CN102924325B - Preparation method for staurosporine medical intermediate - Google Patents
Preparation method for staurosporine medical intermediate Download PDFInfo
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Abstract
The invention relates to a preparation method for a staurosporine medical intermediate. The method comprises the step of: by adopting 2-alkoxy imido acetoacetic ester as a starting material, and bromide/sodium sulfate-hydrogen peroxide-sodium chloride adduct as a brominating reagent, reacting in an organic solvent under the conditions of an acidic reagent and illumination, so as to obtain the staurosporine medical intermediate. The novel preparation method for the staurosporine medical intermediate reduces the corrosion of the production equipment and the pollution of the environment during producing, and is mild and controllable in reaction conditions, and high in utilization rate of the brominating reagent; and the obtained product is high in purity and yield, and can be simply purified and then directly used in the follow-up ring-closure reaction, so that the production is reduced, and higher industrial value is brought.
Description
Technical field
The present invention relates to the medication preparation field, be specifically related to the preparation method of a kind of cephalosporins pharmaceutical intermediate 4-bromo-2-(Z)-alkoxyl group imido grpup acetylacetic ester.
Background technology
Cefotaxime acetic acid, chemistry 2-(thiazolamine-4-yl)-(Z) by name-2-methoxyl group imido grpup acetic acid is preparation such as: cefotaxime (cefotaxime), Cefodizime (cefodizime), ceftriaxone (ceftriaxone), cefuzonam (cefuzonam), cefetamet (cefetamet), cefepime (cefepime), cefpirome (cefpirome) wait the essential intermediate of third and fourth semi-synthetic cephalosporins antibiotic medicine in generation.
According to present many bibliographical informations: cefotaxime acetic acid synthetic, adopting methyl acetoacetate or methyl aceto acetate is starting raw material, prepares through polystep reactions such as nitrosification, etherificate, bromo, cyclization and hydrolysis.Wherein, by synthetic 4-bromo-2-(Z)-methoxyl group imido grpup etheric acid first (second) ester of bromo-reaction, be the important intermediate during cefotaxime acetic acid synthesizes.
Cefotaxime acetic acid bromo intermediate
R
1=-CH
3,-CH
2CH
3；R
2=-CH
3,-CH
2CH
3,t-Bu-,-CH
2COOH
US Patent No. 4843164 reports are raw material with 2-oxyethyl group imido grpup methyl acetoacetate, make solvent with methylene dichloride, need not heating, drip brominated reagent at ambient temperature--bromine prepares product 4-bromo-2-oxyethyl group imido grpup methyl acetoacetate.
Chinese patent CN1036563 report is raw material with 2-methoxyl group imido grpup methyl aceto acetate, and under condition of no solvent, direct and bromine effect generates product 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate.
Chinese patent CN101096362 report is raw material with 2-methoxyl group imido grpup methyl aceto acetate, do at methylene dichloride under the condition of solvent, feed the mixture of bromine or bromine and chlorine, reaction obtains bromination product 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate.
" fine chemistry industry " 2005 the 22nd the 10th phases of volume 792-794 page or leaf report is raw material with 2-methoxyl group imido grpup methyl acetoacetate, drips bromine and prepare bromo intermediate 4-bromo-2-(Z)-methoxyl group imido grpup methyl acetoacetate in 40 ℃ methylene dichloride system.
" chemistry world " the 4th phase 185-186 page or leaf in 1999 is reported the method for synthesizing 2-(thiazolamine-4-yl)-(Z)-2-methoxy imino ethyl acetate with 2-methoxy imino methyl aceto acetate, in building-up process, add a small amount of hydrogen peroxide, reduced the purpose of polluting, reducing cost to reach.But the later stage of this bromination reaction carries out slowly, even speed of response is also undesirable under the reflux conditions.
In the cefotaxime acetic acid of above-mentioned report, all to directly use toxicity is higher, corrodibility is strong, pungency is big bromine as brominated reagent, give transportation, store and use and bring very big inconvenience and potential safety hazard.
For solving problems such as directly using the existing operation inconvenience of bromine in the prior art, the applicant has found the preparation method of cephalosporins pharmaceutical intermediate 4-bromo-2-(Z) of the present invention-alkoxyl group imido grpup acetylacetic ester on the basis of lot of experiments, special proposition the present invention.
Summary of the invention
The present invention is intended to overcome shortcoming and the unfavorable factor of prior art, provides a kind of novelty, the reaction conditions gentleness, the preparation method of cephalosporins pharmaceutical intermediate 4-bromo-2-(Z)-alkoxyl group imido grpup acetylacetic ester (formula I structure) that the brominated reagent utilization ratio is high, that avoid directly using bromine.
Wherein, R
1Be methyl or ethyl; R
2Be methyl, ethyl, the tertiary butyl or carboxymethyl.
Purpose of the present invention is achieved through the following technical solutions:
The preparation method of a kind of cephalosporins pharmaceutical intermediate 4-bromo-2-(Z) of formula I structure-alkoxyl group imido grpup acetylacetic ester, this method comprises: the 2-alkoxyl group imido grpup acetylacetic ester with formula II structure is starting raw material, be brominated reagent with bromide/sodium sulfate-hydrogen peroxide-sodium chloride adduct, under acidic conditions and illumination effect, in organic solvent, react and obtain.Concrete synthesis route is as follows:
R
1=-CH
3,-CH
2CH
3；R
2=-CH
3,-CH
2CH
3,t-Bu-,-CH
2COOH
Organic?Solvent=dichloromethane,1,2-dichloroethane,chloroform
In the technical scheme of the present invention, R
1Group is a kind of in methyl or the ethyl, R
2Group is a kind of in methyl, ethyl, the tertiary butyl or the carboxymethyl.
Organic solvent of the present invention is methylene dichloride, 1, a kind of in 2-ethylene dichloride or the chloroform.
Bromide anion (Br of the present invention
-) provided by bromide.
Bromide of the present invention is Hydrogen bromide or its inorganic salt, the mixture of one or more in preferred Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.Bromide anion (Br in the bromide
-) molar weight be 0.8 ~ 3.0 times of starting raw material 2-alkoxyl group imido grpup acetylacetic ester molar weight, preferred 1.0 ~ 2.0 times.Bromide anion (Br in bromide
-) with the mol ratio of starting raw material 2-alkoxyl group imido grpup acetylacetic ester during less than 0.8 times, feed stock conversion is low, product yield is low.Bromide anion (Br in bromide
-) molar weight when being 0.8 ~ 1.0 times of starting raw material 2-alkoxyl group imido grpup acetylacetic ester molar weight, raw material can transform fully substantially, the product yield height; Bromide anion (Br in bromide
-) molar weight when being 1.0 ~ 2.0 times of starting raw material 2-alkoxyl group imido grpup acetylacetic ester molar weight, reaction is carried out more fully, yield improves; And in the bromide bromide anion (Br
-) molar weight when being 2.0 ~ 3.0 times of starting raw material 2-alkoxyl group imido grpup acetylacetic ester molar weight, product keeps higher yields.When the mol ratio of bromide anion in the bromide (Br-) and starting raw material 2-alkoxyl group imido grpup acetylacetic ester during greater than 3.0 times, the utilization ratio of bromide descends.
Described acid reagent molar weight is 1.5 ~ 5.0 times of bromide anion in the bromide (Br-) molar weight, preferred 2.0 ~ 3.0 times.When the mol ratio of bromide anion (Br-) in acid reagent and the bromide during less than 1.5 times, speed of response is very low.When the acid reagent molar weight was 1.5 ~ 2.0 times of bromide anion in the bromide (Br-) molar weight, speed of response improved greatly, and product yield is higher; When the acid reagent molar weight was 2.0 ~ 3.0 times of bromide anion in the bromide (Br-) molar weight, speed of reaction was further accelerated, and feedstock conversion is more complete, and product yield improves; And the acid reagent molar weight can keep higher product yield when being 3.0 ~ 5.0 times of bromide anion in the bromide (Br-) molar weight.When bromide anion (Br-) mol ratio was greater than 5.0 times in acid reagent and the bromide, the utilization ratio of acid reagent descended.Acid reagent of the present invention is that bright sulfur acid or water content are not higher than the sulfuric acid of 25% (w/w), and the preferred mass mark is 98% sulfuric acid.
The chemical formula of sodium sulfate-hydrogen peroxide of the present invention-sodium chloride adduct is 4Na
2SO
4-2H
2O
2-NaCl, the Theoretical Mass percentage composition of its hydrogen peroxide is about 9.8%.The molar weight of hydrogen peroxide is 0.5 ~ 2.0 times of bromide anion molar weight in the bromide in the described adducts, preferred 1.0 ~ 1.5 times.When the mol ratio of bromide anion in hydrogen peroxide in the adducts and the bromide during less than 0.5 times, conversion of raw material is lower usually, and product yield is undesirable.When the molar weight of hydrogen peroxide in the adducts is in the bromide during 0.5 ~ 1.0 times of bromide anion, raw material can transform fully substantially, the product yield ideal; When the mole dosage of hydrogen peroxide in the adducts is in the bromide during 1.0 ~ 1.5 times of bromide anion, speed of reaction is further accelerated, and feedstock conversion is more complete, the product yield height; When the mole dosage of hydrogen peroxide in the adducts is in the bromide during 1.5 ~ 2.0 times of bromide anion, product keeps higher yields constant.When the mole dosage of hydrogen peroxide further increases (in greater than bromide 2.0 of the bromide anion mole dosage times), cause speed of response to descend on the contrary.
Preparation method of the present invention is the conventional stirring operation under the illumination.The increase of intensity of illumination can improve speed of reaction.
Illumination of the present invention is visible light or UV-light.Described visible light or UV-light can be provided by incandescent light, luminescent lamp (electricity-saving lamp), halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, ultraviolet lamp, sunlight etc., preferred luminescent lamp and Metal-halogen lamp.
Bromo-reaction of the present invention can carry out under the condition of low temperature, room temperature or heating, preferably carries out under room temperature (25 ~ 30 ℃) condition.
The preparation method of cephalosporins pharmaceutical intermediate of the present invention can also comprise follow-up purification step: add weak base and regulate pH value 6 ~ 7 in reaction solution, add S-WAT, standing demix.Organic layer washes with water, and anhydrous sodium sulfate drying is removed organic solvent, namely gets 4-bromo-2-(Z)-alkoxyl group imido grpup acetylacetic ester.
The described weak base of purification step is a kind of in sodium bicarbonate, saleratus, Sodium phosphate dibasic or the dipotassium hydrogen phosphate.
Purification process of the present invention is easier, and the product solution after the washing can be directly used in follow-up and ring-closure reaction thiocarbamide.
Below concrete technical scheme can further specify preparation method of the present invention:
Scheme one
Step comprises: (a) add bromide in organic solvent, stir and drip acid reagent down; (b) treat that hydrogen bromide fully generates after, add raw material 2-alkoxyl group imido grpup acetylacetic ester; (c) under visible light or UV-irradiation, divide 3 ~ 4 batches to add sodium sulfate-hydrogen peroxide-sodium chloride adduct; (d) treat that feedstock conversion fully after, obtain 4-bromo-2-(Z)-alkoxyl group imido grpup acetylacetic ester.
Scheme two
Step comprises: (a) add bromide in organic solvent, stir and drip acid reagent down; (b) treat that hydrogen bromide fully generates after, add raw material 2-alkoxyl group imido grpup acetylacetic ester; (c) disposable adding is equivalent to the sodium sulfate-hydrogen peroxide-sodium chloride adduct of 0.25 times of bromide molar weight, places under visible light or the UV-light and shines; (d) after question response system color obviously disappears and takes off, divide 3 batches to add remaining sodium sulfate-hydrogen peroxide-sodium chloride adduct again, continue to keep illumination, reaction obtains 4-bromo-2-(Z)-alkoxyl group imido grpup acetylacetic ester.
The definition of organic solvent, sodium sulfate-hydrogen peroxide-sodium chloride adduct, visible light or UV-light, the acid reagent etc. described in above-mentioned two schemes is consistent with the definition described in the aforementioned summary of the invention.
Compared with prior art, preparation method of the present invention has following advantage and beneficial effect:
1, preparation method of the present invention directly avoids using the brominated reagent of high toxicity, severe corrosive, strong and stimulating--bromine.
2, preparation method of the present invention carries out under illumination condition, can accelerate speed of reaction by increasing intensity of illumination, and the controllability of reaction is strong.
3, brominated reagent utilization ratio height among the preparation method of the present invention has reduced production cost.
Embodiment
The present invention is described further for the following examples, but do not limit the scope of the invention.
The preparation of embodiment 1 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate
Add methylene dichloride 20mL and Sodium Bromide 3.58g (34.8mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 6.96g (69.6mmol).Drip and finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 5.0g (28.9mmol), add sodium sulfate-hydrogen peroxide-sodium chloride adduct 6.1g (8.7mmol) subsequently.Under the room temperature reaction vessel placed apart from 25W energy-saving fluorescent lamp (colour temperature 6400K) 5cm place and shine.After the reddish-brown of reaction solution is obviously taken off, add remaining sodium sulfate-hydrogen peroxide-sodium chloride adduct 8.4g (12mmol) altogether in three batches, keep illumination.Raw material transformed substantially fully by HPLC detection reaction process in 6 hours.Stop illumination, add water 15mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 15mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 6.0g pale yellow oily liquid body, yield 83% after concentrating and reclaiming solvent.It is 94% that HPLC detects product purity.Through being accredited as title compound.
The preparation of embodiment 2 4-bromo-2-(Z)-oxyethyl group imido grpup methyl acetoacetate
Add methylene dichloride 12mL and Potassium Bromide 2.47g (20.8mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 5.2g (52mmol).Drip to finish, add 2-(Z)-oxyethyl group imido grpup methyl acetoacetate 3.0g (17.3mmol), under the room temperature reaction vessel placed apart from 50W Metal-halogen lamp 5cm place and shine.Add sodium sulfate-hydrogen peroxide-sodium chloride adduct 7.20g (10.4mmol) altogether subsequently in four batches.Reaction solution presents reddish-brown, and color is thin out gradually under the illumination.Stop illumination after 4 hours, add water 10mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 10mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 3.7g pale yellow oily liquid body, yield 85% after concentrating and reclaiming solvent.It is 92% that HPLC detects product purity.Through being accredited as title compound.
The preparation of embodiment 3 4-bromo-2-(Z)-oxyethyl group imido grpup methyl aceto acetate
Add methylene dichloride 20mL and Sodium Bromide 5.86g (57.0mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 11.4g (114mmol).Drip and finish, add 2-(Z)-oxyethyl group imido grpup methyl aceto acetate 5.0g (28.5mmol), add sodium sulfate-hydrogen peroxide-sodium chloride adduct 9.9g (14.3mmol) subsequently.Under the room temperature reaction vessel placed apart from 25W energy-saving fluorescent lamp (colour temperature 6400K) 5cm place and shine.Reaction solution presents reddish-brown, and color is thin out gradually under the illumination, divides 2 batches to add remaining sodium sulfate-hydrogen peroxide-sodium chloride adduct 5.9g (8.5mmol) altogether again, keeps illumination.Stop illumination after 4 hours, add water 15mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 15mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 6.4g pale yellow oily liquid body, yield 90% after concentrating and reclaiming solvent.It is 96% that HPLC detects product purity.Through being accredited as title compound.
The preparation of embodiment 4 4-bromo-2-(Z)-oxyethyl group imido grpup methyl acetoacetate
Add trichloromethane 12mL and Sodium Bromide 1.42g (13.8mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 2.76g (27.6mmol).Drip to finish, add 2-(Z)-oxyethyl group imido grpup methyl acetoacetate 3.0g (17.3mmol), under the room temperature reaction vessel placed apart from 50W Metal-halogen lamp 5cm place and shine.Add sodium sulfate-hydrogen peroxide-sodium chloride adduct 9.58g (13.8mmol) altogether subsequently in four batches.Stop illumination after 6 hours, add water 10mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 10mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 3.5g pale yellow oily liquid body, yield 80% after concentrating and reclaiming solvent.It is 75% that HPLC detects product purity.Through being accredited as title compound.
The preparation of embodiment 5 4-bromo-2-(Z)-oxyethyl group imido grpup methyl aceto acetate
Add methylene dichloride 20mL and Potassium Bromide 3.39g (28.5mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 8.56g (85.5mmol).Drip and finish, add 2-(Z)-oxyethyl group imido grpup methyl aceto acetate 5.0g (28.5mmol). add sodium sulfate-hydrogen peroxide-sodium chloride adduct 14.83g (21.4mmol) altogether subsequently more in four batches, under the room temperature reaction vessel placed apart from 50W Metal-halogen lamp 5cm place simultaneously and shine.Reaction solution presents reddish-brown, and color is thin out gradually under the illumination.Stop illumination after 3 hours, add water 15mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 15mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 5.9g pale yellow oily liquid body, yield 83% after concentrating and reclaiming solvent.It is 87% that HPLC detects product purity, through being accredited as title compound.
The preparation of embodiment 6 4-bromo-2-(Z)-oxyethyl group imido grpup methyl acetoacetate
Add methylene dichloride 20mL and Sodium Bromide 3.27g (31.8mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 15.91g (159mmol).Drip and finish, add 2-(Z)-oxyethyl group imido grpup methyl acetoacetate 5.0g (28.9mmol).Add altogether 13.24g (19.1mmol) of sodium sulfate-hydrogen peroxide-sodium chloride adduct subsequently in four batches, under the room temperature reaction vessel placed apart from 25W energy-saving fluorescent lamp (colour temperature 6400K) 5cm place simultaneously and shine.Reaction solution presents reddish-brown, and color is thin out gradually under the illumination.Stop illumination after 4 hours, add water 15mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 15mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 6g pale yellow oily liquid body, yield 83% after concentrating and reclaiming solvent.It is 94% that HPLC detects product purity, through being accredited as title compound.
The preparation of embodiment 7 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate
Add 1,2-ethylene dichloride 20mL and Sodium Bromide 3.87g (37.6mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 5.64g (56.4mmol).Drip and finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 5.0g (28.9mmol), add sodium sulfate-hydrogen peroxide-sodium chloride adduct 6.52g (9.39mmol) subsequently.Under the room temperature reaction vessel placed apart from 25W energy-saving fluorescent lamp (colour temperature 6400K) 5cm place and shine.Reaction solution presents reddish-brown, and color is thin out gradually under the illumination, adds remaining sodium sulfate-hydrogen peroxide-solid sodium chloride adducts 6.52g (9.39mmol) altogether more in three batches, keeps stirring.Stop illumination after 5 hours, add water 15mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 15mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 6.0g yellow oily liquid, yield 83% after concentrating and reclaiming solvent.It is 93% that HPLC detects product purity, through being accredited as title compound.
The preparation of embodiment 8 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate
Add methylene dichloride 12mL and Potassium Bromide 6.18g (51.9mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 10.4g (104mmol).Drip and finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 3.0g (17.3mmol), add sodium sulfate-hydrogen peroxide-sodium chloride adduct 9.01g (13.0mmol) subsequently.Under the room temperature reaction vessel placed apart from 25W energy-saving fluorescent lamp (colour temperature 6400K) 5cm place and shine.Raw material transformed substantially fully by HPLC monitoring reaction process in 3 hours.Stop illumination, add water 10mL, regulate pH 6 ~ 7 with sodium bicarbonate under the vigorous stirring, and add an amount of S-WAT and make reddish-brown take off.Leave standstill, layering, organic layer water 10mL washing again, anhydrous sodium sulfate drying filters.Filtrate decompression obtains 4g yellow oily liquid, yield 92% after concentrating and reclaiming solvent.It is 95% that HPLC detects product purity, through being accredited as title compound.
The preparation of embodiment 9 2-(thiazolamine-4-yl)-2-(Z)-methoxy imino ethyl acetate (ring-closure reaction product)
In the 100mL round-bottomed flask, add successively by embodiment 1 described method and prepare 4-bromo-2-(Z)-methoxyl group imido grpup methyl aceto acetate 3.0g (11.9mmol), methylene dichloride 10mL, temperature control is 20 ℃ under the magnetic agitation, add thiocarbamide 1.0g (13.0mmol), drip triethylamine 1.3g (13.1mmol) again.Drip and finish, continue stirring reaction 3h to HPLC monitoring bromo-derivative and transform fully.Add water 8mL * 2 washing reaction liquid, tell organic layer, anhydrous sodium sulfate drying filters, and filtrate decompression obtains faint yellow crystalline particle 2.3g after concentrating and reclaiming solvent, yield 85%, and it is 96.5% that HPLC detects purity.Through being accredited as title compound.
The comparative example 1
In the 100mL round-bottomed flask, add methylene dichloride 10ml, water 10ml and 2-(Z)-methoxyl group imido grpup methyl aceto acetate 3.0g (17.3mmol) successively.Under the magnetic agitation, slowly drip bromine 3.33g (20.8mmol), reaction system crossfades into reddish-brown.Under the room temperature reaction vessel is placed the dark place, stir more than 24 hours, detect feed stock conversion less than 1% through HPLC.
This shows, use bromine at Aquo System and in the dark, this bromo-reaction almost can not carry out.
The comparative example 2
In the 100mL round-bottomed flask, add methylene dichloride 10ml, water 10ml and 2-(Z)-methoxyl group imido grpup methyl aceto acetate 3.0g (17.3mmol) successively.Under the magnetic agitation, slowly drip bromine 3.33g (20.8mmol), reaction system crossfades into reddish-brown.With the reaction vessel fluorescent lamp, stir more than 16 hours under the room temperature, detect feed stock conversion less than 5% through HPLC.
This shows, use bromine at Aquo System and at room temperature in daylight, this bromo-reaction almost can not carry out.
The comparative example 3
Add methylene dichloride 20mL in the 100mL round-bottomed flask, add Sodium Bromide 3.58g (34.8mmol), under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 1.73g (17.3mmol).Drip to finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 5.0g (28.9mmol), slow Dropwise 35 % aqueous hydrogen peroxide solution 1.69g (amount of substance of hydrogen peroxide is 17.4mmol) more subsequently, reaction system crossfades into reddish-brown.Under the room temperature reaction vessel is placed the dark place, stir more than 24 hours, detect through HPLC, feed stock conversion is 0%.
This shows that make oxygenant with aqueous hydrogen peroxide solution, system is placed in the dark place, this bromo-reaction can't carry out.
The comparative example 4
Add methylene dichloride 20mL and Sodium Bromide 3.58g (34.8mmol) in the 100mL round-bottomed flask, under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 1.73g (17.3mmol).Drip to finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 5.0g (28.9mmol), slow Dropwise 35 % aqueous hydrogen peroxide solution 1.69g (amount of substance of hydrogen peroxide is 17.4mmol) more subsequently, reaction system crossfades into reddish-brown.With the reaction vessel fluorescent lamp, stirred 12 hours under the room temperature, detect through HPLC, feed stock conversion is 0%.
This shows, make oxygenant with aqueous hydrogen peroxide solution, system adopts illumination under room temperature, and this bromo-reaction can't carry out.
The comparative example 5
Measure in the 100mL round-bottomed flask into methylene dichloride 20mL, add Sodium Bromide 3.87g (37.6mmol), under the magnetic agitation, the dropping massfraction is 98% sulfuric acid 5.64g (56.4mmol).Drip to finish, add 2-(Z)-methoxyl group imido grpup methyl aceto acetate 5.0g (28.9mmol), disposable adding sodium sulfate-hydrogen peroxide-sodium chloride adduct 6.5g (9.4mmol) subsequently, reaction solution presents reddish-brown.Under the room temperature reaction vessel is placed the dark place, stirred 24 hours, detect feed stock conversion less than 10% through HPLC.
This shows that adopt the hydrogen peroxide solid adduct to substitute aqueous hydrogen peroxide solution and make oxygenant, system is almost being placed in the dark place under the anhydrous situation, this bromo-reaction speed is very slow.
Above-described embodiment is the comparatively desirable embodiment of present technique invention; but embodiments of the present invention are not restricted to the described embodiments entirely; other are any not to deviate from change, the modification made under spirit of the present invention and the principle, substitute, combination, simplify; all should be the substitute mode of equivalence, be included within the protection domain of present technique invention.
Claims (26)
1. the preparation method of cephalosporins pharmaceutical intermediate 4 ?bromine ?2 ?(Z) the ?alkoxyl group imido grpup acetylacetic esters of a formula I structure, it is characterized in that: this method comprises: with formula II structure 2 ?alkoxyl group imido grpup acetylacetic ester be starting raw material, with bromide/Liu Suan Na ?Guo Yangization Qing ?sodium chloride adduct be brominated reagent, in organic solvent, reacting and obtaining under the acid reagent condition and under the illumination effect;
Wherein, R in formula I, the formula II structure
1Be methyl or ethyl; R
2Be methyl, ethyl, the tertiary butyl or carboxymethyl.
2. the preparation method of cephalosporins pharmaceutical intermediate 4-bromo-2-as claimed in claim 1 (Z)-alkoxyl group imido grpup acetylacetic ester is characterized in that: described acid reagent molar weight is 1.5～5.0 times of bromide anion molar weight in the bromide.
Cephalosporins pharmaceutical intermediate as claimed in claim 14 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described acid reagent molar weight is 2.0～3.0 times of bromide anion molar weight in the bromide.
Cephalosporins pharmaceutical intermediate as claimed in claim 14 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described acid reagent is sulfuric acid.
Cephalosporins pharmaceutical intermediate as claimed in claim 24 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described acid reagent is sulfuric acid.
Cephalosporins pharmaceutical intermediate as claimed in claim 34 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described acid reagent is sulfuric acid.
As each described cephalosporins pharmaceutical intermediate of claim 1～6 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: in the described bromide bromide anion molar weight be 2 ?0.8～3.0 times of alkoxyl group imido grpup acetylacetic ester molar weight.
As each described cephalosporins pharmaceutical intermediate of claim 1～6 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: in the described bromide bromide anion molar weight be 2 ?1.0～2.0 times of alkoxyl group imido grpup acetylacetic ester molar weight.
As each described cephalosporins pharmaceutical intermediate of claim 1～6 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 0.5～2.0 times of bromide anion molar weight in the bromide.
Cephalosporins pharmaceutical intermediate as claimed in claim 74 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 0.5～2.0 times of bromide anion molar weight in the bromide.
11. cephalosporins pharmaceutical intermediate as claimed in claim 84 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 0.5～2.0 times of bromide anion molar weight in the bromide.
12. as claim 1～6,10～11 each described cephalosporins pharmaceutical intermediates 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 1.0～1.5 times of bromide anion in the bromide.
13. cephalosporins pharmaceutical intermediate as claimed in claim 74 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 1.0～1.5 times of bromide anion in the bromide.
14. cephalosporins pharmaceutical intermediate as claimed in claim 84 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described Liu Suan Na ?Guo Yangization Qing ?in the sodium chloride adduct hydrogen peroxide molar weight be 1.0～1.5 times of bromide anion in the bromide.
15. as claim 1～6,10～11,13～14 each described cephalosporins pharmaceutical intermediates 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described bromide is one or more the mixture in Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.
16. cephalosporins pharmaceutical intermediate as claimed in claim 74 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described bromide is one or more the mixture in Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.
17. cephalosporins pharmaceutical intermediate as claimed in claim 84 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described bromide is one or more the mixture in Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.
18. cephalosporins pharmaceutical intermediate as claimed in claim 94 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described bromide is one or more the mixture in Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.
19. cephalosporins pharmaceutical intermediate as claimed in claim 12 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described bromide is one or more the mixture in Hydrogen bromide, Sodium Bromide, Potassium Bromide, magnesium bromide, lithiumbromide or the brometo de amonio.
20. as claim 1～6,10～11,13～14,16～19 each described cephalosporins pharmaceutical intermediates 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
21. cephalosporins pharmaceutical intermediate as claimed in claim 74 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
22. cephalosporins pharmaceutical intermediate as claimed in claim 84 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
23. cephalosporins pharmaceutical intermediate as claimed in claim 94 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
24. cephalosporins pharmaceutical intermediate as claimed in claim 12 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
25. cephalosporins pharmaceutical intermediate as claimed in claim 15 4 ?Xiu ?2 ?(Z) ?the preparation method of alkoxyl group imido grpup acetylacetic ester, it is characterized in that: described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform; Described illumination is that visible light shines or ultraviolet lighting; Described illumination light source is incandescent light, luminescent lamp, ultraviolet lamp, halogen lamp, Metal-halogen lamp, xenon lamp, high voltage mercury lamp, high-pressure mercury lamp, electrodeless lamp, LED lamp, sunlight.
26. preparation method as each described cephalosporins pharmaceutical intermediate 4 ?bromine ?2 ?(Z) ?alkoxyl group imido grpup acetylacetic esters of claim 1～25, it is characterized in that: described method also further comprises purification step: add weak base and regulate pH value 6～7 in reaction solution, add S-WAT, standing demix, wash organic solvent layer then with water, anhydrous sodium sulfate drying, filter, remove organic solvent be drying to obtain bromination product 4 ?Xiu ?2 ?(Z) ?alkoxyl group imido grpup acetylacetic ester; Described weak base is a kind of in sodium bicarbonate, saleratus, Sodium phosphate dibasic or the dipotassium hydrogen phosphate; Described organic solvent be methylene dichloride, 1,2 ? a kind of in ethylene dichloride or the chloroform.
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