CN102285978B - A kind of synthetic method prepared containing benzofuraxan lopps antihypertensive drug - Google Patents
A kind of synthetic method prepared containing benzofuraxan lopps antihypertensive drug Download PDFInfo
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- CN102285978B CN102285978B CN201110175691.5A CN201110175691A CN102285978B CN 102285978 B CN102285978 B CN 102285978B CN 201110175691 A CN201110175691 A CN 201110175691A CN 102285978 B CN102285978 B CN 102285978B
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- benzofuraxan
- lopps
- darodipine
- formyl radical
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Abstract
The present invention relates to a kind of synthetic method prepared containing furazan lopps antihypertensive drug; with 4-methyl benzofuraxan for raw material, prepare important intermediate 4-formyl radical benzofuraxan through bromination, oxidizing reaction, again Hantzsch occur with acetylacetic ester and react and prepare target compound.The present invention is compared with other technique, and it has reaction conditions gentleness, simple to operate, and efficiently, yield high, has certain industrial production prospect.
Description
One, technical field
The present invention relates to a kind of synthetic method containing furazan lopps antihypertensive drug, relate more specifically to the preparation method of medicine Darodipine.
Two, background technology
Darodipine (darodipine) is potent dihydropyridine type calcium antagonists, there is good antihypertensive effect, and effective to stable angina pectoris, be characterized in having larger drug level distribution, in human plasma, the transformation period reaches 11h.Clinical have bronchiectatic activity apart from outside obvious step-down and antianginal effect to asthma patient, can prevent bronchospasm.Darodipine effect is better than nifedipine, for light, Moderate Essential Hypertension patient, can reduce and lie on the back and standard arteriotony, have no adverse effects to heart rate.
Darodipine (Darodipine), nicardipine and Ni Fen Horizon are 10
-6at lower concentration 5.5mM during M) and high density (22mM) glucose response in rat Langerhans islet release Regular Insulin be restraining effect.
Show through the double blinding of 12 routine asthma volunteers, intersection, random, placebo-controlled trial, Darodipine or placebo oral administration, first day dosage is 75mg, second and third sky is 150mg, after within second day, taking Darodipine, see with regard to baseline value, a second, firmly maximum exhalation amount significantly increased, on average maximum, rate of increase is 15 ± 4%, and is 3 ± 2% after giving placebo.This product suppresses the bronchospasm of exercise induced.
19 routine patient with angina pectoris show through double blinding, cross matching, take Darodipine 75 or 150mg, every day 3 times, continuous 2 weeks, and when the tread-mill of 16/18 routine patient moves as a result, what extends, and two kinds of dosage all increase run duration 50%.This product to resting heart rate and maximum heart rate without obvious effect, but the vertical position property systolic blood pressure bringing out stationary state time heavy dose of reduces (from 130 ~ 123mmHg) slightly.Do not find blood picture and biochemistry extremely.
Show through the double blinding of 6 example chronic, stability heart line pain patient, intersection, random test, oral Darodipine 25mg and 50mg shows medium antianginal effectiveness rapidly.Contrast the chronic test of original animal and human. observe reflexive tachycardia effect, this explanation needs some times just to produce to the suppression of the sinus node of people.
The asthma adult patients that 12 routine exercise induced are more serious, compare take Darodipine 75mg through double blinding, random test, 150mg, the effect of the fragrant Horizon 30mg of Buddhist nun and placebo, take Darodipine 150mg and Ni Fen Horizon can be observed to move before slight bronchiectasis, but only after the fragrant Horizon medication of Buddhist nun obviously.Have Darodipine 150mg only and significantly can suppress exercise-induced asthma, one is exerted oneself second, and to measure maximum reduced rate be 24 ± 13% in exhalation.And placebo is 40 ± 16%.Take Buddhist nun fragrant Horizon, Darodipine 150mg, have 6 respectively after Darodipine 75mg and placebo, 5,1, the report of 0 example headache, subjective think take the fragrant Horizon of Buddhist nun after particularly serious.
US Patent No. 4466972 and European patent EP 0000150 disclose the synthetic method of Darodipine.Synthetic method and the structure thereof of compound are as follows:
In addition, key intermediate 4-formyl radical benzofuraxan is related in existing preparation technology.But the preparation method of this key intermediate is still unsatisfactory.Such as, disclose a kind of preparation method of intermediate 4-formyl radical benzofuraxan in Chinese patent application 200510125267 (publication number CN1847233A), its preparation flow is as follows:
Obviously when preparation two bromo-derivative, with the NBS of 3 times amount and produce a small amount of single bromination product, produce this comparatively greatly, and make troubles to aftertreatment.
The patents such as CH661270 and CH661728 are with 2; 1; 3-benzofuraxan is starting raw material; with highly basic butyllithium, LDA; reaction generates lithium salts under cryogenic, generates 4-formyl radical benzofuraxan react with DMF, due to conditional request harshness; post-processing operation is loaded down with trivial details, purification difficult, makes troubles to suitability for industrialized production.
Disclose a kind of preparation method of intermediate 4-formyl radical benzofuraxan in Chinese patent application 200810205014.1 (publication number CN101768153A) and document Eur.J.Med.Chem (1996) 31,3-10, its preparation flow is as follows:
Because first bromo is hydrolyzed preparation 4-methylol benzofuraxan again, during preparation 4-formyl radical benzofuraxan, use DMP, IBX, active MnO
2in oxygenant, cause production cost high.
Disclose the preparation method of 4-formyl radical benzofuraxan in WO patent 2005/023787, its preparation flow is as follows:
Similar with aforesaid method, difference is different from the use of oxygenant, and PCC, as conventional oxygenant, has the advantage of mild condition, but reaction conditions require anhydrous, require equipment acidproof and the shortcoming such as chromium ion environmental pollution is larger.
Therefore; associated problem in above-mentioned technology in the urgent need to address; the present invention also provides a kind of method prepared high-efficient simple and prepare Darodipine and important intermediate 4-formyl radical benzofuraxan thereof, avoids using expensive reagent, operation and aftertreatment cumbersome approaches.
The innovative point of this patent is: with 4-methyl benzofuraxan for raw material is through single bromination; oxidation one kettle way prepares 4-formyl radical benzofuraxan; adopt green catalyst as the environment-friendly type such as bicarbonate of ammonia, ammonium acetate catalyzer synthesising target compound Darodipine when synthesizing Isosorbide-5-Nitrae-dihydrogen pyridine derivative.
Three, summary of the invention
The object of this invention is to provide a kind of synthetic method containing furazan lopps antihypertensive drug; With 4-methyl benzofuraxan for starting raw material is prepared important intermediate 4-formyl radical benzofuraxan through bromination, oxidizing reaction, Hantzsch occurs with acetylacetic ester reacted and prepare target compound.
Target compound synthetic route of the present invention is as follows:
Four, specific embodiment mode
By following examples better the present invention to be described.But the present invention is not by the restriction of following embodiment.
Embodiment 1
The synthesis of 4-brooethyl benzofuraxan
4-methyl benzofuraxan (13.4g, 100mmol) is dissolved in tetracol phenixin (150m1), then adds NBS (23.5g, 132mmol) and Bz
20
2(0.29g, 1.2mmol), mixture is warming up to 80-85 DEG C of reaction, and react complete, system is down to 40 DEG C, filter, filter and use chloroform, decompression and solvent recovery has to obtain crude product (25.6g), petroleum ether-ethyl acetate recrystallization, faint yellow needle crystal, 4-brooethyl benzo bark we (15.3g).Productive rate is 77.6%, mp94-95 DEG C.
Embodiment 2
4-formyl radical benzofuraxan
4-brooethyl benzofuraxan (19.7g, 0.1mol), DMSO15ml, sodium bicarbonate (10g, 0.12mol) add in reaction flask.100-150 DEG C is heated under nitrogen protection.Reaction is finished, and is cooled to room temperature, with water, extraction into ethyl acetate.Merge organic layer, wash with saturated brine.Anhydrous sodium sulfate drying, pressure reducing and steaming solvent, obtains light yellow solid 10.6g, yield 71.6%, mp108-109 DEG C.
Embodiment 3
The synthesis of Darodipine
In 500mL tri-mouthfuls of round-bottomed flasks, add 4-formyl radical benzofuraxan (14.8g, 0.1mol), methyl aceto acetate (28g, 0.2mol), volatile salt (15.8g, 0.2mol), under agitation in 70 DEG C of reactions, TLC follows the tracks of.After reaction terminates, add 200ml water, the extraction into ethyl acetate of reaction mixture 200mL 3 times, merge organic layer, washing, dry, decompression and solvent recovery, cooling crystallization, recrystallization obtains yellow solid Darodipine 29.5g, productive rate 79.5%, mp153-154 DEG C.
1H-NMR(CDCl
3400MHz)δ:7.61(m,1H,Ar-H),7.29(m,2H,Ar-H),5.98(s,1H,N-H),5.49(s,1H,Ar-CH),4.04(q,J＝7.2Hz,4H,COOCH
2),2.32(s,6H,2×CH
3)，1.13(t,J＝7.2Hz,6H,COOCH
2CH
3)。
Be only embodiments of the invention in sum, be not used for limiting practical range of the present invention.Namely all equivalences done according to the content of the present patent application the scope of the claims change and modify, and all should be technology category of the present invention.
Claims (1)
1. prepare the method containing furazan lopps antihypertensive drug, it is characterized in that, step is as follows:
A, in inert solvent tetracol phenixin, under initiator benzoyl peroxide existent condition, halogenating agent NBS is used to carry out replacements halogenation to 4-methyl benzofuraxan, formation 4-brooethyl benzofuraxan;
B, in inert solvent, 4-brooethyl benzofuraxan and oxygenant methyl-sulphoxide carry out reacting, finally obtaining 4-formyl radical benzofuraxan;
, under catalyzer volatile salt existent condition, there is Hantzsch reaction preparation Darodipine in C, 4-formyl radical benzofuraxan and methyl aceto acetate.
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942534A (en) * | 2012-12-13 | 2013-02-27 | 牟英迪 | Preparation of drug intermediate 4-formoxyl benzofuroxan |
| CN103319432B (en) * | 2013-06-28 | 2015-02-18 | 江苏倍达医药科技有限公司 | Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4466972A (en) * | 1977-06-20 | 1984-08-21 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| US4567271A (en) * | 1977-06-20 | 1986-01-28 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles |
| CN1847233A (en) * | 2005-04-12 | 2006-10-18 | 圣玛精细化工有限责任公司 | Method for preparing 4-formoxylbenzofuran |
-
2011
- 2011-06-27 CN CN201110175691.5A patent/CN102285978B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4466972A (en) * | 1977-06-20 | 1984-08-21 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| US4567271A (en) * | 1977-06-20 | 1986-01-28 | Sandoz Ltd. | Benzoxadiazoles and benzothiadiazoles |
| CN1847233A (en) * | 2005-04-12 | 2006-10-18 | 圣玛精细化工有限责任公司 | Method for preparing 4-formoxylbenzofuran |
Non-Patent Citations (2)
| Title |
|---|
| 两步法合成间硝基苯甲醛;朱燕等;《精细化工》;20110228;第28卷(第2期);第1.2.2节 * |
| 邻硝基苯甲醛的合成方法综述;王宏丽等;《广东化工》;20051231(第5期);第27-31页 * |
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