CN107286148B - A kind of preparation method of Cefdinir and its new midbody compound - Google Patents
A kind of preparation method of Cefdinir and its new midbody compound Download PDFInfo
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- CN107286148B CN107286148B CN201710470932.6A CN201710470932A CN107286148B CN 107286148 B CN107286148 B CN 107286148B CN 201710470932 A CN201710470932 A CN 201710470932A CN 107286148 B CN107286148 B CN 107286148B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
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- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- 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
Abstract
The present invention is that a kind of preparation method of Cefdinir and its new midbody compound, the present invention prepare Cefdinir using a kind of method simpler, that route is shorter, more environmentally friendly, the Cefdinir high income being prepared, and purity is also higher.Preparation method of the invention is using following reaction formula:
Description
Technical field
The present invention relates to the preparation method technical fields of compound, and in particular to a kind of preparation method of Cefdinir and its
New midbody compound.
Background technique
Cefdinir (Cefdinir) is the third generation oral cephalosporin of Japanese Fujisawa Pharmaceutical Co., Ltd's research and development,
It is to improve the third generation cephalosporins such as Cefixime to G+The deficiency of bacterium effect difference, is transformed Cefixime structure
It arrives, C7Position is demethyl cefotaxime side chain, C3Position is vinyl, maintains the high stability to beta-lactamase, improves
To G+The effect of bacterium is the antibacterial activity agent of wide spectrum, can be used for treating the staphylococcus sensitive to Cefdinir, streptococcus
Category, pneumococcus, peptostreptococcus, Propionibacterium, Neisseria gonorrhoeae, moraxelle catarrhalis, escherichia coli, klebsiella
Infection caused by the Pseudomonas such as category, proteus mirabilis, Pu Luweidengsi Pseudomonas, haemophilus influenzae.
The preparation method research of Cefdinir is more at present, as US4559334, Takaya etc. report 7- amino -3- second
The active reaction object of -3 cephem -4- carboxylate (7-AVCA ester) of alkenyl and compound ii open chain acid is condensed, and generates 7- amide groups
Compound III is handled with nitrosation agent, obtains IV N- oxime compound, then uses thiocarbamide magically change, and deprotection agent obtains cephalo
Ground Buddhist nun, is shown below:
There is also chloride methods to prepare Cefdinir, active thioester method prepares Cefdinir etc., such as WO97/24358,
Lee GS etc. discloses the active sulfur ester process of trityl as protecting group, using active ester BTATA and 7-AVCA in N, N- dimethyl second
Condensation reaction is carried out in amide (DMAc) solvent, condensation product is with the DMAc solvate of trityl Cefdinir to toluene
Sulfonic acid obtains Cefdinir with sour water solution removing trityl at salt, 90% or more yield, and yield is 90% or more, such as following formula
It is shown:
Side chain, then cyclization are first introduced in these methods, the method for then removing parent nucleus 4- carboxyl-protecting group, synthetic route
Long, yield is low, and product quality not can guarantee, and is suitable only for a small amount of preparation in laboratory；Side chain is introduced using chloride method, is needed
It is reacted in solvent existing for inactive hydrogen, although condensation course high income, needs to remove 4- carboxyl-protecting groups, side chain acyl chlorides
It is not easy the problem of obtaining and saving, equally causes yield low, it is at high cost, it is not suitable for large-scale production；Pass through active sulfur ester process structure
Amido bond is built, the method reaction condition for carrying out the modification of 7- amino side chain is mild, and easily operated, yield is higher, but reaction used tries
Agent is more toxic, and is unfavorable for environmental protection.
Summary of the invention
For defect existing for Cefdinir preparation method in the prior art, the present invention provide a kind of preparation method it is simple,
The preparation method of the Cefdinir of environmental protection.
Realize the technical solution of the object of the invention are as follows:
A kind of preparation method of Cefdinir, includes the following steps:
1) hexamethylene is added, in triethylamine in compound 1, controls temperature at -78~10 DEG C, stirring instills the tertiary fourth of hypochlorous acid
Base ester, addition finish, and the reaction was continued 20 minutes, obtain compound 2；
2) 2 solution of compound cools to -10~0 DEG C, with ultraviolet light irradiation 1-10 minutes, obtains the solution of compound 3；
3) solution of compound 3 is warming up to 30~35 DEG C, divides 2-8 addition 7-AVCA, the reaction was continued 1h after adding；
4) solution for obtaining step 3) is cooled to 0 DEG C, and filtering, 35~40 DEG C of dryings obtain Cefdinir triethylamine salt；
5) deionized water is added into reaction vessel, controls temperature at 20~25 DEG C, Cefdinir triethylamine salt is added, adds
Enter dilution heat of sulfuric acid, adjust PH5-6, active carbon is added, is stirred 30 minutes at 20~30 DEG C, activated carbon is filtered to remove, by filtrate
30~35 DEG C are warming up to, the sulfuric acid solution of 8wt% is added dropwise, adjusts pH to 2.7 ± 0.2, stirs 20 minutes, is cooled to 0~5 DEG C,
Stirring 30 minutes, filtering, filter cake are washed with deionized, and at 40~45 DEG C, vacuum degree -0.08Mpa is dry, obtain Cefdinir.
The present invention also provides the new midbody compound for preparing Cefdinir, structural formula is as follows:
The present invention also endures the new midbody compound of prepare compound 3, and mechanism is as follows:
The invention has the benefit that
1, the method and step of the invention for preparing Cefdinir is few, therefore the time expended and cost are few, and it is big to be suitable for industrialization
Production.
2, the present invention prepares the method agents useful for same small toxicity of Cefdinir, and the health and environmental protection for operator are all
Favorably.
3, the Cefdinir high income prepared using method of the invention, is reached 96% or more, and purity is higher, reached
99% or more.
Specific embodiment
1 prepare compound 2 of embodiment
80ml hexamethylene, 45ml triethylamine are put into reaction flask, 20g compound 1 controls temperature -78~10 DEG C, opens and stir
It mixes, then instills 15.3g hypochlorous acid tertiary butyl ester, addition finishes, and the reaction was continued 20 minutes, obtains the solution of compound 2.Compound
1 can be commercially available by market.
2 prepare compound 2 of embodiment
80ml hexamethylene, 45ml triethylamine are put into reaction flask, 20g compound 1 controls temperature -78~-50 DEG C, opens
Stirring, then 15.3g hypochlorous acid tertiary butyl ester is instilled, addition finishes, and the reaction was continued 20 minutes, obtains the solution of compound 2.
3 prepare compound 2 of embodiment
80ml hexamethylene, 45ml triethylamine are put into reaction flask, 20g compound 1 controls temperature -50~10 DEG C, opens and stir
It mixes, then instills 15.3g hypochlorous acid tertiary butyl ester, addition finishes, and the reaction was continued 20 minutes, obtains the solution of compound 2.
4 prepare compound 3 of embodiment
The solution of compound 2 is cooled to -10~0 DEG C, with ultraviolet light irradiation 5 minutes, obtains the solution of compound 3.
5 prepare compound 3 of embodiment
The solution of compound 2 is cooled to -10~0 DEG C, with ultraviolet light irradiation 1 minute, obtains the solution of compound 3.
6 prepare compound 3 of embodiment
The solution of compound 2 is cooled to -10~0 DEG C, with ultraviolet light irradiation 10 minutes, obtains the solution of compound 3.
Embodiment 7 prepares Cefdinir
The solution temperature of compound 3 is risen to 32 DEG C, total 26g 7-AVCA are added points for 4 times, the 1h that adds that the reaction was continued afterwards；Drop
Temperature is to 0 DEG C, filtering, 35 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 84%；200ml deionization is put into reaction flask
20 DEG C of temperature control, Cefdinir triethylamine salt 40g is added in water, adds the dilution heat of sulfuric acid of 8wt%, and adjustment pH5 adds 4g active, 25
DEG C stirring 30 minutes, it is filtered to remove activity, filtrate is warming up to 33 DEG C, is added dropwise the sulfuric acid solution of 8wt%, pH to 2.5 is adjusted, stirs
It mixes 20 minutes.3 DEG C are cooled to, is stirred 30 minutes, filtering.Filter cake is washed with deionized, and at 43 DEG C, vacuum degree -0.08Mpa is dry
It is dry, obtain Cefdinir 29.6g, yield 98%, purity 99%.
Embodiment 8 prepares Cefdinir
The solution temperature of compound 3 is risen to 30 DEG C, total 26g 7-AVCA are added points for 2 times, the 1h that adds that the reaction was continued afterwards；Drop
Temperature is to 0 DEG C, filtering, 40 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 89%；200ml deionization is put into reaction flask
23 DEG C of temperature control, Cefdinir triethylamine salt 40g is added in water, adds the dilution heat of sulfuric acid of 8wt%, and adjustment pH6 adds 4g active, 30
DEG C stirring 30 minutes, it is filtered to remove activity, filtrate is warming up to 30 DEG C, is added dropwise the sulfuric acid solution of 8wt%, pH to 2.9 is adjusted, stirs
It mixes 20 minutes.It is cooled to 0 DEG C, is stirred 30 minutes, filtering.Filter cake is washed with deionized, and at 40 DEG C, vacuum degree -0.09Mpa is dry
It is dry, obtain Cefdinir 29.6g, yield 96%, purity 99.1%.
Embodiment 9 prepares Cefdinir
The solution temperature of compound 3 is risen to 35 DEG C, total 26g 7-AVCA are added points for 8 times, the 1h that adds that the reaction was continued afterwards；Drop
Temperature is to 0 DEG C, filtering, 38 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 88%；200ml deionization is put into reaction flask
25 DEG C of temperature control, Cefdinir triethylamine salt 40g is added in water, adds the dilution heat of sulfuric acid of 8wt%, and adjustment pH5.5 adds 4g active,
20 DEG C are stirred 30 minutes, are filtered to remove activity, filtrate is warming up to 35 DEG C, and the sulfuric acid solution of 8wt% is added dropwise, and adjust pH to 2.9,
Stirring 20 minutes.5 DEG C are cooled to, is stirred 30 minutes, filtering.Filter cake is washed with deionized, at 45 DEG C, vacuum degree -0.1Mpa
It is dry, obtain Cefdinir 29.6g, yield 97%, purity 99%.
Above-described embodiment is only the specific embodiment of the invention, but is not limited to embodiment, all not depart from structure of the present invention
In the case where think of, equivalent modification and the prior art addition done according to the application are accordingly to be regarded as the technology of the present invention scope.
Claims (10)
1. a kind of preparation method of Cefdinir, characterized by the following steps:
2. the preparation method of Cefdinir according to claim 1, it is characterised in that: compound 3 reacts temperature with 7-AVCA
Degree is 30-35 DEG C.
3. the preparation method of Cefdinir according to claim 2, it is characterised in that: 7-AVCA divides 2-8 being added to
In the solution for closing object 3.
4. a kind of midbody compound for preparing Cefdinir, it is characterised in that: its structural formula is as follows:
5. the preparation method of midbody compound according to claim 4, it is characterised in that: compound 3 is made by compound 2
It is standby to form, the structural formula of compound 2 are as follows:
6. according to the method described in claim 5, use is ultraviolet it is characterized by: 2 solution of the compound cools to -10~0 DEG C
Light irradiation obtains compound 3.
7. preparation method according to claim 5 or 6, it is characterised in that: the compound 2 is prepared by compound 1,
The structural formula of compound 1 are as follows:
8. preparation method according to claim 7, it is characterised in that: in the addition of compound 1 hexamethylene, triethylamine,
Then prepare compound 2 is reacted with hypochlorous acid tertiary butyl ester.
9. preparation method according to claim 8, it is characterised in that: in the addition of compound 1 hexamethylene, triethylamine,
Temperature is controlled at -78~10 DEG C, and hypochlorous acid tertiary butyl ester is then added dropwise.
10. a kind of preparation method of Cefdinir, characterized by the following steps:
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251590A (en) * | 1997-04-04 | 2000-04-26 | 生物化学有限公司 | Crystalline amine salt of cefdinir |
| CN102020664A (en) * | 2010-11-30 | 2011-04-20 | 浙江工业大学 | Synthesis method for cefdinir |
| CN102617601A (en) * | 2011-01-31 | 2012-08-01 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefdinir |
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2017
- 2017-06-20 CN CN201710470932.6A patent/CN107286148B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251590A (en) * | 1997-04-04 | 2000-04-26 | 生物化学有限公司 | Crystalline amine salt of cefdinir |
| CN102020664A (en) * | 2010-11-30 | 2011-04-20 | 浙江工业大学 | Synthesis method for cefdinir |
| CN102617601A (en) * | 2011-01-31 | 2012-08-01 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefdinir |
Non-Patent Citations (1)
| Title |
|---|
| 头孢地尼的合成;林桂椿等;《合成化学》;20011231;第9卷(第5期);第383-385页 * |
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Effective date of registration: 20220816 Address after: Room 502, Building 6, No. 11, Nanxiang 3rd Road, Huangpu District, Guangzhou City, Guangdong Province, 510700 Patentee after: Guangzhou jiulongda Pharmaceutical Technology Co.,Ltd. Address before: Room 401, No. 3, Kehui 2nd Street, Science City, High-tech Industrial Development Zone, Guangzhou City, Guangdong Province, 510335 Patentee before: GUANGZHOU TONGHUITONG MEDICINE TECHNOLOGY CO.,LTD. |