CN103588847A - Preparation method for rocuronium bromide intermediate - Google Patents
Preparation method for rocuronium bromide intermediate Download PDFInfo
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- CN103588847A CN103588847A CN201210293977.8A CN201210293977A CN103588847A CN 103588847 A CN103588847 A CN 103588847A CN 201210293977 A CN201210293977 A CN 201210293977A CN 103588847 A CN103588847 A CN 103588847A
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Abstract
The invention relates to a preparation method for a high-purity rocuronium bromide intermediate (2beta, 3alpha, 5alpha, 16beta, 17beta)-16-(1-pyrrolidinyl)-2-(4-morpholinyl)-3-hydroxy-androstane-17-ol acetate (a compound 2). According to the method, the rocuronium bromide intermediate (the compound 2) is prepared through selective acetylation of (2beta, 3alpha, 5alpha, 16beta, 17beta)-16-(1-pyrrolidinyl)-2-(4-morpholinyl)-androstane-3, 17-diol. The method has the advantages of environment friendliness, easy and convenient operation, rapid reaction, high yield and HPLC purity of 99.8% or more than 99.8%.
Description
Technical field
The invention belongs to chemistry or pharmaceutical chemistry field, be specifically related to a kind of highly purified Zemuron intermediate (2 β, 3 α, 5 α, 16 β, 17 β) preparation method of-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates.
Background technology
Zemuron (Rocuronium Bromide), is researched and developed by Dutch Ou Jianong company, in June, 1994, in the U.S., goes on the market, and go on the market July in the same year in Britain.Zemuron is a kind of novel non depolarization sterols muscle relaxant, can organize stagnant effect to the generation of nerve-muscle contact, thereby between temporary interference nerve-muscle, excited transmission makes skeletal muscle relaxation, has rapid-action, middle timeliness and recovers feature more rapidly.(2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetate is the important intermediate (compound 2) of synthetic Zemuron, and compound 2 can conveniently be prepared Zemuron with allyl bromide 98 salify.
At US4894369, US5817803, and in the patent such as CN1803826, the preparation method of compound 2 has been described.Preparation method in US Patent No. 4894369 is: Acetyl Chloride 98Min. is as acylating reagent, with (2 β, 3 α; 5 α; 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3,17-glycol (compound 1) reaction obtains.But Acetyl Chloride 98Min. does not have selectivity to 2 of compound 1 hydroxyls, therefore produce (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3,17-diacetate (compound 3) by product, need to obtain compound 2 by column chromatography, yield 47.8%(molar yield, below all with).The method complex operation, yield is low.
US5817803 has described the method for another kind of possible synthetic compound 2, and its reaction scheme is as follows.
The method adopts first acetylize; use again the method synthetic compound 2 of morpholine addition; although avoided after synthetic compound 1; 3 of highly selective acylations; the problem of 17 hydroxyls, but compound 5 is used morpholine in compound 2 synthetic, and morpholine be alkaline; can cause 17 acetoxyl group degradeds in compound 5, thereby cause yield to reduce (repeating to test yield approximately 40%).
CN101125878, CN101824066 patent discloses a kind of synthetic method of compound 2, and the method is first reacted and is obtained compound 3 with excessive acylating reagent with compound 1, then under acidic conditions, through 3 acetyl oxygen of degradation selectivity, obtains compound 2 with compound 3.The compound 2 of the method gained has passed through 2 secondary responses, and operation is trouble, yield lower (66%).
A kind of method that highly selective acylation is prepared compound 2 is disclosed in WO2009016648 patent; select N-acetyl imidazole as acetylation reagent; 25 ℃ of reactions of room temperature obtain for 48 hours; this reaction can produce the by products such as imidazoles; aftertreatment needs extraction; select the more dangerous mixed solvent multiple fines such as ether/sherwood oil to make, this method long reaction time, operation is trouble.
US7569687 patent discloses with halohydrocarbon, ester and has made solvent; under nitrogen protection; with Acetyl Chloride 98Min. or diacetyl oxide, 20 ℃ ~ 22 ℃ of room temperatures, react 22h, after having reacted, with alkali, neutralize; organic layer washes with water; use dried over sodium sulfate again, filter, filtrate is concentrated into a certain amount of acetonitrile refining that adds; again with the refining compound 2, yield 68% of once obtaining of halohydrocarbon/acetonitrile mixed solvent.The method needs nitrogen protection, long reaction time, and post-processing operation is loaded down with trivial details, and yield is lower.
Therefore; select highly selective acylation reaction; by quick, simple operations; obtain high yield, highly purified (2 β; 3 α, 5 α, 16 β; 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetate (compound 2), thus the method that obtains high-purity rocuronium is necessary.
Summary of the invention
The invention provides the preparation method of a kind of high-purity rocuronium intermediate (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates.Method of the present invention is by highly selective acylation (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3, 17-glycol (compound 1), obtain Zemuron important intermediate (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetate (compound 2), the method is environmentally friendly, easy and simple to handle, reaction fast, yield is higher, HPLC purity reach 99.8% or more than, be more suitable for suitability for industrialized production, particularly at GMP(Good Manufacturing Practice and Quality Control of Drug) produce under condition.
For realizing object of the present invention, provide following embodiment:
In one embodiment, a kind of method of preparing Zemuron midbody compound 2, comprising:
I) by (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3,17-glycol (compound 1) joins in acetonitrile, then adds acetylation reagent, add acid binding agent, reacting by heating obtains (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates (compound 2);
Ii) above-mentioned reaction solution, through cooling crystallization, filters and obtains crude product compound 2;
Iii) in acetonitrile, to add thermosol clear for this crude product, then the crystallization that cools, and filters and obtain refining first product;
Iv) repeating step (iii) operation, obtains highly purified Zemuron midbody compound 2.
The method of the invention described above, in rapid step (i), described acetylation reagent comprises diacetyl oxide, Acetyl Chloride 98Min., preferably diacetyl oxide; Described acid binding agent is alkylamine organic bases, preferred alkyl tertiary amine, and said alkyl tertiary amine is triethylamine, Trimethylamine 99, diisopropylethylamine, Tributylamine and composition thereof, preferably triethylamine, Trimethylamine 99 etc.; The temperature of described reacting by heating is 55 ℃ ~ 85 ℃, preferably 77 ℃ ~ 82 ℃; The time of above-mentioned reaction is 1 hour ~ 4 hours; The molar ratio of above-mentioned acetylation reagent and starting material compound 1 is 1.05:1 ~ 2.5:1, preferably 1.1:1 ~ 2:1, more preferably 1.4:1 ~ 1.5:1; The molar ratio of described acid binding agent and starting material compound 1 is 2:1 ~ 6:1, preferably 4:1.
The method of the invention described above, in rapid step (iii), described Heating temperature is 77 ℃ ~ 82 ℃.
The method of the invention described above, resulting Zemuron important intermediate (2 β, 3 α, 5 α, 16 β, 17 β) the HPLC purity of-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates is more than 99.8%, preferably more than 99.9%.
In another preferred specific embodiments, a kind of method of preparing Zemuron midbody compound 2 of the present invention, comprising:
I) by (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3,17-glycol (compound 1) joins in acetonitrile solvent, add acetylation reagent diacetyl oxide, add acid binding agent triethylamine or Trimethylamine 99, be heated to 55 ℃ ~ 85 ℃, preferably 77 ℃ ~ 82 ℃, react and within 1 ~ 4 hour, obtain (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates (compound 2);
Ii) above-mentioned reaction solution, through cooling crystallization, filters and obtains crude product compound 2;
Iii) in acetonitrile, to add thermosol clear for this crude product, then the crystallization that cools, and filters and obtain refining first product;
Iv) repeating step (iii) operation, obtains highly purified Zemuron midbody compound 2.
In above-mentioned preferred specific embodiments, method of the present invention, the molar ratio of acetylation reagent and starting material compound 1 is 1.05:1 ~ 2.5:1, preferably 1.1:1 ~ 2:1, more preferably 1.4:1 ~ 1.5:1; The molar ratio of described acid binding agent and starting material compound 1 is 2:1 ~ 6:1, preferably 4:1.
In above-mentioned preferred specific embodiments, method of the present invention, in rapid step (iii), the temperature of described heating is 77 ℃ ~ 82 ℃.
The method of the invention described above, resulting Zemuron important intermediate (2 β, 3 α, 5 α, 16 β, 17 β) the HPLC purity of-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetates is more than 99.8%, preferably more than 99.9%.
In method of the present invention, compound 1 used can make according to the method for patent WO2010118699, introduces reference in full, also can buy by business.
Embodiment
Embodiment is used for further explaining or understanding content of the present invention below, but can not limit the scope of the invention, and comprises mixed solvent, and selects other acetylation reagent etc.
Embodiment 1
A adds 100g (2 β in a reaction flask, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-androstane-3,17-glycol (compound 1) (0.22mol), 32g diacetyl oxide (0.31mol), 92g triethylamine (0.90mol), 2L acetonitrile, be heated to 77 ℃-82 ℃, react after 3 hours stopped reaction.Gained reaction solution cooling crystallize out, continue to be cooled to-5 ℃ of crystallizatioies, filter to obtain (2 β, 3 α, 5 α, 16 β, 17 β)-16-(1-pyrrolidyl)-2-(4-morpholinyl)-3-hydroxyl-androstane-17-alcohol acetate (compound 2) crude products, HPLC detects compound 2 content in gained solid and is greater than 97%.1.4：1，4.1：1
The above-mentioned gained crude product of B adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, filters to obtain a fine work, and HPLC detects compound 2 content in gained solid and is greater than 99%.
Fine work of the above-mentioned gained of C adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, obtains compound 2 fine work 92g(yields 84%), HPLC 99.91%.
Embodiment 2
A presses the method for embodiment 1, in a reaction flask, add 100g compound 1(0.22mol), 45g diacetyl oxide (0.44mol), 133.6g triethylamine (1.32mol), react after 1 hour stopped reaction, crystallization, filter to obtain compound 2 crude products, HPLC detects compound 2 content in gained solid and is greater than 97%.2：1，6：1
The above-mentioned gained crude product of B adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, filters to obtain a fine work, and HPLC detects compound 2 content in gained solid and is greater than 99%;
Fine work of the above-mentioned gained of C adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, obtains compound 2 fine work 90.7 g(yields 82.9%), HPLC 99.9%.
Embodiment 3
A presses the method for embodiment 1, in a reaction flask, add 100g compound 1(0.22mol), 27g diacetyl oxide (0.26mol), 44.5g triethylamine (0.44mol), react after 4 hours stopped reaction, crystallization, filter to obtain compound 2 crude products, HPLC detects compound 2 content in gained solid and is greater than 97%;
The above-mentioned gained crude product of B adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, filters to obtain a fine work, and HPLC detects compound 2 content in gained solid and is greater than 99%;
Fine work of the above-mentioned gained of C adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, obtains compound 2 fine work 89.6 g(yields 81.9%), HPLC 99.9%.
Embodiment 4
A presses the method for embodiment 1, in a reaction flask, add successively 100g compound 1(0.22mol), 32g diacetyl oxide (0.31mol), 52g Trimethylamine 99 (0.88mol), react after 3 hours stopped reaction, crystallization, filter to obtain compound 2 crude products, HPLC detects compound 2 content in gained solid and is greater than 97%;
The above-mentioned gained crude product of B adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, filters to obtain a fine work, and HPLC detects compound 2 content in gained solid and is greater than 99%;
Fine work of the above-mentioned gained of C adds 1L acetonitrile, is heated to after 77 ℃-82 ℃, and cooling crystallize out, continues to be cooled to-5 ℃ of crystallizatioies, obtains compound 2 fine work 90g(yields 82.2%), HPLC 99.9%.
Above-mentioned " pressing the method for embodiment 1 ", refers to that reaction parameter unlisted in embodiment and operating process are all identical with embodiment 1.
Claims (12)
1. a method of preparing Zemuron midbody compound 2; comprise by compound 1 with acetylation reagent, acid binding agent in acetonitrile solvent; under 55 ℃ ~ 85 ℃ temperature of reaction, react certain hour and obtain compound 2 crude products, this crude product is refined and is obtained highly purified compound 2 again in acetonitrile
2. the method for claim 1, described acetylation reagent is diacetyl oxide or Acetyl Chloride 98Min., preferably diacetyl oxide.
3. the method as described in claim 1 and 2, the mol ratio that acetylation reagent reacts with compound 1 is 1.05:1 ~ 2.5:1, preferably 1.1:1 ~ 2:1.
4. method as claimed in claim 3, the mol ratio that acetylation reagent reacts with compound 1 is 1.4:1 ~ 1.5:1.
5. the method for claim 1, the mol ratio of acid binding agent and compound 1 is 2:1 ~ 6:1, preferred molar ratio is 4:1.
6. the method as described in claim 1 or 6, described acid binding agent is alkylamine organic bases.
7. method as claimed in claim 6, described alkylamine organic bases is selected from triethylamine, Trimethylamine 99, diisopropylethylamine, Tributylamine and its mixture, preferably triethylamine or Trimethylamine 99.
8. the method for claim 1, temperature of reaction is 77 ℃ ~ 82 ℃.
9. the method for claim 1, described reaction certain hour is 1 ~ 4 hour.
10. the method for claim 1, add compound 2 crude products in acetonitrile described refining comprising, is heated to 77 ℃ ~ 82 ℃, then the crystallization of lowering the temperature, and filters.
11. methods as claimed in claim 10, further comprise the treating process of a claim 10 of repetition.
12. the method for claim 1, the purity of described highly purified compound 2 be 99.0% or more than, preferably 99.9% or more than.
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| CN201210293977.8A CN103588847A (en) | 2012-08-17 | 2012-08-17 | Preparation method for rocuronium bromide intermediate |
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| CN201210293977.8A CN103588847A (en) | 2012-08-17 | 2012-08-17 | Preparation method for rocuronium bromide intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005068487A2 (en) * | 2004-01-15 | 2005-07-28 | Chemagis Ltd. | Processes for the preparation of rocuronium bromide and intermediates thereof |
| CN101687905A (en) * | 2005-09-13 | 2010-03-31 | 西科尔公司 | Pure rocuronium bromide |
| CN101863948A (en) * | 2009-04-17 | 2010-10-20 | 重庆医药工业研究院有限责任公司 | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof |
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- 2012-08-17 CN CN201210293977.8A patent/CN103588847A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005068487A2 (en) * | 2004-01-15 | 2005-07-28 | Chemagis Ltd. | Processes for the preparation of rocuronium bromide and intermediates thereof |
| CN101687905A (en) * | 2005-09-13 | 2010-03-31 | 西科尔公司 | Pure rocuronium bromide |
| CN101863948A (en) * | 2009-04-17 | 2010-10-20 | 重庆医药工业研究院有限责任公司 | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof |
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Application publication date: 20140219 |