CN103554032A - Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone - Google Patents
Preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone Download PDFInfo
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- CN103554032A CN103554032A CN201310556109.9A CN201310556109A CN103554032A CN 103554032 A CN103554032 A CN 103554032A CN 201310556109 A CN201310556109 A CN 201310556109A CN 103554032 A CN103554032 A CN 103554032A
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Abstract
The invention provides a preparation method of high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. The preparation method comprises the steps of enabling (+/-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone to react with a resolving agent, then performing alkalization, and performing refining through re-crystallization to obtain single high-optical-purity (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. A chiral resolution method provided by the invention has a significant technical effect, and the optical purity of an obtained resolution product can reach more than 99.5%.
Description
Technical field
The present invention relates to a kind of method of resolving chiral compound, be specifically related to split (±)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone is to obtain the single configuration of high-optical-purity (-)-6-(4-aminophenyl)-4, the method for 5-dihydro-5-methyl-3 (2H)-pyridazinone.
Background technology
At field of medicaments, further investigation along with medicine chirality and medicine efficacy relation, people more and more recognize the clinical meaning of chiral drug: pharmacologically active, metabolic process and toxicity containing the drug enantiomer of chirality factor in human body exist significant difference, in most cases only have a kind of drug enantiomer to have significant pharmacologically active, and another kind of enantiomorph activity is lower or do not have activity or activity even to cause on the contrary toxic side effect.U.S. food in 1992 and the drug evaluation of medicine Supervision Bureau (FDA) and the development outline that research and development centre (CDER) has announced optics drugs, requirement must clearly quantize drug effect and the toxicological effect of each enantiomer in the operation instruction of new drug, and when two kinds of isomer have obvious drug effect and toxicological effect difference, must be with optically pure medicine form listing.This decision has promoted development and the exploitation of chiral drug greatly, research, the direction that development is low-cost, high efficiency chiral drug separation technology becomes numerous investigators' effort.
Adopting chiral separation method resolution of racemic chiral isomer, is the main method of current separating chiral enantiomorph material.The chiral solvent abstraction technique that recent development is got up extracts owing to having that separation efficiency is high, throughput large, good separating effect, the rate of recovery is high and reagent consumption is few, equipment simple, production process easily is automated is subject to numerous investigators' great attention with the advantage such as serialization.Chiral solvent extraction is for the fractionation of various racemic modifications, and the selection of separation system has certain rule to follow, and the scope of application is also widened greatly.
The present invention improves on the basis of former fractionation invention of grinding, and original fractionation effect is significantly improved, and utilizes two component solvent to split than existing technology and has improved 20%.Present method is simple to operate, productive rate is high, environmental protection, resolving agent are easy to reclaim, and has good industrial prospect.
Summary of the invention
The object of this invention is to provide a kind of production cost low, aftertreatment is easy, facility investment is few, the single configuration 6-(4-aminophenyl)-4 that is applicable to suitability for industrialized production, the method for 5-dihydro-5-methyl-3 (2H)-pyridazinone or its salt, its structural formula is as follows:
(±)-6-(4-aminophenyl)-4, the splitting step of 5-dihydro-5-methyl-3 (2H)-pyridazinone is as follows:
A) split
Raceme compound (formula I) is added in two component mixed solvents and resolving agent hybrid reaction, split;
Reaction solvent is selected from C
1-4alkyl alcohol and the mixed solvent system of acetonitrile two components, in two component mixed solvents, the volume ratio of alkyl alcohol and acetonitrile is 1:0.5 ~ 2.。
Described chiral resolving agent is D/L type, is selected from tartrate, dibenzoyl tartaric acid, camphorsulfonic acid, amygdalic acid, N-acetyl phenyl alanine or N-Boc-leucine; Chiral resolving agent and raceme (±)-6-(4-aminophenyl)-4, the mol ratio of 5-dihydro-5-methyl-3 (2H)-pyridazinone is 1:0.5 ~ 2.
The temperature of reaction is the minimum boiling point of all solvents in described solvent system, and the reaction times is 2 ~ 8 hours.
B) alkalization
The product of step a) gained is alkalized with weakly alkaline reagent, obtain (+)-6-(4-aminophenyl)-4 of single configuration, 5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
) or (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
) crude product; Adding weak base reagent is that alkaline reagents is selected from salt of wormwood, sodium carbonate, sodium-acetate, Lithium Acetate, sodium hydroxide or potassium hydroxide, and the consumption of alkaline reagents is pH value to 8 ~ 10 that regulate reaction system for the product after fractionation is dissociated out.
Chemical formula:
Formula I formula
formula
In formula I ~ III, R
1for nitrophenyl, anilino, phenyl aldehyde base or benzoyl group; R
2for C
1-4alkyl.
C) recrystallization
The product of step b) gained is carried out to recrystallization with organic solvent, after refining, obtain more than 99% (+)-6-(4-aminophenyl)-4 of optical purity, 5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
) or (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
).
Recrystallizing and refining solvent used is selected from C
1-4alkyl alcohol, toluene, DMF, ethylene glycol monomethyl ether, dioxane, methylene dichloride, ethyl acetate, acetonitrile or tetrahydrofuran (THF), recrystallization number of times can be for one or repeatedly.
From embodiment 1, can find out, the method of split-type I compound provided by the invention, can realize preferably compound raceme (±)-6-(4-aminophenyl)-4, the fractionation of 5-dihydro-5-methyl-3 (2H)-pyridazinone, obtain the 6-(4-aminophenyl)-4 of the single configuration of high-optical-purity, 5-dihydro-5-methyl-3 (2H)-pyridazinone.Increase after re-crystallization step, the optical purity of product is higher, can reach more than 99.5%, has larger using value.
Accompanying drawing explanation: Fig. 1 is the HPLC collection of illustrative plates of embodiment 1 Raw.
Fig. 2 is the HPLC collection of illustrative plates of embodiment 1 final product.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and only limit to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change, include within the scope of the invention
.
Example 1 raceme (±)-6-(4-aminophenyl)-4, the fractionation of 5-dihydro-5-methyl-3 (2H)-pyridazinone
Raceme (±)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone 202g(1mol) (by HPLC method, measure its optical purity, ee value=50.72%, detected result is shown in Fig. 1 in Table 1, HPLC collection of illustrative plates), the mixed solvent that adds 5L propyl alcohol and 5L acetonitrile, be heated to after refluxing add 150g(1mol) L-TARTARIC ACID, keep back flow reaction after 1 hour, slowly cool to room temperature, after stirring is spent the night, filter and obtain white crystal.
White crystal is dry, obtain 246g product, productive rate 69.88%.
By dried white crystal, add purified water and dissolve, the wet chemical that drips 2mol/L is adjusted to system after pH=10, places and stirs 1 hour.Filtering product, and use purified water washing leaching cake, finally, by the filter cake vacuum-drying obtaining, obtain 142.7g product, productive rate 58%.
Dried product is carried out to recrystallization with methyl alcohol, the mother liquor obtaining is spin-dried for; And recrystallization 2 times again, obtain 46.3g product, productive rate 32.4%.Sampling detects, and by HPLC method, measures its optical purity, and ee value reaches more than 99.5%, and detected result is shown in Fig. 2 in Table 2, HPLC collection of illustrative plates.
The optical purity detected result of table 1 raw material
The optical purity detected result of table 2 product
Claims (9)
1. high-optical-purity (-)-6-(4-aminophenyl)-4, the preparation method of 5-dihydro-5-methyl-3 (2H)-pyridazinone, step is:
A) split
Raceme compound (formula I) is added in two component solvent and resolving agent hybrid reaction, split; Described chiral resolving agent is D/L type, is selected from tartrate, dibenzoyl tartaric acid, camphorsulfonic acid, amygdalic acid, N-acetyl phenyl alanine or N-Boc-leucine;
B) alkalization
The product of step a) gained is alkalized with weakly alkaline reagent, obtain (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
) or (+)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3 (2H)-pyridazinone (formula
) crude product;
C) recrystallization
The product of step b) gained is carried out to recrystallization with organic solvent, after refining, obtain more than 99.5% (-)-6-(4-aminophenyl)-4 of optical purity, 5-dihydro-5-methyl-3 (2H)-pyridazinone, chemical formula is as follows:
Formula I formula
formula
In formula I ~ III, R
1for nitrophenyl, anilino, phenyl aldehyde base or benzoyl group; R
2for C
1-4alkyl.
2. method claimed in claim 1, in step a), the mol ratio of chiral selectors and compound is 1:0.5 ~ 2.
3. method claimed in claim 1, in step a), reaction solvent is selected from C
1-4alkyl alcohol and the mixed solvent system of acetonitrile two components.
4. method claimed in claim 1, in step a), in two component mixed solvents, the volume ratio of alkyl alcohol and acetonitrile is 1:0.5 ~ 2.
5. method claimed in claim 1, in step a), temperature of reaction is the boiling point of lower solvent in system; Reaction times is 2 ~ 8 hours, then slowly cools to room temperature crystallize out.
6. method claimed in claim 1, in step b), described alkaline reagents is selected from salt of wormwood, sodium carbonate, sodium-acetate, Lithium Acetate, sodium hydroxide or potassium hydroxide.
7. method claimed in claim 1, in step b), the consumption of described alkaline reagents is pH value to 8 ~ 10 that regulate reaction system.
8. method claimed in claim 1, in step c), recrystallizing and refining solvent used is selected from C
1-4alkyl alcohol, toluene, DMF, ethylene glycol monomethyl ether, dioxane, methylene dichloride, ethyl acetate, acetonitrile or tetrahydrofuran (THF).
9. method claimed in claim 8, the number of times of described recrystallization is one or many.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110885315A (en) * | 2019-12-13 | 2020-03-17 | 武汉嘉诺康医药技术有限公司 | Preparation method of important intermediate of levosimendan |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424428A (en) * | 1991-01-03 | 1995-06-13 | Orion-Yhtyma Oy | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]pr |
| JPH10109977A (en) * | 1996-10-04 | 1998-04-28 | Nippon Soda Co Ltd | Production of optically active pyridazinone derivative |
| CN1271282A (en) * | 1997-09-26 | 2000-10-25 | 欧里恩公司 | Oral compositions of levosimendan |
| CN1348445A (en) * | 1999-03-31 | 2002-05-08 | 巴斯福股份公司 | Method for producing 4-amino-5-chloro-1-phenyl pyridazinone-(6) |
| CN1616437A (en) * | 2004-09-27 | 2005-05-18 | 广西大学 | Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone |
| EP1619186A1 (en) * | 1996-03-27 | 2006-01-25 | Orion Corporation | Method for obtaining pure enantiomers of a pyridazinone derivative |
-
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- 2013-11-12 CN CN201310556109.9A patent/CN103554032A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5424428A (en) * | 1991-01-03 | 1995-06-13 | Orion-Yhtyma Oy | (-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]-hydrazono]pr |
| EP1619186A1 (en) * | 1996-03-27 | 2006-01-25 | Orion Corporation | Method for obtaining pure enantiomers of a pyridazinone derivative |
| JPH10109977A (en) * | 1996-10-04 | 1998-04-28 | Nippon Soda Co Ltd | Production of optically active pyridazinone derivative |
| CN1271282A (en) * | 1997-09-26 | 2000-10-25 | 欧里恩公司 | Oral compositions of levosimendan |
| CN1348445A (en) * | 1999-03-31 | 2002-05-08 | 巴斯福股份公司 | Method for producing 4-amino-5-chloro-1-phenyl pyridazinone-(6) |
| CN1616437A (en) * | 2004-09-27 | 2005-05-18 | 广西大学 | Racemization method of 6-4-(4-amino pheny)-4, 5-dihydro-5-methyl-3-(2H)-pyridazinone |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110885315A (en) * | 2019-12-13 | 2020-03-17 | 武汉嘉诺康医药技术有限公司 | Preparation method of important intermediate of levosimendan |
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Application publication date: 20140205 |