CN101121716A - Synthesis method for biapenem - Google Patents
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- CN101121716A CN101121716A CNA2007101520840A CN200710152084A CN101121716A CN 101121716 A CN101121716 A CN 101121716A CN A2007101520840 A CNA2007101520840 A CN A2007101520840A CN 200710152084 A CN200710152084 A CN 200710152084A CN 101121716 A CN101121716 A CN 101121716A
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Abstract
The invention is a synthesis method of the biapenem, with the MAP ((1R, 5R, 6R) 2-(drophenyl phosphate)-6-[(R)-1- hydroxyethyl]-1-methyl-1-1 - carbapenems-2-en-3-formic acid benzyl ester of p-nitrophenol)) and the 6, 7-dihydro-6-mercapto-5 H-pyrazol [1,2 - a] [1,2 , 4]-triazole chloride ( the intermediate III) as the starting materials; after the condensation, hydrolysis and the fine preparation reaction and synthesis, the biapenem is made.
Description
Technical field
The present invention relates to the synthetic method of a kind of synthetic method of antibiotic medicine, particularly a kind of biapenem.
Background technology
The blue or green alkene antibiotic medicine of carbon has a wide range of applications.From the discovery of sulfomycin in 1976 so far, find and developed the blue or green alkene microbiotic of a series of new carbon in succession, as imipenum (Imipenem), panipenem (Panipenem), Meropenem (meropenem), Fa Luopeinan (faropenem), biapenem (Biapenem), ritipenem acoxil (ritipenem acexil) etc.The topmost characteristics of this type of microbiotic are that extremely strong anti-microbial activity is not only arranged, extremely wide antimicrobial spectrum, and it is highly stable to multiple beta-lactam enzyme, still can bring into play potent anti-microbial effect to the cynnematin resistant organism, there is not cross resistance in bacterium to such medicine and other beta-lactam class microbiotic.The Application and Development of carbapenem antibiotic is expected to become the first-line treatment medicine of intractable severe infection.That uses clinically at present, all has a curative effect preferably.Merck company was from Ka Teli streptomycete (Streptomyces cattleya) in 1976, found 1 new carbon penicillin vinyl compound, it is penetration cell effectively, and it is stable to multiple important beta lactamase, has anti-microbial activity widely, but its toxicity is bigger, is not used for clinical.On this basis, the 1st carbapenem antibiotics imipenum-cilastatin in 1985 goes on the market in Japan; Panipenem Japan in 1994 listing; The same year, biapenem was in Japan's exploitation listing in 2002 by Italy's exploitation Meropenem listing.
The chemical name of biapenem is: and (1R, 5S, 6S)-2-[(6,7-dihydro-5H-pyrazoles [1,2-α] is [1,2,4] triazole-6 base also)] sulphur-6R-1-hydroxyethyl]-1-methyl-phosphinylidyne penem-3-carboxylate salt.Molecular formula is C15H18N4O4S, and molecular weight is 350.40, and structure is:
Biapenem is the outer carbapenems antimicrobial drug that absorbs of a kind of novel gastroenteritic, and mainly bacteria cell wall is synthetic to reach antibacterial purpose by suppressing, and it can tolerate the hydrolysis of multiple B lactamase.Imipenum/the cilastatin that has gone on the market more, the introducing of β methyl makes biapenem stable to dehydropeptidase of kidney (DHP-I), need not and dehydropeptidase of kidney (DHP-I) inhibitor drug combination; Quaternary ammonium cation structure on 2 side chains makes it have good outer membrane permeability.Have broad spectrum antibiotic activity, powerful quick sterilization power is arranged, and the favorable tissue perviousness is arranged, pharmacokinetic properties is good, and adverse drug reaction is slight.Be widely used in the microbial acute and chronic infection of gram negative aerobic bacteria, gram positive aerobic bacteria and anaerobism clinically to the biapenem sensitivity. in addition, biapenem all has better curative effect power when treatment Cosmetics Surgery infection, gynecological infection and otorhinolaryngology infect.
The synthesis technique of existing biapenem is: MAP ((1R, 5R, 6R)-2-(diphenylphosphoric acid)-6-[(1R)-1-hydroxyethyl]-1-methyl isophthalic acid-1-carbon mould-2-alkene-3-formic acid is to the nitrobenzyl ester)) and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2,4]-triazole muriate (intermediate III) is a starting raw material, through condensation, hydrolysis, the synthetic biapenem of refining reaction.
The weak point of this technology is MAP ((1R; 5R; 6R)-2-(diphenylphosphoric acid)-6-[(1R)-1-hydroxyethyl]-1-methyl isophthalic acid-1-carbon mould-2-alkene-3-formic acid is to the nitrobenzyl ester)) and 6; 7-dihydro-6-sulfydryl-5H-pyrazoles [1; 2-a] [1; 2; 4]-triazole muriate (intermediate III) is a starting raw material; through condensation; hydrolysis; refining reaction synthesizes biapenem, though raw material is easy to get the reaction conditions gentleness; but it exists synthetic difficulty bigger; polystep reaction needed column chromatography, and yield is low, and produce in the reaction process can by product be not suitable for the labour protection of suitability for industrialized production.
Summary of the invention
The present invention proposes a kind of new synthetic method of biapenem.With MAP and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2, the 4]-synthetic biapenem of triazole muriate (intermediate III) reaction.Wherein, intermediate MAP is buied by Yisite Chemical Co., Ltd., Changzhou; And intermediate III is to be starting raw material with 85% hydrazine hydrate, through condensation, condensation, hydrolysis, addition, ring and, replacement, hydrolysis, condensation, hydrolysis, ring and, 11 steps reaction synthetic such as hydrolysis.
Synthetic route of the present invention is as follows:
1) preparation of intermediate III:
2) the synthetic biapenem of intermediate III and MAP reaction.Synthetic route is as follows:
The title of compound wherein:
XIII 1-carboxaldehyde radicals-2-isopropylidene hydrazine
The rare propyl group of XII 1--1-carboxaldehyde radicals-2-isopropylidene hydrazine
XI 1-rare propyl group-1,2-diformazan aldehyde radical hydrazine
X 1-(2,3-dibromo third is rare)-1,2-diformazan aldehyde radical hydrazine
IX 4-bromo-1,2-diformazan aldehyde radical pyrazoles
VIII 4-(thioacetyl)-1,2-diformazan aldehyde radical pyrazoles
VII 1-carboxaldehyde radicals-4-sulfydryl pyrazoles
Two (the 1-carboxaldehyde radicals pyrazoles-4-yl) disulphide of VI
Two (4-pyrazoles) the two sulphur dihydrochlorides of V
Two (6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] triazole-6-yl) the two sulphur dichloride of IV
III 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2,4]-triazole muriate
II p-oil of mirbane (1R, 5S, 6S)-and 2-[(6,7-dihydro-5H-pyrazoles-[1,2-a] [1,2,4] triazole-6-yl) sulfo-]-6-[(R)-the 1-hydroxyethyl]-1-methyl carbazole-2-alkene-3-carbonyl chlorine
The I biapenem ((-) { [(4R, 5S, 6S)-and 2-carboxyl-((1-R)-1-hydroxyethyl)-4-methyl-7-oxygen-1-nitrogen dicyclo [3.2.0] seven-2-alkene-3-yl] sulphur }-6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] triazole-4-inner salt)
The synthetic route of biapenem of the present invention, with 85% hydrazine hydrate is starting raw material, through condensation, condensation, hydrolysis, addition, ring and, replacement, hydrolysis, condensation, hydrolysis, ring and, hydrolysis, condensation, hydrolysis, 14 step prepared in reaction such as refining, be 2.8% in raw material 85% hydrazine hydrate total recovery.Synthetic product biapenem through HPLC, IR, UV,
1HNMR,
13Each spectrum of CNMR, DEPT, HSQC, Ms, PXRD and TG-DTA is all consistent with document.
Process innovation point of the present invention is:
First: synthetic intermediate VIII 4-(thioacetyl)-1, the method for 2-diformazan aldehyde radical pyrazoles is as follows:
What the present invention adopted is with 4-bromo-1, and 2-diformazan aldehyde radical pyrazoles is dissolved in the ethyl acetate, gets yellow solution, add thioacetic acid potassium, 40 ℃ were stirred 6 hours, and reaction solution is a light brown, filter, and with amount of ethyl acetate filter wash cake, merging filtrate, pressure reducing and steaming solvent, obtain light brown oily thing (intermediate VIII), yield reaches 99.2%, exceeds 18.9% than the synthetic method yield of reporting in the document, has just improved the yield of product greatly from the source.
In addition, the synthetic method that the present invention adopts is at the method that adds the charcoal absorption color in the document in this step, proposition adds gac again and decolours when biapenem is refining, simultaneously by to the time control time of repose that takes off charcoal, optimize stirring velocity, it is the biapenem crude product can obtain the evenly suitable direct can of particle diameter through an one-step refining aseptic finished product, lay good basis in making preparation, need not to add auxiliary material, reduce production cost of products, improved the security of product clinical application simultaneously.
Second: the synthetic method of two (6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] triazole-6-yl) two sulphur dichloride is as follows:
Bibliographical information, two (6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] triazole-6-yl) in two sulphur dichloride synthetic, 0 ℃ will two (4-pyrazoles) two sulphur dihydrochlorides (intermediate V) and sodium hydroxide add in the entry, stir, add methylamino ethoxy inferior amine salt hydrochlorate again, regulate the pH value, concentrating under reduced pressure, the back produces a large amount of white solids, is suspended in the methyl alcohol, filters.The filtrate evaporate to dryness gets faint yellow sticky solid.Behind dissolve with methanol, the elimination white precipitate repeats this process once.Use recrystallizing methanol, get white solid.In the reaction, sodium hydroxide corrodibility is strong, is unfavorable for labour protection; This step reaction simultaneously need carry out twice, and is not only consuming time longer, increase production cost and reduced the yield of product.
The present invention is for addressing the above problem through groping to adopt the saleratus replace sodium hydroxide repeatedly, under the situation that does not influence quality product, reduced operation easier, adopt strongly acidic cation-exchange to come separated product simultaneously, this reaction thinking has not only shortened the yield of reaction times nearly 31% but also product from bibliographical information 57.6%, brought up to 79.3%, improved 37.7%, for the raising of whole yield is had laid a good foundation.
With synthesis technique of the present invention carry out 3 batches amplify to produce after, through all up to specification after complete the check, synthetic total recovery 3.7%, and the total recovery of document synthetic route is only about 1.8%, synthetic method product yield of the present invention has improved 106% than document.
The synthesis route of biapenem of the present invention, particularly screening obtains through the technology key Study on Problems, has the following advantages:
1, be starting raw material with 85% hydrazine hydrate, through condensation, condensation, hydrolysis, addition, ring and, replacement, hydrolysis, condensation, hydrolysis, ring and, ten single step reactions such as hydrolysis make 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2,4]-and the technology of triazole chlorination (being intermediate III), reduce by above improvement and to use macroporous resin to separate, it is about 31% to have saved generated time, has reduced production cost.
2, in the synthetic route of biapenem raw material, ((1R in the end, 5R, 6R)-2-(diphenylphosphoric acid)-6-[(1R)-1-hydroxyethyl]-1-methyl isophthalic acid-1-carbon mould-2-alkene-3-formic acid is to the nitrobenzyl ester) (being MAP) and 6,7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2,4]-triazole muriate (being intermediate III) is a starting raw material, through condensation, hydrolysis, refining reaction synthesizes the biapenem finished product, we drip N by control in this process, temperature control when the N-diisopropylethylamine drips, back control stirring velocity and the proper extension churning time of feeding intake during biapenem crude product synthetic changes the time that gac adds simultaneously, improved the yield of product.
3, because this product is an injection, its usage intravenous drip; In the preparation production process, should reduce the introducing of impurity as far as possible.My company by screening stirring velocity, temperature, optimizes the crystallization condition and makes and obtain the crystal that raw material is a uniform particle diameter in biapenem refining, can establish good basis for preparation can adopt comparatively simple process.
4, technology is simple, by product is few, purity is high, and the preparation production cost is reduced greatly.
5, technology can not cause any pollution, is environmental protection technology, and this synthesis technique is at the encloses container internal reaction, and waste gas directly feeds and chemical reaction takes place in the waste gas reaction liquid is converted into pollution-free gas, organic solvent and catalyst recovery utilization
6, this preparation production technique is simple, and quality is controlled easily.
Description of drawings:
Fig. 1 is a biapenem preparation technology schema.
Embodiment:
Below in conjunction with embodiment the present invention is described further.
Embodiment 1: the preparation of biapenem
Detailed synthesis technique:
1,1-carboxaldehyde radicals-2-isopropylidene hydrazine synthetic (yield is: 85.9%)
Feed ratio: 85% hydrazine hydrate: ethyl formate: acetone=1: 1.64: 2.65 (W/V/V)
With after 7L ethanol mixes, cryosel is bathed and is cooled to-5 ℃, drips ethyl formate 4319ml then with the hydrazine hydrate of 2639g 85%, temperature keeps-5 ℃ to 0 ℃, drips off in about 1 hour, continues to stir 0.5 hour at-4 ℃, rise to room temperature then gradually, stirred 14 hours, reaction solution is a water white transparency, be added dropwise to acetone 7L, dripped off in 30 minutes, stirring at room is 30 minutes then, get yellow solution, concentrating under reduced pressure obtains faint yellow solid, obtains white crystal (intermediate X III) 3853g behind the ethyl alcohol recrystallization; Fusing point: 67～68 ℃
Quality control standard: fusing point: 68～69 ℃
2, the rare propyl group of 1--1-carboxaldehyde radicals-2-isopropylidene hydrazine synthetic (yield is: 71.9%)
Feed ratio: intermediate X III: rare propyl bromide: salt of wormwood=1: 1.30: 3.46 (W/V/W)
1905gXIII is dissolved in the 13.5L ethyl acetate, add the rare propyl bromide of 2475ml, 6600g salt of wormwood is heated to 80 ℃ under stirring, be incubated after 5 hours, reaction solution is a light brown, is cooled to room temperature, filters, filtrate concentrates, obtain light brown oily thing, (60 ℃/4mmHg), obtain colourless transparent liquid (intermediate X II) 1918g of underpressure distillation.
3,1-rare propyl group-1, (yield is: 91.4%) for 2-diformazan aldehyde radical hydrazine synthetic
3150g intermediate X II is dissolved in the 6.3L formic acid, is heated to 80 ℃ under stirring, and is incubated 15 hours, and reaction solution is a light brown, and the excessive formic acid of pressure reducing and steaming obtains light brown oily thing (intermediate X I) 2632g.
TLC detects: developping agent: ethyl acetate
The iodine colour developing
Product Rf=0.8
Raw material Rf=0.4
This batch product detects two spots under above-mentioned TLC condition.
4,1-(2,3-dibromo third is rare)-1, (yield is: 92.8%) for 2-diformazan aldehyde radical hydrazine synthetic
Feed ratio: intermediate X I: a hydration bromine lithium: bromine: sodium bicarbonate: S-WAT=1: 1.27: 2.04: 4.43: 2.58 (W/W/W/W/V)
438g intermediate X I is dissolved in the 3400ml methylene dichloride, methyl alcohol (1130ml) solution that adds a hydration bromine lithium 558g, be cooled to 0 ℃ then, splash into methylene dichloride (1130ml) solution of 895g bromine, when beginning to drip, brown horse back took off after bromine dripped, color fade speed slows down gradually, dropping temperature remains on 0～5 ℃, drips off the back and stirs 10 minutes at 0 ℃, adds the suspension that is made into by 1940g sodium bicarbonate and 1130ml water then in reaction solution, add saturated sodium bisulfite solution 1130ml again, separatory, tell methylene dichloride after, water layer extracts with ethyl acetate 3 * 2.25L, combined dichloromethane and acetic acid ethyl acetate extract, anhydrous magnesium sulfate drying boils off solvent, obtains brown oil (intermediate X) 913g.
TLC detects: developping agent: ethyl acetate: sherwood oil=3: 1
The iodine colour developing
Product Rf=0.5
Raw material Rf=0.25
This batch product detects 1 spot under above-mentioned TLC condition.
5, the 4-bromo-1, and (yield is: 58.5%) for 2-diformazan aldehyde radical pyrazoles synthetic
Feed ratio: intermediate X: salt of wormwood: isopropyl ether=1: 0.76: 0.55 (W/W/V)
Intermediate X 2928g is dissolved in the dried ethyl acetate of 16L, adds Anhydrous potassium carbonate powder 2224g, be heated to 40 ℃ then, stirred 6 hours, and filtered the pressure reducing and steaming solvent, obtain brown oil, ethyl acetate 800ml is after the dissolving, splash into isopropyl ether 1.6L under stirring, dripped off in 10 minutes, at room temperature stir 1 hour after, separate out the crystal of yellowish white, filter the dry intermediate compound I X1232g that gets.
TLC detects: developping agent: ethyl acetate: sherwood oil=3: 1
The iodine colour developing
Product Rf=0.4
Raw material Rf=0.5
This batch product detects 2 spots under above-mentioned TLC condition.
6,4-(thioacetyl)-1-diformazan aldehyde radical pyrazoles synthetic (yield is: 99.2%)
Feed ratio: intermediate compound I X: thioacetic acid potassium=1: 0.80 (W/W)
Get IX2160g and be dissolved among the ethyl acetate 8.7L, get yellow solution, add the 1730g thioacetic acid potassium, 40 ℃ were stirred 6 hours, reaction solution is a light brown, filters, and with amount of ethyl acetate filter wash cake, merging filtrate, the pressure reducing and steaming solvent obtains light brown oily thing (intermediate VIII) 2094g.
TLC detects: developping agent: ethyl acetate: sherwood oil=3: 1
The iodine colour developing
Product Rf=0.3
Raw material Rf=0.4
This batch product detects 1 spot under above-mentioned TLC condition.
7,1-carboxaldehyde radicals-4-sulfydryl pyrazoles synthetic (yield is: 92.4%)
Feed ratio: intermediate VIII: potassium hydroxide=1: 0.32 (W/W)
Intermediate VIII667g is dissolved in the 2.9L methyl alcohol, be cooled to 0 ℃, methyl alcohol (1910ml) solution that adds 214g potassium hydroxide, stir after 10 minutes, add the neutralization of 73ml formic acid, be concentrated into dried, the residue 5.75L that adds methylene chloride extracts, filter, filtrate decompression concentrates, and obtains light brown oily thing (intermediate VIII) 403g.
TLC detects: developping agent: ethyl acetate
The iodine colour developing
Product Rf=0.4
Raw material Rf=0.5
This batch product detects 1 spot under above-mentioned TLC condition.
8, two (1-carboxaldehyde radicals pyrazoles-4-yl) disulphide synthetic (yield is: 56.5%)
Feed ratio: intermediate VII: ferric chloride (FeCl36H2O)=1: 0.013 (W/W)
VII402g is dissolved in the 4.3L methyl alcohol, is cooled to 0 ℃, add methyl alcohol (575ml) solution of ferric chloride (FeCl36H2O) (5175mg), reaction solution is brown, blasts air then, and reaction solution darkens, and is evaporated to driedly, obtains brown oil (intermediate VI).Quality is: 451g.
TLC detects: developping agent: methylene dichloride: ethanol=9: 1
The iodine colour developing
Product Rf=0.4
This batch product detects 2 spots under above-mentioned TLC condition.
9, two (4-pyrazoles) two sulphur dihydrochlorides synthetic (yield is: 60.4%)
Feed ratio: intermediate VI: concentrated hydrochloric acid=1: 1.54 (W/V)
VI448g is dissolved in 4.3L methyl alcohol, adds concentrated hydrochloric acid 690ml, stirred 6 hours under the room temperature, have light yellow crystal to separate out, filter, filtrate is concentrated into dried, adds small amount of methanol, and stirring down has crystal to separate out again, filter, two portions merge intermediate V288g; Fusing point: 194 ℃.
Quality control standard: fusing point: 194 ℃
10, the synthetic (yield: 60.7%) of two (6,7-dihydro-5H-pyrazoles [1,2-a] [1,2,4] triazole-6-yl) two sulphur dichloride
Feed ratio: intermediate V: saleratus: methylamino ethoxy inferior amine salt hydrochlorate=(W/W/W) 280g intermediate V was dissolved in 7L water in 1: 0.71: 3.89.Add saleratus 200g then gradually, produce bubble, be cooled to 0 ℃, add methylamino ethoxy inferior amine salt hydrochlorate 1090g, 0 ℃ was stirred after 10 minutes, the reaction solution water white transparency is transferred pH2, evaporated under reduced pressure then with 6N hydrochloric acid, obtain solid 4.2L methanol extraction, filter, methanol extract liquid concentrates, the oily matter that obtains home-made 732 type strongly acidic cation-exchange separated products, after the absorption, with the mixed solvent wash-out of methanol-water (1: 1), use the mixed solvent of 6N hydrochloric acid-methyl alcohol (1: 1) to wash out product more earlier, collect pickle solution, concentrating under reduced pressure obtains oily matter, add the small amount of methanol crystallization, obtain light yellow crystal, get intermediate compound IV 215g with recrystallizing methanol again; Fusing point: 182～184 ℃
Quality control standard: fusing point: 182～183 ℃
11,6, the muriatic synthetic (yield: 72.9%) of 7-dihydro-6-sulfydryl-5H-pyrazoles [1,2-a] [1,2,4]-triazole
Feed ratio: intermediate compound IV: tributyl phosphorus=1: 1.15 (W/W)
After 600g intermediate VI is dissolved in 3L water, add the 3L tetrahydrofuran (THF), be cooled to 0 ℃, add tributyl phosphorus 688g, 0 ℃ was stirred the pressure reducing and steaming tetrahydrofuran (THF) 1 hour down, ethyl acetate 3 * 3L extracts, and water layer is concentrated into dried, obtains faint yellow oily thing, use the SP207 resin purification, water elution is collected elutriant, be concentrated into do after, obtain faint yellow solid, get intermediate III 440g with the isopropylcarbinol recrystallization then; Fusing point: 125～129 ℃
Quality control standard: fusing point: 127～128 ℃
12, p-oil of mirbane (1R, 5S, 6S)-2-[(6,7-dihydro-5H-pyrazoles-[1,2-a] [1,2,4] triazole-6-yl) sulfo-]-6-[(R)-the 1-hydroxyethyl]-synthetic (yield: 85.7%) of 1-methyl carbazole-3-carbonyl chloride
Feed ratio: intermediate III: MAP: N, N-diisopropylethylamine=1: 2.64: 0.93 (W/W/W)
Intermediate III 180g and MAP 476g are suspended in acetonitrile 2.16L, in the mixing solutions of acetone 2.16L, be cooled to 0 ℃, be added dropwise to N, N-diisopropylethylamine 168g maintains the temperature at during dropping between 0～5 ℃, dripping off the back continues to stir 2 hours, separate out a large amount of faint yellow solids in the reaction solution, filter, vacuum-drying gets intermediate II 358g; Fusing point: 163～167 ℃ (decomposition)
Quality control standard: fusing point: 163～166 ℃ (decomposition)
13, the synthetic (yield: 79.7%) of biapenem crude product (intermediate compound I)
Feed ratio: intermediate II: zinc powder=1: 8.3 (W/W)
Intermediate II 170g is dissolved in the 6L0.35N phosphoric acid buffer (pH=5.6), add zinc powder 1411g, stirred 1 hour under the room temperature then, reaction finishes, reaction solution filters with diatomite layer, filtrate collection, get yellow solution, with 12.8L washing diatomite filter cake, merging filtrate, transfer filtrate pH=5.5 with 0.1N HCl, concentrating under reduced pressure then, thickening temperature is lower than 35 ℃, concentrates the oily matter that obtains with SP207 macroporous resin column column chromatography, use isopropylcarbinol: the mixed solvent of water (5: 95) is collected the elutriant that contains product as elutriant.Elutriant lyophilize after the collection obtains white solid (intermediate compound I) 91g, fusing point: 210～217 ℃; Chromatographic purity: 97.4%
Quality control standard: fusing point: 210～217 ℃
Chromatographic purity 〉=90%
14, the refining (yield: 96.4%) of biapenem
Feed ratio: intermediate compound I: water for injection=1: 62 (W/V)
Get intermediate compound I 390g, be dissolved in the 24L water for injection, stir and make dissolving, add 0.1% (v/v) needle-use activated carbon 24g, stir, left standstill 15 minutes, with 0.22 μ membrane filtration degerming, in filtrate, slowly add 72L dehydrated alcohol (earlier through filtration sterilization and bacterial endotoxin), stirred 10 minutes, leave standstill and separated out crystallization (maintenance room temperature to 10 degree is following) in 2 hours, filter, after draining solvent as far as possible, take off filter cake to 25 ℃ vacuum-drying, promptly get the biapenem elaboration.Quality: 375.8g; Chromatographic purity: 99.7%
Quality control standard: chromatographic purity 〉=98%.
By three batches of above test method pilot scales, testing data sees the following form.
| Lot number | 040601 | 040602 | 040603 |
| Synthetic quantity (g) proterties solubleness specific optical rotation acidity related substance (%) content (%) weight loss on drying (%) residue on ignition (%) heavy metal sterility test bacterial endotoxin is checked methyl alcohol (%) | Not 375.8 white crystalline powder-33.2 ° of 5.4 0.24 100.0 2.61 0.06 up to specification not detecting up to specification up to specification | Not 377.4 white crystalline powder-33.6 ° of 5.3 0.25 100.2 2.79 0.05 up to specification not detecting up to specification up to specification | Not 376.5 white crystalline powder-34.2 ° of 5.4 0.25 99.5 2.90 0.06 up to specification not detecting up to specification up to specification |
| Ethanol (%) acetone (%) acetonitrile (%) methylene dichloride (%) ethyl acetate (%) tetrahydrofuran (THF) (%) isopropylcarbinol (%) | 0.40 do not detect | 0.41 do not detect | 0.39 do not detect |
Claims (5)
1. the synthetic method of a biapenem is characterized in that, the process following steps:
The preparation of step 1) intermediate III:
Step 2) the synthetic biapenem of intermediate III and MAP reaction
2. the synthetic method of claim 1 is characterized in that, the synthetic method of intermediate VIII wherein is as follows:
3. the synthetic method of claim 2 is characterized in that, is with 4-bromo-1,2-diformazan aldehyde radical pyrazoles is dissolved in the ethyl acetate, get yellow solution, add thioacetic acid potassium, 40 ℃ were stirred 6 hours, reaction solution is a light brown, filter, and with amount of ethyl acetate filter wash cake, merging filtrate, the pressure reducing and steaming solvent, obtaining light brown oily thing is intermediate VIII.
4. the synthetic method of claim 1 is characterized in that, the synthetic method of intermediate III is as follows:
5. the synthetic method of claim 4 is characterized in that, adopts strongly acidic cation-exchange to come separated product.
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| CN102180831A (en) * | 2011-03-11 | 2011-09-14 | 同济大学 | Preparation method of biapenem intermediate |
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