CN109836411A - A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid - Google Patents
A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid Download PDFInfo
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- CN109836411A CN109836411A CN201711198059.6A CN201711198059A CN109836411A CN 109836411 A CN109836411 A CN 109836411A CN 201711198059 A CN201711198059 A CN 201711198059A CN 109836411 A CN109836411 A CN 109836411A
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- Prior art keywords
- ketanserin
- tartaric acid
- preparation
- ethyl alcohol
- acid
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- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 title claims abstract description 49
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 235000002906 tartaric acid Nutrition 0.000 title claims abstract description 16
- 239000011975 tartaric acid Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000002327 cardiovascular agent Substances 0.000 title description 3
- 229940125692 cardiovascular agent Drugs 0.000 title description 3
- 229960005417 ketanserin Drugs 0.000 claims abstract description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 229960001367 tartaric acid Drugs 0.000 claims abstract description 15
- 235000019441 ethanol Nutrition 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 10
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims abstract description 9
- 229940048879 dl tartaric acid Drugs 0.000 claims abstract description 9
- 238000004090 dissolution Methods 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 13
- 229960004756 ethanol Drugs 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000011084 recovery Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 238000010907 mechanical stirring Methods 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 8
- 239000004575 stone Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 210000004351 coronary vessel Anatomy 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 208000031225 myocardial ischemia Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000003790 Foot Ulcer Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical synthesis fields, provide a kind of preparation method of ketanserin tartaric acid, using ketanserin and DL- tartaric acid as raw material, using ethyl alcohol as the heated dissolution of solvent, crystallization directly obtains target product, and total recovery can achieve 80%, and product purity is more than 99.0%.Technique synthesis step is simple, significantly reduces production cost, and small pollution of the environment alleviates environmental problem caused by the production of ketanserin tartaric acid significantly.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of cardiovascular drugs Ketanserine tartaric acid.
Background technique
Ketanserin (ketanserin), chemical structure are pyridine derivate.Alternative blocks 5-HT2A receptor, no portion
Divide agonist effect；There is the blocking effect of weak alpha-receptor simultaneously.As the clinical main use of novel antihypertensive medicine ketanserin
In the treatment of the cardiovascular diseases such as hypertension.In recent years, numerous studies are made that new expansion to the clinical application of ketanserin.Such as
Kyriakides etc. observes Stable angina pectorsis patient caused by 44 single blood vessel blockages with the clinical trial that ketanserin is treated
Show in coronary artery balloon angioplasty art, injection ketanserin can dramatically increase coronary collateral in coronary artery
Blood flow reduce myocardial ischemia generation.This result not only illustrates that ketanserin has in coronary artery balloon angioplasty
Prevent the effect of myocardial ischemia, also prompts ketanserin that there may be new application in terms for the treatment of myocardial ischemia.Quatresooz P
Ketanserin ointment Deng on probation 2% locally embrocates the leg foot ulcers for the treatment of diabetes, the results showed that ketanserin can significantly improve
Ulcer symptoms prompt ketanserin centainly valuable to the treatment of the leg foot ulcers of diabetes, and speculate its therapy mechanism and resistance
Disconnected two type Serotonin receptors, expansion blood vessel and improvement local microcirculation are related.In endotoxemia animal, ketanserin can be with
Improve microcirculation and the Mast cell activation by endotaxin induction can be substantially reduced.But in human body due to ketanserin
Bioavilability substantially reduces, in water dissolubility and its bad.
Meaning of the present invention is to find a kind of combination of ketanserin -- ketanserin tartaric acid.Ketanserin tartaric acid is more readily soluble
Yu Shui, so that bioavilability greatly improves in human body.The highly selective of ketanserin tartaric acid, high efficiency and invertibity make
Clinical manipulation is obtained to be easier to realize.Ketanserin tartaric acid has good clinical treatment as a kind of novel novel antihypertensive medicine
And higher safety, it is easy to use, work it is small with food drug interaction rapidly, bleeding risk is lower, be not required to by
When detect coagulation indexes.Due to its various advantages, keep its potential applicability in clinical practice optimistic.But the preparation method of ketanserin tartaric acid
There is presently no do not report.
Summary of the invention
The present invention provides a kind of preparation methods of ketanserin tartaric acid, using ketanserin and DL- tartaric acid as raw material, with second
Alcohol is the heated dissolution of solvent, and crystallization directly obtains target product, and total recovery can achieve 80%, and product purity is more than
99.0%.Technique synthesis step is simple, significantly reduces production cost, and small pollution of the environment alleviates ketanserin wine significantly
Environmental problem caused by the production of stone acid.
The specific preparation method of the present invention includes the following steps:
By ketanserin and DL- tartaric acid, 1:1~10 react 1~12 hour at 60~100 DEG C in molar ratio, through adding
Heat of solution, crystallization, final filtration dry to obtain ketanserin tartaric acid.
Starting material in the present invention is ketanserin and DL- tartaric acid, and ketanserin is 99% commercially available product of content；DL- winestone
Acid is DL optically-active mixture tartaric acid, and content is 99% commercially available, and DL- tartaric acid includes anhydrous DL- tartaric acid and (ties containing the crystallization water
Brilliant water number be 1~4) DL- tartaric acid.
Ketanserin and DL- tartaric acid match excellent 1:1~5 in molar ratio in the present invention.
Using ethyl alcohol as reaction reagent in the present invention, ethyl alcohol includes the ethanol water of dehydrated alcohol and various concentration, concentration
It is preferred that 50%~75% ethanol water.
Preferably 78~90 DEG C of reaction temperature of the invention.Reaction time preferably 4~8 hours.
The advantages of preparation method of the present invention is, in crude product ketanserin tartaric acid in addition to a large amount of tartrate it
Outside, there is also other impurities.For the method for purification of these impurity, generallys use column chromatography and purified, it is complicated for operation, in addition to
Also a large amount of solvent consumed according to the yield of production and be eluted except chromatographic column using customization, increase synthesis at
This.Therefore paratartaric acid salt is formed after we cleverly dissociate product, and product is purified, chromatographic column is avoided completely and mentions
Pure method, substantially increases production efficiency, reduces to the use of a large amount of organic solvents and recovery operation, reduces this step
Synthesis cost.
Ketanserin tartrate technique overcomes the shortcomings of ketanserin bulk pharmaceutical chemicals, and dissolubility obtains fabulous in water
Improve, bioavilability greatly improves, and synthetic route is simple to operation, high income, at low cost etc., new process product technology feature
As follows: the product purity of acquisition is high, can reach 99.0% or more, product impurity grinds declining lower than 0.5% for unit requirement from original
To 0.3%, quality is completely superior to the former quality standard for grinding unit, and bulk pharmaceutical chemicals quality is better than external listing criteria, at the world
In top standard.
Specific embodiment
Case study on implementation 1
Mechanical stirring is being housed, 10g ketanserin, 10g wine is added in the 2000ml four-necked bottle of reflux condenser and thermometer
Stone acid and 1000ml dehydrated alcohol under stirring, are heated to 78 DEG C, the reaction time 8 hours.It is cooling, crystallization.Filter white solid
Body, it is dry to constant weight 13g white crystalline powder, calculated yield 81%.Mp:187-189 DEG C (dec.), content reaches 99.1%.
Case study on implementation 2
Mechanical stirring is being housed, 10g ketanserin, 10g wine is added in the 1000ml four-necked bottle of reflux condenser and thermometer
95% ethyl alcohol of stone acid and 400ml；Under stirring, it is heated to 80 DEG C, the reaction time 8 hours.It is cooling, crystallization.Filter white solid
Body, it is dry to constant weight 12.8g white crystalline powder, calculated yield 80%.Mp:187-189 DEG C (dec.), content reaches
99.2%.
Case study on implementation 3
Mechanical stirring is being housed, 10g ketanserin, 10g wine is added in the 1000ml four-necked bottle of reflux condenser and thermometer
85% ethyl alcohol of stone acid and 350ml；Under stirring, it is heated to 85 DEG C, the reaction time 6 hours.It is cooling, crystallization.Filter white solid
Body, it is dry to constant weight 12.0g white crystalline powder, calculated yield 75%.Mp:187-189 DEG C (dec.), content reaches
99.3%.
Case study on implementation 4
Mechanical stirring is being housed, 10g ketanserin, 10g winestone is added in the 500ml four-necked bottle of reflux condenser and thermometer
Acid and 75% ethyl alcohol of 290ml；Under stirring, it is heated to 90 DEG C, the reaction time 4 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 11.5g white crystalline powder, calculated yield 72%.Mp:187-189 DEG C (dec.), content reaches 99.5%.
Case study on implementation 5
Mechanical stirring is being housed, 10g ketanserin, 6g winestone is added in the 2000ml four-necked bottle of reflux condenser and thermometer
Acid and 1000ml dehydrated alcohol；Under stirring, it is heated to 78 DEG C, the reaction time 8 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 13g white crystalline powder, calculated yield 81%.Mp:187-189 DEG C (dec.), content reaches 99.1%.
Case study on implementation 6
Mechanical stirring is being housed, 10g ketanserin, 6g winestone is added in the 1000ml four-necked bottle of reflux condenser and thermometer
Acid and 95% ethyl alcohol of 400ml；Under stirring, it is heated to 80 DEG C, the reaction time 8 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 12.7g white crystalline powder, calculated yield 79%.Mp:187-189 DEG C (dec.), content reaches 99.2%.
Case study on implementation 7
Mechanical stirring is being housed, 10g ketanserin, 6g winestone is added in the 1000ml four-necked bottle of reflux condenser and thermometer
Acid and 350ml85% ethyl alcohol；Under stirring, it is heated to 85 DEG C, the reaction time 6 hours.It is cooling, crystallization.White solid is filtered to obtain, is done
It is dry to constant weight 12.0g white crystalline powder, calculated yield 75%.Mp:187-189 DEG C (dec.), content reaches 99.4%.
Case study on implementation 8
Mechanical stirring is being housed, 10g ketanserin, 6g winestone is added in the 500ml four-necked bottle of reflux condenser and thermometer
Acid and 75% ethyl alcohol of 290ml；Under stirring, it is heated to 90 DEG C, the reaction time 4 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 11.5g white crystalline powder, calculated yield 72%.Mp:187-189 DEG C (dec.), content reaches 99.5%.
Case study on implementation 9
Mechanical stirring is being housed, 10g ketanserin, 8g winestone is added in the 2000ml four-necked bottle of reflux condenser and thermometer
Acid and 60% ethyl alcohol of 240ml, under stirring, are heated to 90 DEG C, the reaction time 8 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 12.8g white crystalline powder, calculated yield 80%.Mp:187-189 DEG C (dec.), content reaches 99.4%.
Case study on implementation 10
Mechanical stirring is being housed, 10g ketanserin, 8g winestone is added in the 2000ml four-necked bottle of reflux condenser and thermometer
Acid and 50% ethyl alcohol of 200ml, under stirring, are heated to 90 DEG C, the reaction time 8 hours.It is cooling, crystallization.White solid is filtered to obtain,
It dries to constant weight 13.2g white crystalline powder, calculated yield 82%.Mp:187-189 DEG C (dec.), content reaches 99.5%.
Claims (4)
1. providing a kind of preparation method of ketanserin tartaric acid, preparation method includes the following steps: ketanserin and DL- winestone
1:1 ~ 10 react 1 ~ 12 hour acid at 60 ~ 100 DEG C in molar ratio, heated dissolution, crystallization, and final filtration dries to obtain
Ketanserin tartaric acid.
2. method described in claim 1, which is characterized in that ketanserin and DL- tartaric acid match excellent 1:1 ~ 5 in molar ratio.
3. method described in claim 1, which is characterized in that ethyl alcohol is reaction reagent, and ethyl alcohol includes dehydrated alcohol and various dense
The ethanol water of degree, the ethanol water of concentration preferably 50% ~ 75%.
4. method described in claim 1, which is characterized in that preferably 78 ~ 90 DEG C of reaction temperature, the reaction time preferably 4 ~ 8
Hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711198059.6A CN109836411A (en) | 2017-11-25 | 2017-11-25 | A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711198059.6A CN109836411A (en) | 2017-11-25 | 2017-11-25 | A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid |
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| Publication Number | Publication Date |
|---|---|
| CN109836411A true CN109836411A (en) | 2019-06-04 |
Family
ID=66878379
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711198059.6A Pending CN109836411A (en) | 2017-11-25 | 2017-11-25 | A kind of preparation method of cardiovascular drugs Ketanserine tartaric acid |
Country Status (1)
| Country | Link |
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| CN (1) | CN109836411A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023129976A1 (en) * | 2021-12-29 | 2023-07-06 | Terran Biosciences, Inc. | Salt and solid forms of ketanserin |
-
2017
- 2017-11-25 CN CN201711198059.6A patent/CN109836411A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023129976A1 (en) * | 2021-12-29 | 2023-07-06 | Terran Biosciences, Inc. | Salt and solid forms of ketanserin |
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Application publication date: 20190604 |