CN104447622A - Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form - Google Patents
Novel preparation method of hydrobromic acid Vortioxetine beta crystalline form Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title abstract 9
- 229960002263 vortioxetine Drugs 0.000 title abstract 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 title abstract 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 15
- LLXAJNFTZXRYIU-UHFFFAOYSA-N 1-(2-chlorophenyl)sulfanyl-2,4-dimethylbenzene Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1Cl LLXAJNFTZXRYIU-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims abstract description 10
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical compound SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 claims abstract description 7
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims abstract description 5
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 86
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 21
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000011858 nanopowder Substances 0.000 claims description 10
- 229910052759 nickel Inorganic materials 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 8
- 235000011152 sodium sulphate Nutrition 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- -1 1, 4-dimethylphenylsulfanyl Chemical group 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000010025 steaming Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 2
- 238000004140 cleaning Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- MNVMYTVDDOXZLS-UHFFFAOYSA-N 4-methoxyguaiacol Natural products COC1=CC=C(O)C(OC)=C1 MNVMYTVDDOXZLS-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel preparation method of a hydrobromic acid Vortioxetine beta crystalline form. The novel preparation method comprises the steps of firstly synthesizing 2-(2,4-dimethyl-phenylsulfanyl)chlorobenzene from 2-chlorobenzenethiol and 2,4-dimethylphenol, adding bi(dibenzylidene acetone)palladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphino, sodium tert-butoxide and toluene into a reaction bottle, mixing, adding other substances to prepare Vortioxetine, dissolving prepared Vortioxetine by virtue of ethyl acetate with the weight of 14-16 times of that of Vortioxetine to obtain rough hydrobromic acid Vortioxetine, and finally purifying rough hydrobromic acid Vortioxetine to obtain finished hydrobromic acid Vortioxetine. The preparation method has the beneficial effects that the raw materials are easily available, process reaction conditions are mild, a product is high in yield and purity, and industrial production is easily realized; prepared hydrobromic acid Vortioxetine is white crystalline powder, and the purity is more than 99.5%.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to a kind of Hydrogen bromide and irrigate novel preparation method for western spit of fland beta crystal.
Background technology
Fertile is a kind of newly-developed antidepressant researched and developed by Ling Bei drugmaker of Denmark and Japan military field drug company for Xi Ting, in September, 2013 by the treatment of FDA (Food and Drug Adminstration) (FDA) approval for major depression of being grown up, the fertile structural formula for Xi Ting is as follows:
In prior art, the fertile synthetic method for Xi Ting is little, and at present, prior art processes route is longer, complex operation, some processes long reaction time, and reaction conditions is high, adopts solvent toxicity comparatively large, is unfavorable for suitability for industrialized production; And adopting the method for " treating different things alike ", the by product that in reaction process, side reaction generates is many, and product purity is low, and later-period purification difficulty is large.The method cost is higher, complex operation, and technology difficulty is comparatively large, and does not fundamentally solve the competition side reaction of two halogen, makes the purity of products therefrom lower, only has about 90%.How to obtain the highly purified fertile technical problem being pharmacy field for Xi Ting and need solving.
Summary of the invention
The object of the invention is to make the problems such as purity is not high, cost intensive for fertile in prior art for Xi Ting, a kind of Hydrogen bromide is provided to irrigate novel preparation method for western spit of fland beta crystal, the method adopts low in raw material price, cost is low, operation is simple, and made Hydrogen bromide is fertile replaces that western spit of fland purity is high, impurity is few.
For achieving the above object, the present invention adopts following technical scheme: the novel preparation method for western spit of fland beta crystal irrigated by a kind of Hydrogen bromide, and the method comprises the following steps:
Step one, synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene, is specially:
Ready reaction bottle, nitrogen is passed in bottle, get 2-chlorothio-phenol (formula I) and 2,4-xylenol (formula II) in molar ratio 1: 1 amount join in reaction flask, add a certain amount of ethyl acetate, nickel nano powder, sodium isopropylate and anhydrous sodium sulphate; Stirred at ambient temperature 10 ~ 30min, is warming up to 40 ~ 60 DEG C, stirring reaction 6 ~ 10h, TLC monitors reaction process, after question response terminates, stops heating, question response liquid filters after being down to room temperature, filtrate washing 2 ~ 4 times, gets organic phase, adds anhydrous sodium sulfate drying and spend the night, filter, filtrate desolventizes with vacuum tightness 0.06 ~ 1MPa, 40 ~ 60 DEG C of steamings with Rotary Evaporators, obtains 2-(2,4-dimethylphenylsulfanyl) chlorobenzene (formula III); Reaction formula is as follows:
Step 2, preparation is fertile for Xi Ting, is specially:
Get reaction flask, pass into nitrogen, be that the amount of 1: 2: 390: 1400 ~ 1420 is respectively by two (dibenzalacetone) palladium in molar ratio, 1, 1 '-dinaphthalene-2, 2 '-bis-diphenyl phosphine, sodium tert-butoxide and toluene join mix and blend 0.5 ~ 1.5h in reaction flask, add the 2-(2 prepared by step 1, 4-dimethylphenylsulfanyl) chlorobenzene, and press and 2-(2, 4-dimethylphenylsulfanyl) amount of chlorobenzene mol ratio 3: 1 adds quadrol and is heated to backflow, reaction 2 ~ 4h, stop heating, be cooled to room temperature, add diatomite and stir 15 ~ 25min, filter, filtrate goes in reaction flask, hydrogen is passed in bottle, press and 2-(2, 4-dimethylphenylsulfanyl) amount of chlorobenzene mol ratio 1: 10 adds nickel nano powder, be warming up to 40 ~ 60 DEG C of stirring reaction 8 ~ 12h, TLC monitors reaction process, after reaction terminates, stop heating, be down to room temperature, filter, reaction solution washes 2 ~ 4 times with water, 1 ~ 3 time is washed again with 30% sodium chloride aqueous solution, get organic phase, add anhydrous sodium sulfate drying, filter, filtrate with Rotary Evaporators with vacuum tightness 0.06 ~ 1MPa, 40 ~ 60 DEG C of steamings desolventize, must irrigate for Xi Ting (formula V), reaction formula is as follows:
Step 3, prepare Hydrogen bromide fertile for Xi Ting, be specially:
Obtained is irrigated for the acetic acid ethyl dissolution of Xi Ting with 14 ~ 16 times, be cooled to 18 ~ 25 DEG C, pass into nitrogen, slow dropping Hydrogen bromide, after dropwising, continue stirring and crystallizing and spend the night, filter, filter cake 0 ~ 1 DEG C of ethyl acetate rinse 1 ~ 3 time, dry 4 ~ 6h under room temperature, obtains Hydrogen bromide fertile for western spit of fland crude product;
Step 4, purifying, is specially:
Join in reaction flask by fertile for the Hydrogen bromide obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 14 ~ 16 times, be heated to whole dissolving, adding concentration is 6 ~ 9% gac backflow 20 ~ 40min, heat filtering, crystal seed is added in filtrate, naturally cool to room temperature, filter, dry 4 ~ 7h under solid room temperature, obtain Hydrogen bromide fertile for western spit of fland highly finished product, preparation technology is complete.
Based on technique scheme, the ethyl acetate, nickel nano powder, sodium isopropylate and the anhydrous sodium sulphate weight ratio that add in described above-mentioned preparation method's step one are: 190 ~ 195: 1: 40 ~ 45: 10 ~ 15.
Beneficial effect of the present invention: the invention provides a kind of synthesis of high purity and irrigate novel method for Xi Ting, raw material is easy to get, technological reaction mild condition, and product yield is high, and purity is high, is easy to suitability for industrialized production.Hydrogen bromide prepared by the present invention is fertile is white crystalline powder for Xi Ting, and purity is greater than 99.5%.
Figure of description
Fig. 1 is that Hydrogen bromide of the present invention is fertile for western spit of fland beta crystal high performance liquid phase spectrogram;
The X-ray powder diffraction figure for western spit of fland beta crystal sample irrigated by Fig. 2 Hydrogen bromide of the present invention;
Fig. 3 is that existing Hydrogen bromide is fertile for western spit of fland beta crystal X-ray powder diffraction comparison diagram.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1: the present embodiment provides a kind of Hydrogen bromide to irrigate novel preparation method for western spit of fland beta crystal, and concrete steps are as follows:
Step one: synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
Get 250ml reaction flask, nitrogen is passed in bottle, get 2-chlorothio-phenol (formula I) 20g (0.14mol) and 2, 4-xylenol (formula II) 17.1g (0.14mol) joins in reaction flask, add 153g ethyl acetate, nickel nano powder 0.8g (0.014mol), sodium isopropylate 34.4g (0.42mol) and anhydrous sodium sulphate 10g, stirred at ambient temperature 20min, be warming up to 50 DEG C, stirring reaction 8h, TLC monitors reaction process, after question response terminates, stop heating, question response liquid filters after being down to room temperature, filtrate washes 3 times, each 50ml, get organic phase, filter with anhydrous sodium sulfate drying, filtrate with Rotary Evaporators with vacuum tightness 0.09MPa, the temperature of 50 DEG C is steamed and is desolventized, obtain 2-(2, 4-dimethylphenylsulfanyl) chlorobenzene 28.2g (formula III), yield 81%:
Step 2: the fertile preparation for Xi Ting
Get 250ml reaction flask, pass into nitrogen, add two (dibenzalacetone) palladium 0.58g (0.001mol), 1, 1 '-dinaphthalene-2, 2 '-bis-diphenyl phosphine 1.2g (0.002mol), sodium tert-butoxide 31.7g (0.39mol) and toluene 130g (1.41mol) stirs 1h, add the 2-(2 prepared by step 1, 4-dimethylphenylsulfanyl) chlorobenzene 28.2g (0.11mol), quadrol 19.7g (0.33mol), be heated to backflow, reaction 3h, stop heating, be cooled to room temperature, add diatomite and stir 20min, filter, filtrate goes in reaction flask, hydrogen is passed in bottle, add nickel nano powder 0.6g (0.011mol), be warming up to 50 DEG C of stirring reaction 10h, TLC monitors reaction process, after reaction terminates, stop heating, be down to room temperature (20 ~ 25 DEG C), filter, reaction solution washes 3 times with water, each 70ml, 2 times are washed again with 30% sodium chloride aqueous solution, each 70ml, get organic phase, add anhydrous sodium sulphate 12g, dry 2 hours, filter, filtrate with Rotary Evaporators with vacuum tightness 0.09MPa, the temperature of 50 DEG C is steamed and is desolventized, must irrigate for Xi Ting (formula V),
Step 3: prepare Hydrogen bromide fertile for Xi Ting
Irrigating of obtaining in step 2 is replaced in western spit of fland with 15 times of acetic acid ethyl dissolutions, be cooled to 20 DEG C, pass into nitrogen, slowly drip Hydrogen bromide, after dropwising, continue stirring and crystallizing to spend the night, filter, filter cake 0 DEG C of ethyl acetate rinse 2 times, each 50ml, dry 5h under room temperature, obtain Hydrogen bromide fertile for western spit of fland crude product 19.3g, yield 46.3%;
Step 4: purifying
Join in reaction flask by fertile for the Hydrogen bromide obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 15 times, be heated to whole dissolving, add 7% gac backflow 30min.Heat filtering, adds crystal seed (Hydrogen bromide is fertile for Xi Ting), naturally cools to room temperature (20 ~ 25 DEG C) in filtrate.Filter, dry 5h under solid room temperature, obtain Hydrogen bromide fertile for western spit of fland highly finished product 15g, yield 78%.
Embodiment 2: the present embodiment provides another kind of Hydrogen bromide to irrigate novel preparation method for western spit of fland beta crystal, and concrete steps are as follows:
Step one: synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
Get 500ml reaction flask, nitrogen is passed in bottle, get 2-chlorothio-phenol (formula I) 40g (0.28mol) and 2, 4-xylenol (formula II) 34.2g (0.28mol) joins in reaction flask, add 306g ethyl acetate, nickel nano powder 1.58g (0.027mol), sodium isopropylate 71.1g (0.87mol) and anhydrous sodium sulphate 23.7g, stirred at ambient temperature 30min, be warming up to 60 DEG C, stirring reaction 9h, TLC monitors reaction process, after question response terminates, stop heating, question response liquid filters after being down to room temperature (20 ~ 25 DEG C), filtrate washes 4 times, each 50ml, get organic phase, spend the night with anhydrous sodium sulfate drying, filter, filtrate with Rotary Evaporators with vacuum tightness 0.07MPa, the temperature of 60 DEG C is steamed and is desolventized, obtain 2-(2, 4-dimethylphenylsulfanyl) chlorobenzene 56.4g (formula III), yield 81%,
Step 2: the fertile preparation for Xi Ting
Get 500ml reaction flask, pass into nitrogen, add two (dibenzalacetone) palladium 1.16g (0.002mol), 1, 1 '-dinaphthalene-2, 2 '-bis-diphenyl phosphine 2.4g (0.004mol), sodium tert-butoxide 63.4g (0.78mol) and toluene 261.28g (2.84mol) stirs 1.5h, add the 2-(2 prepared by step 1, 4-dimethylphenylsulfanyl) chlorobenzene 56.4g (0.22mol), quadrol 39.4g (0.66mol), be heated to backflow, reaction 4h, stop heating, be cooled to room temperature (20 ~ 25 DEG C), add diatomite and stir 25min, filter, filtrate goes in reaction flask, hydrogen is passed in bottle, add nickel nano powder 1.2g (0.022mol), be warming up to 60 DEG C of stirring reaction 12h, TLC monitors reaction process, after reaction terminates, stop heating, be down to room temperature (20 ~ 25 DEG C), filter, reaction solution washes 4 times with water, each 60ml, 3 times are washed again with 30% sodium chloride aqueous solution, each 60ml, get organic phase, add anhydrous sodium sulphate 15g, dry 2.5 hours, filter, filtrate with Rotary Evaporators with vacuum tightness 0.07MPa, the temperature of 60 DEG C is steamed and is desolventized, must irrigate for Xi Ting (formula V),
Step 3: prepare Hydrogen bromide fertile for Xi Ting
Irrigating of obtaining in step 2 is replaced in western spit of fland with 14 times of acetic acid ethyl dissolutions, be cooled to 25 DEG C, pass into nitrogen, slowly drip Hydrogen bromide, after dropwising, continue stirring and crystallizing to spend the night, filter, filter cake 1 DEG C of ethyl acetate rinse 3 times, each 60ml, dry 6h under room temperature, obtain Hydrogen bromide fertile for western spit of fland crude product 38.6g, yield 46.3%;
Step 4: purifying
Join in reaction flask by fertile for the Hydrogen bromide obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 14 times, be heated to whole dissolving, add 6% gac backflow 35min.Heat filtering, adds crystal seed (Hydrogen bromide is fertile for Xi Ting), naturally cools to room temperature (20 ~ 25 DEG C) in filtrate.Filter, dry 7h under solid room temperature, obtain Hydrogen bromide fertile for western spit of fland highly finished product 30g, yield 78%.
The Hydrogen bromide that above-described embodiment obtains is fertile as follows for the product analysis of western spit of fland: Hydrogen bromide is as shown in Figure 1 fertile for western spit of fland beta crystal high-efficient liquid phase chromatogram, and the purity shown in figure reaches 99.8%.And the fertile western spit of fland purity of replacing of the Hydrogen bromide of ordinary method only has 96% ~ 98.2%; The present embodiment prepares purity >=99.5%.The X-ray powder diffraction figure for western spit of fland beta crystal sample irrigated by Hydrogen bromide shown in Fig. 2, as can be seen from the spectrogram of sample, each diffraction peak is sharp-pointed, interpret sample is crystalline compound, existing Hydrogen bromide shown in Figure 3 is fertile for western spit of fland beta crystal X-ray powder diffraction comparison diagram, comparison diagram 2, Fig. 3 can find out, two figure to go out peak position basically identical, and after testing, the fusing point that above-described embodiment obtains sample is 230 ~ 231 DEG C, and the Hydrogen bromide of contrast fertile be 231 DEG C for western spit of fland beta crystal fusing point, the measurement result of the powder x-ray diffraction of above-described embodiment sample is consistent with the result that the powder x-ray diffraction recorded for western spit of fland beta crystal irrigated by existing Hydrogen bromide thus.Adopting above-described embodiment preparation method to obtain product is that Hydrogen bromide is fertile for western spit of fland beta crystal compound.
Claims (2)
1. the novel preparation method for western spit of fland beta crystal irrigated by Hydrogen bromide, it is characterized in that: the method comprises the following steps:
Step one, synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene, is specially:
Ready reaction bottle, nitrogen is passed in bottle, get 2-chlorothio-phenol (formula I) and 2,4-xylenol (formula II) in molar ratio 1: 1 amount join in reaction flask, add a certain amount of ethyl acetate, nickel nano powder, sodium isopropylate and anhydrous sodium sulphate; Stirred at ambient temperature 10 ~ 30min, is warming up to 40 ~ 60 DEG C, stirring reaction 6 ~ 10h, TLC monitors reaction process, after question response terminates, stops heating, question response liquid filters after being down to room temperature, filtrate washing 2 ~ 4 times, gets organic phase, adds anhydrous sodium sulfate drying and spend the night, filter, filtrate desolventizes with vacuum tightness 0.06 ~ 1MPa, 40 ~ 60 DEG C of steamings with Rotary Evaporators, obtains 2-(2,4-dimethylphenylsulfanyl) chlorobenzene (formula III); Reaction formula is as follows:
Step 2, preparation is fertile for Xi Ting, is specially:
Get reaction flask, pass into nitrogen, be that the amount of 1: 2: 390: 1400 ~ 1420 is respectively by two (dibenzalacetone) palladium in molar ratio, 1, 1 '-dinaphthalene-2, 2 '-bis-diphenyl phosphine, sodium tert-butoxide and toluene join mix and blend 0.5 ~ 1.5h in reaction flask, add the 2-(2 prepared by step 1, 4-dimethylphenylsulfanyl) chlorobenzene, and press and 2-(2, 4-dimethylphenylsulfanyl) amount of chlorobenzene mol ratio 3: 1 adds quadrol and is heated to backflow, reaction 2 ~ 4h, stop heating, be cooled to room temperature, add diatomite and stir 15 ~ 25min, filter, filtrate goes in reaction flask, hydrogen is passed in bottle, press and 2-(2, 4-dimethylphenylsulfanyl) amount of chlorobenzene mol ratio 1: 10 adds nickel nano powder, be warming up to 40 ~ 60 DEG C of stirring reaction 8 ~ 12h, TLC monitors reaction process, after reaction terminates, stop heating, be down to room temperature, filter, reaction solution washes 2 ~ 4 times with water, again with 30% sodium chloride aqueous solution cleaning, get organic phase, add anhydrous sodium sulfate drying, filter, filtrate with Rotary Evaporators with vacuum tightness 0.06 ~ 1MPa, 40 ~ 60 DEG C of steamings desolventize, must irrigate for Xi Ting (formula V), reaction formula is as follows:
Step 3, prepare Hydrogen bromide fertile for Xi Ting, be specially:
Obtained is irrigated for the acetic acid ethyl dissolution of Xi Ting with 14 ~ 16 times, be cooled to 18 ~ 25 DEG C, pass into nitrogen, slow dropping Hydrogen bromide, after dropwising, continue stirring and crystallizing and spend the night, filter, filter cake 0 ~ 1 DEG C of ethyl acetate rinse 1 ~ 3 time, dry 4 ~ 6h under room temperature, obtains Hydrogen bromide fertile for western spit of fland crude product;
Step 4, purifying, is specially:
Join in reaction flask by fertile for the Hydrogen bromide obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 14 ~ 16 times, be heated to whole dissolving, adding concentration is 6 ~ 9% gac backflow 20 ~ 40min, heat filtering, crystal seed is added in filtrate, naturally cool to room temperature, filter, dry 4 ~ 7h under solid room temperature, obtain Hydrogen bromide fertile for western spit of fland highly finished product, preparation technology is complete.
2. the novel preparation method for western spit of fland beta crystal irrigated by Hydrogen bromide according to claim 1, it is characterized in that: the ethyl acetate added in described step one, nickel nano powder, sodium isopropylate and anhydrous sodium sulphate weight ratio are: 190 ~ 195: 1: 40 ~ 45: 10 ~ 15.
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