CN101531642B - Method for preparing pinaverium bromide and application thereof - Google Patents
Method for preparing pinaverium bromide and application thereof Download PDFInfo
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- CN101531642B CN101531642B CN2008100346076A CN200810034607A CN101531642B CN 101531642 B CN101531642 B CN 101531642B CN 2008100346076 A CN2008100346076 A CN 2008100346076A CN 200810034607 A CN200810034607 A CN 200810034607A CN 101531642 B CN101531642 B CN 101531642B
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Abstract
The invention provides a method for preparing pinaverium bromide and an intermediate thereof, which relate to the pharmaceutical process. The cis isomer content of the intermediate 2-[2-(2-morpholino-2-ethoxy-ethyl)]-6, 6-dimethyl nopyl alkyl is high and the cis-isomer content of the obtained pinaverium bromide is more than or equal to 99 percent. The intermediate 2-[2-(2-morpholino-2-ethoxy-ethyl)]-6, 6-dimethyl nopyl alkyl is prepared by collecting cut fraction of 133-134 DEG C under 270 Pa.
Description
Technical field
The present invention relates to pharmaceutical technology, relate to a kind of preparation technology of Pinaverium Bromide particularly.
Background technology
Pinaverium Bromide is a kind of calcium antagonist, and is clinical in treatment intestinal function disorderly relevant pain, abnormal defecation and gastrointestinal upset, and the relevant pain of biliary tract dysfunction.The synthetic route of external report is 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, and alkane (formula II) and 2-bromo-4 are foretold in 6-diformazan Jino, and 5-dimethoxy-benzyl bromine (formula III) reaction obtains Pinaverium Bromide (formula I).
Pinaverium Bromide has opticity, and what have result of treatment clinically is its cis-isomeride.In the resulting Pinaverium Bromide of prior art, often require the content of its trans-isomer(ide) to be no more than 9%, lowly more then be difficult to reach, the result makes the Pinaverium Bromide cis isomerism body burden with result of treatment on the low side, influences result of treatment.
The opticity of Pinaverium Bromide is come in its main midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6; Alkane (formula II) is foretold in 6-diformazan Jino; Be starting raw material with the nopol in the prior art; With become ether to obtain midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6 after its hydrogenation again with 2-chloroethyl morpholine (formula VI), alkane (formula II) is foretold in 6-diformazan Jino.
But the cis isomerism body burden 95% of the midbody that obtains, trans-isomer content 5%, the cis isomerism body burden of the synthetic Pinaverium Bromide (formula I) that obtains of midbody is not high thus, has above-mentioned defective.
Therefore; This area presses for a kind of new preparation midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6; The method of alkane (formula II) is foretold in 6-diformazan Jino, improves cis isomerism body burden wherein, thereby the cis isomerism body burden of the Pinaverium Bromide (formula I) that finally obtains is raise.
Summary of the invention
The present invention aims to provide a kind of midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, and alkane (formula II) and preparation method thereof is foretold in 6-diformazan Jino.
The present invention also will provide a kind of Pinaverium Bromide (formula I) and preparation method thereof.
Aspect first, a kind of compound intermediate is provided of the present invention, chemical structure is suc as formula II
The weight percentage of cis-isomeride>=95% in the described midbody, the weight percentage of trans-isomer(ide)≤5%.
In another preference, the weight percentage of cis-isomeride>=97% in the described midbody, the weight percentage of trans-isomer(ide)≤3%.
In second aspect of the present invention, a kind of preparation method like above-mentioned compound intermediate is provided, it comprises step:
(a),, behind the filtration catalizer, obtain the compound of chemical structure after filtrate decompression removed methyl alcohol suc as formula V through hydrogenation catalyst reduction reaction 2-8 hour with after nopol, palladium carbon and the methanol mixed of chemical structure suc as formula IV;
(b) formula V compound, toluene and the sodium hydroxide with step (a) gained mixes heating reflux reaction 1-5 hour;
(c) add chemical structure suc as formula the compound of VI and the mixed solution of toluene, 60-100 ℃ was reacted 30-150 minute, and was cooled to room temperature;
(d) add the water extraction, separate organic layer, behind reclaim under reduced pressure toluene, residue is carried out underpressure distillation at 260-410Pa, collect 130-170 ℃ cut, promptly get like above-mentioned compound intermediate.
In another preference, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 130 ℃-138 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 132 ℃-136 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 133 ℃-134 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 140 ℃-150 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 142 ℃-148 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 144 ℃-145 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 160 ℃-170 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 162 ℃-168 ℃ cut.
In another preference, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 166 ℃-167 ℃ cut.
In another preference, being reflected under the 3-10 kilogram hydrogen pressure in the step (a) carried out 2-8 hour.
In another preference, the hybrid reaction described in the step (a) was reacted 4-6 hour under 6-7 kilogram hydrogen pressure.
In another preference, the back flow reaction described in the step (b) 2 hours.
In the third aspect of the invention, a kind of compound Pinaverium Bromide is provided, chemical structure is suc as formula I
The weight percentage of cis-isomeride>=97% in the described Pinaverium Bromide, the weight percentage of trans-isomer(ide)≤3%.
In another preference, the weight percentage of cis-isomeride>=99% in the described Pinaverium Bromide, the weight percentage of trans-isomer(ide)≤1%.
In fourth aspect of the present invention, a kind of preparation method like above-mentioned compound Pinaverium Bromide is provided, it comprises step:
(1) with the 2-bromo-4 of chemical structure such as formula III, 5-dimethoxy-benzyl bromine and as above-mentioned formula II compound intermediate in butanone, be heated to 60-90 ℃, backflow 4-8 hour postcooling to 10-30 ℃;
(2) quench liquid stirring, filtration, the oven dry with step (1) gained obtains the Pinaverium Bromide bullion;
(3) in the Pinaverium Bromide bullion of step (2) gained, add ethanol, gac and EDTA, be heated to 50-70 ℃, remove ethanol after stirring, filtering, add butanone, 20-30 ℃ of stirring and crystallizing, filtration, oven dry obtain like above-mentioned compound Pinaverium Bromide.
In another preference, in the step (1) with the formula III compound with as above-mentioned formula II compound intermediate is heated to 80 ℃ in butanone, 6 hours postcooling to 25 ℃ reflux.
In another preference, with adding ethanol, gac and EDTA in the Pinaverium Bromide bullion, be heated to 65 ℃ in the step (3), remove ethanol after stirring, filtering, add butanone, 25 ℃ of stirring and crystallizing, filtration, oven dry obtain like above-mentioned compound Pinaverium Bromide.
Aspect the of the present invention the 5th, a kind of pharmaceutical composition is provided, described pharmaceutical composition contains
(i) treatment significant quantity like above-mentioned compound Pinaverium Bromide; And
(ii)) pharmaceutically acceptable carrier.
In another preference, described pharmaceutical composition is oral prepns such as tablet, capsule.
Aspect the of the present invention the 6th, a kind of as above-mentioned application of compound Pinaverium Bromide in the medicine of preparation treatment intestinal function disorders is provided.
In view of the above, midbody 2-provided by the invention [2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the cis isomerism body burden that alkane (formula II) is foretold in 6-diformazan Jino is high, and the cis isomerism body burden of the synthetic Pinaverium Bromide (formula I) that obtains is high thus.
Description of drawings
Fig. 1 has shown the gas chromatogram of the Pinaverium Bromide that embodiment 4 obtains, and has wherein shown the appearance time and the peak area of cis and trans-isomer(ide).
Embodiment
The contriver is surprised to find that through extensive and deep research, is starting raw material with the nopol; With reacting with 2-chloroethyl morpholine (formula VI) after its hydrogenation, add the water extraction then, get organic layer; The prepared midbody 2-of underpressure distillation [2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6 under given conditions; The cis isomerism body burden that alkane (formula II) is foretold in 6-diformazan Jino is high, >=95%, and the cis isomerism body burden of the Pinaverium Bromide (formula I) that this midbody is made through single step reaction can >=99%.
Midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, alkane (formula II) is foretold in 6-diformazan Jino
Provided by the invention suc as formula cis isomerism body burden>=95% in the midbody compound shown in the II, trans-isomer content≤5%, preferably, cis isomerism body burden>=97%, trans-isomer content≤3%.
Midbody 2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, alkane (formula II) preparation method is foretold in 6-diformazan Jino
Preparing method suc as formula the midbody compound shown in the II provided by the invention comprises step:
(a) chemical structure is obtained the compound of chemical structure suc as formula V suc as formula the nopol of IV, palladium carbon and methanol mixed reaction;
(b) formula V compound, toluene and the sodium hydroxide with step (a) gained mixes reacting by heating;
(c) add chemical structure suc as formula the compound of VI and the mixed solution of toluene, reflux, be cooled to room temperature;
(d) add the water extraction, get organic layer, underpressure distillation makes the compound intermediate suc as formula II.
A preferred scheme is:
(a) chemical structure was reacted 2-8 hour suc as formula nopol, palladium carbon and the methanol mixed of IV, filter, remove methyl alcohol and obtain the compound of chemical structure suc as formula V;
(b) formula V compound, toluene and the sodium hydroxide with step (a) gained mixes heating reflux reaction 1-5 hour;
(c) add chemical structure suc as formula the compound of VI and the mixed solution of toluene, back flow reaction 30-150 minute, be cooled to room temperature;
(d) add the water extraction, separate organic layer, behind the reclaim under reduced pressure toluene, residue is carried out underpressure distillation, collect the distillation under 166 ℃ of-168 ℃/400Pa ± 5Pa conditions, that is to say the compound intermediate that makes suc as formula II.
Preferably, be the cut of collecting under 144 ℃ of-146 ℃/300Pa ± 5Pa conditions in the underpressure distillation described in the step (d); More preferably, underpressure distillation is the cut of collecting under 133 ℃ of-135 ℃/270Pa ± 5Pa conditions.
Preferably, the hybrid reaction in the step (a) is carried out under 3-10 kilogram hydrogen pressure; More preferably, under 6-7 kilogram hydrogen pressure, carried out hybrid reaction 4-6 hour.
Preferably, the back flow reaction in the step (b) is 2 hours.
Pinaverium Bromide (formula I)
The weight percentage of cis-isomeride>=97% in the Pinaverium Bromide provided by the invention, the weight percentage of trans-isomer(ide)≤3%.
More preferably, the weight percentage of cis-isomeride>=99% in the described Pinaverium Bromide, the weight percentage of trans-isomer(ide)≤1%.
Pinaverium Bromide (formula I) preparation method
Pinaverium Bromide provided by the invention is with the midbody 2-of structural formula as I I [2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, and alkane and 2-bromo-4 like formula III are foretold in 6-diformazan Jino, and 5-dimethoxy-benzyl bromine reaction makes.
A preferable methods comprises step:
(a) with the 2-bromo-4 of chemical structure such as formula III, the compound intermediate of 5-dimethoxy-benzyl bromine and formula II is heated to 70-90 ℃, backflow 4-8 hour postcooling to 20-30 ℃ in butanone;
(b) quench liquid stirring, filtration, the oven dry with step (a) gained obtains the Pinaverium Bromide bullion;
(c) in the Pinaverium Bromide bullion of step (b) gained, add ethanol, gac and EDTA, be heated to 60-70 ℃, remove ethanol after stirring, filtering, add butanone, 20-30 ℃ of stirring and crystallizing, filtration, oven dry obtain like above-mentioned formula I compound Pinaverium Bromide.
Preferably, in the step (a) with formula III compound and formula II compound intermediate in butanone, be heated to 80 ℃, 6 hours postcooling to 25 ℃ reflux.
Preferably, with adding ethanol, gac and EDTA in the Pinaverium Bromide bullion, be heated to 65 ℃ in the step (c), remove ethanol after stirring, filtering, add butanone, 25 ℃ of stirring and crystallizing, filtration, oven dry obtain the compound Pinaverium Bromide.
Pharmaceutical composition
Pinaverium Bromide provided by the invention (formula I) can be used for preparing the pharmaceutical composition of treatment intestinal function disorders.
Pharmaceutical composition provided by the invention comprises the Pinaverium Bromide (formula I) of treating significant quantity and the pharmaceutically acceptable vehicle of surplus.
In the present invention, the content of Pinaverium Bromide is the 10-35% of gross weight, preferred 20-30%.
In Pinaverium Bromide pharmaceutical composition provided by the invention, comprise pharmaceutically acceptable vehicle or its mixture, play respectively and hide flavor, keep sheet weight, sheet shape, solubilising, bonding, painted, wetting, flavored action.Usually, said vehicle accounts for the 65-90% of said tablet total weight amount, preferred 70-80%.
Vehicle in the pharmaceutical composition of the present invention can be the pharmaceutically acceptable vehicle of using always, for example pharmaceutically acceptable weighting agent, tackiness agent, lubricant or its mixture etc.
In tablet of the present invention, described weighting agent is selected from carbohydrate, glycitols, one or more in derivatived cellulose and the starch.Said tackiness agent is selected from derivatived cellulose, natural gum, one or more in water-soluble vinyl pyrrolidone polymer and the carbohydrate.Described lubricant is selected from Magnesium Stearate, talcum, one or more in FUMARIC ACID TECH GRADE sodium stearyl ester and the colloidal silica.
In preference, contain pharmaceutically acceptable glidant and optional pharmaceutically acceptable tinting material, perfume compound, correctives in the pharmaceutically acceptable vehicle of tablet of the present invention.
Pharmaceutical composition of the present invention can be tablet or capsule, its method of application, and the consumption of consumption and existing Pinaverium Bromide preparation is basic identical.
Major advantage of the present invention is:
1. the midbody 2-of structural formula as I I [2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the cis isomerism body burden that alkane is foretold in 6-diformazan Jino is high;
2. high suc as formula the cis isomerism body burden of the Pinaverium Bromide of I through the structural formula that single step reaction obtains by above-mentioned midbody, thus result of treatment can be improved.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all per-cent and umber by weight.
2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the detection method that trans-isomer(ide) in the alkane (formula II) is foretold in 6-diformazan Jino is following;
Get compound (formula II), add dissolve with methanol and process the solution that contains 20mg among every 1ml approximately, measure according to vapor-phase chromatography (Chinese Pharmacopoeia version appendix in 2005 V E).With OV-225 (30.0m * 0.25mm * 0.25 μ m) is capillary chromatographic column, and initial column temperature is 120 ℃, rises to 220 ℃ with rise 3 ℃ speed of PM, keeps 5 minutes.Precision is measured 1.0 μ l inject gas chromatographs.The record color atlas, the order that goes out the peak is followed successively by trans-isomer(ide) and cis-isomeride.
Embodiment 1
2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the preparation of alkane (formula II) is foretold in 6-diformazan Jino
1. under the room temperature, drop into methyl alcohol 600L in the autoclave, nopol 100Kg (formula IV), palladium carbon 10Kg, reaction is 4-6 hour under 6-7 kilogram hydrogen pressure, and filtering catalyst is used methanol wash, and pressure reducing and steaming methyl alcohol obtains formula V compound 90Kg, yield 88.7%;
2. in the 1000L reaction kettle, add toluene 300L then, formula V compound 50Kg drops into sodium hydroxide 13kg under the room temperature, be warming up to backflow, reacts 2 hours;
3. the mixed solution that adds 45kg2-chloroethyl morpholine (formula VI) and 100L toluene then added the back back flow reaction 1 hour, and cooling adds the extraction of 300L water, tells organic layer;
4. water layer is with extracted in toluene twice, and each 200L merges organic layer, 200L washing, pressure reducing and steaming toluene;
5. under the pressure of 400Pa ± 5Pa, carry out underpressure distillation then, collect 166 ℃-168 ℃ cut, obtain 2-[2-morpholinyl-(2-oxyethyl group-ethyl)]-6, alkane (formula II) 75kg, yield: 73.5% are foretold in 6-diformazan Jino.
The result shows: the cis isomerism body burden: 95.8%, and trans-isomer content: 4.2%.
Embodiment 2
2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the preparation of alkane (formula II) is foretold in 6-diformazan Jino
1. under the room temperature, drop into methyl alcohol 600L in the autoclave, nopol 100Kg (formula IV), palladium carbon 10Kg, reaction is 2 hours under 9-10 kilogram hydrogen pressure, and filtering catalyst is used methanol wash, and pressure reducing and steaming methyl alcohol obtains formula V compound 91.3Kg, yield 90.4%;
2. in the 1000L reaction kettle, add toluene 300L then, formula V compound 50Kg drops into sodium hydroxide 13kg under the room temperature, be warming up to backflow, reacts 2 hours;
3. the mixed solution that adds 45kg2-chloroethyl morpholine (formula VI) and 100L toluene then added the back back flow reaction 1 hour, and cooling adds the extraction of 300L water, tells organic layer;
4. water layer is with extracted in toluene twice, and each 200L merges organic layer, 200L washing, pressure reducing and steaming toluene;
5. under the pressure of 300Pa ± 5Pa, carry out underpressure distillation then, collect 144 ℃-146 ℃ cut, obtain 2-[2-morpholinyl-(2-oxyethyl group-ethyl)]-6, alkane (formula II) 73kg, yield: 71.4% are foretold in 6-diformazan Jino.
The result shows: the cis isomerism body burden: 97.3%, and trans-isomer content: 2.7%.
Embodiment 3
2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the preparation of alkane (formula II) is foretold in 6-diformazan Jino
1. under the room temperature, drop into methyl alcohol 600L in the autoclave, nopol 100Kg (formula IV), palladium carbon 10Kg, reaction is 2.5 hours under 8-9 kilogram hydrogen pressure, and filtering catalyst is used methanol wash, and pressure reducing and steaming methyl alcohol obtains formula V compound 89Kg, yield 87.5%;
2. in the 1000L reaction kettle, add toluene 300L then, formula V compound 50Kg drops into sodium hydroxide 13kg under the room temperature, be warming up to backflow, reacts 2 hours;
3. the mixed solution that adds 45kg2-chloroethyl morpholine (formula VI) and 100L toluene then added the back back flow reaction 1 hour, and cooling adds the extraction of 300L water, tells organic layer;
4. water layer is with extracted in toluene twice, and each 200L merges organic layer, 200L washing, pressure reducing and steaming toluene;
5. under the pressure of 270Pa ± 5Pa, carry out underpressure distillation then, collect 133 ℃-135 ℃ cut, obtain 2-[2-morpholinyl-(2-oxyethyl group-ethyl)]-6, alkane (formula II) 73kg, yield: 71.4% are foretold in 6-diformazan Jino.
The result shows: the cis isomerism body burden: 98.4%, and trans-isomer content: 1.6%.
Comparative Examples
2-[2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, the preparation of alkane (formula II) is foretold in 6-diformazan Jino
1. under the room temperature, drop into methyl alcohol 600L in the autoclave, nopol 100Kg (formula IV), palladium carbon 10Kg, reaction is 2.5 hours under 8-9 kilogram hydrogen pressure, and filtering catalyst is used methanol wash, and pressure reducing and steaming methyl alcohol obtains formula V compound 89Kg, yield 87.5%;
2. in the 1000L reaction kettle, add toluene 300L then, formula V compound 50Kg drops into sodium hydroxide 13kg under the room temperature, be warming up to backflow, reacts 2 hours;
3. the mixed solution that adds 45kg2-chloroethyl morpholine (formula VI) and 100L toluene then added the back back flow reaction 1 hour, and cooling adds the extraction of 300L water, tells organic layer;
4. water layer is with extracted in toluene twice, and each 200L merges organic layer, 200L washing, pressure reducing and steaming toluene;
5. under the pressure of 500Pa ± 5Pa, carry out underpressure distillation then, collect 181 ℃-185 ℃ cut, obtain 2-[2-morpholinyl-(2-oxyethyl group-ethyl)]-6, alkane (formula II) 73kg, yield: 71.4% are foretold in 6-diformazan Jino.
The result shows: the cis isomerism body burden: 94.8%, and trans-isomer content: 5.2%.
Embodiment 4
The preparation of Pinaverium Bromide (formula I)
1.5L three-necked bottle in drop into butanone 2400ml, 2-bromo-4,5-dimethoxy-benzyl bromine (formula III) 600g, the 2-of embodiment 1 gained [2-(2-morpholinyl-2-oxyethyl group-ethyl)]-6, alkane (formula II) 600g is foretold in 6-diformazan Jino, slowly is warming up to 80 ℃;
2. refluxed 6 hours, and be cooled to 25 ℃, stirred 4 hours, filter, 240ml butanone wash solids in 60 ℃ of decompression oven dry, gets Pinaverium Bromide bullion 547.0g then;
3. add ethanol 2700ml, activated carbon 10g, EDTA1g is warming up to 65 ℃, stirs decolouring 0.5 hour; Filter, after most ethanol is removed in the mother liquor underpressure distillation, add the 2700ml butanone, in 25 ℃ of stirring and crystallizing; Filter, the washing of 100ml butanone, 60 ℃ of decompression oven dry get pinaverium bromide 406g.
The result sees that Fig. 1 shows: cis-isomeride (appearance time 16.344 minutes) content 98.5%, trans-isomer(ide) (appearance time 15.956 minutes) content 1.2%.
The detection method of trans-isomer(ide) in the Pinaverium Bromide (formula I)
These article of getting add dissolve with methanol and process the solution that contains 20mg among every 1ml approximately, measure according to vapor-phase chromatography (Chinese Pharmacopoeia version appendix in 2005 V E).With OV-225 (30.0m * 0.25mm * 0.25 μ m) is capillary chromatographic column, and initial column temperature is 160 ℃, rises to 220 ℃ with rise 3 ℃ speed of PM, keeps 5 minutes.Precision is measured 1.0 μ l inject gas chromatographs.The record color atlas, the order that goes out the peak is followed successively by trans-isomer(ide) and cis-isomeride.
Pinaverium Bromide (formula I) with embodiment 5 makes is accomplished the following example:
Pinaverium Bromide (formula I) tablet
Prepare the Pinaverium Bromide tablet by following prescription:
Pinaverium Bromide 50g
Lactose 45g
Microcrystalline Cellulose 68g
Pregelatinized Starch 40g
Micropowder silica gel 2g
Talcum powder 3g
Magnesium Stearate 2g
You Teqi E100 24g
Macrogol 4000 4g
Talcum powder 12g
Water 12g
Ethanol 330g
Preparation technology:
1, will write out a prescription in Pinaverium Bromide pulverized 80 mesh sieves, evenly mixed with the lactose of recipe quantity, Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, 3g talcum powder, with mixed direct powder compression, obtain plain sheet.
2, coating liquid preparation: the strange E100 of the You Te of recipe quantity, Macrogol 4000 are mixed appearance agent dissolving with the pure water and the alcoholic acid of recipe quantity, again the 12g talcum powder is added to be uniformly dispersed, subsequent use.
3, dressing: the above-mentioned plain sheet that obtains put in the coating pan with gained coating liquid in 2 carries out dressing, finished product.
Embodiment 6
Pinaverium Bromide (formula I) tablet
Prepare the Pinaverium Bromide tablet by following prescription:
Pinaverium Bromide 50g
Lactose 25g
Microcrystalline Cellulose 38g
Pregelatinized Starch 30g
Micropowder silica gel 2g
Talcum powder 3g
Magnesium Stearate 2g
You Teqi E100 10g
Macrogol 4000 2g
Talcum powder 5g
Water 6g
Ethanol 150g
Preparation technology:
1, will write out a prescription in Pinaverium Bromide pulverized 80 mesh sieves, evenly mixed with the lactose of recipe quantity, Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, 3g talcum powder, with mixed direct powder compression, obtain plain sheet.
2, coating liquid preparation: the strange E100 of the You Te of recipe quantity, Macrogol 4000 are mixed appearance agent dissolving with the pure water and the alcoholic acid of recipe quantity, again the 5g talcum powder is added to be uniformly dispersed, subsequent use.
3, dressing: the above-mentioned plain sheet that obtains put in the coating pan with gained coating liquid in 2 carries out dressing, finished product.
Embodiment 7
Pinaverium Bromide (formula I) tablet
Prepare the Pinaverium Bromide tablet by following prescription:
Pinaverium Bromide 50g
Lactose 25g
Microcrystalline Cellulose 68g
Pregelatinized Starch 20g
Micropowder silica gel 2g
Talcum powder 3g
Magnesium Stearate 2g
You Teqi E100 12g
Macrogol 4000 2g
Talcum powder 6g
Water 6g
Ethanol 165g
Preparation technology:
1, will write out a prescription in Pinaverium Bromide pulverized 80 mesh sieves, evenly mixed with the lactose of recipe quantity, Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, 3g talcum powder, with mixed direct powder compression, obtain plain sheet.
2, coating liquid preparation: the strange E100 of the You Te of recipe quantity, Macrogol 4000 are mixed appearance agent dissolving with the pure water and the alcoholic acid of recipe quantity, again the 6g talcum powder is added to be uniformly dispersed, subsequent use.
3, dressing: the above-mentioned plain sheet that obtains put in the coating pan with gained coating liquid in 2 carries out dressing, finished product.
Embodiment 8
Pinaverium Bromide (formula I) capsule
Prepare the Pinaverium Bromide capsule by following prescription:
Pinaverium Bromide 50g
Lactose 45g
Microcrystalline Cellulose 68g
Pregelatinized Starch 40g
Micropowder silica gel 2g
Talcum powder 3g
Magnesium Stearate 2g
Preparation technology:
Pinaverium Bromide was pulverized 80 mesh sieves in will writing out a prescription, and was evenly mixed with lactose, Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, the talcum powder of recipe quantity, with the mixed direct capsule charge of powder, obtained finished product.
Embodiment 9
Pinaverium Bromide (formula I) capsule
Prepare the Pinaverium Bromide capsule by following prescription:
Pinaverium Bromide 50g
Lactose 45g
Microcrystalline Cellulose 80g
Pregelatinized Starch 60g
Micropowder silica gel 4g
Talcum powder 7g
Magnesium Stearate 4g
Preparation technology:
Pinaverium Bromide was pulverized 80 mesh sieves in will writing out a prescription, and was evenly mixed with lactose, Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, the talcum powder of recipe quantity, with the mixed direct capsule charge of powder, obtained finished product.
Pinaverium Bromide (formula I) capsule
Prepare the Pinaverium Bromide capsule by following prescription:
Pinaverium Bromide 50g
Microcrystalline Cellulose 50g
Pregelatinized Starch 60g
Micropowder silica gel 2g
Talcum powder 3g
Magnesium Stearate 2g
Preparation technology:
Pinaverium Bromide was pulverized 80 mesh sieves in will writing out a prescription, and was evenly mixed with Microcrystalline Cellulose, pregelatinized Starch, micropowder silica gel, the talcum powder of recipe quantity, with the mixed direct capsule charge of powder, obtained finished product.
All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (18)
1. a chemical structure is characterized in that suc as formula the preparation method of the compound intermediate of II it comprises step:
(a),, behind the filtration catalizer, obtain the compound of chemical structure after filtrate decompression removed methyl alcohol suc as formula V through hydrogenation catalyst reduction reaction 2-8 hour with after nopol, palladium carbon and the methanol mixed of chemical structure suc as formula IV;
(b) formula V compound, toluene and the sodium hydroxide with step (a) gained mixes heating reflux reaction 1-5 hour;
(c) add chemical structure suc as formula the compound of VI and the mixed solution of toluene, 60-100 ℃ was reacted 30-150 minute, and was cooled to room temperature;
(d) add the water extraction, separate organic layer, behind reclaim under reduced pressure toluene, residue is carried out underpressure distillation at 260-410Pa, collect 130-170 ℃ cut, promptly get the compound intermediate of chemical structure suc as formula II;
The weight percentage of cis-isomeride>=95% in the described midbody, the weight percentage of trans-isomer(ide)≤5%;
2. preparation method as claimed in claim 1 is characterized in that, the weight percentage of cis-isomeride>=97% in the described midbody, the weight percentage of trans-isomer(ide)≤3%.
3. preparation method as claimed in claim 1 is characterized in that, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 130 ℃-138 ℃ cut.
4. preparation method as claimed in claim 3 is characterized in that, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 132 ℃-136 ℃ cut.
5. preparation method as claimed in claim 3 is characterized in that, step (d) is carried out underpressure distillation with residue at 270 ± 5Pa behind reclaim under reduced pressure toluene, collects 133 ℃-134 ℃ cut.
6. preparation method as claimed in claim 1 is characterized in that, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 140 ℃-150 ℃ cut.
7. preparation method as claimed in claim 6 is characterized in that, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 142 ℃-148 ℃ cut.
8. preparation method as claimed in claim 6 is characterized in that, step (d) is carried out underpressure distillation with residue at 300 ± 5Pa behind reclaim under reduced pressure toluene, collects 144 ℃-145 ℃ cut.
9. preparation method as claimed in claim 1 is characterized in that, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 160 ℃-170 ℃ cut.
10. preparation method as claimed in claim 9 is characterized in that, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 162 ℃-168 ℃ cut.
11. preparation method as claimed in claim 9 is characterized in that, step (d) is carried out underpressure distillation with residue at 400 ± 5Pa behind reclaim under reduced pressure toluene, collects 166 ℃-167 ℃ cut.
12. preparation method as claimed in claim 1 is characterized in that, being reflected under the 3-10 kilogram hydrogen pressure in the step (a) carried out 2-8 hour.
13. preparation method as claimed in claim 1 is characterized in that, being reflected under the 6-7 kilogram hydrogen pressure described in the step (a) reacted 4-6 hour.
14. preparation method as claimed in claim 1 is characterized in that, the back flow reaction described in the step (b) 2 hours.
15. a chemical structure is characterized in that suc as formula the preparation method of the compound Pinaverium Bromide of I, the weight percentage of cis-isomeride>=97% in the described Pinaverium Bromide, and the weight percentage of trans-isomer(ide)≤3%, it comprises step:
Prepare the compound intermediate of chemical structure through the method for claim 1 suc as formula II; With
(1) with the 2-bromo-4 of chemical structure such as formula III, 5-dimethoxy-benzyl bromine and chemical structure are heated to 60-90 ℃, backflow 4-8 hour postcooling to 10-30 ℃ suc as formula the compound intermediate of II in butanone; The weight percentage of cis-isomeride>=95% in the described midbody, the weight percentage of trans-isomer(ide)≤5%;
(2) quench liquid stirring, filtration, the oven dry with step (1) gained obtains the Pinaverium Bromide bullion;
(3) in the Pinaverium Bromide bullion of step (2) gained, add ethanol, gac and EDTA; Be heated to 50-70 ℃, remove ethanol after stirring, filtering, add butanone; 20-30 ℃ of stirring and crystallizing, filtration, oven dry obtain the compound Pinaverium Bromide of chemical structure suc as formula I;
16. preparation method as claimed in claim 15 is characterized in that, the weight percentage of cis-isomeride>=97% in the described midbody, the weight percentage of trans-isomer(ide)≤3%.
17. preparation method as claimed in claim 15 is characterized in that, in the step (1) with the formula III compound with as above-mentioned formula II compound intermediate is heated to 80 ℃ in butanone, 6 hours postcooling to 25 ℃ reflux.
18. preparation method as claimed in claim 15; It is characterized in that, with adding ethanol, gac and EDTA in the Pinaverium Bromide bullion, be heated to 65 ℃ in the step (3); Remove ethanol after stirring, filtering; Add butanone, 25 ℃ of stirring and crystallizing, filtration, oven dry obtain the compound Pinaverium Bromide of chemical structure suc as formula I.
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| CN116459222A (en) * | 2023-04-20 | 2023-07-21 | 山东中医药大学附属医院 | Pivelum bromide composition, preparation and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1351505A (en) * | 1970-07-29 | 1974-05-01 | Berri Balzac | Terpene derivatives method for their preparation and applications thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1351505A (en) * | 1970-07-29 | 1974-05-01 | Berri Balzac | Terpene derivatives method for their preparation and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| Rene Baronnet et al.Synthese et etude pharmacodynamique comparee d’ammoniums quaternaires derives du dimethyl-6,6 norpinane:leur action spasmolytique.《European Journal of Medicinal Chemistry》.1974,第9卷(第2期),182-187. * |
| ReneBaronnetetal.Syntheseetetudepharmacodynamiquecompareed’ammoniumsquaternairesderivesdudimethyl-6 6 norpinane:leur action spasmolytique.《European Journal of Medicinal Chemistry》.1974 |
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