CN109369681A - A kind of preparation method of cefditoren pivoxil - Google Patents
A kind of preparation method of cefditoren pivoxil Download PDFInfo
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- CN109369681A CN109369681A CN201811555437.6A CN201811555437A CN109369681A CN 109369681 A CN109369681 A CN 109369681A CN 201811555437 A CN201811555437 A CN 201811555437A CN 109369681 A CN109369681 A CN 109369681A
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- compound
- reaction
- cefditoren pivoxil
- preparation
- chloromethyl
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- 229960002142 cefditoren pivoxil Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 title claims description 10
- -1 Cefditoren pivoxil Cephalosporins Chemical class 0.000 claims abstract description 23
- BUDIODLBJBTUJD-HWZXHQHMSA-N (6r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CCl)=C(C(O)=O)N2C(=O)C(N)[C@H]21 BUDIODLBJBTUJD-HWZXHQHMSA-N 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- PLRLZJVFYFPUJP-QHDYGNBISA-N 2,2-dimethylpropanoyloxymethyl (6R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound CC(C(=O)OCOC(=O)C1=C(CS[C@H]2N1C(C2N)=O)CCl)(C)C PLRLZJVFYFPUJP-QHDYGNBISA-N 0.000 claims description 13
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 10
- 239000011777 magnesium Substances 0.000 claims description 10
- 229910052749 magnesium Inorganic materials 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 8
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 230000000977 initiatory effect Effects 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- QYNYCFHHMAVVQB-UHFFFAOYSA-N 5-(chloromethyl)-4-methyl-1,3-thiazole Chemical compound CC=1N=CSC=1CCl QYNYCFHHMAVVQB-UHFFFAOYSA-N 0.000 claims 3
- NLARCUDOUOQRPB-UHFFFAOYSA-N 2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetic acid Chemical compound CON=C(C(O)=O)C1=CSC(N)=N1 NLARCUDOUOQRPB-UHFFFAOYSA-N 0.000 claims 2
- AOKQVZMGDMUIAO-UHFFFAOYSA-N 2,2-dimethylpropanoic acid iodomethane Chemical compound C(C(C)(C)C)(=O)O.CI AOKQVZMGDMUIAO-UHFFFAOYSA-N 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 150000002466 imines Chemical class 0.000 claims 1
- JSPZULPOZBGXGJ-UHFFFAOYSA-N iodomethyl pentanoate Chemical compound CCCCC(=O)OCI JSPZULPOZBGXGJ-UHFFFAOYSA-N 0.000 claims 1
- 229930186147 Cephalosporin Natural products 0.000 abstract description 18
- 229940124587 cephalosporin Drugs 0.000 abstract description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 12
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 4
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 abstract description 3
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 3
- 238000003747 Grignard reaction Methods 0.000 abstract description 2
- 230000009435 amidation Effects 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 abstract 1
- 238000006206 glycosylation reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- KSVOOXKOWOCYLP-UHFFFAOYSA-N 5-chloro-2,4-dimethyl-1,3-thiazole Chemical compound CC1=NC(C)=C(Cl)S1 KSVOOXKOWOCYLP-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 5
- 229960004011 methenamine Drugs 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002910 solid waste Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PLSLMECRZUEMBM-QHDYGNBISA-N 2,2-dimethylpropanoyloxymethyl (6R)-4-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C(C(C)(C)C)(=O)OCOC(=O)C1=CC(S[C@H]2N1C(C2)=O)C PLSLMECRZUEMBM-QHDYGNBISA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- WLIMJCNCVLQJMJ-UHFFFAOYSA-N 4-chloro-2-methyl-1,3-thiazole Chemical compound CC1=NC(Cl)=CS1 WLIMJCNCVLQJMJ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 201000005010 Streptococcus pneumonia Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 230000003462 zymogenic effect Effects 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
- C07D501/02—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
- C07D501/14—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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to the preparation technical fields of antibiotic, a kind of preparation method of Cefditoren pivoxil Cephalosporins is specifically disclosed, using 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid as starting material, first iodometyl pivalate is used to react with the carboxyl in structure, then the trimethylacetoxymethyl ester of 7-ATCA is obtained after carrying out the aldehyde glycosylation reaction, grignard reaction, dehydration of chloromethyl again, then is allowed to obtain Cefditoren pivoxil Cephalosporins with the progress amidation of 2- methoxyimino -2- (thiazolamine -4- base) acetic acid.The method of the present invention high income, it is at low cost, it is time-consuming short and more environmentally friendly.
Description
Technical field
The present invention relates to antibiotic preparation technical fields, and in particular to a kind of preparation method of Cefditoren pivoxil Cephalosporins.
Background technique
Cefditoren pivoxil Cephalosporins is Third generation Cephalosporins antibiotic, is developed by Japanese Meiji Seika Kaisba company, in 1994
It is listed in Japan, in April, 2001 is in Discussion on Chinese Listed, trade name Meiact (Meiact), to streptococcus pneumonia, the bloodthirsty bar of influenza
Bacterium, micrococcus scarlatinae, staphylococcus aureus, the microbial Community-acquired respiratory tract of the big principal causative of moraxelle catarrhalis 5
It infects significant in efficacy, Zhuo especially is all shown to penicillin resistance pneumococcus, staphylococcus aureus and some zymogenic bacterias
Antibacterial activity more.The structural formula of Cefditoren pivoxil Cephalosporins is as follows:
At present in the synthetic method of Cefditoren pivoxil Cephalosporins, the ethylene linkage between cephalosporin nucleus and thiazole ring is stood by phosphorus leaf mostly
Moral and aldehyde reaction generate, although the reaction of this method is simple, need using toxic triphenylphosphine, and wittig reaction yield
It is lower, it takes a long time, configuration preference is poor, and the solid waste triphenylphosphinc oxide not good utilisation that simultaneous reactions generate can only make solid waste
Processing increases cost.
Summary of the invention
For problem above of the existing technology, it is friendly that the present invention provides a kind of high income, time-consuming short, with high purity and environment
The preparation method of good Cefditoren pivoxil Cephalosporins.
To achieve the above object of the invention, present invention employs the following technical solutions:
A kind of preparation method of Cefditoren pivoxil Cephalosporins, its step are as follows:
(1) with 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid (I) for starting material, under alkaline condition, organic molten
With iodometyl pivalate back flow reaction in agent, 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid trimethyl acetoxyl is generated
Methyl ester (II)；
(2) 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid trimethylacetoxymethyl ester (II) is in organic solvent
Methenamine reaction is neutralized, chloromethyl aldehyde radical is obtained into aldehyde radical product (III)；
(3) 4- methyl-5-chloro methylthiazol (IV) and magnesium are heated to flowing back, and react after initiation with aldehyde radical product (III),
Hydrolysis obtains compound (V)；
(4) compound (V) be dehydrated 7-ATCA trimethylacetoxymethyl ester (VI)；
(5) compound (VI) reacts to obtain target production with 2- methoxyimino -2- (thiazolamine -4- base) acetic acid (VII)
Object Cefditoren pivoxil Cephalosporins.
Reaction process is shown below:
Further, in step (1), the organic solvent is toluene, and the alkali is sodium hydroxide, compound (I), spy
The molar ratio of valeric acid iodine methyl esters and sodium hydroxide is 1:(1~1.5): (1.2~1.5), 1~2h of reflux time.
Further, in step (2), the organic solvent is acetic anhydride, and the molar ratio of compound (I) and methenamine is
1:1.2~1.5,20~30 DEG C of reaction temperature, 2~4h of reaction time.
Further, the solvent of step (3) is tetrahydrofuran, and the molar ratio of compound (III), magnesium and compound (IV) is
1:(1.1~1.2): (1~1.5).
Further, in step (4), the dehydration is that compound (V) reacts de- with p-methyl benzenesulfonic acid in toluene solvant
Water, the additional amount of p-methyl benzenesulfonic acid are the 10~15% of compound (V) quality, 1~2h of back flow reaction.
Further, the solvent of step (5) described reaction is methylene chloride, in N, N'- Dicyclohexylcarbodiimide and 4-
Reacted in the presence of dimethylamino naphthyridine, compound (VI), 2- methoxyimino -2- (thiazolamine -4- base) acetic acid (VII),
The molar ratio of N, N'- Dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) is 1:(1~1.2): (1~
1.5): (0.1~0.3).
Compared with the existing technology, the method for the present invention first reacts the carboxyl on cephalosporin nucleus with iodometyl pivalate, can be same
When play the role of protect carboxyl, then will carry out grignard reaction after chloromethyl aldehyde radical again, be remarkably improved the selection of reaction
Property.The present invention prepares phosphorus ylide without using toxic triphenylphosphine, does not generate triphen oxygen phosphorus solid waste, more environmentally friendly, reacts road
Line does not need wittig reaction, and cost is lower.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1
A kind of preparation method of Cefditoren pivoxil Cephalosporins, the specific steps are as follows:
24.9g 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid (I) is dissolved in toluene, addition 4g NaOH, then plus
Enter 29g iodometyl pivalate, back flow reaction 1.5h, reaction solution is washed with water after reaction, obtains 7- amino -3- after solvent is evaporated off
Chloromethyl -3- cephem -4- carboxylic acid trimethylacetoxymethyl ester (II) 34.8g；(II) is added in acetic anhydride and is dissolved, is added
Enter 16.8g methenamine, 2h is reacted at 30 DEG C, reaction solution is poured into after reaction in 10% sodium hydrate aqueous solution, stirred
5min is mixed, is extracted with ethyl acetate, organic phase is evaporated off solvent and obtains compound (III) 31.7g；2.7g magnesium is immersed in tetrahydrofuran
In, then 14.8g 4- methyl-5-chloro methylthiazol (IV) is dissolved in tetrahydrofuran, instills the Tetrahydrofuran System for being soaked with magnesium
In, it is heated to reflux initiation reaction, drips and finishes back flow reaction 1h, obtain A system, above-mentioned resulting compound (III) is dissolved in tetrahydro furan
In muttering, B system is obtained, B system is added drop-wise in aforementioned A system, drips and finishes back flow reaction 1h, pour into water in 20% ammonium chloride solution
Solution, ethyl acetate extraction, organic phase are evaporated off solvent and obtain compound (V) 42.4g；Compound (V) is dissolved in toluene, is added
4.5g p-methyl benzenesulfonic acid, back flow reaction 1h are evaporated off solvent after reaction solution washing, obtain compound (VI) 41.0g；By 20.6g DCC
It is dissolved in methylene chloride with 1.2g DMAP, resulting compound (VI) and compound (VII) is added, react at room temperature 2h, reaction knot
Shu Hou washes liquid separation, and solvent is evaporated off, obtains Cefditoren pivoxil Cephalosporins 54.6g, yield 88.1%, purity after dehydrated alcohol recrystallization
99.1%.
Embodiment 2
A kind of preparation method of Cefditoren pivoxil Cephalosporins, the specific steps are as follows:
24.9g 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid (I) is dissolved in toluene, addition 6g NaOH, then plus
Enter 36g iodometyl pivalate, back flow reaction 1h, reaction solution is washed with water after reaction, obtains 7- amino -3- chlorine after solvent is evaporated off
Methyl -3- cephem -4- carboxylic acid trimethylacetoxymethyl ester (II) 35.5g；(II) is added in acetic anhydride and is dissolved, is added
20g methenamine reacts 3h at 20 DEG C, after reaction pours into reaction solution in 10% sodium hydrate aqueous solution, stirs
5min is extracted with ethyl acetate, and organic phase is evaporated off solvent and obtains compound (III) 32.4g；2.8g magnesium is immersed in tetrahydrofuran,
Then 22g 4- methyl-5-chloro methylthiazol (IV) is dissolved in tetrahydrofuran, instillation is soaked in the Tetrahydrofuran System of magnesium, is added
Heat reflux initiation reaction, drips and finishes back flow reaction 1h, obtain A system, above-mentioned resulting compound (III) is dissolved in tetrahydrofuran,
B system is obtained, B system is added drop-wise in aforementioned A system, drips and finishes back flow reaction 1h, pour into 20% ammonium chloride solution and hydrolyze, second
Acetoacetic ester extraction, organic phase are evaporated off solvent and obtain compound (V) 43.3g；Compound (V) is dissolved in toluene, is added 4.5g pairs
Toluenesulfonic acid, back flow reaction 1h are evaporated off solvent after reaction solution washing, obtain compound (VI) 41.9g；By 30g DCC and 3.3g
DMAP is dissolved in methylene chloride, and resulting compound (VI) and compound (VII) is added, and reacts at room temperature 2h, after reaction, water
Liquid separation is washed, solvent is evaporated off, obtains Cefditoren pivoxil Cephalosporins 55.4g, yield 89.4%, purity 99.3% after dehydrated alcohol recrystallization.
Embodiment 3
A kind of preparation method of Cefditoren pivoxil Cephalosporins, the specific steps are as follows:
24.9g 7- amino -3- chloromethyl -3- cephem -4- carboxylic acid (I) is dissolved in toluene, addition 6g NaOH, then plus
Enter 31g iodometyl pivalate, back flow reaction 1h, reaction solution is washed with water after reaction, obtains 7- amino -3- chlorine after solvent is evaporated off
Methyl -3- cephem -4- carboxylic acid trimethylacetoxymethyl ester (II) 35.0g；(II) is added in acetic anhydride and is dissolved, is added
18g methenamine reacts 3h at 20 DEG C, after reaction pours into reaction solution in 10% sodium hydrate aqueous solution, stirs
5min is extracted with ethyl acetate, and organic phase is evaporated off solvent and obtains compound (III) 32.1g；2.8g magnesium is immersed in tetrahydrofuran,
- 5 chloro- methylthiazol (IV) of 19g4- methyl is dissolved in tetrahydrofuran, and instillation is soaked in the Tetrahydrofuran System of magnesium, is heated to reflux
Initiation reaction drips and finishes back flow reaction 1h, obtains A system, above-mentioned resulting compound (III) is dissolved in tetrahydrofuran, B is obtained
B system is added drop-wise in aforementioned A system by system, is dripped and is finished back flow reaction 1h, pours into 20% ammonium chloride solution and hydrolyze, acetic acid second
Ester extraction, organic phase are evaporated off solvent and obtain compound (V) 42.9g；Compound (V) is dissolved in toluene, 4.5g is added to toluene
Sulfonic acid, back flow reaction 1h are evaporated off solvent after reaction solution washing, obtain compound (VI) 41.4g；30g DCC and 3.3g DMAP is molten
In methylene chloride, resulting compound (VI) and compound (VII) is added, reacts at room temperature 2h, after reaction, washes liquid separation,
Solvent is evaporated off, obtains Cefditoren pivoxil Cephalosporins 55.0g, yield 88.7%, purity 99.0% after dehydrated alcohol recrystallization.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modification, equivalent replacement or improvement etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (6)
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|---|---|---|---|
| CN201811555437.6A CN109369681B (en) | 2018-12-19 | 2018-12-19 | A kind of preparation method of cefditoren pivoxil |
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|---|---|---|---|
| CN201811555437.6A CN109369681B (en) | 2018-12-19 | 2018-12-19 | A kind of preparation method of cefditoren pivoxil |
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| Publication Number | Publication Date |
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| CN109369681A true CN109369681A (en) | 2019-02-22 |
| CN109369681B CN109369681B (en) | 2020-04-28 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010130708A1 (en) * | 2009-05-12 | 2010-11-18 | Novartis International Pharmaceutical Ltd. | Beta-lactamase inhibitors |
| CN103059047A (en) * | 2013-01-18 | 2013-04-24 | 郑州大学 | Method for preparing ceftizoxime alapivoxil hydrochloride |
| CN105732664A (en) * | 2016-02-05 | 2016-07-06 | 青岛麦瑞特医药技术有限公司 | Method for preparing cefditoren pivoxil cephalosporins |
| WO2016128867A1 (en) * | 2015-02-12 | 2016-08-18 | Wockhardt Limited | Azetidinone containing compounds and their use in treatment of bacterial infections |
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2018
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| WO2010130708A1 (en) * | 2009-05-12 | 2010-11-18 | Novartis International Pharmaceutical Ltd. | Beta-lactamase inhibitors |
| CN103059047A (en) * | 2013-01-18 | 2013-04-24 | 郑州大学 | Method for preparing ceftizoxime alapivoxil hydrochloride |
| WO2016128867A1 (en) * | 2015-02-12 | 2016-08-18 | Wockhardt Limited | Azetidinone containing compounds and their use in treatment of bacterial infections |
| CN105732664A (en) * | 2016-02-05 | 2016-07-06 | 青岛麦瑞特医药技术有限公司 | Method for preparing cefditoren pivoxil cephalosporins |
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Address after: 441000 Xiangcheng Economic Development Zone, Xiangcheng District, Xiangyang City, Hubei Province Patentee after: Hubei Lingsheng Pharmaceutical Co.,Ltd. Address before: 441141 Xiangcheng Economic Development Zone, Xiangcheng District, Xiangyang City, Hubei Province Patentee before: HUBEI LINGSHENG PHARMACEUTICAL CO.,LTD. |
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Denomination of invention: A method for preparing ceftriaxone pivoxil Granted publication date: 20200428 Pledgee: Agricultural Bank of China Limited Xiangyang High tech Zone Branch Pledgor: Hubei Lingsheng Pharmaceutical Co.,Ltd. Registration number: Y2024980002009 |