CN1033163C - Process for preparation of lifumycin of isobuty piperazine - Google Patents
Process for preparation of lifumycin of isobuty piperazine Download PDFInfo
- Publication number
- CN1033163C CN1033163C CN 92106014 CN92106014A CN1033163C CN 1033163 C CN1033163 C CN 1033163C CN 92106014 CN92106014 CN 92106014 CN 92106014 A CN92106014 A CN 92106014A CN 1033163 C CN1033163 C CN 1033163C
- Authority
- CN
- China
- Prior art keywords
- rifin
- product
- crude product
- good fortune
- piperazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a method for simply and conveniently synthesizing lifumycin of isobuty piperazine. The method is characterized in that rifo S reacts with excess isobutyl piperazine; the isobutyl piperazine is used as reaction solvent to generate isobutyl piperazine rifo S; the isobutyl piperazine rifo S is then crystallized in alcohol which contains water to generate IV type crystals with the existence of stabilizing agents. The present invention has the advantages that the present invention uses the isobutyl piperazine as the reaction solvent; the excess solvent can be recovered and reused; the kinds and the use level of the solvent are reduced; the reaction period is shortened; the yield rate is high, the cost is low, the inherent quality of products is good, and the present invention is suitable for industrial production.
Description
The present invention relates to the anti-leprosy medicine of a kind of tuberculosis---the improved synthetic method of Rifin.
Its chemistry is by name: 3-(4-isobutyl--1-piperazinyl) rifomycin SV.Structural formula;
Rifin is the Rifampin multiple antibiotic derivative of mould class of another power afterwards.It is three times of Rifampin to Bacillus tuberculosis bovis infected animals protection test antibacterial ability, toxicity be its 1/3, dosage is little, can supply the oral anti-leprosy medicine of tuberculosis.Quinhydrones and complicated petioliform bridged ring are arranged, the hydrogen bond between having intramolecularly, having divided, between molecule and the solvent in such compound structure.When crystallization condition changes, can form different hydrogen bonds and make product different crystal forms occur.There is polymorphic equally in Rifin, i.e. I-IV type, crystal formation are different and different with production technique.And crystal formation and bioavailability have direct relation, are effective type through clinical verification I type and IV type, II type and III type be of no curative effect (Ger 0ffen-2444728,28 Sep 1973; Kump W et al:Helv chim Acta56,2348-2377,1973; Bickel etal (ciba-Geigy A-G) Swiss 605,974; China's tuberculosis and respiratory system disease magazine 5,74-77,1982; Microbiotic magazine 1982,3, P150.
A kind of synthetic method of Rifin is disclosed in Ger offen-2444728.Purpose is a synthesizing series rifomycin SV derivative, screens to find out to have the curative effect sick novel drugs of tuberculosis and synthesized this compound preferably.
This invention utilizes sharp good fortune S to generate the sharp good fortune S of intermediate product 3-(4-isobutyl--1-piperazinyl) for raw material and side chain isobutyl piperazine react in dioxane, this intermediate product carries out reduction reaction and generates the Rifin crude product in acidic medium in methyl alcohol and water, this crude product secondary in chloroform-methanol-water mixed solvent changes brilliant, gets IV type Rifin finished product.
The deficiency that this synthetic method exists is; Sharp good fortune S and the condensation reaction of side switch isobutyl piperazine are solvent with the dioxane, the inconvenience of dioxane source, price is expensive, post-reaction treatment need add 15-20 times of water dilution of dioxane consumption, could use chloroform extraction, the both water-soluble chloroform that also is dissolved in of dioxane forms the three-phase emulsion layer that dissolves each other, the extraction separation difficulty, influence intermediate product yield and quality, reaction time is long, carries out three kinds of difficult controls of solvent ratio when particularly changing into the crystallization of IV type in mixed solvent, solvent can not be recycled, bring the cost height, the shortcoming that yield is low is unfavorable for suitability for industrialized production.
The purpose of this invention is to provide a kind of improvement synthetic method that is suitable for the suitability for industrialized production Rifin.The organic solvent source of this processing method is wide, and operation is simplified during condensation reaction, and obviously shorten reaction time, cancelled mixed solvent, improves product yield and quality effectively, significantly reduces manufacturing cost.
The object of the present invention is achieved like this: adopt sharp good fortune S and the excessive sharp good fortune S of isobutyl piperazine reaction generation intermediate product isobutyl piperazine; isobutyl piperazine is not only made reaction raw materials but also make action solvent; slice off dioxane solvent of the prior art; removed simultaneously with a large amount of water treatment operations; only add in condensation reaction that minimum of chloroform protection isobutyl piperazine and sharp good fortune S fully react and not by inclusion; thereby simplified technology, reduced manufacturing cost, guaranteed intermediate yield and quality.When particularly the Rifin crude product changes into the crystallization of IV type,, add the acid stabilizer vitamins C of the 25-30% that accounts for gross weight, improved the product inner quality, slice off mixed solvent at aqueous ethanol transfer crystalline substance.The mol proportioning of wherein sharp good fortune S and isobutyl piperazine is 1: 10-12, and adding chloroform amount is 0.5 times of sharp good fortune S consumption, Heating temperature is 40-55 ℃.For effectively utilizing aqueous ethanol, used aqueous ethanol percentage composition is preferably between the 85-96, and consumption is that the 8-10 of Rifin crude product consumption doubly is advisable.
Advantage of the present invention and positively effect:
Step of condensation of the present invention utilizes isobutyl piperazine to do action solvent, slice off the source difficulty, the dioxane organic solvent that price is expensive has removed the thin up operation, and extraction separation guarantees the intermediate quality easily, unreacted isobutyl piperazine adds sour salify band water distillation recovery and directly applies mechanically, make raw materials cost reduce by 1/2, yield reaches 68%, and condensation reaction time of the present invention foreshortened to 4-6 hour by original 26-28 hour, shortened reaction time, for suitability for industrialized production creates favorable conditions.Particularly change brilliant step and utilize aqueous ethanol to be solvent, make Rifin form solvate, the recyclable utilization of solvent ethanol is not reversed into quinone because the adding vitamins C can prevent the hydroxyl in the product structure, has improved the product inner quality.The also available 1-3 carbon of solvent chloroform of the present invention lower aliphatic alcohols, methylene dichloride replace.
For a better understanding of the present invention, enumerate the embodiment explanation below.
Embodiment 1
With sharp good fortune S42g, chloroform 20g, isobutyl piperazine 98g adds in the 500ml three-necked bottle that thermometer, reflux exchanger and agitator are housed successively, warming while stirring is all dissolved sharp good fortune S, is warming up to 55 ℃, stirring reaction 5 hours, adding acid then makes unreacted isobutyl piperazine salify soluble in water, divide three extractions with the 250ml chloroform again, the combined chloroform extracting solution is concentrated into dried.Get the sharp good fortune S of intermediate product isobutyl piperazine, yield 68% (to sharp good fortune S meter).Reclaim unreacted side chain isobutyl piperazine, recycled with remainder water solution band water distillation behind the chloroform extraction.
In the sharp good fortune S of intermediate product isobutyl piperazine, add the 350ml industrial alcohol, stirring heats up dissolves under the backflow situation, the vitamins C 15g that adds the sharp good fortune S of intermediate product isobutyl piperazine weight 18%, continue backflow 20-30 minute, place cooling, filtration, dry cake get the Rifin crude product.
The adding of 7g Rifin crude product is equipped with in the 150ml three-necked bottle of reflux exchanger, thermometer, agitator, add 95% ethanol 70g then, rising temperature for dissolving, complete molten back adds vitamins C 0.48g, continues at 70-75 ℃ of stirring and refluxing 20-30 minute, stop to stir, elder generation's room temperature is placed and is cooled to 40 ℃, continues freezing placement and spends the night, and filters, drying gets IV type Rifin product.Content average 97%.
Embodiment 2
With embodiment 1 same apparatus, with the sharp good fortune S of 42g, 20g chloroform, 100g isobutyl piperazine add in the three-necked bottle successively, and stirring heats up makes its dissolving, be heated to 50-55 ℃ of stirring reaction 6 hours, add acid then and make the whole salifies of unreacted isobutyl piperazine soluble in water, divide three extractions, combined chloroform extracting solution with the 300ml chloroform, be concentrated into dried, the sharp good fortune S of isobutyl piperazine.Yield 67% (to sharp good fortune S meter).Handle with remainder water solution behind the chloroform extraction and embodiment 1 same procedure, reclaim the isobutyl piperazine recycled.
In the sharp good fortune S of intermediate product isobutyl piperazine, add the 350ml industrial alcohol, stir and heat up, backflow makes its dissolving, the vitamins C 14g that adds the sharp good fortune S of intermediate product isobutyl piperazine weight 20%, continue backflow 20-30 minute, place cooling, filtration, dry cake get the Rifin crude product.
The adding of 7g Rifin crude product is equipped with in the 150ml three-necked bottle of reflux exchanger, thermometer, agitator, add 92% ethanol 70g then, heating for dissolving, complete molten back adds vitamins C 0.48g, continues at 70-75 ℃ of stirring and refluxing 20-30 minute, stop to stir, elder generation's room temperature is placed and is cooled to 40 ℃, continues freezing placement and spends the night, and filters, drying gets IV type Rifin product.Content average 97%.
Embodiment 3
Change brilliant with the Rifin crude product that makes with embodiment 1 or embodiment 2 same procedure, in the Rifin crude product, add 85% ethanol or 90% ethanol or 96% ethanol 70g, other condition of changeing brilliant is identical with embodiment 1 or embodiment 2, obtains IV type Rifin product equally.
With the Rifin of the inventive method preparation, through the X-ray diffraction test, its crystal formation is consistent with standard diagram to be the crystallization of IV type, as shown in Figure 1.
Test through thermal stability the product and the commercially available prod of the inventive method preparation, and in 150 ℃ of bakings 6 hours, commercially available prod content descended 64.7% as a result equally, and biological value descends 40.7%, and this product content descends 29.7%, and biological value descends 1.3%.
Analyze (DTA+TG) with chemical method, vapor-phase chromatography, heat and measure the residual solvent total amount respectively, the residual solvent qualitative, quantitative, guarantee the existence form of water, the result shows the whole bag of tricks test result unanimity, be the Rifin IV type crystallization that makes of the inventive method except that the attached water that contains pure solvent band, still have three crystal water, it removes temperature is 60 ℃ and 105 ℃, because the existence of crystal water has increased the blood absorption of product, has improved bioavailability.
Analysis is selected 40 ℃ according to heat, 93 ℃ and the baking of 126 ℃ of three differing tempss are after 4 hours, do the X-ray diffraction test result and show that residual solvent loses, and crystalline form there is not change, only raise with temperature, indivedual peak intensities weaken gradually, but still keep this basic feature of IV type crystal formation, and this product IV stable crystal form is described.Shown in Fig. 3,4,5,6.
With powerful microscope this product crystal formation is taken pictures as shown in Figure 7.
This product is carried out the each side test, and it is good that the result shows with the Rifin IV type crystal formation product inner quality of the inventive method preparation.
Wherein Fig. 1 is the IV type crystal form X-diffracting spectrum of the inventive method preparation.
Fig. 2 is Rifin IV type crystal formation standard x-diffracting spectrum.
Fig. 3 is the Rifin heating differential analysis collection of illustrative plates of the inventive method preparation.
Fig. 4 is a heating differential analysis collection of illustrative plates after 40 ℃ of bakings.
Fig. 5 is a heating differential analysis collection of illustrative plates after 93 ℃ of bakings.
Fig. 6 is a heating differential analysis collection of illustrative plates after 126 ℃ of bakings.
Fig. 7 is that product of the present invention is taken pictures with the powerful microscope crystal formation.
Fig. 8 is to take pictures with the powerful microscope crystal formation in the commercially available prod.
Claims (2)
1, a kind of method of synthetic Rifin, it adopts sharp good fortune S and isobutyl piperazine is raw material, carry out condensation, reduction reaction generates the sharp good fortune S of intermediate product isobutyl piperazine, handle through routine again and be reduced into the Rifin crude product, in crude product, add aqueous ethanol and change brilliant, generate IV type Rifin product, the mol proportioning that it is characterized in that used sharp good fortune S and excessive isobutyl piperazine is 1: 10-12, reacting by heating under organic solvent chloroform existence condition, used chloroform amount is 0.5 times of sharp good fortune S consumption, Heating temperature is 40-55 ℃, be reduced into crude product and crude product commentaries on classics crystalline substance at intermediate product, when adding aqueous ethanol, adding the stablizer vitamins C altogether is the 25-30% of sharp good fortune S of intermediate product isobutyl piperazine and crude product Rifin gross weight.
2, the preparation method of Rifin according to claim 1, when it is characterized in that by the brilliant IV of generation of Rifin crude product commentaries on classics type Rifin product, is solvent with the percentage composition for 85-96 ethanol, consumption is 8-10 a times of Rifin crude product consumption, and stirring under 70-75 ℃ of condition changeed brilliant 20-30 minute.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92106014 CN1033163C (en) | 1992-01-10 | 1992-01-10 | Process for preparation of lifumycin of isobuty piperazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 92106014 CN1033163C (en) | 1992-01-10 | 1992-01-10 | Process for preparation of lifumycin of isobuty piperazine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1063105A CN1063105A (en) | 1992-07-29 |
| CN1033163C true CN1033163C (en) | 1996-10-30 |
Family
ID=4941714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92106014 Expired - Fee Related CN1033163C (en) | 1992-01-10 | 1992-01-10 | Process for preparation of lifumycin of isobuty piperazine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1033163C (en) |
-
1992
- 1992-01-10 CN CN 92106014 patent/CN1033163C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1063105A (en) | 1992-07-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1033163C (en) | Process for preparation of lifumycin of isobuty piperazine | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| CN105130795A (en) | Preparation method for high-purity fenofibric acid crude drugs | |
| JPH0291035A (en) | Collection of l-quebrachitol in natural rubber serum | |
| CN107118246A (en) | A kind of synthesis technique of neohesperidin | |
| CN102336701A (en) | Carvedilol sulphate crystals, preparation method and application thereof in medicine | |
| CN102010345A (en) | Method for preparing D-phenylalanine through dynamic kinetic resolution | |
| CN113354581A (en) | Preparation method and application of chiral chloroquine and phosphate thereof | |
| CN112110879A (en) | Preparation method of sulcardine free alkali | |
| CN114057640A (en) | Asymmetric synthesis method of optically pure (R)/(S) -hydroxychloroquine side chain | |
| CN111087380B (en) | Preparation method of ticagrelor intermediate | |
| CN111039814A (en) | Propacetamol crystal form and preparation method thereof | |
| CN1155566C (en) | Process for separating and purifying N-ethyl carbazole | |
| CN102702196A (en) | Method for synthesizing 3-methyl-7-diazaindene | |
| CN114133421B (en) | Preparation method of beta-mouse cholic acid | |
| JP4093608B2 (en) | Process for producing optically active 2-phenoxypropionic acid | |
| JPH05500205A (en) | Hemin purification method, new hemin derivatives and their production method | |
| CN110684066B (en) | Cytophosphocholine medicinal preparation and new application thereof in cerebral infarction acute-stage disturbance of consciousness | |
| CN106967000B (en) | Preparation method of medical intermediate for preventing and treating tumor chemotherapy | |
| CN109970822B (en) | Preparation method for synthesizing emamectin benzoate intermediate | |
| JP2728735B2 (en) | Method for collecting L-quebrachitol in natural rubber serum | |
| CN117624238A (en) | Zoledronic acid impurity and preparation method thereof | |
| TWI693209B (en) | Method for preparing sacubitril sodium salt and application thereof | |
| CN106496089A (en) | A kind of method for preparing Oxiracetam | |
| JPS607629B2 (en) | Method for producing r-pyrone derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |