CN104230876A - New synthetic method for key intermediate cis-bromo-ester of conazole medicines - Google Patents
New synthetic method for key intermediate cis-bromo-ester of conazole medicines Download PDFInfo
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- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses a new synthetic method for key intermediate cis-bromo-ester of conazole medicines, and the method is a one-pot reaction method. The method comprises: dissolving 2,4-dichloroacetophenone and glycerin in a solvent, utilizing a bromination reagent to perform bromination on methyl nearby keto carbonyl in the presence of a catalyst, and also realizing ketalization of carbonyl and glycerin, so as to realize one pot reaction of ketalization and bromination; after the solution of bromo-ketal is obtained, directly applying the solution to reaction of bromo-ketal hydroxyl and benzoyl chloride, so as to finally obtain a bromo-ester mixture with a relatively high cis-trans ratio; and using a known method to perform resolution and recrystallization on the cis and trans bromo-esters, so as to obtain the cis-bromo-ester with a relatively high yield. The method is simple has the characteristics of simple operation, high safety, low cost and less pollution, and is a technological route suitable for industrialization.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, relate to the preparation method of antifungal drug key intermediate, relate to the synthetic method of the key intermediate cis-bromic ester of KETOKONAZOL, itraconazole, new health azoles and Triaconazole in particular.
Background technology
Fungi infestation is the class principal disease threatening human health all along.
Particularly in recent years, because of the abuse of microbiotic, cortin, antitumor drug and immunosuppressor and the extensive application of aggressive operation, cause flora imbalance and body to reduce the resistibility of fungi, cause the sickness rate of fungi infestation day by day to increase.
Particularly deep fungal infection is concerning a fatal threat especially critical patient.
Statistic data shows that in the past in many decades, the sickness rate of fungi infestation not only increases year by year, and mortality ratio remains on the high level of 40 ~ 60% always.
The medicine of therefore antifungal drug, the particularly s-generation, the anti-deep fungal infection of the third generation remains and increases fast, and in occupation of critical positions in whole sales amount of medicine.
KETOKONAZOL, new health azoles, itraconazole and Triaconazole as the representative inside antifungal drug, in clinical middle extensive application; Particularly KETOKONAZOL and itraconazole, is used in various forms of fungi infestation as first-line drug all the time.
But to synthesize these medicines be a quite loaded down with trivial details job; Wherein not only synthesis step is long, and the synthesis technique yield related to used is low, and three-waste pollution is large, and can there is certain potential safety hazard.
Wherein their shared key intermediates: cis-(2 one (2,4 one dichlorophenyls) one 2 one (brooethyls) 1,3 one dioxolane 1 methyl benzoate (being also known as cis-bromic ester, as follows) are exactly a typical example.
Due to the raw material that cis-bromic ester is synthesis KETOKONAZOL, newly health azoles, itraconazole and Triaconazole are the most initial, the direct industrialization on these antifungal drugs just brings and the most directly affects by complexity of therefore its synthesis and the height of synthesis cost.
At present general, be also that the route of the synthesizing cis brominated esters generally having realized suitability for industrialized production is as follows.
The method is raw material by 2,4 dichloro benzene ethyl ketone and glycerine, utilizes refluxing toluene to dewater and form ketal intermediate.
This reaction needed uses the toluene with larger toxicity, and the simultaneous reactions time is long, low conversion rate, also higher to matching requirements in industrialization; Therefore no matter from production cost angle, or all not bery desirable from safety in production angle.
The ketal intermediate obtained in above-mentioned synthetic method, then react with bromine, obtain along anti-bromo ketal mixture through aftertreatment.
The suitable reverse proportionality of this ketal mixture is roughly 1.5/1, and this mixture needs to react with Benzoyl chloride in trichloromethane equal solvent afterwards, obtains along after anti-brominated esters mixture, then through splitting crystallization, just can obtain required cis-bromic ester.
In the method bromo ketal mixture 1.5/1 suitable reverse proportionality, the theoretical yield just determining last required cis-bromic ester is the highest also only has 60%.
Therefore general this synthetic method total recovery is actual only has about 40%; All the other products of nearly 60% then discard as waste material.
This shows, this synthetic method not only can cause the very large wasting of resources, also can bring larger difficulty to environment protection simultaneously.
Although there is document (WO9629325) report can replace glycerine by chirality glyceryl ester at present, thus solve this problem of generation trans-isomer(ide); But used chirality glyceryl ester is expensive, this is unacceptable for low-cost bulk drugs such as such as KETOKONAZOL on cost.
Summary of the invention
The object of the invention is to overcome shortcoming and defect of the prior art, develop the novel method of utilization " a treating different things alike " method synthesis health azole drug key intermediate cis-bromic ester.
Being characterised in that of method of this invention comprises following step: by 2,4-dichloroacetophenone and glycerine are in a solvent and in the presence of a catalyst, utilize brominated reagent while the methyl other to ketone carbonyl carries out bromination, and realize the ketal reaction of carbonyl and glycerine, realize ketal and bromination reaction " treating different things alike "; After the solution obtaining bromo ketal, this solution is directly used in the reaction of bromo ketal hydroxyl and Benzoyl chloride, finally can obtain brominated esters mixture with comparatively high cis-to-trans ratio example, then split and recrystallization along anti-brominated esters through currently known methods, just can obtain cis-bromic ester with higher yields.
Use tetrahydrofuran (THF) in the method, dioxane, methylene dichloride, chloroform etc. are solvent, preferred dioxane and chloroform.
The amount of glycerine used in reaction is 1.0 ~ 5 times of 2,4 dichloro benzene ethyl ketone molar weight, preferably 1.2 ~ 2 times.
The catalyzer used is benzyltrimethylammonium bromide, cupric bromide and dioxane or their mixture; The amount used is 0.05 ~ 20 times of 2,4 dichloro benzene ethyl ketone molar weight, preferably 0.1 ~ 5 times.
Temperature of reaction is between 0 degree ~ 50 degree, between preferably 20 degree ~ 40 degree.
The bromide reagent used is bromine, cupric bromide, benzyl trimethyl tribromide ammonium, bromine dioxane complex compound or their mixture.Preferred bromine and benzyl trimethyl tribromide ammonium; The amount used is 1.0 ~ 1.5 times of 2,4 dichloro benzene ethyl ketone molar weight.
Reaction times generally in 10 ~ 20 little times, middle control reaction to be transformed completely after, can obtain containing the reaction solution along anti-bromo ketal mixture through conventional aftertreatment.
The suitable reverse proportionality of gained bromo ketal mixture is generally about 3.6/1.
After directly reacting with Benzoyl chloride containing the reaction solution along anti-bromo ketal mixture, after currently known methods fractionation crystallization, cis-bromic ester can be obtained.
This invention is by 2,4 dichloro benzene ethyl ketone, and the total recovery to last cis-bromic ester can reach 70%.
This invention is compared with known method, there is following distinguishing feature: whole reaction process adopts " treating different things alike " method, all carry out in same solvent system from start to finish, avoid in original technological process and repeatedly carry out the cost that solvent exchange brings and increase and security risk.
Whole reaction process is carried out at a lower temperature, avoids former technique and uses the operation of refluxing toluene band water; This technique not only shortens the time, is more suitable for factory's operation, also saves energy consumption simultaneously, reduce production cost.
Due to the change of technique, make the suitable reverse proportionality of original technique gained brominated esters bring up to present 3.6/1 by original 1.5/1, total recovery also brings up to present 70% by original 40%; This not only significantly reduces the material cost of cis-bromic ester, and the minimizing of trans brominated esters as offal treatment, also for economize on resources and environment protection brings facility.
Therefore this invention utilizes " treating different things alike " method, synthesis health azole drug key intermediate cis-bromic ester, have simple to operate, security is high, and cost is low, pollutes few feature, is one and is applicable to industrialized operational path.
Embodiment
To contribute to understanding the present invention by following embodiment, but content of the present invention can not be limited.
Simultaneously in order to simple and clearly object, the hereafter appropriate description eliminating known technology, the description of the details avoiding those unnecessary impact to the technical program.
Tribromo quaternary ammonium salt mentioned in the present invention and 2,4 dichloro benzene ethyl ketone can be buied easily from the market, or with reference to pertinent literature (Bull. Chem. Soc. Jpn., 60,2667 (1987); Chemical reaction engineering and technique, 4(20), 380(2004)) prepare.
Embodiment 1
Get 189 grams of 2,4 dichloro benzene ethyl ketones, 165.7 grams of glycerine and 11 grams of cupric bromides are placed in the trichloromethane of 1100 grams, and control temperature, between 20 ~ 30 degree, stirs and constantly slowly adds 429 grams and cross bromobenzyl trimethylammonium bromides down; Stirring reaction is continued 20 hours after adding; After control reacts completely in HPLC, use the aqueous solution of sodium bisulfite of 5% successively, salt solution and deionized water wash, namely obtain the chloroform soln of bromo ketal afterwards; This solution can be directly used in follow-up reaction and not need through being separated after anhydrous sodium sulfate drying; As by this reaction solution evaporate to dryness, the suitable anti-bromo ketal mixture of 338 grams of oilies can be obtained, HPLC purity: be greater than 92%.
Embodiment 2
Get 189 grams of 2,4 dichloro benzene ethyl ketones and 184 grams of glycerine are dissolved in the dioxane of 812 grams, under room temperature, constantly slowly drip the bromine of 161 grams; At room temperature stirring reaction 11 hours after adding; After control reacts completely in HPLC, regulate reaction solution pH value to neutral with strong aqua, remove dioxane under reduced pressure afterwards, then add the trichloromethane of 800 grams; After gained chloroform soln uses salt solution and deionized water wash more successively, obtain the chloroform soln of bromo ketal; Solution H PLC purity: 94%.
Embodiment 3
The chloroform soln of the bromo ketal obtained in Example 2, after anhydrous sodium sulfate drying, adds 136 grams of triethylamines, is chilled to less than 0 degree, slowly add the Benzoyl chloride of 154 grams afterwards; Reacting control to HPLC after adding transforms completely; Use the aqueous sodium carbonate of 10% successively, salt solution and deionized water wash; Underpressure distillation solvent is to dry, and finally obtain the mixture of brominated esters, the suitable reverse proportionality of this brominated esters is 3.6/1; This mixture splits and recrystallization through known method afterwards, finally can obtain the cis-bromic ester of 316 grams.Yield: 71%; HPLC purity: 97.5%; Fusing point: 117 ~ 119 degree.
Embodiment 4
The chloroform soln of the bromo ketal obtained in Example 1, utilizes the method in embodiment 3, finally can obtain the cis-bromic ester of 303 grams; Yield: 68%; HPLC purity: 98.2%.
Claims (6)
1. utilize a novel method for " treating different things alike " method synthesis health azole drug key intermediate cis-bromic ester, it is characterized in that:
(1) 2,4 dichloro benzene ethyl ketone and glycerine utilize brominated reagent in a solvent;
(2) under catalyzer existence and certain temperature;
(3) while the methyl other to ketone carbonyl carries out bromination, and realize the ketal reaction of carbonyl and glycerine, realize ketal and bromination reaction " treating different things alike ";
(4) after the solution obtaining bromo ketal, this solution is directly used in bromo ketal and Benzoyl chloride reacts, and finally obtains brominated esters.
2. method according to claim 1, is characterized in that: the solvent used is tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform and their mixture.
3. method according to claim 1, is characterized in that: the amount of glycerine used in reaction is 1.0 ~ 5 times of 2,4 dichloro benzene ethyl ketone molar weight.
4. method according to claim 1, is characterized in that: the catalyzer used is benzyltrimethylammonium bromide, cupric bromide, dioxane and their mixture; The amount used is 0.05 ~ 20 times of 2,4 dichloro benzene ethyl ketone molar weight.
5. method according to claim 1, is characterized in that: temperature of reaction is between 0 degree ~ 50 degree.
6. method according to claim 1, is characterized in that: the bromide reagent used is bromine, cupric bromide, benzyl trimethyl tribromide ammonium, bromine dioxane complex compound and their mixture; The amount used is 1.0 ~ 1.5 times of 2,4 dichloro benzene ethyl ketone molar weight.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4490540A (en) * | 1981-09-14 | 1984-12-25 | Janssen Pharmaceutica N.V. | (2-Aryl-4-phenylthioalkyl-1,3-dioxolan-2-ylmethyl)azole derivatives |
| WO2000043390A1 (en) * | 1999-01-19 | 2000-07-27 | Korea Research Institute Of Chemical Technology | Antifungal azole derivatives having a fluorinated vinyl group and process for preparing same |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4490540A (en) * | 1981-09-14 | 1984-12-25 | Janssen Pharmaceutica N.V. | (2-Aryl-4-phenylthioalkyl-1,3-dioxolan-2-ylmethyl)azole derivatives |
| WO2000043390A1 (en) * | 1999-01-19 | 2000-07-27 | Korea Research Institute Of Chemical Technology | Antifungal azole derivatives having a fluorinated vinyl group and process for preparing same |
Non-Patent Citations (4)
| Title |
|---|
| JIřÍ SVOBODA等: "One Step Synthesis of Substituted 2-Aryl-2-Bromoalkyl-1,3-Dioxolanes", 《COLLECTION CZECHOSLOVAK CHEM. COMMUN.》, vol. 49, 31 December 1984 (1984-12-31), pages 1515 - 1520, XP001091320 * |
| SANDHYA VISWESWARIAH等: "One-Pot α-Bromoacetalization of Carbonyl Compounds", 《SYNTHESIS》, 30 April 1982 (1982-04-30), pages 309 - 310 * |
| 李海波等: "改进顺-[2-(2,4-二氯苯基)-2-(1H-咪唑基-1-甲基)-1,3-二氧戊环-4-]对甲苯磺酸酯的合成工艺", 《华西药学杂志》, vol. 22, no. 6, 31 December 2007 (2007-12-31), pages 645 - 647 * |
| 李鲁等: "酮康唑衍生物的合成", 《中国药物化学杂志》, vol. 5, no. 4, 31 December 1995 (1995-12-31), pages 271 - 273 * |
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