CN101200472A - Method for preparing 3-amido-4-imino rifamycin S - Google Patents
Method for preparing 3-amido-4-imino rifamycin S Download PDFInfo
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- CN101200472A CN101200472A CNA2006100225091A CN200610022509A CN101200472A CN 101200472 A CN101200472 A CN 101200472A CN A2006100225091 A CNA2006100225091 A CN A2006100225091A CN 200610022509 A CN200610022509 A CN 200610022509A CN 101200472 A CN101200472 A CN 101200472A
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Abstract
The invention relates to a preparation method of 3-amino-4-imino rifamycin S and belongs to the medicine technology field. The preparation method is that 3-halogenated rifamycin S is dissolved in ether, halohydrocarbon, alcohols or esters solvent, the dosage is that the ratio of 3-halogenated rifamycin S to the solvent equals to the ratio of 1 (weight) to the range of 4 to 7.5 (volume), and ammonia is introduced, the reaction temperature is minus 20 to 60 DEG C and the time endures 7 to 30 hours, then 3-amino-4-imino rifamycin S is obtained. The invention has the advantages that the 3-halogenated rifamycin S is taken as the raw material, the 3-amino-4-imino rifamycin S is obtained only by one-step reaction after the ammonia is introduced, reaction condition is mild, the yield (above 80 percent in most situations) is higher and the product purity (no need of purification and direct application on other reactions) is better.
Description
Technical field:
The invention belongs to medical technical field, be specifically related to the preparation method of 3-amino-4-imino rifamycin S.
Background technology:
3-amino-4-imino rifamycin S has very high anti-microbial activity, is again the important intermediate during many Ryfamycin derivatives (as: Mycobutin) synthesize.At present main synthetic method is to be that raw material is synthetic by following two lines with 3-halo rifamycin-S or SV.Route (1) be with 3-halo rifamycin-S nitrated after, reoxidize with the active metal reduction, logical then ammonia obtains (as: US4017481 and US2417277), and this method route is longer, and need through steps such as extraction, distillation, filtrations in the operation, so process is loaded down with trivial details.Route (2) though shorter, use the introducing agent (US4007169) of sodiumazide as amino, therefore sodiumazide severe toxicity and very easily blasting can't realize large-scale industrialization production.
Route (1): (wherein X is a halogen atom)
Route (2): (wherein X is a halogen atom)
Summary of the invention:
The objective of the invention is to overcome the deficiency of the long or severe reaction conditions of 3-amino in the prior art-4-imino rifamycin S synthetic route, for people provide that a kind of synthetic route weak point, reaction process mild condition, yield are higher, the product purity preparation method of 3-amino-4-imino rifamycin S preferably.
The objective of the invention is to realize by following technical proposals.
The preparation method of 3-amino of the present invention-4-imino rifamycin S is dissolved in 3-halo rifamycin-S in ethers, halogenated hydrocarbon, alcohols or the esters solvent, consumption is a 3-halo rifamycin-S: solvent=1 (quality): 4～7.5 (volumes), feed ammonia, temperature of reaction is at-20 ℃～60 ℃, reacted 7～30 hours, and obtained 3-amino-4-imino rifamycin S.
The halo of 3-described in such scheme rifamycin-S is meant 3-bromo rifamycin-S, 3-iodo rifamycin-S, 3-fluoro rifamycin-S or 3-chloro rifamycin-S.
In the such scheme, reaction pressure is at normal pressure～0.5Mpa.
In the such scheme, the reaction solution that finishes of reaction is removed solid after filtration, and filtrate is lower than 50 ℃ and is evaporated to driedly, obtains thick 3-amino-4-imino rifamycin S solid, and this solid recrystallization is obtained purer 3-amino-4-imino rifamycin S.
The preparation method's of 3-amino of the present invention-4-imino rifamycin S synthetic route is as follows:
X wherein is a halogen atom, and Me is a methyl, (I) is 3-halo rifamycin-S, (II) is 3-amino-4-imino rifamycin S.Originally be reflected at more and also can react under the high pressure, higher to equipment requirements simultaneously but speed of response and result do not have clear superiority, therefore there is not practical significance.This reaction is lower than-20 ℃ also can react, but higher to the cooling system requirement, and is higher than 60 ℃ of reaction impurities showed increased.
Advantage of the present invention is: the present invention is a raw material with 3-halo rifamycin-S (I), only obtains 3-amino-4-imino rifamycin S (II) by logical ammonia react of a step.The reaction process mild condition, yield higher (in most cases more than 80%), and product purity better (need not make with extra care and can be directly used in other reactions).
Further specify the present invention below by embodiment, the present invention is not limited only to described embodiment.
Embodiment:
Embodiment one
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 100ml dehydrated alcohol with 20g 3-bromo rifamycin-S and are added in the reaction flask, maintain the temperature at about 0 ℃, and normal pressure fed the ammonia stirring reaction 18 hours down.Remove by filter the solid in the reaction solution, filtrate is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 16.1g with 20ml ethyl acetate and 100ml sherwood oil recrystallization, yield 88%, HPLC (efficient liquid phase chromatographic analysis) purity 97.1%.
Embodiment two
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 100ml dehydrated alcohol with 25g 3-iodo rifamycin-S and are added in the reaction flask, maintain the temperature under-10 ℃ of left and right sides normal pressures and feed the ammonia stirring reaction 7.5 hours.Remove by filter the solid in the reaction solution, filtrate is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 17.5g, yield 81%, HPLC purity 94.7% with 20ml ethyl acetate and 100ml sherwood oil recrystallization.
Embodiment three
Other conditions are with embodiment one, but reaction raw materials is a 3-chloro rifamycin-S, yield 81%, HPLC purity 93.1%.
Embodiment four
Other conditions are with embodiment one, but reaction raw materials is a 3-fluoro rifamycin-S, yield 42%, HPLC purity 85.6%.
Embodiment five
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 100ml dehydrated alcohol with 20g 3-bromo rifamycin-S and are added in the reaction flask, maintain the temperature at about 0 ℃ and feed the ammonia stirring reaction 10 hours down in 0.5Mpa pressure.Remove by filter the solid in the reaction solution, filtrate is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 15.2g, yield 83%, HPLC purity 95.2% with 20ml ethyl acetate and 100ml sherwood oil recrystallization.
Embodiment six
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 150ml Virahol with 20g 3-bromo rifamycin-S and are added in the reaction flask, maintain the temperature at about 40 ℃ and feed the ammonia stirring reaction 30 hours down in normal pressure.Remove by filter the solid in the reaction solution, filtrate is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 14.6g, yield 80%, HPLC purity 93.8% with 20ml ethyl acetate and 100ml sherwood oil recrystallization.
Embodiment seven
Other conditions are with embodiment one, but reaction solvent is a glycol dimethyl ether, yield 84%, HPLC purity 95.6%.
Embodiment eight
Other conditions are with embodiment one, but reaction solvent is a tetrahydrofuran (THF), yield 81%, HPLC purity 91.8%.
Embodiment nine
Other conditions are with embodiment one, but reaction solvent is a methylene dichloride, yield 74%, HPLC purity 92.2%.
Embodiment ten
Other conditions are with embodiment one, but reaction solvent is 1,2-ethylene dichloride, yield 62%, HPLC purity 87.1%.
Embodiment 11
Other conditions are with embodiment one, but reaction solvent is an ethyl acetate, yield 71%, HPLC purity 94.7%.
Embodiment 12
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 100ml dehydrated alcohol with 20g 3-bromo rifamycin-S and are added in the reaction flask, maintain the temperature under-20 ℃ of left and right sides normal pressures and feed the ammonia stirring reaction 26 hours.Remove by filter the solid in the reaction solution, filtrate is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 15.6g, yield 85%, HPLC purity 96.4% with 20ml ethyl acetate and 100ml sherwood oil recrystallization.
Embodiment 13
Three mouthfuls of round-bottomed flask dresses of 250ml thermometer, ventpipe and magnetic agitation seed are dissolved in the 100ml dehydrated alcohol with 20g 3-bromo rifamycin-S and are added in the reaction flask, maintain the temperature under 60 ℃ of left and right sides normal pressures and feed the ammonia stirring reaction 10 hours.Remove by filter the solid in the reaction solution, reaction solution is lower than 50 ℃ is evaporated to the dried dark red solid that obtains, this solid is obtained 3-amino-4-imino rifamycin S red-purple crystal 13.9g, yield 76%, HPLC purity 93.4% with 20ml ethyl acetate and 100ml sherwood oil recrystallization.
Claims (4)
1. the preparation method of 3-amino-4-imino rifamycin S, it is characterized in that it being that 3-halo rifamycin-S is dissolved in ethers, halogenated hydrocarbon, alcohols or the esters solvent, consumption is a 3-halo rifamycin-S: solvent=1 (quality): 4～7.5 (volumes), feed ammonia, temperature of reaction is at-20 ℃～60 ℃, reacted 7～30 hours, and obtained 3-amino-4-imino rifamycin S.
2. the preparation method of 3-amino according to claim 1-4-imino rifamycin S is characterized in that 3-halo rifamycin-S is meant 3-bromo rifamycin-S, 3-iodo rifamycin-S, 3-fluoro rifamycin-S or 3-chloro rifamycin-S.
3. the preparation method of the amino 4-imino rifamycin S of 3-according to claim 1 is characterized in that reaction pressure is at normal pressure～0.5Mpa.
4. the preparation method of 3-amino according to claim 1-4-imino rifamycin S, it is characterized in that reacting the reaction solution that finishes and remove solid after filtration, filtrate is lower than 50 ℃ and is evaporated to dried, obtain thick 3-amino-4-imino rifamycin S solid, this solid recrystallization is obtained purer 3-amino-4-imino rifamycin S.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2006100225091A CN101200472A (en) | 2006-12-15 | 2006-12-15 | Method for preparing 3-amido-4-imino rifamycin S |
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| CNA2006100225091A CN101200472A (en) | 2006-12-15 | 2006-12-15 | Method for preparing 3-amido-4-imino rifamycin S |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001236A (en) * | 2015-06-26 | 2015-10-28 | 重庆华邦制药有限公司 | Preparation method of 3-amino-rifamycin S |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001236A (en) * | 2015-06-26 | 2015-10-28 | 重庆华邦制药有限公司 | Preparation method of 3-amino-rifamycin S |
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Open date: 20080618 |