CN106279109A - A kind of preparation method of azelnidipine - Google Patents

Abstract

The present invention relates to the preparation method of a kind of azelnidipine, belong to field of medicaments, open new way for synthesizing dihydro pyridines calcium antagonist.The method is with nitrile acetic acid as raw material, 2 amino 3 carboxyls 1 are synthesized successively through Pinner reaction, Hantzsch, 4 dihydro 6 methyl 4 (3 nitrobenzophenone) 5 isopropyl formates, prepare azelnidipine crude product with 1 benzhydryl 3 hydroxy azetidine hydrochlorate through DCC dehydration esterification again, turn crystalline substance further and obtain the azelnidipine of alpha-crystal form.

Description

A kind of preparation method of azelnidipine

Technical field

The present invention relates to the preparation method of a kind of azelnidipine, belong to pharmaceutical technology field.

Background technology

Azelnidipine (Azelnidipine) is Sankyo Co., Ltd of Japan and Ube Industries, Ltd's joint development A kind of dihydropyridine calcium channel blocker, has good antihypertensive function, lists in Japan first in May, 2003:

List of references about azelnidipine preparation method is a lot of the most both at home and abroad, such as European patent EP 0266922；China is specially Profit ZL87107150；Chem. Pharm. Bull.43(5), 1995, P788-796；The clear 63-253082 of TOHKEMY；JP Laid-Open 11-116570；Drug of Future Vol.15, NO.7,1990, P671-673 etc..The preparation method that these routes are provided It is all that (m-nitrobenzaldehyde a, isopropyl acetoacetate b) and compound c are in strong basicity by compound 3 or two synthesis material Under the conditions of, with isopropanol as solvent, the prepared azelnidipine of high temperature reflux reaction (as shown in reaction equation 1 or 2):

Reaction equation 1:

Reaction equation 2:

Wherein, the synthesis of compound c with epoxychloropropane and .alpha.-aminodiphenylmethane. as initiation material, through N-alkylation cyclization, esterification, Pinner reaction obtains:

Chinese patent 200510104895.4(page 7) preparation method that uses document to provide according to reaction equation 1 prepares Ah folding ground At ordinary times, finding complex operation, and yield, quality are the most undesirable, actual recovery only has about 15%, the yield provided with document 85.6% differs greatly.

Open closely related group etc. to disclose in " synthesis of antihypertensive nitrendipine " (" medical industry ", 1984,15:41) The reaction under conditions of dehydrated alcohol, backflow of 3-nitrobenzaldehyde, ethyl acetoacetate and β-amino crotonate generates nitre benzene Horizon:

Although the method has certain advantage when preparing nifedipine, but after β-amino crotonate is replaced with compound c But azelnidipine is hardly resulted in by the method.Its reason is probably: compound c chemical group is relatively big, chemical property compared to β-amino crotonate changes the most greatly, and ring butylamine and diphenyl make spatial obstacle increase, and has slackened the work of Hantzsch reaction Property.

Summary of the invention

It is an object of the invention to provide the preparation method of a kind of azelnidipine.

The technical scheme is that the preparation method of a kind of azelnidipine, it is characterised in that

The first step, can selectively be carried out

(1) compound 1 is under dehydrated alcohol, dry hydrogen chloride gas effect, reaction preparation amidine acetic acid 2, or

(2) .alpha.-aminodiphenylmethane. and epichlorohydrin reaction prepare compound 5；

Second step, compound 2 and compound 3 prepare compound 4 under alkali effect；

3rd step, compound 4 and compound 5 prepare azelnidipine by dehydration esterification.

According to the present invention, when preparing described compound 5, first .alpha.-aminodiphenylmethane. is stirred with epoxychloropropane at room temperature shading Mix to substrate reactions complete, then reaction system is transferred in autoclave heating, it is preferred that in autoclave, Stress control is at 1- 2MPa, reaction temperature controls at 150-160 DEG C.

According to the invention it is preferred to, alkali used by second step course of reaction is Feldalat NM.

According to the present invention, when the 3rd step compound 4 prepares azelnidipine with compound 5, esterification is anti-to use dehydrant to promote The carrying out answered, dehydrant is preferredN, N '-dicyclohexylcarbodiimide (DCC).

Traditional route is when being prepared compound c by compound 6, owing to there is ester exchange side reaction under the conditions of HCl/EtOH, Can produce following by-product:

When using route disclosed by the invention to prepare amidine acetic acid 2, then can avoid above-mentioned two by-product completely to finished product Impact:

The invention has the beneficial effects as follows, compound 4 is the key intermediate of synthesis azelnidipine, first by compound 2 and compound 3 This dihydropyridine parent nucleus is synthesized, when significantly reducing final step ring-closure reaction in linear type synthesis technique through Hantzsch The impurity existed is many, and purification difficulty is big, the low equal pressure of yield, and this strategy is more beneficial for improving product quality, meets medicinal mark Quasi need.

Detailed description of the invention:

Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but the present invention is not only limited to This.

Embodiment 1

First step Pinner is reacted

Dichloromethane 750g, dehydrated alcohol 65.65g(1.43mol it is sequentially added in reaction bulb) and nitrile acetic acid 120g (1.42mol) (compound 1), mix and blend, is cooled to-10 DEG C ~ 0 DEG C.It is passed through dry hydrogen chloride gas to saturated, insulation Reaction 8 ~ 12h is to terminal.Reduced pressure at room temperature recycling design, adds dichloromethane 600g in residue, and mix and blend being cooled to- 5 DEG C ~ 0 DEG C, being passed through dry ammonia to saturated, insulation reaction 3 ~ 5h is to terminal.Reduced pressure at room temperature recycling design is to doing to obtain amidine second Acid (compound 2) 137.4g.This step yield is 94.8%, and HPLC purity is 99.6%.

Second step Hantzsch reacts

Isopropanol 520g, amidine acetic acid 106g(1.04mol it is sequentially added in reaction bulb) (compound 2) and 288.6g (1.06mol) compound 3, mix to dissolve completely, are subsequently added Feldalat NM 57.3g(1.06mol), it is heated to backflow anti- Answer 6 ~ 8h.TLC monitors reaction end, is down to 0 ~ 5 DEG C, insulation crystallize 2 hours.Filter cake is collected by filtration, 50 ~ 60 DEG C of forced air dryings, Obtain 2-amino-3-carboxyl-1,4-dihydro-6-methyl-4-(3-nitrobenzophenone)-5-isopropyl formate (compound 4) 315.3g.This Step yield is 83.9%, and HPLC purity is 98.9%.

3rd step addition, cyclization

In reaction bulb, be sequentially added into methanol 400g .alpha.-aminodiphenylmethane. 270g(1.47mol), epoxychloropropane 142.5g (1.54mol), room temperature shading stirring reaction 48h, HPLC detection .alpha.-aminodiphenylmethane. surplus no more than 0.2% is considered as reaction end, will Feed liquid is transferred in autoclave, and under nitrogen protection, (pressure limit is: 1-2MPa) react 4 ~ 6h in 150 ~ 160 DEG C.Cooling To room temperature.Concentrating under reduced pressure falls the solvent of more 1/2 volume, and after being cooled to 0 ~ 10 DEG C, growing the grain 1h, is collected by filtration filter cake.By filter cake second Acetoacetic ester 125g pulls an oar, and sucking filtration obtains off-white color solid 251.4g(compound 5, it may be assumed that 1-benzhydryl-3-hydroxy azetidine Hydrochlorate).This step yield is 62.0%, and HPLC purity is 99.2%.

4th step esterification

Dichloromethane 2.17kg, compound (4) 271g(0.75mol it is sequentially added in reaction bulb) and compound (5) 215g (0.90mol), stirring mixing, it is cooled to 0 ~ 10 DEG C.It is slowly added toN, N '-dicyclohexylcarbodiimide, finishes, and continues insulation and stirs Mix 0.5 hour.Subsequently, being warming up to 50 ~ 60 DEG C, insulation reaction 8 ~ 10 hours is to reaction end.It is cooled to-5 ~ 5 DEG C, filters, subtract Pressure recycling design.In residue, add methanol 1.80L, recrystallization, obtain product 398.5g(azelnidipine crude product).This step yield Being 91.2%, HPLC purity is 99.6%.

5th step crude product refining

In reaction bulb, it is sequentially added into azelnidipine crude product 400g, ethyl acetate/normal hexane (2:1, V/V) 4L, stirring mixing, delays Slowly material dissolution it is warming up to.Adding activated carbon 20g, insulation decolouring 0.5h, filtered while hot, filtrate is cooled to 0 ~ 5 DEG C of crystallize.Cross Filter, collects product, and in air dry oven, 50 ~ 60 DEG C are dried.Obtain azelnidipine fine work 381.2g.This step yield is 95.3%, HPLC purity 99.7%.

This route total recovery is: 42.9%.

Claims (1)

1. the new preparation process of an azelnidipine, it is characterised in that:

The first step, can selectively be carried out

(1) compound 1 is under dehydrated alcohol, dry hydrogen chloride gas effect, reaction preparation amidine acetic acid 2, or

(2) .alpha.-aminodiphenylmethane. and epichlorohydrin reaction prepare compound 5；

Second step, amidine acetic acid 2 and compound 3 prepare compound 4 under alkali effect；

3rd step, compound 4 and compound 5 prepare azelnidipine by dehydration esterification；

Wherein, when preparing compound 5, first by complete to substrate reactions with epoxychloropropane at room temperature shading stirring for .alpha.-aminodiphenylmethane. Finish, then reaction system is transferred in autoclave heating, it is preferred that in autoclave, Stress control is in 1-2MPa, reaction temperature control System is at 150-160 DEG C.