CN105017286B - A kind of preparation method of cephalo-type anti-infectives - Google Patents
A kind of preparation method of cephalo-type anti-infectives Download PDFInfo
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- CN105017286B CN105017286B CN201510398656.8A CN201510398656A CN105017286B CN 105017286 B CN105017286 B CN 105017286B CN 201510398656 A CN201510398656 A CN 201510398656A CN 105017286 B CN105017286 B CN 105017286B
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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
- C07D501/24—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
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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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
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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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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Abstract
The invention belongs to pharmaceutical synthesis field, is related to a kind of preparation method of cephalo-type anti-infectives cefazedone sodium.The inventive method substitutes 7 ACA as raw material using GCLE, overcome the defects of yield existing for prior art is low, pollution is big, it is gentle to provide a kind of reaction condition, side reaction is few, the simple preparation method of technique, this method raw material is cheap and easy to get, cost is relatively low, and product yield is high, purity is high, is adapted to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to a kind of preparation side of cephalo-type anti-infectives cefazedone sodium
Method.
Background technology
Cefazedone sodium (cefazedone sodium) is tested in late 1970s by E Merck, Darmstadt
Room develops, and is first generation cephalosporin class antibiotic.1979, take the lead in listing in Germany by E Merck ＆ Co., Inc.s, thereafter,
The countries and regions listing such as surrounding countries and South Korea, Romania, TaiWan, China.Cefazedone sodium is semi-synthetic cephalosporins
Antibiotic mainly by disturbing and preventing the synthesis of bacteria cell wall, reaches the purpose for suppressing and sterilizing.To clinical common leather
Blue positive and part gram-negative bacteria, part anaerobic bacteria have preferable antibacterial activity, available for respiratory system, urinary system,
The sensitivity such as alimentary infection and gynaecology, peritonaeum, skin, soft tissue and plastic surgery causes the treatment of infection.
The chemical name of cefazedone sodium is：(6R, 7R) -7- (2- (chloro- 4- oxos -1 (the 4H)-pyridine radicals of 3,5- bis-) second
Acylamino-) -3- (((5- methyl isophthalic acids, 3,4- thiadiazoles -2- bases) sulphur) methyl) -8- oxo -5- thia -1- azabicyclos
[4.2.0] oct-2-ene -2- sodium formates；Molecular formula is C18H25Cl2N5O5S3；Molecular weight is 570.42；CAS registration numbers 63521-
15-3.Cefazedone sodium easily dissolves in water, in ethanol slightly soluble, is not dissolved in acetone, chloroform or ether.It is changed
It is as follows to learn structural formula：
Synthesis technique about cefazedone sodium mainly has following several：
1st, the synthetic method of Cefazedone is disclosed in United States Patent (USP) US5945414, is first original by glutaryl 7-ACA
Material reacts 2-10 hours under the conditions of temperature is 90 DEG C in aqueous with mercaptan, and the compound of generation obtains mesh by deacylated
Mark product.
The synthetic route of above-mentioned Cefazedone is longer, and the more impurity of side reaction are more, purification difficult.
2nd, also had been reported that by Material synthesis Cefazedone of 7-ACA, 7-ACA first and 1- methyl thiadiazoles -5- mercaptan is anti-
Should, then obtain Cefazedone with 3,5- dichloropyridine ketone acetic acid.Specific synthetic route is as follows：
The synthetic route is relatively short, but the yield of final Cefazedone is relatively low, and it synthesizes cost and will accordingly carried
Height, be not suitable for industrialization large-scale production.
The content of the invention
In view of the defects of prior art is present, the present invention provides a kind of preparation of cephalo-type anti-infectives cefazedone sodium
Method.Raw material used in this method is that GCLE substitutes 7-ACA, reduces production cost；Simple production process, reaction condition temperature
With side reaction is few, and products obtained therefrom yield, purity are higher.
The present invention is realized using following technical scheme：
A kind of preparation method of cephalo-type anti-infectives, it is characterised in that this method comprises the following steps：
(1) by 7- phenylacetylamino -3- chloromethyl cephalosporanics to methoxy benzyl ester (GCLE) and 2- sulfydryl -5- methyl -
1,3,4- thiadiazoles (MMTD) is reacted in organic solvent, adds elutriation brilliant, is filtered, is washed, vacuum drying obtains 7- benzene second
Acylamino- -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids are to methoxy benzyl ester (GTDE)；
(2) GTDE removes benzhydryl, immobilized penicillin G acylase removing phenylacetyl group, crystallization, mistake with paracresol
Filter, vacuum drying obtain 7- amino -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids
(TDA)；
(3) the chloro- 4- pyridones -1- acetic acid of 3,5- bis- and dibenzothiazyl disulfide (DM) are dissolved in organic solvent, with
Triethyl phosphite is reducing agent, and organic base is catalyst, and reaction obtains Cefazedone side-chain acid active ester；
(4) triethylamine, DMAP and TDA reaction condensation generation cephalos is added dropwise in Cefazedone side-chain acid active ester in ethanol
Western ketone, activated carbon decolorizing is added, filtered, washing, salt forming agent reaction is added dropwise, slowly stirred to muddiness, control temperature and add acetone
Crystallization, filter, wash, dry, obtain cefazedone sodium；Its synthetic route is as follows：
Preferably, in step (1), GCLE and MMTD mol ratio are 1 ﹕ 1.1~1.2；The organic solvent is acetone,
The mass volume ratio of GCLE and organic solvent is 1 ﹕ 3~6；Reaction temperature is 50~55 DEG C, and the reaction time is 2~3 hours.
Preferably, in step (2), when GTDE removes benzhydryl with paracresol, reaction temperature is 45-50 DEG C, reaction
Time is 0.5-6 hours；It is cooled to 40 DEG C after reaction completely, adds ethyl acetate, continues to be cooled to less than 10 DEG C, add 2% carbonic acid
Hydrogen sodium solution extracts, and collects extract, stand-by；GTDE：Paracresol：Ethyl acetate：The mass ratio of 2% sodium bicarbonate solution=
1：2-10：5-15：10-30；Immobilized penicillin G acylase will be added in above-mentioned extract, materials quality proportioning is：GTDE：
Immobilized penicillin G acylase=1：0.6-1；Reaction temperature is 30-37 DEG C, hour in reaction time 1-3, is continuously added into during reaction
2% sodium bicarbonate solution control ph is in 6.5-8.0；After the completion of reaction, crystallization, filtering, vacuum drying obtain TDA.
Preferably, in step (3), the chloro- 4- pyridones -1- acetic acid of 3,5- bis- is dissolved in dibenzothiazyl disulfide (DM)
In organic solvent, organic base is added, reaction 1 hour is stirred at room temperature, then the organic solvent solution dissolved with reducing agent, 1- is slowly added dropwise
It is added dropwise, 20-25 DEG C of stirring reaction 1-2 hour of temperature control, filters in 2 hours, below 10 DEG C of filtrate cooling down, separates out knot
Crystalline substance, filter, dry, produce Cefazedone side-chain acid active ester；Preferably, in step (3), the organic solvent is dichloromethane
Or tetrahydrofuran；The chloro- 4- pyridones -1- acetic acid of 3,5- bis-, dibenzothiazyl disulfide (DM) and reducing agent triethyl phosphite
Molar ratio be the ﹕ 1.10~1.20 of 1.00 ﹕ 1.05~1.10；The organic alkali catalyst is triethylamine or pyridine, organic base
Molar ratio with the chloro- 4- pyridones -1- acetic acid of 3,5- bis- is 1.1-1.3 ﹕ 1.
Preferably, in step (4), the volume of the ethanol is 10-20 times of TDA mass；TDA, Cefazedone side-chain acid
The reaction mol ratio of active ester, triethylamine and DMAP is 1：1.1~1.3：1.05~1.15：0.01~0.02, control temperature 5~
After 20 DEG C are reacted 3~4 hours, activated carbon decolorizing, filtering are added, filtrate controls temperature as 30-50 DEG C of dropwise addition reaction of sodium bicarbonate
For 2-4 hours, it is 6-8 to adjust pH value with sodium acid carbonate；Slowly stir to muddiness, then control temperature to add one for 10-20 DEG C
Quantitative acetone, stir 2 hours, separate out crystallization, be cooled to 0-5 DEG C with 5-10 DEG C/h of rate of temperature fall, be then kept stirring for
80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3 hours；Filtering, washs filter cake, less than 40 DEG C vacuum are done with ethyl acetate
It is dry, obtain product cefazedone sodium.
Present invention improves over the preparation technology of cefazedone sodium, using GCLE as raw material, and 2- sulfydryl -5- methyl isophthalic acids, 3,4-
Thiadiazoles (MMTD) reaction generation intermediate GTDE；Respectively p-cresol and PGA effect under, hydrolysis generation TDA, then with cephalo
Western ketone side-chain acid active ester reaction is successfully prepared cefazedone sodium.Relative to prior art, the invention has the advantages that：
(1) it is initiation material that GCLE is replaced 7-ACA by the present invention, and the reactivity of 3 chloromethyls in GCLE structures is wanted
Better than 3 acetyl-o-methyls in 7-ACA structures, and C-4 positions carboxyl, C-7 bit aminos are protected, carry out C-3 positions anti-
Should be more single-minded, side reaction can be reduced during reaction, it is initiation material synthesis Cefazedone to select GCLE to replace 7-ACA, makes life
Production condition milder, the generation for reducing accessory substance, production technology is simpler, production cost is lower；Products obtained therefrom yield and purity
Higher, appearance color is good.
(2) method of C-7 positions condensation has chloride method, active ester method and dicyclohexylcarbodiimide (DCC) Direct Dehydration etc.
Method, DCC is expensive, and side-chain amino group needs to protect, and the high impurity of reaction temperature is high, yield is relatively low；Chloride method requires waterless operation,
And need to carry out at low temperature, of the invention therefore selection active ester method, synthetic route is simplified, and reaction condition is gently easy to grasp
Make, select ethanol as solvent, simplify operation, and after addition DMAP, accelerate reaction process, 3-4 hours can quantify anti-
Should；Yield is improved, reaches more than 95%.
(3) present invention is using paracresol and immobilized penicillin acylated enzyme substep one kettle way removing carboxyl and amido protecting
Base, original trifluoroacetic acid technique is instead of, reaction yield is improved, simplifies processing step；Have to product quality more apparent
Raising, and immobilized penicillin acylated enzyme can recycle more than 300 times, reduce production cost, and environmental pollution is small,
With the more preferable feature of environmental protection, technique is set to meet the requirement of industrialization.
Embodiment
Technical scheme is further described with embodiment below, it will help to the technical side of the present invention
, there are a further understanding the advantages of case, effect, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim determines.
Embodiment 1：
1) 7- phenylacetylaminos -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids are to first
The preparation of epoxide benzyl ester (GTDE)
600mL acetone is added in dry reaction vessel, is heated to 50 DEG C, by 102.5gGCLE (content 95%, industry
Level, 0.2mol) add in acetone, stirring and dissolving, addition 29.1g 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles (MMTD,
0.22mol), controlling reaction temperature is 50~55 DEG C, and the reaction time is 2 hours, after completion of the reaction, adds elutriation brilliant, filters, be a small amount of
Water cleaning, less than 40 DEG C vacuum drying obtain 112.8g GTDE (0.192mol), yield 96%, and HPLC purity is 99.2%.
2) system of 7- amino -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids (TDA)
It is standby
Obtained 112.8g GTDE (0.192mol), 225.6g paracresol in step 1) are added in reactor, control temperature
Degree is at 45-50 DEG C, stirring reaction 6 hours；Be cooled to 40 DEG C after reaction completely, add 564g ethyl acetate, continue to be cooled to 10 DEG C with
Under, the extraction of 1130mL2% sodium bicarbonate solutions is added in three batches, collects extract, it is stand-by；It will be added in above-mentioned extract
73.3g immobilized penicillin G acylase IPA-750, reaction temperature are 30 DEG C, in 3 hours reaction time, are continuously added into during reaction
2% sodium bicarbonate solution control ph is in 7.8-8.0.Reaction is finished, and is cooled to room temperature, is filtered out IPA-750.And with a little water washing,
Filtrate and washing lotion are cooled to 3~5 DEG C, adjust pH value to be filtered to white solid is separated out after 1-2 with hydrochloric acid, dry 63.1gTDA
(0.1824mol), yield 95%, HPLC purity 99.5%.
3) preparation of Cefazedone side-chain acid active ester：
In dry reaction bulb, by the chloro- 4- pyridones -1- acetic acid (0.25mol) of 55.5g 3,5- bis- with 91.4g's
Dibenzothiazyl disulfide (DM, 0.275mol) is dissolved in 500mL dichloromethane, addition triethylamine 27.8g (0.275mol),
Reaction 1 hour is stirred at room temperature, then dichloromethane solution (the triethyl phosphite 45.7g dissolved with triethyl phosphite is slowly added dropwise
It is dissolved in 150mL dichloromethane, 0.275mol), it is added dropwise in 1 hour, 20-25 DEG C of stirring reaction of temperature control 2 hours, filters, filter
Below 10 DEG C of liquid cooling down, crystallization is separated out, is filtered, is dried, reaction obtains 94g Cefazedone side-chain acid active esters
(0.24125mol)；Yield is that 96.5%, HPLC purity is 99.4%.
4) preparation of cefazedone sodium
Obtained 62gTDA (0.18mol) in step 2) is added in 1000mL ethanol, be cooled to 0 DEG C, triethylamine is added dropwise
19g (0.189mol), 30min is stirred, add 90.6g Cefazedones side-chain acid active ester (0.234mol), add DMAP
0.44g (0.0036mol), after the reaction 3 hours of 5~20 DEG C of control temperature, add 5g activated carbon decolorizings 0.5 hour, filtering, filtrate
It is that 40-50 DEG C of dropwise addition 5% sodium bicarbonate solution reaction is 2 hours to control temperature, and it is 7- to adjust pH value with 5% sodium bicarbonate solution
8；Slowly stir to muddiness, then control temperature to stir 2 hours for 10-20 DEG C of addition 500mL acetone, crystallization is separated out, with 5-10
DEG C/h rate of temperature fall be cooled to 0-5 DEG C, it is small to be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed, growing the grain 1-3
When；Filtering, filter cake is washed with a small amount of ethyl acetate, less than 40 DEG C vacuum drying, obtains product cefazedone sodium 96.5g
(0.1692mol), yield 94%, HPLC purity are 99.8%, and color level is less than yellow 2, and high polymer 0.03% is total miscellaneous
0.083%, maximum single miscellaneous 0.034%.
Embodiment 2：
1) 7- phenylacetylaminos -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids are to first
The preparation of epoxide benzyl ester (GTDE)
600mL acetone is added in dry reaction vessel, 50 DEG C are heated to, by 198.2gGCLE (content 98.3%, work
Industry level, 0.4mol) add in acetone, stirring and dissolving, addition 63.5g 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles (MMTD,
0.48mol), controlling reaction temperature is 50~55 DEG C, and the reaction time is 3 hours, after completion of the reaction, adds elutriation brilliant, filters, be a small amount of
Water cleaning, less than 40 DEG C vacuum drying obtain 223.9g GTDE (0.38mol), yield 95%, and HPLC purity is 98.9%.
2) system of 7- amino -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids (TDA)
It is standby
Obtained 223.9g GTDE (0.38mol), 2239g paracresol in step 1) are added in reactor, control temperature
At 45-50 DEG C, stirring reaction 1 hour；Be cooled to 40 DEG C after reaction completely, add 3360g ethyl acetate, continue to be cooled to 10 DEG C with
Under, the extraction of 6700mL2% sodium bicarbonate solutions is added in three batches, collects extract, it is stand-by；224g will be added in above-mentioned extract
Immobilized penicillin G acylase IPA-450, reaction temperature are 37 DEG C, in 1 hour reaction time, are continuously added into 2% carbonic acid during reaction
Hydrogen sodium solution control ph is in 7.0-7.5.Reaction is finished, and is cooled to room temperature, is filtered out IPA-450.And with a little water washing, filtrate and wash
Liquid is cooled to 3~5 DEG C, adjusts pH value to be filtered to white solid is separated out after 1-2 with hydrochloric acid, dry 128.1gTDA
(0.3686mol), yield 97%, HPLC purity 99.1%.
3) preparation of Cefazedone side-chain acid active ester：
In dry reaction bulb, by the chloro- 4- pyridones -1- acetic acid (0.45mol) of 99.9g 3,5- bis- with 157.1g's
Dibenzothiazyl disulfide (DM, 0.4725mol) is dissolved in 1000mL tetrahydrofuran, adds triethylamine 59g (0.585mol),
Reaction 1 hour is stirred at room temperature, then tetrahydrofuran solution (the triethyl phosphite 89.7g dissolved with triethyl phosphite is slowly added dropwise
It is dissolved in 300mL tetrahydrofurans, 0.54mol), it is added dropwise in 2 hours, 20-25 DEG C of stirring reaction of temperature control 2 hours, filtering, filtrate
Below 10 DEG C of cooling down, crystallization is separated out, is filtered, is dried, reaction obtains 169.7g Cefazedone side-chain acid active esters
(0.4361mol)；Yield is that 96.9%, HPLC purity is 99.5%.
4) preparation of cefazedone sodium
Obtained 124gTDA (0.36mol) in step 2) is added in 1250mL ethanol, be cooled to 0 DEG C, three second are added dropwise
Amine 41.89g (0.414mol), 30min is stirred, add 153.4g Cefazedones side-chain acid active ester (0.396mol), added
DMAP 0.45g (0.0037mol), after the reaction 4 hours of 5~20 DEG C of control temperature, add 5g activated carbon decolorizings 0.5 hour, mistake
Filter, it is that 30-40 DEG C of dropwise addition 5% sodium bicarbonate solution reaction is 4 hours that filtrate, which controls temperature, is adjusted with 5% sodium bicarbonate solution
PH value is 6-7；Slowly stir to muddiness, then control temperature to stir 2 hours for 10-20 DEG C of addition 1000mL acetone, separate out knot
Crystalline substance, 0-5 DEG C is cooled to 5-10 DEG C/h of rate of temperature fall, be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed,
Growing the grain 1-3 hours；Filtering, filter cake is washed with a small amount of ethyl acetate, less than 40 DEG C vacuum drying, obtains product cefazedone sodium
198.6g (0.3457mol), yield 93.8%, HPLC purity are 99.9%, and color level is less than yellow 2, high polymer 0.02%,
Total miscellaneous 0.077%, maximum single miscellaneous 0.033%.
Embodiment 3：
1) 7- phenylacetylaminos -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids are to first
The preparation of epoxide benzyl ester (GTDE)
1000mL acetone is added in dry reaction vessel, 50 DEG C are heated to, by 263gGCLE (content 92.5%, work
Industry level, 0.5mol) add in acetone, stirring and dissolving, addition 76.02g 2- sulfydryl -5- methyl isophthalic acids, 3,4- thiadiazoles (MMTD,
0.575mol), controlling reaction temperature is 50~55 DEG C, and the reaction time is 3 hours, after completion of the reaction, adds elutriation brilliant, filters, be few
The cleaning of amount water, less than 40 DEG C vacuum drying obtain 284.6g GTDE (0.485mol), yield 97%, and HPLC purity is
99.3%.
2) system of 7- amino -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids (TDA)
It is standby
Obtained 284.6g GTDE (0.485mol), 1707.6g paracresol in step 1) are added in reactor, control
Temperature is at 45-50 DEG C, stirring reaction 3 hours；It is cooled to 40 DEG C after reaction completely, adds 2846g ethyl acetate, continue to be cooled to 10 DEG C
Hereinafter, the extraction of 5700mL2% sodium bicarbonate solutions is added in three batches, collects extract, it is stand-by；It will be added in above-mentioned extract
228g immobilized penicillin G acylase IPA-450, reaction temperature are 34 DEG C, in 2 hours reaction time, are continuously added into 2% during reaction
Sodium bicarbonate solution control ph is in 7.0-7.5.Reaction is finished, and is cooled to room temperature, is filtered out IPA-450.And with a little water washing, filtrate
3~5 DEG C are cooled to washing lotion, adjusts pH value to be filtered to white solid is separated out after 1-2 with hydrochloric acid, dry 159.5gTDA
(0.46mol), yield 95%, HPLC purity 99.5%.
3) preparation of Cefazedone side-chain acid active ester：
In dry reaction bulb, by the chloro- 4- pyridones -1- acetic acid (0.62mol) of 137.66g 3,5- bis- with
222.64g dibenzothiazyl disulfide (DM, 0.6696mol) is dissolved in 500mL dichloromethane, adds pyridine 54g
(0.682mol), reaction 1 hour is stirred at room temperature, then the organic solvent solution (phosphorous acid dissolved with triethyl phosphite is slowly added dropwise
Triethyl 118.47g is dissolved in 150mL dichloromethane, 0.713mol), 1-2 is added dropwise in hour, and 20-25 DEG C of stirring of temperature control is anti-
Answer 1-2 hours, filter, below 10 DEG C of filtrate cooling down, separate out crystallization, filter, dry, reaction obtains 234.8g Cefazedones
Side-chain acid active ester (0.6063mol)；Yield is that 97.1%, HPLC purity is 99.3%.
4) preparation of cefazedone sodium
Obtained 159.5gTDA (0.46mol) in step 2) is added in 1600mL ethanol, is cooled to 0 DEG C, three second are added dropwise
Amine (0.506mol) 51.2g, 30min is stirred, add 213.77g Cefazedones side-chain acid active ester (0.552mol), added
DMAP 0.84g (0.0069mol), after the reaction 4 hours of 5~20 DEG C of control temperature, add 5g activated carbon decolorizings 0.5 hour, mistake
Filter, filtrate control temperature that 5% sodium bicarbonate solution reaction 4 hours is added dropwise for 30-50 DEG C, and pH is adjusted with 5% sodium bicarbonate solution
It is worth for 6-8；Slowly stir to muddiness, then control temperature to stir 2 hours for 10-20 DEG C of addition 1300mL acetone, separate out knot
Crystalline substance, 0-5 DEG C is cooled to 5-10 DEG C/h of rate of temperature fall, be then kept stirring for 80-120 revs/min of stirring and crystallizing of speed,
Growing the grain 1-3 hours；Filtering, filter cake is washed with a small amount of ethyl acetate, less than 40 DEG C vacuum drying, obtains product cefazedone sodium
248.17g (0.4351mol), yield 94.2%, HPLC purity are 99.8%, and color level is less than yellow 2, high polymer
0.03%, total miscellaneous 0.076%, maximum single miscellaneous 0.034%.
Claims (3)
1. a kind of preparation method of cephalo-type anti-infectives, it is characterised in that this method comprises the following steps：
（1）By 7- phenylacetylamino -3- chloromethyl cephalosporanics to methoxy benzyl ester (GCLE) and 2- sulfydryl -5- methyl isophthalic acids, 3,
4- thiadiazoles（MMTD）Reacted in organic solvent, add elutriation brilliant, filtered, wash, vacuum drying obtains 7- phenylacetyl ammonia
Base -3- (2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases) sulfidomethyl -3- cephem -4- carboxylic acids are to methoxy benzyl ester（GTDE）；
（2）GTDE is removed to methoxy-benzyl, immobilized penicillin G acylase removing phenylacetyl group, crystallization, mistake with paracresol
Filter, vacuum drying obtain 7- amino -3-（2- methyl isophthalic acids, 3,4- thiadiazoles -5- bases）Sulfidomethyl -3- cephem -4- carboxylic acids
（TDA）；
（3）By the chloro- 4- pyridones -1- acetic acid of 3,5- bis- and dibenzothiazyl disulfide（DM）It is dissolved in organic solvent, addition has
Machine alkali, reaction 1 hour is stirred at room temperature, then the organic solvent solution dissolved with triethyl phosphite is slowly added dropwise, be added dropwise in 1-2 hours
Finish, 20-25 DEG C of stirring reaction 1-2 hour of temperature control, filter, below 10 DEG C of filtrate cooling down, separate out crystallization, filter, dry,
Produce Cefazedone side-chain acid active ester；
（4）Triethylamine, DMAP and TDA reaction condensation generation cephalos west is added dropwise in Cefazedone side-chain acid active ester in ethanol
Ketone, activated carbon decolorizing is added, filtered, washing, filtrate controls temperature to use carbon for 30-50 DEG C of dropwise addition reaction of sodium bicarbonate 2-4 hour
Sour hydrogen sodium regulation pH value is 6-8；Slowly stir to muddiness, then control temperature to add a certain amount of acetone, stirring for 10-20 DEG C
2 hours, crystallization is separated out, 0-5 DEG C is cooled to 5-10 DEG C/h of rate of temperature fall, is then kept stirring for 80-120 revs/min of speed
Clock stirring and crystallizing, growing the grain 1-3 hours；Filtering, filter cake is washed with ethyl acetate, less than 40 DEG C vacuum drying, obtains product cephalo west
Ketone sodium；
Step（1）In, GCLE and MMTD mol ratio are 1：1.1~1.2；The organic solvent is acetone, GCLE with it is organic molten
The mass volume ratio of agent is 1：3~6；Reaction temperature is 50~55 DEG C, and the reaction time is 2~3 hours；
Step（2）In, when GTDE is removed to methoxy-benzyl with paracresol, reaction temperature is 45-50 DEG C, reaction time 0.5-
6 hours；It is cooled to 40 DEG C after reaction completely, adds ethyl acetate, continue to be cooled to less than 10 DEG C, adds 2% sodium bicarbonate solution extraction
Take, collect extract, it is stand-by；Immobilized penicillin G acylase will be added in above-mentioned extract, reaction temperature is 30-37 DEG C, instead
1-3 hours between seasonable, 2% sodium bicarbonate solution control ph is continuously added into 6.5-8.0 during reaction；After the completion of reaction, crystallization,
Filtering, vacuum drying obtain TDA；
In step (3), the organic solvent is dichloromethane or tetrahydrofuran；
In step (4), the TDA, Cefazedone side-chain acid active ester, triethylamine and DMAP reaction mol ratio are 1：1.1~
1.3：1.05~1.15：0.01~0.02,5~20 DEG C of reactions of control temperature generation Cefazedone of after-condensation in 3~4 hours is described
The volume of ethanol is 10-20 times of TDA mass；
Synthetic route is as follows：
Explanation:Explanation: D:\360Downloads\cases\inventions\a55ec61c-d831-49b8-bb02-69f6b0784baa\others\3b53a208-bb63-4a14-ab10-553d389f41ca\100001\dest_path_image002.jpg。
2. preparation method as claimed in claim 1, it is characterised in that in step（2）In, GTDE：Paracresol：Ethyl acetate：
Mass ratio=1 of 2% sodium bicarbonate solution：2-10：5-15：10-30；Materials quality proportioning is：GTDE：Immobilized penicillin G acyl
Change enzyme=1：0.6-1.
3. preparation method as claimed in claim 1, it is characterised in that：In step (3), 3,5- bis- chloro- 4- pyridones -1- second
Acid, dibenzothiazyl disulfide（DM）Molar ratio with reducing agent triethyl phosphite is 1.00：1.05~1.10：1.10
~1.20；The organic alkali catalyst is mole of triethylamine or pyridine, organic base and the chloro- 4- pyridones -1- acetic acid of 3,5- bis-
Ratio is 1.1-1.3：1.
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| CN110143972A (en) * | 2018-02-12 | 2019-08-20 | 罗欣药业(上海)有限公司 | A kind of Cefazedone sodium novel crystal form and preparation method thereof |
| CN109553630B (en) * | 2018-12-29 | 2020-06-09 | 山东罗欣药业集团股份有限公司 | Synthesis method of cefazedone sodium |
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| CN111187283A (en) * | 2020-03-20 | 2020-05-22 | 陶志泽 | Synthesis process of cefazedone sodium |
| CN112552316B (en) * | 2020-12-28 | 2022-08-23 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of cefotetan disodium raw material medicine |
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