CN1854141B - Production of furo urea penicillin sodium - Google Patents
Production of furo urea penicillin sodium Download PDFInfo
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- CN1854141B CN1854141B CN2006100775975A CN200610077597A CN1854141B CN 1854141 B CN1854141 B CN 1854141B CN 2006100775975 A CN2006100775975 A CN 2006100775975A CN 200610077597 A CN200610077597 A CN 200610077597A CN 1854141 B CN1854141 B CN 1854141B
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Abstract
Production of fuureidoparasiticin sodium is simple. It has short production period, less organic solvent, more yield and higher crystal purity.
Description
Technical field
The present invention relates to a kind of method for preparing Furbenicillin Sodium, relate in particular to a kind of method for preparing the high purity Furbenicillin Sodium.
Background technology
The chemical structural formula of Furbenicillin Sodium is as follows:
Furbenicillin Sodium is a kind of semisynthetic penicillin, has anti-negative bacterium, stronger to effects such as Pseudomonas aeruginosa, meningococcus, intestinal bacteria, Corynebacterium diphtheriae and Bacillus proteuss especially, especially the effect of Pseudomonas aeruginosa is eager to excel several times than carboxylic benzyl and piperacillin, be mainly used in diseases such as traumatic infection, septicemia, respiratory tract, urinary tract infection clinically, purposes is very wide.
The synthetic method of Furbenicillin Sodium mainly contains two kinds at present.The 655-656 page or leaf of " medicine intermediate preparation method " first [M] of calendar year 2001 discloses the synthetic method of 2-(2-furoyl) urea groups toluylic acid: 2-furoyl isocyanic ester (being called for short the isocyanic acid carbamoyl ester) reacts in benzole soln with phenylglycine and obtains 2-(2-furoyl) urea groups toluylic acid, wherein mentions this intermediate and is mainly used in synthetic Furbencillin.It can obtain mixed acid anhydride with the Vinyl chloroformate reaction, obtains Furbenicillin Sodium with the condensation of 6-amino-penicillanic acid sodium again.There are many weak points in this method: synthetic route is long, and reaction and treatment step are more, need use a large amount of organic solvents, and produces a large amount of waste water in phase transition behavior, and environment is polluted, and reaction yield only can reach 60-70%." Institutes Of Technology Of Taiyuan's journal " 2004 the 35th volumes the 5th phase 575-576 page or leaf discloses second kind of synthetic method, this method is to adopt ampicillin anhydrous acid to generate the penbritin triethylamine salt in the presence of triethylamine, becomes Furbencillin triethylenetetraminehexaacetic acid amine salt with 2-furoyl isocyanate reaction subsequently.And under phosphatizing, generate Furbencillin acid, after vacuum-drying, in water, obtain the Furbenicillin Sodium aqueous solution with the sodium bicarbonate aqueous solution reaction again.But also there are many deficiencies in this synthetic method: synthesis step is complicated, and synthesis technique also carries out at aqueous phase at last, therefore also needs to carry out phase transition, thereby produces a large amount of waste water.And above-mentioned two kinds of methods all need to handle through freeze-drying, and to the equipment requirements height, production cost is higher.The purity of products obtained therefrom is lower, only is 50%～60% through high-pressure liquid chromatography content.
Therefore, need a kind of method simple to operate, that production cost is low of exploitation to prepare highly purified Furbenicillin Sodium at present.
Summary of the invention
The invention provides a kind of method of synthetic Furbenicillin Sodium, this method can be described below with chemical equation:
This method comprises the steps:
(1) penbritin acid is joined a kind ofly do not dissolve penbritin acid but can dissolve in the solvent of Furbencillin acid, make it to form a kind of suspension liquid system; Cool off this system to-5 ℃ to 20 ℃, 2-furoyl isocyanic ester progressively is added in this system, make it to finish reaction with penbritin acid;
(2) in reaction system, add sodium methylate-ethanol solution until the pH value to slightly acidic;
(3) slough solvent, obtain Furbenicillin Sodium.
Penbritin acid described in the above-mentioned steps (1) is preferably ampicillin anhydrous acid.The described solvent that does not dissolve penbritin acid but can dissolve Furbencillin acid can be tetrahydrofuran (THF), the perhaps mixed solvent of one of tetrahydrofuran (THF) and methylene dichloride, ethylene dichloride or acetone, and the volume ratio of tetrahydrofuran (THF) and another kind of solvent is 1: 3 to 5: 1, more preferably 1: 1 to 3: 1.
The weight ratio of solvent described in the above-mentioned steps (1) and penbritin acid can be preferably 4: 1 for 2: 1 to 6: 1.Preferably the solution system with the penbritin acid in the step (1) is cooled to 0-10 ℃.The mol ratio of 2-furoyl isocyanic ester described in the step (1) and penbritin acid is 1: 1 to 1.2: 1.
Can progressively add in the above-mentioned steps (2) sodium methylate-dehydrated alcohol until the pH value to 5.1-6.8, be preferably 5.8-6.8.The concentration of described sodium methylate-dehydrated alcohol is preferably in per 100 gram solvents and contains 2-10 gram sodium methylate, and described solvent is selected from anhydrous methanol or dehydrated alcohol.
Adopt ordinary method to remove solvent the reaction soln of completing steps (2), preferred employing decompression removes solvent.Remove the Furbenicillin Sodium that obtains behind the solvent and be the white or the off-white powder of amorphous basically.Productive rate can reach 90-95%, and the purity of product can reach more than 88%.
Resulting Furbenicillin Sodium can be carried out crystallization, the crystalline step is as follows: adopt 95% ethanol, methyl alcohol or dimethyl formamide dissolving Furbenicillin Sodium, add one or more following anti-solvents then in solution: Virahol, isopropyl ether, acetone, tetrahydrofuran (THF) or ethyl acetate separate out Furbenicillin Sodium.Purity through the crystalline Furbenicillin Sodium can reach more than 91%.Described anti-solvent is meant and does not dissolve Furbenicillin Sodium, and the solvent that it is separated out from solution.
Synthetic method route of the present invention is simple, easy to operate, with short production cycle, and yield has reached 90-95%; And action solvent is chosen rationally, so the existing operational path of solvent amount ratio has decline by a relatively large margin, drops to 1: 11 by existing 1: 50.And existing operational path also needs the extraction of phase transition and a large amount of solvents, complex operation, and have a large amount of waste water to produce.Owing to solvent amount of the present invention is few and recyclable, extract unlike the desired a large amount of solvents of existing operational path again to cause labour intensity big, smell is big.Therefore to improving in-situ production environment and health of operators has positive effect.
It is few that the present invention produces required equipment, invests lowly, and reaction conditions is less demanding, and energy consumption is low; And the lyophilize of still needing of existing technology, reaction requires-18 ℃ of reactions down, and not only personnel are many, and energy consumption is big, and cost of equipment is big and the production cycle is long, and is extremely unreasonable from economic angle, causes cost to rise significantly.
Through high pressure liquid chromatographic analysis, the purity of the Furbenicillin Sodium product that the inventive method obtained has reached more than 88%, and the purity of the Furbenicillin Sodium product of being sold in the market only is 50-60%.
Embodiment
Describe the present invention in detail below in conjunction with specific embodiment, still, the embodiment that provides below is not a limitation of the present invention just for the present invention is described.
Embodiment 1
In 250 milliliters of four-hole bottles, add 40 milliliters of tetrahydrofuran (THF)s, stir adding ampicillin anhydrous acid 10 grams down.Because ampicillin anhydrous acid is insoluble to tetrahydrofuran (THF), so reaction solution is the suspension liquid state.Drip 2-furoyl isocyanic ester 4.5 in 3 ℃ and restrain, question response liquid becomes clarification, stirs 20 minutes, in 2 ℃ of adding sodium methylate-ethanol solutions (configuration proportions of sodium methylate 5 gram adding dehydrated alcohols 65 grams), treats that pH reaches 6.8 and is terminal point then.Stir the desolventizing that reduces pressure after 20 minutes, finally obtain white powder, get 13.83 grams after the drying, yield is 95%.High-pressure liquid chromatography content is 89.2%; Moisture 3.25%, optically-active+186.8 °.
Embodiment 2
In 250 milliliters of four-hole bottles, add 45 milliliters of tetrahydrofuran (THF)s, be cooled to 0 ℃, stir and add ampicillin anhydrous acid 10 grams down, slowly add 2-furoyl isocyanic ester 4.55 grams in 3 ℃, question response liquid becomes clarification, stir and in clear soln, add the solution of forming by sodium methylate 5 gram dehydrated alcohols 65 grams after 30 minutes, treat that pH reaches 6.8 backs and stirred 30 minutes, the pH value is constant, temperature is controlled at 20 ℃ of decompressions and sloughs solvent, drying gets Furbenicillin Sodium 13.82 grams, and high-pressure liquid chromatography content is 88.81%; Moisture 1.66%, optically-active+188.6 °.
Embodiment 3
In 250 milliliters of four-hole bottles, add 40 milliliters of tetrahydrofuran (THF)s, be cooled to below 0 ℃, stir gradation and add 10 gram ampicillin anhydrous acid, under the refrigerative situation, add 2-furoyl isocyanic ester 4.4 grams, question response liquid becomes clarification, stirs 20 minutes, adds sodium methylate-ethanol solution (part by weight of sodium methylate and dehydrated alcohol is 1: 13).When pH reaches 6.8, stirred 20 minutes, the pH value is constant, and temperature is controlled at 17 ℃ of decompressions and removes solvent, obtains white powder 13.85 grams after the drying, and productive rate is 95.12%, and high-pressure liquid chromatography content is 89.25%; Moisture 3.74%, optically-active+189.0 °.
Claims (7)
1. method for preparing the following Furbenicillin Sodium of structural formula,
This method comprises the steps:
(1) penbritin acid is joined a kind of tetrahydrofuran (THF), or tetrahydrofuran (THF) mixes with one of methylene dichloride, ethylene dichloride or acetone and the volume ratio of tetrahydrofuran (THF) and another kind of solvent is in 1: 3 to 5: 1 the solvent, to make it to form a kind of suspension liquid system; Cool off this system to-5 ℃ to 20 ℃, 2-furoyl isocyanic ester progressively is added in this system, make it to finish reaction with penbritin acid;
(2) in reaction system, add sodium methylate-ethanol solution until the pH value to slightly acidic;
(3) slough solvent, obtain Furbenicillin Sodium.
2. method according to claim 1 is characterized in that, the penbritin acid described in the step (1) is ampicillin anhydrous acid.
3. method according to claim 2 is characterized in that, the mol ratio of 2-furoyl isocyanic ester described in the step (1) and penbritin acid is 1: 1 to 1.2: 1.
4. method according to claim 3 is characterized in that, the concentration of the sodium methylate-dehydrated alcohol described in the step (2) is to contain 2-10 gram sodium methylate in per 100 gram solvents.
5. method according to claim 1 is characterized in that, adopts decompression to slough solvent in the step (3).
6. according to each the described method among the claim 1-5, it is characterized in that the weight ratio of solvent described in the step (1) and penbritin acid is 2: 1 to 6: 1.
7. method according to claim 6, it is characterized in that, the solution system of the penbritin in the step (1) is cooled to 0-10 ℃, and the weight ratio of solvent and penbritin acid is 4: 1, and progressively add in the step (2) sodium methylate-ethanol solution to the pH value to 5.8-6.8.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100775975A CN1854141B (en) | 2005-04-28 | 2006-04-28 | Production of furo urea penicillin sodium |
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| Application Number | Priority Date | Filing Date | Title |
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| CN200510066559 | 2005-04-28 | ||
| CN200510066559.5 | 2005-04-28 | ||
| CN2006100775975A CN1854141B (en) | 2005-04-28 | 2006-04-28 | Production of furo urea penicillin sodium |
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| CN1854141B true CN1854141B (en) | 2010-06-30 |
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| CN2006100775975A Expired - Fee Related CN1854141B (en) | 2005-04-28 | 2006-04-28 | Production of furo urea penicillin sodium |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3479339A (en) * | 1968-06-13 | 1969-11-18 | Bristol Myers Co | 6-(alpha-3 - acylureidophenylacetamido)- and 6-(alpha - 3 - acylureidothienylacetamido)-penicillanic acids |
| CA966853A (en) * | 1968-06-13 | 1975-04-29 | Charles T. Holdrege | Intermediates useful in the preparation of synthetic penicillins |
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2006
- 2006-04-28 CN CN2006100775975A patent/CN1854141B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3479339A (en) * | 1968-06-13 | 1969-11-18 | Bristol Myers Co | 6-(alpha-3 - acylureidophenylacetamido)- and 6-(alpha - 3 - acylureidothienylacetamido)-penicillanic acids |
| CA966853A (en) * | 1968-06-13 | 1975-04-29 | Charles T. Holdrege | Intermediates useful in the preparation of synthetic penicillins |
Non-Patent Citations (2)
| Title |
|---|
| 李忠华等.呋脲苄西林钠的合成新工艺.太原理工大学学报第35卷 第5期.2004,第35卷(第5期),第575-576页. |
| 李忠华等.呋脲苄西林钠的合成新工艺.太原理工大学学报第35卷 第5期.2004,第35卷(第5期),第575-576页. * |
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