CN107325114B - A kind of preparation method of Ceftaroline Fosamil intermediate - Google Patents
A kind of preparation method of Ceftaroline Fosamil intermediate Download PDFInfo
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- CN107325114B CN107325114B CN201710537327.6A CN201710537327A CN107325114B CN 107325114 B CN107325114 B CN 107325114B CN 201710537327 A CN201710537327 A CN 201710537327A CN 107325114 B CN107325114 B CN 107325114B
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- 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
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Abstract
The present invention provides a kind of preparation methods of Ceftaroline Fosamil intermediate, comprising the following steps: under radical initiator catalysis, condensation reaction occurs for 3- chlorine cephalo and 4- (4- pyridyl group) -2- thyroidan, then quaternization reaction occurs, and obtains pyridiniujm；Then it is deprotected with one kettle way, obtains Ceftaroline Fosamil intermediate.Compared with prior art, the present invention is using 3- chlorine cephalo as initial reactant, to apply for the first time；3- chlorine cephalo and the condensation reaction of 4- (4- pyridyl group) -2- thyroidan are catalyzed by radical initiator, and reaction safety, processing is convenient, belongs to environmental-friendly reaction type, while the reaction greatly reduces the generation of isomers；The protecting group for removing 4 and 7 simultaneously using one kettle way, to enormously simplify reaction process, and improves the quality of reaction yield and product.The synthetic method has simple process, without harsh reaction condition the advantages that, be very suitable to industrialized production.
Description
Technical field
The invention belongs to cephalo-type medicine intermediate preparation fields, and in particular to a kind of preparation of Ceftaroline Fosamil intermediate
Method.
Background technique
Ceftaroline is the 5th generation cephalosporin analog antibiotic, is to be obtained by forth generation cephalosporin Cefozopran derivative, by day
The exploitation of this Takeda Pharmaceutical Company Limited, ForestLaborstories company, the U.S. obtain market authorization, obtain on October 29th, 2010
U.S. FDA approval listing is obtained, for treating the acquired bacillary enteritis in Adults Community, acute bacterial skin and soft tissue sense
Dye, including infection caused by MRSA.Ceftaroline Fosamil is the pro-drug of ceftaroline, increases its stability, in vivo can
It is hydrolyzed to ceftaroline rapidly and plays drug effect.Ceftaroline Fosamil to most of gram-negative bacteria, Grain-negative anaerobic bacteria and
Grain-positive anaerobic bacteria have stronger antibacterial activity, and its adverse reaction with other cephalosporins compared with relatively gently, safety compared with
It is good.
7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride is head
The key intermediate of spore Lorraine ester, often referred to simply as ceftaroline intermediate parent nucleus.Existing literature (Bioorg&Med.Chem.11
(2003), 2427-2437) and patent report all using 3- hydroxy-cepham as starting material.The priming reaction of 3- hydroxy-cepham can be led
The appearance for causing S-3 isomers, to substantially reduce the yield of reaction and the quality of product.
Summary of the invention
The present invention provides a kind of preparation methods of Ceftaroline Fosamil intermediate, are catalyzed 3- chlorine head using radical initiator
Condensation reaction occurs for spore and 4- (4- pyridyl group) -2- thyroidan, obtains pyridiniujm by methylation reaction；Then one is utilized
Pot method removes 4 and 7 protecting groups simultaneously, obtains Ceftaroline Fosamil intermediate.
Specific reaction step is as follows:
Step 1) is in nonpolar solvent A, under radical initiator catalysis, 3- chlorine cephalo and 4- (4- pyridyl group) -2-
Condensation reaction occurs for thyroidan；The peak area of 3- chlorine cephalo is stirred to react into HPLC less than 0.2%, reaction solution is concentrated into
It is cooled to low temperature after half volume, filters the crystal of precipitation；It is washed with organic solvent B, it is dry, obtain 7- phenylacetylamino -3-
[4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate hydrochloride；
Step 2) reacts the product of step 1) with methylating reagent, obtains 7- phenylacetylamino -3- [4- (1- methyl -4-
Pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate iodide；
The product that step 3) obtains step 2) is dissolved in organic solvent C, phosphorus pentachloride is added, in inert gas shielding
Under, organic base is added dropwise under cryogenic conditions, after fully reacting, then is cooled to -40 DEG C, vicinal diamines, fully reacting is slowly added dropwise
Afterwards；Then phenol is added dropwise, low-temp reaction is complete；Reaction solution is added dropwise to abundant crystallization in organic solvent D, is filtered, filter cake is with organic
Solvent E mashing washing, it is dry, obtain 7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4-
Carboxylic acid dihydrochloride.
Wherein, organic solvent A used in step 1) reaction are as follows: dichloroethanes, carbon tetrachloride, tetrahydrofuran, DMF, first
Benzene, preferably tetrahydrofuran；3- chlorine cephalo and the molar ratio of 4- (4- pyridyl group) -2- thyroidan are Instead
The temperature is answered to beRadical initiator are as follows: cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide
Hydrogen, azodiisobutyronitrile, azobisisoheptonitrile, preferably azodiisobutyronitrile；The input amount of radical initiator is 3- chlorine head
Spore input amountPreferablyOrganic solvent B are as follows: petroleum ether, n-hexane, hexamethylene, preferably stone
Oily ether.
Methylating reagent is iodomethane, dimethyl suflfate or dimethyl carbonate, preferably iodomethane in step 2) reaction.
Reaction dissolvent C described in step 3) reaction are as follows: methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, DMF, it is excellent
It is selected as methylene chloride；The reagent for removing 7 protecting groups is phosphorus pentachloride, organic base and vicinal diamines；The organic base is front three
Amine, triethylamine, pyridine；Preferably pyridine；The vicinal diamines are ethylene glycol, 1,2- propylene glycol, 1,2- butanediol, 2,3- fourth two
Alcohol, preferably 1,2-PD；The reagent for removing 4 protecting groups is fortified phenol, preferably metacresol；Organic solvent D are as follows: stone
Oily ether, n-hexane, hexamethylene, preferably petroleum ether；Organic solvent E are as follows: methylene chloride, chloroform, ethyl acetate, butyl acetate,
Preferably methylene chloride.
The beneficial effects of the present invention are: the present invention is using 3- chlorine cephalo as initial reactant, to apply for the first time；3- chlorine cephalo
It is the precursor of cefaclor key intermediate 7-ACCA, using than wide, yield is also bigger, and also compares in synthesis process
3- hydroxy-cepham has greater advantage；Under radical initiator catalysis, 3- chlorine cephalo and 4- (4- pyridyl group) -2- thyroidan are straight
Condensation reaction is given birth in sending and receiving, thus the step of reducing activation, reaction safety, processing is convenient, belongs to environmental-friendly reaction type,
Also avoid the generation of S-3 isomers；Quaternization reaction occurs again, obtains pyridiniujm；Then 4 are removed simultaneously using one kettle way
Position and 7 protecting groups, carry out the reaction for removing two protecting groups successively in a reaction interval, to enormously simplify
Reaction process, and the quality of reaction yield and product is improved, molar yield about 67.6% (in terms of 3- chlorine cephalo).The conjunction
Have simple process at method, without harsh reaction condition the advantages that, be very suitable to industrialized production.
Specific embodiment
For the preparation method for making the clear Ceftaroline Fosamil intermediate provided by the invention of those skilled in the art, below
It further illustrates in conjunction with the embodiments, but these embodiments are not to be construed as limiting the scope of the invention.
The preparation method of Ceftaroline Fosamil intermediate, reaction step are as follows:
Step 1) is drawn in nonpolar solvent (dichloroethanes, carbon tetrachloride, tetrahydrofuran, DMF, toluene) in free radical
Hair agent (cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, azodiisobutyronitrile, azobisisoheptonitrile) is urged
Under change, condensation reaction, 3- chlorine cephalo and 4- (4- pyridyl group) -2- occur for 3- chlorine cephalo and 4- (4- pyridyl group) -2- thyroidan
The molar ratio of thyroidan isReaction temperature is3- chlorine head is stirred to react into HPLC
The peak area of spore is cooled to low temperature after reaction solution is concentrated into half volume less than 0.2%, filters the crystal of precipitation；With organic
Solvent (petroleum ether, n-hexane, hexamethylene) washing, it is dry, obtain 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2-
Thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate hydrochloride；
Step 2) reacts the product of step 1) with methylating reagent (iodomethane, dimethyl suflfate or dimethyl carbonate),
Obtain 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate iodine
Compound；
The product that step 3) obtains step 2) be dissolved in organic solvent (methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran,
DMF in), phosphorus pentachloride is added, organic base is added dropwise under cryogenic conditions under inert gas protection, after fully reacting, then cool down
To -40 DEG C, vicinal diamines are slowly added dropwise, after fully reacting；Then phenol is added dropwise, low-temp reaction is complete；Reaction solution is added dropwise to organic
Abundant crystallization in solvent (petroleum ether, n-hexane, hexamethylene), filtering, filter cake organic solvent (methylene chloride, chloroform, acetic acid second
Ester, butyl acetate) mashing washing, it is dry, obtain 7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- head
Spore alkene -4- carboxylic acid dihydrochloride.
Embodiment 1
Step 1:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid two
The synthesis of benzene methyl hydrochloride:
24.2g3- chlorine cephalo and 7.8g4- (4- pyridyl group) -2- thyroidan is taken to be dissolved in 200ml dichloroethanes, nitrogen
Gas shielded under the conditions of being protected from light, is slowly added to 0.82g azodiisobutyronitrile, after mixing evenly, is warming up to 83 in 30 minutes internal programs
DEG C, the peak area of 3- chlorine cephalo is stirred to react into HPLC less than 0.2%；Reaction solution is transferred to depressurize on Rotary Evaporators and is steamed
Fall the solvent of 1/2 volume, for reaction solution slow cooling to 0 DEG C, crystallization is overnight；It filters, filter cake is eluted with 400ml petroleum ether, dry；
Obtain (7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole the sulfydryl] -3- cephem -4- carboxylic acid hexichol of compound 1
Methyl ester hydrochloride) 30.9g, molar yield 96.5%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol first
Ester hydrochloride has carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；5.24 (d, J=6.0Hz, 1H)；5.36 (d, J=6.0Hz, 1H)；7.07-7.14(m,6H)；
7.24-7.26(m,1H)；7.30-7.34(m,3H)；7.38-7.41(m,2H)；7.44-7.48(m,4H)；8.45 (d, J=
6.0Hz,2H)；8.94 (d, J=6.0Hz, 2H)；8.95(s,1H)；9.01(s,1H).
Step 2:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of benzhydryl ester iodide:
30.9g compound 1 is dissolved in 300ml THF, at room temperature in dropwise addition 10.6g iodomethane, room temperature in half an hour
Under be stirred to react into HPLC the peak area of compound 1 less than 0.2%；Reaction solution is transferred to Rotary Evaporators by end of reaction
It is upper to depressurize the solvent for evaporating 1/2 volume, then reaction solution is slowly dropped into the methylene chloride (400ml) stirred at low speed, is reacted
For liquid slow cooling to 0 DEG C, crystallization is overnight；It filters, filter cake 400ml eluent methylene chloride, it is dry；Obtain (the 7- benzene second of compound 2
Acylamino- -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate iodide)
32.8g, molar yield 99.2%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol
Methyl esters iodide have carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；4.35 (s, J=6.0Hz, 3H)；5.26 (d, J=6.0Hz, 1H)；5.35 (d, J=6.0Hz, 1H)；
7.06-7.15(m,6H)；7.22-7.24(m,1H)；7.28-7.31(m,3H)；7.33-7.35(m,2H)；7.39-7.43(m,
4H)；8.18 (d, J=6.0Hz, 2H)；8.64 (d, J=6.0Hz, 2H)；8.97(s,1H)；9.08(s,1H).
Two hydrochloric acid of step 3:7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of salt:
32.8g compound 2 is dissolved in 300ml methylene chloride, 20.6g phosphorus pentachloride is added, nitrogen protection is protected from light item
Under part, 5 DEG C are cooled to, in 9.8ml pyridine is added dropwise in half an hour, 0 DEG C is subsequently cooled to, is stirred to react into HPLC compound 2
Peak area less than 0.2%, be cooled to -40 DEG C rapidly, in being added dropwise 25ml1 in half an hour, 2- propylene glycol, be stirred to react to
The peak area of imines chloromethylated intermediate is less than 0.3% in HPLC；In 90ml metacresol is added dropwise in half an hour, temperature is no more than 10
DEG C, the peak area of de- 7 protecting group intermediates is stirred to react into HPLC less than 0.2%；Fully reacting.Under the conditions of 0-2 DEG C,
Reaction solution is added dropwise in 500ml petroleum ether, stirring and crystallizing, product filtering, three times with 200ml methylene chloride mashing washing, is obtained
To compound 3 (7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride)
21.7g, molar yield: 81.3%.
To 7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride into
Nmr analysis and characterization are gone.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.82 (d, J=18.0Hz, 1H)；3.94 (d, J=
18.0Hz,1H)；4.38 (s, J=6.0Hz, 3H)；5.27 (d, J=6.0Hz, 1H)；5.39 (d, J=6.0Hz, 1H)；8.45
(d, J=6.0Hz, 2H)；8.94 (d, J=6.0Hz, 2H)；9.05(s,1H).
The specific synthetic route of embodiment 1 is as follows:
Embodiment 2
Step 1:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid two
The synthesis of benzene methyl hydrochloride:
24.2g3- chlorine cephalo and 7.8g4- (4- pyridyl group) -2- thyroidan is taken to be dissolved in 200ml carbon tetrachloride, nitrogen
Gas shielded under the conditions of being protected from light, is slowly added to 0.58g tert-butyl hydroperoxide, after mixing evenly, is warming up in 30 minutes internal programs
88 DEG C, the peak area of 3- chlorine cephalo is stirred to react into HPLC less than 0.2%；Reaction solution is transferred on Rotary Evaporators and is depressurized
The solvent of 1/2 volume is evaporated, for reaction solution slow cooling to 0 DEG C, crystallization is overnight；It filters, filter cake is eluted with 400ml n-hexane, is done
It is dry；Obtain (7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole the sulfydryl] -3- cephem -4- carboxylic acid of compound 1
Benzhydryl ester hydrochloride) 31.1g, molar yield 97.1%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol first
Ester hydrochloride has carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；5.24 (d, J=6.0Hz, 1H)；5.36 (d, J=6.0Hz, 1H)；7.07-7.14(m,6H)；
7.24-7.26(m,1H)；7.30-7.34(m,3H)；7.38-7.41(m,2H)；7.44-7.48(m,4H)；8.45 (d, J=
6.0Hz,2H)；8.94 (d, J=6.0Hz, 2H)；8.95(s,1H)；9.01(s,1H).
Step 2:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of benzhydryl ester iodide:
31.1g compound 1 is dissolved in 300ml THF, at room temperature in half an hour be added dropwise 19.7g dimethyl suflfate,
It is stirred to react the peak area of the compound 1 into HPLC at room temperature less than 0.2%；Reaction solution is transferred to rotation and steamed by end of reaction
Decompression evaporates the solvent of 1/2 volume on hair instrument, is then slowly dropped into reaction solution in the methylene chloride (400ml) stirred at low speed,
For reaction solution slow cooling to 0 DEG C, crystallization is overnight；It filters, filter cake 400ml eluent methylene chloride, it is dry；Obtain 2 (7- of compound
Phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate iodide)
31.4g, molar yield 97.8%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol
Methyl esters iodide have carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；4.35 (s, J=6.0Hz, 3H)；5.26 (d, J=6.0Hz, 1H)；5.35 (d, J=6.0Hz, 1H)；
7.06-7.15(m,6H)；7.22-7.24(m,1H)；7.28-7.31(m,3H)；7.33-7.35(m,2H)；7.39-7.43(m,
4H)；8.18 (d, J=6.0Hz, 2H)；8.64 (d, J=6.0Hz, 2H)；8.97(s,1H)；9.08(s,1H).
Two hydrochloric acid of step 3:7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of salt
31.4g compound 2 is dissolved in 300ml THF, 20.6g phosphorus pentachloride is added, nitrogen protection is protected from light condition
Under, 5 DEG C are cooled to, in 9.8ml pyridine is added dropwise in half an hour, 0 DEG C is subsequently cooled to, is stirred to react into HPLC compound 2
Peak area is cooled to rapidly -40 DEG C less than 0.2%, in 22ml ethylene glycol is added dropwise in half an hour, is stirred to react to the Central Asia HPLC
The peak area of amine chloromethylated intermediate is less than 0.3%；In 100g phenol is added in half an hour, temperature is stirred to react no more than 10 DEG C
The peak area of 7 protecting group intermediates is taken off into HPLC less than 0.2%；Fully reacting.Under the conditions of 0-2 DEG C, reaction solution is added dropwise
Enter in 500ml n-hexane, stirring and crystallizing, product filtering, three times with 200ml chloroform mashing washing, obtains (the 7- amino-of compound 3
3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride) 20.1g, molar yield:
80.9%.
To 7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride into
Nmr analysis and characterization are gone.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.82 (d, J=18.0Hz, 1H)；3.94 (d, J=
18.0Hz,1H)；4.38 (s, J=6.0Hz, 3H)；5.27 (d, J=6.0Hz, 1H)；5.39 (d, J=6.0Hz, 1H)；8.45
(d, J=6.0Hz, 2H)；8.94 (d, J=6.0Hz, 2H)；9.05(s,1H).
Embodiment 3
Step 1:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid two
The synthesis of benzene methyl hydrochloride:
24.2g3- chlorine cephalo and 7.8g4- (4- pyridyl group) -2- thyroidan is taken to be dissolved in 200ml toluene, nitrogen is protected
Shield, under the conditions of being protected from light, is slowly added to 1.25g dibenzoyl peroxide, after mixing evenly, is warming up to 95 in 30 minutes internal programs
DEG C, the peak area of 3- chlorine cephalo is stirred to react into HPLC less than 0.2%；Reaction solution is transferred to depressurize on Rotary Evaporators and is steamed
Fall the solvent of 1/2 volume, for reaction solution slow cooling to 0 DEG C, crystallization is overnight.It filters, filter cake is eluted with 400ml hexamethylene, dry；
Obtain (7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole the sulfydryl] -3- cephem -4- carboxylic acid hexichol of compound 1
Methyl ester hydrochloride) 30.8g, molar yield 96.4%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol first
Ester hydrochloride has carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；5.24 (d, J=6.0Hz, 1H)；5.36 (d, J=6.0Hz, 1H)；7.07-7.14(m,6H)；
7.24-7.26(m,1H)；7.30-7.34(m,3H)；7.38-7.41(m,2H)；7.44-7.48(m,4H)；8.45 (d, J=
6.0Hz,2H)；8.94 (d, J=6.0Hz, 2H)；8.95(s,1H)；9.01(s,1H).
Step 2:7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of benzhydryl ester iodide:
30.8g compound 1 is dissolved in 300ml DMF, at room temperature in half an hour be added dropwise 16.2g dimethyl carbonate,
It is stirred to react the peak area of the compound 1 into HPLC at room temperature less than 0.2%；Reaction solution is transferred to rotation and steamed by end of reaction
Decompression evaporates the solvent of 1/2 volume on hair instrument, is then slowly dropped into reaction solution in the methylene chloride (400ml) stirred at low speed,
For reaction solution slow cooling to 0 DEG C, crystallization is overnight；It filters, filter cake 400ml eluent methylene chloride, it is dry；Obtain 2 (7- of compound
Phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- diphenylmethyl carboxylate iodide)
32.2g, molar yield 99.0%.
To 7- phenylacetylamino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid hexichol
Methyl esters iodide have carried out nmr analysis and characterization.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.52(s,2H)；3.86 (d, J=18.0Hz, 1H)；3.99
(d, J=18.0Hz, 1H)；4.35 (s, J=6.0Hz, 3H)；5.26 (d, J=6.0Hz, 1H)；5.35 (d, J=6.0Hz, 1H)；
7.06-7.15(m,6H)；7.22-7.24(m,1H)；7.28-7.31(m,3H)；7.33-7.35(m,2H)；7.39-7.43(m,
4H)；8.18 (d, J=6.0Hz, 2H)；8.64 (d, J=6.0Hz, 2H)；8.97(s,1H)；9.08(s,1H).
Two hydrochloric acid of step 3:7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid
The synthesis of salt
32.2g compound 2 is dissolved in 300ml DMF, 20.6g phosphorus pentachloride is added, nitrogen protection is protected from light condition
Under, 5 DEG C are cooled to, in 9.8ml pyridine is added dropwise in half an hour, 0 DEG C is subsequently cooled to, is stirred to react into HPLC compound 2
Peak area is cooled to rapidly -40 DEG C less than 0.2%, in half an hour be added dropwise 31ml 1,2- butanediol, be stirred to react to
The peak area of imines chloromethylated intermediate is less than 0.3% in HPLC；In 90ml paracresol is added dropwise in half an hour, temperature is no more than 10
DEG C, the peak area of de- 7 protecting group intermediates is stirred to react into HPLC less than 0.2%；Fully reacting.Under the conditions of 0-2 DEG C,
Reaction solution is added dropwise in 500ml hexamethylene, stirring and crystallizing, product filtering, three times with 200ml ethyl acetate mashing washing, is obtained
To compound 3 (7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride)
21.5g, molar yield: 81.1%.
To 7- amino -3- [4- (1- methyl -4- pyridine) -2- thiazole sulfydryl] -3- cephem -4- carboxylic acid dihydrochloride into
Nmr analysis and characterization are gone.
Nuclear magnetic data:1HNMR(500MHz,d6-DMS0)δ；3.82 (d, J=18.0Hz, 1H)；3.94 (d, J=
18.0Hz,1H)；4.38 (s, J=6.0Hz, 3H)；5.27 (d, J=6.0Hz, 1H)；5.39 (d, J=6.0Hz, 1H)；8.45
(d, J=6.0Hz, 2H)；8.94 (d, J=6.0Hz, 2H)；9.05(s,1H).
Claims (8)
1. a kind of preparation method of Ceftaroline Fosamil intermediate, it is characterised in that: used starting material is 3- chlorine cephalo, instead
Answer process the following steps are included:
Step 1) is in organic solvent A, under radical initiator catalysis, 3- chlorine cephalo and 4- (4- pyridyl group) -2- sulfydryl thiophene
Condensation reaction occurs for azoles；The peak area of 3- chlorine cephalo is stirred to react into HPLC less than 0.2%, reaction solution is concentrated into a halfbody
It is cooled to low temperature after product, filters the crystal of precipitation；It is washed with organic solvent B, final to obtain intermediate shown in following formula:
The organic solvent A are as follows: dichloroethanes, carbon tetrachloride, tetrahydrofuran, DMF or toluene；The organic solvent B are as follows: stone
Oily ether, n-hexane or hexamethylene；The radical initiator are as follows: cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl mistake
Hydrogen oxide, azodiisobutyronitrile or azobisisoheptonitrile；
The molar ratio of the 3- chlorine cephalo and 4- (4- pyridyl group) -2- thyroidan is l:1.05~1.55；Reaction temperature is 50
DEG C~100 DEG C；The input amount of the radical initiator is the 2%~12% of 3- chlorine cephalo input amount；
Step 2) reacts the product of step 1) with methylating reagent, obtains intermediate shown in following formula:
The product that step 3) obtains step 2) is dissolved in organic solvent C, and phosphorus pentachloride is added, under inert gas protection, in
Organic base is added dropwise under cryogenic conditions, after fully reacting, then is cooled to -40 DEG C, vicinal diamines are slowly added dropwise, after fully reacting；Then
Phenol is added dropwise, low-temp reaction is complete；Reaction solution is added dropwise to abundant crystallization in organic solvent D, is filtered, filter cake is beaten with organic solvent E
Plasm scouring finally obtains intermediate shown in following formula:
The vicinal diamines are as follows: ethylene glycol, 1,2- propylene glycol, 1,2- butanediol or 2,3- butanediol；The phenol is metacresol.
2. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 1, it is characterised in that: institute in step 2)
The methylating reagent stated is iodomethane, dimethyl suflfate or dimethyl carbonate.
3. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 1, which is characterized in that institute in step 3)
The organic solvent C stated are as follows: methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran or DMF；The organic solvent D are as follows: petroleum
Ether, n-hexane or hexamethylene；The organic solvent E are as follows: methylene chloride, chloroform, ethyl acetate or butyl acetate.
4. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 1, which is characterized in that step 3) is described
Organic base are as follows: trimethylamine, triethylamine or pyridine.
5. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 1, which is characterized in that described organic molten
Agent A is tetrahydrofuran；The organic solvent B is petroleum ether；The radical initiator is azodiisobutyronitrile.
6. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 1, it is characterised in that: the free radical
The input amount of initiator is 9%~11%.
7. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 3, it is characterised in that: described organic molten
Agent D is petroleum ether；The organic solvent E is methylene chloride.
8. a kind of preparation method of Ceftaroline Fosamil intermediate according to claim 4, it is characterised in that: described is organic
Alkali is pyridine.
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| CN108440566A (en) * | 2018-01-04 | 2018-08-24 | 北京满格医药科技有限公司 | A kind of process for purification of Ceftaroline Fosamil intermediate 1 |
| CN110878101A (en) * | 2019-12-11 | 2020-03-13 | 华中药业股份有限公司 | Novel method for preparing cefixime mother nucleus 7-AMOCA |
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