CN103880837A - Synthetic method of cimetropium bromide - Google Patents
Synthetic method of cimetropium bromide Download PDFInfo
- Publication number
- CN103880837A CN103880837A CN201410116250.1A CN201410116250A CN103880837A CN 103880837 A CN103880837 A CN 103880837A CN 201410116250 A CN201410116250 A CN 201410116250A CN 103880837 A CN103880837 A CN 103880837A
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- CN
- China
- Prior art keywords
- cimetropium bromide
- synthetic method
- water
- cimetropium
- bromide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of organic synthesis and specifically relates to a synthetic method of cimetropium bromide. The synthetic method comprises the following steps of stirring scopolamine hydrobromide and water, dropwise adding saturated potassium carbonate liquor under an ice bath, extracting by applying dichloromethane, washing with water after extracting, adding cyclopropylmethyl bromide, reacting under refluxing, cooling and separating out crystals, and carrying out suction-filtering and re-crystallizing to obtain cimetropium bromide, wherein total yield is over 50%. The synthetic method disclosed by the invention adopts dichloromethane as a single reaction organic solvent, so that reaction steps are simplified, dichloromethane can be recycled, and therefore, production cost is lowered, and environmental pollution is reduced.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of synthetic method of cimetropium bromide.
Background technology
Cimetropium bromide, its chemistry bromination 8-by name encircles the third methyl-6, and 7-epoxy-3-hydroxyl-1 α H-tropane-(-) tropate, has another name called bromination N-(cyclopropyl methyl) Scopolamine, and within 1984, first it go on the market in Italy.Main mechanism is that the muscarinic receptor of blocking-up visceral smooth muscle has Antimuscarinic effect, also can directly act on unstriated muscle, remove smooth muscle spasm etc.Clinically be mainly used in treating biliary colic, cramps of gastrointestinal tract pain, biliary tract and urethrospasm pain, dysmenorrhoea, pain of childbirth and vomiting in children, tell milk, stomachache and pylorospasm.
The synthetic method of the cimetropium bromide of bibliographical information is to make through quaterisation with Scopolamine and brooethyl cyclopropane, but free Scopolamine is unstable, and storage process is easily degraded, and reaction yield is low; Another kind is to use scopolamine hydrobromide to make with brooethyl cyclopropane quaterisation after hydrolysis, but its reaction solvent kind is many, and step is more loaded down with trivial details.
Summary of the invention
The object of the invention is to overcome the above-mentioned shortcoming of prior art, provide a kind of stability high, reactions steps is simple, the synthetic method of the cimetropium bromide that reaction solvent is single.
Concrete, a synthesis technique for cimetropium bromide, it comprises the following steps: by scopolamine hydrobromide, water, stir, under ice bath, drip unsaturated carbonate potassium solution, with dichloromethane extraction, after extraction, wash with water, add brooethyl cyclopropane, back flow reaction, cooling crystallization, suction filtration, recrystallization had both obtained cimetropium bromide.
Scopolamine hydrobromide in above-mentioned preparation method: water weight ratio is about 1:6 ~ 8; After dropping saturated solution of potassium carbonate, adjusting pH is 8 ~ 9; Scopolamine hydrobromide: brooethyl cyclopropane weight ratio is about 1.5 ~ 1.8:1; Return time is 10 ~ 15h.
Embodiment
Embodiment 1:
By 20g scopolamine hydrobromide, 150ml water, stir, under ice bath, drip unsaturated carbonate potassium solution and adjust pH to 8, with 100ml dichloromethane extraction twice, collect methylene dichloride 40ml washing 2 times, add 11g brooethyl cyclopropane, backflow 12h reaction, cooling crystallization, suction filtration, recrystallization had both obtained cimetropium bromide 11.5g, and total recovery is 50%.
Embodiment 2:
By 40g scopolamine hydrobromide, 3000ml water, stir, under ice bath, drip unsaturated carbonate potassium solution and adjust pH to 9, with 200ml dichloromethane extraction twice, collect methylene dichloride 80ml washing 2 times, add 23g brooethyl cyclopropane, backflow 14h reaction, cooling crystallization, suction filtration, recrystallization had both obtained cimetropium bromide 23.2g, and total recovery is 50%.
Embodiment 3:
By 100g scopolamine hydrobromide, 750ml water, stir, under ice bath, drip unsaturated carbonate potassium solution and adjust pH to 9, with 500ml dichloromethane extraction twice, collect methylene dichloride 200ml washing 2 times, add 60g brooethyl cyclopropane, backflow 10h reaction, cooling crystallization, suction filtration, recrystallization had both obtained cimetropium bromide 47.3g, and total recovery is 51%.
Embodiment 4:
By 50g scopolamine hydrobromide, 370ml water, stir, under ice bath, drip unsaturated carbonate potassium solution and adjust pH to 8, with 250ml dichloromethane extraction twice, collect methylene dichloride 100ml washing 2 times, add 28g brooethyl cyclopropane, backflow 15h reaction, cooling crystallization, suction filtration, recrystallization had both obtained cimetropium bromide 28g, and total recovery is 48.3%.
Claims (4)
1. the synthesis technique of a cimetropium bromide, it is characterized in that scopolamine hydrobromide soluble in water, under ice bath, add unsaturated carbonate aqueous solutions of potassium, dichloromethane extraction, adds brooethyl cyclopropane, back flow reaction, be cooled to after completion of the reaction room temperature, obtain cimetropium bromide crude product, by cimetropium bromide recrystallization, obtain cimetropium bromide fine work.
2. the synthesis technique of a kind of cimetropium bromide according to claim 1, is characterized in that scopolamine hydrobromide: water weight ratio is about 1:6 ~ 8.
3. the synthesis technique of a kind of cimetropium bromide according to claim 1, is characterized in that dripping that to adjust pH after saturated solution of potassium carbonate be 8 ~ 9.
4. the synthesis technique of a kind of cimetropium bromide according to claim 1, is characterized in that scopolamine hydrobromide: brooethyl cyclopropane weight ratio is about 1.5 ~ 1.8:1; Reflux time is 10 ~ 15h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410116250.1A CN103880837A (en) | 2014-03-27 | 2014-03-27 | Synthetic method of cimetropium bromide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410116250.1A CN103880837A (en) | 2014-03-27 | 2014-03-27 | Synthetic method of cimetropium bromide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103880837A true CN103880837A (en) | 2014-06-25 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410116250.1A Pending CN103880837A (en) | 2014-03-27 | 2014-03-27 | Synthetic method of cimetropium bromide |
Country Status (1)
| Country | Link |
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| CN (1) | CN103880837A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3853886A (en) * | 1972-04-18 | 1974-12-10 | Angeli Inst Spa | Certain n-substituted scopolammonium compounds |
| CN101230063A (en) * | 2008-02-20 | 2008-07-30 | 南昌弘益科技有限公司 | Method for preparing tiotropium bromide |
| CN102146079A (en) * | 2011-02-28 | 2011-08-10 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CN103319478A (en) * | 2013-05-14 | 2013-09-25 | 张家港威胜生物医药有限公司 | Synthesis process of important medicinal chemical raw material bromomethyl scopolamine |
-
2014
- 2014-03-27 CN CN201410116250.1A patent/CN103880837A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3853886A (en) * | 1972-04-18 | 1974-12-10 | Angeli Inst Spa | Certain n-substituted scopolammonium compounds |
| CN101230063A (en) * | 2008-02-20 | 2008-07-30 | 南昌弘益科技有限公司 | Method for preparing tiotropium bromide |
| CN102146079A (en) * | 2011-02-28 | 2011-08-10 | 广州瑞尔医药科技有限公司 | Preparation method of scopolamine butylbromide |
| CN103319478A (en) * | 2013-05-14 | 2013-09-25 | 张家港威胜生物医药有限公司 | Synthesis process of important medicinal chemical raw material bromomethyl scopolamine |
Non-Patent Citations (1)
| Title |
|---|
| 柴雨柱 等: "西托溴铵的合成", 《药学与临床研究》 * |
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| PB01 | Publication | ||
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140625 |