CN101974021A - Method for synthesizing cefuroxime acid - Google Patents
Method for synthesizing cefuroxime acid Download PDFInfo
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Abstract
The invention provides a method for synthesizing cefuroxime acid. In the method, a phosphorus acyl active resin is subjected to hydrolysis reaction, the product of the hydrolysis reaction is subjected to aminoacylation, and a 3-decarba-moyl cefuroxime acid intermediate is synthesized by a one-pot method without separating the intermediate, the step of cefuroxime acid synthesis is saved, and the yield of the product is improved greatly.
Description
Technical field
The present invention relates to a kind of synthetic method of cefuroxime acid, particularly relate to a kind of method of utilizing the synthetic cefuroxime acid of phosphinylidyne class active ester, belong to technical field of chemistry.
Background technology
Cephalofruxin (cefuroxime) be by Britain Glaxo company in 1975 at first exploitation listing two generation cynnematin.Multinational pharmacopeia and China version pharmacopeia in 2000 such as English, U.S., day are all recorded.Its good and isostatic anti-microbial activity be other each generations antibiotic irreplaceable.
The synthetic route of cefuroxime acid is to be raw material with 7-ACA the earliest, successively introduces the blocking group of amino and carboxyl in intermediate steps, and finally sloughs protecting group, obtains product through 8 step reactions steps altogether, and the yield of this method is low especially, only is 21%.After update, method in common mainly is prepared by following three steps at present, and route 1 as follows:
Route 1: document prepares the operational path of cefuroxime acid
(1) the first step is a hydrolysis reaction, and promptly the 3-position carboxyl groups of 7-ACA utilizes the method hydrolysis of alkaline hydrolysis, and generation deacetylate-7-amino-cephalosporanic acid (3-deacetyl-7-aminocephalosporin acid, DACA);
(2) second steps were acyl chloride reactions, promptly DACA and intermediate (Z)-2-furyl-2-methoxy imino Acetyl Chloride 98Min. (SMIA-Cl) carry out reaction on the 7-position obtain 3-deammoniation formyl radical-cefuroxime acid (3-decarbamoyl-cefuroxime, DCCF);
(3) final step utilizes Sulfuryl chloride isocyanate and DCCF to carry out the carbamylation reaction of 3-position alcoholic extract hydroxyl group, obtains cefuroxime acid (Cefuroxime Acid).
Than original technology,, but still exist certain deficiency though above-mentioned technology reaction yield is enhanced.Mainly show: the hydrolysis reaction of (1) the first step is to carry out under strong alkaline condition, and the lactam nucleus of 7-ACA also can hydrolysis with this understanding, causes the yield of hydrolysis very low; The acyl chloride reaction in (2) second steps, reaction reagent is used reagent such as oxalyl chloride, phosgene, p-methyl benzene sulfonic chloride always, and these reagent react activity are too high, easily generate more side reaction, make the product color darker; And it is anhydrous response that reaction requires, and operational requirement is higher, and particularly this technology has the very strong acid mist of pungency to produce, and environmental pollution is serious; The carbamylation reaction of the 3-position alcoholic extract hydroxyl group in (3) the 3rd steps utilizes Sulfuryl chloride isocyanate to react, and reactive activity is on the low side, efficient is poor (reaction yield only is 75%), and this raw material also is difficult to obtain.Therefore, the tackling key problem to the innovative approach of above-mentioned technology is the key that cefuroxime acid is produced always.To the existing comparatively detailed report of the improvement of the first step hydrolysis and the 3-position carbamylation technology in the 3rd step.And react for the aminoacylation of the second step 7-position; though also there is the higher relatively and active ester (AE-active ester) that react relatively mild benzothiazoles of bibliographical information utilization activity to substitute the method for acyl chlorides; but can emit 2-mercaptobenzothiazole (captax) simultaneously after this type of active ester and the 7-ACA reaction; and captax residual in medicine has certain influence to human body, so country of Europe, the United States has all carried out strict regulation to the content of the captax in the cephalo series products.
With 2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-acetate diethyl phosphinylidyne active ester is the novel phosphinylidyne active ester of representative; have high activity and noresidue poisonous substance, now in products such as cefepime, ceftriaxone, used and obtained result preferably.
Summary of the invention
At the deficiencies in the prior art, the invention provides a kind of synthetic method of cefuroxime acid, particularly utilize the method for the synthetic cefuroxime acid of phosphinylidyne class active ester.
Terminological interpretation:
The 7-ACA:7-amino-cephemcarboxylic acid;
DCCF:(6R, 7R)-7-[2-furyl kharophen]-3-methylol-Cephalosporanic acid;
DACA:3-deacetylation-7-amino-Cephalosporanic acid;
SMIA:(Z)-2-(2-furyl)-2-methoxy imino ammonium acetate;
SMIA-Cl:(Z)-2-furyl-2-methoxy imino Acetyl Chloride 98Min.;
SMIF-DP: diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester;
Cefuroxime acid: cefuroxime acid.
Summary of the invention:
The present invention has improved the synthetic method of cefuroxime acid according to cefuroxime acid synthetic process characteristic.Mainly be that the 7-position aminoacylation reaction in the former reactions steps is improved to the synthetic high reactivity intermediate SMIF-DP that obtains of novel method; utilize this active ester with the hydrolysis reaction of the first step and the aminoacylation reaction in the 3rd step; without separation of intermediates; one kettle way has synthesized intermediate 3-deammoniation formyl radical-cefuroxime acid (DCCF); so both reduced the synthetic step of cefuroxime acid, the yield of product is enhanced.
The present invention is achieved through the following technical solutions:
Shown in the following route 2 of the synthetic route of preparation cefuroxime acid of the present invention:
Route 2 the present invention prepare the operational path of cefuroxime acid
A kind of synthetic method of cefuroxime acid comprises the steps:
(1) preparation of SMIF-DP
In the four-hole boiling flask of 250ml, add (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate (SMIA) 18.6-27.9g (0.10-0.15mol), be dissolved in 50-100mlCH
2Cl
2In, add Tributylamine 6.5-7.5g (0.035-0.040mol) then, stir and be cooled to 0 ℃, 22.8-34.2g (0.12-0.18mol) the diethoxy thiophosphoryl chloride of packing in the dropping funnel, be added dropwise to complete in the 30-50min, continued insulation reaction 2-3 hour, HPLC detects the SMIA total overall reaction and finishes, wash with water 2 times, each water 25ml, agitator treating 20-30min, separatory, organic phase is again at 0 ℃ of continuation 30-80ml, 3% NaHCO
3The aqueous solution and the water washing of 30-100ml saturated common salt, separatory, organic phase anhydrous magnesium sulfate drying, filtration, obtain faint yellow organic solution compound (1) diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester (SMIF-DP), need not separate, the purity 98% of HPLC testing product, cryopreservation is standby.
(2) preparation of DACA
With 7-ACA13.6-40.8g, (0.05-0.15mol) add in five mouthfuls of bottles, add purified water 50-150ml then, methyl alcohol 80-150ml is cooled to-20 ℃, the solution that dropping sodium 4-8g and purified water 10-20ml are made in 15-30min, drip off insulated and stirred 15-30min, add the solution that sodium hydroxide 2-4g and purified water 6-10ml are made into again, insulated and stirred 15-30min uses 4mol.l
-1Hydrochloric acid transfer pH to 7～8, obtain white powder compound (2) 3-deacetylation-7-amino-Cephalosporanic acid (DACA).
(3) preparation of deammoniation formyl radical-cefuroxime acid
Get compound (2) (DACA) 34.5-57.5g (0.15-0.25mol) in the there-necked flask of 500ml, temperature control-10 ℃, solution 60-100g with compound S MIF-DP joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate pH value, keep pH=6.5～7.5, insulation reaction 2-3 hour revolution mark＜1.0% to HPLC detection 7-DACA, add purified water 150-250ml, adjust pH to 8.0 with 10% sodium hydroxide solution.Tell the water on upper strata behind the stirring 30min, add 15-25g ethanol at aqueous phase, the back that stirs adds activated carbon 3-5g, decolouring 30-40min, and filtration, the solution that obtains cools to 0 ℃ again.Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9-2.2 of solution, and insulated and stirred 2h separates out crystal, suction filtration, and solid 12% methanol wash, vacuum-drying obtains the product-deammoniation formyl radical cefuroxime acid (DCCF) of white powder;
(4) preparation of cefuroxime acid
In the there-necked flask of 500ml, add 35-40g DCCF and 150-200ml acetone stirring and dissolving, control reaction temperature is in about-20 ℃, slowly in reaction flask, drip the mixed solution of 10-20ml tribromo-acetyl isocyanic ester and acetone 30-50ml, at-15 ℃ of left and right sides stirring reaction 1-2h, add frozen water 30-80ml, add saturated NaHCO again
3Solution 80-120ml regulates pH to 6.5-7.0, and it is clear that solution changes.Washing with alcohol 3 times of above-mentioned solution, each 10ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion.Water carries out acidifying with 2mol/LHCl, drop to and just separate out crystallization, stop to add acid, after stirring 0.5-1h, continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, leaches crystal behind the 0.5-1h, the frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight gets cefuroxime acid (Cefuroxime Acid).
Preferably, a kind of synthetic method of cefuroxime acid, step is as follows:
(1) preparation of SMIF-DP
In the four-hole boiling flask of 250ml, add (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate (SMIA) 23.4g (0.125mol), be dissolved in 75mlCH
2Cl
2In, add Tributylamine 6.5g (0.035mol) then, stir and be cooled to 0 ℃, 25.5g (0.13mol) the diethoxy thiophosphoryl chloride of packing in the dropping funnel, be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes, wash with water 2 times, each water 25ml, agitator treating 20min, separatory, organic phase is again at 0 ℃ of continuation 50ml, 3% NaHCO
3The aqueous solution and the water washing of 50ml saturated common salt, separatory, organic phase anhydrous magnesium sulfate drying, filtration, obtain faint yellow organic solution compound (1) (SMIF-DP), diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester (SMIF-DP), need not separate, the purity 98% of HPLC testing product, cryopreservation is standby.
(2) preparation of DACA
7-ACA 27.2g (0.1mol) is added in five mouthfuls of bottles; add purified water 80ml then; methyl alcohol 100ml; be cooled to-20 ℃; the solution that dropping sodium 4g and purified water 12ml are made in 15min; drip off insulated and stirred 15min; add the solution that sodium hydroxide 2g and purified water 8ml are made into again; insulated and stirred 15min; hydrochloric acid with 4mol.l-1 is transferred pH to 7 ~ 8; obtain white powder compound (2) 3-deacetylation-7-amino-Cephalosporanic acid (3-deactyl-7-amino-cephalosporinacid, DACA).
(3) preparation of deammoniation formyl radical-cefuroxime acid
Get compound (2) (DACA) 46g (0.2mol) in the there-necked flask of 500ml, temperature control-10 ℃, solution 80g with compound S MIF-DP joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate pH value, keep pH=6.5～7.5, revolution mark＜1.0% of insulation reaction 2h to HPLC detection 7-DACA, add purified water 200ml, adjust pH to 8.0 with 10% sodium hydroxide solution.Tell the water on upper strata behind the stirring 30min, add 20g ethanol at aqueous phase, the back that stirs adds activated carbon 4g, decolouring 30min, and filtration, the solution that obtains cools to 0 ℃ again.Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9 of solution, and insulated and stirred 2h separates out crystal, suction filtration, solid 12% methanol wash, vacuum-drying obtain white powder product-deammoniation formyl radical cefuroxime acid (3-decarbamoyl cefuroxime, DCCF).
(4) preparation of cefuroxime acid
In the there-necked flask of 500ml, add 38.1g (0.1mol) DCCF and 200ml acetone stirring and dissolving, control reaction temperature slowly drips 15ml tribromo-acetyl isocyanic ester (Cl in reaction flask in about-20 ℃
3CONCO) and the mixed solution of acetone 40ml,, add frozen water 50ml, add saturated NaHCO again at-15 ℃ of left and right sides stirring reaction 1h
3Solution 100ml regulates pH to 6.5, and it is clear that solution changes.Washing with alcohol 3 times of above-mentioned solution, each 10ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion.Water carries out acidifying with 2mol/LHCl, drops to just to separate out crystallization, stops to add acid, after stirring 0.5h, continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, 0.5h after leach crystal, the frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight gets cefuroxime acid.
Excellent results of the present invention is as follows:
1, adopt phosphinylidyne class active ester to prepare deammoniation formyl radical-cefuroxime acid (DCCF); the selectivity height of reaction; improved the yield of product; the total recovery of cephalofruxin acid product reaches 67.7%; than document [Li Aijun, Zhou Xueqin, Liu Dongzhi. Cefuroxime sodium optimization of synthesis [J]. University Of Tianjin's journal; 2007,40 (11): 1342-1345.] yield 44.6% has improved 23%.
2; in the reaction of phosphinylidyne class active ester; excessive o,o-diethylthiophosphoryl chloride in the reaction is met water decomposition; the back forms ammonium salt with Tributylamine and is soluble in the aqueous phase; the SMIA of trace itself is exactly an ammonium salt simultaneously; water soluble and separated; therefore the purity of active ester in organic phase of preparation can reach 98%; therefore need not an active ester product separation crystallizes out; can be directly its 3-deacetylation-7-amino-Cephalosporanic acid (DACA) of finishing as stock liquid and hydrolysis be prepared the reaction of DCCF; thereby can save single step reaction; the purity of the DCCF of preparation is 98.5～99%, content 97.5～100%.
3, selected for use comparatively cheap and active moderate tribromo-acetyl isocyanic ester to substitute Sulfuryl chloride isocyanate, made reaction comparatively gentle, control easily.The tribromo-acetyl isocyanic ester both can with hydroxyl reaction also can with carboxyl reaction, for avoiding the side reaction of itself and carboxyl, reaction system should remain in the alkaline environment, will be strict controlled in anhydrous environment simultaneously, to guarantee the yield and the purity of product.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited thereto.Instrument and reagent are described as follows:
Waters 515HPLC Pump, Bruker ARX-300 type nuclear magnetic resonance analyser, elemental analyser CARLO-ERBA 1106,7-amino-cephalosporanic acid (7-ACA) (North China Zhong Run grease company limited produces and sells), (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate (SMIA, Hebei Bai Qi pharmaceutcal corporation, Ltd), diethoxy phosphorus is for sulfuryl chloride (Shanghai Badische biological medicine company produces and sells), and all the other reagent are chemical pure.
Embodiment:
(1) preparation of SMIF-DP
In the four-hole boiling flask of 250ml, add (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate (SMIA) 23.4g (0.125mol), be dissolved in 75mlCH
2Cl
2In, add Tributylamine 6.5g (0.035mol) then, stir and be cooled to 0 ℃, 25.5g (0.13mol) the diethoxy thiophosphoryl chloride of packing in the dropping funnel, be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes, wash with water 2 times, each water 25ml, agitator treating 20min, separatory, organic phase is again at 0 ℃ of continuation 50ml, 3% NaHCO
3The aqueous solution and the water washing of 50ml saturated common salt, separatory, organic phase anhydrous magnesium sulfate drying, filtration, obtain faint yellow organic solution compound (1) diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester (SMIF-DP), need not separate, the purity 98% of HPLC testing product, cryopreservation is standby.
(2) preparation of DACA
7-ACA 27.2g (0.1mol) is added in five mouthfuls of bottles; add purified water 80ml then, methyl alcohol 100ml is cooled to-20 ℃; the solution that dropping sodium 4g and purified water 12ml are made in 15min; drip off insulated and stirred 15min, add the solution that sodium hydroxide 2g and purified water 8ml are made into again, insulated and stirred 15min; hydrochloric acid with 4mol.l-1 is transferred pH to 7 ~ 8; obtain white powder compound (2) 3-deacetylation-7-amino-Cephalosporanic acid (DACA), (21.1g, yield: 92%).HPLC testing product purity is 98～99%, content 98.5～100%.1H?NMR(DMSO)，δ：12.31(s，1H)，8.81(d，2H)，5.56(m，1H)，4.70(m，1H)，4.48(m，1H)，4.20(s，2H)，3.10(bs，2H)。
(3) deammoniation formyl radical-cefuroxime acid (3-decarbamoyl cefuroxime, preparation DCCF)
Get compound (2) (DACA) 46g (0.2mol) in the there-necked flask of 500ml, temperature control-10 ℃, solution 80g with compound S MIF-DP joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate pH value, keep pH=6.5～7.5, revolution mark＜1.0% of insulation reaction 2h to HPLC detection 7-DACA, add purified water 200ml, adjust pH to 8.0 with 10% sodium hydroxide solution.Tell the water on upper strata behind the stirring 30min, add 20g ethanol at aqueous phase, the back that stirs adds activated carbon 4g, decolouring 30min, and filtration, the solution that obtains cools to 0 ℃ again.Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9 of solution; insulated and stirred 2h separates out crystal, suction filtration; solid 12% methanol wash; vacuum-drying obtain white powder product-deammoniation formyl radical cefuroxime acid (3-decarbamoyl cefuroxime, DCCF), 66.3g; productive rate: 87%; (document: 77%), HPLC testing product purity is 98.5～99%, content 97.5～100%.
1H?NMR(DMSO，δ)：9.84(d，1H)，7.76(1H，bs)，
6.81(m，2H)，5.71(s，1H)，5.10(m，1H)，4.75(m，2H)，3.82(s，3H)，1.99(s，3H).
(4) preparation of cefuroxime acid
In the there-necked flask of 500ml, add 38.1g (0.1mol) DCCF and 200ml acetone stirring and dissolving, control reaction temperature slowly drips 15ml tribromo-acetyl isocyanic ester (Cl in reaction flask in about-20 ℃
3CONCO) and the mixed solution of acetone 40ml,, add frozen water 50ml, add saturated NaHCO again at-15 ℃ of left and right sides stirring reaction 1h
3Solution 100ml regulates pH to 6.5, and it is clear that solution changes.Washing with alcohol 3 times of above-mentioned solution, each 10ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion.Water carries out acidifying with 2mol/LHCl, drops to just to separate out crystallization, stops to add acid, after stirring 0.5h, continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, 0.5h after leach crystal, frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight get cefuroxime acid (Cefuroxime Acid) 31.6g, yield 84.5%, fusing point: 174-175 ℃, (document, 75%, 173.5-175 ℃), HPLC normalization method purity is more than 98%, content 98.5-99%.Ultimate analysis (C
16H
16N
4O
8S) theoretical value (measured value, %): C:45.28 (45.30), H:3.70 (3.76), N:13.25 (13.25), O:30.20 (30.10), S:7.57 (7.59).
1H NMR (D
2O, δ): 7.55 (1H, d, furans-5H), 6.61 (1H, d, furans-3H), 6.62 (1H, q, furans-4H), 5.88 (1H, d, cephalo main ring 6-CH), 4.62 (2H, q, cephalo main ring C
3-CH
2), 4.05 (3H, s, NOCH
3), 3.23 (2H, q, cephalo main ring 4-CH
2).
Comparative Examples 1: the preparation of deammoniation formyl radical-cefuroxime acid (DCCF)
Get compound (DACA) 115.0g (0.5mol) in the there-necked flask of 1000ml, temperature control-10 ℃, solution 200g with compound S MIF-Cl joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate the pH value, keep pH=6.5, insulation reaction 5h to HPLC detects revolution mark＜1.0% of 7-DACA, adds purified water 500ml, adjusts pH to 8.0 with 10% sodium hydroxide solution.Tell the water on upper strata behind the stirring 90min, add 50g ethanol at aqueous phase, the back that stirs adds activated carbon 10g, decolouring 60min, and filtration, the solution that obtains cools to 0 ℃ again.Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9 of solution; insulated and stirred 3h separates out crystal, suction filtration; solid 12% methanol wash; vacuum-drying obtains the product-deammoniation formyl radical cefuroxime acid (DCCF) of white powder, 100.3g, productive rate: 77%; (patent US; 5084568[p] .19921-28-0:77%), HPLC testing product purity is 97.5%, content 98.5%.
Comparative Examples 2: the preparation of cefuroxime acid
In the there-necked flask of 2000ml, add 190.1g (0.5mol) DCCF and 1000ml acetone stirring and dissolving, control reaction temperature slowly drips 80ml Sulfuryl chloride isocyanate (Cl in reaction flask in about-20 ℃
3CONCO) and the mixed solution of acetone 200ml,, add frozen water 250ml, add saturated NaHCO again at-15 ℃ of left and right sides stirring reaction 1h
3Solution 500ml regulates pH to 6.5, and it is clear that solution changes.Washing with alcohol 3 times of above-mentioned solution, each 50ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion.Water carries out acidifying with 2mol/L HCl, drops to just to separate out crystallization, stops to add acid, after stirring 2.0h, continue to add acid again to pH2.0 ~ 2.5, ice bath is cooled to below-5 ℃, 1.0h after leach crystal, the frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight gets cefuroxime acid 140.6g, yield 73.5%, fusing point: 174-175 ℃, (patent US, 4284767[P] .1981-08-18.:75%, 173.5-175 ℃), HPLC normalization method purity is more than 98%, content 98.5%.
Conclusion:
Comparative Examples 1 adopts the method for traditional acyl chlorides to prepare intermediate DCCF; embodiment 3 contrasts among this method and the present invention; the harsh requirement of the condition of reaction carried out under complete anhydrous condition; the hydrogen chloride gas that discharges is seriously polluted to environment; the poor selectivity of this method particularly; the impurity of product is many, and the yield of product and purity all are lower than the DCCF that utilizes the preparation of phosphinylidyne active ester among the present invention.The experimental data contrast that different activation methods prepares DCCF sees Table 1.
Table 1: different activation methods prepare the comparison of DCCF
| Activation method | The yield of DCCF | The purity of product | " three wastes " situation |
| Chloride method | 77％ | 97.5~98.5％ | Acid waste water, gas |
| The phosphinylidyne active ester method | 87％ | 98.5~99.0％ | No three wastes material |
Sulfuryl chloride isocyanate of selecting for use in the Comparative Examples 2 and DCCF carry out the carbamylation reaction of 3-position alcoholic extract hydroxyl group; this technology is compared with the tribromo-acetyl isocyanic ester among the present invention; raw material is difficult to be obtained, and reactive activity is on the low side, and the yield of product is lower than the present invention 10%.
Claims (2)
1. the synthetic method of a cefuroxime acid, synthetic route is as follows:
Comprise the steps:
(1) preparation of SMIF-DP
In the four-hole boiling flask of 250ml, add (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate 18.6-27.9g, be dissolved in 50-100mlCH
2Cl
2In, add Tributylamine 6.5-7.5g then, stir and be cooled to 0 ℃, the 22.8-34.2g diethoxy thiophosphoryl chloride of packing in the dropping funnel, be added dropwise to complete in the 30-50min, continued insulation reaction 2-3 hour, HPLC detects the SMIA total overall reaction and finishes, wash with water 2 times, each water 25ml, agitator treating 20-30min, separatory, organic phase is again at 0 ℃ of continuation 30-80ml, 3% NaHCO
3The aqueous solution and the water washing of 30-100ml saturated common salt, separatory, organic phase anhydrous magnesium sulfate drying, filtration, obtain faint yellow organic solution compound (1) diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester, need not separate, the purity 98% of HPLC testing product, cryopreservation is standby;
(2) preparation of DACA
7-ACA13.6-40.8g is added in five mouthfuls of bottles, add purified water 50-150ml then, methyl alcohol 80-150ml, be cooled to-20 ℃, the solution that dropping sodium 4-8g and purified water 10-20ml are made in 15-30min drips off insulated and stirred 15-30min, adds the solution that sodium hydroxide 2-4g and purified water 6-10ml are made into again, insulated and stirred 15-30min uses 4mol.l
-1Hydrochloric acid transfer pH to 7～8, obtain white powder compound (2) 3-deacetylation-7-amino-Cephalosporanic acid;
(3) preparation of deammoniation formyl radical-cefuroxime acid
Get compound (2) 34.5-57.5g in the there-necked flask of 500ml, temperature control-10 ℃, solution 60-100g with compound S MIF-DP joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate the pH value, keep pH=6.5 ~ 7.5, revolution mark＜1.0% that detected 7-DACA to HPLC in insulation reaction 2-3 hour adds purified water 150-250ml, with 10% sodium hydroxide solution adjustment pH to 8.0; Tell the water on upper strata behind the stirring 30min, add 15-25g ethanol at aqueous phase, the back that stirs adds activated carbon 3-5g, decolouring 30-40min, and filtration, the solution that obtains cools to 0 ℃ again; Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9-2.2 of solution, and insulated and stirred 2h separates out crystal, suction filtration, and solid 12% methanol wash, vacuum-drying obtains the product-deammoniation formyl radical cefuroxime acid of white powder;
(4) preparation of cefuroxime acid
In the there-necked flask of 500ml, add 35-40g DCCF and 150-200ml acetone stirring and dissolving, control reaction temperature is in about-20 ℃, slowly in reaction flask, drip the mixed solution of 10-20ml tribromo-acetyl isocyanic ester and acetone 30-50ml, at-15 ℃ of left and right sides stirring reaction 1-2h, add frozen water 30-80ml, add saturated NaHCO again
3Solution 80-120ml regulates pH to 6.5-7.0, and it is clear that solution changes; Washing with alcohol 3 times of above-mentioned solution, each 10ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion; Water carries out acidifying with 2mol/L HCl, drops to just to separate out crystallization, stops to add acid, after stirring 0.5-1h, continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, 0.5-1h after leach crystal, the frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight gets cefuroxime acid.
2. the synthetic method of cefuroxime acid as claimed in claim 1, step is as follows:
(1) preparation of SMIF-DP
In the four-hole boiling flask of 250ml, add (Z)-2-(2-furyl)-2-methoxy imino ammonium acetate 23.4g, be dissolved in 75mlCH
2Cl
2In, add Tributylamine 6.5g then, stir and be cooled to 0 ℃, the 25.5g diethoxy thiophosphoryl chloride of packing in the dropping funnel, be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes, wash with water 2 times, each water 25ml, agitator treating 20min, separatory, organic phase is again at 0 ℃ of continuation 50ml, 3% NaHCO
3The aqueous solution and the water washing of 50ml saturated common salt, separatory, organic phase anhydrous magnesium sulfate drying, filtration, obtain faint yellow organic solution compound (1), diethoxy thiophosphoryl (Z)-2-furyl-2-methoxy imino acetic ester, need not separate, the purity 98% of HPLC testing product, cryopreservation is standby;
(2) preparation of DACA
7-ACA 27.2g is added in five mouthfuls of bottles, add purified water 80ml then, methyl alcohol 100ml, be cooled to-20 ℃, the solution that dropping sodium 4g and purified water 12ml are made in 15min drips off insulated and stirred 15min, add the solution that sodium hydroxide 2g and purified water 8ml are made into again, insulated and stirred 15min transfers pH to 7 ~ 8 with the hydrochloric acid of 4mol.l-1, obtains white powder compound (2) 3-deacetylation-7-amino-Cephalosporanic acid;
(3) preparation of deammoniation formyl radical-cefuroxime acid
Get compound (2) 46g in the there-necked flask of 500ml, temperature control-10 ℃, solution 80g with compound S MIF-DP joins among the Compound D ACA then, drip 10% sodium hydroxide solution again and regulate pH value, keep pH=6.5～7.5, revolution mark＜1.0% of insulation reaction 2h to HPLC detection 7-DACA, add purified water 200ml, adjust pH to 8.0 with 10% sodium hydroxide solution; Tell the water on upper strata behind the stirring 30min, add 20g ethanol at aqueous phase, the back that stirs adds activated carbon 4g, decolouring 30min, and filtration, the solution that obtains cools to 0 ℃ again; Drip 4mol.L then
-1Hydrochloric acid is transferred the pH to 1.9 of solution, and insulated and stirred 2h separates out crystal, suction filtration, and solid 12% methanol wash, vacuum-drying obtains the product-deammoniation formyl radical cefuroxime acid of white powder;
(4) preparation of cefuroxime acid
In the there-necked flask of 500ml, add 38.1gDCCF and 200ml acetone stirring and dissolving, control reaction temperature is in about-20 ℃, slowly in reaction flask, drip the mixed solution of 15ml tribromo-acetyl isocyanic ester and acetone 40ml, at-15 ℃ of left and right sides stirring reaction 1h, add frozen water 50ml, add saturated NaHCO again
3Solution 100ml regulates pH to 6.5, and it is clear that solution changes; Washing with alcohol 3 times of above-mentioned solution, each 10ml keeps water, adds a small amount of activated carbon agitation and filtration, washing filter residue, merging filtrate washing lotion; Water carries out acidifying with 2mol/LHCl, drops to just to separate out crystallization, stops to add acid, after stirring 0.5h, continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, 0.5h after leach crystal, the frozen water washed twice, the air-dry low-temperature vacuum drying again of room temperature to constant weight gets cefuroxime acid.
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| CN105440055A (en) * | 2015-12-30 | 2016-03-30 | 中山市金城道勃法制药有限公司 | Original quality cefuroxime acid and drug preparation thereof |
| CN113372363A (en) * | 2021-04-15 | 2021-09-10 | 深圳市立国药物研究有限公司 | Preparation method of descarbamoyl cefuroxime |
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| CN105440055A (en) * | 2015-12-30 | 2016-03-30 | 中山市金城道勃法制药有限公司 | Original quality cefuroxime acid and drug preparation thereof |
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| CN113372363A (en) * | 2021-04-15 | 2021-09-10 | 深圳市立国药物研究有限公司 | Preparation method of descarbamoyl cefuroxime |
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