CN106117212B

CN106117212B - A kind of improved silaenafil synthesis technology

Info

Publication number: CN106117212B
Application number: CN201610468826.XA
Authority: CN
Inventors: 梁承武; 李善姬; 张林豪; 罗苗
Original assignee: Jilin Medical College
Current assignee: Jilin Medical College
Priority date: 2016-06-25
Filing date: 2016-06-25
Publication date: 2019-10-11
Anticipated expiration: 2036-06-25
Also published as: CN106117212A

Abstract

The present invention relates to a kind of improved synthesis technologies of male erectile disorder [ED] bulk pharmaceutical chemicals silaenafil, it is characterized in that with different synthetic routes, so that N methyl piperazine reaction occurs in water for compound (I), crystallization is directly realized by by adjusting pH value, obtain pure compound (IV), it is swift in response, no coupling product；Compound (IV) under alkaline condition, is reacted in solvent miscible with water, after reaction, is reached direct crystallization by the way that dilute hydrochloric acid adjusting pH value is added, is obtained pure silaenafil.The synthesis technology for preparing silaenafil is easy to operate, reaction condition is mild, yield is high, with high purity, is suitble to industrialized production.

Description

A kind of improved silaenafil synthesis technology

Technical field

The present invention relates to a kind of synthesis technologies of male erectile disorder [ED] bulk pharmaceutical chemicals silaenafil, belong to medical science neck Domain is especially first condensed, sulfonating chlorinating, then carries out N methyl piperazine reaction and cyclization reaction in water.

Background technique

Silaenafil (Sildenafil), chemical name are as follows: and 5- [2- ethyoxyl -5-(4- methyl piperazine -1- sulfonyl) benzene Base] -1- methyl -3- n-propyl -1,6- dihydro -7H- pyrazolo [4,3-d] pyrimidin-7-ones.Silaenafil is earliest for treating The drug of male ED, the mechanism of action are mainly that high selectivity inhibits PED5, improve cGMP level, penis discharges the effect of NO It improves, so that corpus cavernosal smooth muscle relaxation, increases penile blood flow amount and erect.

The document (Shenyang Pharmaceutical University's journal, 2002,19(3) of domestic report at present, 173-175 etc.) in it is mainly following Route 1, as shown in Figure 1:

The route uses " route " synthesis mode, and synthetic route is long, and gross production rate is low；The last two steps use in synthetic route Toxic high chlorosulfonic acid reagent, the residual of reagent is so that need repeatedly processing to can be only achieved quality standard.

The synthetic route 2 of United States Patent (USP) US673719B1, as shown in Figure 2:

Although avoiding rear two-step reaction in the synthetic route uses the high poisonous reagent such as sulfonic acid chloride, with N, N- carbonyl Diimidazole (CDI) needs the reaction time of 70h or so, greatly reduces combined coefficient；Use stickiness opposite during cyclization The biggish tert-butyl alcohol, reaction finally need to handle solvent to reach quality standards.

The synthetic route 3 of European patent EP 1002798A1, as shown in Figure 3:

Two steps use the high poisonous reagents such as sulfonic acid chloride after the synthetic route also avoids, but when synthesizing compound (IV), With heterogeneous system methylene chloride-water, need first to dissolve in methylene chloride substrate, N methyl piperazine is soluble in water, Then in hybrid reaction, the post-processing that subsequent reactions terminate is also more troublesome；Final step uses that stickiness is big and boiling point is high 1,3-BDO makees solvent, and product solvent residual amount is difficult to the requirement that reaches quality standards.

The present inventor has several patents announcement in the research later period discovery country, and wherein patent CN105085526A uses route (2) advantage is larger, but makees solvent in synthesis compound (IV) Shi Yunyong methylene chloride, in heterogeneous solvent when adjusting pH value Middle progress, it is complicated for operation, and exist in final step cyclization process, it needs to be extracted repeatedly with ethyl acetate, reduced pressure etc. is numerous Trivial step improves the difficulty for further industrializing amplification；The present inventor should have been surprisingly found that when carrying out N methyl piperazine, product In water with the reduction of pH value, yield can be increased significantly；And during cyclization, it equally may be implemented to adjust pH value realization Crystallization.

Summary of the invention

For the limitation that the above reaction route respectively has, the present inventor carries out the synthesis route (3) of silaenafil It improves, in rear two step of synthesis technology, realizes and crystallization is precipitated twice, and chlorosulfonic acid in reaction process is successfully made to react high poisonous substance Residue be eliminated, so that products pure degree is reached quality standards.

The present invention solves the above technical problem and is realized with following technique:

A kind of synthesis route of the silaenafil improved, as shown in Figure 4:

Compound (I) directly reacts in water as solvent in reaction route, and N methyl piperazine reaction is added, controls pH value, Crystal ice water washing is precipitated, filters, obtains compound (IV) dried for standby.

Alkaline matter is added in the solution for being dissolved in water and dissolving each other in compound (IV), reaction a period of time, under cryogenic, Bronsted acid is added, crystallization is directly precipitated, obtains pure silaenafil compound.

First step reaction, compound (I) are added to the water dissolution, and under cryogenic conditions, N methyl piperazine is slowly added dropwise, stirs one After the section time, under condition of ice bath, with dilute acid for adjusting pH value, crystallization, filtering is precipitated；The dosage of water is 10 ~ 50 equivalents；Mixing time For 2 ~ 5h；It is 2 ~ 6 that pH value, which obtains range,.

Second step reaction, compound (IV) are poured into solvent, and alkaline matter, heating 3 ~ 8h of reaction is added, and cooling is added After distilled water stirs a period of time, pH value is adjusted equal to 7 with dilute hydrochloric acid, under cryogenic conditions, pure white solid is precipitated；Wherein Solvent can be the mixing of one or more of methanol, acetone, ethylene glycol, isopropanol, glycerine etc.；Alkaline matter can be first Sodium alkoxide, potassium methoxide, ethylene glycol sodium, ethylene glycol potassium, sodium isopropylate, potassium isopropoxide, propionic acid sodium alkoxide, glycerine potassium, sodium bicarbonate, carbon The mixture of one or more of sour sodium, potassium carbonate etc.；The amount of solvent is 15 ~ 30 equivalents；The amount of alkaline matter is worked as 0.3 ~ 3 Amount；The amount of dilute hydrochloric acid is 2% ~ 50%.

The advantages of the present invention over the prior art are that:

1. using water as solvent most cheap and easy to get in first step reaction, N methyl piperazine need to only be added, adjust pH and be precipitated Crystallization is directly filtered, and eliminates the complex operations of heterogeneous system's reaction and cumbersome post-processing step in document, crystallization, which is precipitated, to be made The purity of product is higher and occurs without by-product, and the reaction time is shorter, and reaction condition is room temperature, not only increases labour Efficiency and utilization rate of equipment and installations, there are no additional energy consumptions.

2. during cyclization, using solvent miscible with water, after the completion of reaction, directly plus water, exist in low temperature, dilute hydrochloric acid Under conditions of be precipitated crystallization, filtering, do not need to extract in document, the operating procedure that concentrated by rotary evaporation etc. is more troublesome, and be precipitated knot The advantages that brilliant silaenafil products pure degree is high, reaches quality standards, at low cost, yield is high, with high purity, easy to operate, fits Close industrial amplification production.

The problem of originally a direct step can carrying out in water in two steps of the invention, but considering degree of purity, use two steps The method that crystallization is precipitated, substantially increases the degree of purity of silaenafil.

Detailed description of the invention

Fig. 1 is the principal synthetic routes of domestic report synthesis silaenafil；

Fig. 2 is the route of United States Patent (USP) US673719B1 synthesis silaenafil；

Fig. 3 is the route of European patent EP 1002798A1 synthesis silaenafil；

Fig. 4 is the process route of present invention synthesis silaenafil；

Fig. 5 is the yield and purity table figure of compound (IV) under different pH condition.

Specific embodiment

Below with reference to example, invention is further explained, but following explanation does not limit not invention scope.

Embodiment 1:

Compound (I) 100g is taken, is added in 100ml water and dissolves, later under condition of ice bath, N- methyl piperazine is slowly added dropwise Piperazine.28.6g reacts at room temperature 3h, dilute acid for adjusting pH value is added dropwise in 3 ~ 4 ranges, and crystallization 1h is precipitated, and filtering is washed with a small amount, Dry intermediate (IV) 110.6g, yield 95%.

According to the method for embodiment 1, the yield and purity for the intermediate (IV) for adjusting pH value to obtain in different values are summarized such as Shown in Fig. 5.

Embodiment 2:

Compound (IV) 50g is taken, is added in 167.1g isopropanol, potassium isopropoxide 12.3g, back flow reaction are added later 6h is cooled to room temperature, and ice water 330ml is added, and the dilute hydrochloric acid for being added 10% adjusts pH value equal to 7, crystallization is precipitated, filtration drying obtains Silaenafil 49.45g, yield 93.6%.

Claims

1. a kind of improved silaenafil synthesis technology, its feature is as follows:

N methyl piperazine reaction occurs in water with compound (I) for the first step, is directly realized by crystallization by adjusting pH value, obtains Pure compound (IV), is swift in response, no coupling product；Second step uses compound (IV) under alkaline condition, miscible with water Solvent in reacted, after reaction, by be added 2%~50% salt acid for adjusting pH value reach direct crystallization, obtain To pure silaenafil；

Described with the solvent that aqueous solution dissolves each other includes that methanol, acetone, ethylene glycol, isopropanol or glycerine are one such or several Mixing；

The structural formula of the compound (I) is

The structural formula of the compound (IV) is

2. a kind of improved silaenafil synthesis technology as described in claim 1, it is characterised in that first step reaction response It carries out in water, the pH value range that crystallization is directly precipitated is 2~6.

3. a kind of improved silaenafil synthesis technology as described in claim 1, it is characterised in that it is anti-that the first step reacts room temperature Answer 2~5h.

4. a kind of improved silaenafil synthesis technology as described in claim 1, it is characterised in that second step reacts basic species Matter includes sodium methoxide, potassium methoxide, ethylene glycol sodium, ethylene glycol potassium, sodium isopropylate, potassium isopropoxide, propionic acid sodium alkoxide, glycerine potassium, carbon The mixture of one or more of sour hydrogen sodium, sodium carbonate, potassium carbonate.

5. a kind of improved silaenafil synthesis technology as described in claim 1, it is characterised in that solvent in second step reaction Amount be 15~30 equivalents.

6. a kind of improved silaenafil synthesis technology as described in claim 1, it is characterised in that second step reaction；Basic species The amount of matter is 0.3~3 equivalent.