CN104447622B - Hydrobromic acid irrigates the preparation method for western spit of fland beta crystal - Google Patents
Hydrobromic acid irrigates the preparation method for western spit of fland beta crystal Download PDFInfo
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- CN104447622B CN104447622B CN201410729639.3A CN201410729639A CN104447622B CN 104447622 B CN104447622 B CN 104447622B CN 201410729639 A CN201410729639 A CN 201410729639A CN 104447622 B CN104447622 B CN 104447622B
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- hydrobromic acid
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- western spit
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 239000013078 crystal Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 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 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000047 product Substances 0.000 claims abstract description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 9
- PWOBDMNCYMQTCE-UHFFFAOYSA-N 2-chlorobenzenethiol Chemical class SC1=CC=CC=C1Cl PWOBDMNCYMQTCE-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000004090 dissolution Methods 0.000 claims abstract description 5
- 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 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 22
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 20
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 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
- 239000002904 solvent Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 208000035126 Facies Diseases 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 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 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 238000005516 engineering process Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 229960002668 sodium chloride Drugs 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- PCNMALATRPXTKX-UHFFFAOYSA-N 1,4-dimethylcyclohexa-2,4-dien-1-ol Chemical compound CC1=CCC(C)(O)C=C1 PCNMALATRPXTKX-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- KUFFULVDNCHOFZ-UHFFFAOYSA-N 2,4-xylenol Chemical compound CC1=CC=C(O)C(C)=C1 KUFFULVDNCHOFZ-UHFFFAOYSA-N 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000843 powder Substances 0.000 abstract description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical class C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 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
- 238000007086 side reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- VLHRNBAOKGAKBW-UHFFFAOYSA-N Sc1ccccc1[ClH]I Chemical compound Sc1ccccc1[ClH]I VLHRNBAOKGAKBW-UHFFFAOYSA-N 0.000 description 1
- -1 Sodium alkoxide Chemical class 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002689 soil 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of hydrobromic acid and irrigate the preparation method for western spit of fland beta crystal, the method first takes 2 chlorothio-phenols and 2,4 xylenol synthesis 2 (2,4 dimethylphenylsulfanyl) chlorobenzene, then will double (dibenzalacetone) palladiums, 1,1 ' dinaphthalene 2,2 ' double diphenyl phosphines, sodium tert-butoxide and toluene join in reaction bulb and mix, add the preparation of other materials fertile for Xi Ting, then by prepared fertile for Xi Ting with the acetic acid ethyl dissolution of 14～16 times, obtain hydrobromic acid fertile for western spit of fland crude product, finally purifying crude is obtained hydrobromic acid fertile for western spit of fland highly finished product.Preparation method raw material of the present invention is easy to get, technological reaction mild condition, and product yield is high, and purity is high, it is easy to industrialized production.Prepared hydrobromic acid is fertile is white crystalline powder for Xi Ting, and purity is more than 99.5%.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to a kind of hydrobromic acid and irrigate the preparation method for western spit of fland beta crystal.
Background technology
Fertile is a kind of novel antidepressant researched and developed by Ling Bei drugmaker of Denmark and Japan's force field drug company for Xi Ting
Thing, is ratified the treatment for major depression of being grown up in JIUYUE, 2013 by FDA (Food and Drug Adminstration) (FDA), fertile for Xi Ting
Structural formula 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,
The some processes response time is long, and reaction condition is high, uses solvent toxicity relatively big, is unfavorable for industrialized production；And use " one pot
Boil " method, the by-product that in course of reaction, side reaction is generated is many, and product purity is low, and later-period purification difficulty is big.The method becomes
This is higher, complex operation, and technology difficulty is relatively big, and the most fundamentally solves the competition side reaction of double halogen so that gained
The purity of product is relatively low, and only about 90%.How obtaining highly purified irrigating for Xi Ting is pharmaceutical field and the technology that need to solve
Problem.
Summary of the invention
It is an object of the invention to for fertile for problems such as Xi Ting making the highest, the cost intensive of purity in prior art, it is provided that
A kind of hydrobromic acid irrigates the preparation method for western spit of fland beta crystal, and the method uses low in raw material price, low cost, operation simple, made
Hydrobromic acid is fertile replaces western spit of fland purity height, impurity few.
For achieving the above object, the present invention adopts the following technical scheme that a kind of hydrobromic acid irrigates the preparation side for western spit of fland beta crystal
Method, the method comprises the following steps:
Step one, synthesizes 2-(2,4-dimethylphenylsulfanyl) chlorobenzene, particularly as follows:
Preparing reaction bulb, be passed through nitrogen in bottle, take 2-chlorothio-phenol (Formulas I) and 2,4-xylenol (Formula II) is massaged
You than 1: 1 amount join in reaction bulb, add a certain amount of ethyl acetate, nickel nano powder, sodium isopropylate and anhydrous slufuric acid
Sodium；Stirring 10～30min under room temperature, be warming up to 40～60 DEG C, stirring reaction 6～10h, TLC monitors reaction process, and question response is tied
Shu Hou, stops heating, and question response liquid filters after being down to room temperature, and filtrate is washed 2～4 times, takes organic facies, adds anhydrous sodium sulfate
Being dried overnight, filter, filtrate is evaporated off solvent with Rotary Evaporators with vacuum 0.06～1MPa, 40～60 DEG C, obtains 2-(2,4-bis-
Methyl phefzylsulfanyl) chlorobenzene (formula III)；Reaction equation is as follows:
Step 2, preparation is fertile for Xi Ting, particularly as follows:
Take reaction bulb, be passed through nitrogen, be that the amount of 1: 2: 390: 1400～1420 respectively will double (dibenzylidenes third in molar ratio
Ketone) palladium, 1,1 '-dinaphthalene-2,2 '-bis-diphenyl phosphines, sodium tert-butoxide and toluene joins mix and blend 0.5～1.5h in reaction bulb,
Add 2-(2, the 4-dimethylphenylsulfanyl) chlorobenzene prepared by step 1, and press and 2-(2,4-dimethylphenylsulfanyl)
The amount of chlorobenzene mol ratio 3: 1 adds ethylenediamine and is heated to backflow, reacts 2～4h, stops heating, is cooled to room temperature, adds diatom
Soil stirring 15～25min, filters, and filtrate goes in reaction bulb, is passed through hydrogen in bottle, presses and 2-(2,4-3,5-dimethylphenyl sulfur
Alkyl) chlorobenzene mol ratio 1: 10 amount add nickel nano powder, be warming up to 40～60 DEG C stirring reaction 8～12h, TLC monitors reaction
Process, after reaction terminates, stops heating, is down to room temperature, filter, and reactant liquor washes with water 2～4 times, then uses 30% aqueous sodium chloride
Liquid is washed 1～3 time, takes organic facies, adds anhydrous sodium sulfate and is dried, filter, filtrate with Rotary Evaporators with vacuum 0.06～1MPa,
40～60 DEG C are evaporated off solvent, must irrigate for Xi Ting (Formula V)；Reaction equation is as follows:
Step 3, prepares hydrobromic acid fertile for Xi Ting, particularly as follows:
Prepared is irrigated for Xi Ting with the acetic acid ethyl dissolution of 14～16 times, is cooled to 18～25 DEG C, is passed through nitrogen, slowly
Dropping hydrobromic acid, after dropping, continue stirring and crystallizing overnight, filter, filter cake 0～1 DEG C of ethyl acetate rinse 1～3 times, room
Temperature is lower is dried 4～6h, obtains hydrobromic acid fertile for western spit of fland crude product；
Step 4, purification, particularly as follows:
Join in reaction bulb by fertile for the hydrobromic acid obtained in step 3 for western spit of fland crude product, add the anhydrous second of 14～16 times
Alcohol, is heated to all dissolving, add concentration be 6～9% activated carbon backflow 20～40min, heat filtering, in filtrate add crystal seed,
Naturally cooling to room temperature, filter, be dried 4～7h under solid room temperature, obtain hydrobromic acid fertile for western spit of fland highly finished product, preparation technology is complete.
Based on technique scheme, the ethyl acetate of addition, nickel nano powder, isopropyl in described above-mentioned preparation method step one
Sodium alkoxide and anhydrous sodium sulfate weight ratio be: 190～195: 1: 40～45: 10～15.
Beneficial effects of the present invention: the invention provides a kind of synthesis of high purity and irrigate the new method for Xi Ting, raw material is easy to get,
Technological reaction mild condition, product yield is high, and purity is high, it is easy to industrialized production.Hydrobromic acid prepared by the present invention is fertile for west
Spit of fland is white crystalline powder, and purity is more than 99.5%.
Figure of description
Fig. 1 is that hydrobromic acid of the present invention is fertile for western spit of fland beta crystal high-efficient liquid phase spectrogram；
Fig. 2 hydrobromic acid of the present invention irrigates the X-ray powder diffraction figure for western spit of fland beta crystal sample；
Fig. 3 is that existing hydrobromic acid is fertile for western spit of fland beta crystal X-ray powder diffraction comparison diagram.
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1: the present embodiment provides a kind of hydrobromic acid to irrigate the preparation method for western spit of fland beta crystal, specifically comprises the following steps that
Step one: synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
Take 250ml reaction bulb, in bottle, be passed through nitrogen, take 2-chlorothio-phenol (Formulas I) 20g (0.14mol) and 2,4-diformazan
Base phenol (Formula II) 17.1g (0.14mol) joins in reaction bulb, adds 153g ethyl acetate, nickel nano powder 0.8g
(0.014mol), sodium isopropylate 34.4g (0.42mol) and anhydrous sodium sulfate 10g, under room temperature stir 20min, be warming up to 50 DEG C,
Stirring reaction 8h, TLC monitor reaction process, after question response terminates, stop heating, and question response liquid filters after being down to room temperature,
Filtrate wash 3 times, each 50ml, take organic facies, use anhydrous sodium sulfate dry filter, filtrate with Rotary Evaporators with vacuum
0.09MPa, the temperature of 50 DEG C are evaporated off solvent, obtain 2-(2,4-dimethylphenylsulfanyl) chlorobenzene 28.2g (formula III), yield
81%；
Step 2: the fertile preparation for Xi Ting
Take 250ml reaction bulb, be passed through nitrogen, add double (dibenzalacetone) palladium 0.58g (0.001mol), 1,1 '-connection
Naphthalene-2,2 '-bis-diphenyl phosphine 1.2g (0.002mol), sodium tert-butoxide 31.7g (0.39mol) and toluene 130g (1.41mol) stir
Mix 1h, add 2-(2,4-dimethylphenylsulfanyl) chlorobenzene 28.2g (0.11mol), ethylenediamine 19.7g prepared by step 1
(0.33mol), it is heated to backflow, reacts 3h, stop heating, be cooled to room temperature, add kieselguhr stirring 20min, filter, filtrate
Go in reaction bulb, in bottle, be passed through hydrogen, 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, stops heating, is down to room temperature (20～25 DEG C), filters, and reactant liquor washes with water 3 times,
70ml every time, then wash 2 times with 30% sodium-chloride water solution, each 70ml, take organic facies, add anhydrous sodium sulfate 12g, be dried 2 little
Time, to filter, filtrate is evaporated off solvent with Rotary Evaporators with the temperature of vacuum 0.09MPa, 50 DEG C, must irrigate for Xi Ting (Formula V)；
Step 3: prepare hydrobromic acid 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, is cooled to 20 DEG C, is passed through nitrogen, slowly
Dropping hydrobromic acid, after dropping, continue stirring and crystallizing overnight, filter, filter cake 0 DEG C of ethyl acetate rinse 2 times, every time
50ml, is dried 5h under room temperature, obtain hydrobromic acid fertile for western spit of fland crude product 19.3g, yield 46.3%；
Step 4: purification
Join in reaction bulb by fertile for the hydrobromic acid obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 15 times,
It is heated to all dissolving, adds 7% activated carbon backflow 30min.Heat filtering, adds crystal seed (hydrobromic acid is fertile for Xi Ting) in filtrate,
Naturally cool to room temperature (20～25 DEG C).Filter, under solid room temperature, be dried 5h, obtain hydrobromic acid fertile for western spit of fland highly finished product 15g, yield
78%.
Embodiment 2: the present embodiment provides another kind of hydrobromic acid to irrigate the preparation method for western spit of fland beta crystal, specifically comprises the following steps that
Step one: synthesis 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
Take 500ml reaction bulb, in bottle, be passed through nitrogen, take 2-chlorothio-phenol (Formulas I) 40g (0.28mol) and 2,4-diformazan
Base phenol (Formula II) 34.2g (0.28mol) joins in reaction bulb, adds 306g ethyl acetate, nickel nano powder 1.58g
(0.027mol), sodium isopropylate 71.1g (0.87mol) and anhydrous sodium sulfate 23.7g, under room temperature stir 30min, be warming up to 60
DEG C, stirring reaction 9h, TLC monitor reaction process, after question response terminates, stop heating, and question response liquid is down to room temperature (20～25
DEG C) after filter, filtrate wash 4 times, each 50ml, take organic facies, be dried overnight with anhydrous sodium sulfate, filter, filtrate use
Rotary Evaporators is evaporated off solvent with the temperature of vacuum 0.07MPa, 60 DEG C, obtains 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
56.4g (formula III), yield 81%；
Step 2: the fertile preparation for Xi Ting
Take 500ml reaction bulb, be passed through nitrogen, add double (dibenzalacetone) palladium 1.16g (0.002mol), 1,1 '-connection
Naphthalene-2,2 '-bis-diphenyl phosphine 2.4g (0.004mol), sodium tert-butoxide 63.4g (0.78mol) and toluene 261.28g (2.84mol)
Stirring 1.5h, adds 2-(2,4-dimethylphenylsulfanyl) the chlorobenzene 56.4g (0.22mol) prepared by step 1, ethylenediamine
39.4g (0.66mol), is heated to backflow, reacts 4h, stops heating, is cooled to room temperature (20～25 DEG C), adds kieselguhr stirring
25min, filters, and filtrate goes in reaction bulb, is passed through hydrogen in bottle, adds nickel nano powder 1.2g (0.022mol), is warming up to
60 DEG C of stirrings reaction 12h, TLC monitor reaction process, after reaction terminates, stop heating, are down to room temperature (20～25 DEG C), filter,
Reactant liquor washes with water 4 times, each 60ml, then washes 3 times with 30% sodium-chloride water solution, each 60ml, takes organic facies, adds anhydrous sulfur
Acid sodium 15g, is dried 2.5 hours, filters, and filtrate is evaporated off solvent with Rotary Evaporators with the temperature of vacuum 0.07MPa, 60 DEG C,
Must irrigate for Xi Ting (Formula V)；
Step 3: prepare hydrobromic acid 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, is cooled to 25 DEG C, is passed through nitrogen, slowly
Dropping hydrobromic acid, after dropping, continue stirring and crystallizing overnight, filter, filter cake 1 DEG C of ethyl acetate rinse 3 times, every time
60ml, is dried 6h under room temperature, obtain hydrobromic acid fertile for western spit of fland crude product 38.6g, yield 46.3%；
Step 4: purification
Join in reaction bulb by fertile for the hydrobromic acid obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 14 times,
It is heated to all dissolving, adds 6% activated carbon backflow 35min.Heat filtering, adds crystal seed (hydrobromic acid is fertile for Xi Ting) in filtrate,
Naturally cool to room temperature (20～25 DEG C).Filter, under solid room temperature, be dried 7h, obtain hydrobromic acid fertile for western spit of fland highly finished product 30g, yield
78%.
The hydrobromic acid that above-described embodiment prepares is fertile as follows for the product analysis of western spit of fland: hydrobromic acid as shown in Figure 1 is fertile for western spit of fland β
Crystal formation high-efficient liquid phase chromatogram, the purity shown in figure reaches 99.8%.And the hydrobromic acid of conventional method is fertile for western spit of fland purity
Only 96%～98.2%；The present embodiment prepares purity >=99.5%.Hydrobromic acid shown in Fig. 2 is fertile for western spit of fland beta crystal sample
X-ray powder diffraction figure, from the spectrogram of sample it can be seen that each diffraction maximum is sharp-pointed, illustrate that sample is crystalline compound, joins
Existing hydrobromic acid as shown in Figure 3 is fertile for western spit of fland beta crystal X-ray powder diffraction comparison diagram, comparison diagram 2, Fig. 3 it can be seen that
Two figures to go out peak position basically identical, and after testing, it is 230～231 DEG C that above-described embodiment prepares the fusing point of sample, and contrasts
Hydrobromic acid is fertile is 231 DEG C for western spit of fland beta crystal fusing point, thus the measurement result of the powder x-ray diffraction of above-described embodiment sample with
The result that existing hydrobromic acid irrigates the powder x-ray diffraction recorded for western spit of fland beta crystal is consistent.Use above-described embodiment preparation side
It is that hydrobromic acid is fertile for western spit of fland beta crystal compound that legal system obtains product.
Claims (2)
1. hydrobromic acid irrigates the preparation method for western spit of fland beta crystal, it is characterized in that: the method comprises the following steps:
Step one, synthesizes 2-(2,4-dimethylphenylsulfanyl) chlorobenzene, particularly as follows:
Preparing reaction bulb, be passed through nitrogen, take 2-chlorothio-phenol (Formulas I) and 2 in bottle, 4-xylenol (Formula II) is in molar ratio
The amount of 1: 1 joins in reaction bulb, adds a certain amount of ethyl acetate, nickel nano powder, sodium isopropylate and anhydrous sodium sulfate；Room temperature
Lower stirring 10～30min, is warming up to 40～60 DEG C, and stirring reaction 6～10h, TLC monitors reaction process, after question response terminates, stops
Only heating, question response liquid filters after being down to room temperature, and filtrate is washed 2～4 times, takes organic facies, adds anhydrous sodium sulfate dried
At night, filtering, filtrate is evaporated off solvent with Rotary Evaporators with vacuum 0.06～1MPa, 40～60 DEG C, obtains 2-(2,4-dimethyl benzenes
Base sulfanyl) chlorobenzene (formula III)；Reaction equation is as follows:
Step 2, preparation is fertile for Xi Ting, particularly as follows:
Take reaction bulb, be passed through nitrogen, be that the amount of 1: 2: 390: 1400～1420 is incited somebody to action double (dibenzalacetone) respectively in molar ratio
Palladium, 1,1 '-dinaphthalene-2,2 '-bis-diphenyl phosphines, sodium tert-butoxide and toluene joins mix and blend 0.5～1.5h in reaction bulb, adds
2-(2,4-dimethylphenylsulfanyl) chlorobenzene prepared by step one, and press and 2-(2,4-dimethylphenylsulfanyl) chlorobenzene
The amount of mol ratio 3: 1 adds ethylenediamine and is heated to backflow, reacts 2～4h, stops heating, is cooled to room temperature, adds kieselguhr and stirs
Mixing 15～25min, filter, filtrate goes in reaction bulb, is passed through hydrogen in bottle, presses and 2-(2,4-dimethylphenylsulfanyl)
The amount of chlorobenzene mol ratio 1: 10 adds nickel nano powder, is warming up to 40～60 DEG C of stirring reactions 8～12h, and TLC monitors reaction process,
After reaction terminates, stopping heating, be down to room temperature, filter, reactant liquor washes with water 2～4 times, more clear with 30% sodium-chloride water solution
Wash, take organic facies, add anhydrous sodium sulfate and be dried, filter, filtrate with Rotary Evaporators with vacuum 0.06～1MPa, 40～60 DEG C
Solvent is evaporated off, must irrigate for Xi Ting (Formula V)；Reaction equation is as follows:
Step 3, prepares hydrobromic acid fertile for Xi Ting, particularly as follows:
Prepared is irrigated for Xi Ting with the acetic acid ethyl dissolution of 14～16 times, is cooled to 18～25 DEG C, is passed through nitrogen, be slowly added dropwise
Hydrobromic acid, after dropping, continue stirring and crystallizing overnight, filter, filter cake 0～1 DEG C of ethyl acetate rinse 1～3 times, under room temperature
It is dried 4～6h, obtains hydrobromic acid fertile for western spit of fland crude product；
Step 4, purification, particularly as follows:
Join in reaction bulb by fertile for the hydrobromic acid obtained in step 3 for western spit of fland crude product, add the dehydrated alcohol of 14～16 times,
It is heated to all dissolving, adds the activated carbon backflow 20～40min of 6～9%, heat filtering, filtrate adds crystal seed, natural cooling
To room temperature, filtering, be dried 4～7h under solid room temperature, obtain hydrobromic acid fertile for western spit of fland highly finished product, preparation technology is complete.
Hydrobromic acid the most according to claim 1 irrigates the preparation method for western spit of fland beta crystal, it is characterized in that: in described step one
Add ethyl acetate, nickel nano powder, sodium isopropylate and anhydrous sodium sulfate weight ratio be: 190～195: 1: 40～45: 10～
15。
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| CN106279065A (en) * | 2015-05-12 | 2017-01-04 | 北京深蓝海生物医药科技有限公司 | A kind of hydrobromic acid irrigates the refined rotating crystal method for Xi Ting |
| CN104910099B (en) * | 2015-05-22 | 2017-03-08 | 扬子江药业集团有限公司 | The preparation method for western spit of fland crystal irrigated by a kind of hydrobromic acid |
| CN106316985B (en) * | 2015-06-18 | 2021-11-09 | 郑州深蓝海生物医药科技有限公司 | Beta type efficient vortioxetine hydrobromide crystal transformation method |
| CN106316986B (en) * | 2015-07-03 | 2019-02-05 | 成都弘达药业有限公司 | A kind of preparation method of 1- [2- (2,4- dimethylphenylsulfanyl) phenyl] piperazine hydrobromide alpha type crystal |
| GB2557867A (en) * | 2015-11-18 | 2018-07-04 | Azad Pharmaceutical Ingredients Ag | New synthetic path to vortioxetine salts |
| CN109521102A (en) * | 2017-09-18 | 2019-03-26 | 万全万特制药（厦门）有限公司 | Method of separating and assaying of the hydrobromic acid Vortioxetine finished product in relation to substance |
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