CN103058879B - The preparation method of Agomelatine - Google Patents

Abstract

The present invention relates to technical field of medicine synthesis, be specifically related to a kind of preparation method of Agomelatine.To in magnetic force reactor, add cholamine solution 38.5 ~ 39.5L, formula (I) compound 5290 ~ 5305g and Raney/Ni catalyzer 519 ~ 521g, logical ammonia displacement, closed reactor, logical pressurized with hydrogen to 4.5 ~ 5MPa, check reactor resistance to air loss, temperature rises to 70 ~ 90 DEG C, stirring reaction 4 ~ 5h; After completion of the reaction, be cooled to 30 ~ 45 DEG C, in reactor, hydrogen is slowly emptying, and reaction solution extrudes through liquid outlet opening, load transfer container, filtration catalizer, filtrate decompression is distilled, concentrated end, be cooled to 25 ~ 35 DEG C, obtain oily matter, be i.e. formula (II) compound.The preparation method of Agomelatine of the present invention, preparation technology is simple and direct, is suitable for suitability for industrialized production, and yield is higher, effective Reaction time shorten.Meanwhile, process for refining is comparatively simple and direct, and product purity is higher.

Description

The preparation method of Agomelatine

Technical field

The present invention relates to technical field of medicine synthesis, be specifically related to a kind of preparation method of Agomelatine.

Background technology

Agomelatine is developed by Servier company, at present list marketing.Melatonin analogue Agomelatine (agomelatine) is first melatonin receptors agonist, is also serotonin 2C (S-HTx) receptor antagonist.Animal experiment and clinical study show that this medicine has antidepressant, anxiety, adjustment sleep rhythm and regulates physiological clock effect, and its untoward reaction is simultaneously few, has no adverse effects to sexual function, also have no withdrawal reaction.

The avidity Ki of melatonin and its acceptor MT1 and MT2 is respectively 8.85x10-11 and 2.63x10-11, Agomelatine is similar to it, people's melatonin receptors MT1 and MT2 of clone is also had to the avidity (Ki is respectively 6.15X10-11 and 2.68X10-11) of height.Clinical study shows, Agomelatine has good curative effect to patients with depression, and untoward reaction is considerably less.

The preparation technology of Agomelatine of the prior art, synthetic route is more, there is the defects such as yield is lower, severe reaction conditions, product purity are lower more.

Summary of the invention

The present invention is intended to overcome the technical problem existed in above-mentioned prior art, proposes a kind of yield high, is convenient to the preparation method of the Agomelatine of suitability for industrialized production.

The technical solution used in the present invention is as follows:

The preparation method of Agomelatine, is characterized in that, comprises the steps:

1., by formula (I) preparation of compounds of formula (II) compound

To in magnetic force reactor, add cholamine solution 38.5 ~ 39.5L, formula (I) compound 5290 ~ 5305g and Raney/Ni catalyzer 519 ~ 521g, logical ammonia displacement, closed reactor, logical pressurized with hydrogen to 4.5 ~ 5MPa, check reactor resistance to air loss, temperature rises to 70 ~ 90 DEG C, stirring reaction 4 ~ 5h;

After completion of the reaction, be cooled to 30 ~ 45 DEG C, in reactor, hydrogen is slowly emptying, and reaction solution extrudes through liquid outlet opening, load transfer container, filtration catalizer, filtrate decompression is distilled, concentrated end, be cooled to 25 ~ 35 DEG C, obtain oily matter, be i.e. formula (II) compound;

2., the preparation of formula (III) compound

In reaction vessel, add ethyl acetate 6.5 ~ 7.5kg, stir and oily matter is dissolved, measure 570 ~ 580ml concentrated hydrochloric acid and be added dropwise to fast in solution, separate out white solid, be cooled to 10 ~ 20 DEG C, stirring and crystallizing 5 ~ 6h;

Reaction solution is released, centrifugal, washing leaching cake, crushing filter cake, dry, obtains white solid powder, i.e. formula (III) compound;

3., the preparation of formula (IV) compound

Methylene dichloride 30 ~ 35kg, formula (III) compound 1195 ~ 1205g and triethylamine 1120 ~ 1125g is added successively in reaction vessel, stirring at room temperature 20 ~ 40min, be cooled to-5 ~ 5 DEG C, slow dropping Acetyl Chloride 98Min. 435 ~ 440g, drip process control temp 0 ~ 5 DEG C, dropwise and continue stirring 20 ~ 40min, be warming up to 30 ~ 40 DEG C, continue stirring reaction 8 ~ 10h;

Purified water 8 ~ 10kg is added in agitation condition downhill reaction liquid, stir 50 ~ 60 minutes, leave standstill 10 ~ 15 minutes, separatory, discards water layer, retain organic phase, wash twice with each 10 ~ 15kg of the saturated NaCl aqueous solution, merge organic phase, concentrating under reduced pressure, obtain off-white color Agomelatine crude solid powder, i.e. formula (IV) compound.

Preferably, the preparation method of described cholamine solution is: in reaction vessel, add 30 ~ 35kg dehydrated alcohol, stirring cools to-5 ~ 5 DEG C, ammonia is passed into below dehydrated alcohol liquid level, produce stable bubble, keep ventilation 2h, obtain cholamine solution, put into encloses container, 0 ~ 10 DEG C of preservation.

Further, the process for purification of described Agomelatine crude product is:

In reaction vessel, add toluene 3400 ~ 3500g, gac 58 ~ 62g, be heated with stirring to 75 ~ 80 DEG C, insulated and stirred 40 ~ 50min, while hot suction filtration;

Filtrate adds in clean container while hot, adds normal hexane 1315 ~ 1325g, and material is separated out, and is heated with stirring to 85 ~ 90 DEG C, makes it to dissolve;

Then be cooled to 0 ~ 15 DEG C, stirring and crystallizing 20 ~ 25h, suction filtration, filter cake crushes, dry, obtains white solid powder;

White solid powder is added in clean container, continue to add the dehydrated alcohol of 4 ~ 6 times amount and the purified water of 7 ~ 9 times amount, be heated with stirring to 75 ~ 80 DEG C and make solid entirely molten, obtain clear transparent solutions, stir 10 ~ 15min, by feed liquid in foldable filter element press-in crystallizer;

Be heated with stirring to 75 ~ 80 DEG C in crystallizer, stop stirring, gradient cooling to 0 ~ 5 DEG C, crystallize out;

Start and stir, smashed by the bulk crystals of precipitation, crystal solution is released, centrifugal, and filter cake crushes, dry, obtains white crystal, i.e. Agomelatine highly finished product.

The preparation method of Agomelatine of the present invention, preparation technology is simple and direct, is suitable for suitability for industrialized production, and yield is higher, effective Reaction time shorten.Meanwhile, process for refining is comparatively simple and direct, and product purity is higher.

Accompanying drawing explanation

Fig. 1 is synthetic route chart of the present invention.

Embodiment

Below in conjunction with embodiment and accompanying drawing 1, the present invention is further illustrated.

1., the preparation of cholamine solution

In 50L glass-lined reactor, add 32kg dehydrated alcohol, 50 ~ 80rpm cools to less than 5 DEG C under stirring, and ammonia is passed into below dehydrated alcohol liquid level, produce stable bubble, keep temperature less than 5 DEG C 2h that ventilate, obtain cholamine solution, put into encloses container, less than 10 DEG C preservations, for subsequent use.

2., by formula (I) preparation of compounds of formula (II) compound

By cholamine solution 39L through liquid addition pipeline vacuum suction 50L magnetic force reactor, 5 ~ 7Hz adds starting material 5300g and Raney/Ni catalyzer 520g successively through solid feed inlet under stirring, normal temperature and pressure leads to ammonia 30min to replace the air in still through intake ducting, air outlet is made to produce stable bubble, closed reactor, logical pressurized with hydrogen to 4.5 ~ 5MPa, checks reactor resistance to air loss, mixing speed is adjusted to 17 ~ 19Hz, and temperature rises to stirring reaction 4 ~ 5h under the condition of 70 ~ 90 DEG C.

After completion of the reaction, mixing speed is adjusted to 5 ~ 7Hz, and in reactor, logical water coolant makes reaction solution be down to less than 45 DEG C, and hydrogen in reactor is slowly emptying, then to inflated with nitrogen in reactor 10 minutes to replace the hydrogen in still; Reaction solution extrudes through liquid outlet opening by nitrogen pressurization 0.05 ~ 0.1MPa, load transfer container, with 250mm Büchner funnel filtration catalizer, filtrate is joined in batches in 50L glass-lined reactor, underpressure distillation, vacuum tightness is not less than 0.08MPa, concentrated end, retort interlayer leads to tap water, retort is cooled to less than 35 DEG C, obtain oily matter and be about 1.3kg, i.e. formula (II) compound.

3., the preparation of formula (III) compound

Ethyl acetate 7kg in 50L glass-lined reactor, stirs and oily matter is dissolved, measure 578ml concentrated hydrochloric acid and be added dropwise to fast in the middle of solution, and separate out white solid, reactor leads to refrigerated water and is cooled to less than 20 DEG C, stirring and crystallizing 5h.

Reaction solution is released, at the uniform velocity add SS450 type centrifuge, centrifugal filter cake is washed after rinsing reactor inwall with cold ethyl acetate 1kg, continue centrifugal 20 minutes, collect filter cake, crush, load ZD79-E type vacuum drying oven drying (50 ± 1 DEG C/0.098MPa) dry 4h, obtain white solid powder, i.e. formula (III) compound.

4., the preparation of formula (IV) compound

Methylene dichloride 32kg, formula (III) compound 1200g and triethylamine 1123g is added successively in 50L glass-lined reactor, stirring at room temperature 30min, by about reaction solution frozen cooling to 0 DEG C, slow dropping Acetyl Chloride 98Min. 436g, drip process control temp 0 ~ 5 DEG C, dropwise and continue to stir 30min, rise to 30 ~ 40 DEG C, continue stirring reaction 8h.

Reaction solution proceeds to 100L retort, adds purified water 9kg under stirring, stirs 55 minutes, leave standstill 10 minutes, separatory, discards water layer, retains organic phase, add 100L glass-lined reactor, wash twice with method with each 10kg of the saturated NaCl aqueous solution again, separate organic phase and add 50L glass-lined reactor concentrating under reduced pressure, obtain off-white color Agomelatine crude solid powder, i.e. formula (IV) compound, about 1200g.

5., Agomelatine crude product is refining

In 50L glass-lined reactor, add toluene 3456g, gac 60g, be heated with stirring to 80 DEG C, insulated and stirred 40min, with 250mm Büchner funnel suction filtration while hot.

Filtrate adds 100L glass-lined reactor while hot, in 100L glass-lined reactor, add normal hexane 1320g, and material is separated out, and is heated with stirring to 90 DEG C, makes it to dissolve.

Frozen cooling to 0 ~ 15 DEG C stirring and crystallizing 20h, with 250mm Büchner funnel suction filtration, filter cake crushes, and loads ZD79-E type vacuum drying oven vacuum-drying (50 DEG C/0.09MPa) 4h, obtains Agomelatine white solid powder and be about 1050g.

Take Agomelatine white solid powder, add 50L glass-lined reactor, continue to add the dehydrated alcohol of 5 times amount (w/w) and the purified water of 8 times amount (w/w), being heated with stirring to 75 DEG C makes solid entirely molten, obtain clear transparent solutions, stir 10min, by feed liquid through 0.45 μm of foldable filter element press-in 50L stainless steel crystallizer.

Start 50L stainless steel crystallizer hot water circulation, be heated with stirring to 75 DEG C.Stop stirring, close heater power source, keep hot water circulation to make below 50L stainless steel crystallizer gradient cooling to 5 DEG C separate out white crystal (1 DEG C/1h).

Start and stir, smashed by the bulk crystals of precipitation, crystal solution is released, and with the flat centrifuge of PS300 type, collect filter cake and crush, with vacuum drying oven in 50 ~ 70 DEG C of vacuum-drying 18h, vacuum tightness is not less than 0.09MPa.

Obtain white crystal (Agomelatine highly finished product) about 900g, detect weight loss on drying < 0.5%.

Above content is only conceive example and explanation to the present invention; affiliated those skilled in the art make various amendment to described specific embodiment or supplement or adopt similar mode to substitute; only otherwise depart from the design of invention or surmount this scope as defined in the claims, protection scope of the present invention all should be belonged to.

Claims (2)

1. the preparation method of Agomelatine, is characterized in that, comprises the steps:

1., by formula (I) preparation of compounds of formula (II) compound

To in magnetic force reactor, add cholamine solution 38.5 ~ 39.5L, formula (I) compound 5290 ~ 5305g and Raney/Ni catalyzer 519 ~ 521g, logical ammonia displacement, closed reactor, logical pressurized with hydrogen to 4.5 ~ 5MPa, check reactor resistance to air loss, temperature rises to 70 ~ 90 DEG C, stirring reaction 4 ~ 5h;

After completion of the reaction, be cooled to 30 ~ 45 DEG C, in reactor, hydrogen is slowly emptying, and reaction solution extrudes through liquid outlet opening, load transfer container, filtration catalizer, filtrate decompression is distilled, concentrated end, be cooled to 25 ~ 35 DEG C, obtain oily matter, be i.e. formula (II) compound;

2., the preparation of formula (III) compound

In reaction vessel, add ethyl acetate 6.5 ~ 7.5kg, stir and oily matter is dissolved, measure 570 ~ 580ml concentrated hydrochloric acid and be added dropwise to fast in solution, separate out white solid, be cooled to 10 ~ 20 DEG C, stirring and crystallizing 5 ~ 6h;

Reaction solution is released, centrifugal, washing leaching cake, crushing filter cake, dry, obtains white solid powder, i.e. formula (III) compound;

3., the preparation of formula (IV) compound

Methylene dichloride 30 ~ 35kg, formula (III) compound 1195 ~ 1205g and triethylamine 1120 ~ 1125g is added successively in reaction vessel, stirring at room temperature 20 ~ 40min, be cooled to-5 ~ 5 DEG C, slow dropping Acetyl Chloride 98Min. 435 ~ 440g, drip process control temp 0 ~ 5 DEG C, dropwise and continue stirring 20 ~ 40min, be warming up to 30 ~ 40 DEG C, continue stirring reaction 8 ~ 10h;

Purified water 8 ~ 10kg is added in agitation condition downhill reaction liquid, stir 50 ~ 60 minutes, leave standstill 10 ~ 15 minutes, separatory, discards water layer, retain organic phase, wash twice with each 10 ~ 15kg of the saturated NaCl aqueous solution, merge organic phase, concentrating under reduced pressure, obtain off-white color Agomelatine crude solid powder, i.e. formula (IV) compound;

The preparation method of described cholamine solution is: in reaction vessel, add 30 ~ 35kg dehydrated alcohol, stirs and cools to-5 ~ 5 DEG C, ammonia is passed into below dehydrated alcohol liquid level, produce stable bubble, keep ventilation 2h, obtain cholamine solution, put into encloses container, 0 ~ 10 DEG C of preservation.

2. the preparation method of Agomelatine according to claim 1, is characterized in that, the process for purification of described Agomelatine crude product is:

In reaction vessel, add toluene 3400 ~ 3500g, gac 58 ~ 62g, be heated with stirring to 75 ~ 80 DEG C, insulated and stirred 40 ~ 50min, while hot suction filtration;

Filtrate adds in clean container while hot, adds normal hexane 1315 ~ 1325g, and material is separated out, and is heated with stirring to 85 ~ 90 DEG C, makes it to dissolve;

Then be cooled to 0 ~ 15 DEG C, stirring and crystallizing 20 ~ 25h, suction filtration, filter cake crushes, dry, obtains white solid powder;

White solid powder is added in clean container, continue to add the dehydrated alcohol of 4 ~ 6 times amount and the purified water of 7 ~ 9 times amount, be heated with stirring to 75 ~ 80 DEG C and make solid entirely molten, obtain clear transparent solutions, stir 10 ~ 15min, by feed liquid in foldable filter element press-in crystallizer;

Be heated with stirring to 75 ~ 80 DEG C in crystallizer, stop stirring, gradient cooling to 0 ~ 5 DEG C, crystallize out;

Start and stir, smashed by the bulk crystals of precipitation, crystal solution is released, centrifugal, and filter cake crushes, dry, obtains white crystal, i.e. Agomelatine highly finished product.