CN103772367B - Preparation method and the application thereof of Vilazodone Hydrochloride V crystal formation - Google Patents

Abstract

The invention discloses crystal form V of high-purity 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride The preparation method and application thereof comprise the following steps: 1) 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl)benzofuran-2- Dissolving formamide in an organic solvent to obtain a solution; 2) heating the solution obtained in step 1) to 30-60°C; 3) slowly adding dilute hydrochloric acid dropwise; 4) raising the temperature of the system obtained in step 3) to 40°C-reflux temperature; 5 ) Insulate and react the system obtained in step 4) for 0.5-12 hours; 6) filter to obtain the wet product of crystal form V; 7) vacuum-dry the wet product obtained in step 6) at a certain temperature to constant weight to obtain crystal form V. By adopting this technical solution, the process is simplified, the complexity of the existing V crystal preparation process is overcome, the occurrence of mixed crystals is avoided, and a method capable of obtaining high crystal purity, stable mass production, high yield, and easy Direct preparation method for industrial production.

Description

Preparation method and application of vilazodone hydrochloride V crystal form

technical field

The present invention relates to the preparation method of 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) benzofuran-2-carboxamide hydrochloride type V and application.

Background technique

5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride (Vilazodone Hydrochloride) , is an antidepressant developed by ClinicalDate, which was approved by the U.S. Food and Drug Administration (FDA) on January 21, 2011. It is used to treat moderate to severe depression in adults. Its trade name is Viibryd. The structural formula is shown in Figure 6.

Vilazodone hydrochloride is a dual-action potent and selective serotonin (5-HT) reuptake inhibitor and 5-HT1A receptor partial agonist, and it is also the first new type of indolealkylamine antidepressant , compared with the existing clinical antidepressants, it has the characteristics of rapid onset of action and no side effects of sexual dysfunction, so it has important practical value in the research of its preparation technology.

5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzo A series of polymorphs of furan-2-carboxamide hydrochloride, including 15 crystals such as solvate (6 types), hydrate (3 types), dehydrate (4 types), dihydrochloride and amorphous type, as shown in Figure 7.

Generally, products in crystalline form have many advantages, such as reducing the hygroscopicity of the drug; having better fluidity, handling and compressibility during the tableting process; having better thermodynamic stability, that is, resistance to heat and humidity stability; better resistance to sunlight (UV light); increased bulk density; improved solubility; improved consistency of bioavailability between batches. The various crystal forms of vilazodone hydrochloride reported in the patent ZL02812226.7 have relatively large differences in solubility and thermodynamic stability and other physical and chemical properties, and the solvates are difficult to obtain through conventional methods because of their organic solvents. If it is removed, it is easy to cause its dissolution residue to exceed the standard in the process of druggability research, which cannot meet the control requirements of modern pharmaceutical research for solvent residues. Amorphous substances are prone to crystal transformation in the later preparation process due to their unstable crystal state, which is not conducive to the stability of the process. Hydrates and dehydrates do not have the problems of dissolution residue and stability, but their bulk density, solubility and other influencing factors still need to be considered in the process of druggability research.

5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride Form V in hydrate, in The solubility in water is 0.18 mg/mL (see Document 2 for details: Rik Lostritto, ONDQA Division I, DPAMS, Center for Drug Evaluation and Research, Application number: 022567Orig1s000, Chemistry Review (s) (ReferenceID: 2888631), Document 3: Pei-IChu, NDA22-567, Vilazodone10,20 ,40mgTabletsPGxHealth,LLC,October30,2010P7of147(ReferenceID:2859217)) The V crystal form obtained is a white solid substance, which is a reproducible and relatively stable crystal form, considering its advantages in dissolution, solubility and stability , which has a great possibility of becoming a drug, so it is an advantageous crystal form.

The relevant reports on the solubility of V crystal form in Example 16 of Chinese invention patent application ZL02812226.7 are as follows:

AlexAvdeef et al., Pharm.Pharmacol.Commun. 1998, 4, 165-178 and AlexAvdeef et al., Pharmaceutical Research 2000, 7, 5-89, Solubility data for Forms II, III, IV, V and VIII via potentiometric titration.

Solubility data expressed in mg/ml Type I Type II Type III Type IV V type Type VI Type VIII 0.08 0.03 0.12 0.33 0.18 0.23 0.10

Chinese invention patent application ZL02812226.7 and its divisional application CN200710180229 for hydrates all report the preparation method of vilazodone hydrochloride V crystal form, including the direct preparation of vilazodone hydrochloride in concentrated hydrochloric acid, through IV type crystallization and Through three methods such as type XIII transformation. The corresponding examples are excerpted as follows (ZL02812226.7 Specification Example 7, pages 24-25/40):

method 1

Add 2.1 g of hydrochloric acid ( 37% by weight), after stirring, the precipitated crystals were suction-filtered and dried to constant weight in vacuum at room temperature to obtain 5-(4-(4-(5-cyano-3-indolyl) butyl )-1-piperazinyl)benzofuran-2-carboxamide hydrochloride hydrate type V.

Method 2

2.25g 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) benzofuran-2-carboxamide hydrochloride type IV was dispersed in 10 to ( bis) in 20 g of water, after stirring for 24 to 48 hours, the crystals were recovered by filtration, and dried in vacuum at room temperature to constant weight to obtain 5-(4-(4-(5-cyano-3-indolyl) butyl)- 1-piperazinyl)benzofuran-2-carboxamide hydrochloride hydrate type V.

Method 3

Disperse 10 g of 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide dihydrochloride Form XIII in 1 L of water, After stirring for 48 hours, the crystals were recovered by filtration and dried in vacuum at room temperature to constant weight to obtain 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzene And furan-2-carboxamide hydrochloride hydrate type V.

Among the above-mentioned three preparation methods of Form V, Method 1 uses vilazodone base and concentrated hydrochloric acid to directly form a salt in an organic solvent to prepare Form V. The common point of Methods 2 and 3 is that other crystals of vilazodone hydrochloride Form V is obtained by vacuum drying and crystallization under different temperature conditions, which is very easy to cause the occurrence of mixed crystals. Compared with method 1, the preparation process of the V crystal is more complicated.

It should be pointed out that the V-type preparation method reported in ZL02812226.7 and CN200710180229 is insufficiently disclosed, and the crystallization temperature and other conditions that are critical to the preparation of the crystal form are hidden. According to the method of Example 7, under the condition of 37% by weight of concentrated hydrochloric acid , it is difficult to prepare V crystal form of vilazodone hydrochloride.

Although the method 1 reported in ZL02812226.7 and CN200710180229 is direct preparation, its solvent tetrahydrofuran consumption is very large, and the ratio of vilazodone and solvent tetrahydrofuran exceeds 1:30 (weight/volume), and the price of tetrahydrofuran is higher in addition, this Undoubtedly, the cost of the process will be greatly increased. Even if it can be recycled, it will also increase the energy consumption of the entire preparation process of the product, which will also limit the batch output of the enlarged production. Generally speaking, the three methods reported in ZL02812226.7 and CN200710180229 have their obvious disadvantages and limitations, namely high cost, complex process, and easy to cause mixed crystals.

In summary, because the drugs listed in the U.S. use type IV of vilazodone hydrochloride, ZL02812226.7 and CN200710180229 also reported that type IV and type V can be interconverted under certain conditions, and type V has the advantages of druggability. The potential advantage of the potential advantages, and many deficiencies of the existing known V-type preparation methods, so that the direct preparation method of a low-cost, easy-to-operate, and suitable for industrial production of vilazodone hydrochloride V-type has unique creativity, and it will definitely be realized. Double harvest of economic and social benefits.

In view of this, the inventor combined years of experience in the field of research on the production of vilazodone hydrochloride and its derivatives to conduct long-term research on the defects in the above-mentioned technical field, and this case came about.

Contents of the invention

The main purpose of the present invention is to provide 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) benzofuran-2-carboxamide hydrochloride type V The preparation method and application thereof, to overcome existing technical defects.

In order to solve the above technical problems, the present invention is achieved through the following technical solutions:

The preparation method and application of 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride type V, including Follow the steps below:

1) Dissolve 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide in an organic solvent at a certain temperature , to obtain a solution; wherein the dissolution temperature is 5-45 ° C, the organic solvent volume (unit: milliliter): 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piper The weight of azinyl)benzofuran-2-carboxamide (unit: gram) is 15-50:1;

2) Warm up the solution obtained in step 1) to 30-60°C;

3) Slowly add dilute hydrochloric acid dropwise, wherein the mass concentration of dilute hydrochloric acid is 2-5%, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl) The weight of benzofuran-2-carboxamide (unit: gram): the weight of dilute hydrochloric acid (unit: gram) is 1:1.8-4.5;

4) heating up the system obtained in step 3) to 40°C-reflux temperature;

5) Insulate and react the system obtained in step 4) for 0.5-12 hours;

6) Filtration to obtain the V crystal form wet product;

7) Vacuum-dry the wet product obtained in step 6) at a certain temperature to a constant weight to obtain Form V.

Further, the technical solution of the present invention is preferably:

In step 1), the certain temperature refers to room temperature, and the dissolution temperature is preferably 15-35°C; the organic solvent is preferably tetrahydrofuran; the organic solvent volume (unit: milliliter): 5-(4-(4-(5-cyano- The weight ratio of 3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide (unit: gram) is preferably 20-30:1;

In step 2), the heating range is preferably 30-45°C;

In step 3), the mass concentration of dilute hydrochloric acid is preferably 2.5-4.0%, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran- The ratio of 2-formamide weight (unit: gram): dilute hydrochloric acid weight (unit: gram) is preferably 1:2.0-3.3;

In step 4), the heating interval is preferably 45-55°C;

In step 5), the preferred heat preservation reaction time is 1.0-3.0 hours;

In step 7), preferably, the vacuum drying temperature is preferably 20-35° C., and the drying time is preferably 6-24 hours.

Wherein, the above-mentioned preparation method, as a key step, can be used to prepare vilazodone and pharmaceutically acceptable salts thereof.

Among them, the above-mentioned preparation method is used as a key step in the manufacture of the drug, which can be used for the treatment and prevention of depression, anxiety, bipolar disorder, mania, dementia, mental disorders related to psychoactive substances, functional disorders, eating disorders , obesity, fibromyalgia, sleep disorders, psychotic disorders, cerebral infarction, tension, side effects of hypertension treatment, brain disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, Presyndrome and unwanted postpartum lactation etc.

Adopt this technical scheme, the present invention obtains following beneficial technical effect: the first, can be by a certain proportion of 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) Benzofuran-2-carboxamide and dilute hydrochloric acid are directly prepared to obtain V-type hydrochloride, which simplifies the process and greatly overcomes the existing 5-(4-(4-(5-cyano-3-indolyl) butane base)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride V crystal form preparation process of high cost, high energy consumption, complex operation and other issues; second, effectively solved the problem that the product is easy to mix crystals, The occurrence of mixed crystals is avoided; thirdly, the process can be stably enlarged, easy to industrialized production, and the product crystal form has high purity, which has significant creativity and practical application value; fourthly, it provides a method that can obtain high crystal form purity and can A direct preparation method with stable mass production, high yield and easy industrial production.

In order to further explain the technical solution of the present invention, the present invention will be further described in detail below in conjunction with the accompanying drawings and embodiments.

Description of drawings

Figure 1: X-ray diffraction data of Form V reported in patent CN200710180229;

Figure 2: X-ray diffraction pattern of Form V reported in patent CN200710180229;

Fig. 3: the X-ray diffractogram of embodiment one gained product;

Fig. 4: the X-ray diffraction pattern of the product obtained in embodiment two;

Fig. 5: the X-ray diffractogram of embodiment three gained products;

Figure 6: Structural formula of VilazodoneHydrochloride;

Figure 7: 15 crystal forms of 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide hydrochloride induction;

Figure 8: Key parameters for X-ray diffraction detection.

detailed description

Specifically, the present invention relates to 5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) benzofuran-2-carboxamide as raw material, in Preparation of high-purity 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran- The method and application of V crystal form of 2-formamide hydrochloride.

The implementation of the present invention will be further described in detail below in conjunction with the accompanying drawings.

Embodiment 1 (20120901)

At room temperature, tetrahydrofuran (124.0ml) was added into a three-necked flask, and 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran was added under stirring -2-Carboxamide (4.96g), stirred at 35-40°C until dissolved, then slowly added 3.5% dilute hydrochloric acid (11.52g) dropwise, after dropping, stirred at 45-50°C for 1 hour, filtered to obtain a white solid wet The product was put into a vacuum oven at 25-30° C. and dried under reduced pressure to constant weight to obtain a dry product (5.10 g, 95.0%). The X-ray diffraction pattern is shown in Figure 3.

Embodiment two (batch number 20120902)

At room temperature, tetrahydrofuran (4000.0ml) was added into a three-necked flask, and 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran was added under stirring -2-Carboxamide 159.72g), stirred at 35-40°C until dissolved, then slowly added 3.5% dilute hydrochloric acid (360.32g) dropwise, after dropping, stirred at 45-50°C for 5 hours, filtered to obtain a white solid wet product , placed in a vacuum oven at 5-30° C. and dried under reduced pressure to constant weight to obtain a dry product (160.23 g, 92.65%), whose X-ray diffraction pattern is shown in Figure 4.

Example Three (20120903)

At room temperature, tetrahydrofuran (1900ml) was added into a three-necked flask, and 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran was added under stirring- 2-Carboxamide (75.61g), stirred at 35-40°C until dissolved, then slowly added 3.5% dilute hydrochloric acid (171.23g) dropwise, after dropping, stirred at 45-50°C for 12 hours, filtered to obtain a white solid wet product , placed in a vacuum oven at 5-30°C and dried under reduced pressure to constant weight to obtain a dry product (74.65g, 91.18%), the X-ray diffraction pattern of which is shown in Figure 5.

The above preparation method, as a key step, can be used to prepare vilazodone and pharmaceutically acceptable salts thereof.

The above-mentioned preparation method serves as a key step in the manufacture of a drug that can be used for the treatment and prevention of depression, anxiety, bipolar disorder, mania, dementia, mental disorders related to psychoactive substances, functional disorders, eating disorders, obesity , fibromyalgia, sleep disorders, psychotic disorders, cerebral infarction, tension, side effects of hypertension treatment, brain disorders, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome symptoms and unwanted postpartum lactation, etc.

Among them, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide is passed through 5-(piperazin-1-yl ) Benzofuran-2-carboxamide (CAS No.: 183288-46-2) and 3-(4-chlorobutyl)-5-cyanindole (CAS No.: 143612-79-7) ; 1-[4-(5-cyanindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine was produced by Hangzhou Hesu Chemical Technology Co., Ltd. Provided, batch number: 20120506, purity >99.5%; tetrahydrofuran was purchased from Zhejiang Changqing Chemical Co., Ltd., batch number: 20120518, industrial grade; concentrated hydrochloric acid was purchased from Shanghai Sanying Chemical Reagent Co., Ltd., batch number: 20120301, analytically pure; vacuum drying oven It is Shanghai Jinghong Experimental Equipment Co., Ltd., model: DZF-6020.

X-ray diffraction:

Detector: Zhejiang Sci-tech University

Main detection equipment: BrukerD8DiscoverXRD.

The key parameters are shown in Figure 8.

Testing environment: temperature 23°C; humidity 62%RH

The above descriptions are only specific embodiments of the present invention, and are not limitations to the design of this case. All equivalent changes made according to the design key of this case all fall within the scope of protection of this case.

Claims (1)

The preparation method of 1.5-(4-(4-(5-cyano-3-indolyl) butyl)-1-piperazinyl) benzofuran-2-carboxamide hydrochloride type V is characterized in that : Including the following steps: 1) Dissolve 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-carboxamide in an organic solvent at a certain temperature , to obtain a solution; where the temperature of dissolution is 15-35 ° C, tetrahydrofuran and 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran- The ratio of 2-formamide is 20-30:1, wherein, the volume unit of tetrahydrofuran is ml, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl ) The weight unit of benzofuran-2-carboxamide is gram; 2) Warm up the solution obtained in step 1) to 30°C-45°C; 3) Slowly add dilute hydrochloric acid dropwise, wherein the mass concentration of dilute hydrochloric acid is 2.5-4.0%, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazine base) benzofuran-2-carboxamide to dilute hydrochloric acid ratio of 1:2.0-3.3, wherein, 5-(4-(4-(5-cyano-3-indolyl)butyl)-1- Piperazinyl) benzofuran-2-carboxamide weight unit is gram, dilute hydrochloric acid weight unit is gram; 4) Raise the temperature of the system obtained in step 3) to 45-55°C; 5) Insulate the system obtained in step 4) for 1.0-3.0 hours; 6) Filtration to obtain the V crystal form wet product; 7) The wet product obtained in step 6) was vacuum-dried at 20-35° C. to constant weight for 6-24 hours to obtain Form V; the X-ray diffraction pattern of Form V is shown in FIG. 5 .