CN107286148A - 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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- CN107286148A CN107286148A CN201710470932.6A CN201710470932A CN107286148A CN 107286148 A CN107286148 A CN 107286148A CN 201710470932 A CN201710470932 A CN 201710470932A CN 107286148 A CN107286148 A CN 107286148A
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- cefdinir
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention is the preparation method and its new midbody compound of a kind of Cefdinir, and of the invention to prepare Cefdinir using a kind of shorter, the more environmentally friendly method of simpler, circuit, the Cefdinir high income prepared, purity is also higher.The preparation method of the present invention is to use following reaction equation.
Description
Technical field
The present invention relates to the preparation method technical field of compound, and in particular to a kind of preparation method of Cefdinir and its
New midbody compound.
Background technology
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, carries out transforming to Cefixime structure
Arrive, 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, available for treatment to the sensitive staphylococcus of Cefdinir, streptococcus
Category, pneumococcus, peptostreptococcus, Propionibacterium, Neisseria gonorrhoeae, moraxelle catarrhalis, EHEC, klebsiella
Infection caused by the Pseudomonas such as category, proteus mirabilis, Pu Luweidengsi Pseudomonas, haemophilus influenzae.
The preparation method research of current Cefdinir is more, such as US4559334, and Takaya etc. reports 7- amino -3- second
The active reaction thing of the cephem -4- of alkenyl -3 carboxylates (7-AVCA esters) and compound ii open chain acid is condensed, and generates 7- amide groups
Compound III, is handled with nitrosation agent, obtains IV N- oxime compounds, then uses thiocarbamide magically change, and deprotection agent obtains cephalo
Ground Buddhist nun, is shown below：
Other also have chloride method to prepare Cefdinir, active thioester method to prepare Cefdinir etc., such as WO97/24358,
Lee GS etc. disclose 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 acid amides (DMAc) solvent, condensation product is with the DMAc solvates of trityl Cefdinir to toluene
Sulfonic acid obtains Cefdinir into salt, yield more than 90% with sour water solution removing trityl, and yield is more than 90%, 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 groups, synthetic route
Long, yield is low, and product quality can not ensure, be suitable only for a small amount of preparation in laboratory；Using chloride method introduce side chain, it is necessary to
Reacted in the solvent that inactive hydrogen is present, although condensation course high income, need to remove 4- carboxyl-protecting groups, side chain acyl chlorides
The problem of being difficult to obtain and preserve, equally causes yield low, and cost is high, does not apply to large-scale production；Pass through active sulfur ester process structure
Amido link is built, the method reaction condition for carrying out 7- amino side chain modifications is gentle, it is easy to operate, yield is higher, but reaction examination used
Agent toxicity is larger, is unfavorable for environmental protection.
The content of the invention
The defect existed 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.
The technical scheme for realizing the object of the invention is：
A kind of preparation method of Cefdinir, comprises the following steps：
1) compound 1 is added in hexamethylene, triethylamine, and control temperature is at -78~10 DEG C, and stirring instills the tertiary fourth of hypochlorous acid
Base ester, addition is finished, and is continued to react 20 minutes, is obtained compound 2；
2) solution of compound 2 cools to -10~0 DEG C, with ultra violet lamp 1-10 minutes, obtains the solution of compound 3；
3) solution of compound 3 is warming up to 30~35 DEG C, point 2-8 addition 7-AVCA continues to react 1h after adding；
4) by step 3) obtained solution 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, control temperature adds Cefdinir triethylamine salt at 20~25 DEG C, plus
Enter dilution heat of sulfuric acid, adjust PH5-6, add activated carbon, stirred 30 minutes at 20~30 DEG C, activated carbon is filtered to remove, by filtrate
30~35 DEG C are warming up to, 8wt% sulfuric acid solution is added dropwise, pH to 2.7 ± 0.2 is adjusted, stirs 20 minutes, is cooled to 0~5 DEG C,
Stirring 30 minutes, filtering, filter cake is washed with deionized, and at 40~45 DEG C, vacuum -0.08Mpa is dried, and obtains Cefdinir.
The present invention also offer prepares the new midbody compound of Cefdinir, and its structural formula is as follows：
The present invention also endures the new midbody compound of prepare compound 3, and its mechanism is as follows：
Beneficial effects of the present invention are：
1st, the method and step of the invention for preparing Cefdinir is few, therefore the time expended and cost are few, big suitable for industrialization
Production.
2nd, the present invention prepares the method agents useful for same small toxicity of Cefdinir, for operator it is healthy and environmentally friendly all
Favorably.
3rd, the Cefdinir high income prepared using the method for the present invention, reaches more than 96%, and purity is higher, reaches
More than 99%.
Embodiment
The prepare compound 2 of embodiment 1
80ml hexamethylenes are put into reaction bulb, 45ml triethylamines, 20g compounds 1 control temperature -78~10 DEG C, open and stir
Mix, then instill 15.3g hypochlorous acid tertiary butyl esters, addition is finished, continue to react 20 minutes, obtain the solution of compound 2.Compound
1 can be commercially available by market.
The prepare compound 2 of embodiment 2
80ml hexamethylenes are put into reaction bulb, 45ml triethylamines, 20g compounds 1 control temperature -78~-50 DEG C, opened
Stirring, then 15.3g hypochlorous acid tertiary butyl esters are instilled, addition is finished, and is continued to react 20 minutes, is obtained the solution of compound 2.
The prepare compound 2 of embodiment 3
80ml hexamethylenes are put into reaction bulb, 45ml triethylamines, 20g compounds 1 control temperature -50~10 DEG C, open and stir
Mix, then instill 15.3g hypochlorous acid tertiary butyl esters, addition is finished, continue to react 20 minutes, obtain the solution of compound 2.
The prepare compound 3 of embodiment 4
The solution of compound 2 is cooled to -10~0 DEG C, with ultra violet lamp 5 minutes, the solution of compound 3 is obtained.
The prepare compound 3 of embodiment 5
The solution of compound 2 is cooled to -10~0 DEG C, with ultra violet lamp 1 minute, the solution of compound 3 is obtained.
The prepare compound 3 of embodiment 6
The solution of compound 2 is cooled to -10~0 DEG C, with ultra violet lamp 10 minutes, the solution of compound 3 is obtained.
Embodiment 7 prepares Cefdinir
The solution temperature of compound 3 is risen to 32 DEG C, point 4 common 26g 7-AVCA of addition continue to react 1h after adding；Drop
Temperature is to 0 DEG C, filtering, 35 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 84%；200ml deionizations are put into reaction bulb
Water, 20 DEG C of temperature control, addition Cefdinir triethylamine salt 40g, plus 8wt% dilution heat of sulfuric acid, adjustment pH5, plus 4g activity, 25
DEG C stirring 30 minutes, is filtered to remove activity, filtrate is warming up into 33 DEG C, 8wt% sulfuric acid solution is added dropwise, pH is to 2.5 for regulation, stirs
Mix 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 -0.08Mpa is done
It is dry, Cefdinir 29.6g is obtained, yield 98%, purity is 99%.
Embodiment 8 prepares Cefdinir
The solution temperature of compound 3 is risen to 30 DEG C, point 2 common 26g 7-AVCA of addition continue to react 1h after adding；Drop
Temperature is to 0 DEG C, filtering, 40 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 89%；200ml deionizations are put into reaction bulb
Water, 23 DEG C of temperature control, addition Cefdinir triethylamine salt 40g, plus 8wt% dilution heat of sulfuric acid, adjustment pH6, plus 4g activity, 30
DEG C stirring 30 minutes, is filtered to remove activity, filtrate is warming up into 30 DEG C, 8wt% sulfuric acid solution is added dropwise, pH is to 2.9 for regulation, stirs
Mix 20 minutes.0 DEG C is cooled to, is stirred 30 minutes, filtering.Filter cake is washed with deionized, and at 40 DEG C, vacuum -0.09Mpa is done
It is dry, Cefdinir 29.6g is obtained, yield 96%, purity is 99.1%.
Embodiment 9 prepares Cefdinir
The solution temperature of compound 3 is risen to 35 DEG C, point 8 common 26g 7-AVCA of addition continue to react 1h after adding；Drop
Temperature is to 0 DEG C, filtering, 38 DEG C of dryings.Obtain Cefdinir triethylamine salt 48g, yield 88%；200ml deionizations are put into reaction bulb
Water, 25 DEG C of temperature control, addition Cefdinir triethylamine salt 40g, plus 8wt% dilution heat of sulfuric acid, adjustment pH5.5, plus 4g activity,
20 DEG C are stirred 30 minutes, are filtered to remove activity, and filtrate is warming up into 35 DEG C, 8wt% sulfuric acid solution are added dropwise, pH is to 2.9 for regulation,
Stirring 20 minutes.5 DEG C are cooled to, is stirred 30 minutes, filtering.Filter cake is washed with deionized, in 45 DEG C, vacuum -0.1Mpa
Dry, obtain Cefdinir 29.6g, yield 97%, purity is 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 of 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 category.
Claims (10)
1. a kind of preparation method of Cefdinir, it is characterised in that：Comprise the following steps：
2. the preparation method of Cefdinir according to claim 1, it is characterised in that：Compound 3 and 7-AVCA reacts temperature
Spend for 30-35 DEG C.
3. the preparation method of Cefdinir according to claim 2, it is characterised in that：7-AVCA points of 2-8 being added to
In the solution of compound 3.
4. a kind of midbody compound for preparing Cefdinir, it is characterised in that：Its structural formula is as follows：
5. midbody compound according to claim 4, it is characterised in that：Compound 3 is prepared from by compound 2, is changed
The structural formula of compound 2 is：
6. method according to claim 5, it is characterised in that：The solution of compound 2 cools to -10~0 DEG C, with ultraviolet
Light irradiation, obtains compound 3.
7. the preparation method according to claim 5 or 6, it is characterised in that：The compound 2 is prepared from by compound 1,
The structural formula of compound 1 is：
8. preparation method according to claim 7, it is characterised in that：The compound 1 is added in 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：The compound 1 is added in hexamethylene, triethylamine,
Then temperature control is added dropwise hypochlorous acid tertiary butyl ester at -78~10 DEG C.
10. a kind of preparation method of Cefdinir, it is characterised in that：Comprise the following steps：
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| CN201710470932.6A CN107286148B (en) | 2017-06-20 | 2017-06-20 | A kind of preparation method of Cefdinir and its new midbody compound |
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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 |
|---|
| 林桂椿等: "头孢地尼的合成", 《合成化学》 * |
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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. |