CN1616437A - Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone - Google Patents
Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone Download PDFInfo
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- CN1616437A CN1616437A CN 200410078368 CN200410078368A CN1616437A CN 1616437 A CN1616437 A CN 1616437A CN 200410078368 CN200410078368 CN 200410078368 CN 200410078368 A CN200410078368 A CN 200410078368A CN 1616437 A CN1616437 A CN 1616437A
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Abstract
The present invention relates to the processing method of 6-(4-amino phenyl)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone as the intermediate material for levosimendan and pimobendan as cardiac and cerebral vascular diseases medicine. The processing includes the first mixing of 6-(4-amino phenyl)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone dextroisomer with alkali or acid in 50 %, dissolving with solvent and reflux, evaporation to dry, water washing, and drying to obtain product. The said method can raise material utilization rate and lower product cost, and through four times one racemization and five times of resolution, the accumulated yield may reach 30-40 %, with the single time resolution yield being 8-12 %.
Description
Technical field
The present invention relates to the intermediate feed 6-(4-aminophenyl)-4 of a kind of cardio-cerebrovascular medicine Simdax and pimobendan, the treatment process of 5-dihydro-5-methyl-3-(2H)-pyridazinone, 6-(4-aminophenyl)-4 particularly, the method for 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization.
Background technology
Acute heart failure is to change diseases associated with haemodynamics, and treatment needs to start with from the haemodynamics angle.Chronic heart failure is then relevant with neurohormone, need regulate neurohormone during treatment.Existing acute heart failure treatment means mainly contains quiet notes diuretic(s), vasodilator and myocardial contraction toughener.The medical expert thinks that the treatment of acute heart failure should be identical with chronic heart failure, promptly improves symptom, reduces the danger of dead or serious heart failure, and myocardial contraction toughener prolonged application is harmful, but short application use is useful.New myocardial contraction toughener mainly contains: quick dose of phosphodiesterase inhibitor and receptor-blocking agent and calcium.But calcium can not increase calcium round-robin energy requirement for quick dose, can increase myocardial contraction by the cAMP approach separately.It has equal effect to normal and depleted heart.Simdax (levosimendan) is quick dose of the new calcium of extremely promising treatment heart failure, and this product has convergent force forward regulating effect, by combining with clothes calsequestrin C, has increased the susceptibility of myofiber to calcium.This effect depends on the calcium level in the born of the same parents, have only after intracellular calcium contents improves the calcium sensitivity of myofiber layer is improved thereupon, so this acts on flesh maximum and minimum when opening well when shrinking.In addition, by opening the potassium channel to the ATP sensitivity, this product also has vasorelaxation action.
Pimobendan (pimobendan, UD-CG115BS.acardi) also be a cardiac tonic that gets a good chance of with calcium ion effect, pharmacology and clinical trial show that this medical instrument has stronger positive inotropic action and stronger vasorelaxation action and platelet aggregation effect.It is not only the inhibitor of di(2-ethylhexyl)phosphate garden enzyme 1, and its cardiotonic mainly is to increase myocardial contraction albumen to the susceptibility of calcium ion and suppress due to the vasoconstriction effect of vasotonia case n.It does not increase intracellular calcium concentration, so security is higher.Some countries went on the market before 10 years, were used for the treatment of chronic and disease acute heart failure.
When preparation Simdax and pimobendan, one of important intermediate feed is 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone, pyridazinone is that a class has the active heterogeneous ring compound of good biological, at agricultural chemicals, aspects such as medicine have a wide range of applications, therefore caused that the investigator pays close attention to greatly, the open source literature report, pyridazinone compound 9612 gastric infusions (i.g) can effectively suppress rat artery-vein bypass thrombosis, collagen is caused lung thrombus dead mouse stronger provide protection is also arranged, dosage is 75,150 or during 300mg/kg, inhibiting rate is respectively 36.04%, 45.97% and 78.25%; Protection ratio is respectively 48%, 64% and 72%; When 9612 (i.g) dosage is 100mg/kg or 200mg/kg, the mouse bleeding time is obviously prolonged, rate elongation is respectively 39.6% and 76.3%, and the radioimmunoassay determination result shows that 9612 can make washing rabbit platelet cyclic adenosine monophosphate level obviously raise (P＜0.001) when final concentration is 1～100umol/L.Illustrate that 9612 have stronger anti thrombotic action, increased platelets counts cAMP level may be its main mechanism of action.
Yet, in the process of preparation Simdax and pimobendan, only need 6-(4-aminophenyl)-4, the levo form of 5-dihydro-5-methyl-3-(2H)-pyridazinone, reaction process has produced a large amount of dextrorotatory forms, if outwell and will be very big waste.In order to cut the waste, reduce cost, many pharmaceutical chemistry men have carried out many effort, want to address this problem, but all fail all the time.
Summary of the invention
The inventor has found 6-(4-aminophenyl)-4 through many tests and research, a kind of racemization method of 5-dihydro-5-methyl-3-(2H)-pyridazinone, and this method can improve raw material and get utilization ratio, reduces the cost of product.
Technical scheme of the present invention is as follows: earlier with 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form and 50% alkali or 50% acid are mixed, reflux with dissolution with solvents, and evaporate to dryness, washing, drying can obtain DL body [α] then
D 25=0.
NaOH, KOH, Ca (OH) are adopted in above-described alkali or acid
2, HCl, H
2SO
4, H
3PO
4, H
2SO
3, HNO
3, perhaps adopt mixing acid, mixed base.Consumption is the 30%--100% of raw material weight.
Above-described solvent adopts methyl alcohol, ethanol, acetone, ether, tetrahydrofuran (THF), 1,4-dioxane etc.
Above-described water washing process is washed till pH7-8 for adopting tap water or distilled water.
Above-described drying process is for selecting for use drying oven or vacuum drying oven at 60 ℃--105 ℃ dry 5-2 hour.
Substantive distinguishing features of the present invention and obvious improvement are:
The invention provides (+) 6-(4-aminophenyl)-4, a kind of racemization method of 5-dihydro-5-methyl-3-(2H)-pyridazinone.This method can improve raw material availability, reduces the cost of product.Can reach 30%--40% through four racemizations, five fractionation back accumulative total yields.The single resolution yield is 8%--12%.
Embodiment
Embodiment 1
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gNaOH 100ml dissolve with methanol, behind the backflow 24h, evaporate to dryness is washed till pH7-8 with tap water, with 70 ℃ of oven dryings 5 hours, the 7.8g solid.[α]
D 25＝0
Embodiment 2
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gNaOH 100ml dissolve with ethanol, behind the backflow 24h, evaporate to dryness is washed to pH7-8 with distilled water, with 80 ℃ of oven dryings 4 hours, the 8g solid.[α]
D 25＝0
Embodiment 3
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gNaOH dissolves with 100ml 1,4-dioxane, behind the backflow 24h, is washed till pH7-8 with tap water, gets the 8.1g solid in 3 hours with 90 ℃ of oven dryings.[α]
D 25＝0
Embodiment 4
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gKOH 100ml dissolve with methanol, behind the backflow 24h, evaporate to dryness is washed to pH7-8 with distilled water, gets the 7.9g solid in 2.5 hours with 100 ℃ of oven dryings.[α]
D 25＝0
Embodiment 5
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gKOH 100ml dissolve with ethanol, behind the backflow 24h, evaporate to dryness is washed till pH7-8 with tap water, gets the 8g solid in 3 hours with 105 ℃ of oven dryings.[α]
D 25＝0
Embodiment 6
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gNaOH 100ml water dissolution, behind the backflow 24h, evaporate to dryness is washed to pH7-8 with distilled water, and 60 ℃ of vacuum-dryings get the 7.7g solid.[α]
D 25＝0
Embodiment 7
With 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 100ml water 5ml concentrated hydrochloric acid mixing backflow 8h, cooling is regulated pH=8 with NaOH solution, filters, and gets 6.8g DL body with 105 ℃ of baking ovens.
Embodiment 8
With 10g6-(4-aminophenyl)-4, the dense stream acid of 5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 100ml water 5ml mixes backflow 8h, and cooling is regulated pH=8 with NaOH solution, filters, and 65 ℃ of vacuum-dryings get 7.0g DL body.
Embodiment 9
With 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 100ml water 6ml phosphoric acid mixing backflow 8h, cooling is regulated pH=8 with NaOH solution, filters, the dry 7.1g DL body that gets.
Embodiment 10
With 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 100ml water 5ml concentrated nitric acid mixing backflow 8h, cooling is regulated pH=8 with NaOH solution, filters, and 70 ℃ of vacuum-dryings get 6.9g DL body.
Embodiment 11
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gKOH dissolves with the 100ml tetrahydrofuran (THF), behind the backflow 24h, and evaporate to dryness, washing, the dry 7.6g solid that gets.[α]
D 25＝0
Embodiment 12
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 5gKOH dissolves with 100ml 1,4-dioxane, behind the backflow 24h, and evaporate to dryness, washing, the dry 7.5g solid that gets.[α]
D 25＝0
Embodiment 13
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 6g Ca (OH)
2Use the 100ml dissolve with methanol, behind the backflow 24h, evaporate to dryness, washing, the dry 7.8g solid that gets.[α]
D 25＝0
Embodiment 14
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 6g Ca (OH)
2Use the 100ml dissolve with ethanol, behind the backflow 24h, evaporate to dryness, washing, the dry 77g solid that gets.[α]
D 25＝0
Embodiment 15
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 3gNaOH and 3gKOH 100ml dissolve with methanol, behind the backflow 24h, evaporate to dryness is washed till pH7-8 with pure water, gets the 8.0g solid in 3 hours with 105 ℃ of oven dryings.[α]
D 25＝0
Embodiment 16
Get 10g6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form 3ml concentrated hydrochloric acid and 3ml phosphoric acid 100ml dissolve with methanol, behind the backflow 24h, evaporate to dryness, washing, 65 ℃ of vacuum-dryings get the 7.2g solid.[α]
D 25＝0
Claims (5)
1, a kind of 6-(4-aminophenyl)-4, the method of 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization, it is characterized in that: earlier with 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone dextrorotatory form and 50% alkali or 50% acid are mixed, reflux with dissolution with solvents, evaporate to dryness, washing, drying obtain product then.
2,6-according to claim 1 (4-aminophenyl)-4, the method for 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization is characterized in that: NaOH, KOH, Ca (OH) are adopted in described alkali or acid
2, HCl, H
2SO
4, H
3PO
4, H
2SO
3, HNO
3, perhaps adopting their mixing acid, mixed base, consumption is the 30%--100% of raw material weight.
3,6-according to claim 1 (4-aminophenyl)-4, the method for 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization is characterized in that: described solvent adopts methyl alcohol, ethanol, acetone, ether, tetrahydrofuran (THF), 1,4-dioxane.
4,6-according to claim 1 (4-aminophenyl)-4, the method for 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization is characterized in that: described water washing process is washed till pH7-8 for adopting tap water or distilled water, pure water.
5,6-according to claim 1 (4-aminophenyl)-4, the method of 5-dihydro-5-methyl-3-(2H)-pyridazinone racemization is characterized in that: described drying process is for selecting for use drying oven or vacuum drying oven at 60 ℃--105 ℃ dry 5-2 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410078368 CN1616437A (en) | 2004-09-27 | 2004-09-27 | Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410078368 CN1616437A (en) | 2004-09-27 | 2004-09-27 | Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone |
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|---|---|---|---|
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007123A1 (en) | 2009-07-14 | 2011-01-20 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| CN102464619A (en) * | 2010-11-17 | 2012-05-23 | 桑迪亚医药技术（上海）有限责任公司 | Racemization method for L-4-[1-(2,3-dimethylphenyl)ethyl]-1R-imidazole |
| CN103554033A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Splitting method for despinner (+/-)-6-(4-aminophenyl)-4, 5-dihydro-5-methyl-3(2H)-pyridazinone |
| CN103554032A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone |
| CN104230816A (en) * | 2014-09-19 | 2014-12-24 | 成都新恒创药业有限公司 | Levosimendan potential genotoxic impurity as well as preparation and detection methods thereof |
| CN104418810A (en) * | 2013-09-04 | 2015-03-18 | 北京博时安泰科技发展有限公司 | New synthetic route of levosimendan |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
-
2004
- 2004-09-27 CN CN 200410078368 patent/CN1616437A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011007123A1 (en) | 2009-07-14 | 2011-01-20 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| US9000158B2 (en) | 2009-07-14 | 2015-04-07 | Cipla Limited | Process for preparing levosimendan and intermediates for use in the process |
| CN102464619A (en) * | 2010-11-17 | 2012-05-23 | 桑迪亚医药技术（上海）有限责任公司 | Racemization method for L-4-[1-(2,3-dimethylphenyl)ethyl]-1R-imidazole |
| CN104418810A (en) * | 2013-09-04 | 2015-03-18 | 北京博时安泰科技发展有限公司 | New synthetic route of levosimendan |
| CN103554033A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Splitting method for despinner (+/-)-6-(4-aminophenyl)-4, 5-dihydro-5-methyl-3(2H)-pyridazinone |
| CN103554032A (en) * | 2013-11-12 | 2014-02-05 | 江苏正大清江制药有限公司 | Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone |
| CN104230816A (en) * | 2014-09-19 | 2014-12-24 | 成都新恒创药业有限公司 | Levosimendan potential genotoxic impurity as well as preparation and detection methods thereof |
| CN104230816B (en) * | 2014-09-19 | 2017-02-15 | 成都新恒创药业有限公司 | Levosimendan potential genotoxic impurity as well as preparation and detection methods thereof |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
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