CN103772367B - Preparation method and the application thereof of Vilazodone Hydrochloride V crystal formation - Google Patents
Preparation method and the application thereof of Vilazodone Hydrochloride V crystal formation Download PDFInfo
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- CN103772367B CN103772367B CN201210407180.6A CN201210407180A CN103772367B CN 103772367 B CN103772367 B CN 103772367B CN 201210407180 A CN201210407180 A CN 201210407180A CN 103772367 B CN103772367 B CN 103772367B
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- butyl
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- 239000013078 crystal Substances 0.000 title claims abstract description 42
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 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 description 13
- 229960003381 vilazodone hydrochloride Drugs 0.000 title description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 41
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 benzofuran-2-carboxamides hydrochloride Chemical class 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 238000001291 vacuum drying Methods 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- 238000010792 warming Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 20
- 238000002441 X-ray diffraction Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000010992 reflux Methods 0.000 abstract description 2
- 238000005755 formation reaction Methods 0.000 description 21
- 239000003814 drug Substances 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960003740 vilazodone Drugs 0.000 description 5
- 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 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- 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
- 201000000736 Amenorrhea Diseases 0.000 description 2
- 206010001928 Amenorrhoea Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 206010058359 Hypogonadism Diseases 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 description 2
- 231100000540 amenorrhea Toxicity 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 208000020685 sleep-wake disease Diseases 0.000 description 2
- 239000002904 solvent Substances 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
- 208000030814 Eating disease Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 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
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 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
- 201000010099 disease Diseases 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940001789 viibryd Drugs 0.000 description 1
Classifications
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses preparation method and the application thereof of high-purity 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V crystal formation, comprise the steps: 1) 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides is dissolved in organic solvent, obtain solution; 2) by step 1) gained solution is warming up to 30-60 DEG C; 3) slowly drip watery hydrochloric acid; 4) by step 3) 40 DEG C-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. Adopt the technical program, simplified operation, overcome the complexity of existing V crystal formation preparation process, avoided the generation of mixed crystal, provide a kind of and can obtain high crystal formation purity, can stably produce, high yield, be easy to the direct preparation method of suitability for industrialized production.
Description
Technical field
The present invention relates to 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides saltThe preparation method of hydrochlorate V-type and application.
Background technology
5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride is hydrochloric acidVilazodone (VilazodoneHydrochloride), is a kind of antidepressants of being developed by ClinicalDate company,January 21 in 2011 Nikkei U.S. food and Drug Administration (FDA) approval listing, the middle severe that is used for the treatment of adult presses downStrongly fragrant disease, commodity are called Viibryd, and its structural formula is as shown in Figure 6.
Vilazodone Hydrochloride is potent and selective five hydroxytryptamine (5-HT) reuptaking inhibitor of a kind of double action and 5-HT1A acceptor portion agonist, is also first indolyl amine novel antidepressant, with clinical existing antidepressants phaseRatio, has rapid-actionly, without features such as sex dysfunction side effects, therefore its Study on Preparation is had to important practical valencyValue.
In patent WO2002/102794 (domestic ZL02812226.7 of the same clan) (document 1), introduce 5-(4-(4-(5-cyanogenBase-3-indyl) butyl)-1-piperazinyl) the serial polymorph of benzofuran-2-carboxamides hydrochloride, comprise solvate15 kinds of crystal formations such as (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 hygroscopicity of medicine; In compressing tablet processThere is better mobility, handling and compressibility; There is better thermodynamic stability, namely steady to heat resistanceheat resistant and humidityQualitative; There is the better tolerance to daylight (UV light); Increase bulk density; Improve solubility; Improve multiple batches of biologyThe constancy of availability. The various crystal formations of Vilazodone Hydrochloride of reporting in patent ZL02812226.7, at solubility and heating powerLearning each physicochemical property aspects such as stability has larger difference, and solvate is wherein because its contained organic solvent is by routine sideMethod is difficult to remove, and easily causes its molten residual exceeding standard in patent medicine Journal of Sex Research process, cannot meet modern medicines research residual to solventThe control requirement of staying. Amorphous article, because of its crystal formation state labile, easily turns brilliant phenomenon, no in the preparation process in later stageBe beneficial to 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 mistakeIn journey, still need to consider the influence factors such as its bulk density, solubility.
5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides salt in hydrateHydrochlorate V crystal formation, the solubility in water is that 0.18mg/mL(refers to document 2:RikLostritto, ONDQADivisionI,DPAMS,CenterforDrugEvaluationandResearch,Applicationnumber:022567Orig1s000, ChemistryReview (s) (ReferenceID:2888631), document 3:Pei-IChu,NDA22-567,Vilazodone10,20,40mgTabletsPGxHealth,LLC,October30,2010P7Of147 (ReferenceID:2859217)) the V crystal formation that obtains is white solid matter, belongs to repeating to determine and relatively steadyFixed crystal form, considers its advantage at aspects such as molten residual, solubility and stability, can thereby had great patent medicineCan property, because of but advantage crystal formation thing.
As follows about the relevant report of V crystal formation solubility in Chinese invention patent application ZL02812226.7 embodiment 16:
The people such as AlexAvdeef, Pharm.Pharmacol.Commun.1998,4,165-178 and AlexAvdeefDeng people, PharmaceuticalResearch2000,7,5-89, measures II, III, IV, V and VIII via potentiometric titrationThe dissolubility data of 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 reportsThe preparation method of Vilazodone Hydrochloride V crystal formation, comprise by vilazodone directly preparation in concentrated hydrochloric acid, by IV type turn brilliant andTurn the brilliant three kinds of methods that wait by XIII type. Corresponding embodiment takes passages as follows (ZL02812226.7 description embodiment 7, the 24-25/40 page):
Method 1
To the 32.6g of 1g5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamidesIn tetrahydrofuran solution, add 2.1g hydrochloric acid (37 % by weight), after stirring, precipitated crystal is carried out to suction filtration, in room temperatureIn vacuum, be dried to constant weight, obtain 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-formylAmine hydrochlorate hydrate V-type.
Method 2
By 2.25g5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloric acidSalt IV type is dispersed in 10 to (bis) 20g water, stirs after 24 to 48 hours, and filtered and recycled crystal is dried in room temperature vacuumConstant weight, obtains 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride hydrationThing V-type.
Method 3
By 10g5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides two hydrochloric acidSalt XIII type is dispersed in 1L water, stirs after 48 hours, and filtered and recycled crystal is dried to constant weight in room temperature vacuum, obtains 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride hydrate V-type.
In above-mentioned three kinds of V crystal formation preparation methods, method 1 has been used vilazodone alkali and concentrated hydrochloric acid direct in organic solventSalify is prepared V-type, and the common ground of method 2 and 3 is other crystal formations by Vilazodone Hydrochloride, vacuum under condition of different temperaturesDry turn brilliant and obtain, this is very easy to cause the generation of mixed crystal phenomenon, phase ratio method 1, the aobvious complexity of its V crystal formation preparation technology.
It may be noted that the V-type preparation method who reports in ZL02812226.7 and CN200710180229 does not openly fillPoint, hide the conditions such as the crystallization temperature very crucial to crystal formation preparation, according to embodiment 7 methods, the concentrated hydrochloric acid of 37 % by weightUnder condition, 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, its solvent tetrahydrochysene furanThe consumption of muttering is very large, and the ratio of vilazodone and solvents tetrahydrofurane exceedes 1:30 (weight per volume), the in addition valency of oxolaneLattice are higher, and this will increase process costs undoubtedly greatly, enable to recycle, and 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, in ZL02812226.7 and CN200710180229, reportThree kinds of methods have its obvious shortcomings and limitations, i.e. high, the complex process of cost, and easily cause mixed crystal.
In sum because U.S. marketed drug adopts the IV type thing of Vilazodone Hydrochloride, ZL02812226.7 andIn CN200710180229, also reported that the mutual transformation of ownership under certain condition of IV type and V-type obtains, V-type has in the one-tenth property of medicinePotential advantages, and now know many deficiencies of V-type preparation method, thus make to study a kind of low cost, easy to operate, be applicable to industryThe direct preparation method who changes the Vilazodone Hydrochloride V-type of producing has unique creativeness, also must realize economy and societyBenefit 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 for many yearsExperience, the defect of above-mentioned technical field is studied for a long period of time, 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) benzoPreparation method and the application of furans-2-carboxamide 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:
5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-typePreparation method and application, comprise the steps:
1) at a certain temperature, by 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-Formamide is dissolved in organic solvent, obtains solution; Wherein solution temperature is 5-45 DEG C, 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 DEG C;
3) slowly drip watery hydrochloric acid, wherein, watery hydrochloric acid mass concentration is 2-5%, 5-(4-(4-(5-cyano group-3-indyl)Butyl)-1-piperazinyl) benzofuran-2-carboxamides weight (unit: gram): watery hydrochloric acid weight (unit: gram) be 1:1.8-4.5;
4) by step 3) 40 DEG C-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 uniform temperature refers to room temperature, solution temperature is preferably 15-35 DEG C; Organic solvent is preferably tetrahydrochyseneFurans; Organic solvent volume (unit: milliliter): 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzo furanThe ratio of mutter-2-formamide weight (unit: gram) is preferably 20-30:1;
Step 2) in, calefactive interzone is preferably 30-45 DEG C;
Step 3) in, watery 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 watery hydrochloric acid weight (unit: gram) is preferably 1:2.0-3.3；
Step 4) in, calefactive interzone is preferably 45-55 DEG C;
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 DEG C, is preferably 6-24 hour drying time.
Wherein, above-mentioned preparation method, as committed step, can be used for preparing vilazodone and pharmaceutically acceptable salt thereof.
Wherein, above-mentioned preparation method is as manufacturing the committed step of medicine, this medicine can be used for treatment and prevention of depression,Anxiety disorder, bipolar disorder, manic, dull-witted, relevant with mentation material phrenoblabia, functional disorder, feedPair in obstacle, obesity, fibromyalgia, sleep-disorder, mental disease sample phrenoblabia, cerebral infarction, anxiety, hypertension therapeutic is doneWith, brain illness, chronic ache, acromegalia, hypogonadism, secondary amenorrhea, premenstrual syndrome and do not needPostpartum milk secretion etc.
Adopt the technical program, the present invention obtains following useful technique effect: the first, and can be by a certain proportion of 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides and watery hydrochloric acid directly prepares V-type hydrochloric acidSalt, has simplified operation, greatly overcome existing 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-The problems such as 2-carboxamide hydrochloride V crystal formation preparation technology's expensive, high energy consumption, complicated operation; The second, efficiently solve productEasily the problem of mixed crystal, has avoided the generation of mixed crystal; The 3rd, technique can be stablized amplification, is easy to suitability for industrialized production, and product crystal formation is pureSpend highly, there is significant creativeness and actual application value; The 4th, provide a kind of can obtain high crystal formation purity, can stablizeVolume production, high yield, to be easy to suitability for industrialized production direct preparation method.
In order further to explain technical scheme of the present invention, below in conjunction with drawings and Examples, the present invention is done furtherDescribe in detail.
Brief description of the drawings
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;
The structural formula of Fig. 6: VilazodoneHydrochloride;
Fig. 7: 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride15 kinds of crystal formations are specifically concluded;
Fig. 8: X-ray diffraction detects key parameter.
Detailed description of the invention
Specifically, the present invention relates to the benzo furan with 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl)Mutter-2-formamide is raw material, under organic solvent and uniform temperature condition, prepares high-purity 5-(4-with the direct salify of aqueous hydrochloric acid(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) method and the application of benzofuran-2-carboxamides hydrochloride V crystal formation.
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 oxolane (124.0ml), under stirring, add 5-(4-(4-(5-cyano group-3-YinDiindyl base) butyl)-1-piperazinyl) benzofuran-2-carboxamides (4.96g), 35-40 DEG C be stirred to molten clear after, slowly drip 3.5%Watery hydrochloric acid (11.52g), drips and finishes, and 45-50 DEG C was stirred after 1 hour, filtered, and obtained white solid wet product, put into vacuum drying oven 25-30 DEG C of drying under reduced pressure are to constant weight, obtain dry product (5.10g,, 95.0%), and its x-ray diffraction pattern is shown in accompanying drawing 3.
Embodiment bis-(lot number 20120902)
Under room temperature, in there-necked flask, add oxolane (4000.0ml), under stirring, add 5-(4-(4-(5-cyano group-3-Indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides 159.72g), 35-40 DEG C be stirred to molten clear after, slowly drip3.5% watery hydrochloric acid (360.32g), drips and finishes, and 45-50 DEG C was stirred after 5 hours, filtered, and obtained white solid wet product, put into vacuum and driedCase 5-30 DEG C drying under reduced pressure, to constant weight, obtains dry product (160.23g, 92.65%), and its x-ray diffraction pattern is shown in accompanying drawing 4.
Embodiment tri-(20120903)
Under room temperature, in there-necked flask, add oxolane (1900ml), under stirring, add 5-(4-(4-(5-cyano group-3-YinDiindyl base) butyl)-1-piperazinyl) benzofuran-2-carboxamides (75.61g), 35-40 DEG C be stirred to molten clear after, slowly drip3.5% watery hydrochloric acid (171.23g), drips and finishes, and 45-50 DEG C was stirred after 12 hours, filtered, and obtained white solid wet product, put into vacuum and driedCase 5-30 DEG C drying under reduced pressure, to constant weight, obtains dry product (74.65g, 91.18%), and 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 pharmaceutically acceptable salt thereof.
Above-mentioned preparation method is as manufacturing the committed step of medicine, and this medicine can be used for treatment and prevention of depression, anxietyDisease, bipolar disorder, manic, dull-witted, relevant with mentation material phrenoblabia, functional disorder, eating disorder,Side effect, brain in obesity, fibromyalgia, sleep-disorder, mental disease sample phrenoblabia, cerebral infarction, anxiety, hypertension therapeuticIllness, chronic ache, acromegalia, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted postpartum secreteBreast etc.
Wherein, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides passes through 5-(piperazine-1-yl) benzofuran-2-carboxamides (No. CAS: 183288-46-2) and 3-(4-chloro butyl)-5-cyanoindole(No. CAS: 143612-79-7) prepared and obtained; 1-[4-(5-cyanoindole-3-yl) butyl]-4-(2-carbamyl-benzo furanMutter-5-yl)-piperazine provides by Hangzhou Hexo Chemical Technology Co., Ltd., lot number: 20120506, purity > 99.5%; OxolanePurchased from the evergreen Chemical Co., Ltd. in Zhejiang, lot number: 20120518, technical grade; Concentrated hydrochloric acid is limited purchased from Shanghai three hawk chemical reagentCompany, lot number: 20120301, analyze pure; Vacuum drying chamber is the grand experimental facilities of upper Nereid Co., Ltd, model: DZF-6020Type.
X-ray diffraction:
Detection side: Institutes Of Technology Of Zhejiang
Main checkout equipment: BrukerD8DiscoverXRD.
Key parameter as shown in Figure 8.
Testing environment: 23 DEG C of temperature; Humidity 62%RH
The foregoing is only specific embodiments of the invention, the not restriction to this case design, all designs according to this case are closedThe equivalent variations that key does, all falls into the protection domain of this case.
Claims (1)
- The system of 1.5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides hydrochloride V-typePreparation Method, is characterized in that: comprise the steps:1) under uniform temperature, by 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamidesBe dissolved in organic solvent, obtain solution; The temperature of wherein dissolving is 15-35 DEG C, oxolane and 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) ratio of benzofuran-2-carboxamides is 20-30:1, wherein, oxolane volume listPosition be milliliter, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides unit of weight isGram;2) step 1) gained solution is warming up to 30 DEG C-45 DEG C;3) slowly drip watery hydrochloric acid, wherein, the hydrochloric acid mass concentration of watery hydrochloric acid is 2.5-4.0%, 5-(4-(4-(5-cyano group-3-YinDiindyl base) butyl)-1-piperazinyl) ratio of benzofuran-2-carboxamides and watery hydrochloric acid is 1:2.0-3.3, wherein, 5-(4-(4-(5-cyano group-3-indyl) butyl)-1-piperazinyl) benzofuran-2-carboxamides unit of weight is gram, watery hydrochloric acid unit of weightFor gram;4) step 3) gained system is heated up for 45-55 DEG C;5) by step 4) gained architecture heat preservation reaction 1.0-3.0 hour;6) filter, obtain V crystal formation wet product;7) by step 6) gained wet product 20-35 DEG C of vacuum drying to constant weight, be 6-24 hour drying time, obtains V crystal formation; InstituteState the x-ray diffraction pattern of V crystal formation as shown in Figure 5.
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