CN103772367A - Preparation method and application of vilazodone hydrochloride V crystal - Google Patents
Preparation method and application of vilazodone hydrochloride V crystal Download PDFInfo
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- CN103772367A CN103772367A CN201210407180.6A CN201210407180A CN103772367A CN 103772367 A CN103772367 A CN 103772367A CN 201210407180 A CN201210407180 A CN 201210407180A CN 103772367 A CN103772367 A CN 103772367A
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- benzofuran
- butyl
- piperazinyl
- indyl
- cyano group
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- 239000013078 crystal Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- RPZBRGFNBNQSOP-UHFFFAOYSA-N vilazodone hydrochloride Chemical compound Cl.C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 RPZBRGFNBNQSOP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960003381 vilazodone hydrochloride Drugs 0.000 title claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000001291 vacuum drying Methods 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- -1 benzofuran-2-carboxamides hydrochloride Chemical class 0.000 claims description 20
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 208000020016 psychiatric disease Diseases 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 206010000599 Acromegaly Diseases 0.000 claims description 3
- 201000000736 Amenorrhea Diseases 0.000 claims description 3
- 206010001928 Amenorrhoea Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 3
- 208000000094 Chronic Pain Diseases 0.000 claims description 3
- 208000030814 Eating disease Diseases 0.000 claims description 3
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 3
- 208000001640 Fibromyalgia Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 206010058359 Hypogonadism Diseases 0.000 claims description 3
- 206010026749 Mania Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 231100000540 amenorrhea Toxicity 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 235000014632 disordered eating Nutrition 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000008267 milk Substances 0.000 claims description 3
- 210000004080 milk Anatomy 0.000 claims description 3
- 235000013336 milk Nutrition 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000028327 secretion Effects 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 206010029216 Nervousness Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- SGEGOXDYSFKCPT-UHFFFAOYSA-N vilazodone Chemical compound C1=C(C#N)C=C2C(CCCCN3CCN(CC3)C=3C=C4C=C(OC4=CC=3)C(=O)N)=CNC2=C1 SGEGOXDYSFKCPT-UHFFFAOYSA-N 0.000 abstract description 7
- 238000010438 heat treatment Methods 0.000 abstract 2
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 21
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960003740 vilazodone Drugs 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 3
- NJJWMEJWFYRORL-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(CCCCCl)=CNC2=C1 NJJWMEJWFYRORL-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000003918 potentiometric titration Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940001789 viibryd Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a preparation method and application of a high purity 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-formamide hydrochloride V crystal. The method comprises the steps of: 1) dissolving 5-(4-(4-(5-cyano-3-indolyl)butyl)-1-piperazinyl)benzofuran-2-formamide in an organic solvent to obtain a solution; 2) heating the solution obtained in step 1) to 30-60DEG C; 3) slowly adding diluted hydrochloric acid dropwise; 4) heating the system obtained in step 3) to a reflux temperature of 40DEG C) system of; 5) subjecting the system obtained in step 4) to heat preservation reaction for 0.5-12 hours; 6) conducting filtering to obtain a V crystal type wet product; and 7) carrying out vacuum drying to the wet product obtained in step 6) under certain temperature to a constant weight, thus obtaining the V crystal. By adopting the technical scheme, the process is simplified, and the complexity in the existing V crystal preparation process is overcome, and a mixed crystal can be avoided. The provided direct preparation method can achieve high crystal purity, stable production, high yield, and easy industrial production.
Description
Technical field
The present invention relates to preparation method and the application of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type.
Background technology
5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride is Vilazodone Hydrochloride (Vilazodone Hydrochloride), a kind of thymoleptic by the exploitation of Clinical Date company, January 21 in 2011 Nikkei U.S. food and Drug Administration (FDA) approval listing, be used for the treatment of grownup's middle major depressive disorder, commodity are called Viibryd, and its structural formula as shown in Figure 6.
Vilazodone Hydrochloride is potent and selectivity five hydroxytryptamine (5-HT) reuptake inhibitor and 5-HT1A acceptor portion agonist of a kind of dual function, also be first indolyl amine novel antidepressant, compared with clinical existing thymoleptic, have rapid-action, without features such as sexual dysfunction side effects, therefore its Study on Preparation is had to important practical value.
In patent WO2002/102794 (domestic ZL02812226.7 of the same clan) (document 1), introduce the serial polymorphic form of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride, comprise 15 kinds of crystal formations such as solvate (6 kinds), hydrate (3 kinds), dehydrate (4 kinds), dihydrochloride and amorphous substance, concrete conclusion as shown in Figure 7.
General, the product of crystal habit, has lot of advantages, if reduce the water absorbability of medicine; In compressing tablet process, there is better mobility, handling and compressibility; There is better thermodynamic stability, namely the stability to heat resistanceheat resistant and humidity; There is the better tolerance to daylight (UV light); Increase tap density; Improve solubleness; Improve the homoeostasis of multiple batches of bioavailability.The various crystal formations of Vilazodone Hydrochloride of reporting in patent ZL02812226.7, aspect each physico-chemical property such as solubleness and thermodynamic stability, there iing larger difference, solvate is wherein difficult to remove by ordinary method because of its contained organic solvent, easily cause its molten residual exceeding standard in patent medicine Journal of Sex Research process, cannot meet modern medicines and study the control requirement to dissolvent residual.Amorphous article, because of its crystal formation state labile, easily turns brilliant phenomenon in the preparation process in later stage, is unfavorable for the stable of technique.There is not the problem of molten residual and stability aspect in hydrate and dehydrate, but in patent medicine Journal of Sex Research process, still needs to consider the influence factors such as its bulk density, solubleness.
5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V crystal formation in hydrate, solubleness in water is that 0.18mg/mL(refers to document 2:Rik Lostritto, ONDQA Division I, DPAMS, Center for Drug Evaluation and Research, Application number:022567Orig1s000, Chemistry Review (s) (Reference ID:2888631), document 3:Pei-I Chu, NDA 22-567, Vilazodone 10, 20, 40mg Tablets PGxHealth, LLC, October 30, 2010 P7 of 147 (Reference ID:2859217)) the V crystal formation that obtains is white solid matter, belong to and repeat to determine and metastable crystalline form, consider that it is molten residual, the advantage of the aspect such as solubleness and stability, thereby have great patent medicine possibility, because of but advantage crystal formation thing.
As follows about the relevant report of V crystal formation solubleness in Chinese invention patent application ZL02812226.7 embodiment 16:
The people such as Alex Avdeef, Pharm. Pharmacol. Commun.1998,4, the people such as 165-178 and Alex Avdeef, Pharmaceutical Research 2000,7,5-89, via the dissolubility data of potentiometric titration measurement II, III, IV, V and VIII type.
Dissolubility data, represents with mg/ml
| I type | II type | III type | IV type | V-type | VI type | VIII type |
| 0.08 | 0.03 | 0.12 | 0.33 | 0.18 | 0.23 | 0.10 |
The divisional application CN200710180229 of Chinese invention patent application ZL02812226.7 and hydrate thereof has reported the preparation method of Vilazodone Hydrochloride V crystal formation, comprises by vilazodone directly preparation in concentrated hydrochloric acid, is turned brilliant and turned three kinds of methods such as crystalline substance by XIII type by IV type.Corresponding embodiment takes passages as follows (ZL02812226.7 specification sheets embodiment 7, the 24-25/40 pages):
In the 32.6g tetrahydrofuran solution of 1g 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides, add 2.1g hydrochloric acid (37 % by weight), after stirring, precipitated crystal is carried out to suction filtration, in room temperature vacuum, be dried to constant weight, obtain 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride hydrate V-type.
2.25g 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride IV type is dispersed in 10 to (bis) 20g water, stir after 24 to 48 hours, filtered and recycled crystal, in room temperature vacuum, be dried to constant weight, obtain 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride hydrate V-type.
10g5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides dihydrochloride XIII type is dispersed in 1L water, stir after 48 hours, filtered and recycled crystal, in room temperature vacuum, be dried to constant weight, obtain 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride hydrate V-type.
[0008] in above-mentioned three kinds of V crystal formation preparation methods, method 1 has been used vilazodone alkali and concentrated hydrochloric acid direct salify in organic solvent to prepare V-type, the common ground of method 2 and 3 is other crystal formations by Vilazodone Hydrochloride, under condition of different temperatures, vacuum-drying turns brilliant and obtains, this is very easy to cause the generation of mixed crystal phenomenon, phase ratio method 1, its V crystal formation preparation technology is aobvious complicated.
It may be noted that, the V-type preparation method who reports in ZL02812226.7 and CN200710180229, insufficient disclosure, the conditions such as the Tc very crucial to crystal formation preparation are hidden, according to embodiment 7 methods, under the concentrated hydrochloric acid condition of 37 % by weight, be difficult to prepare the V crystal formation thing of Vilazodone Hydrochloride.
Though the method 1 of reporting in ZL02812226.7 and CN200710180229 is directly preparation, but its solvents tetrahydrofurane consumption is very large, the ratio of vilazodone and solvents tetrahydrofurane exceedes 1:30 (weight/volume), in addition the price of tetrahydrofuran (THF) is higher, this will increase process costs undoubtedly greatly, enable to recycle, also can increase the full preparation technology's of product energy consumption, this also can limit and amplify batch output of producing simultaneously.In general, three kinds of methods reporting in ZL02812226.7 and CN200710180229 have its obvious shortcomings and limitations, i.e. high, the complex process of cost, and easily cause mixed crystal.
In sum, because U.S.'s marketed drug adopts the IV type thing of Vilazodone Hydrochloride, in ZL02812226.7 and CN200710180229, also report that the mutual transformation of ownership under certain condition of IV type and V-type obtains, V-type is becoming the potential advantages that have in the property of medicine, and now know many deficiencies of V-type preparation method, thereby make the direct preparation method of the Vilazodone Hydrochloride V-type of studying a kind of low cost, easy to operate, applicable suitability for industrialized production there is unique creativeness, also must realize economic and social profit bumper harvests.
In view of this, the inventor, in conjunction with the production field research work of being engaged in Vilazodone Hydrochloride and derivative thereof experience for many years, studies for a long period of time to the defect of above-mentioned technical field, and this case produces thus.
Summary of the invention
Main purpose of the present invention is to provide 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) preparation method and the application of benzofuran-2-carboxamides hydrochloride V-type, to overcome existing technological deficiency.
In order to solve the problems of the technologies described above, the present invention is achieved through the following technical solutions:
Preparation method and the application of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type, comprise the steps:
1) at a certain temperature, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides is dissolved in organic solvent, obtains solution; Wherein solvent temperature is 5-45 ℃, organic solvent volume (unit: milliliter): 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram) be 15-50:1;
2) by step 1) gained solution is warming up to 30-60 ℃;
3) slowly drip dilute hydrochloric acid, wherein, dilute hydrochloric acid mass concentration is 2-5%, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram): dilute hydrochloric acid weight (unit: gram) be 1:1.8-4.5;
4) by step 3) 40 ℃-reflux temperature of gained system intensification;
5) by step 4) gained architecture heat preservation reaction 0.5-12 hour;
6) filter, obtain V crystal formation wet product;
7) by step 6) vacuum-drying at a certain temperature of gained wet product is to constant weight, obtains V crystal formation.
Further, technical scheme of the present invention is preferably:
Step 1) in, described certain temperature refers to room temperature, solvent temperature is preferably 15-35 ℃; Organic solvent is preferably tetrahydrofuran (THF); Organic solvent volume (unit: milliliter): the ratio of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram) is preferably 20-30:1;
Step 2) in, calefactive interzone is preferably 30-45 ℃;
Step 3) in, dilute hydrochloric acid mass concentration is preferably 2.5-4.0%, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram): the ratio of dilute hydrochloric acid weight (unit: gram) is preferably 1:2.0-3.3;
Step 4) in, calefactive interzone is preferably 45-55 ℃;
Step 5) in, the preferred insulation reaction time is 1.0-3.0 hour;
Step 7) in, preferred, vacuum-drying temperature is preferably 20-35 ℃, is preferably 6-24 hour time of drying.
Wherein, above-mentioned preparation method, as committed step, can be used for preparing vilazodone and pharmacy acceptable salt thereof.
Wherein, above-mentioned preparation method is as manufacturing the committed step of medicine, and this medicine can be used for side effect, brain illness, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual tension syndrome and the unwanted postpartum milk secretion etc. in treatment and prevention of depression, anxiety disorder, bipolar disorder, manic, dull-witted, relevant with mentation material mental disorder, functional disorder, eating disorder, obesity, fibromyalgia, somnopathy, psychosis sample mental disorder, cerebral infarction, anxiety, hypertension therapeutic.
Adopt the technical program, the present invention obtains following useful technique effect: first, can directly prepare V-type hydrochloride by a certain proportion of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides and dilute hydrochloric acid, simplify operation, greatly overcome the problems such as existing 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V crystal formation preparation technology's expensive, high energy consumption, complicated operation; The second, efficiently solve the problem of the easy mixed crystal of product, avoid the generation of mixed crystal; The 3rd, technique can be stablized amplification, is easy to suitability for industrialized production, and product crystal formation purity is high, has significant creativeness and actual application value; The 4th, provide a kind of energy to obtain high crystal formation purity, that can stably produce, high yield, to be easy to suitability for industrialized production direct preparation method.
Below in conjunction with drawings and Examples, the present invention is described in further detail technical scheme of the present invention in order further to explain.
Accompanying drawing explanation
V crystal form X-the ray diffraction data of Fig. 1: patent CN200710180229 report;
V crystal form X-the x ray diffration pattern x of Fig. 2: patent CN200710180229 report;
The x-ray diffraction pattern of Fig. 3: embodiment mono-products obtained therefrom;
The x-ray diffraction pattern of Fig. 4: embodiment bis-products obtained therefroms;
The x-ray diffraction pattern of Fig. 5: embodiment tri-products obtained therefroms;
Fig. 6: the structural formula of Vilazodone Hydrochloride;
Fig. 7: 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) 15 kinds of crystal formations of benzofuran-2-carboxamides hydrochloride specifically conclude;
Fig. 8: X-ray diffraction detects key parameter.
Embodiment
Specifically, the present invention relates to, take 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides as raw material, under organic solvent and certain temperature condition, prepare method and the application of high purity 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V crystal formation with the direct salify of aqueous hydrochloric acid.
Below in conjunction with accompanying drawing to enforcement further detailed description of the present invention.
Embodiment mono-(20120901)
Under room temperature, in there-necked flask, add tetrahydrofuran (THF) (124.0ml), under stirring, add 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides (4.96g), 35-40 ℃ be stirred to molten clear after, slowly drip 3.5% dilute hydrochloric acid (11.52g), drip and finish, 45-50 ℃ was stirred after 1 hour, filter, obtain white solid wet product, put into vacuum drying oven 25-30 ℃ drying under reduced pressure to constant weight, obtain dry product (5.10g,, 95.0%), its x-ray diffraction pattern is shown in accompanying drawing 3.
Embodiment bis-(lot number 20120902)
Under room temperature, in there-necked flask, add tetrahydrofuran (THF) (4000.0ml), under stirring, add 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides 159.72g), 35-40 ℃ be stirred to molten clear after, slowly drip 3.5% dilute hydrochloric acid (360.32g), drip and finish, 45-50 ℃ was stirred after 5 hours, filter, obtain white solid wet product, put into vacuum drying oven 5-30 ℃ drying under reduced pressure to constant weight, obtain dry product (160.23g, 92.65%), its x-ray diffraction pattern is shown in accompanying drawing 4.
Embodiment tri-(20120903)
Under room temperature, in there-necked flask, add tetrahydrofuran (THF) (1900ml), under stirring, add 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides (75.61g), 35-40 ℃ be stirred to molten clear after, slowly drip 3.5% dilute hydrochloric acid (171.23g), drip and finish, 45-50 ℃ was stirred after 12 hours, filter, obtain white solid wet product, put into vacuum drying oven 5-30 ℃ drying under reduced pressure to constant weight, obtain dry product (74.65g, 91.18%), its x-ray diffraction pattern is shown in accompanying drawing 5.
Above-mentioned preparation method, as committed step, can be used for preparing vilazodone and pharmacy acceptable salt thereof.
Above-mentioned preparation method is as manufacturing the committed step of medicine, and this medicine can be used for side effect, brain illness, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual tension syndrome and the unwanted postpartum milk secretion etc. in treatment and prevention of depression, anxiety disorder, bipolar disorder, manic, dull-witted, relevant with mentation material mental disorder, functional disorder, eating disorder, obesity, fibromyalgia, somnopathy, psychosis sample mental disorder, cerebral infarction, anxiety, hypertension therapeutic.
Wherein, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides obtains by 5-(piperazine-1-yl) benzofuran-2-carboxamides (No. CAS: 183288-46-2) and 3-(4-chloro butyl)-5-cyanoindole (No. CAS: 143612-79-7) preparation; 1-[4-(5-cyanoindole-3-yl) butyl]-4-(2-carboxamide-cumarone-5-yl)-piperazine provides by Hangzhou Hexo Chemical Technology Co., Ltd., lot number: 20120506, purity >99.5%; Tetrahydrofuran (THF) is purchased from the evergreen Chemical Co., Ltd. in Zhejiang, lot number: 20120518, and technical grade; Concentrated hydrochloric acid is purchased from Shanghai three hawk chemical reagent company limiteds, lot number: 20120301, and analytical pure; Vacuum drying oven is the grand experimental installation of upper Nereid company limited, model: DZF-6020 type.
X-ray diffraction:
Detection side: Institutes Of Technology Of Zhejiang
Main test set: Bruker D8 Discover XRD.
Key parameter as shown in Figure 8.
Testing environment: 23 ℃ of temperature; Humidity 62%RH
The foregoing is only specific embodiments of the invention, the not restriction to this case design, all equivalent variations of doing according to the design key of this case, all fall into the protection domain of this case.
Claims (4)
- Preparation method and the application of 1.5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type, is characterized in that: comprise the steps:1) at a certain temperature, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides is dissolved in organic solvent, obtains solution; Wherein solvent temperature is 5-45 ℃, organic solvent volume (unit: milliliter): 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram) be 15-50:1;2) by step 1) gained solution is warming up to 30-60 ℃;3) slowly drip dilute hydrochloric acid, wherein, dilute hydrochloric acid mass concentration is 2-5%, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram): dilute hydrochloric acid weight (unit: gram) be 1:1.8-4.5;4) by step 3) 40 ℃-reflux temperature of gained system intensification;5) by step 4) gained architecture heat preservation reaction 0.5-12 hour;6) filter, obtain V crystal formation wet product;7) by step 6) vacuum-drying at a certain temperature of gained wet product is to constant weight, obtains V crystal formation.
- 2. preparation method and the application of 5-as claimed in claim 1 (4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type, is characterized in that:Step 1) in, described certain temperature refers to room temperature, solvent temperature is preferably 15-35 ℃; Organic solvent is preferably tetrahydrofuran (THF); Organic solvent volume (unit: milliliter): the ratio of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram) is preferably 20-30:1;Step 2) in, calefactive interzone is preferably 30-45 ℃;Step 3) in, dilute hydrochloric acid mass concentration is preferably 2.5-4.0%, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram): the ratio of dilute hydrochloric acid weight (unit: gram) is preferably 1:2.0-3.3;Step 4) in, calefactive interzone is preferably 45-55 ℃;Step 5) in, the preferred insulation reaction time is 1.0-3.0 hour;Step 7) in, preferred, vacuum-drying temperature is preferably 20-35 ℃, is preferably 6-24 hour time of drying.
- 3. preparation method and the application of 5-as claimed in claim 1 or 2 (4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type, it is characterized in that: as committed step, for the preparation of Vilazodone Hydrochloride and pharmacy acceptable salt thereof.
- 4. preparation method and the application of 5-as claimed in claim 1 or 2 (4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-type, it is characterized in that: as the committed step of manufacturing medicine, this medicine can be used for treatment and prevention of depression, anxiety disorder, bipolar disorder, manic, dull-witted, the mental disorder relevant with mentation material, functional disorder, eating disorder, fat, fibromyalgia, somnopathy, psychosis sample mental disorder, cerebral infarction, nervous, side effect in hypertension therapeutic, brain illness, chronic pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual tension syndrome and unwanted postpartum milk secretion etc.
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