CN102285978A - Synthesis method for preparing antihypertensive medicine having benzofuroxan ring - Google Patents

Synthesis method for preparing antihypertensive medicine having benzofuroxan ring Download PDF

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CN102285978A
CN102285978A CN201110175691A CN201110175691A CN102285978A CN 102285978 A CN102285978 A CN 102285978A CN 201110175691 A CN201110175691 A CN 201110175691A CN 201110175691 A CN201110175691 A CN 201110175691A CN 102285978 A CN102285978 A CN 102285978A
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furazan
meant
lopps
synthetic method
antihypertensive drug
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CN102285978B (en
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何勇
吴宗好
陈仕云
李甲甲
高永好
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Hefei Huafang Pharmaceutical Sciences & Technology Co Ltd
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Abstract

The invention relates to a synthesis method for preparing an antihypertensive medicine having a benzofuroxan ring. In the method, 4-methylbenzofuroxan is used as a raw material, the 2,1,3-benzoxadiazole-4-aldehyde serving as an important intermediate is prepared by bromination and oxidation reactions, and the 2,1,3-benzoxadiazole-4-aldehyde and acetoacetic ester undergo a Hantzsch reaction to form the target compound. Compared with other processes, the method has the characteristics of mild reaction conditions, simple and efficient operation, high yield and the like and has a certain industrial production prospect.

Description

A kind of preparation contains the synthetic method of benzo furazan lopps antihypertensive drug
One, technical field
The present invention relates to a kind of synthetic method that contains 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, has good antihypertensive effect, and effective to stable angina pectoris, is characterized in having bigger drug level and distributes, and the transformation period reaches 11h in human plasma.Clinical have bronchiectatic activity to asthma patient except that tangible step-down and antianginal effect are arranged, can prevent bronchospasm.The Darodipine effect is better than nifedipine, is used for light, moderate primary hypertension patient, can reduce and lie on the back and the standard arteriotony, and heart rate is had no adverse effects.
Darodipine (Darodipine), nicardipine and Ni Fen Horizon are 10 -6During M at lower concentration 5.5mM) and the glucose response of high density (22mM) in Regular Insulin that rat Langerhans islet is discharged be restraining effect.
Through 12 routine asthma volunteers' double blinding, intersection, at random, placebo-controlled trial shows, Darodipine or placebo oral administration, first day dosage is 75mg, second and third day is 150mg, after taking Darodipine in second day, see that the maximum exhalation amount of exerting oneself a second significantly increases with regard to baseline value, average maximum, rate of increase is 15 ± 4%, is 3 ± 2% and give behind the 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, and every day 3 times, in continuous 2 weeks, what prolongs during 16/18 routine patient's tread-mill motion as a result, and two kinds of dosage all increase run duration 50%.This product does not have obvious effect to static heart rate and maximum heart rate, and the upright position property systolic blood pressure that brings out stationary state when still heavy dose of reduces (from 130~123mm Hg) slightly.Do not find blood picture and biochemical unusual.
Double blinding, intersection, random test through chronic, the stable heart line pain of 6 examples patient show that oral Darodipine 25mg and 50mg have shown medium antianginal effectiveness rapidly.Contrast original animal and human's chronic test. observe reflexive tachycardia effect, this explanation needs some times just to produce to the inhibition of people's sinus node.
The asthma adult patients that 12 routine exercise induced are more serious, compared through double blinding, random test and to have taken Darodipine 75mg, 150mg, the effect of fragrant Horizon 30mg of Buddhist nun and placebo, take Darodipine 150mg and Ni Fen Horizon and can be observed the preceding slight bronchiectasis of motion, but only obvious after the fragrant Horizon medication of Buddhist nun.Have Darodipine 150mg only and can significantly suppress exercise-induced asthma, the one maximum reduced rate of exhalation amount of exerting oneself second is 24 ± 13%.And placebo is 40 ± 16%.Take the fragrant Horizon of Buddhist nun, Darodipine 150mg, the report of 6,5,1,0 example headache arranged respectively behind Darodipine 75mg and the placebo, subjective think take behind the fragrant Horizon of Buddhist nun particularly serious.
U.S. Pat 4466972 and European patent EP 0000150 disclose the synthetic method of Darodipine.The synthetic method and the structure thereof of compound are as follows:
Figure BSA00000525923000021
In addition, relate to key intermediate 4-formyl radical benzo furazan among the existing preparation technology.Yet the preparation method of this key intermediate still is difficult to satisfactory.For example, disclose a kind of preparation method of intermediate 4-formyl radical benzo furazan in the Chinese patent application 200510125267 (publication number CN1847233A), its preparation flow is as follows:
Figure BSA00000525923000022
Obviously in preparation during two bromo-derivatives, with the NBS of 3 times of amounts and produce a spot of single bromination product, produce greatlyyer, and make troubles to aftertreatment.
Patent such as CH661270 and CH661728 is with 2; 1; 3-benzo furazan is a starting raw material; with highly basic butyllithium, LDA; reaction generates lithium salts under cold condition, generating 4-formyl radical benzo furazan with the DMF reaction, because the conditional request harshness; loaded down with trivial details, the purification difficult of post-processing operation is made troubles to suitability for industrialized production.
Figure BSA00000525923000023
Disclose a kind of preparation method of intermediate 4-formyl radical benzo furazan among Chinese patent application 200810205014.1 (publication number CN101768153A) and document Eur.J.Med.Chem (1996) 31, the 3-10, its preparation flow is as follows:
Figure BSA00000525923000031
Because first bromo hydrolysis again prepares 4-methylol benzo furazan, during preparation 4-formyl radical benzo furazan, use DMP, IBX, active MnO 2In oxygenant, cause the production cost height.
Disclose the preparation method of 4-formyl radical benzo furazan in the WO patent 2005/023787, its preparation flow is as follows:
Figure BSA00000525923000032
Similar with aforesaid method, difference is different with the use of oxygenant, and PCC has the advantage of mild condition as oxygenant commonly used, but that reaction conditions requires is anhydrous, require shortcomings such as the acidproof and chromium ion environmental pollution of equipment is bigger.
Therefore; press for the associated problem that solve in the above-mentioned technology; the present invention also provides a kind of method that high-efficient simple prepares Darodipine and important intermediate 4-formyl radical benzo furazan thereof for preparing, and avoids using expensive reagent, operation and aftertreatment cumbersome approaches.
The innovative point of this patent is: with 4-methyl benzo furazan is that raw material is through single bromination; the oxidation one kettle way prepares 4-formyl radical benzo furazan; synthesizing 1, adopting green catalyst during the 4-dihydrogen pyridine derivative as environment-friendly type catalyzer synthesising target compound Darodipine such as bicarbonate of ammonia, ammonium acetates.
Three, summary of the invention
The purpose of this invention is to provide a kind of synthetic method that contains furazan lopps antihypertensive drug; With 4-methyl benzo furazan is that starting raw material prepares important intermediate 4-formyl radical benzo furazan, with acetylacetic ester Hantzsch prepared in reaction target compound takes place through bromination, oxidizing reaction.
Target compound synthetic route of the present invention is as follows:
Figure BSA00000525923000033
Four, embodiment
By following examples with better explanation the present invention.But the present invention is not subjected to the restriction of following embodiment.
Embodiment 1
Synthesizing of 4-brooethyl benzo furazan
4-methyl benzo furazan (13.4g 100mmol) is dissolved in the tetracol phenixin (150ml), add then NBS (23.5g, 132mmol) and Bz 2O 2(0.29g, 1.2mmol), mixture is warming up to 80-85 ℃ of reaction, and reaction finishes, system is reduced to 40 ℃, filter, filter and with the chloroform washing, decompression and solvent recovery have crude product (25.6g), the petroleum ether-ethyl acetate recrystallization, faint yellow needle crystal, 4-brooethyl benzo bark we (15.3g).Productive rate is 77.6%, mp94-95 ℃.
Embodiment 2
4-formyl radical benzo furazan
4-brooethyl benzo furazan (19.7g, 0.1mol), DMSO 15ml, (10g 0.12mol) adds in the reaction flask sodium bicarbonate.Be heated to 100-150 ℃ under the nitrogen protection.Reaction is finished, and is cooled to room temperature, water, ethyl acetate extraction.Merge organic layer, wash with saturated brine.Anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets light yellow solid 10.6g, yield 71.6%, mp 108-109 ℃.
Embodiment 3
Synthesizing of Darodipine
In three mouthfuls of round-bottomed flasks of 500mL, add 4-formyl radical benzo furazan (14.8g, 0.1mol), methyl aceto acetate (28g, 0.2mol), (15.8g, 0.2mol), under agitation in 70 ℃ of reactions, TLC follows the tracks of volatile salt.After reaction finishes, add 200ml water, reaction mixture merges organic layer with the ethyl acetate extraction of 200mL 3 times, washing, dry, decompression and solvent recovery, and cooling crystallization, recrystallization get yellow solid Darodipine 29.5g, productive rate 79.5%, mp 153-154 ℃. 1H-NMR(CDCl 3?400MHz)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)。
Being embodiments of the invention only in sum, is not to be used for limiting practical range of the present invention.Be that all equivalences of doing according to the content of the present patent application claim change and modification, all should be technology category of the present invention.

Claims (5)

1. one kind prepares the synthetic method that contains furazan lopps antihypertensive drug, it is characterized in that, comprises step:
A, in inert solvent, under the condition that initiator exists, use halogenating agent that 4-methyl benzo furazan is replaced halogenation, form 4-monochloromethyl benzo furazan;
B, in inert solvent, 4-monochloromethyl benzo furazan and oxygenant reacts, finally obtain 4-formyl radical benzo furazan
Hantzsch prepared in reaction Darodipine under the condition that catalyzer exists, takes place in C, 4-formyl radical benzo furazan and acetylacetic ester.
2. a kind of preparation according to claim 1 contains the synthetic method of furazan lopps antihypertensive drug, is characterised in that: inert solvent is meant tetracol phenixin, chlorobenzene in the steps A; Initiator is meant benzoyl peroxide, Diisopropyl azodicarboxylate; Halo reagent is meant bromine, NBS, NCS, 1,3-two bromo-5,5-dimethyl acetylurea;
3. a kind of preparation according to claim 1 contains the synthetic method of furazan lopps antihypertensive drug, be characterised in that: oxygenant is meant methyl-sulphoxide (DMSO), 5-N-oxide compound (DMAPO), N-pyridine oxide, trimethylamine oxide (TMAO), nitroparaffins sodium salt, NDMA pyridine oxide father-in-law salt among the step B.
4. a kind of preparation according to claim 1 contains the synthetic method of furazan lopps antihypertensive drug, is characterised in that: catalyzer is meant magnesium nitride, volatile salt, bicarbonate of ammonia, ammonium acetate among the step C.
5. a kind of preparation according to claim 1 contains the synthetic method of furazan lopps antihypertensive drug, is characterised in that: acetylacetic ester is meant methyl acetoacetate, methyl aceto acetate, ISOPROPYL ACETOACETATE among the step C.
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Cited By (2)

* Cited by examiner, † Cited by third party
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
CN103319432A (en) * 2013-06-28 2013-09-25 江苏倍达医药科技有限公司 Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan

Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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

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Title
朱燕等: "两步法合成间硝基苯甲醛", 《精细化工》, vol. 28, no. 2, 28 February 2011 (2011-02-28) *
王宏丽等: "邻硝基苯甲醛的合成方法综述", 《广东化工》, no. 5, 31 December 2005 (2005-12-31), pages 27 - 31 *

Cited By (3)

* Cited by examiner, † Cited by third party
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
CN103319432A (en) * 2013-06-28 2013-09-25 江苏倍达医药科技有限公司 Method for synthesizing isradipine medicament midbody 4-formyl benzo furazan
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

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