CN103159671A

CN103159671A - Method for scale lercanidipine hydrochloride preparation

Info

Publication number: CN103159671A
Application number: CN2011104062728A
Authority: CN
Inventors: 吴锋; 陈锋; 贺莲; 张静; 朱敏; 陈敏; 周江; 杨述; 刘栋华; 罗玲; 唐清萍
Original assignee: Kamp Pharmaceuticals Co Ltd
Current assignee: Kamp Pharmaceuticals Co Ltd
Priority date: 2011-12-09
Filing date: 2011-12-09
Publication date: 2013-06-19

Abstract

The present invention relates to a lercanidipine hydrochloride preparation method, which comprises the following steps that: m-nitrobenzaldehyde, methyl acetoacetate and ammonium bicarbonate are subjected to a reaction in methanol, and cooling and suction filtration are performed to obtain 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (DHPCOOCH3); in the presence of methanol, DHPCOOCH3 reacts with a sodium hydroxide solution to obtain 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (DHPCOOH); and the DHPCOOH, triethylamine, diethyl chlorophosphate, and a side chain of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol form an ester and a hydrochloride in a methylbenzene solution to prepare the lercanidipine hydrochloride, wherein the 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol is lercanidipine.

Description

A kind of mass-producing prepares the method for R-75

Technical field

The invention belongs to the fine chemical product production field, particularly a kind of preparation technology of R-75, purposes produce the hypertension medicine.

Background technology

Chemistry by name 1 at R-75 (Lercanidipine hydrochloride), 4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 2-[N-(3,3-two hydrocinnamyl) methylamino--1,1-dimethyl ethyl methyl ester hydrochloride (structural formula is seen Fig. 1), it is a kind of third generation calcium ion antagonist of high selectivity, have close ester, height endurability, the advantage such as plasma half-life is short, curative effect is lasting and adverse reaction rate is low, in being applicable to, mild hypertension.

As existing preparation method, introduced in U.S. Patent No. 4705797 with compound N-methyl-3, the 3-diphenylpropylamine is starting raw material, react in dimethylbenzene with the 1-chloro-2-methyl-2-propanol and obtain side chain alcohol (structural formula is seen Fig. 2), then with after the ketene dimer esterification carry out condensation with m-nitrobenzaldehyde, condensation product and amino methyl crotonate cyclization get target compound lercanidipine (structural formula is seen Fig. 3), and its reaction principle is seen Fig. 4.In this route, the final step by product is many, and purification need to be difficult to industrialized technology with column chromatography etc., and the reactant ketene dimer is toxic, is difficult for transportation, and whole piece route productive rate is only 23%.

In document [synthesizing of R-75, fine chemistry industry, 2005,22(12): 950 ~ 952] take styracin, sulfur oxychloride, methylamine etc. as raw material, using CH2Cl2 instead is solvent, the KBH4/ZnCl2 reducing amide first extracts redistillation with product with ethyl acetate, in whole process without side reaction, the reaction easy handling, aftertreatment is simple, is easier to industrialization, but its 6 step overall yield is only 23.2%.

In document [synthesizing of R-75, Chinese Journal of Pharmaceuticals, 2008,39(1): 3 ~ 6], with iso-butylene, m-nitrobenzaldehyde and methyl acetoacetate etc. is raw material, through bromo, hydration, hydrolysis, the step such as chloride and esterification obtains R-75, and total recovery is 30%, but has used the thionyl chloride of toxicity and strong and stimulating.

Summary of the invention

The present invention is intended to overcome the weak point of existing R-75 synthesis technique; the preparation method of a kind of high yield, acquisition high-purity hydrochloric acid lercanidipine safe, pollution-free, with low cost, easy and simple to handle is provided; be fit to large-scale production, can satisfy the requirement of field of medicaments.

The concrete preparation process of the present invention is as follows:

(1) 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethyl dicarboxylate's (DHPCOOCH3) is synthetic: m-nitrobenzaldehyde and methyl acetoacetate react in methyl alcohol, add wherein ammoniacal liquor, ammonia or bicarbonate of ammonia, preferred bicarbonate of ammonia; Temperature of reaction is 55 ~ 60 ℃, preferred 58 ℃; Reaction times is 2 ~ 6 hours, preferred 5 hours.

(2) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-mono methyl dicarboxylate (DHPCOOH, structural formula is seen Fig. 5) synthetic: DHPCOOCH3 and sodium hydroxide solution (NaOH) react in methyl alcohol, the mol ratio of two reactant reactions can be selected 1:5 ~ 1:15, preferred 1:8; The massfraction of sodium hydroxide solution preferred 23.5%; Temperature of reaction is 70 ~ 80 ℃, preferred 75 ℃; Reaction times is 4 ~ 6 hours, preferred 5 hours.

(3) lercanidipine is synthetic: DHPCOOH and triethylamine or dicyclohexylcarbodiimide reaction, preferred triethylamine; Solvent is benzene, toluene or acetonitrile, preferred toluene; Reaction times is 4 ~ 6 hours, preferred 5 hours.

(4) R-75 is synthetic: lercanidipine and 6 N HCl solution or 2N HCl solution reaction, preferred 6 N HCl solution.After processing finally by dry, distillation, with tetrahydrofuran (THF), ethanol or glycol dimethyl ether recrystallization, preferred glycol dimethyl ether.

Reaction principle of the present invention is seen Fig. 6.

The present invention and R-75 synthesis technique ratio in the past, innovative point is as follows:

(1) the synthesis technique yield high (〉 40.0% that adopts);

(2) resulting R-75 purity high (〉 99.5%);

(3) avoided adopting the vitriol oil of severe corrosive and the thionyl chloride of strong and stimulating, increased security;

(4) cancel expensive 2-methallyl chloride as raw material, saved cost;

(5) in whole preparation process, without separation of intermediates, easy and simple to handle.

Description of drawings

Fig. 1 is the structural formula of R-75 of the present invention;

Fig. 2 is side chain alcohol 2, the structural formula of N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propyl alcohol;

Fig. 3 is the structural formula of lercanidipine;

Fig. 4 is reaction principle in U.S. Patent No. 4705797;

Fig. 5 is the present invention 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-mono methyl dicarboxylate's (DHPCOOH) synthetic structural formula;

Fig. 6 is reaction principle of the present invention.

Embodiment

(1) 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethyl dicarboxylate (DHPCOOCH ₃) preparation: get 5g (0.033mol) m-nitrobenzaldehyde, 8mL (0.072mol) methyl acetoacetate, 10mL ethanol, add in the there-necked flask of 100 mL, be warming up to 58 ℃ under stirring, add wherein 4g (0.05mol) bicarbonate of ammonia, 4mL water is stirred to without Bubble formation.The rising temperature adds zeolite, stirring and refluxing 5h.Cooling, suction filtration, drying, the yellow solid 9.4g that weighs.

(2) 2, 6-dimethyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-mono methyl dicarboxylate's (DHPCOOH) preparation: get 7.0g (0.02mol) DHPCOOCH3 and 120mL methyl alcohol in the 500mL there-necked flask, stir, 6.4g (0.16mol) the NaOH aqueous solution adds reaction flask after cooling, slowly be heated to 75 ℃ of back flow reaction 5h, underpressure distillation goes out part methyl alcohol, add 400mL water in residuum, add the 0.5g gac, stir half an hour under 55 ℃, suction filtration, filtrate is regulated pH=2.5 with 6N HCl solution, suction filtration, dry, get khaki color powder 3.89g, with recrystallizing methanol 2 times, get light yellow solid.

(3) preparation of R-75: get 5.0g (0.015mol) DHPCOOH, 2.6mL (0.018mol) triethylamine and 50mL toluene are in the 250mL there-necked flask, stir, drip 2.4mL (0.0166mol) diethyl chloro-phosphate under ice-water bath, drip off rear stirring reaction 3h, add 4.49g (0.015mol) 2 in batches, N-dimethyl-N-(3, the 3-diphenyl propyl)-1-amino-2-propyl alcohol is the lercanidipine side chain, back flow reaction 5h, steam except toluene, remaining oily matter dissolves with the ethyl acetate reflux, use successively 11mL10%NaOH solution, 11mL water, 13mL 6N HCl solution, the 11mL water washing, anhydrous sodium sulfate drying, get organic phase rotary evaporation solvent, get garnet oily matter, spent glycol dme recrystallization, add crystal seed, stir 24 ~ 96h crystallization in 25 ℃, suction filtration, filter cake is in 70 ℃ of dryings, 4.23g weighs to get, use again twice, THF recrystallization, get yellow solid (liquid chromatogram measuring purity is greater than 99.91%), fusing point is 186 ~ 188 ℃, the spectrum of product is consistent with bibliographical information.

Claims

1. the preparation method of a R-75 (Lercanidipine hydrochloride, formula I compound) is characterized in that comprising the following steps:

(1) m-nitrobenzaldehyde, methyl acetoacetate and bicarbonate of ammonia react in ethanol, obtain 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-dimethyl dicarboxylate (DHPCOOCH ₃);

(2) DHPCOOCH ₃React in methyl alcohol with sodium hydroxide solution, obtain 2,6-dimethyl-4-(3-nitrophenyl)-Isosorbide-5-Nitrae-dihydropyridine-3,5-mono methyl dicarboxylate (DHPCOOH);

(3) DHPCOOH and triethylamine, chlorine dimethyl phosphate and 2, N-dimethyl-N-(3,3-diphenyl propyl)-1-amino-2-propyl alcohol (lercanidipine side chain) reacts in toluene, obtains lercanidipine;

(4) lercanidipine and hydrochloric acid reaction, obtain R-75 through aftertreatment.

2. according to claim 1 method is characterized in that the reactant DHPCOOCH of preparation formula II (DHPCOOH) compound ₃With the ratio of sodium hydroxide solution amount of substance be 1:8.

3. according to claim 1 method, is characterized in that the massfraction of the reactant hydrogen sodium hydroxide solution of preparation formula II (DHPCOOH) compound is 23.5%.

4. according to claim 1 method, the reaction solvent that it is characterized in that preparation formula I R-75 compound is a kind of or its mixture in benzene, toluene, acetonitrile.

5. according to claim 1 method, is characterized in that the reactant of preparation formula I R-75 compound is triethylamine or dicyclohexylcarbodiimide.

6. method according to claim 1, is characterized in that final product is R-75.

7. according to claim 1 method, is characterized in that the solvent of preparation formula I R-75 compound recrystallization is tetrahydrofuran (THF), ethanol or glycol dimethyl ether.