CN107176948B - The preparation of pimobendan - Google Patents
The preparation of pimobendan Download PDFInfo
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- CN107176948B CN107176948B CN201710595181.0A CN201710595181A CN107176948B CN 107176948 B CN107176948 B CN 107176948B CN 201710595181 A CN201710595181 A CN 201710595181A CN 107176948 B CN107176948 B CN 107176948B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to the new preparation processes of pimobendan.The processing step is short, is not related to industrial a large amount of using by the Br limited to2, KCN, NaH etc. be dangerous and poisonous reagent, and easy to operate, reaction condition is mild, and industrialized production has apparent advantage.
Description
Technical field
The present invention relates to the preparations of pimobendan.
Background technique
Pimobendan (Pimobendan) (trade name Vetmedin) is public by German Boehringer Ingelheim
Department develops, and belongs to di-phosphate ester in a kind of cardiotonic drug with vasorelaxation action of Japan's listing for the first time in 1994
Enzyme inhibitor is clinically mainly used for the treatment of heart failure disease.The compound is inhibited with calcium sensibilization and type III phosphatase
The heart tonifying expander of agent effect, the mechanism of action are different from traditional cardiotonic drug, and positive inotropic effect is mainly due to the enhancing heart
Flesh contractile protein is to Ca2+Sensibility and inhibiting effect to phosphodiesterase iii (PDE III), be the calcium of first listing
Sensitizer class drug.Research shows that the medical instrument has stronger vasorelaxation action and antiplatelet aggregative activity, almost without pair
Effect, can also treat chronic cardiac insufficiency and angina pectoris, can also prevent and treat arterial thrombosis.In addition, a large amount of clinical examinations
It tests it is also show that heart failure patient Long-term Oral mode takes pimobendan and can be effectively improved exercise tolerance and quality of the life.
The chemical name of pimobendan are as follows: 4,5- dihydro -6- [2- (4- methoxyphenyl) -1H- benzimidazole -5- base] -5- methyl -3
(2H)-pyridazinone has following chemical structural formula:
The patent document of the preparation pimobendan of open report is more at present.Early in nineteen eighty-two Austel et al.
(US4361563) report the synthetic route using chlorobenzene as starting material for the first time, through pay-gram acylation reaction, nitration reaction,
The position the α bromination of carbonyl, malonate nucleophilic displacement of fluorine, KOH hydrolysis, heating decarboxylation, ammonification, esterification, anisoyl chloride acyl
Change, hydrazine hydrate cyclization, hydrogenation, cyclization and etc. complete the fully synthetic of pimobendan.The route steps are long (totally 12 steps are reacted),
And the route when needing autoclave, bromination there are aminating reaction need to bromine very strong with corrosivity the disadvantages of, therefore industrialized production
Limited to.Related synthetic route is as follows:
Piao Yang and Duan Yongxi et al. (Chinese journal of Medicinal Chemistry, 1994,4,41) are developed using antifebrin as raw material
Synthetic route.The route by pay-gram acylation reaction, Mannich reaction, quaternary amine salinization, cyaniding replace, nitrify etc. 10 steps
Reaction completes the synthesis of pimobendan.Although the route is shortened compared to 4361563 route of US, due to reacting
It is related to the KCN using severe toxicity in journey, thus is not suitable for amplification production.The specific synthetic route of the technique of the reports such as Piao Yang is such as
Shown in lower:
Wang Sisi et al. (Chinese journal of Medicinal Chemistry, 1997,7,185) combines patent US 4361563 and Piao Yang etc.
The technique of people, it was recently reported that using antifebrin as raw material, by paying-gram acylation reaction, bromo-reaction, diethyl malonate nucleophilic
The synthetic route of 9 step such as substitution reaction reaction preparation pimobendan.Although the route step is shortened, due to reacting
The reagent strong using corrosivity such as bromines is not only related equally in journey, but also uses the NaH of high-risk, thus industrialized production
It is similarly subjected to limit to.The specific synthetic route of the technique is as follows:
Xu Youjun et al. (synthesis chemistry, 1999,7,194) reports the route of a synthesis pimobendan.The route is same
Sample uses antifebrin as starting material, first by and 3- chloro-2-methyl propionyl chloride carry out pay-gram acylation reaction, one
Step obtains 4- (3- chloro-2-methyl propiono) antifebrin, and the latter is using cyano substitution reaction, nitration reaction, Zn/NH4Cl
The synthesis of the realization pimobendan such as reduction reaction.Although the route synthesis step is short, due to 3- chloro-2-methyl propionyl chloride quotient
Industry is not easy largely to purchase and relates equally to the KCN using severe toxicity in reaction process, thus industrialized production is restricted.
The specific synthetic route of the technique is as follows:
In summary the method for disclosing the synthesis pimobendan of report, the conjunction of the reports such as US4361563 patent, Piao Yang
Having used respectively at the synthetic route that the synthetic route and being permitted of the reports such as route, Wang Sisi helps the reports such as monarch industrially largely makes
With by the Br2 limited to, KCN, NaH/Br2 etc., and it is directed to the implementation of nitration reaction, these routes are not appropriate for industry
Change amplification production.For this purpose, the pimobendan synthetic route of one suitable industrial amplification production of exploitation is for pimobendan drug
Industrialization be even more important.
Summary of the invention
Key of the invention is the method for one newly developed suitable industrialized production pimobendan, the following institute of synthetic route
Show:
The first step is related to 5- (the halogenated propiono of 2-) -1,3- dihydro -2H- benzo [d] imidazoles -2- ketone (Formulas I) and malonic acid
Nucleophilic substitution occurs for dimethyl ester or diethyl malonate, generates 2- (1- oxo -1- (2- oxo -2,3- dihydro -1H- benzo
[d] imidazoles -5- base) -1- propionyl -2- base) diester malonate (formula III)；
The X of Formulas I1For Cl, Br.
The R of Formula II1For Me, Et.
The R of formula III1For Me, Et.
It includes K that the first step, which reacts used alkali,2CO3,Na2CO3,Cs2CO3, t-BuOK, LiHMDS, NaHMDS, LDA etc.；
It includes THF, DMF, Dioxane, CH that the first step, which reacts used solvent,3CN, DMSO etc..
Second step is 2- (1- oxo -1- (2- oxo -2,3- dihydro -1H- benzo [d] imidazoles -5- base) -1- propionyl -2-
Base) diester malonate (formula III) is in POCl3Or POBr3Effect is lower to occur the halogenating reaction generation 2- (1- (halogenated -1H- benzo of 2-
[d] imidazoles -6- base) -1- propionyl -2- base) diester malonate (formula IV).
The reaction dissolvent of second step includes toluene, benzene, ethyl acetate, THF or directly uses POCl3、POBr3Make simultaneously
It is carried out for solvent and reaction reagent.
Third step is 2- (1- (halogenated -1H- benzo [d] imidazoles -6- base of 2-) -1- propionyl -2- base) diester malonate (formula
IV Suzuki coupling) occurs instead with p-methoxyphenyl boric acid or 4- methoxyphenylboronic acid pinacol ester under Pd catalysts conditions
It answers, realizes 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base) diester malonate (formula
V preparation).
The R of Formula V1For Me, Et.
It includes Pd (OAc) that third step, which reacts used Pd catalyst,2、Pd(PPh3)4、PdCl2、PdCl2(PPh3)2、
PdCl2(dppf)·CH2Cl2、Pd2(dba)3、Pd2(dba)3·CHCl3(t-Bu3P)2One of Pd or a variety of；Wherein,
Dppf represents bis- (diphenyl see base) ferrocene；Dba represents dibenzalacetone；OAc indicates acetate；
It includes i-PrOH, benzene, THF, glycol dimethyl ether, CH that third step, which reacts used solvent,3CN、NMP、
One of Dioxane, toluene, EtOH and DMF or a variety of；
It includes NaHCO that third step, which reacts used alkali,3、KF、KHCO3、K2CO3、Na2CO3、Et3N、CsF、Cs2CO3、
NaOH、KOH、LiOH、(iPr)2NEt、Et3N and K3PO4One of or it is a variety of；
Four-step reaction is 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base)
Under the action of inorganic base ester hydrolysis reaction occurs for diester malonate (Formula V), obtains 2- (1- (2- (4- methoxyphenyl) -1H-
Benzo [d] imidazoles -6- base) -1- propionyl -2- base) malonic acid (Formula IV).
Alkali used in four-step reaction includes NaOH, LiOH, KOH, CsOH etc..
Solvent used in four-step reaction includes EtOH, MeOH, THF, DMF, CH3One of CN, i-PrOH or this
The mixed solvent of a little solvents and water composition.
The reaction of 5th step is 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base)
Malonic acid (Formula IV) is performed under heating conditions decarboxylic reaction, obtains 4- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -
6- yl) -3- methyl -4- ketobutyric acid (Formula VII)；
It includes DMF, DMSO, CH that 5th step, which reacts used solvent,3CN, NMP, PhOPh etc.；
The temperature of 5th step reaction is 80-150 DEG C；
Six-step process is 4- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -3- methyl -4- oxo fourth
Sour (Formula VII) and hydration hydrazine reaction, obtains pimobendan compound.
The solvent of six-step process includes MeOH, EtOH, THF, CH3CN etc..
The preparation process for the pimobendan that the present invention describes, step is short, is not related to industrial a large amount of uses and is limited to
Br2, KCN, NaH etc. be dangerous and poisonous reagent, and easy to operate, reaction condition is mild, and industrialized production has apparent advantage.
Specific embodiment
The present invention can be more specifically understood by the following examples, but it illustrates rather than the limitation present invention
Range.
Embodiment
1. preparing 2- (1- oxo -1- (2- oxo -2,3- dihydro -1H- benzo [d] imidazoles -5- base) -1- propionyl -2- base)
Dimethyl malenate (formula III) (R1=Me)
Under nitrogen protection, potassium tert-butoxide (150g, 1338mmol) is added into reaction flask, then anhydrous DMSO (600mL)
It is added, 10min is stirred at room temperature in system.Dimethyl malenate (120g, 908mmol), which divides 10 times, to be carefully added into reaction system,
Pay attention to that temperature of reaction system is kept to be no more than 40 DEG C when addition.System stirs 20min after addition.Then, Formula I
(X1=Cl) (202g, 899mmol) be added by several times, and keep temperature of reaction system to be no more than 40 DEG C in adition process, addition finishes
System is stirred to react to TLC and shows reaction raw materials compound of formula I (X afterwards1=Cl) it disappears.System is slowly added to H2O (2000mL) quenches
It goes out reaction, the careful regulation system pH of glacial acetic acid is then added between 6-7.CH is added in system2Cl2(3 × 1500mL) extraction, is closed
And organic phase use saturated common salt water washing 2 times (2 × 1000mL), solvent is removed under reduced pressure after drying, filtering in anhydrous sodium sulfate
Obtain compound formula III (R1=Me) (262g, crude product), which is not further purified, and is directly used in and reacts in next step).
2. preparing 2- (1- (chloro- 1H- benzo [d] imidazoles -6- base of 2-) -1- propionyl -2- base) dimethyl malenate (formula IV)
(R1=Me, X2=Cl)
The resulting formula III compound (R of embodiment 11=Me) crude product (262g) is dissolved in dry toluene (2000mL), system
Ice salt bath is cooled to 0-5 DEG C, and POCl then is slowly added dropwise by dropping funel under nitrogen protection3(450mL), body after addition
System is slowly heated to back flow reaction 2 hours to TLC contact plate tracking mode III compound and disappears.System slow cooling to 50 DEG C or so,
Then careful removed under reduced pressure solvent and the complete POCl of unreacted3.CH is added into residue2Cl2(1000mL) and H2O
(500mL), system is carefully added into saturation NaHCO after stirring 10min3Regulation system pH to 6.5 or so.Separate organic phase, water phase
CH is added2Cl2(2 × 500mL) extraction.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 500mL), anhydrous
Sodium sulphate obtains yellowish-brown crude product after solvent is removed under reduced pressure after drying, filtering.The crude product is recrystallized using EtOAc/ heptane system
To compound formula IV (R1=Me, X2=Cl) (227g, two step yields 75%).
3. preparing 2- (1- oxo -1- (2- oxo -2,3- dihydro -1H- benzo [d] imidazoles -5- base) -1- propionyl -2- base)
Diethyl malonate (formula III) (R1=Et)
Under nitrogen protection, Cs2CO3(120g, 368mmol) is added into reaction flask, and then DMF (150mL) is added, system
10min is stirred at room temperature.Diethyl malonate (20g, 125mmol) is added in reaction system.System stirs after addition
30min.Then, Formula I (X1=Br) (33.5g, 124.5mmol) is added, and system is warming up to 80 DEG C instead after addition
It should stay overnight.System slow cooling, then removed under reduced pressure organic solvent.H is added in residue2O (800mL) and CH2Cl2(500mL)。
System separates organic phase, water phase CH after being sufficiently stirred2Cl2(2 × 300mL) is extracted twice, and merges organic phase, and organic phase uses full
With brine It 2 times (2 × 300mL), anhydrous sodium sulfate is removed under reduced pressure solvent and obtains compound formula III (R1=after drying, filtering
Et) (38.3g, crude product), which is not further purified, and is directly used in and reacts in next step).
4. preparing 2- (1- (bromo- 1H- benzo [d] imidazoles -6- base of 2-) -1- propionyl -2- base) diethyl malonate (formula IV)
(R1=Et, X2=Br)
Under nitrogen protection, resulting formula III compound (R1=Et) crude product (38.3g) of embodiment 3 is dissolved in THF (100mL)
In, system ice salt bath is cooled to 0-5 DEG C, and POBr3 (26mL) then is slowly added dropwise by dropping funel under nitrogen protection, has been added
System is slowly heated to back flow reaction 2 hours to TLC contact plate tracking mode III compound and disappears after finishing.System slow cooling, then
Careful heating removed under reduced pressure solvent and the complete POBr of unreacted3.CH is added into residue2Cl2(200mL) and H2O
(200mL), system is carefully added into saturation NaHCO after stirring 10min3Regulation system pH to 6.5 or so.Separate organic phase, water phase
CH is added2Cl2(2 × 150mL) extraction.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 150mL), nothing
Aqueous sodium persulfate obtains brown crude product after solvent is removed under reduced pressure after drying, filtering.The crude product uses EtOAc/ heptane system recrystallization two
It is secondary to obtain compound formula IV (R1=Et, X2=Br) (30.6g, two step yields 59.8%).
5. preparing 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base) malonic acid
Dimethyl ester (Formula V) (R1=Me)
Compound formula IV (2 product of embodiment) (R is added in reaction flask1=Me, X2=Cl) (125g, 370mmol) and
K2CO3(153.5g, 1110.6mmol, 3.0eq) Dioxane (5.0L) and DMF (1.5L) are added under nitrogen protection.Addition finishes
System stirs lower room temperature and vacuumizes degassing 1 hour (removal oxygen) afterwards, is then added into reaction system to first under nitrogen protection
Phenyl boric acid (84.5g, 556mmol, 1.5eq) and Pd (PPh3)4(43g,37.2mmol,0.1eq).Body after addition
System is replaced 3 times using nitrogen.System is heated to 80 DEG C and reacts 6 hours, is then naturally cooling to room temperature.System removed under reduced pressure is molten
CH is added in agent, residue2Cl2(1500mL) is vigorously stirred 2 hours, filtering, and solid uses CH after collecting2Cl2(500mL) is violent
It agitator treating 2 hours, then filters again.Merge the filtrate filtered twice, is separately added into H2O (500mL) washing, saturated common salt
Water (500mL) washing, organic phase are dried, filtered using anhydrous sodium sulfate, and removed under reduced pressure solvent, residue uses methanol/heptane
Polishing purification obtains Formula V (R1=Me) (112g, 73.8%).
6. preparing 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base) malonic acid
Diethylester (Formula V) (R1=Et)
Compound formula IV (4 product of embodiment) (R is added in reaction flask1=Et) (28g, 68mmol) and (iPr)2NEt
DMF (1.0L) is added under nitrogen protection in (22.0g, 170mmol, 2.5eq).System stirs lower room temperature and vacuumizes after addition
Degassing 1 hour (removal oxygen), 4- methoxyphenylboronic acid pinacol ester is then added under nitrogen protection into reaction system
(19.1g, 81.6mmol, 1.2eq) and PdCl2(dppf).CH2Cl2(2.8g,3.43mmol,0.05eq).Body after addition
System is replaced 3 times using nitrogen.System is heated to 100 DEG C and reacts 12 hours, is then naturally cooling to room temperature.System removed under reduced pressure is molten
CH is added in agent, residue2Cl2(500mL) and H2O (200mL), separates organic phase after stirring, CH is added in water phase2Cl2(2×
100mL) extract.Merge organic phase, organic phase uses saturated common salt water washing 2 times (2 × 150mL), and anhydrous sodium sulfate is dry, mistake
It is removed under reduced pressure after filter after solvent using ethyl alcohol/heptane polishing purification, obtains Formula V (R1=Et) (20.3g, 68.2%).
7. preparing 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base) malonic acid
(Formula IV)
Formula V (R1=Me) (95g, 231mmol) prepared by embodiment 5 is dissolved in EtOH (150mL), then to
The aqueous solution of NaOH is added in system (37g NaOH is dissolved in 520mL H2O, 4.0eq).After addition, system is stirred at room temperature
Overnight.Alcohol solvent is carefully removed under reduced pressure in 50 DEG C of system, and remaining aqueous solution uses 3M HCl regulation system pH value to 1.0-
1.5.EtOAc extraction (3 × 500mL) is added in system, and organic phase uses saturated common salt water washing 2 times (2 × 300mL), anhydrous sulphur
Sour sodium obtains compound Formula IV (83.8g) after solvent is removed under reduced pressure after drying, filtering, and is not required to purify, and is directly used in next step.
8. 4- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- the base) -3- methyl -4- ketobutyric acid (formula of preparation
VII)
Compound Formula IV (83.8g) prepared by embodiment 7 is dissolved in DMF (150mL), and system is to slowly warm up to 130-
140 DEG C, insulation reaction 3 hours.System Temperature fall, then Rotary Evaporators high vacuum removed under reduced pressure organic solvent.Gained is residual
Excess is that the compound (72.1g) of Formula VII is not required to purify, and is directly used in and reacts in next step.
9. preparing pimobendan
Ethyl alcohol EtOH (250mL) and hydrazine hydrate are directly added into compound Formula VII (72.1g) prepared by embodiment 8
(120mL), the slow temperature rising reflux of system 12 hours after addition.System Temperature fall, then high vacuum removed under reduced pressure is organic
Solvent and the complete hydrazine hydrate of unreacted.DMF (250mL) is added into residue, slowly heating stirring is to dissolved clarification, then to molten
H is slowly added dropwise in clear system2O (250mL) is stirred 1 hour after being added dropwise, and system is cooled to 60 DEG C, filtered on buchner funnel, institute
Obtain after solid is dried is that (67%) 51.6g, three step total recoverys are to pimobendan.
10. preparing 2- (1- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- base) -1- propionyl -2- base) malonic acid
(Formula IV)
Formula V (R1=Et) (15g, 34.2mmol) prepared by embodiment 6 is dissolved in THF (50mL), then to
(11.3g CsOH is dissolved in 200mL H to the aqueous solution of addition CsOH in system2In O, 2.2eq).After addition, system room temperature is stirred
It mixes overnight.After completion of the reaction, then EtOAc extraction is added using the careful regulation system pH value of 6M HCl between 1-1.5 in system
(3 × 100mL), organic phase use saturated common salt water washing 2 times (2 × 60mL), and anhydrous sodium sulfate is removed under reduced pressure after drying, filtering
Compound Formula IV (14.3g) is obtained after solvent, is not required to purify, is directly used in next step.
11. 4- (2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -6- the base) -3- methyl -4- ketobutyric acid (formula of preparation
VII)
Compound Formula IV (14.3g) prepared by embodiment 10 is dissolved in NMP (40mL), and system is to slowly warm up to 130-
140 DEG C, insulation reaction 3 hours.System Temperature fall, then Rotary Evaporators high vacuum removed under reduced pressure organic solvent.Gained is residual
Excess is that the compound (13.5g) of Formula VII is not required to purify, and is directly used in and reacts in next step.
12. preparing pimobendan
CH is directly added into compound Formula VII (13.5g) prepared by embodiment 113CN (50mL) and hydrazine hydrate
(25mL), the slow temperature rising reflux of system 12 hours after addition.System Temperature fall, then high vacuum removed under reduced pressure is organic molten
Agent and the complete hydrazine hydrate of unreacted.DMF (50mL) is added into residue, slowly heating stirring is to dissolved clarification, then to dissolved clarification
H is slowly added dropwise in system2O (50mL) is stirred 1 hour after being added dropwise, and system is cooled to 60 DEG C, filtered on buchner funnel, and gained is solid
Body is that (62.1%) 7.10g, three step total recoverys are to pimobendan after drying.
Claims (5)
1. the preparation process of a preparation pimobendan, has following synthetic route:
2. the preparation method of formula III compound shown in claim 1, be reacted by Formula I and compound Formula II into
Row is prepared, wherein X in Formulas I1R for Br, Cl, in Formula II1R for Me, Et, in formula III1For Me, Et.
3. the preparation method of formula IV compound shown in claim 1 is by formula III compound in POCl3Or POBr3Effect
Lower react is prepared, wherein X in formula IV2For Br, Cl, R1For Me, Et.
4. the preparation method of Formula V compound shown in claim 1 is under Pd catalysts conditions and right by formula IV compound
Methoxyphenyl-boronic acid or 4- methoxyphenylboronic acid pinacol ester occur what coupling reaction was prepared.
5. the preparation method of Formula IV compound shown in claim 1 is hydrolyzed under alkaline condition by Formula V compound
It is prepared.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987003201A1 (en) * | 1985-11-22 | 1987-06-04 | Rorer International (Overseas) Inc. | Benzodiazinone-pyridazinone and hydroxy-pyrazolyl compounds, cardiotonic compositions including the same, and their uses |
| WO2016180472A1 (en) * | 2015-05-11 | 2016-11-17 | Kancera Ab | Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity |
| CN106518850A (en) * | 2016-11-15 | 2017-03-22 | 青岛农业大学 | Chemical synthesis method of Pimobendan |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987003201A1 (en) * | 1985-11-22 | 1987-06-04 | Rorer International (Overseas) Inc. | Benzodiazinone-pyridazinone and hydroxy-pyrazolyl compounds, cardiotonic compositions including the same, and their uses |
| WO2016180472A1 (en) * | 2015-05-11 | 2016-11-17 | Kancera Ab | Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity |
| CN106518850A (en) * | 2016-11-15 | 2017-03-22 | 青岛农业大学 | Chemical synthesis method of Pimobendan |
Non-Patent Citations (1)
| Title |
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| 新型强心药物匹莫苯的合成;王恩思;《中国药物化学杂志》;19970930;第7卷(第3期);185-190 |
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