CN107312055A - A kind of new preparation method of rocuronium - Google Patents
A kind of new preparation method of rocuronium Download PDFInfo
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- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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Abstract
The present invention relates to a kind of rocuronium 1 [β of 17 β acetoxyl groups, 3 α hydroxyls 2（4 morpholinyls）The β yls of androstane 16] 1（2 acrylic）The new preparation method of pyrroles's bromide, it is to avoid in original route the problem of the chemo-selective of nafoxidine open loop oxygen, it is to avoid the generation of accessory substance, substantially increase reaction yield, reduce production cost, and avoid column chromatography for separation, it is easy to post processing purifying.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, and in particular to a kind of rocuronium（Ⅰ）1- [17 β-acetoxy-3 α-
The β of hydroxyl-2-（4- morpholinyls）The beta-yl of-androstane -16] -1-（2- acrylic）A kind of new preparation method of pyrroles's bromide.
Background technology
Rocuronium（Rocuronium bromide）It is public by Dutch Organon to imitate muscle relaxant in single cropping ammonium steroids
Department's research and development, 1994 in U.S.'s Initial Public Offering.This product is as anesthesia adjuvant drug, when trachea cannula during for anaesthetizing and operation
It is of flaccid muscles, with rapid-action, the duration is short, recovers rapid, does not produce tachycardia and blood pressure, no histamine release
The features such as.The medicine is current muscle relaxant most widely used in the world.
The synthesis for the rocuronium that European patent EP 0287150 is reported, with 2 α, 3 α, 16 α, the 17 α-β of diepoxy-17-acetyl
The α of epoxide-5-androstane is initiation material, and 16,17 epoxies of nafoxidine attack, open loop introduces 16 β pyrrolidinyls, then uses morpholine
2,3 epoxies of attack, open loop introduces 2 β morpholinyls, then through reduction, acetylation is reacted, quaternized obtained Luo Ku with allyl bromide, bromoallylene
Bromine ammonium, during the route nafoxidine attack epoxy reaction, has 2 epoxide groups, chemo-selective is poor.
The content of the invention
Goal of the invention：It is improved that there is provided a kind of new preparation method of rocuronium to above-mentioned synthetic method.
In order to reach as above purpose, the present invention is adopted the following technical scheme that：
With (5 α-androstane -2- alkene -17- ketone of compound 1）For raw material, epoxy addition on hexatomic ring is first carried out, morpholine ring is introduced, then
Function dough α nafoxidines of five-membered ring ketone are introduced, then through reduction, target compound is made with allyl bromide, bromoallylene reaction in esterification.
Specific synthetic route is as follows：
。
First by compound 1（5 α-androstane -2- alkene -17- ketone）It is oxidized agent oxidation and obtains epoxide compound 2（2 α, 3
- 5 α of alpha-epoxy-17 -one-androstane）；
Then compound 2 passes through epoxy addition, introduces morpholine ring and obtains compound 3（2β-（4- morpholinyls）- 3 α -ol -17- ketone -5
α-androstane）；
Then β hydrogen of 3 carbonyl of compound are replaced by bromine obtains compound 4（2β-（4- morpholinyls）- β of 3 α -ol-16-bromo- 17- ketone-
5 α-androstane）；
Then compound 4 is coupled with pyrrolidines, restores generation compound 5（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）-
5 α-α of androstane -3,17 beta-diols）；
Then compound 5 is esterified with chloroacetic chloride, and compound 6 is made（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）- 17 β-second
The α of acyloxy-5-α -ol of androstane-3）
Final compound 6 and 3- bromopropenes reaction generation target product rocuronium Formula（Ⅰ）
Using the present invention of as above technical scheme, had the advantages that relative to existing technology：
The problem of avoiding the chemo-selective of nafoxidine open loop oxygen in original route, it is to avoid the generation of accessory substance, greatly improves
Reaction yield, reduces production cost, and avoid column chromatography for separation, it is easy to post processing purifying.
Brief description of the drawings：Fig. 1 rocuroniums（Ⅰ）1- [17 β-acetoxy-3 alpha-hydroxy-2 beta-（4- morpholinyls）- androstane-
16 beta-yls] -1-（2- acrylic）Pyrroles's bromide liquid phase spectrogram.
Fig. 2 rocuroniums（Ⅰ）1- [17 β-acetoxy-3 alpha-hydroxy-2 beta-（4- morpholinyls）The beta-yl of-androstane -16] -1-
（2- acrylic）Pyrroles's bromide nuclear magnetic spectrogram.
Form is described in further details to present disclosure again by the following examples, but not this should not be interpreted as with regard to this
Invent in above-mentioned subject area and be only limitted to following examples.It is general according to this area under the premise of above-mentioned technology of the invention is not departed from
The modification of corresponding replacement or change that logical technological know-how and customary means are made, is included in the present invention.
Embodiment 1：
1st, compound 2（2 α, 3-5 α of alpha-epoxy-17 -one-androstane）Synthesis.
5 α-androstane -2- alkene -17- ketone is added into 250ml that is clean, drying there-necked flask（27.2g, 0.1mol）, trichlorine
Methane（140ml）, stirring and dissolving is cooled to 0-5 DEG C, and controls interior temperature to be less than 5 DEG C, is slowly added to contain m-CPBA（16.0g,
0.102mol）Chloroform soln（32ml）, interior 0-5 DEG C of the temperature of control, stirring reaction 5-6h, reaction solution 1.5mol/L ammoniacal liquor
（60ml*2）Washing, is washed with water and washs to neutrality, and with starch potassium iodide paper detection m-CPBA remove it is clean untill, organic phase
Use saturated aqueous common salt（30ml）Washing, adds 5g anhydrous sodium sulfate drying 4-5h, filters, be concentrated under reduced pressure to obtain 25.7g grease,
Recrystallizing methanol, vacuum drying, obtains target compound compound 2（2 α, 3-5 α of alpha-epoxy-17 -one-androstane）22.4g, receive
Rate：77.7%.
2nd, compound 3（2β-（4- morpholinyls）- 3-5 α of α -ol-17- ketone-androstane）Synthesis
2 α, 3-5 α of alpha-epoxy-17 -one-androstane are added into 250ml that is clean, drying there-necked flask（20.0g,
0.069mol）, ferric trichloride（0.2g）, morpholine（60g, 0.689mol）, purified water（200g）It is warming up to backflow, stirring reaction
12-15h, is removed under reduced pressure water and morpholine, obtains crude material, then with acetone recrystallization, obtain target compound compound 3（2β-
（4- morpholinyls）- 3-5 α of α -ol-17- ketone-androstane）18.7g, yield：72.2%.
3rd, compound 4（2β-（4- morpholinyls）The β of-3 α -ol-16-- 5 α of bromo- 17- ketone-androstane）Synthesis
Added into 250ml that is clean, drying there-necked flask 2 β-（4- morpholinyls）- 3-5 α of α -ol-17- ketone-androstane
（15.0g, 0.04mol）, methanol（60ml）, copper bromide（26.8g, 0.12mol）Backflow is warming up to, stirring reaction 12-13h subtracts
Dense dry solvent is pressed, 100g purified waters are added, then is extracted with 60ml*2 dichloromethane, merges organic phase, then eaten with 30ml saturations
Salt water washing, then 5g anhydrous sodium sulfate dryings, filtering, depressurize dense dry solvent, then with acetone recrystallization, obtain target compound
Compound 4（2β-（4- morpholinyls）The β of-3 α -ol-16-- 5 α of bromo- 17- ketone-androstane）14.2g, yield：78.2%.
4th, compound 5（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）- 5 α-α of androstane -3,17 beta-diols）Conjunction
Into.
Added into 250ml that is clean, drying there-necked flask 2 β-（4- morpholinyls）- 3-5 α of α -ol-17- ketone-androstane
（12.0g, 0.026mol）, acetonitrile（60ml）, pyrrolidines（9.4g, 0.132mol）It is warming up to backflow, stirring reaction 4-6h, decompression
Dense dry solvent, adds methanol（60ml）, it is cooled to temperature in -5 DEG C -0 DEG C, control and is less than 0 DEG C, adds sodium borohydride（1.93g,
0.052mol）, nitrogen displacement simultaneously protects, and is warming up to room temperature（20-25℃）2-3h is stirred, reaction finishes, reaction solution is poured into
In 200ml purified waters, a large amount of off-white powders are separated out, filtering is dried under reduced pressure, then by solid acetone recrystallization, obtain compound 5
（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）- 5 α-α of androstane -3,17 beta-diols）7.2g, yield 62.1%.
5th, compound 6（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）- 17 beta-acetoxyl group-5 α-α of androstane-3-
Alcohol）Synthesis
Compound 5 is added into 100ml there-necked flasks that are clean, drying（6.0g, 0.013mol）, dichloromethane（30ml）, acetyl
Chlorine（1.1g, 0.014mol）, room temperature（20-25℃）Stirring reaction 5-6h, adds 30ml water, separates dichloromethane phase, then use
15ml saturated common salt water washings, then with 5g anhydrous sodium sulfate drying 4-5h, filter, depressurize dense dry solvent and obtain pale yellow oil
Compound 6（2β-（4- morpholinyls）-16β-（1- pyrrolidinyls）- 17 beta-acetoxyl group-5 α-α -ol of androstane -3）5.7g, yield：
89.7%。
7th, target compound rocuronium（Ⅰ）Synthesis
Compound 6 is added into 100ml there-necked flasks that are clean, drying（5.0g, 0.010mol）, dichloromethane（30ml）, 3- bromines
Propylene（1.4g, 0.012mol）, lucifuge room temperature（20-25℃）Stirring reaction 5-6h, depressurizes dense dry solvent, obtains crude product, crude product
5ml acetone stirring and dissolvings are added, then are slowly added dropwise into 20ml methyl tertiary butyl ether(MTBE)s, stirring and crystallizing, filtered under nitrogen, decompression
Dry target product rocuronium 5.1g, yield：83.6%.
Embodiment 2：
The product rocuronium HPLC purity 99.79% of the gained of embodiment 1, is shown in Fig. 1；
Structural identification data：mp：162-166 DEG C, H-NMR（500MHz, DMSO）：δ0.694-0.797（M, 4H）, δ 0.902-
1.030（M, 4H）, δ 1.052-1.092（M, 1H）, δ 1.075-1.390（M, 6H）, δ 1.400-1.925（M, 9H）, δ 1.930-
2.170（M, 6H）, δ 2.203（S, 3H）, δ 2.300-2.490（D, 4H）, δ 3.244（S, 3H）, δ 3.533（S, 5H）, δ 3.610-
3.740（M, 3H）, δ 3.900-4.100（M, 2H）, δ 4.098（S, 1H）, δ 4.247-4.262（Dd, 1H）, δ 4.357（S, 1H）,
δ5.074-5.093（D, 1H）, δ 5.608-5.673（M, 2H）, δ 6.131-6.213（M, 1H）, see Fig. 2.
The present invention has advantages below compared with prior art：
1st, with compound 1（5 α-androstane -2- alkene -17- ketone）For raw material, by first carrying out epoxy addition on hexatomic ring, morpholine is introduced
Ring, is re-introduced into function dough α nafoxidines of five-membered ring ketone, it is to avoid the chemo-selective of nafoxidine open loop oxygen in original route
The problem of, it is to avoid the generation of accessory substance.
2nd, present invention gained target product purity is high, can reach more than 99.0%, simplify post processing, be convenient for work
Industry metaplasia is produced.
Claims (6)
1. a kind of rocuronium（Ⅰ）1- [17 β-acetoxy-3 alpha-hydroxy-2 beta-（4- morpholinyls）The beta-yl of-androstane -16] -1-
（2- acrylic）The new preparation method of pyrroles's bromide,
By compound 1（5 α-androstane -2- alkene -17- ketone）For starting material, epoxy addition on hexatomic ring is first carried out, morpholine is introduced
Ring, is re-introduced into function dough α nafoxidines of five-membered ring ketone, reduction, esterification, quaternized obtained target compound,
Specific synthetic route is as follows：
。
2. the Formula described in claim 1（Ⅰ）Synthetic method, its feature step one be hexatomic ring alkene epoxidation,
It is reaction substrate with compound 1, oxidant can select the oxidants such as hydrogen peroxide, metachloroperbenzoic acid, ozone, wherein excellent
Select metachloroperbenzoic acid, compound 1 and the equivalent proportion preferably 1 of oxidant:1.02；Solvent can select chloroform, dichloro
The atent solvents such as methane, DMF, wherein it is preferred that chloroform；Reaction temperature can select -5 DEG C -30 DEG C, wherein it is preferred that 0 DEG C -5 DEG C
Reaction.
3. the Formula described in claim 1（Ⅰ）Synthetic method, it is characterised in that step 2 be epoxy ring-opening introduce
Quinoline ring, using compound 2 and morpholine as reaction substrate, compound 2 and the equivalent proportion preferably 1 of morpholine:10, ferric trichloride is catalysis
Agent；Solvent can select water, tetrahydrofuran, morpholine etc., wherein it is preferred that water；Temperature can select 0 DEG C-reflux state, wherein excellent
Select reflux temperature（Water is solvent, 100 DEG C）.
4. the Formula described in claim 1（Ⅰ）Synthetic method, it is characterised in that step 3 be β hydrogen of five-membered ring carbonyl
Replaced by bromine, be reaction substrate with compound 3, brominated reagent can select NBS, bromine, hydrogen bromide, copper bromide etc., wherein excellent
Select copper bromide, compound 3 and the equivalent proportion preferably 1 of brominated reagent:3；Solvent can select methanol, ethanol, acetone, tetrahydrochysene furan
Mutter, DMF etc., wherein it is preferred that methanol, reaction temperature is 0 DEG C-reflux state, preferably reflux temperature（Methanol is solvent, 65 DEG C）.
5. the Formula described in a claim 1（Ⅰ）Synthetic method, it is characterised in that step 4 introduce pyrrole ring, with change
Compound 4 and pyrrolidines are reaction substrate, compound 4 and the equivalent proportion preferably 1 of pyrrolidines:5；Solvent can select acetonitrile, tetrahydrochysene
Furans, acetone etc., wherein it is preferred that acetonitrile；Reaction temperature can select 0 DEG C-reflux state, wherein it is preferred that reflux state（Acetonitrile is
Solvent, 82 DEG C）.
6. the Formula described in claim 1（Ⅰ）Synthetic method, it is characterised in that step 4 introduces pyrrole ring, rear reduction
Carbonyl, to introduce the product after pyrrolidines as reaction substrate, reducing agent can select potassium borohydride, sodium borohydride, borine etc., its
In preferably sodium borohydride, the ratio preferably 1 of compound 4 and reducing agent:2；Solvent can select methanol, ethanol etc., wherein it is preferred that
Methanol；Reaction temperature can select -10 DEG C-reflux state, wherein it is preferred that 20-25 DEG C.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570090A (en) * | 2018-05-25 | 2018-09-25 | 江苏盈科生物制药有限公司 | A kind of preparation method of high-purity rocuronium |
| CN108676052A (en) * | 2018-08-16 | 2018-10-19 | 宋雪萍 | A kind of preparation method and its pharmaceutical composition of rocuronium |
| CN110563789A (en) * | 2019-10-05 | 2019-12-13 | 湖北竹溪人福药业有限责任公司 | clean production preparation method of testosterone propionate |
| CN110734468A (en) * | 2018-07-20 | 2020-01-31 | 济南高德医药科技有限公司 | Refining method of rocuronium bromide crude product |
| CN110790810A (en) * | 2019-11-18 | 2020-02-14 | 重庆仁泽医药科技有限公司 | Rocuronium bromide intermediate and preparation method of rocuronium bromide |
| CN111057122A (en) * | 2019-12-25 | 2020-04-24 | 武汉华龙生物制药有限公司 | Preparation method of rocuronium bromide |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108570090A (en) * | 2018-05-25 | 2018-09-25 | 江苏盈科生物制药有限公司 | A kind of preparation method of high-purity rocuronium |
| CN108570090B (en) * | 2018-05-25 | 2021-02-02 | 江苏盈科生物制药有限公司 | Preparation method of high-purity rocuronium bromide |
| US11466049B2 (en) | 2018-07-20 | 2022-10-11 | Jinan Good Medical Technology Co., Ltd. | Method for purifying crude rocuronium bromide |
| CN110734468B (en) * | 2018-07-20 | 2021-04-16 | 济南高德医药科技有限公司 | Refining method of rocuronium bromide crude product |
| CN110734468A (en) * | 2018-07-20 | 2020-01-31 | 济南高德医药科技有限公司 | Refining method of rocuronium bromide crude product |
| CN108676052B (en) * | 2018-08-16 | 2020-05-22 | 北京市新里程医药科技有限公司 | Preparation method of rocuronium bromide and pharmaceutical composition thereof |
| CN108676052A (en) * | 2018-08-16 | 2018-10-19 | 宋雪萍 | A kind of preparation method and its pharmaceutical composition of rocuronium |
| CN110563789A (en) * | 2019-10-05 | 2019-12-13 | 湖北竹溪人福药业有限责任公司 | clean production preparation method of testosterone propionate |
| CN110563789B (en) * | 2019-10-05 | 2022-03-25 | 湖北竹溪人福药业有限责任公司 | Clean production preparation method of testosterone propionate |
| CN110790810A (en) * | 2019-11-18 | 2020-02-14 | 重庆仁泽医药科技有限公司 | Rocuronium bromide intermediate and preparation method of rocuronium bromide |
| CN110790810B (en) * | 2019-11-18 | 2022-01-28 | 重庆仁泽医药科技有限公司 | Rocuronium bromide intermediate and preparation method of rocuronium bromide |
| CN111057122A (en) * | 2019-12-25 | 2020-04-24 | 武汉华龙生物制药有限公司 | Preparation method of rocuronium bromide |
| CN111057122B (en) * | 2019-12-25 | 2021-04-30 | 武汉华龙生物制药有限公司 | Preparation method of rocuronium bromide |
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Application publication date: 20171103 |