CN106279207A - A kind of synthetic method of cefdinir - Google Patents
A kind of synthetic method of cefdinir Download PDFInfo
- Publication number
- CN106279207A CN106279207A CN201610663189.1A CN201610663189A CN106279207A CN 106279207 A CN106279207 A CN 106279207A CN 201610663189 A CN201610663189 A CN 201610663189A CN 106279207 A CN106279207 A CN 106279207A
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- CN
- China
- Prior art keywords
- cefdinir
- synthetic method
- reaction
- hydrogen chloride
- reactant liquor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 0 CCC(C*C1C2*(C=N)C(C(Cc3c[s]c(*)n3)=N*)=*)=C(C(O)=O)N1C2=O Chemical compound CCC(C*C1C2*(C=N)C(C(Cc3c[s]c(*)n3)=N*)=*)=C(C(O)=O)N1C2=O 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
-
- 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
Abstract
The present invention relates to the synthetic method of a kind of cefdinir; the method is with cefdinir parent nucleus 7 AVCA as raw material; itself and cefdinir pendant reactive ester generation condensation reaction is made to prepare the cefdinir of band protection group; reactant liquor without isolation, directly adds hydrogen chloride in reactant liquor and catalyst is sloughed protection group and prepared cefdinir.Intermediate product (cefdinir of band protection group) is the most first separated by the method, but directly carries out sloughing the reaction of protection group, and high yield obtains cefdinir, and yield is up to more than 85%, and this synthesis process route is short, the reagent low price of employing, low cost.
Description
Technical field
The invention belongs to biology,drug and chemical industry technology synthesis field, be specifically related to the synthetic method of a kind of cefdinir.
Background technology
Cefdinir is belonging to the third generation and wide spectrum cephalosporins is administered orally, and all has excellent to Grain-positive and gram-negative bacteria
Good antibacterial action, by the exploitation of Fujisawa Pharmaceutical of Japan, in October, 1991 lists.Chemistry entitled [6R-[6 α, 7 β
(Z)]]-7-[[(2-Amino-4-thiazolyl)-(hydroxyl imido) secondAcyl group] amino]-3-EthyleneBase-8-oxo-5-thia-1-
Azabicyclic [4.2.0]-2-octene-2-carboxylic acid.Molecular formula is C14H13N5O5S2, molecular weight is 395.42, and its structural formula is:
Cefdinir synthetic route the earliest is longer, and method is the most more.Owing to synthetic route is long, yield is low, the most relevant
Impurity is wayward, easily exceeds standard, and causes defective, and therefore cost is high, and various solvents and adjuvant in reaction are many, give back to
Receive and environment all brings bigger difficulty.
In prior art, as Chinese patent CN102010427A discloses the preparation method of a kind of cefdinir, the method
First 7-AVCA is carried out the silanization protection of carboxyl, then occurs with CAEM acylation reaction to obtain carboxyl and be silylated the second of protection
Acyl cefdinir, then will obtain acetyl cefdinir hexanamine salt by hydrolysis or alcoholysis and simple salt-forming reaction,
Again this salt hydrolysis is obtained cefdinir.It is with cefdinir parent nucleus 7-that prior art also discloses the synthetic method of cefdinir
After AVCA and pendant reactive ester condensation reaction, utilize p-methyl benzenesulfonic acid to carry out de-side chain again after becoming the method for salt or the separation that adds water and protect
After protecting base, carrying out crystallization and obtain cefdinir crude product, crude product is again through forming dicyclohexylamine complex or phosphoric acid composite etc., refined
Obtain cefdinir again.It is long all to there is synthetic route in above-mentioned synthetic method, high in cost of production defect.
Summary of the invention
The technical problem to be solved is to overcome the deficiencies in the prior art, it is provided that the conjunction of a kind of new cefdinir
One-tenth method.
For solving above technical problem, the present invention adopts the following technical scheme that
A kind of synthetic method of cefdinir, described synthetic method includes:
(1) make cefdinir parent nucleus 7-AVCA and cefdinir pendant reactive ester carry out condensation reaction and prepare band protection group
Cefdinir；
(2) catalyst and hydrogen chloride are added in the reactant liquor that step (1) obtains so that the cefdinir of band protection group enters
Row deprotection reaction, prepares cefdinir；
Wherein, the structural formula of described 7-AVCA as shown in formula I,
The structural formula of described cefdinir pendant reactive ester as shown in formula II,
R is
Further, in step (1), described condensation reaction is carried out in the presence of organic base and solvent, described organic base
For triethylamine or diethylamine, described solvent is the one in dimethyl formyl, dimethyl acetylamide, oxolane, acetonitrile or many
The combination planted, the reaction temperature of described condensation reaction is 5 DEG C～25 DEG C.
Further, the reactant liquor that step (1) obtains directly carries out next step reaction.
Further, in step (2), the reaction temperature of described deprotection reaction is-25 DEG C～0 DEG C, described catalyst
For methyl phenyl ethers anisole, described hydrogen chloride is hydrogen chloride gas.
Further, in step (2), in system, also add extractant, being embodied as of step (2): in step
(1) reactant liquor obtained adds extractant, methyl phenyl ethers anisole, at a temperature of-25 DEG C～0 DEG C, is passed through hydrogen chloride gas, carries out remove-insurance
Protect base reaction, after reaction terminates, prepare the reactant liquor containing cefdinir.
It is further preferred that after the deprotection reaction of step (2) terminates, at a temperature of 0 DEG C～25 DEG C, add alkali and adjust
Joint pH to 5.0～7.5, layering obtains aqueous phase, adds activated carbon decolorizing, filter in aqueous phase, and regulation filtrate pH is 2.0～3.5, knot
Crystalline substance, separates, is dried to obtain described cefdinir.
Specifically, described alkali be mass concentration be the aqueous slkali of 5%～10%, described aqueous slkali is NaHCO3、Na2CO3、
K2CO3Or KHCO3In one.
Specifically, the aqueous phase that described layering obtains is before adding activated carbon decolorizing process, by dichloromethane or acetic acid second
Ester back extraction.
Specifically, the reactant liquor containing cefdinir that step (2) obtains is first in system before being for further processing
In be passed through N2The hydrogen chloride being dissolved in system with removal.
Specifically, described activated carbon decolorizing temperature is 5 DEG C～25 DEG C.
It is further preferred that described extractant is dichloromethane or ethyl acetate.
Due to the enforcement of technique scheme, the present invention compared with prior art has the advantage that
The synthetic method of the cefdinir of the present invention, after the method condensation reaction, reactant liquor is without isolation, directly in reaction
Liquid adds hydrogen chloride and catalyst is sloughed protection group and prepared cefdinir.The method the most first by intermediate product (band protection group
Cefdinir) separate, but directly carry out sloughing the reaction of protection group, high yield obtains cefdinir, is initial with 7-AVCA
Raw material calculates, and total recovery is up to more than 85%, and this synthesis process route is short, products obtained therefrom quality good (impurity is lower), adopts
Reagent low price, low cost, it is easy to industrialized production.
Detailed description of the invention
The route that the synthetic method of cefdinir of the present invention uses is: with cefdinir parent nucleus 7-AVCA as initiation material,
In organic solvent, under the conditions of organic base catalytic, carry out condensation reaction with cefdinir pendant reactive ester, obtain band protection group
Cefdinir, form intermediate product without isolation, but be directly added into methyl phenyl ethers anisole catalyst, be passed through dry hydrogen chloride gas,
Slough protection group and obtain cefdinir, then allow the cefdinir in system form sodium salt or potassium salt separates with organic facies, aqueous phase
After purified decolouring, acid adding, crystallization, separate, be dried to obtain cefdinir.Wherein, described setting-up point 5 DEG C～20
DEG C, be passed through dry hydrogen chloride gas temperature and be-25 DEG C～0 DEG C, add the temperature of alkali be 0 DEG C～25 DEG C, pH value be 5.0～7.5.
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
The present embodiment provides the synthetic method of a kind of cefdinir, the cefdinir pendant reactive ester used in this embodiment
Meet molecular formula shown in formula II, and R is
Synthetic method particularly as follows: in dry reaction bulb, adds 30g 7-AVCA, 85g cefdinir pendant reactive ester,
100mL dimethyl acetylamide, temperature control 15 DEG C～20 DEG C, drip 30g triethylamine, stirring reaction 4h, to react complete molten clearly, reaction
After end, add 250mL dichloromethane, be cooled to-15 DEG C～-10 DEG C, add 50mL methyl phenyl ethers anisole, be passed through dry hydrogen chloride gas
After body, about 2h, HPLC measured reaction terminal, after reaction terminates, logical N2Drive the hydrogen chloride gas of excess in system away.It is subsequently adding
100mL H2O, the Na of dropping 10%2CO3Solution, adjusting pH value is 5.5～6.0, and temperature control is less than 5 DEG C, layering.Aqueous phase adds
100mL CH2Cl2Extraction, layering, aqueous phase adds 3g activated carbon decolorizing, filters, add 500mL water, use 2mol/L salt after decolouring 1h
Acid adjust pH value to 2.2～2.4, temperature control 20 DEG C～25 DEG C, after growing the grain 2h filter, washing, ethanol wash, be dried, obtain cephalo ground
Buddhist nun 45g, yield 85.8%, purity is >=99%.
Embodiment 2
The present embodiment provides the synthetic method of a kind of cefdinir, the cefdinir pendant reactive ester used in this embodiment
Meet molecular formula shown in formula II, and R is
Synthetic method is particularly as follows: in dry reaction bulb, add 22.6g 7-AVCA, 43g cefdinir pendant reactive
Ester, 150mL oxolane, temperature control 20 DEG C～23 DEG C, drip 12g triethylamine, stirring reaction 5h, HPLC measured reaction terminal, reaction
Add 200mL dichloromethane, methyl phenyl ethers anisole 30mL after end, lower the temperature-25 DEG C～-20 DEG C, be passed through dry hydrogen chloride gas, about
After 1.5h, HPLC measured reaction terminal.After reaction terminates, logical N2Driving the hydrogen chloride gas of excess in system away, temperature control is less than 0
DEG C, the K of dropping 5%2CO3, control ph is 5.5～6.0, layering, adds 80mLCH in aqueous phase2Cl2Extraction, layering, in aqueous phase
Add 2g activated carbon decolorizing 1h, filter, add water 400mL, with 2mol/L hydrochloric acid adjust pH value to 2.2～2.4, temperature control 25 DEG C～28
DEG C, filtering after growing the grain 2h, washing, ethanol wash, be dried, obtain cefdinir 35g, yield 88.6%, purity is 99.2%.
Above the present invention is described in detail, its object is to allow the personage being familiar with this art will appreciate that this
Invention content and be carried out, can not limit the scope of the invention with this, and the invention is not restricted to above-mentioned enforcement
Example, all equivalence changes made according to the spirit of the present invention or modification, all should contain within protection scope of the present invention.
Claims (10)
1. the synthetic method of a cefdinir, it is characterised in that: described synthetic method includes:
(1) make cefdinir parent nucleus 7-AVCA and cefdinir pendant reactive ester carry out condensation reaction and prepare the cephalo of band protection group
Ground Buddhist nun；
(2) catalyst and hydrogen chloride are added in the reactant liquor that step (1) obtains so that the cefdinir of band protection group takes off
Protection group is reacted, and prepares cefdinir；
Wherein, the structural formula of described 7-AVCA as shown in formula I,
The structural formula of described cefdinir pendant reactive ester as shown in formula II,
R is
The synthetic method of cefdinir the most according to claim 1, it is characterised in that: in step (1), described condensation reaction
Carrying out in the presence of organic base and solvent, described organic base is triethylamine or diethylamine, described solvent be dimethyl formyl, two
The combination of one or more in methylacetamide, oxolane, acetonitrile, the reaction temperature of described condensation reaction is 5 DEG C～25
℃。
The synthetic method of cefdinir the most according to claim 1, it is characterised in that: the reactant liquor that step (1) obtains is straight
Tap into next step reaction of row.
The synthetic method of cefdinir the most according to claim 1, it is characterised in that: in step (2), described Deprotection
The reaction temperature of reaction is-25 DEG C～0 DEG C, and described catalyst is methyl phenyl ethers anisole, and described hydrogen chloride is hydrogen chloride gas.
5. according to the synthetic method of the cefdinir described in claim 1 or 4, it is characterised in that: in step (2), also in system
Middle addition extractant, being embodied as of step (2): add extractant, methyl phenyl ethers anisole in the reactant liquor that step (1) obtains, in-
It is passed through hydrogen chloride gas at a temperature of 25 DEG C～0 DEG C, carries out deprotection reaction, after reaction terminates, prepare containing cefdinir
Reactant liquor.
The synthetic method of cefdinir the most according to claim 5, it is characterised in that: the deprotection reaction of step (2)
After end, at a temperature of 0 DEG C～25 DEG C, adding alkali regulation pH to 5.0～7.5, layering obtains aqueous phase, adds activated carbon in aqueous phase
Decolouring, filters, and regulation filtrate pH is 2.0～3.5, and crystallization separates, is dried to obtain described cefdinir.
The synthetic method of cefdinir the most according to claim 6, it is characterised in that: described alkali be mass concentration be 5%
～the aqueous slkali of 10%, described aqueous slkali is NaHCO3、Na2CO3、K2CO3Or KHCO3In one.
The synthetic method of cefdinir the most according to claim 6, it is characterised in that: the aqueous phase that described layering obtains is adding
Before entering activated carbon decolorizing process, with dichloromethane or ethyl acetate back extraction.
The synthetic method of cefdinir the most according to claim 6, it is characterised in that: step (2) obtain containing cephalo
The reactant liquor of ground Buddhist nun was first passed through N before being for further processing in system2The hydrogen chloride being dissolved in system with removal.
The synthetic method of cefdinir the most according to claim 5, it is characterised in that: described extractant is dichloromethane
Or ethyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610663189.1A CN106279207A (en) | 2016-08-15 | 2016-08-15 | A kind of synthetic method of cefdinir |
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| CN201610663189.1A CN106279207A (en) | 2016-08-15 | 2016-08-15 | A kind of synthetic method of cefdinir |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108002966A (en) * | 2017-12-11 | 2018-05-08 | 苏州大学 | A kind of method of synthesis 1,2- diarylethane class compounds |
| CN110759933A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefdinir impurity G |
| CN111072687A (en) * | 2020-03-03 | 2020-04-28 | 刘方涛 | Preparation method of cefdinir |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108002966A (en) * | 2017-12-11 | 2018-05-08 | 苏州大学 | A kind of method of synthesis 1,2- diarylethane class compounds |
| CN110759933A (en) * | 2019-10-30 | 2020-02-07 | 广州牌牌生物科技有限公司 | Preparation method of cefdinir impurity G |
| CN111072687A (en) * | 2020-03-03 | 2020-04-28 | 刘方涛 | Preparation method of cefdinir |
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Application publication date: 20170104 |