CN102336771A - Method for preparing sulfuric acid cefoselis intermediate - Google Patents
Method for preparing sulfuric acid cefoselis intermediate Download PDFInfo
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- CN102336771A CN102336771A CN2011101926935A CN201110192693A CN102336771A CN 102336771 A CN102336771 A CN 102336771A CN 2011101926935 A CN2011101926935 A CN 2011101926935A CN 201110192693 A CN201110192693 A CN 201110192693A CN 102336771 A CN102336771 A CN 102336771A
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- amino
- cephem
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- carboxylic acid
- tertbutyloxycarbonyl
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- 229950001580 cefoselis Drugs 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 title abstract 4
- ZINFAXPQMLDEEJ-GFVOIPPFSA-N cefoselis Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1C=CC(=N)N1CCO ZINFAXPQMLDEEJ-GFVOIPPFSA-N 0.000 title abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006467 substitution reaction Methods 0.000 claims abstract description 10
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 20
- LZOLCSVRFKCSEM-ZQCAECPKSA-N cefoselis sulfate Chemical compound OS(O)(=O)=O.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1C=CC(=N)N1CCO LZOLCSVRFKCSEM-ZQCAECPKSA-N 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000000543 intermediate Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- FQUHYJGZZOWPRJ-JANGERMGSA-N benzhydryl (6R)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1(=CC=CC=C1)C(C1=CC=CC=C1)OC(=O)C1=CC(S[C@H]2N1C(C2)=O)C FQUHYJGZZOWPRJ-JANGERMGSA-N 0.000 claims description 12
- KPJFHRWTWFSZIW-ZDDDBRQOSA-N Cl.Cl.Cl.CC1S[C@H]2N(C(=C1)C(=O)O)C(C2)=O Chemical compound Cl.Cl.Cl.CC1S[C@H]2N(C(=C1)C(=O)O)C(C2)=O KPJFHRWTWFSZIW-ZDDDBRQOSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000011347 resin Substances 0.000 abstract description 4
- 229920005989 resin Polymers 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 29
- 238000005406 washing Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
- 239000007791 liquid phase Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 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 5
- -1 cephalosporins cefoselis sulfate Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940099204 ritalin Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for preparing a sulfuric acid cefoselis intermediate, which comprises the following steps: dissolving 7bata-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-diphenylmethyl carboxylate and 5-formamido-1-(2-formamido)-ethyl pyrazole into an organic solvent, adding NaI to perform a substitution reaction to obtain 7bata-tertbutyloxycarbonyl-amino-3-[3-formamido-2-(2-formamido)-ethyl pyrazoles]methyl-3-cephem-4-diphenylmethyl carboxylate; then dissolving the obtained compound into an organic acid, add concentrated hydrochloric acid drop by drop to react for removing a protective group to obtain 7bata- amino-3-[3-amino-2-(2-hydroxyethyl)- pyrazoles]methyl-3-cephem-4-carboxylic acid trihydrochloride. According to the invention, the target product can be obtained only two-step reaction without passing through macroporous resin, the required time is less than a half of that of the prior art, the overall yield is more than three times of that of the prior art with about 73%. The method of the invention has the advantages of simple operation, short reaction time, high yield, high purity, low cost and environmental protection, and is suitable for industrialization production.
Description
Technical field
The present invention relates to the preparation technology of medicine midbody, especially relate to a kind of cephalosporins cefoselis sulfate intermediates preparation.
Background technology
The preparation of existing cefoselis sulfate midbody 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is generally four step rule, for example patent EP 0307804A2, US 4952578, WO 9414818; " Studies on 3 '-Quaternary Ammonium Cephalosporins-IV.Synthesis and antibacterial Activity of 3 ' (2-Alkyl-3-aminopyrazolium) cephalosporins Related to FK037 " (Biorganic and Medicinal Chemistry; 1997,5 (8): 1685); " cefoselis sulfate synthesising process research " (Chinese Journal of New Drugs, 2005,14 (3): 322) etc.The step of such technology comprises: (1) is raw material with 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester; With 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles in room temperature reaction 24h; Extraction; Organic phase is evaporated to dried after drying, gets oily midbody 1; (2) midbody 1 is sloughed 4 and 7 protection bases through trifluoroacetic acid, and crystallization gets midbody 2; (3) midbody 2 is sloughed 3 protection bases through concentrated hydrochloric acid again, and crystallization gets midbody 3; (4) midbody 3 is crossed macroporous resin purification and is obtained title product cefoselis sulfate midbody 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride.
Such technology needs to get title product through four-step reaction, and shortcoming is: total reaction time is long, surpasses 40h; Midbody 1 is liquid, and impurity can't be removed, and is second-rate, and stability is bad, is difficult for storing; Midbody 2 is the moisture absorption very easily, and poor stability is not easy to suitability for industrialized production; Use a large amount of trifluoroacetic acids in the reaction, cost an arm and a leg, and big to equipment corrosion; Gained midbody 3 need pass through macroporous resin purifies, complex operation, and yield is low, and solvent-oil ratio is big, total recovery about 20%.
Summary of the invention
The object of the present invention is to provide a kind of cefoselis sulfate intermediates preparation, its cost is low, yield is high, quality is high, be suitable for suitability for industrialized production.
The objective of the invention is to realize like this: a kind of cefoselis sulfate intermediates preparation is characterized in that comprising following sequential steps:
(1) is dissolved in 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles in the organic solvent; Add NaI substitution reaction takes place, get 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester;
(2) be dissolved in the middle gained compound of step (1) in the organic acid, drip the concentrated hydrochloric acid reaction and sloughs the protection base, get 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride.
In the described step (1), the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles and NaI is 1: 1.1: 1～1: 4: 4.
In the described step (1), the temperature of reaction of substitution reaction is 20～80 ℃.
In the described step (1), organic solvent is selected from one or more mixing in acetonitrile, THF, halohydrocarbon, the ketone.
In the described step (1) after the substitution reaction, extract, crystallization, extraction solvent is selected from one or more mixing in THF, halohydrocarbon, the ester class, recrystallisation solvent is selected from one or both mixing in halohydrocarbon, the ester class.
In the described step (2), the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester and concentrated hydrochloric acid is 1: 5～1: 40.
In the described step (2), temperature of reaction is 10～60 ℃.
In the described step (2), organic acid is selected from one or both mixtures in the lipid acid.
In the described step (2), carry out crystallization purifying after the reaction, recrystallisation solvent is selected from one or both mixtures in ester class, the ketone.
The present invention only needs two-step reaction just can get title product; And need not macroporous resin; Half that required time is technological till now; Total recovery is present more than 3 times of technology, and is about 73%, have simple to operate, the reaction times is short, yield is high, purity is high, cost is low, environmental protection, be fit to the advantage of suitability for industrialized production.
Embodiment
The present invention is a kind of cefoselis sulfate intermediates preparation; It is a starting raw material to be prone to purchasing raw material 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester on the market; Carry out condensation reaction with 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles, get 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester (solid intermediate 1) through crystallization; Midbody 1 is sloughed the basic crystallization purifying of protection through concentrated hydrochloric acid and is got title product cefoselis sulfate midbody 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride.Reaction expression is following:
During preparation; At first be dissolved in 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles in the organic solvent; Add NaI 3 substitution reactions take place, get 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester (solid intermediate 1).Preferably, the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles and NaI is 1: 1.1: 1～1: 4: 4, more preferably 1: 3: 2～1: 3: 3.The temperature of reaction of substitution reaction is 20～80 ℃, preferred 30～60 ℃.Organic solvent is selected from one or more mixing in acetonitrile, THF, halohydrocarbon (for example dichloro Party A alkane, chloroform etc.), the ketone (for example acetone, butanone etc.).After the substitution reaction; Extract, crystallization; Extraction solvent is selected from one or more mixing in THF, halohydrocarbon (for example dichloro Party A alkane, chloroform etc.), the lipid (for example ETHYLE ACETATE, ethyl n-butyrate etc.), and recrystallisation solvent is selected from one or both mixing in halohydrocarbon (for example methylene dichloride, chloroform etc.), the lipid (for example ritalin, ETHYLE ACETATE, ethyl n-butyrate etc.).
Then, be dissolved in gained compound in the above-mentioned steps in the organic acid, drip the concentrated hydrochloric acid reaction and slough the protection base, get 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride.Preferably, the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester and concentrated hydrochloric acid is 1: 5～1: 40, more preferably 1: 10～1: 20.Temperature of reaction is 10～60 ℃, preferred 10～30 ℃.Organic acid is selected from one or both mixtures in the lipid acid such as formic acid, acetate, propionic acid, preferable formic acid.Carry out crystallization purifying after the reaction, recrystallisation solvent is selected from one or both mixtures in ester classes such as ETHYLE ACETATE, ethyl n-butyrate, acetone, butanone or the ketones solvent, ethyl acetate, acetone and mixed solvent thereof.
Embodiment 1
(1), 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester is synthetic
In flask, add 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 10g, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles 10.6g, CH
2Cl
220mL, acetone 10ml, NaI 5.8g is heated to 30～40 ℃ of reactions, and liquid phase is followed the tracks of to react to raw material and iodo thing and is reacted completely (about 12h), and stopped reaction is cooled to room temperature, reaction solution impouring water, CH
2Cl
2In the mixed solution, separatory, organic phase is used water washing, organic phase drips into crystallization in the isopropyl ether, growing the grain 1h, suction filtration, the isopropyl ether washing leaching cake, vacuum-drying, yellow solid 12.13g, yield 121.3%.
(2), 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is synthetic
In flask, add above-claimed cpd 10g, formic acid 20mL, stirring and dissolving, 10～15 ℃ slowly drip concentrated hydrochloric acid 15mL down; Finish, be warming up to 20～25 ℃ of reactions, liquid phase is followed the tracks of reaction to terminal, drips into crystallization in the ETHYLE ACETATE and acetone mixed solvent to reaction solution; Stirring at room 2h is cooled to 0～5 ℃ of growing the grain 2h, suction filtration, washing with acetone filter cake; Vacuum-drying gets off-white color solid 6.53g, yield 65.3%, purity 98.5%.
Embodiment 2
(1), 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester is synthetic
In flask, add 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 10g, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles 10.6g, acetone 20mL, NaI 5.8g; Be heated to 40～50 ℃ of reactions, liquid phase is followed the tracks of reaction (about 11h) to terminal, and stopped reaction is cooled to room temperature; In reaction solution impouring water, ETHYLE ACETATE mixed solution, separatory, organic phase is used water washing, and organic phase drips into crystallization in isopropyl ether, the ETHYLE ACETATE mixed solution; Growing the grain 1h, suction filtration, isopropyl ether washing leaching cake; Vacuum-drying gets yellow solid 11.52g, yield 115.2%.
(2), 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is synthetic
In flask, add above-claimed cpd 10g, acetate 20mL, stirring and dissolving, 10～15 ℃ slowly drip concentrated hydrochloric acid 20mL down; Finish, be warming up to 20～25 ℃ of reactions, liquid phase is followed the tracks of reaction (about 2.5h) to terminal, drips into crystallization in the acetone to reaction solution; Stirring at room 2h is cooled to 0～5 ℃ of growing the grain 2h, suction filtration, washing with acetone filter cake; Vacuum-drying gets faint yellow solid 6.16g, yield 61.6%, purity 98.4%.
Embodiment 3
(1), 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester is synthetic
In flask, add 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 10g, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles 4g, acetonitrile 20mL, NaI 3g, nitrogen replacement is 3 times under stirring; Nitrogen protection, lucifuge is heated to 50～60 ℃ of reactions, and liquid phase is followed the tracks of reaction (about 12h) to terminal; Stopped reaction is cooled to room temperature, in reaction solution impouring water, THF mixed solution, and separatory; Organic phase is used water washing, and organic phase drips into crystallization in isopropyl ether, the ETHYLE ACETATE mixed solution, growing the grain 1h, suction filtration; The isopropyl ether washing leaching cake, vacuum-drying gets yellow solid 11.32g, yield 113.2%.
(2), 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is synthetic
In flask, add above-claimed cpd 10g, propionic acid 20mL, stirring and dissolving slowly drips concentrated hydrochloric acid 6mL; Finish, be warming up to 20～25 ℃ of reactions, liquid phase is followed the tracks of reaction (about 2.5h) to terminal, drips into crystallization in the ETHYLE ACETATE to reaction solution; Stirring at room 2h is cooled to 0～5 ℃ of growing the grain 2h, suction filtration, washing with acetone filter cake; Vacuum-drying gets off-white color solid 5.47g, yield 54.7%, purity 98.5%.
Embodiment 4
(1), 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester is synthetic
In flask, add 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 10g, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles 10.6g, DMF 20mL; NaI 5.8g; Be heated to 50～60 ℃ of reactions, liquid phase is followed the tracks of to react to raw material and iodo thing and is reacted completely stopped reaction; Be cooled to room temperature, reaction solution impouring water, CH
2Cl
2In the mixed solution, separatory, organic phase is used water washing, organic phase drips into crystallization in the isopropyl ether, growing the grain 1h, suction filtration, the isopropyl ether washing leaching cake, vacuum-drying, yellow solid 12.43g, yield 124.3%.
(2), 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is synthetic
In flask, add above-claimed cpd 10g, formic acid 20mL, stirring and dissolving slowly drips concentrated hydrochloric acid 42mL; Finish, be warming up to 30～40 ℃ of reactions, liquid phase is followed the tracks of reaction (about 2.5h) to terminal, drips into crystallization in the acetone to reaction solution; Stirring at room 2h is cooled to 0～5 ℃ of growing the grain 2h, suction filtration, washing with acetone filter cake; Vacuum-drying gets off-white color solid 6.03g, yield 60.3%, purity 98.8%.
Embodiment 5
(1), 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester is synthetic
In flask, add 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester 10g, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles 14.2g, DMA20mL; NaI 11.6g; Be heated to 45～55 ℃ of reactions, liquid phase is followed the tracks of to react to raw material and iodo thing and is reacted completely stopped reaction; Be cooled to room temperature, reaction solution impouring water, CH
2Cl
2In the mixed solution, separatory, organic phase is used water washing, organic phase drips into crystallization in the isopropyl ether, growing the grain 1h, suction filtration, the isopropyl ether washing leaching cake, vacuum-drying, yellow solid 11.91g, yield 119.1%.
(2), 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride is synthetic
In flask, add above-claimed cpd 10g, formic acid 15mL, acetate 5ml, stirring and dissolving slowly drips concentrated hydrochloric acid 40mL; Finish, be warming up to 30～40 ℃ of reactions, liquid phase is followed the tracks of reaction to terminal, drips into crystallization in the acetone to reaction solution; Stirring at room 2h is cooled to 0～5 ℃ of growing the grain 2h, suction filtration, washing with acetone filter cake; Vacuum-drying gets off-white color solid 5.93g, yield 59.3%, purity 98.3%.
Claims (9)
1. cefoselis sulfate intermediates preparation is characterized in that comprising following sequential steps:
(1) is dissolved in 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles in the organic solvent; Add NaI substitution reaction takes place, get 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester;
(2) be dissolved in the middle gained compound of step (1) in the organic acid, drip the concentrated hydrochloric acid reaction and sloughs the protection base, get 7 beta-aminos-3-[3-amino-2-(2-hydroxyethyl)-pyrazoles] methyl-3-cephem-4-carboxylic acid tri hydrochloride.
2. cefoselis sulfate intermediates preparation according to claim 1; It is characterized in that: in the described step (1), the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, 5-formamido group-1-(2-methanoyl)-ethyl pyrazoles and NaI is 1: 1.1: 1～1: 4: 4.
3. cefoselis sulfate intermediates preparation according to claim 1 is characterized in that: in the described step (1), the temperature of reaction of substitution reaction is 20～80 ℃.
4. cefoselis sulfate intermediates preparation according to claim 1 is characterized in that: in the described step (1), organic solvent is selected from one or more mixing in acetonitrile, THF, halohydrocarbon, the ketone.
5. cefoselis sulfate intermediates preparation according to claim 1; It is characterized in that: after the middle substitution reaction of described step (1); Extract, crystallization; Extraction solvent is selected from one or more mixing in THF, halohydrocarbon, the ester class, and recrystallisation solvent is selected from one or both mixing in halohydrocarbon, the ester class.
6. cefoselis sulfate intermediates preparation according to claim 1; It is characterized in that: in the described step (2), the mol ratio of 7 β-tertbutyloxycarbonyl-amino-3-[3-formamido group-2-(2-methanoyl)-ethyl pyrazoles] methyl-3-cephem-4-carboxylic acid benzhydryl ester and concentrated hydrochloric acid is 1: 5～1: 40.
7. cefoselis sulfate intermediates preparation according to claim 1 is characterized in that: in the described step (2), temperature of reaction is 10～60 ℃.
8. cefoselis sulfate intermediates preparation according to claim 1 is characterized in that: in the described step (2), organic acid is selected from one or both mixtures in the lipid acid.
9. cefoselis sulfate intermediates preparation according to claim 1 is characterized in that: in the described step (2), carry out crystallization purifying after the reaction, recrystallisation solvent is selected from one or both mixtures in ester class, the ketone.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875572A (en) * | 2012-10-26 | 2013-01-16 | 四川科伦药物研究有限公司 | A kind of refining method of cefotaxime sulfate intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102875572A (en) * | 2012-10-26 | 2013-01-16 | 四川科伦药物研究有限公司 | A kind of refining method of cefotaxime sulfate intermediate |
| CN102875572B (en) * | 2012-10-26 | 2014-07-30 | 四川科伦药物研究有限公司 | Refinement method of cefoselis sulfate intermediate |
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