GQLGFBRMCCVQLU-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 238000010306 acid treatment Methods 0.000 claims description 2
- 238000007792 addition Methods 0.000 claims description 2
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 230000008901 benefit Effects 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 229960003328 benzoyl peroxide Drugs 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- 238000011084 recovery Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000009413 insulation Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- 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)
- Cephalosporin Compounds (AREA)
Abstract
The invention provides a cefdinir synthesizing technology. The technology comprises the steps that (Z)-2-(2-aminothiazole-4-yl)-2-acetoxyl imino thioacetic acid(S-2-benzothiazole)ester and 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyalo[4.2.0]oct-2-alkene-2-carboxylic acid are subjected to condensation; acetyl protection is removed through hydrolysis, and a cefdinir finished product is finally obtained. The method for preparing the cefdinir has the advantages of being short in production cycle, high in yield, high in product quality and suitable for industrial production.
Description
Technical field
The present invention relates to field of medicaments, particularly relate to the new production process of a kind of cefdinir, it is ensured that produce low one-tenth
Originally, high-quality cefdinir crude drug.
Background technology
Cefdinir (Cefdinir) is that the third generation is administered orally cephalosporins, and chemistry is entitled: (6R, 7R)-7-[(Z)-2-
(2-amino-4-thiazolyl)-2-hydroxyl imide base acetylamino]-8-oxo-3-vinyl-5-thia-1-azabicyclo
[4.2.0] oct-2-ene-2-carboxylic acid.Its chemical constitution feature is to introduce hydroxyl Asia on 7 side chains of 7-amino-cephalosporanic acid skeleton
Amido, 3 side chains introduce vinyl.Not only maintain the antibacterial efficacy of Gram-negative coccus, but also enhance existing
During oral cephalosporins, the effect of gram-positive cocci, the particularly antibacterial efficacy to staphylococcus, can suppress
The clinical isolates of 90%～100%.Clinic is primarily adapted for use in acute episode of chronic bronchitis, bacterial pneumonia, upper breathing
The treatment of road infection, skin and soft tissue infection etc..Its chemical structural formula is as follows:
The production technology of traditional cefdinir is: with (Z)-2-(thiazolamine-4-base)-2-triphen methoxyimino
Thiacetic acid. (S-2-benzothiazole) ester (i.e. cefdinir side-chain acid active ester) and 7-amino-3-vinyl-8-oxo-5-sulfur
Miscellaneous-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e. 7-AVCA) is condensed, then sloughs protection group and obtain cefdinir
Finished product.
Its synthesis route is as follows:
Condensation operation:
Deprotection operation (i.e. hydrolyzes, refines):
(i) condensation operation:
7-AVCA, cefdinir side-chain acid active ester are put in retort, is slowly added dropwise into triethylamine with stirring；
After waiting to drip, stir and all dissolve to material, be incubated；In reactant liquor, add quantitative ethyl acetate, add activated carbon mistake
Filter；Add p-methyl benzenesulfonic acid, rejection filter.
(ii) hydrolyzing process:
Dropping formic acid, insulation reaction；After insulation reaction terminates, temperature is down to 5～6 DEG C；And prepare in 5～6 DEG C of additions
Sodium bicarbonate aqueous solution, finish, in 5～6 DEG C of insulation reaction 1 hour；Add activated carbon appropriate, filter to being layered tank, start
Layering；After feed liquid remove impurity, cross to purifying area.
(iii) refining step:
Filter is finished, and adds dilute hydrochloric acid acid and makes its crystallize, obtains cefdinir finished product.
Using traditional synthesis technique, its production cycle is long, and yield is relatively low, though through purification step, but its finished product purity
The defect such as the most relatively low.This application provides a kind of new cefdinir synthesis technique, it effectively prevent above-mentioned tradition preparation work
The defect of skill, is more suitable for industrialized production.
Summary of the invention
The purpose of the present invention, is to provide a kind of new cefdinir synthesis technique, and its route map is as follows:
Specifically include following steps:
Condensation operation: with (Z)-2-(thiazolamine-4-base)-2-acetyl oxyimino group thiacetic acid. (S-2-benzo thiophene
Azoles) ester (i.e. cefdinir side-chain acid active ester) and 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo
[4.2.0] oct-2-ene-2-carboxylic acid (i.e. 7-AVCA) is condensed；
Hydrolyzing process: through hydrolysis deacetylate protection, and generate potassium salt of cefdinir；
Refining step: potassium salt of cefdinir, through acid treatment, crystallize, obtains cefdinir finished product.
Wherein, described
Condensation operation: 7-AVCA, cefdinir side-chain acid active ester, organic solvent A are put in retort, in stirring
Under be slowly added dropwise into alkali liquor；After waiting to drip, stirring to material is all dissolved；Residual≤0.5% of sampling detection 7-AVCA
Time, in reactant liquor, adding quantitative organic solvent B, stirring layering, the organic layer separated discards, and water layer is waited to hydrolyze.
Hydrolyzing process: add wet chemical in water layer, adjust pH=7-9, with stirring clock reaction 30 minutes；
Reaction puts into potassium acetate after terminating, rejection filter of lowering the temperature, and obtains potassium salt of cefdinir.
Refining step: dissolve in potassium salt of cefdinir is put into purified water, adds acid and makes its crystallize, obtain cefdinir
Finished product.
Preferably, described
Condensation operation:
(1) in retort, 30-50Kg 7-AVCA, 70-100Kg active ester, 300-500Kg oxolane, 100-are put into
300Kg water, stirring is cooled to 0-50 DEG C
(2) dropping alkali liquor 18-36Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4KgEDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 500-700Kg stirring 5min, the 100-300Kg that adds water and stir 5min, layering.Water layer is used
331.5Kg*2 dichloromethane is washed twice, and combined dichloromethane layer 130Kg washes, and combining water layer puts into retort, adds
EDTA 0.4Kg, is cooled to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts pH=7-9
(7) clock reaction 30min
(8) add potassium acetate 50-100Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into retort, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into retort, intensification 30-60 DEG C
(13) dropping acid solution, adjusts pH to 1.5-2.5, stirs 1h, and repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product.
It is furthermore preferred that it is described
In condensation operation, organic solvent A is oxolane or ethyl acetate；Alkali liquor is triethylamine, ammonia or sodium hydroxide
Solution；Organic solvent B is dichloromethane or ethyl acetate；
In refining step, acid solution is sulphuric acid, hydrochloric acid, glacial acetic acid etc..
The application new technology, compared with traditional handicraft, has the advantage that
1, the application new technology relatively traditional handicraft simplifies operation, improves production capacity.Condensation is merged with hydrolysis, in
Between without separating condensed product, be directly produced out potassium salt of cefdinir, the quality of monitoring potassium salt of cefdinir, for the number of this product
Foundation is provided according to analysis.The potassium salt of cefdinir of output, it is not necessary to be dried and can carry out deprotection reaction, reduce production process
In energy consumption.Producing traditional handicraft cefdinir product needed and pass through condensation, deprotection operation, its production cycle is 5 days.Utilize
The production cycle of the cefdinir product that the application new technology produces shortens to 4 days.Production in the condensation of cefdinir new technology
During, also have adjusted the feed way of triethylamine, " triethylamine is slowly added to a part, and detects anti-by traditional handicraft
Answer terminal, without reaching reaction end, the most again add ", be adjusted to new technology " calculates condensation reaction triethylamine
Consumption, puts into quantitative triethylamine, timing reaction, finally detects the terminal that feeds intake ".The mode being relatively interrupted input triethylamine is saved
In the response time, it is simple to operation, it is more suitable for industrialized production.
2, reduce cost, decrease the use of raw material.Formic acid in the production of new technology cefdinir not in use by, carry
High this product safety in process of production.The building-up process of new technology cefdinir is compared with the raw material inventory of traditional handicraft
Decrease 20%.Use purified water as solvent in deprotection reaction, decrease cefdinir finished product right in Crystallization Process
The parcel of solvent, it is to avoid the risk that this product dissolvent residual in finished product detection is too high.
3, improve the quality of finished product.The content of conventionally produced cefdinir product, about 98%, utilizes new
The content of the cefdinir product that technique produces can reach more than 99%.In the subtractive process of cefdinir product, crystallization
System is purified water, it is to avoid the appearance of the problem such as solvent residual in finished product crystallizes.By increasing the usage amount of EDTA, significantly
Avoid the metal impact on material in course of reaction.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, but does not limit protection scope of the present invention.
The synthesis of embodiment 1 cefdinir
Condensation operation:
(1) in retort, 30Kg 7-AVCA is put into, 80Kg active ester, 300Kg oxolane, 200Kg water, stirring fall
Temperature is to 0-50 DEG C
(2) dropping triethylamine 24Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 700Kg stirring 5min, the 200Kg that adds water and stir 5min, layering.Water layer 331.5Kg*2 bis-
Chloromethanes is washed twice, and combined dichloromethane layer 130Kg washes, and combining water layer puts into retort, adds EDTA 0.4Kg, fall
Temperature is to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts pH=8
(7) clock reaction 30min
(8) add potassium acetate 50Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into retort, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into retort, intensification 30-60 DEG C
(13) dripping 5% sulphuric acid, adjust pH to 1.5, stir 1h, repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product, total recovery 75%.
The synthesis of embodiment 2 cefdinir
Condensation operation:
(1) in retort, 40Kg 7-AVCA is put into, 90Kg active ester, 400Kg oxolane, 100Kg water, stirring fall
Temperature is to 0-50 DEG C
(2) dropping ammonia 36Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 600Kg stirring 5min, the 200Kg that adds water and stir 5min, layering.Water layer 331.5Kg*2 bis-
Chloromethanes is washed twice, and combined dichloromethane layer 130Kg washes, and combining water layer puts into retort, adds EDTA 0.4Kg, fall
Temperature is to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts pH=7
(7) clock reaction 30min
(8) add potassium acetate 70Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into 3L four-hole bottle, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into 3L four-hole bottle, intensification 30-60 DEG C
(13) dripping 5% sulphuric acid, adjust pH to 2, stir 1h, repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product, total recovery 77%.
The synthesis of embodiment 3 cefdinir
Condensation operation:
(1) in retort, 50Kg 7-AVCA is put into, 70Kg active ester, 500Kg oxolane, 300Kg water, stirring fall
Temperature is to 0-50 DEG C
(2) dropping sodium hydroxide solution 24Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 500Kg stirring 5min, the 200Kg that adds water and stir 5min, layering.Water layer 331.5Kg*2 bis-
Chloromethanes is washed twice, and combined dichloromethane layer 130Kg washes, and combining water layer puts into retort, adds EDTA 0.4Kg, fall
Temperature is to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts PH=9
(7) clock reaction 30min
(8) add potassium acetate 100Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into 3L four-hole bottle, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into 3L four-hole bottle, intensification 30-60 DEG C
(13) dripping 5% sulphuric acid, adjust pH to 2.5, stir 1h, repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product, total recovery 78%.
The synthesis of embodiment 4 cefdinir
Condensation operation:
(1) in retort, 45Kg 7-AVCA is put into, 100Kg active ester, 450Kg oxolane, 300Kg water, stirring fall
Temperature is to 0-50 DEG C
(2) dropping triethylamine solution 30Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 600Kg stirring 5min, the 300Kg that adds water and stir 5min, layering.Water layer 331.5Kg*2 second
Acetoacetic ester is washed twice, and combined ethyl acetate layer 130Kg washes, and combining water layer puts into retort, adds EDTA 0.4Kg, fall
Temperature is to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts PH=8.5
(7) clock reaction 30min
(8) add potassium acetate 90Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into 3L four-hole bottle, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into 3L four-hole bottle, intensification 30-60 DEG C
(13) dripping 5% sulphuric acid, adjust pH to 2.5, stir 1h, repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product, total recovery 80%.
The synthesis of embodiment 5 cefdinir
Condensation operation:
(1) in retort, 35Kg 7-AVCA is put into, 75Kg active ester, 400Kg ethyl acetate, 300Kg water, stirring fall
Temperature is to 0-50 DEG C
(2) dropping ammonia 18Kg
(3) drip finish, clock reaction
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate
(5) add dichloromethane 600Kg stirring 5min, the 100Kg that adds water and stir 5min, layering.Water layer 331.5Kg*2 bis-
Chloromethanes is washed twice, and combined dichloromethane layer 130Kg washes, and combining water layer puts into retort, adds EDTA 0.4Kg, fall
Temperature is to 0-50 DEG C, and water layer is waited to hydrolyze.
Hydrolyzing process:
(6) dropping solution of potassium carbonate, adjusts PH=8
(7) clock reaction 30min
(8) add potassium acetate 90Kg, after being cooled to 0 DEG C, stir 10min
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
Refining step:
(10) filter cake puts into 3L four-hole bottle, adds 2200Kg water, is warming up to 30-60 DEG C
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min
(12) filtering, wash filter cake with 300Kg, filtrate puts into 3L four-hole bottle, intensification 30-60 DEG C
(13) dripping 5% sulphuric acid, adjust pH to 2.5, stir 1h, repetition measurement pH is constant
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain
(15) placing, is dried, obtains cefdinir finished product, total recovery 76%.
The above, be only presently preferred embodiments of the present invention, and technical scheme is not made any form
On restriction.Any simple modification that above example is made by every technical spirit according to the present invention, equivalent variations with repair
Decorations, all still fall within the range of technical scheme.
Claims (9)
1. a cefdinir synthesis technique, it is characterised in that comprise the steps:
Condensation operation: with (Z)-2-(thiazolamine-4-base)-2-acetyl oxyimino group thiacetic acid. (S-2-benzothiazole)
Ester, i.e. cefdinir side-chain acid active ester, with 7-amino-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0]
Oct-2-ene-2-carboxylic acid, i.e. 7-AVCA, it is condensed；
Hydrolyzing process: through hydrolysis deacetylate protection, and generate potassium salt of cefdinir；
Refining step: potassium salt of cefdinir, through acid treatment, crystallize, obtains cefdinir finished product.
2. synthesis technique as claimed in claim 1, it is characterised in that
Described condensation operation, is to put in retort by 7-AVCA, cefdinir side-chain acid active ester, organic solvent A, in stirring
Mix down and be slowly added dropwise into alkali liquor；After waiting to drip, stirring to material is all dissolved；The residual of sampling detection 7-AVCA≤
When 0.5%, adding quantitative organic solvent B in reactant liquor, stirring layering, the organic layer separated discards, and water layer is waited to hydrolyze；
Described hydrolyzing process, is addition wet chemical in water layer, adjusts pH=7-9, with stirring clock reaction 30 points
Clock；Reaction puts into potassium acetate after terminating, rejection filter of lowering the temperature, and obtains potassium salt of cefdinir；
Described refining step, is that potassium salt of cefdinir is put into dissolving in purified water, adds acid and make its crystallize, obtain cephalo ground
Buddhist nun's finished product.
3. as claimed in claim 1 synthesis technique, it is characterised in that described condensation operation specifically includes following steps:
(1) in retort, 30-50Kg 7-AVCA, 70-100Kg active ester, 300-500Kg oxolane, 100-are put into
300Kg water, stirring is cooled to 0-50 DEG C；
(2) dropping alkali liquor 18-36Kg；
(3) drip finish, clock reaction；
(4) complete molten time add 0.4Kg EDTA, sampling detection, during 7-AVCA≤0.5 reaction terminate；
(5) adding dichloromethane 500-700Kg stirring 5min, the 100-300Kg that adds water and stir 5min, layering, water layer is used
331.5Kg*2 dichloromethane is washed twice, combined dichloromethane layer, washes with 130Kg, combining water layer, puts into retort, adds
EDTA 0.4Kg, is cooled to 0-50 DEG C, and water layer is waited to hydrolyze.
4. as claimed in claim 1 synthesis technique, it is characterised in that described hydrolyzing process specifically includes following steps:
(6) condensation operation gained water layer, drips solution of potassium carbonate, adjusts pH=7-9
(7) clock reaction 30min；
(8) add potassium acetate 50-100Kg, after being cooled to 0 DEG C, stir 10min；
(9) filter, with 40Kg acetone drip washing, drain, obtain potassium salt of cefdinir.
5. as claimed in claim 1 synthesis technique, it is characterised in that described refining step specifically includes following steps:
(10) potassium salt of cefdinir filter cake puts into retort, adds 2200Kg water, is warming up to 30-60 DEG C；
(11) add charcoal 12Kg, EDTA 1Kg, stir 30min；
(12) filtering, wash filter cake with 300Kg, filtrate puts into retort, intensification 30-60 DEG C；
(13) dropping acid solution, adjusts pH to 1.5-2.5, stirs 1h, and repetition measurement pH is constant；
(14) filter, wash filter cake with 200Kg, then use 60Kg ethanol rinse, drain；
(15) placing, is dried, obtains cefdinir finished product.
6. as claimed in claim 2 synthesis technique, it is characterised in that in described condensation operation, organic solvent A be oxolane or
Ethyl acetate.
7. synthesis technique as claimed in claim 2, it is characterised in that in described condensation operation, alkali liquor is triethylamine, ammonia or hydrogen
Sodium hydroxide solution.
8. as claimed in claim 2 synthesis technique, it is characterised in that in described condensation operation, organic solvent B be dichloromethane or
Ethyl acetate.
9. synthesis technique as claimed in claim 2, it is characterised in that in described refining step, acid solution is sulphuric acid, hydrochloric acid, ice vinegar
Acid etc..
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|---|---|---|---|---|
| WO2005121154A1 (en) * | 2004-06-08 | 2005-12-22 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cefdinir |
| US7105659B2 (en) * | 2003-06-02 | 2006-09-12 | Aurobind - Pharma Ltd. | Process for preparing cefdinir |
| WO2007053723A2 (en) * | 2005-10-31 | 2007-05-10 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cefdinir |
| CN102153566A (en) * | 2010-02-11 | 2011-08-17 | 深圳市立国药物研究有限公司 | Method for preparing cefdinir |
| CN102516261A (en) * | 2011-12-20 | 2012-06-27 | 浙江国邦药业有限公司 | Preparation method of cefdinir |
| CN102659817A (en) * | 2012-05-08 | 2012-09-12 | 浙江普洛得邦制药有限公司 | Preparation method of cefdinir |
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| US7105659B2 (en) * | 2003-06-02 | 2006-09-12 | Aurobind - Pharma Ltd. | Process for preparing cefdinir |
| WO2005121154A1 (en) * | 2004-06-08 | 2005-12-22 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cefdinir |
| WO2007053723A2 (en) * | 2005-10-31 | 2007-05-10 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of cefdinir |
| CN102153566A (en) * | 2010-02-11 | 2011-08-17 | 深圳市立国药物研究有限公司 | Method for preparing cefdinir |
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