CN100549024C - The preparation method of steroid muscle relaxants ex hoc genus anne compound - Google Patents
The preparation method of steroid muscle relaxants ex hoc genus anne compound Download PDFInfo
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- CN100549024C CN100549024C CNB2006102000552A CN200610200055A CN100549024C CN 100549024 C CN100549024 C CN 100549024C CN B2006102000552 A CNB2006102000552 A CN B2006102000552A CN 200610200055 A CN200610200055 A CN 200610200055A CN 100549024 C CN100549024 C CN 100549024C
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Abstract
The invention provides the preparation method of a kind of steroid muscle relaxants ex hoc genus anne compound, with formula II compound is starting raw material, in the diluted acid of different concns and reaction solvent or in the diluted acid of single different concns, 3 acyl groups of selective hydrolysis formula II compound, with in the weak base and after, water layer with inertia and with the multiple extraction product of the immiscible solvent of water promptly; Compared with prior art, the inventive method need not by column chromatography, and is easy and simple to handle, and the HPLC percentage area purity of products obtained therefrom can reach 98.5%, and the yield of product can reach about 70%; Improvements over the prior art and optimization have been realized.
Description
Technical field:
The present invention relates to the preparation method of a kind of steroid muscle relaxants ex hoc genus anne compound, belong to pharmaceutical chemical technical field
Background technology:
Steroid muscle relaxants belongs to the nondepolarizing type neuromuscular blocking agents, has now replaced the choice drug of traditional muscle relaxants as major operation.Zemuron (Rocuronium Bromide) is that an onset is rapid, the non-depolarizing muscular relaxant thing of middle timeliness.
USP4894369 has described two kinds of preparation methods of formula I compound.
The reaction formula of first method is as follows:
Because the difficult preparation of formula III compound promptly in 20 times of solvents, is adopted the acylating agent selectively acylating of 1.12～1.13 molar equivalents, obtains by the alkali alumina column chromatography again; And after formula III compound and the bromizating agent salt-forming reaction, also need to get product by the alkali alumina column chromatography.
Second method, its reaction formula is as follows:
Formula II compound is in 30 times of water, and hydrolysis reaction is 14 days under room temperature, and distillation is concentrated into dried, adds toluene band water to the greatest extent, and toluene is concentrated into to the greatest extent, gets product by the alkali alumina column chromatography again.
USP2005/0159398A1 has described the improvement to the USP4894369 first method, employing is selectively acylating in solvent, with 3 acyl groups of the two acylates of diluted acid selective hydrolysis by product, after 2 recrystallizations get highly purified formula III compound, but yield is lower; Get formula I compound with the bromizating agent salify again.
Summary of the invention:
The objective of the invention is to: the preparation method that a kind of more convenient effective steroid muscle relaxants ex hoc genus anne compound is provided, the present invention is improved on the basis of USP4894369 second method, with formula II compound is raw material, adopt the diluted acid selective hydrolysis, need not to pass through column chromatography, just can obtain highly purified formula I compound, it is easy and simple to handle, and yield is higher.
The present invention is achieved in that with formula II compound be starting raw material; in the diluted acid of different concns and reaction solvent or in the diluted acid of single different concns; 3 acyl groups of selective hydrolysis formula II compound; with in the weak base and after; water layer with inertia and with the immiscible solvent extraction of water, promptly get steroid muscle relaxants ex hoc genus anne Compound I.
Wherein: R
1=-CH
2-,-O-; R
2=-C
nH
2n-(n=1,2); R
3=-CH
3,-CH
2CH=CH
2
The concentration of formula II compound use 2～12 molar equivalents of every molar equivalent is 9～27% diluted acid.
Used diluted acid is a mineral acid; Mineral acid is Hydrogen bromide, hydrochloric acid or sulfuric acid.
Described reaction solvent is methylene dichloride, trichloromethane or acetone.
Described inertia and with the immiscible extraction solvent of water be methylene dichloride or trichloromethane.
Described hydrolysising reacting temperature is 25～50 ℃, and the reaction times is 2～15 hours.
After reaction finishes, for avoid in the weak base and the time cause the hydrolysis of 17 acyl groups, N-process is taked under 2～5 ℃ of temperature, with the neutralization of weak base aqueous solutions such as sodium bicarbonate, saleratus or ammoniacal liquor, transfers pH value to 7～8; Water layer after the neutralization is in time with extracting the multiple extraction product of solvent.
Following table is the comparison of the inventive method and prior art effect:
Annotate: yield=Zemuron output/acetyl Zemuron charging capacity * 100%
Improve yield=(Zemuron output-contrast Zemuron output)/contrast Zemuron output * 100%
Improve purity=(Zemuron purity-contrast Zemuron purity)/contrast Zemuron purity * 100%
This shows: compared with prior art, the inventive method is under the katalysis of inorganic diluted acid, the selective hydrolysis reaction is very fast, shortened the reaction times, 3 acyl group selectivity to formula II compound are better, reduced the hydrolysis of 17 acyl groups, only need to use the solvent extraction product, need not by column chromatography, easy and simple to handle; The HPLC percentage area purity of gained formula I compound (as Zemuron) can reach 98.5%, and the yield of product can reach about 70%; Improvements over the prior art and optimization have been realized.
Embodiment:
Embodiment 1:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-preparation of 1-(2-propenyl) tetramethyleneimine bromide (Zemuron)
With 3.0g1-[3 α, 17 β-diacetoxy-2 β-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-1-(2-propenyl) tetramethyleneimine bromide (acetyl Zemuron) is dissolved in the 30ml methylene dichloride, adds 18% Hydrogen bromide 9ml, stir down, heating was to 40 ℃ of reactions 4.5 hours; Then, be cooled to 2 ℃, add 5～10% sodium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with methylene dichloride, product extracted, and united extraction solution, extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get Zemuron output 2.2g, HPLC percentage area purity 98.7%.
Embodiment 2:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-preparation of 1-(2-propenyl) tetramethyleneimine bromide (Zemuron)
With 3.0g1-[3 α, 17 β-diacetoxy-2 β-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-1-(2-propenyl) tetramethyleneimine bromide (acetyl Zemuron) is dissolved among the 9% Hydrogen bromide 9ml, stirs down, in 25 ℃ of reactions 15 hours; Then, add the 30ml methylene dichloride, be cooled to 2 ℃, add 2～5% ammonia solns neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with methylene dichloride, product extracted, and united extraction solution, extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get Zemuron output 1.95g, HPLC percentage area purity 98.5%.
Embodiment 3:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-preparation of 1-(2-propenyl) tetramethyleneimine bromide (Zemuron)
With 3.0g 1-[3 α, 17 β-diacetoxy-2 β-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-1-(2-propenyl) tetramethyleneimine bromide (acetyl Zemuron) is dissolved in the 30ml acetone, adds 27% Hydrogen bromide 15ml, stir down, heating was to 50 ℃ of reactions 2 hours; Then, add the 30ml trichloromethane, be cooled to 5 ℃, add 10～15% potassium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with trichloromethane, product extracted, and united extraction solution, extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get Zemuron output 2.1g, HPLC percentage area purity 98.5%.
Embodiment 4:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-preparation of 1-(2-propenyl) tetramethyleneimine bromide (Zemuron)
With 3.0g 1-[3 α, 17 β-diacetoxy-2 β-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-1-(2-propenyl) tetramethyleneimine bromide (acetyl Zemuron) is dissolved in the 30ml methylene dichloride, adds 12% hydrochloric acid 9ml, stir down, heating was to 40 ℃ of reactions 4.5 hours; Then, be cooled to 3 ℃, add 5～10% sodium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with methylene dichloride, product extracted, and united extraction solution, extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get Zemuron output 2.0g, HPLC percentage area purity 98.8%.
Embodiment 5:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-preparation of 1-(2-propenyl) tetramethyleneimine bromide (Zemuron)
With 3.0g 1-[3 α, 17 β-diacetoxy-2 β-(4-morpholinyl)-5 α-etioallocholane-16 beta-yl]-1-(2-propenyl) tetramethyleneimine bromide (acetyl Zemuron) is dissolved in the 30ml methylene dichloride, adds 15% sulfuric acid 9ml, stir down, heating was to 35 ℃ of reactions 4.5 hours; Then, be cooled to 3 ℃, add 10～15% potassium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with methylene dichloride, product extracted, and united extraction solution, extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get Zemuron output 2.1g, HPLC percentage area purity 98.6%.
Embodiment 6:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(piperidino)-5 α-etioallocholane-16 beta-yl]-preparation of 1-methyl piperidine bromide
With 3.0g 1-[3 α, 17 β-diacetoxy-2 β-(piperidino)-5 α-etioallocholane-16 beta-yl]-1-methyl piperidine bromide (vecuronium bromide Vecuronium Bromide) is dissolved in the 30ml methylene dichloride, adds 15% Hydrogen bromide 9ml, stir down, heating was to 40 ℃ of reactions 4 hours; Then, be cooled to 2 ℃, add 5～10% sodium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with methylene dichloride, and united extraction solution is extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get 1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(piperidino)-5 α-etioallocholane-16 beta-yl]-1-methyl piperidine bromide output 1.9g, HPLC percentage area purity 98.4%.
Embodiment 7:1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(piperidino)-5 α-etioallocholane-16 beta-yl]-preparation of 1-methyl piperidine bromide
With 3.0g 1-[3 α, 17 β-diacetoxy-2 β-(piperidino)-5 α-etioallocholane-16 beta-yl]-1-methyl piperidine bromide (vecuronium bromide Vecuronium Bromide) is dissolved in the 30ml trichloromethane, adds 12% hydrochloric acid 9ml, stir down, heating was to 35 ℃ of reactions 4.5 hours; Then, be cooled to 5 ℃, add 10～15% potassium bicarbonate aqueous solutions neutralization through precooling, making pH value is 7～8, leaves standstill layering in good time; Water layer is multiple extraction with trichloromethane, and united extraction solution is extremely clean with anhydrous sodium sulfate dehydration.Dried in being evaporated to below 40 ℃, get 1-[17 β-acetoxy-3 alpha-hydroxy-2 beta-(piperidino)-5 α-etioallocholane-16 beta-yl]-1-methyl piperidine bromide output 1.8g, HPLC percentage area purity 98.2%.
Claims (7)
1. the preparation method of steroid muscle relaxants ex hoc genus anne compound, it is characterized in that: with formula II compound is starting raw material, in the diluted acid of different concns and methylene dichloride, trichloromethane or acetone polar solvent or in the diluted acid of single different concns, 3 acyl groups of selective hydrolysis formula II compound, with in the weak base and after, water layer with inertia and with the immiscible solvent extraction of water, promptly get steroid muscle relaxants ex hoc genus anne Compound I;
Wherein: R
1=-CH
2-,-O-; R
2=-C
nH
2n-, n=1,2; R
3=-CH
3,-CH
2CH=CH
2
2. according to the preparation method of the described steroid muscle relaxants of claim 1 ex hoc genus anne compound, it is characterized in that: the concentration of formula II compound use 2～12 molar equivalents of every molar equivalent is 9～27% diluted acid.
3. according to the preparation method of claim 1 or 2 described steroid muscle relaxants ex hoc genus anne compound, it is characterized in that: used diluted acid is a mineral acid.
4. according to the preparation method of the described steroid muscle relaxants of claim 3 ex hoc genus anne compound, it is characterized in that: described mineral acid is Hydrogen bromide, hydrochloric acid or sulfuric acid.
5. according to the preparation method of the described steroid muscle relaxants of claim 1 ex hoc genus anne compound, it is characterized in that: described inertia and with the immiscible extraction solvent of water be methylene dichloride or trichloromethane.
6. according to the preparation method of the described steroid muscle relaxants of claim 1 ex hoc genus anne compound, it is characterized in that: described hydrolysising reacting temperature is 25～50 ℃, and the reaction times is 2～15 hours.
7. according to the preparation method of the described steroid muscle relaxants of claim 1 ex hoc genus anne compound, it is characterized in that: the weak base N-process after reaction finishes is: under 2～5 ℃ of temperature, with sodium bicarbonate, potassium bicarbonate aqueous solution or ammonia soln neutralization, transfer pH value to 7～8; Water layer after the neutralization is in time with extracting the multiple extraction product of solvent.
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| CN103435675B (en) * | 2013-09-25 | 2015-05-13 | 宜昌人福药业有限责任公司 | Method for refining steroid muscle relaxant |
| CN105566433A (en) * | 2016-01-15 | 2016-05-11 | 安徽悦康凯悦制药有限公司 | Rocuronium bromide production technology |
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