CN101974021B - Method for synthesizing cefuroxime acid - Google Patents

Method for synthesizing cefuroxime acid Download PDF

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CN101974021B
CN101974021B CN201010541293A CN201010541293A CN101974021B CN 101974021 B CN101974021 B CN 101974021B CN 201010541293 A CN201010541293 A CN 201010541293A CN 201010541293 A CN201010541293 A CN 201010541293A CN 101974021 B CN101974021 B CN 101974021B
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CN101974021A (en
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任会学
孙友敏
贾祥风
马永山
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Shandong Jianzhu University
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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

A kind of compound method of cefuroxime acid
Technical field
The present invention relates to a kind of compound 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.A, day are all recorded.Its good and isostatic anti-microbial activity be other each generations microbiotic 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 the protection base, obtains product through 8 step reactions step altogether, and the yield of this method is low especially, is merely 21%.After update, method in common mainly prepares through following three steps at present, and route 1 as follows:
Figure BSA00000342949000011
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 midbody (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 under strong alkaline condition, to carry out, 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, are prone to 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 is merely 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 strict regulation has all been carried out to the content of the captax in the cephalo series products in Europe, U.S. man.
With 2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-acetate diethylammonium phosphinylidyne active ester is the novel phosphinylidyne active ester of representative; Have high activity and noresidue poisonous substance, in products such as cefepime, ceftriaxone, used and obtained at present result preferably.
Summary of the invention
To the deficiency of prior art, the present invention provides a kind of compound method of cefuroxime acid, particularly utilizes 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 compound method of cefuroxime acid according to cefuroxime acid synthetic process characteristic.Mainly be that the 7-position aminoacylation reaction in the former reactions step is improved to the synthetic high reactivity midbody 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 midbody 3-deammoniation formyl radical-cefuroxime acid (DCCF), has so both reduced the synthetic step of cefuroxime acid, and the yield of product is enhanced.
The present invention realizes through following technical scheme:
Shown in the following route 2 of the synthetic route of preparation cefuroxime acid of the present invention:
Figure BSA00000342949000031
Route 2 the present invention prepare the operational path of cefuroxime acid
A kind of compound 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 ℃, the 22.8-34.2g that packs in the tap funnel (0.12-0.18mol) diethoxy thiophosphoryl chloride; Be added dropwise to complete in the 30-50min, continued insulation reaction 2-3 hour, HPLC detects the SMIA total overall reaction and finishes; With water washing 2 times, each water 25ml, agitator treating 20-30min; Separatory, organic phase are used 30-80ml 0 ℃ of continuation again, 3% NaHCO 3The aqueous solution and the water washing of 30-100ml saturated common salt, separatory; Organic phase is with 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 subsequent use.
(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, 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 is used 12% methanol wash, and 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 slowly drips 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 in reaction flask in about-20 ℃; 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.Above-mentioned solution is with washing with alcohol 3 times, and 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 0.5-1h; 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 compound method of cefuroxime acid, step is following:
(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 ℃, the 25.5g that packs in the tap funnel (0.13mol) diethoxy thiophosphoryl chloride; Be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes; With water washing 2 times, each water 25ml, agitator treating 20min; Separatory, organic phase are used 50ml 0 ℃ of continuation again, 3% NaHCO 3The aqueous solution and the water washing of 50ml saturated common salt; Separatory, organic phase are with 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 subsequent use.
(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 drips off insulated and stirred 15min, adds the solution that sodium hydroxide 2g and purified water 8ml are made into again; Insulated and stirred 15min; Transfer pH to 7 ~ 8 with the hydrochloric acid of 4mol.l-1, 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, with 10% sodium hydroxide solution adjustment pH to 8.0.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 is used 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.Above-mentioned solution is with washing with alcohol 3 times, and 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 following:
1, adopt phosphinylidyne class active ester to prepare deammoniation formyl radical-cefuroxime acid (DCCF), the selectivity of reaction is high, has 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, the excessive o,o-diethylthiophosphoryl chloride in the reaction is met water decomposition, and 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 is and separated, and therefore the purity of active ester in organic phase of preparation can reach 98%, therefore need not an active ester product separation and crystallizes out; Can be directly with its reaction that the 3-deacetylation-7-amino-Cephalosporanic acid (DACA) prepares DCCF as liquid stock and hydrolysis completion; 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
Below in conjunction with embodiment the present invention is done further explanation, but be not limited thereto.Instrument and reagent are explained as follows:
Waters 515HPLC Pump; Bruker ARX-300 type NMR, elemental analyser CARLO-ERBA 1106,7-amino-cephalosporanic acid (7-ACA) (North China Zhong Run grease ltd 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 CP.
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 ℃, the 25.5g that packs in the tap funnel (0.13mol) diethoxy thiophosphoryl chloride; Be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes; With water washing 2 times, each water 25ml, agitator treating 20min; Separatory, organic phase are used 50ml 0 ℃ of continuation again, 3% NaHCO 3The aqueous solution and the water washing of 50ml saturated common salt; Separatory, organic phase are with 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 subsequent use.
(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 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; 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, with 10% sodium hydroxide solution adjustment pH to 8.0.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 is used 12% methanol wash, and vacuum-drying obtains product-deammoniation formyl radical cefuroxime acid (the 3-decarbamoyl cefuroxime of white powder; 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.Above-mentioned solution is with washing with alcohol 3 times, and 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, behind the stirring 0.5h; Continue to add acid again to pH2.0～2.5, ice bath is cooled to below-5 ℃, leaches crystal behind the 0.5h, the frozen water washed twice; The air-dry low-temperature vacuum drying again of room temperature to constant weight gets 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 ℃, the solution 200g with compound S MIF-Cl joins among the Compound D ACA then, drips 10% sodium hydroxide solution again and regulates the pH value; Keep pH=6.5; Insulation reaction 5h to HPLC detects revolution mark＜1.0% of 7-DACA, adds purified water 500ml, with 10% sodium hydroxide solution adjustment pH to 8.0.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, and insulated and stirred 3h separates out crystal; Suction filtration, solid is used 12% methanol wash, and 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.Above-mentioned solution is with washing with alcohol 3 times, and 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, behind the stirring 2.0h; Continue to add acid again to pH2.0 ~ 2.5, ice bath is cooled to below-5 ℃, leaches crystal behind the 1.0h, the frozen water washed twice; The air-dry low-temperature vacuum drying again of room temperature gets cefuroxime acid 140.6g to constant weight, 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 midbody 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, and the hydrogen chloride gas that discharges is seriously polluted to environment, particularly the poor selectivity of this method; 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 different activated method prepares the experimental data contrast of DCCF and sees table 1.
Table 1: the different activated method prepares the comparison of DCCF
Activation method The yield of DCCF Product gas purity " 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 compound method of a cefuroxime acid, synthetic route is following:
Figure FSA00000342948900011
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 tap 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; With water washing 2 times, each water 25ml, agitator treating 20-30min; Separatory, organic phase are used 30-80ml 0 ℃ of continuation again, 3% NaHCO 3The aqueous solution and the water washing of 30-100ml saturated common salt, separatory; Organic phase is with 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 subsequent use;
(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 ℃, the solution 60-100g with compound S MIF-DP joins among the Compound D ACA then, drips 10% sodium hydroxide solution again and regulates 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 gac 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 is used 12% methanol wash, and 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 slowly drips 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 in reaction flask in about-20 ℃; 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; Above-mentioned solution is with washing with alcohol 3 times, and each 10ml keeps water, adds the small amount of activated 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 compound method of cefuroxime acid as claimed in claim 1, step is following:
(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 tap funnel; Be added dropwise to complete in the 30min, continued insulation reaction 2 hours, HPLC detects the SMIA total overall reaction and finishes; With water washing 2 times, each water 25ml, agitator treating 20min; Separatory, organic phase are used 50ml 0 ℃ of continuation again, 3% NaHCO 3The aqueous solution and the water washing of 50ml saturated common salt; Separatory, organic phase are with 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 subsequent use;
(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, with 10% sodium hydroxide solution adjustment pH to 8.0; Tell the water on upper strata behind the stirring 30min, add 20g ethanol at aqueous phase, the back that stirs adds gac 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 is used 12% methanol wash, and 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 slowly drips the mixed solution of 15ml tribromo-acetyl isocyanic ester and acetone 40ml, at-15 ℃ of left and right sides stirring reaction 1h in reaction flask in about-20 ℃; Add frozen water 50ml, add saturated NaHCO again 3Solution 100ml regulates pH to 6.5, and it is clear that solution changes; Above-mentioned solution is with washing with alcohol 3 times, and each 10ml keeps water, adds the small amount of activated 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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Publication number Priority date Publication date Assignee Title
CN101289456A (en) * 2008-06-07 2008-10-22 沂源鑫泉化工有限公司 Method for synthesizing cefuroxime sodium

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101289456A (en) * 2008-06-07 2008-10-22 沂源鑫泉化工有限公司 Method for synthesizing cefuroxime sodium

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究;赵卫良等;《齐鲁药事》;20050430;第24卷(第4期);第238页反应路线图以及"实验部分"1.2 *
氨噻肟酸-锅法合成头孢吡肟盐酸盐;郑庚修等;《济南大学学报(自然科学版)》;20071015;第21卷(第4期);第365页左栏第7-9行、图1以及"实验部分"1.2，第366页左栏"结果与讨论"第1段 *
赵卫良等.(6R 7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究.《齐鲁药事》.2005
郑庚修等.氨噻肟酸-锅法合成头孢吡肟盐酸盐.《济南大学学报(自然科学版)》.2007,第21卷(第4期),第365页左栏第7-9行、图1以及"实验部分"1.2，第366页左栏"结果与讨论"第1段.
陈芬儿.头孢呋辛酯.《有机药物合成法》.1999,第600-603页. *

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